Phenotypic plasticity and epithelial-to-mesenchymal transition in the behaviour and therapeutic response of oral squamous cell carcinoma.

PubMed

Vig, Navin; Mackenzie, Ian C; Biddle, Adrian

2015-10-01

It is increasingly recognised that phenotypic plasticity, apparently driven by epigenetic mechanisms, plays a key role in tumour behaviour and markedly influences the important processes of therapeutic survival and metastasis. An important source of plasticity in malignancy is epithelial-to-mesenchymal transition (EMT), a common epigenetically controlled event that results in transition of malignant cells between different phenotypic states that confer motility and enhance survival. In this review, we discuss the importance of phenotypic plasticity and its contribution to cellular heterogeneity in oral squamous cell carcinoma with emphasis on aspects of drug resistance and EMT. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Constitutive Uncoupling of Pathways of Gene Expression That Control Growth and Differentiation in Myeloid Leukemia: A Model for the Origin and Progression of Malignancy

NASA Astrophysics Data System (ADS)

Sachs, Leo

1980-10-01

Chemical carcinogens and tumor promoters have pleiotropic effects. Tumor initiators can produce a variety of mutations and tumor promoters can regulate a variety of physiological molecules that control growth and differentiation. The appropriate mutation and the regulation of the appropriate molecules to induce cell growth can initiate and promote the sequence of changes required for transformation of normal cells into malignant cells. After this sequence of changes, some tumors can still be induced to revert with a high frequency from a malignant phenotype to a nonmalignant phenotype. Results obtained from analysis of regulation of growth and differentiation in normal and leukemic myeloid cells, the phenotypic reversion of malignancy by induction of normal differentiation in myeloid leukemia, and the blocks in differentiation-defective leukemic cell mutants have been used to propose a general model for the origin and progression of malignancy. The model states that malignancy originates by changing specific pathways of gene expression required for growth from inducible to constitutive in cells that can still be induced to differentiate normally by the physiological inducer of differentiation. The malignant cells, unlike the normal cells, then no longer require the physiological inducer for growth. This changes the requirements for growth and uncouples growth from differentiation. Constitutive expression of other specific pathways can uncouple other controls, which then causes blocks in differentiation and the further progression of malignancy. The existence of specific constitutive pathways of gene expression that uncouple controls in malignant cells can also explain the expression of fetal proteins, hormones, and some other specialized products of normal development in various types of tumors.

Complex Roads from Genotype to Phenotype in Dilated Cardiomyopathy: Scientific update from the Working Group of Myocardial Function of the European Society of Cardiology

PubMed

Bondue, Antoine; Arbustini, Eloisa; Bianco, Anna M; Ciccarelli, Michele; Dawson, Dana; De Rosa, Matteo; Hamdani, Nazha; Hilfiker-Kleiner, Denise; Meder, Benjamin; Leite Moreira, Adelino; Thum, Thomas; Gabriele Tocchetti, Carlo; Varricchi, Gilda; Van der Velden, Jolanda; Walsh, Roddy; Heymans, Stephane

2018-05-23

Dilated cardiomyopathy (DCM) frequently affects relatively young, economically and socially active adults, and is an important cause of heart failure and transplantation. DCM is a complex disease and its pathological architecture encounters many genetic determinants interacting with environmental factors. The old perspective that every pathogenic gene mutation would lead to a diseased heart, is now being replaced by the novel observation that the phenotype depends not only on the penetrance -malignancy of the mutated gene- but also on epigenetics, age, toxic factors, pregnancy and a diversity of acquired diseases. This review discusses how gene mutations will result in mutation-specific molecular alterations in the heart including increased mitochondrial oxidation (sarcomeric gene e.g. TTN), decreased calcium sensitivity (sarcomeric genes), fibrosis (e.g. LMNA and TTN) or inflammation. Therefore, getting a complete picture of the DCM patient will include genomic data, molecular assessment by preference from cardiac samples, stratification according to co-morbidities, and phenotypic description. Those data will help to better guide the heart failure and anti-arrhythmic treatment, predict response to therapy, develop novel siRNA-based gene silencing for malignant gene mutations, or intervene with mutation-specific altered gene pathways in the heart.

Mucin glycosylating enzyme GALNT2 suppresses malignancy in gastric adenocarcinoma by reducing MET phosphorylation

PubMed Central

Liu, Shin-Yun; Shun, Chia-Tung; Hung, Kuan-Yu; Juan, Hsueh-Fen; Hsu, Chia-Lang; Huang, Min-Chuan; Lai, I-Rue

2016-01-01

Glycosylation affects malignancy in cancer. Here, we report that N- acetylgalactosaminyltransferase 2 (GALNT2), an enzyme that mediates the initial step of mucin type-O glycosylation, suppresses malignant phenotypes in gastric adenocarcinoma (GCA) by modifying MET (Hepatocyte growth factor receptor) activity. GALNT2 mRNA and protein were downregulated in GCAs, and this reduction was associated with more advanced disease stage and shorter recurrence-free survival. Suppressing GALNT2 expression in GCA cells increased cell growth, migration, and invasion in vitro, and tumor metastasis in vivo. GALNT2 knockdown enhanced phosphorylation of MET and decreased expression of the Tn antigen on MET. Inhibiting MET activity with PHA665752 decreased the malignant phenotypes caused by GALNT2 knockdown in GCA cells. Our results indicate that GALNT2 suppresses the malignant potential of GCA cells and provide novel insights into the significance of O-glycosylation in MET activity and GCA progression. PMID:26848976

Molecularly targeted drug combinations demonstrate selective effectiveness for myeloid- and lymphoid-derived hematologic malignancies

PubMed Central

Eide, Christopher A.; Kaempf, Andy; Khanna, Vishesh; Savage, Samantha L.; Rofelty, Angela; English, Isabel; Ho, Hibery; Pandya, Ravi; Bolosky, William J.; Poon, Hoifung; Deininger, Michael W.; Collins, Robert; Swords, Ronan T.; Watts, Justin; Pollyea, Daniel A.; Medeiros, Bruno C.; Traer, Elie; Tognon, Cristina E.; Mori, Motomi; Druker, Brian J.; Tyner, Jeffrey W.

2017-01-01

Translating the genetic and epigenetic heterogeneity underlying human cancers into therapeutic strategies is an ongoing challenge. Large-scale sequencing efforts have uncovered a spectrum of mutations in many hematologic malignancies, including acute myeloid leukemia (AML), suggesting that combinations of agents will be required to treat these diseases effectively. Combinatorial approaches will also be critical for combating the emergence of genetically heterogeneous subclones, rescue signals in the microenvironment, and tumor-intrinsic feedback pathways that all contribute to disease relapse. To identify novel and effective drug combinations, we performed ex vivo sensitivity profiling of 122 primary patient samples from a variety of hematologic malignancies against a panel of 48 drug combinations. The combinations were designed as drug pairs that target nonoverlapping biological pathways and comprise drugs from different classes, preferably with Food and Drug Administration approval. A combination ratio (CR) was derived for each drug pair, and CRs were evaluated with respect to diagnostic categories as well as against genetic, cytogenetic, and cellular phenotypes of specimens from the two largest disease categories: AML and chronic lymphocytic leukemia (CLL). Nearly all tested combinations involving a BCL2 inhibitor showed additional benefit in patients with myeloid malignancies, whereas select combinations involving PI3K, CSF1R, or bromodomain inhibitors showed preferential benefit in lymphoid malignancies. Expanded analyses of patients with AML and CLL revealed specific patterns of ex vivo drug combination efficacy that were associated with select genetic, cytogenetic, and phenotypic disease subsets, warranting further evaluation. These findings highlight the heuristic value of an integrated functional genomic approach to the identification of novel treatment strategies for hematologic malignancies. PMID:28784769

CRISPR/Cas9-mediated gene knockout of NANOG and NANOGP8 decreases the malignant potential of prostate cancer cells.

PubMed

Kawamura, Norihiko; Nimura, Keisuke; Nagano, Hiromichi; Yamaguchi, Sohei; Nonomura, Norio; Kaneda, Yasufumi

2015-09-08

NANOG expression in prostate cancer is highly correlated with cancer stem cell characteristics and resistance to androgen deprivation. However, it is not clear whether NANOG or its pseudogenes contribute to the malignant potential of cancer. We established NANOG- and NANOGP8-knockout DU145 prostate cancer cell lines using the CRISPR/Cas9 system. Knockouts of NANOG and NANOGP8 significantly attenuated malignant potential, including sphere formation, anchorage-independent growth, migration capability, and drug resistance, compared to parental DU145 cells. NANOG and NANOGP8 knockout did not inhibit in vitro cell proliferation, but in vivo tumorigenic potential decreased significantly. These phenotypes were recovered in NANOG- and NANOGP8-rescued cell lines. These results indicate that NANOG and NANOGP8 proteins are expressed in prostate cancer cell lines, and NANOG and NANOGP8 equally contribute to the high malignant potential of prostate cancer.

Malignancy Risk Models for Oral Lesions

PubMed Central

Zarate, Ana M.; Brezzo, María M.; Secchi, Dante G.; Barra, José L.

2013-01-01

Objectives: The aim of this work was to assess risk habits, clinical and cellular phenotypes and TP53 DNA changes in oral mucosa samples from patients with Oral Potentially Malignant Disorders (OPMD), in order to create models that enable genotypic and phenotypic patterns to be obtained that determine the risk of lesions becoming malignant. Study Design: Clinical phenotypes, family history of cancer and risk habits were collected in clinical histories. TP53 gene mutation and morphometric-morphological features were studied, and multivariate models were applied. Three groups were estabished: a) oral cancer (OC) group (n=10), b) OPMD group (n=10), and c) control group (n=8). Results: An average of 50% of patients with malignancy were found to have smoking and drinking habits. A high percentage of TP53 mutations were observed in OC (30%) and OPMD (average 20%) lesions (p=0.000). The majority of these mutations were GC ? TA transversion mutations (60%). However, patients with OC presented mutations in all the exons and introns studied. Highest diagnostic accuracy (p=0.0001) was observed when incorporating alcohol and tobacco habits variables with TP53 mutations. Conclusions: Our results prove to be statistically reliable, with parameter estimates that are nearly unbiased even for small sample sizes. Models 2 and 3 were the most accurate for assessing the risk of an OPMD becoming cancerous. However, in a public health context, model 3 is the most recommended because the characteristics considered are easier and less costly to evaluate. Key words:TP53, oral potentially malignant disorders, risk factors, genotype, phenotype. PMID:23722122

Suppression of endogenous lipogenesis induces reversion of the malignant phenotype and normalized differentiation in breast cancer

PubMed Central

Schroeder, Barbara; Park, Cheol Hong; Chandra Mohan, KVP; Khurana, Ashwani; Corominas-Faja, Bruna; Cuyàs, Elisabet; Alarcón, Tomás; Kleer, Celina; Menendez, Javier A.; Lupu, Ruth

2016-01-01

The correction of specific signaling defects can reverse the oncogenic phenotype of tumor cells by acting in a dominant manner over the cancer genome. Unfortunately, there have been very few successful attempts at identifying the primary cues that could redirect malignant tissues to a normal phenotype. Here we show that suppression of the lipogenic enzyme fatty acid synthase (FASN) leads to stable reversion of the malignant phenotype and normalizes differentiation in a model of breast cancer (BC) progression. FASN knockdown dramatically reduced tumorigenicity of BC cells and restored tissue architecture, which was reminiscent of normal ductal-like structures in the mammary gland. Loss of FASN signaling was sufficient to direct tumors to a reversed phenotype that was near normal when considering the development of polarized growth-arrested acinar-like structure similar to those formed by nonmalignant breast cells in a 3D reconstituted basement membrane in vitro. This process, in vivo, resulted in a low proliferation index, mesenchymal-epithelial transition, and shut-off of the angiogenic switch in FASN-depleted BC cells orthotopically implanted into mammary fat pads. The role of FASN as a negative regulator of correct breast tissue architecture and terminal epithelial cell differentiation was dominant over the malignant phenotype of tumor cells possessing multiple cancer-driving genetic lesions as it remained stable during the course of serial in vivo passage of orthotopic tumor-derived cells. Transient knockdown of FASN suppressed hallmark structural and cytosolic/secretive proteins (vimentin, N-cadherin, fibronectin) in a model of EMT-induced cancer stem cells (CSC). Indirect pharmacological inhibition of FASN promoted a phenotypic switch from basal- to luminal-like tumorsphere architectures with reduced intrasphere heterogeneity. The fact that sole correction of exacerbated lipogenesis can stably reprogram cancer cells back to normal-like tissue architectures might open a new avenue to chronically restrain BC progression by using FASN-based differentiation therapies. PMID:27223424

LINE-1 couples EMT programming with acquisition of oncogenic phenotypes in human bronchial epithelial cells.

PubMed

Reyes-Reyes, Elsa M; Aispuro, Ivan; Tavera-Garcia, Marco A; Field, Matthew; Moore, Sara; Ramos, Irma; Ramos, Kenneth S

2017-11-28

Although several lines of evidence have established the central role of epithelial-to-mesenchymal-transition (EMT) in malignant progression of non-small cell lung cancers (NSCLCs), the molecular events connecting EMT to malignancy remain poorly understood. This study presents evidence that Long Interspersed Nuclear Element-1 (LINE-1) retrotransposon couples EMT programming with malignancy in human bronchial epithelial cells (BEAS-2B). This conclusion is supported by studies showing that: 1) activation of EMT programming by TGF-β1 increases LINE-1 mRNAs and protein; 2) the lung carcinogen benzo(a)pyrene coregulates TGF-β1 and LINE-1 mRNAs, with LINE-1 positioned downstream of TGF-β1 signaling; and, 3) forced expression of LINE-1 in BEAS-2B cells recapitulates EMT programming and induces malignant phenotypes and tumorigenesis in vivo . These findings identify a TGFβ1-LINE-1 axis as a critical effector pathway that can be targeted for the development of precision therapies during malignant progression of intractable NSCLCs.

[Occurrence of AmpC-positive Klebsiella pneumoniae strains in patients with haematological malignancies].

PubMed

Chromá, Magdaléna; Kolár, Milan; Sauer, Pavel; Faber, Edgar; Stosová, Tatána; Koukalová, Dagmar; Indrák, Karel

2008-10-01

Currently, important bacterial beta-lactamases of increasing clinical significance include AmpC enzymes. The aim was to assess their occurrence in Klebsiella pneumoniae strains isolated from patients with haematological malignancies in a prospective study. Over a 2-month period, strains of the species were isolated from clinical material obtained from patients hospitalized at the Department of Haemato-Oncology of the University Hospital Olomouc. The strains were identified using standard microbiological techniques and the Vitek 2 automated system. Production of AmpC beta-lactamases was roughly determined by phenotypic tests and subsequently confirmed by PCR detection of genes encoding these enzymes. During the above-mentioned period, a total of 35 K. pneumoniae isolates were collected. In 7 of them, production of AmpC beta-lactamases was preliminarily detected by phenotypic test. The multiplex PCR method confirmed phenotyping and determined DHA types in all the isolates. All AmpC-positive isolates were false-susceptible to at least one of the tested third-generation cephalosporins. In one patient, clinically apparent infection caused by this strain was documented. The reported results suggest the possibility of occurrence of AmpC-beta-lactamases in K. pneumoniae strains with clinical significance.

HMGB1 targeting by ethyl pyruvate suppresses malignant phenotype of human mesothelioma.

PubMed

Pellegrini, Laura; Xue, Jiaming; Larson, David; Pastorino, Sandra; Jube, Sandro; Forest, Kelly H; Saad-Jube, Zeyana Salim; Napolitano, Andrea; Pagano, Ian; Negi, Vishal S; Bianchi, Marco E; Morris, Paul; Pass, Harvey I; Gaudino, Giovanni; Carbone, Michele; Yang, Haining

2017-04-04

Human malignant mesothelioma (MM) is an aggressive cancer linked to asbestos and erionite exposure. We previously reported that High-Mobility Group Box-1 protein (HMGB1), a prototypic damage-associated molecular pattern, drives MM development and sustains MM progression. Moreover, we demonstrated that targeting HMGB1 inhibited MM cell growth and motility in vitro, reduced tumor growth in vivo, and prolonged survival of MM-bearing mice. Ethyl pyruvate (EP), the ethyl ester of pyruvic acid, has been shown to be an effective HMGB1 inhibitor in inflammation-related diseases and several cancers. Here, we studied the effect of EP on the malignant phenotype of MM cells in tissue culture and on tumor growth in vivo using an orthotopic MM xenograft model. We found that EP impairs HMGB1 secretion by MM cells leading to reduced RAGE expression and NF-κB activation. As a consequence, EP impaired cell motility, cell proliferation, and anchorage-independent growth of MM cells. Moreover, EP reduced HMGB1 serum levels in mice and inhibited the growth of MM xenografts.Our results indicate that EP effectively hampers the malignant phenotype of MM, offering a novel potential therapeutic approach to patients afflicted with this dismal disease.

Chemical Fluxes in Cellular Steady States Measured by Fluorescence Correlation Spectroscopy

NASA Astrophysics Data System (ADS)

Qian, Hong; Elson, Elliot L.

Genetically, identical cells adopt phenotypes that have different structures, functions, and metabolic properties. In multi-cellular organisms, for example, tissue-specific phenotypes distinguish muscle cells, liver cells, fibroblasts, and blood cells that differ in biochemical functions, geometric forms, and interactions with extracellular environments. Tissue-specific cells usually have different metabolic functions such as synthesis of distinct spectra of secreted proteins, e.g., by liver or pancreatic cells, or of structural proteins, e.g., muscle vs. epithelial cells. But more importantly, a phenotype should include a dynamic aspect: different phenotypes can have distinctly different dynamic functions such as contraction of muscle cells and locomotion of leukocytes. The phenotypes of differentiated tissue cells are typically stable, but they can respond to changes in external conditions, e.g., as in the hypertrophy of muscle cells in response to extra load [1] or the phenotypic shift of fibroblasts to myofibroblasts as part of the wound healing response [2]. Cells pass through sequences of phenotypes during development and also undergo malignant phenotypic transformations as occur in cancer and heart disease.

Gene signature critical to cancer phenotype as a paradigm for anti-cancer drug discovery

PubMed Central

Sampson, Erik R.; McMurray, Helene R.; Hassane, Duane C.; Newman, Laurel; Salzman, Peter; Jordan, Craig T.; Land, Hartmut

2013-01-01

Malignant cell transformation commonly results in the deregulation of thousands of cellular genes, an observation that suggests a complex biological process and an inherently challenging scenario for the development of effective cancer interventions. To better define the genes/pathways essential to regulating the malignant phenotype, we recently described a novel strategy based on the cooperative nature of carcinogenesis that focuses on genes synergistically deregulated in response to cooperating oncogenic mutations. These so-called “cooperation response genes” (CRGs) are highly enriched for genes critical for the cancer phenotype, thereby suggesting their causal role in the malignant state. Here we show that CRGs play an essential role in drug-mediated anti-cancer activity and that anti-cancer agents can be identified through their ability to antagonize the CRG expression profile. These findings provide proof-of-concept for the use of the CRG signature as a novel means of drug discovery with relevance to underlying anti-cancer drug mechanisms. PMID:22964631

GLUT1 expression in pediatric adrenocortical tumors: a promising candidate to predict clinical behavior.

PubMed

Pinheiro, Céline; Granja, Sara; Longatto-Filho, Adhemar; Faria, André M; Fragoso, Maria C B V; Lovisolo, Silvana M; Bonatelli, Murilo; Costa, Ricardo F A; Lerário, Antonio M; Almeida, Madson Q; Baltazar, Fátima; Zerbini, Maria C N

2017-09-08

Discrimination between benign and malignant tumors is a challenging process in pediatric adrenocortical tumors. New insights in the metabolic profile of pediatric adrenocortical tumors may contribute to this distinction, predict prognosis, as well as identify new molecular targets for therapy. The aim of this work is to characterize the expression of the metabolism-related proteins MCT1, MCT2, MCT4, CD147, CD44, GLUT1 and CAIX in a series of pediatric adrenocortical tumors. A total of 50 pediatric patients presenting adrenocortical tumors, including 41 clinically benign and 9 clinically malignant tumors, were included. Protein expression was evaluated using immunohistochemistry in samples arranged in tissue microarrays. The immunohistochemical analysis showed a significant increase in plasma membrane expression of GLUT1 in malignant lesions, when compared to benign lesions ( p =0.004), being the expression of this protein associated with shorter overall and disease-free survival ( p =0.004 and p =0.001, respectively). Although significant differences were not observed for proteins other than GLUT1, MCT1, MCT4 and CD147 were highly expressed in pediatric adrenocortical neoplasias (around 90%). GLUT1 expression was differentially expressed in pediatric adrenocortical tumors, with higher expression in clinically malignant tumors, and associated with shorter survival, suggesting a metabolic remodeling towards a hyperglycolytic phenotype in this malignancy.

A cell-penetrating peptide based on the interaction between c-Src and connexin43 reverses glioma stem cell phenotype

PubMed Central

Gangoso, E; Thirant, C; Chneiweiss, H; Medina, J M; Tabernero, A

2014-01-01

Connexin43 (Cx43), the main gap junction channel-forming protein in astrocytes, is downregulated in malignant gliomas. These tumors are composed of a heterogeneous population of cells that include many with stem-cell-like properties, called glioma stem cells (GSCs), which are highly tumorigenic and lack Cx43 expression. Interestingly, restoring Cx43 reverses GSC phenotype and consequently reduces their tumorigenicity. In this study, we investigated the mechanism by which Cx43 exerts its antitumorigenic effects on GSCs. We have focused on the tyrosine kinase c-Src, which interacts with the intracellular carboxy tail of Cx43. We found that Cx43 regulates c-Src activity and proliferation in human GSCs expanded in adherent culture. Thus, restoring Cx43 in GSCs inhibited c-Src activity, which in turn promoted the downregulation of the inhibitor of differentiation Id1. Id1 sustains stem cell phenotype as it controls the expression of Sox2, responsible for stem cell self-renewal, and promotes cadherin switching, which has been associated to epithelial–mesenchymal transition. Our results show that both the ectopic expression of Cx43 and the inhibition of c-Src reduced Id1, Sox2 expression and promoted the switch from N- to E-cadherin, suggesting that Cx43, by inhibiting c-Src, downregulates Id1 with the subsequent changes in stem cell phenotype. On the basis of this mechanism, we found that a cell-penetrating peptide, containing the region of Cx43 that interacts with c-Src, mimics the effect of Cx43 on GSC phenotype, confirming the relevance of the interaction between Cx43 and c-Src in the regulation of the malignant phenotype and pinpointing this interaction as a promising therapeutic target. PMID:24457967

EGFR-dependent signalling reduced and p38 dependent apoptosis required by Gallic acid in Malignant Mesothelioma cells.

PubMed

Demiroglu-Zergeroglu, Asuman; Candemir, Gulsife; Turhanlar, Ebru; Sagir, Fatma; Ayvali, Nurettin

2016-12-01

The unrestrained EGFR signalling contributes to malignant phenotype in a number of cancers including Malignant Mesotheliomas. Present study was designed to evaluate EGFR-dependent anti-proliferative and apoptotic effects of Gallic acid in transformed Mesothelial (MeT-5A) and Malignant Mesothelioma (SPC212) cells. Gallic acid reduced the viability of Malignant Mesothelioma cells in a concentration and time-dependent manner. However, viability of mesothelial cells reduced only at high concentration and longer time periods. Gallic acid restrained the activation of EGFR, ERK1/2 and AKT proteins and down regulated expression of Cyclin D and Bcl-2 genes, but upregulated the expression of p21 gene in EGF-induced SPC212 cells. GA-induced transitory G1 arrest and triggered mitochondrial and death receptor mediated apoptosis, which requires p38MAPK activation. The data provided here indicate that GA is able to inhibit EGFR dependent proliferation and survival signals and induces p38 pathway dependent apoptosis in Malignant Mesothelioma cells. On the basis of these experimental findings it is worthwhile to investigate further the biological activity of Gallic acid on other Mesothelioma cell lines harbouring aberrant EGFR signals. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Mangiferin inhibits cell migration and invasion through Rac1/WAVE2 signalling in breast cancer.

PubMed

Deng, Qing; Tian, Yan-Xiao; Liang, JianJun

2018-04-01

Breast tumour progression results from the advancement of the disease to a metastatic phenotype. Rac1 and Cdc42 belong to the Rho family of genes that, together with their downstream effectors, Wiskott-Aldrich Syndrome protein-family verprolin-homologous protein 2 (WAVE2) and Arp2/3, assume a vital part in cytoskeletal rearrangement and the arrangement of film projections that advance malignant cell relocation and invasion. Mangiferin is a characteristic polyphenolic compound from Mangifera indica L. (Anacardiaceae), ordinarily referred to as mango, that is consumed worldwide as a natural product, including culinary and seasoning applications. Mangiferin delays breast malignancy development and progression by inhibiting different signalling pathways required in mitogenic signalling and metastatic progression. Studies were performed to analyse the impact of mangiferin on Rac1/WAVE2 flagging, relocation and invasion in highly metastatic human MDA-MB-231 mammary cells. Additional studies led to the observation that comparative treatment with mangiferin caused marked reduction in tumour cell movement and invasion. Taken together, these discoveries demonstrate that mangiferin treatment adequately hinders Rac1/WAVE2 flagging and diminishes metastatic phenotypic expression in malignant mammary cells, indicating that mangiferin may provide a benefit as a novel restorative approach in the treatment of metastatic breast cancer.

Suppression of miR-184 in malignant gliomas upregulates SND1 and promotes tumor aggressiveness

PubMed Central

Emdad, Luni; Janjic, Aleksandar; Alzubi, Mohammad A.; Hu, Bin; Santhekadur, Prasanna K.; Menezes, Mitchell E.; Shen, Xue-Ning; Das, Swadesh K.; Sarkar, Devanand; Fisher, Paul B.

2015-01-01

Background Malignant glioma is an aggressive cancer requiring new therapeutic targets. MicroRNAs (miRNAs) regulate gene expression post transcriptionally and are implicated in cancer development and progression. Deregulated expressions of several miRNAs, specifically hsa-miR-184, correlate with glioma development. Methods Bioinformatic approaches were used to identify potential miR-184-regulated target genes involved in malignant glioma progression. This strategy identified a multifunctional nuclease, SND1, known to be overexpressed in multiple cancers, including breast, colon, and hepatocellular carcinoma, as a putative direct miR-184 target gene. SND1 levels were evaluated in patient tumor samples and human-derived cell lines. We analyzed invasion and signaling in vitro through SND1 gain-of-function and loss-of-function. An orthotopic xenograft model with primary glioma cells demonstrated a role of miR-184/SND1 in glioma pathogenesis in vivo. Results SND1 is highly expressed in human glioma tissue and inversely correlated with miR-184 expression. Transfection of glioma cells with a miR-184 mimic inhibited invasion, suppressed colony formation, and reduced anchorage-independent growth in soft agar. Similar phenotypes were evident when SND1 was knocked down with siRNA. Additionally, knockdown (KD) of SND1 induced senescence and improved the chemoresistant properties of malignant glioma cells. In an orthotopic xenograft model, KD of SND1 or transfection with a miR-184 mimic induced a less invasive tumor phenotype and significantly improved survival of tumor bearing mice. Conclusions Our study is the first to show a novel regulatory role of SND1, a direct target of miR-184, in glioma progression, suggesting that the miR-184/SND1 axis may be a useful diagnostic and therapeutic tool for malignant glioma. PMID:25216670

The activation of human endogenous retrovirus K (HERV-K) is implicated in melanoma cell malignant transformation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Serafino, A.; Balestrieri, E.; Pierimarchi, P.

2009-03-10

Melanoma development is a multi-step process arising from a series of genetic and epigenetic events. Although the sequential stages involved in progression from melanocytes to malignant melanoma are clearly defined, our current understanding of the mechanisms leading to melanoma onset is still incomplete. Growing evidence show that the activation of endogenous retroviral sequences might be involved in transformation of melanocytes as well as in the increased ability of melanoma cells to escape immune surveillance. Here we show that human melanoma cells in vitro undergo a transition from adherent to a more malignant, non-adherent phenotype when exposed to stress conditions. Melanoma-derivedmore » non-adherent cells are characterized by an increased proliferative potential and a decreased expression of both HLA class I molecules and Melan-A/MART-1 antigen, similarly to highly malignant cells. These phenotypic and functional modifications are accompanied by the activation of human endogenous retrovirus K expression (HERV-K) and massive production of viral-like particles. Down-regulation of HERV-K expression by RNA interference prevents the transition from the adherent to the non-adherent growth phenotype in low serum. These results implicate HERV-K in at least some critical steps of melanoma progression.« less

Extreme Growth Failure is a Common Presentation of Ligase IV Deficiency

PubMed Central

Murray, Jennie E; Bicknell, Louise S; Yigit, Gökhan; Duker, Angela L; van Kogelenberg, Margriet; Haghayegh, Sara; Wieczorek, Dagmar; Kayserili, Hülya; Albert, Michael H; Wise, Carol A; Brandon, January; Kleefstra, Tjitske; Warris, Adilia; van der Flier, Michiel; Bamforth, J Steven; Doonanco, Kurston; Adès, Lesley; Ma, Alan; Field, Michael; Johnson, Diana; Shackley, Fiona; Firth, Helen; Woods, C Geoffrey; Nürnberg, Peter; Gatti, Richard A; Hurles, Matthew; Bober, Michael B; Wollnik, Bernd; Jackson, Andrew P

2014-01-01

Ligase IV syndrome is a rare differential diagnosis for Nijmegen breakage syndrome owing to a shared predisposition to lympho-reticular malignancies, significant microcephaly, and radiation hypersensitivity. Only 16 cases with mutations in LIG4 have been described to date with phenotypes varying from malignancy in developmentally normal individuals, to severe combined immunodeficiency and early mortality. Here, we report the identification of biallelic truncating LIG4 mutations in 11 patients with microcephalic primordial dwarfism presenting with restricted prenatal growth and extreme postnatal global growth failure (average OFC −10.1 s.d., height −5.1 s.d.). Subsequently, most patients developed thrombocytopenia and leucopenia later in childhood and many were found to have previously unrecognized immunodeficiency following molecular diagnosis. None have yet developed malignancy, though all patients tested had cellular radiosensitivity. A genotype–phenotype correlation was also noted with position of truncating mutations corresponding to disease severity. This work extends the phenotypic spectrum associated with LIG4 mutations, establishing that extreme growth retardation with microcephaly is a common presentation of bilallelic truncating mutations. Such growth failure is therefore sufficient to consider a diagnosis of LIG4 deficiency and early recognition of such cases is important as bone marrow failure, immunodeficiency, and sometimes malignancy are long term sequelae of this disorder. PMID:24123394

Profiling of normal and malignant breast tissue show CD44high/CD24low phenotype as a predominant stem/progenitor marker when used in combination with Ep-CAM/CD49f markers

PubMed Central

2013-01-01

Background Accumulating evidence supports cancer to initiate and develop from a small population of stem-like cells termed as cancer stem cells (CSC). The exact phenotype of CSC and their counterparts in normal mammary gland is not well characterized. In this study our aim was to evaluate the phenotype and function of stem/progenitor cells in normal mammary epithelial cell populations and their malignant counterparts. Methods Freshly isolated cells from both normal and malignant human breasts were sorted using 13 widely used stem/progenitor cell markers individually or in combination by multi-parametric (up to 9 colors) cell sorting. The sorted populations were functionally evaluated by their ability to form colonies and mammospheres, in vitro. Results We have compared, for the first time, the stem/progenitor markers of normal and malignant breasts side-by-side. Amongst all markers tested, we found CD44high/CD24low cell surface marker combination to be the most efficient at selecting normal epithelial progenitors. Further fractionation of CD44high/CD24low positive cells showed that this phenotype selects for luminal progenitors within Ep-CAMhigh/CD49f + cells, and enriches for basal progenitors within Ep-CAM-/low/CD49f + cells. On the other hand, primary breast cancer samples, which were mainly luminal Ep-CAMhigh, had CD44high/CD24low cells among both CD49fneg and CD49f + cancer cell fractions. However, functionally, CSC were predominantly CD49f + proposing the use of CD44high/CD24low in combination with Ep-CAM/CD49f cell surface markers to further enrich for CSC. Conclusion Our study clearly demonstrates that both normal and malignant breast cells with the CD44high/CD24low phenotype have the highest stem/progenitor cell ability when used in combination with Ep-CAM/CD49f reference markers. We believe that this extensive characterization study will help in understanding breast cancer carcinogenesis, heterogeneity and drug resistance. PMID:23768049

Rethinking the bile acid/gut microbiome axis in cancer

PubMed Central

Phelan, John P.; Reen, F. Jerry; Caparros-Martin, Jose A.; O'Connor, Rosemary; O'Gara, Fergal

2017-01-01

Dietary factors, probiotic agents, aging and antibiotics/medicines impact on gut microbiome composition leading to disturbances in localised microbial populations. The impact can be profound and underlies a plethora of human disorders, including the focus of this review; cancer. Compromised microbiome populations can alter bile acid signalling and produce distinct pathophysiological bile acid profiles. These in turn have been associated with cancer development and progression. Exposure to high levels of bile acids, combined with localised molecular/genome instability leads to the acquisition of bile mediated neoplastic alterations, generating apoptotic resistant proliferation phenotypes. However, in recent years, several studies have emerged advocating the therapeutic benefits of bile acid signalling in suppressing molecular and phenotypic hallmarks of cancer progression. These studies suggest that in some instances, bile acids may reduce cancer phenotypic effects, thereby limiting metastatic potential. In this review, we contextualise the current state of the art to propose that the bile acid/gut microbiome axis can influence cancer progression to the extent that classical in vitro cancer hallmarks of malignancy (cell invasion, cell migration, clonogenicity, and cell adhesion) are significantly reduced. We readily acknowledge the existence of a bile acid/gut microbiome axis in cancer initiation, however, in light of recent advances, we focus exclusively on the role of bile acids as potentially beneficial molecules in suppressing cancer progression. Finally, we theorise that suppressing aggressive malignant phenotypes through bile acid/gut microbiome axis modulation could uncover new and innovative disease management strategies for managing cancers in vulnerable cohorts. PMID:29383197

The androgen receptor malignancy shift in prostate cancer.

PubMed

Copeland, Ben T; Pal, Sumanta K; Bolton, Eric C; Jones, Jeremy O

2018-05-01

Androgens and the androgen receptor (AR) are necessary for the development, function, and homeostatic growth regulation of the prostate gland. However, once prostate cells are transformed, the AR is necessary for the proliferation and survival of the malignant cells. This change in AR function appears to occur in nearly every prostate cancer. We have termed this the AR malignancy shift. In this review, we summarize the current knowledge of the AR malignancy shift, including the DNA-binding patterns that define the shift, the transcriptome changes associated with the shift, the putative drivers of the shift, and its clinical implications. In benign prostate epithelial cells, the AR primarily binds consensus AR binding sites. In carcinoma cells, the AR cistrome is dramatically altered, as the AR associates with FOXA1 and HOXB13 motifs, among others. This shift leads to the transcription of genes associated with a malignant phenotype. In model systems, some mutations commonly found in localized prostate cancer can alter the AR cistrome, consistent with the AR malignancy shift. Current evidence suggests that the AR malignancy shift is necessary but not sufficient for transformation of prostate epithelial cells. Reinterpretation of prostate cancer genomic classification systems in light of the AR malignancy shift may improve our ability to predict clinical outcomes and treat patients appropriately. Identifying and targeting the molecular factors that contribute to the AR malignancy shift is not trivial but by doing so, we may be able to develop new strategies for the treatment or prevention of prostate cancer. © 2018 Wiley Periodicals, Inc.

Use of Monoclonal Antibodies for the Diagnosis of T-cell Malignancies: Applications and Limitations.

PubMed

Hastrup, N; Pallesen, G; Ralfikiaer, E

1990-01-01

Biopsy samples from 136 peripheral T-cell lymphomas have been examined and compared with benign inflammatory T-cell infiltrates in an attempt to establish whether immunohistological methods may help to improve the distinction between these conditions. The results confirm and extend previous reports and indicate that the aberrant T-cell phenotypes constitute the single most reliable criterion for the distinction between benign and malignant T-cell infiltrates. These phenotypes are expressed frequently in T-cell malignancies in. lymphoid organs and are also seen in a substantial number of biopsy samples from advanced cutaneous T-cell lymphomas (CTCL). In contrast, early CTCL do not express aberrant T-cell phenotypes and are indistinguishable from benign cutaneous conditions in terms of their immunophenotypic properties. It is concluded that immunophenotypic techniques form a valuable supplement to routine histological methods for the diagnosis of T-cell lymphomas in lymphoid organs. The methods may also help to improve the diagnosis of advanced CTCL, but are of no or only limited help for the recognition of the early stages.

Update on the imaging of malignant perivascular epithelioid cell tumors (PEComas).

PubMed

Phillips, Catherine H; Keraliya, Abhishek R; Shinagare, Atul B; Ramaiya, Nikhil H; Tirumani, Sree Harsha

2016-02-01

Malignant perivascular epithelioid cell tumors (PEComas) are a histologic group of mesenchymal neoplasms that share a distinctive histological phenotype, the perivascular epithelioid cell. These tumors are known for their perivascular distribution. Malignant PEComas have a female predominance and are associated with aggressive disease and poor prognosis, making timely diagnosis critical to management. Imaging features of malignant PEComas are nonspecific and mimic other benign and malignant neoplasms. Surgery is the mainstay in the management of malignant PEComas. Promising novel molecular targeted therapies like m-TOR inhibitors have been shown to be effective in the metastatic setting. The aim of this review is to familiarize radiologists with the imaging appearances of and potential therapies for primary and metastatic malignant PEComa.

An Unusual Case of Constitutional Mismatch Repair Deficiency Syndrome With Anaplastic Ganglioglioma, Colonic Adenocarcinoma, Osteosarcoma, Acute Myeloid Leukemia, and Signs of Neurofibromatosis Type 1: Case Report.

PubMed

Daou, Badih; Zanello, Marc; Varlet, Pascale; Brugieres, Laurence; Jabbour, Pascal; Caron, Olivier; Lavoine, Noémie; Dhermain, Frederic; Willekens, Christophe; Beuvon, Frederic; Malka, David; Lechapt-Zalcmann, Emmanuèle; Abi Lahoud, Georges

2015-07-01

Constitutional mismatch repair deficiency (CMMRD) syndrome is a disorder with recessive inheritance caused by biallelic mismatch repair gene mutations, in which mismatch repair defects are inherited from both parents. This syndrome is associated with multiple cancers occurring in childhood. The most common tumors observed with CMMRD include brain tumors, digestive tract tumors, and hematological malignancies. The aim of this study was to report new phenotypic expressions of CMMRD syndrome and add new insight to the existing knowledge about this disease. A review of the literature was conducted and recommendation for surveillance and follow-up in patients with CMMRD are proposed. We report for the first time in the literature, the case of a 22-year-old female patient who was diagnosed with CMMRD syndrome, with the development of 2 unusual tumors: an anaplastic ganglioglioma and an osteosarcoma. She presented initially with an anaplastic ganglioglioma and later developed several malignancies including colonic adenocarcinoma, osteosarcoma, and acute myeloid leukemia. The patient had an atypical course of her disease with development of the initial malignancy at an older age and a remarkably long survival period despite developing aggressive tumors. Many aspects of this disease are still unknown. We identified a case of CMMRD in a patient presenting with an anaplastic ganglioglioma, who underwent successful surgical resection, chemotherapy, and radiotherapy and has had one of the longest survival periods known with this disease. This case broadens the tumor spectrum observed with CMMRD syndrome with anaplastic ganglioglioma and osteosarcoma as new phenotypic expressions of this genetic defect.

Clinicopathological findings of primary esophageal malignant melanoma: report of six cases and review of literature.

PubMed

Zheng, Jinfeng; Mo, Haiying; Ma, Shufang; Wang, Zhenzheng

2014-01-01

We studied images and histopathological features of primary esophageal malignant melanoma to explore the clinical pathological features, diagnosis, differential diagnoses, and treatment. Immunolabelling was conducted on six cases of esophageal malignant melanoma using histological and immunohistochemical techniques. Combined with the related literature, the clinical manifestations, imaging, histopathological and immunohistochemical features, treatment, and prognosis of primary esophageal malignant melanoma were observed and analyzed. The six patients with primary esophageal malignant melanoma were all male with an average age of 63.4 years. Poor food intake was observed in all patients, and the symptoms showed progressive aggravation. Endoscopic feed tube revealed dark brown and black nodular and polypoid lesions, 1/4-1/2 loop cavity. Tumor histopathology revealed the following characteristics: tumor cells arranged in nests, sheets and cords, round or polygonal, abundant and red-stained cytoplasm, melanin granules in the cytoplasm, heterogeneous nucleus sizes, centered or deviated nuclei, clearly identifiable nucleoli, and apparent pathological mitosis. The immune phenotype was as follows: tumor cells had diffuse expression of HMB45, Melan A, and S100. The cells were CK negative, and the Ki67-positive cell number was 40%-45%. Primary esophageal malignant melanoma is rare with high malignancy and poor prognosis. Immunohistochemical staining is helpful for diagnosing this tumor. The differential diagnosis includes low differentiated carcinoma, primitive neuroectodermal tumor, esophageal sarcomatoid carcinoma, esophageal lymphoma, and other tumors.

Connections between constitutional mismatch repair deficiency syndrome and neurofibromatosis type 1.

PubMed

Wimmer, K; Rosenbaum, T; Messiaen, L

2017-04-01

Constitutional mismatch repair (MMR) deficiency (CMMRD) is a rare childhood cancer susceptibility syndrome resulting from biallelic germline loss-of-function mutations in one of the MMR genes. Individuals with CMMRD have high risk to develop a broad spectrum of malignancies and frequently display features reminiscent of neurofibromatosis type 1 (NF1). Evaluation of the clinical findings of genetically proven CMMRD patients shows that not only multiple café-au-lait macules but also any of the diagnostic features of NF1 may be present in a CMMRD patient. This phenotypic overlap may lead to misdiagnosis of CMMRD patients as having NF1, which impedes adequate management of the patients and their families. The spectrum of CMMRD-associated childhood malignancies includes high-grade glioma, acute myeloid leukaemia or rhabdomyosarcoma, also reported as associated with NF1. Reported associations between NF1 and these malignancies are to a large extent based on studies that neither proved the presence of an NF1 germline mutation nor ruled-out CMMRD in the affected. Hence, these associations are challenged by our current knowledge of the phenotypic overlap between NF1 and CMMRD and should be re-evaluated in future studies. Recent advances in the diagnostics of CMMRD should render it possible to definitely state or refute this diagnosis in these individuals. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Cell transformation and mutability of different genetic loci in mammalian cells by metabolically activated carcinogenic polycylic hydrocarbons

DOE Office of Scientific and Technical Information (OSTI.GOV)

Huberman, E.

1977-01-01

Treatment of experimental animals with chemical carcinogens, including some polycyclic hydrocarbons, can result in the formation of malignant tumors. The process whereby some chemicals induce malignancy is as yet unknown. However, in a model system using mammalian cells in culture, it was possible to show that the chemical carcinogens induce malignant transformation rather than select for pre-existing tumor cells. In the process of the in vitro cell transformation, the normal cells, which have an oriented pattern of cell growth, a limited life-span in vitro, and are not tumorigenic, are converted into cells that have a hereditary random pattern of cellmore » growth, the ability to grow continuously in culture, and the ability to form tumors in vivo. This stable heritable phenotype of the transformed cells is similar to that of cells derived from spontaneous or experimentally induced tumors. Such stable heritable phenotype changes may arise from alteration in gene expression due to a somatic mutation after interaction of the carcinogen with cellular DNA. In the present experiments we have shown that metabolically activated carcinogenic polycyclic hydrocarbons which have been shown to bind to cellular DNA induce somatic mutations at different genetic loci in mammalian cells and that there is a relationship between the degree of mutant induction and the degree of carcinogenicity of the different hydrocarbons tested.« less

Inhibition of the platelet-derived growth factor receptor beta (PDGFRB) using gene silencing, crenolanib besylate, or imatinib mesylate hampers the malignant phenotype of mesothelioma cell lines

PubMed Central

Melaiu, Ombretta; Catalano, Calogerina; De Santi, Chiara; Cipollini, Monica; Figlioli, Gisella; Pellè, Lucia; Barone, Elisa; Evangelista, Monica; Guazzelli, Alice; Boldrini, Laura; Sensi, Elisa; Bonotti, Alessandra; Foddis, Rudy; Cristaudo, Alfonso; Mutti, Luciano; Fontanini, Gabriella; Gemignani, Federica; Landi, Stefano

2017-01-01

Malignant pleural mesothelioma (MPM) is a cancer of the pleural cavity resistant to chemotherapy. The identification of novel therapeutic targets is needed to improve its poor prognosis. Following a review of literature and a screening of specimens we found that platelet-derived growth factor receptor beta (PDGFRB) is over-expressed, but not somatically mutated, in MPM tissues. We aimed to ascertain whether PDGFRB is a MPM-cancer driver gene. The approaches employed included the use of gene silencing and the administration of small molecules, such as crenolanib and imatinib (PDGFR inhibitors) on MPM cell lines (IstMes2, Mero-14, Mero-25). Met5A cells were used as non-malignant mesothelial cell line. PDGFRB-silencing caused a decrease in the proliferation rate, and a reduced colony formation capacity, as well as an increase of the share of cells in sub-G1 and in G2 phase, and increased apoptotic rate of MPM cell lines. Loss of migration ability was also observed. Similar, or even further enhanced, results were obtained with crenolanib. Imatinib showed the least effective activity on the phenotype. In conclusion, our study highlights PDGFRB as target with a clear role in MPM tumorigenesis and provided a rationale to explore further the efficacy of crenolanib in MPM patients, with promising results. PMID:28435517

Activation of the germ-cell potential of human bone marrow-derived cells by a chemical carcinogen

PubMed Central

Liu, Chunfang; Ma, Zhan; Xu, Songtao; Hou, Jun; Hu, Yao; Yu, Yinglu; Liu, Ruilai; Chen, Zhihong; Lu, Yuan

2014-01-01

Embryonic/germ cell traits are common in malignant tumors and are thought to be involved in malignant tumor behaviors. The reasons why tumors show strong embryonic/germline traits (displaced germ cells or gametogenic programming reactivation) are controversial. Here, we show that a chemical carcinogen, 3-methyl-cholanthrene (3-MCA), can trigger the germ-cell potential of human bone marrow-derived cells (hBMDCs). 3-MCA promoted the generation of germ cell-like cells from induced hBMDCs that had undergone malignant transformation, whereas similar results were not observed in the parallel hBMDC culture at the same time point. The malignant transformed hBMDCs spontaneously and more efficiently generated into germ cell-like cells even at the single-cell level. The germ cell-like cells from induced hBMDCs were similar to natural germ cells in many aspects, including morphology, gene expression, proliferation, migration, further development, and teratocarcinoma formation. Therefore, our results demonstrate that a chemical carcinogen can reactivate the germline phenotypes of human somatic tissue-derived cells, which might provide a novel idea to tumor biology and therapy. PMID:24998261

Cell Motility and Invasiveness of Neurofibromin-Deficient Neural Crest Cells and Malignant Triton Tumor Lines. Addendum

DTIC Science & Technology

2006-06-01

Tumor Foundation, Molecular Biology of NF1, NF2, and Schwannomatosis Meeting, poster presentation. "A mild mutator phenotype arises in NF1-associated...malignancies" June 2006: Children’s Tumor Foundation, Molecular Biology of NF1, NF2, and Schwannomatosis Meeting, platform presentation. “DNA

Molecular and functional analysis of anchorage independent, treatment-evasive neuroblastoma tumorspheres with enhanced malignant properties: A possible explanation for radio-therapy resistance

PubMed Central

Nazarian, Javad; Ghanem, Anthony; Vukmanovic, Stanislav; Sandler, Anthony D.

2018-01-01

Despite significant advances in cancer treatment and management, more than 60% of patients with neuroblastoma present with very poor prognosis in the form of metastatic and aggressive disease. Solid tumors including neuroblastoma are thought to be heterogeneous with a sub-population of stem-like cells that are treatment-evasive with highly malignant characteristics. We previously identified a phenomenon of reversible adaptive plasticity (RAP) between anchorage dependent (AD) cells and anchorage independent (AI) tumorspheres in neuroblastoma cell cultures. To expand our molecular characterization of the AI tumorspheres, we sought to define the comprehensive proteomic profile of murine AD and AI neuroblastoma cells. The proteomic profiles of the two phenotypic cell populations were compared to each other to determine the differential protein expression and molecular pathways of interest. We report exclusive or significant up-regulation of tumorigenic pathways expressed by the AI tumorspheres compared to the AD cancer cells. These pathways govern metastatic potential, enhanced malignancy and epithelial to mesenchymal transition. Furthermore, radio-therapy induced significant up-regulation of specific tumorigenic and proliferative proteins, namely survivin, CDC2 and the enzyme Poly [ADP-ribose] polymerase 1. Bio-functional characteristics of the AI tumorspheres were resistant to sutent inhibition of receptor tyrosine kinases (RTKs) as well as to 2.5 Gy radio-therapy as assessed by cell survival, proliferation, apoptosis and migration. Interestingly, PDGF-BB stimulation of the PDGFRβ led to transactivation of EGFR and VEGFR in AI tumorspheres more potently than in AD cells. Sutent inhibition of PDGFRβ abrogated this transactivation in both cell types. In addition, 48 h sutent treatment significantly down-regulated the protein expression of PDGFRβ, MYCN, SOX2 and Survivin in the AI tumorspheres and inhibited tumorsphere self-renewal. Radio-sensitivity in AI tumorspheres was enhanced when sutent treatment was combined with survivin knock-down. We conclude that AI tumorspheres have a differential protein expression compared to AD cancer cells that contribute to their malignant phenotype and radio-resistance. Specific targeting of both cellular phenotypes is needed to improve outcomes in neuroblastoma patients. PMID:29298329

Molecular and functional analysis of anchorage independent, treatment-evasive neuroblastoma tumorspheres with enhanced malignant properties: A possible explanation for radio-therapy resistance.

PubMed

Abou-Antoun, Tamara J; Nazarian, Javad; Ghanem, Anthony; Vukmanovic, Stanislav; Sandler, Anthony D

2018-01-01

Despite significant advances in cancer treatment and management, more than 60% of patients with neuroblastoma present with very poor prognosis in the form of metastatic and aggressive disease. Solid tumors including neuroblastoma are thought to be heterogeneous with a sub-population of stem-like cells that are treatment-evasive with highly malignant characteristics. We previously identified a phenomenon of reversible adaptive plasticity (RAP) between anchorage dependent (AD) cells and anchorage independent (AI) tumorspheres in neuroblastoma cell cultures. To expand our molecular characterization of the AI tumorspheres, we sought to define the comprehensive proteomic profile of murine AD and AI neuroblastoma cells. The proteomic profiles of the two phenotypic cell populations were compared to each other to determine the differential protein expression and molecular pathways of interest. We report exclusive or significant up-regulation of tumorigenic pathways expressed by the AI tumorspheres compared to the AD cancer cells. These pathways govern metastatic potential, enhanced malignancy and epithelial to mesenchymal transition. Furthermore, radio-therapy induced significant up-regulation of specific tumorigenic and proliferative proteins, namely survivin, CDC2 and the enzyme Poly [ADP-ribose] polymerase 1. Bio-functional characteristics of the AI tumorspheres were resistant to sutent inhibition of receptor tyrosine kinases (RTKs) as well as to 2.5 Gy radio-therapy as assessed by cell survival, proliferation, apoptosis and migration. Interestingly, PDGF-BB stimulation of the PDGFRβ led to transactivation of EGFR and VEGFR in AI tumorspheres more potently than in AD cells. Sutent inhibition of PDGFRβ abrogated this transactivation in both cell types. In addition, 48 h sutent treatment significantly down-regulated the protein expression of PDGFRβ, MYCN, SOX2 and Survivin in the AI tumorspheres and inhibited tumorsphere self-renewal. Radio-sensitivity in AI tumorspheres was enhanced when sutent treatment was combined with survivin knock-down. We conclude that AI tumorspheres have a differential protein expression compared to AD cancer cells that contribute to their malignant phenotype and radio-resistance. Specific targeting of both cellular phenotypes is needed to improve outcomes in neuroblastoma patients.

Restoration of normal phenotype in cancer cells

DOEpatents

Bissell, M.J.; Weaver, V.M.

1998-12-08

A method for reversing expression of malignant phenotype in cancer cells is described. The method comprises applying {beta}{sub 1} integrin function-blocking antibody to the cells. The method can be used to assess the progress of cancer therapy. Human breast epithelial cells were shown to be particularly responsive. 14 figs.

Method for restoration of normal phenotype in cancer cells

DOEpatents

Bissell, Mina J.; Weaver, Valerie M.

2000-01-01

A method for reversing expression of malignant phenotype in cancer cells is described. The method comprises applying .beta..sub.1 integrin function-blocking antibody to the cells. The method can be used to assess the progress of cancer therapy. Human breast epithelial cells were shown to be particularly responsive.

Restoration of normal phenotype in cancer cells

DOEpatents

Bissell, Mina J.; Weaver, Valerie M.

1998-01-01

A method for reversing expression of malignant phenotype in cancer cells is described. The method comprises applying .beta..sub.1 integrin function-blocking antibody to the cells. The method can be used to assess the progress of cancer therapy. Human breast epithelial cells were shown to be particularly responsive.

Role of epigenomics in ovarian and endometrial cancers.

PubMed

Balch, Curtis; Matei, Daniela E; Huang, Tim H-M; Nephew, Kenneth P

2010-06-01

Ovarian cancer is the most lethal gynecologic malignancy and while constituting only 3% of all female cancers, it causes 14,600 deaths in the USA annually. Endometrial cancer, the most diagnosed and second-most fatal gynecologic cancer, afflicts over 40,000 US women annually, causing an estimated 7780 deaths in 2009. In both advanced ovarian and endometrial carcinomas, the majority of initially therapy-responsive tumors eventually evolve to a fully drug-resistant phenotype. In addition to genetic mutations, epigenetic anomalies are frequent in both gynecologic malignancies, including aberrant DNA methylation, atypical histone modifications and dysregulated expression of distinct microRNAs, resulting in altered gene-expression patterns favoring cell survival. In this article, we summarize the most recent hypotheses regarding the role of epigenetics in ovarian and endometrial cancers, including a possible role in tumor 'stemness' and also evaluate the possible therapeutic benefits of reversal of these oncogenic chromatin aberrations.

Nuclear factor E2-related factor-2 has a differential impact on MCT1 and MCT4 lactate carrier expression in colonic epithelial cells: a condition favoring metabolic symbiosis between colorectal cancer and stromal cells.

PubMed

Diehl, K; Dinges, L-A; Helm, O; Ammar, N; Plundrich, D; Arlt, A; Röcken, C; Sebens, S; Schäfer, H

2018-01-04

Malignant tumors, such as colorectal cancer (CRC), are heterogeneous diseases characterized by distinct metabolic phenotypes. These include Warburg- and reverse Warburg phenotypes depending on differential distribution of the lactate carrier proteins monocarboxylate transporter-4 and -1 (MCT4 and MCT1). Here, we elucidated the role of the antioxidant transcription factor nuclear factor E2-related factor-2 (Nrf2) as the key regulator of cellular adaptation to inflammatory/environmental stress in shaping the metabolism toward a reverse Warburg phenotype in malignant and premalignant colonic epithelial cells. Immunohistochemistry of human CRC tissues revealed reciprocal expression of MCT1 and MCT4 in carcinoma and stroma cells, respectively, accompanied by strong epithelial Nrf2 activation. In colorectal tissue from inflammatory bowel disease patients, MCT1 and Nrf2 were coexpressed as well, relating to CD68+inflammatory infiltrates. Indirect coculture of human NCM460 colonocytes with M1- but not M2 macrophages induces MCT1 as well as G6PD, LDHB and TALDO expression, whereas MCT4 expression was decreased. Nrf2 knockdown or reactive oxygen species (ROS) scavenging blocked these coculture effects in NCM460 cells. Likewise, Nrf2 knockdown inhibited similar effects of tBHQ-mediated Nrf2 activation on NCM460 and HCT15 CRC cells. M1 coculture or Nrf2 activation/overexpression greatly altered the lactate uptake but not glucose uptake and mitochondrial activities in these cells, reflecting the reverse Warburg phenotype. Depending on MCT1-mediated lactate uptake, Nrf2 conferred protection from TRAIL-induced apoptosis in NCM460 and HCT15 cells. Moreover, metabolism-dependent clonal growth of HCT15 cells was induced by Nrf2-dependent activation of MCT1-driven lactate exchange. These findings indicate that Nrf2 has an impact on the metabolism already in premalignant colonic epithelial cells exposed to inflammatory M1 macrophages, an effect accompanied by growth and survival alterations. Favoring the reverse Warburg effect, these Nrf2-dependent alterations add to malignant transformation of the colonic epithelium.

The biological role of actinin-4 (ACTN4) in malignant phenotypes of cancer.

PubMed

Honda, Kazufumi

2015-01-01

Invasion and metastasis are malignant phenotypes in cancer that lead to patient death. Cell motility is involved in these processes. In 1998, we identified overexpression of the actin-bundling protein actinin-4 in several types of cancer. Protein expression of actinin-4 is closely associated with the invasive phenotypes of cancers. Actinin-4 is predominantly expressed in the cellular protrusions that stimulate the invasive phenotype in cancer cells and is essential for formation of cellular protrusions such as filopodia and lamellipodia. ACTN4 (gene name encoding actinin-4 protein) is located on human chromosome 19q. ACTN4 amplification is frequently observed in patients with carcinomas of the pancreas, ovary, lung, and salivary gland, and patients with ACTN4 amplifications have worse outcomes than patients without amplification. In addition, nuclear distribution of actinin-4 is frequently observed in small cell lung, breast, and ovarian cancer. Actinin-4, when expressed in cancer cell nuclei, functions as a transcriptional co-activator. In this review, we summarize recent developments regarding the biological roles of actinin-4 in cancer invasion.

The influence of the microenvironment on the malignant phenotype

NASA Technical Reports Server (NTRS)

Park, C. C.; Bissell, M. J.; Barcellos-Hoff, M. H.

2000-01-01

Normal tissue homeostasis is maintained by dynamic interactions between epithelial cells and their microenvironment. As tissue becomes cancerous, there are reciprocal interactions between neoplastic cells, adjacent normal cells such as stroma and endothelium, and their microenvironments. The current dominant paradigm wherein multiple genetic lesions provide both the impetus for, and the Achilles heel of, cancer might be inadequate to understand cancer as a disease process. In the following brief review, we will use selected examples to illustrate the influence of the microenvironment in the evolution of the malignant phenotype. We will also discuss recent studies that suggest novel therapeutic interventions might be derived from focusing on microenvironment and tumor cells interactions.

Therapeutic Potential of Matrix Metalloproteinase Inhibition in Breast Cancer

PubMed Central

Raeeszadeh‐Sarmazdeh, Maryam; Radisky, Derek C.

2017-01-01

ABSTRACT Matrix metalloproteinases (MMPs) are a family of zinc endopeptidases that cleave nearly all components of the extracellular matrix as well as many other soluble and cell‐associated proteins. MMPs have been implicated in normal physiological processes, including development, and in the acquisition and progression of the malignant phenotype. Disappointing results from a series of clinical trials testing small molecule, broad spectrum MMP inhibitors as cancer therapeutics led to a re‐evaluation of how MMPs function in the tumor microenvironment, and ongoing research continues to reveal that these proteins play complex roles in cancer development and progression. It is now clear that effective targeting of MMPs for therapeutic benefit will require selective inhibition of specific MMPs. Here, we provide an overview of the MMP family and its biological regulators, the tissue inhibitors of metalloproteinases (TIMPs). We then summarize recent research from model systems that elucidate how specific MMPs drive the malignant phenotype of breast cancer cells, including acquisition of cancer stem cell features and induction of the epithelial–mesenchymal transition, and we also outline clinical studies that implicate specific MMPs in breast cancer outcomes. We conclude by discussing ongoing strategies for development of inhibitors with therapeutic potential that are capable of selectively targeting the MMPs most responsible for tumor promotion, with special consideration of the potential of biologics including antibodies and engineered proteins based on the TIMP scaffold. J. Cell. Biochem. 118: 3531–3548, 2017. © 2017 The Authors. Journal of Cellular Biochemistry Published by Wiley Periodicals, Inc. PMID:28585723

CpG island methylator phenotype and its association with malignancy in sporadic duodenal adenomas.

PubMed

Sun, Lifeng; Guzzetta, Angela A; Fu, Tao; Chen, Jinming; Jeschke, Jana; Kwak, Ruby; Vatapalli, Rajita; Baylin, Stephen B; Iacobuzio-Donahue, Christine A; Wolfgang, Christopher L; Ahuja, Nita

2014-05-01

CpG island methylator phenotype (CIMP) has been found in multiple precancerous and cancerous lesions, including colorectal adenomas, colorectal cancers, and duodenal adenocarcinomas. There are no reports in the literature of a relationship between CIMP status and clinicopathologic features of sporadic duodenal adenomas. This study sought to elucidate the role of methylation in duodenal adenomas and correlate it with KRAS and BRAF mutations. CIMP+ (with more than 2 markers methylated) was seen in 33.3% of duodenal adenomas; 61% of these CIMP+ adenomas were CIMP-high (with more than 3 markers methylated). Furthermore, CIMP+ status significantly correlated with older age of patients, larger size and villous type of tumor, coexistent dysplasia and periampullary location. MLH1 methylation was seen in 11.1% of duodenal adenomas and was significantly associated with CIMP+ tumors, while p16 methylation was an infrequent event. KRAS mutations were frequent and seen in 26.3% of adenomas; however, no BRAF mutations were detected. Furthermore, CIMP-high status was associated with larger size and villous type of tumor and race (non-white). These results suggest that CIMP+ duodenal adenomas may have a higher risk for developing malignancy and may require more aggressive management and surveillance.

CpG island methylator phenotype and its association with malignancy in sporadic duodenal adenomas

PubMed Central

Sun, Lifeng; Guzzetta, Angela A; Fu, Tao; Chen, Jinming; Jeschke, Jana; Kwak, Ruby; Vatapalli, Rajita; Baylin, Stephen B; Iacobuzio-Donahue, Christine A; Wolfgang, Christopher L; Ahuja, Nita

2014-01-01

CpG island methylator phenotype (CIMP) has been found in multiple precancerous and cancerous lesions, including colorectal adenomas, colorectal cancers, and duodenal adenocarcinomas. There are no reports in the literature of a relationship between CIMP status and clinicopathologic features of sporadic duodenal adenomas. This study sought to elucidate the role of methylation in duodenal adenomas and correlate it with KRAS and BRAF mutations. CIMP+ (with more than 2 markers methylated) was seen in 33.3% of duodenal adenomas; 61% of these CIMP+ adenomas were CIMP-high (with more than 3 markers methylated). Furthermore, CIMP+ status significantly correlated with older age of patients, larger size and villous type of tumor, coexistent dysplasia and periampullary location. MLH1 methylation was seen in 11.1% of duodenal adenomas and was significantly associated with CIMP+ tumors, while p16 methylation was an infrequent event. KRAS mutations were frequent and seen in 26.3% of adenomas; however, no BRAF mutations were detected. Furthermore, CIMP-high status was associated with larger size and villous type of tumor and race (non-white). These results suggest that CIMP+ duodenal adenomas may have a higher risk for developing malignancy and may require more aggressive management and surveillance. PMID:24518818

Dominant Negative Pleiotrophin Induces Tetraploidy and Aneuploidy in U87MG Human Glioblastoma Cells

PubMed Central

Chang, Yunchao; Berenson, James R.; Wang, Zhaoyi; Deuel, Thomas F.

2007-01-01

Summary Pleiotrophin (PTN, Ptn) is an 18 kD secretory cytokine that is expressed in many human cancers, including glioblastoma. In previous experiments, interruption of the constitutive PTN signaling in human U87MG glioblastoma cells that inappropriately express endogenous Ptn reversed their rapid growth in vitro and their malignant phenotype in vivo. To seek a mechanism for the effect of the dominant negative PTN, flow cytometry was used to compare the profiles of U87MG cells and four clones of U87MG cells that express the dominant negative PTN (U87MG/PTN 1–40 cells); here, we report that the dominant negative PTN in U87MG cells induces tetraploidy and aneuploidy and arrests the tetraploid and aneuploid cells in the G1 phase of the cell cycle. The data suggest that PTN signaling may have a critical role in chromosomal segregation and cell cycle progression; the data suggest induction of tetraploidy and aneuploidy in U87MG glioblastoma cells may be an important mechanism that contributes to the loss of the malignant phenotype of U87MG cells. PMID:17067552

Biallelic BRCA2 mutations in two black South African children with Fanconi anaemia.

PubMed

Feben, Candice; Spencer, Careni; Lochan, Anneline; Laing, Nakita; Fieggen, Karen; Honey, Engela; Wainstein, Tasha; Krause, Amanda

2017-07-01

Fanconi anaemia (FA) is a genotypically and phenotypically heterogeneous genetic condition, characterized cytogenetically by chromosomal instability and breakage secondary to impaired DNA repair mechanisms. Affected individuals typically manifest growth restriction and congenital physical abnormalities and most progress to hematological disease including bone marrow aplasia. A rare genetic subtype of FA (FA-D1) is caused by biallelic mutations in the BRCA2 gene. Affected individuals manifest severe congenital anomalies and significant pigmentary changes and are additionally at risk for early onset leukemia and certain solid organ malignancies, including Wilms tumors and brain tumors. Parents of affected individuals are obligate carriers for heterozygous BRCA2 mutations and are thus potentially at risk for adult onset cancers which fall within the hereditary breast and ovarian cancer spectrum. We present two cases of black South African patients with FA diagnosed with biallelic BRCA2 mutations and discuss the phenotypic consequences and implications for them and their families. Recognition of this severe end of the phenotypic spectrum of FA is critical in allowing for confirmation of the diagnosis as well as cascade screening and appropriate care of family members.

Genetic and Epigenetic Differences in Monozygotic Twins with NF1

DTIC Science & Technology

2011-10-01

second hit event as a likely etiology for these tumors. Three pairs of twins were discordant for scoliosis , and one pair was concordant for scoliosis ...have included: plexiform neurofibromas (number and location), scoliosis , and malignancy (MPNST). Correlation between CNVs and clinical phenotype will...D E Age (years) 18 10 9 6 5 Gender F F F F F CAL#s Cut. NF Lisch Plexiform# OPG T2 Hyperint Scoliosis Pectus MPNST MR LD Speech ADHD

Overlapping SETBP1 gain-of-function mutations in Schinzel-Giedion syndrome and hematologic malignancies

PubMed Central

Steehouwer, Marloes; Gilissen, Christian; Graham, Sarah A.; Hoover-Fong, Julie; Telegrafi, Aida B.; Destree, Anne; Smigiel, Robert; Lambie, Lindsday A.; Kayserili, Hülya; Altunoglu, Umut; Lapi, Elisabetta; Uzielli, Maria Luisa; Aracena, Mariana; Nur, Banu G.; Mihci, Ercan; Moreira, Lilia M. A.; Borges Ferreira, Viviane; Horovitz, Dafne D. G.; da Rocha, Katia M.; Jezela-Stanek, Aleksandra; Brooks, Alice S.; Reutter, Heiko; Cohen, Julie S.; Fatemi, Ali; Smitka, Martin; Grebe, Theresa A.; Di Donato, Nataliya; Deshpande, Charu; Vandersteen, Anthony; Marques Lourenço, Charles; Dufke, Andreas; Rossier, Eva; Andre, Gwenaelle; Baumer, Alessandra; Spencer, Careni; McGaughran, Julie; Franke, Lude; Veltman, Joris A.; De Vries, Bert B. A.; Schinzel, Albert; Fisher, Simon E.; Hoischen, Alexander

2017-01-01

Schinzel-Giedion syndrome (SGS) is a rare developmental disorder characterized by multiple malformations, severe neurological alterations and increased risk of malignancy. SGS is caused by de novo germline mutations clustering to a 12bp hotspot in exon 4 of SETBP1. Mutations in this hotspot disrupt a degron, a signal for the regulation of protein degradation, and lead to the accumulation of SETBP1 protein. Overlapping SETBP1 hotspot mutations have been observed recurrently as somatic events in leukemia. We collected clinical information of 47 SGS patients (including 26 novel cases) with germline SETBP1 mutations and of four individuals with a milder phenotype caused by de novo germline mutations adjacent to the SETBP1 hotspot. Different mutations within and around the SETBP1 hotspot have varying effects on SETBP1 stability and protein levels in vitro and in in silico modeling. Substitutions in SETBP1 residue I871 result in a weak increase in protein levels and mutations affecting this residue are significantly more frequent in SGS than in leukemia. On the other hand, substitutions in residue D868 lead to the largest increase in protein levels. Individuals with germline mutations affecting D868 have enhanced cell proliferation in vitro and higher incidence of cancer compared to patients with other germline SETBP1 mutations. Our findings substantiate that, despite their overlap, somatic SETBP1 mutations driving malignancy are more disruptive to the degron than germline SETBP1 mutations causing SGS. Additionally, this suggests that the functional threshold for the development of cancer driven by the disruption of the SETBP1 degron is higher than for the alteration in prenatal development in SGS. Drawing on previous studies of somatic SETBP1 mutations in leukemia, our results reveal a genotype-phenotype correlation in germline SETBP1 mutations spanning a molecular, cellular and clinical phenotype. PMID:28346496

Population-based surveillance for scedosporiosis in Australia: epidemiology, disease manifestations and emergence of Scedosporium aurantiacum infection.

PubMed

Heath, C H; Slavin, M A; Sorrell, T C; Handke, R; Harun, A; Phillips, M; Nguyen, Q; Delhaes, L; Ellis, D; Meyer, W; Chen, S C A

2009-07-01

Australia-wide population-based surveillance for scedosporiosis identified 180 cases, with 118 (65.6%) cases of colonization and 62 (34.4%) cases of infection. Predisposing factors for isolation of Scedosporium spp. included chronic lung disease in 37.8% and malignancy in 21.7% of cases. Predictors of invasive disease (n=62) included haematological stem cell transplantation (n=7), leukaemia (n=16) and diabetes mellitus (n=8). Of 183 phenotypically-speciated isolates, 75 (41%) were Scedosporium prolificans (risk factors: haematologic cancer (n=17), neutropaenia (n=14)) and 108 (59%) had Scedosporium apiospermum/Pseudallescheria boydii phenotype [risk factor: diabetes (n=15)]. Scedosporium prolificans (p 0.01) and leukaemia (p 0.03) independently predicted death. Epidemiological and antifungal susceptibility profiles of Scedosporium aurantiacum (prevalence>or=15.8%) and S. apiospermum were similar. No patient with S. aurantiacum infection (n=6) died. This is the first description of clinical features associated with S. aurantiacum.

Heterozygous Germline Mutations in the CBL Tumor-Suppressor Gene Cause a Noonan Syndrome-like Phenotype

PubMed Central

Martinelli, Simone; De Luca, Alessandro; Stellacci, Emilia; Rossi, Cesare; Checquolo, Saula; Lepri, Francesca; Caputo, Viviana; Silvano, Marianna; Buscherini, Francesco; Consoli, Federica; Ferrara, Grazia; Digilio, Maria C.; Cavaliere, Maria L.; van Hagen, Johanna M.; Zampino, Giuseppe; van der Burgt, Ineke; Ferrero, Giovanni B.; Mazzanti, Laura; Screpanti, Isabella; Yntema, Helger G.; Nillesen, Willy M.; Savarirayan, Ravi; Zenker, Martin; Dallapiccola, Bruno; Gelb, Bruce D.; Tartaglia, Marco

2010-01-01

RAS signaling plays a key role in controlling appropriate cell responses to extracellular stimuli and participates in early and late developmental processes. Although enhanced flow through this pathway has been established as a major contributor to oncogenesis, recent discoveries have revealed that aberrant RAS activation causes a group of clinically related developmental disorders characterized by facial dysmorphism, a wide spectrum of cardiac disease, reduced growth, variable cognitive deficits, ectodermal and musculoskeletal anomalies, and increased risk for certain malignancies. Here, we report that heterozygous germline mutations in CBL, a tumor-suppressor gene that is mutated in myeloid malignancies and encodes a multivalent adaptor protein with E3 ubiquitin ligase activity, can underlie a phenotype with clinical features fitting or partially overlapping Noonan syndrome (NS), the most common condition of this disease family. Independent CBL mutations were identified in two sporadic cases and two families from among 365 unrelated subjects who had NS or suggestive features and were negative for mutations in previously identified disease genes. Phenotypic heterogeneity and variable expressivity were documented. Mutations were missense changes altering evolutionarily conserved residues located in the RING finger domain or the linker connecting this domain to the N-terminal tyrosine kinase binding domain, a known mutational hot spot in myeloid malignancies. Mutations were shown to affect CBL-mediated receptor ubiquitylation and dysregulate signal flow through RAS. These findings document that germline mutations in CBL alter development to cause a clinically variable condition that resembles NS and that possibly predisposes to malignancies. PMID:20619386

Estrogen Enhances Malignant Phenotypes in Human Salivary Adenoid Cystic Carcinoma Cells.

PubMed

Sumida, Tomoki; Ishikawa, Akiko; Kamata, Y U; Nakano, Hiroyuki; Yamada, Tomohiro; Mori, Yoshihide

2016-06-01

Adenoid cystic carcinoma (SGC) is a common type of salivary gland cancer (SGC). Surgery is the first treatment choice because chemoradiotherapy is usually not effective. Therefore, new treatment modalities are urgently needed. In this study, it was investigated whether the estrogen axis could be a treatment target or not. Adenoid cystic carcinoma (ACC) ACCM cells, were used. The specific cell line lacks estrogen receptor (ER). ER was introduced in ACCM cells, and the effect of 17β-estradiol (E2) was investigated on cell proliferation, cell-cycle distribution, and cell motility. E2 induced cell proliferation, and the S-phase fraction increased in a dose-dependent manner. Cell motility was also up-regulated compared to control cells. The estrogen/ER system up-regulated malignant phenotypes in ER-positive ACC, and hormone therapy may have a potential as effective treatment for this malignancy. Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

Malignant melanoma with a rhabdoid phenotype: histologic, immunohistochemical, and ultrastructural study of a case and review of the literature.

PubMed

Abbott, Jared J; Amirkhan, Robin H; Hoang, Mai P

2004-06-01

Malignant melanoma is known to display tremendous histologic diversity. One rare variant is the rhabdoid phenotype, so called because of the appearance of cells resembling rhabdomyoblasts seen in malignant rhabdoid tumors of the kidney. We present the histologic, immunohistochemical, and ultrastructural features of a malignant melanoma composed entirely of rhabdoid cells. A 62-year-old man presented with a 6.5-cm lung mass. Although presumed to be a metastatic lesion, extensive workup failed to reveal a primary tumor site. Histologic sections showed a mass composed entirely of polygonal neoplastic cells with prominent nucleoli and large hyaline cytoplasmic inclusions. The tumor cells were strongly immunoreactive with S100 protein, vimentin, and CD56, and were focally reactive with Mart-1. Tumor cells were negative for Melan-A, tyrosinase, HMB-45, AE1/AE3, cytokeratin (CK) 7, CK8/ 18, CK20, CK903, CAM 5.2, epithelial membrane antigen, smooth muscle actin, desmin, leukocyte common antigen, Bcl-2, CD3, CD20, CD30, CD138, kappa and lambda light chains, CD68, CD34, factor VIII, synaptophysin, and glial fibrillary acidic protein. Electron microscopy showed cytoplasmic whorls of intermediate filaments containing entrapped rough endoplasmic reticulum, mitochondria, and lipid. Recognition of this rare variant of malignant melanoma is important in the evaluation of tumors with rhabdoid morphology.

Zebrafish neurofibromatosis type 1 genes have redundant functions in tumorigenesis and embryonic development

PubMed Central

Shin, Jimann; Padmanabhan, Arun; de Groh, Eric D.; Lee, Jeong-Soo; Haidar, Sam; Dahlberg, Suzanne; Guo, Feng; He, Shuning; Wolman, Marc A.; Granato, Michael; Lawson, Nathan D.; Wolfe, Scot A.; Kim, Seok-Hyung; Solnica-Krezel, Lilianna; Kanki, John P.; Ligon, Keith L.; Epstein, Jonathan A.; Look, A. Thomas

2012-01-01

SUMMARY Neurofibromatosis type 1 (NF1) is a common, dominantly inherited genetic disorder that results from mutations in the neurofibromin 1 (NF1) gene. Affected individuals demonstrate abnormalities in neural-crest-derived tissues that include hyperpigmented skin lesions and benign peripheral nerve sheath tumors. NF1 patients also have a predisposition to malignancies including juvenile myelomonocytic leukemia (JMML), optic glioma, glioblastoma, schwannoma and malignant peripheral nerve sheath tumors (MPNSTs). In an effort to better define the molecular and cellular determinants of NF1 disease pathogenesis in vivo, we employed targeted mutagenesis strategies to generate zebrafish harboring stable germline mutations in nf1a and nf1b, orthologues of NF1. Animals homozygous for loss-of-function alleles of nf1a or nf1b alone are phenotypically normal and viable. Homozygous loss of both alleles in combination generates larval phenotypes that resemble aspects of the human disease and results in larval lethality between 7 and 10 days post fertilization. nf1-null larvae demonstrate significant central and peripheral nervous system defects. These include aberrant proliferation and differentiation of oligodendrocyte progenitor cells (OPCs), dysmorphic myelin sheaths and hyperplasia of Schwann cells. Loss of nf1 contributes to tumorigenesis as demonstrated by an accelerated onset and increased penetrance of high-grade gliomas and MPNSTs in adult nf1a+/−; nf1b−/−; p53e7/e7 animals. nf1-null larvae also demonstrate significant motor and learning defects. Importantly, we identify and quantitatively analyze a novel melanophore phenotype in nf1-null larvae, providing the first animal model of the pathognomonic pigmentation lesions of NF1. Together, these findings support a role for nf1a and nf1b as potent tumor suppressor genes that also function in the development of both central and peripheral glial cells as well as melanophores in zebrafish. PMID:22773753

Classification of malignant and benign liver tumors using a radiomics approach

NASA Astrophysics Data System (ADS)

Starmans, Martijn P. A.; Miclea, Razvan L.; van der Voort, Sebastian R.; Niessen, Wiro J.; Thomeer, Maarten G.; Klein, Stefan

2018-03-01

Correct diagnosis of the liver tumor phenotype is crucial for treatment planning, especially the distinction between malignant and benign lesions. Clinical practice includes manual scoring of the tumors on Magnetic Resonance (MR) images by a radiologist. As this is challenging and subjective, it is often followed by a biopsy. In this study, we propose a radiomics approach as an objective and non-invasive alternative for distinguishing between malignant and benign phenotypes. T2-weighted (T2w) MR sequences of 119 patients from multiple centers were collected. We developed an efficient semi-automatic segmentation method, which was used by a radiologist to delineate the tumors. Within these regions, features quantifying tumor shape, intensity, texture, heterogeneity and orientation were extracted. Patient characteristics and semantic features were added for a total of 424 features. Classification was performed using Support Vector Machines (SVMs). The performance was evaluated using internal random-split cross-validation. On the training set within each iteration, feature selection and hyperparameter optimization were performed. To this end, another cross validation was performed by splitting the training sets in training and validation parts. The optimal settings were evaluated on the independent test sets. Manual scoring by a radiologist was also performed. The radiomics approach resulted in 95% confidence intervals of the AUC of [0.75, 0.92], specificity [0.76, 0.96] and sensitivity [0.52, 0.82]. These approach the performance of the radiologist, which were an AUC of 0.93, specificity 0.70 and sensitivity 0.93. Hence, radiomics has the potential to predict the liver tumor benignity in an objective and non-invasive manner.

Malignant ovarian germ cell tumor - role of surgical staging and gonadal dysgenesis.

PubMed

Lin, Ken Y; Bryant, Stefanie; Miller, David S; Kehoe, Siobhan M; Richardson, Debra L; Lea, Jayanthi S

2014-07-01

To evaluate the effect of comprehensive surgical staging and gonadal dysgenesis on the outcomes of patients with malignant ovarian germ cell tumor. We performed a retrospective review of patients with ovarian germ cell tumors who were treated at our institution between 1976 and 2012. Malignant ovarian germ cell tumors (MOGCTs) were identified in 50 females. The median age was 24 years (range 13 to 49). Of all MOGCT patients, 42% had dysgerminoma, 20% immature teratoma, 16% endodermal sinus tumor, and 22% mixed germ cell tumor. Univariate analyses revealed that the lack of surgical staging (p=0.048) and endodermal sinus tumor (p=0.0085) were associated with disease recurrence, while age at diagnosis, ethnicity, and stage of the disease were not. Multivariate analyses revealed that the lack of surgical staging (p=0.029) and endodermal sinus tumor (p=0.016) were independently associated with disease recurrence. In addition, 7 patients (14%) had 46 XY karyotype, including 6 with pure dysgerminoma and 1 with mixed germ cell tumor. Five had Swyer syndrome and 2 had complete androgen insensitivity syndrome. Concurrent gonadoblastoma was found in 5 of the patients. No difference was found in the mean age at presentation, stage distribution, or recurrence rate for MOGCT patients with or without XY phenotype. Comprehensive surgical staging was associated with a lower rate of recurrence. Fourteen percent of phenotypic females with MOGCT and 29% of those with dysgerminoma had XY karyotype. The clinical outcome of these patients is similar to that of MOGCT patients with XX karyotype. Published by Elsevier Inc.

Culture models of human mammary epithelial cell transformation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Stampfer, Martha R.; Yaswen, Paul

2000-11-10

Human pre-malignant breast diseases, particularly ductal carcinoma in situ (DCIS)3 already display several of the aberrant phenotypes found in primary breast cancers, including chromosomal abnormalities, telomerase activity, inactivation of the p53 gene and overexpression of some oncogenes. Efforts to model early breast carcinogenesis in human cell cultures have largely involved studies in vitro transformation of normal finite lifespan human mammary epithelial cells (HMEC) to immortality and malignancy. We present a model of HMEC immortal transformation consistent with the know in vivo data. This model includes a recently described, presumably epigenetic process, termed conversion, which occurs in cells that have overcomemore » stringent replicative senescence and are thus able to maintain proliferation with critically short telomeres. The conversion process involves reactivation of telomerase activity, and acquisition of good uniform growth in the absence and presence of TFGB. We propose th at overcoming the proliferative constraints set by senescence, and undergoing conversion, represent key rate-limiting steps in human breast carcinogenesis, and occur during early stage breast cancer progression.« less

Waves of gene regulation suppress and then restore oxidative phosphorylation in cancer cells.

PubMed

Smolková, Katarína; Plecitá-Hlavatá, Lydie; Bellance, Nadége; Benard, Giovanni; Rossignol, Rodrigue; Ježek, Petr

2011-07-01

We posit the following hypothesis: Independently of whether malignant tumors are initiated by a fundamental reprogramming of gene expression or seeded by stem cells, "waves" of gene expression that promote metabolic changes occur during carcinogenesis, beginning with oncogene-mediated changes, followed by hypoxia-induced factor (HIF)-mediated gene expression, both resulting in the highly glycolytic "Warburg" phenotype and suppression of mitochondrial biogenesis. Because high proliferation rates in malignancies cause aglycemia and nutrient shortage, the third (second oncogene) "wave" of adaptation stimulates glutaminolysis, which in certain cases partially re-establishes oxidative phosphorylation; this involves the LKB1-AMPK-p53, PI3K-Akt-mTOR axes and MYC dysregulation. Oxidative glutaminolysis serves as an alternative pathway compensating for cellular ATP. Together with anoxic glutaminolysis it provides pyruvate, lactate, and the NADPH pool (alternatively to pentose phosphate pathway). Retrograde signaling from revitalized mitochondria might constitute the fourth "wave" of gene reprogramming. In turn, upon reversal of the two Krebs cycle enzymes, glutaminolysis may partially (transiently) function even during anoxia, thereby further promoting malignancy. The history of the carcinogenic process within each malignant tumor determines the final metabolic phenotype of the selected surviving cells, resulting in distinct cancer bioenergetic phenotypes ranging from the highly glycolytic "classic Warburg" to partial or enhanced oxidative phosphorylation. We discuss the bioenergetically relevant functions of oncogenes, the involvement of mitochondrial biogenesis/degradation in carcinogenesis, the yet unexplained Crabtree effect of instant glucose blockade of respiration, and metabolic signaling stemming from the accumulation of succinate, fumarate, pyruvate, lactate, and oxoglutarate by interfering with prolyl hydroxylase domain enzyme-mediated hydroxylation of HIFα prolines. Copyright © 2010 Elsevier Ltd. All rights reserved.

Phenotypic characterization of telomerase-immortalized primary non-malignant and malignant tumor-derived human prostate epithelial cell lines

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gu Yongpeng; Li Hongzhen; Miki, Jun

2006-04-01

In vitro human prostate cell culture models are critical for clarifying the mechanism of prostate cancer progression and for testing preventive and therapeutic agents. Cell lines ideal for the study of human primary prostate tumors would be those derived from spontaneously immortalized tumor cells; unfortunately, explanted primary prostate cells survive only short-term in culture, and rarely immortalize spontaneously. Therefore, we recently have generated five immortal human prostate epithelial cell cultures derived from both the benign and malignant tissues of prostate cancer patients with telomerase, a gene that prevents cellular senescence. Examination of these cell lines for their morphologies and proliferativemore » capacities, their abilities to grow in low serum, to respond to androgen stimulation, to grow above the agar layer, to form tumors in SCID mice, suggests that they may serve as valid, useful tools for the elucidation of early events in prostate tumorigenesis. Furthermore, the chromosome alterations observed in these immortalized cell lines expressing aspects of the malignant phenotypes imply that these cell lines accurately recapitulate the genetic composition of primary tumors. These novel in vitro models may offer unique models for the study of prostate carcinogenesis and also provide the means for testing both chemopreventive and chemotherapeutic agents.« less

Oncogenic Viruses and Tumor Glucose Metabolism: Like Kids in a Candy Store

PubMed Central

Noch, Evan; Khalili, Kamel

2011-01-01

Oncogenic viruses represent a significant public health burden in light of the multitude of malignancies resulting from chronic or spontaneous viral infection and transformation. Though many of the molecular signaling pathways underlying virus-mediated cellular transformation are known, the impact of these viruses on metabolic signaling and phenotype within proliferating tumor cells is less well understood. Whether the interaction of oncogenic viruses with metabolic signaling pathways involves enhanced glucose uptake and glycolysis, both hallmark features of transformed cells, or dysregulation of molecular pathways regulating oxidative stress, viruses are adept at facilitating tumor expansion. Through their effects on cell proliferation pathways, such as the PI3K and MAPK pathways, the cell cycle regulatory proteins, p53 and ATM, and the cell stress response proteins, HIF-1α and AMPK, viruses exert control over critical metabolic signaling cascades. Additionally, oncogenic viruses modulate the tumor metabolomic profile through direct and indirect interaction with glucose transporters, such as GLUT1, and specific glycolytic enzymes, including pyruvate kinase, glucose 6-phosphate dehydrogenase, and hexokinase. Through these pathways, oncogenic viruses alter the phenotypic characteristics of transformed cells and their methods of energy utilization, and it may be possible to develop novel anti-glycolytic therapies to target these dysregulated pathways in virus-derived malignancies. PMID:22234809

Self-Styled ZnO Nanostructures Promotes the Cancer Cell Damage and Supresses the Epithelial Phenotype of Glioblastoma

NASA Astrophysics Data System (ADS)

Wahab, Rizwan; Kaushik, Neha; Khan, Farheen; Kaushik, Nagendra Kumar; Choi, Eun Ha; Musarrat, Javed; Al-Khedhairy, Abdulaziz A.

2016-01-01

Extensive researches have been done on the applications of zinc oxide nanoparticles (ZnO-NPs) for the biological purposes. However, the role and toxicity mechanisms of ZnO nanostructures (ZnO-NSts) such as nanoplates (NPls), nanorods (NRs), nanosheets (NSs), nanoflowers (NFs) on cancer cells are not largely known. Present study was focused to investigate the possible mechanisms of apoptosis induced by self-designed ZnO-NSts, prepared at fix pH via solution process and exposed against human T98G gliomas including various cancers and non-malignant embryonic kidney HEK293, MRC5 fibroblast cells. NSts were used for the induction of cell death in malignant human T98G gliomas including various cancers and compared with the non-malignant cells. Notably, NRs were found to induce higher cytotoxicity, inhibitory effects on cancer and normal cells in a dose dependent manner. We also showed that NRs induced cancer cell death through oxidative stress and caspase-dependent pathways. Furthermore, quantitative and qualitative analysis of ZnO-NSts have also been confirmed by statistical analytical parameters such as precision, accuracy, linearity, limits of detection and limit of quantitation. These self-styled NSts could provide new perception in the research of targeted cancer nanotechnology and have potentiality to improve new therapeutic outcomes with poor diagnosis.

Single-Cell Analysis Reveals Early Manifestation of Cancerous Phenotype in Pre-Malignant Esophageal Cells

PubMed Central

Wang, Jiangxin; Shi, Xu; Johnson, Roger H.; Kelbauskas, Laimonas; Zhang, Weiwen; Meldrum, Deirdre R.

2013-01-01

Cellular heterogeneity plays a pivotal role in a variety of functional processes in vivo including carcinogenesis. However, our knowledge about cell-to-cell diversity and how differences in individual cells manifest in alterations at the population level remains very limited mainly due to the lack of appropriate tools enabling studies at the single-cell level. We present a study on changes in cellular heterogeneity in the context of pre-malignant progression in response to hypoxic stress. Utilizing pre-malignant progression of Barrett’s esophagus (BE) as a disease model system we studied molecular mechanisms underlying the progression from metaplastic to dysplastic (pre-cancerous) stage. We used newly developed methods enabling measurements of cell-to-cell differences in copy numbers of mitochondrial DNA, expression levels of a set of mitochondrial and nuclear genes involved in hypoxia response pathways, and mitochondrial membrane potential. In contrast to bulk cell studies reported earlier, our study shows significant differences between metaplastic and dysplastic BE cells in both average values and single-cell parameter distributions of mtDNA copy numbers, mitochondrial function, and mRNA expression levels of studied genes. Based on single-cell data analysis, we propose that mitochondria may be one of the key factors in pre-malignant progression in BE. PMID:24116039

Cell of origin associated classification of B-cell malignancies by gene signatures of the normal B-cell hierarchy.

PubMed

Johnsen, Hans Erik; Bergkvist, Kim Steve; Schmitz, Alexander; Kjeldsen, Malene Krag; Hansen, Steen Møller; Gaihede, Michael; Nørgaard, Martin Agge; Bæch, John; Grønholdt, Marie-Louise; Jensen, Frank Svendsen; Johansen, Preben; Bødker, Julie Støve; Bøgsted, Martin; Dybkær, Karen

2014-06-01

Recent findings have suggested biological classification of B-cell malignancies as exemplified by the "activated B-cell-like" (ABC), the "germinal-center B-cell-like" (GCB) and primary mediastinal B-cell lymphoma (PMBL) subtypes of diffuse large B-cell lymphoma and "recurrent translocation and cyclin D" (TC) classification of multiple myeloma. Biological classification of B-cell derived cancers may be refined by a direct and systematic strategy where identification and characterization of normal B-cell differentiation subsets are used to define the cancer cell of origin phenotype. Here we propose a strategy combining multiparametric flow cytometry, global gene expression profiling and biostatistical modeling to generate B-cell subset specific gene signatures from sorted normal human immature, naive, germinal centrocytes and centroblasts, post-germinal memory B-cells, plasmablasts and plasma cells from available lymphoid tissues including lymph nodes, tonsils, thymus, peripheral blood and bone marrow. This strategy will provide an accurate image of the stage of differentiation, which prospectively can be used to classify any B-cell malignancy and eventually purify tumor cells. This report briefly describes the current models of the normal B-cell subset differentiation in multiple tissues and the pathogenesis of malignancies originating from the normal germinal B-cell hierarchy.

Malignant and Tuberculous Pleural Effusions: Immunophenotypic Cellular Characterization

PubMed Central

de Aguiar, Lucia Maria Zanatta; Antonangelo, Leila; Vargas, Francisco S.; Zerbini, Maria Cláudia Nogueira; Sales, Maria Mirtes; Uip, David E.; Saldiva, Paulo Hilário Nascimento

2008-01-01

INTRODUCTION AND OBJECTIVES Tuberculosis and cancer are the main causes of pleural effusion. Pleural involvement is associated with migration of immune cells to the pleural cavity. We sought to characterize the immunophenotype of leukocytes in the pleural effusion and peripheral blood of patients with tuberculosis or malignancy. METHODS Thirty patients with tuberculosis (14) or malignancy (16) were studied. A control group included 20 healthy blood donors. RESULTS Malignant phycoerythrin pleural effusions showed higher percentages of CD3, CD4, CD3CD45RO, and CD20CD25 lymphocytes and lower percentages of CD3CD25 and CD20HLA-DR when compared to PB lymphocytes. Compared to PB, tuberculous effusions had a higher percentage of lymphocytes that co-expressed CD3, CD4, CD3CD45RO, CD3TCRαβ, CD3CD28, and CD20 and a lower percentage of CD14, CD8 and CD3TCRγδ-positive lymphocytes. Malignant effusions presented higher expression of CD14 whereas tuberculous effusions had higher expression of CD3 and CD3CD95L. Peripheral blood cells from tuberculosis patients showed higher expression of CD14, CD20CD25 and CD3CD95L. Compared with the control cells, tuberculosis and cancer peripheral blood cells presented a lower percentage of CD3CD4 and CD3CD28-positive cells as well as a higher percentage of CD3CD8, CD3CD25 and CD3CD80-positive cells. CONCLUSIONS Tuberculous and malignant peripheral blood is enriched with lymphocytes with a helper/inducer T cell phenotype, which are mainly of memory cells. CD14-positive cells were more frequently found in malignant effusions, while CD3-positive cells expressing Fas ligand were more frequently found in tuberculous effusions. PMID:18925324

The lipid phenotype of breast cancer cells characterized by Raman microspectroscopy: towards a stratification of malignancy.

PubMed

Nieva, Claudia; Marro, Monica; Santana-Codina, Naiara; Rao, Satish; Petrov, Dmitri; Sierra, Angels

2012-01-01

Although molecular classification brings interesting insights into breast cancer taxonomy, its implementation in daily clinical care is questionable because of its expense and the information supplied in a single sample allocation is not sufficiently reliable. New approaches, based on a panel of small molecules derived from the global or targeted analysis of metabolic profiles of cells, have found a correlation between activation of de novo lipogenesis and poorer prognosis and shorter disease-free survival for many tumors. We hypothesized that the lipid content of breast cancer cells might be a useful indirect measure of a variety of functions coupled to breast cancer progression. Raman microspectroscopy was used to characterize metabolism of breast cancer cells with different degrees of malignancy. Raman spectra from MDA-MB-435, MDA-MB-468, MDA-MB-231, SKBR3, MCF7 and MCF10A cells were acquired with an InVia Raman microscope (Renishaw) with a backscattered configuration. We used Principal Component Analysis and Partial Least Squares Discriminant Analyses to assess the different profiling of the lipid composition of breast cancer cells. Characteristic bands related to lipid content were found at 3014, 2935, 2890 and 2845 cm(-1), and related to lipid and protein content at 2940 cm(-1). A classificatory model was generated which segregated metastatic cells and non-metastatic cells without basal-like phenotype with a sensitivity of 90% and a specificity of 82.1%. Moreover, expression of SREBP-1c and ABCA1 genes validated the assignation of the lipid phenotype of breast cancer cells. Indeed, changes in fatty acid unsaturation were related with the epithelial-to-mesenchymal transition phenotype. Raman microspectroscopy is a promising technique for characterizing and classifying the malignant phenotype of breast cancer cells on the basis of their lipid profiling. The algorithm for the discrimination of metastatic ability is a first step towards stratifying breast cancer cells using this rapid and reagent-free tool.

Critical high-dimensional state transitions in cell populations or why cancers follow the principle ``What does not kill me makes me stronger''

NASA Astrophysics Data System (ADS)

Huang, Sui

Transitions between high-dimensional attractor states in the quasi-potential landscape of the gene regulatory network, induced by environmental perturbations and/or facilitated by mutational rewiring of the network, underlie cell phenotype switching in development as well as in cancer progression, including acquisition of drug-resistant phenotypes. Considering heterogeneous cell populations as statistical ensembles of cells, and single-cell resolution gene expression profiling of cell populations undergoing a cell phenotype shift allow us now to map the topography of the landscape and its distortion. From snapshots of single-cell expression patterns of a cell population measured during major transitions we compute a quantity that identifies symmetry-breaking destabilization of attractors (bifurcation) and concomitant dimension-reduction of the state space manifold (landscape distortion) which precede critical transitions to new attractor states. The model predicts, and we show experimentally, the almost inevitable generation of aberrant cells associated with such critical transitions in multi-attractor landscapes: therapeutic perturbations which seek to push cancer cells to the apoptotic state, almost always produce ``rebellious'' cells which move in the ``opposite direction'': instead of dying they become more stem-cell-like and malignant. We show experimentally that the inadvertent generation of more malignant cancer cells by therapy indeed results from transition of surviving (but stressed) cells into unforeseen attractor states and not simply from selection of inherently more resistant cells. Thus, cancer cells follow not so much Darwin, as generally thought (survival of the fittest), but rather Nietzsche (What does not kill me makes me stronger). Supported by NIH (NCI, NIGMS), Alberta Innovates.

EG-13GENOME-WIDE METHYLATION ANALYSIS IDENTIFIES GENOMIC DNA DEMETHYLATION DURING MALIGNANT PROGRESSION OF GLIOMAS

PubMed Central

Saito, Kuniaki; Mukasa, Akitake; Nagae, Genta; Aihara, Koki; Otani, Ryohei; Takayanagi, Shunsaku; Omata, Mayu; Tanaka, Shota; Shibahara, Junji; Takahashi, Miwako; Momose, Toshimitsu; Shimamura, Teppei; Miyano, Satoru; Narita, Yoshitaka; Ueki, Keisuke; Nishikawa, Ryo; Nagane, Motoo; Aburatani, Hiroyuki; Saito, Nobuhito

2014-01-01

Low-grade gliomas often undergo malignant progression, and these transformations are a leading cause of death in patients with low-grade gliomas. However, the molecular mechanisms underlying malignant tumor progression are still not well understood. Recent evidence indicates that epigenetic deregulation is an important cause of gliomagenesis; therefore, we examined the impact of epigenetic changes during malignant progression of low-grade gliomas. Specifically, we used the Illumina Infinium Human Methylation 450K BeadChip to perform genome-wide DNA methylation analysis of 120 gliomas and four normal brains. This study sample included 25 matched-pairs of initial low-grade gliomas and recurrent tumors (temporal heterogeneity) and 20 of the 25 recurring tumors recurred as malignant progressions, and one matched-pair of newly emerging malignant lesions and pre-existing lesions (spatial heterogeneity). Analyses of methylation profiles demonstrated that most low-grade gliomas in our sample (43/51; 84%) had a CpG island methylator phenotype (G-CIMP). Remarkably, approximately 50% of secondary glioblastomas that had progressed from low-grade tumors with the G-CIMP status exhibited a characteristic partial demethylation of genomic DNA during malignant progression, but other recurrent gliomas showed no apparent change in DNA methylation pattern. Interestingly, we found that most loci that were demethylated during malignant progression were located outside of CpG islands. The information of histone modifications patterns in normal human astrocytes and embryonal stem cells also showed that the ratio of active marks at the site corresponding to DNA demethylated loci in G-CIMP-demethylated tumors was significantly lower; this finding indicated that most demethylated loci in G-CIMP-demethylated tumors were likely transcriptionally inactive. A small number of the genes that were upregulated and had demethylated CpG islands were associated with cell cycle-related pathway. In summary, we demonstrated that characteristic DNA demethylation occurred during malignant progression of a subset of low-grade gliomas. The mechanisms underlying and consequences of such DNA demethylation should be studied further.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Itoh, Masahiko; Nelson, Celeste M.; Myers, Connie A.

Maintenance of apico-basal polarity in normal breast epithelial acini requires a balance between cell proliferation, cell death, and proper cell-cell and cell-extracellular matrix signaling. Aberrations in any of these processes can disrupt tissue architecture and initiate tumor formation. Here we show that the small GTPase Rap1 is a crucial element in organizing acinar structure and inducing lumen formation. Rap1 activity in malignant HMT-3522 T4-2 cells is appreciably higher than in S1 cells, their non-malignant counterparts. Expression of dominant-negative Rap1 resulted in phenotypic reversion of T4-2 cells, led to formation of acinar structures with correct apico-basal polarity, and dramatically reduced tumormore » incidence despite the persistence of genomic abnormalities. The resulting acini contained prominent central lumina not observed when other reverting agents were used. Conversely, expression of dominant-active Rap1 in T4-2 cells inhibited phenotypic reversion and led to increased invasiveness and tumorigenicity. Thus, Rap1 acts as a central regulator of breast architecture, with normal levels of activation instructing apical polarity during acinar morphogenesis, and increased activation inducing tumor formation and progression to malignancy.« less

CXCL7 promotes proliferation and invasion of cholangiocarcinoma cells.

PubMed

Guo, Qian; Jian, Zhixiang; Jia, Baoqing; Chang, Liang

2017-02-01

CXCL7 is an important chemoattractant cytokine, which signals through binding to its receptor CXCR2. Recent studies have demonstrated that the CXCL7/CXCR2 signaling plays a promoting role in several common malignancies, including lung, renal, colon, and breast cancer. However, the regulatory role of CXCL7, in cholangiocarcinoma, as well as the underlying mechanism, has not been previously reported. Herein, we found more positive expression of CXCL7 in cholangiocarcinoma tissues compared to adjacent non-tumor tissues. High CXCL7 expression was significantly correlated with poor differentiation, lymph node metastasis, vascular invasion and advanced clinical stage, but was not associated with age, gender, or tumor size. Besides, the expression of CXCL7 was significantly associated with the Ki67 expression, but not associated with CA199, AFP, or P53 expression in cholangiocarcinoma. Moreover, the overall survival of cholangiocarcinoma patients with high CXCL7 expression was significantly shorter than those with low CXCL7 expression. In vitro study indicated that CXCL7 and CXCR2 were also positively expressed in several common cholangiocarcinoma cell lines, including HuCCT1, HuH28, QBC939, EGI-1, OZ and WITT. SiRNA-induced inhibition of CXCL7 significantly reduced the proliferation and invasion of QBC939 cells. On the contrary, overexpression of CXCL7 markedly promoted these malignant phenotypes of QBC939 cells. Of note, the conditioned medium of CXCL7-overexpresing human hepatic stellate cells could also promote the proliferation and invasion of QBC939 cells, suggesting that CXCL7 may also play an oncogenic role in cholangiocarcinoma in a paracrine-dependent manner, not only in an autocrine-dependent manner. Molecular assay data suggested that the AKT signaling pathway was involved in the CXCL7-mediated malignant phenotypes of QBC939 cells. In summary, our study suggests that CXCL7 plays a promoting role in regulating the growth and metastasis of cholangiocarcinoma.

Preclinical investigation of ibrutinib, a Bruton's kinase tyrosine (Btk) inhibitor, in suppressing glioma tumorigenesis and stem cell phenotypes

PubMed Central

Wei, Li; Su, Yu-Kai; Lin, Chien-Min; Chao, Tsu-Yi; Huang, Shang-Pen; Huynh, Thanh-Tuan; Jan, Hsun-Jin; Whang-Peng, Jacqueline; Chiou, Jeng-Fong; Wu, Alexander T.H.; Hsiao, Michael

2016-01-01

Standard interventions for glioma include surgery, radiation and chemotherapies but the prognosis for malignant cases such as glioblastoma multiforme remain grim. Even with targeted therapeutic agent, bevacitumab, malignant glioma often develops resistance and recurrence. Thus, developing alternative interventions (therapeutic targets, biomarkers) is urgently required. Bruton's tyrosine kinase (Btk) has been long implicated in B cell malignancies but surprisingly it has recently been shown to also play a tumorigenic role in solid tumors such as ovarian and prostate cancer. Bioinformatics data indicates that Btk is significantly higher in clinical glioma samples as compared to normal brain cells and Btk expression level is associated with stage progression. This prompts us to investigate the potential role of Btk as a therapeutic target for glioma. Here, we demonstrate Btk expression is associated with GBM tumorigenesis. Down-regulation of Btk in GBM cell lines showed a significantly reduced abilities in colony formation, migration and GBM sphere-forming potential. Mechanistically, Btk-silenced cells showed a concomitant reduction in the expression of CD133 and Akt/mTOR signaling. In parallel, Ibrutinib (a Btk inhibitor) treatment led to a similar anti-tumorigenic response. Using xenograft mouse model, tumorigenesis was significantly reduced in Btk-silenced or ibrutinib-treated mice as compared to control counterparts. Finally, our glioma tissue microarray analysis indicated a higher Btk staining in the malignant tumors than less malignant and normal brain tissues. Collectively, Btk may represent a novel therapeutic target for glioma and ibrunitib may be used as an adjuvant treatment for malignant GBM. PMID:27564106

Preclinical investigation of ibrutinib, a Bruton's kinase tyrosine (Btk) inhibitor, in suppressing glioma tumorigenesis and stem cell phenotypes.

PubMed

Wei, Li; Su, Yu-Kai; Lin, Chien-Min; Chao, Tsu-Yi; Huang, Shang-Pen; Huynh, Thanh-Tuan; Jan, Hsun-Jin; Whang-Peng, Jacqueline; Chiou, Jeng-Fong; Wu, Alexander T H; Hsiao, Michael

2016-10-25

Standard interventions for glioma include surgery, radiation and chemotherapies but the prognosis for malignant cases such as glioblastoma multiforme remain grim. Even with targeted therapeutic agent, bevacitumab, malignant glioma often develops resistance and recurrence. Thus, developing alternative interventions (therapeutic targets, biomarkers) is urgently required. Bruton's tyrosine kinase (Btk) has been long implicated in B cell malignancies but surprisingly it has recently been shown to also play a tumorigenic role in solid tumors such as ovarian and prostate cancer. Bioinformatics data indicates that Btk is significantly higher in clinical glioma samples as compared to normal brain cells and Btk expression level is associated with stage progression. This prompts us to investigate the potential role of Btk as a therapeutic target for glioma. Here, we demonstrate Btk expression is associated with GBM tumorigenesis. Down-regulation of Btk in GBM cell lines showed a significantly reduced abilities in colony formation, migration and GBM sphere-forming potential. Mechanistically, Btk-silenced cells showed a concomitant reduction in the expression of CD133 and Akt/mTOR signaling. In parallel, Ibrutinib (a Btk inhibitor) treatment led to a similar anti-tumorigenic response. Using xenograft mouse model, tumorigenesis was significantly reduced in Btk-silenced or ibrutinib-treated mice as compared to control counterparts. Finally, our glioma tissue microarray analysis indicated a higher Btk staining in the malignant tumors than less malignant and normal brain tissues. Collectively, Btk may represent a novel therapeutic target for glioma and ibrunitib may be used as an adjuvant treatment for malignant GBM.

Macrophage polarization at the crossroad between HIV-1 infection and cancer development.

PubMed

Alfano, Massimo; Graziano, Francesca; Genovese, Luca; Poli, Guido

2013-06-01

Mononuclear phagocytes play a fundamental role in the tissue homeostasis and innate defenses against viruses and other microbial pathogens. In addition, they are likely involved in several steps of cancer development. Circulating monocytes and tissue macrophages are target cells of viral infections, including human cytomegalovirus, human herpes virus 8, and the HIV, and alterations of their functional and phenotypic properties are likely involved in many tissue-degenerative diseases, including atherosclerosis and cancer. Different tissue microenvironments as well as their pathological alterations can profoundly affect the polarization state of macrophages toward the extreme phenotypes conventionally termed M1 and M2. Thus, targeting disease-associated macrophages is considered a potential approach particularly in the context of cancer-associated tumor-associated macrophages, supporting malignant cell growth and progression toward a metastatic phenotype. Of note is the fact that tumor-associated macrophages isolated from established tumors display phenotypic and functional features similar to those of in vitro-derived M2-polarized cells. Concerning HIV-1 infection, viral eradication strategies in the context of combination antiretroviral therapy should also consider the possibility to deplete, at least transiently, certain mononuclear phagocytes subsets, although the possibility of distinguishing those that are either infected or pathogenically altered remains a goal of future research. In the present review, we will focus on the recent literature concerning the role of human macrophage polarization in viral infections and cancer.

Cytogenetics of melanoma and nonmelanoma skin cancer.

PubMed

Carless, Melanie A; Griffiths, Lyn R

2014-01-01

Cytogenetic analysis of melanoma and nonmelanoma skin cancers has revealed recurrent aberrations, the frequency of which is reflective of malignant potential. Highly aberrant karyotypes are seen in melanoma, squamous cell carcinoma, actinic keratosis, Merkel cell carcinoma and cutaneous lymphomas with more stable karyotypes seen in basal cell carcinoma, keratoacanthoma, Bowen's disease and dermatofibrosarcoma protuberans. Some aberrations are common among a number of skin cancer types including rearrangements and numerical abnormalities of chromosome 1, -3p, +3q, partial or entire trisomy 6, trisomy 7, +8q, -9p, +9q, partial or entire loss of chromosome 10, -17p, +17q and partial or entire gain of chromosome 20. Combination of cytogenetic analysis with other molecular genetic techniques has enabled the identification of not only aberrant chromosomal regions, but also the genes that contribute to a malignant phenotype. This review provides a comprehensive summary of the pertinent cytogenetic aberrations associated with a variety of melanoma and nonmelanoma skin cancers.

The role of hypoxia-inducible factor-2 in digestive system cancers.

PubMed

Zhao, J; Du, F; Shen, G; Zheng, F; Xu, B

2015-01-15

Hypoxia is an all but ubiquitous phenomenon in cancers. Two known hypoxia-inducible factors (HIFs), HIF-1α and HIF-2α, primarily mediate the transcriptional response to hypoxia. Despite the high homology between HIF-1α and HIF-2α, emerging evidence suggests differences between both molecules in terms of transcriptional targets as well as impact on multiple physiological pathways and tumorigenesis. To date, much progress has been made toward understanding the roles of HIF-2α in digestive system cancers. Indeed, HIF-2α has been shown to regulate multiple aspects of digestive system cancers, including cell proliferation, angiogenesis and apoptosis, metabolism, metastasis and resistance to chemotherapy. These findings make HIF-2α a critical regulator of this malignant phenotype. Here we summarize the function of HIF-2 during cancer development as well as its contribution to tumorigenesis in digestive system malignancies.

The role of hypoxia-inducible factor-2 in digestive system cancers

PubMed Central

Zhao, J; Du, F; Shen, G; Zheng, F; Xu, B

2015-01-01

Hypoxia is an all but ubiquitous phenomenon in cancers. Two known hypoxia-inducible factors (HIFs), HIF-1α and HIF-2α, primarily mediate the transcriptional response to hypoxia. Despite the high homology between HIF-1α and HIF-2α, emerging evidence suggests differences between both molecules in terms of transcriptional targets as well as impact on multiple physiological pathways and tumorigenesis. To date, much progress has been made toward understanding the roles of HIF-2α in digestive system cancers. Indeed, HIF-2α has been shown to regulate multiple aspects of digestive system cancers, including cell proliferation, angiogenesis and apoptosis, metabolism, metastasis and resistance to chemotherapy. These findings make HIF-2α a critical regulator of this malignant phenotype. Here we summarize the function of HIF-2 during cancer development as well as its contribution to tumorigenesis in digestive system malignancies. PMID:25590810

[CHARACTERISTICS AND INCIDENCE OF HEAD AND NECK SKIN MALIGNANT NEOPLASMS IN THE POPULATION OF THE OSIJEK-BARANYA COUNTY 2004-2012].

PubMed

Orkić, Želimir; Puntarić, Dinko; Puntarić, Eda; Puntarić, Ida; Vidosavljević, Domagoj; Gvozdić, Vlatka; Mayer, Dijana

2015-03-01

The aim of this study was to investigate the incidence and characteristics of malignant neoplasms of the skin of the head and neck region in the Osijek-Baranya County during the 2004-2012 period according to gender, age, place of residence, place of work, occupation, type and location of the neoplasm, and phenotypic characteristics of patients. The study included all subjects with the diagnosis confirmed by histopathology finding and residents of the Osijek-Baranya County. The study included a total of 2952 persons, 1487 (50.4%) male and 1465 (49.6%) female, yielding an approximate annual incidence of 104/100,000. Mean age was 72 years. Respondents were mostly from rural areas (n = 1952, 66.2%). There were 2137 (72.4%) of respondents mostly working outdoors, mainly farmers (n = 907, 42.4%) and construction workers (n = 889, 41.6%). According to the type of neoplasm, the basal cell type was most common with 2160 (73.2%) patients. Ninety-three (3.1 %) patients had malignant melanoma. According to localization, face was the most common site of malignant neoplasms with 839 (28.7%) and nose with 643 (22.0%) patients. Squamous cell carcinoma was significantly more common in men (n = 341, 56.6%) as compared with women (n = 262, (43.4%; p = 0.005). Subjects with malignant melanoma were significantly younger, with median age of 67 years. There were no significant differences according to the type of malignant neoplasms and place of residence, place of business, and occupation with regard to working outdoors or indoors. According to localization, significantly more squamous cell malignancies were found on the ears and lips (p = 0.039 and p < 0.001, respectively), malignant melanomas on the neck, head and eyes (p = 0.004, p < 0.001 and p = 0.026, respectively), and basal cell neoplasms on the nose (p = 0.002). There were no significant differences in the type and frequency of malignant neoplasms according to hair and eye color. It is obvious that the disease occurs after a decades-long incubation period and the cumulative effect of exposure to risk factors, with direct sun exposure, seems to have a significant role. Additional research is needed.

Molecular pathogenesis of ovarian clear cell carcinoma.

PubMed

Gounaris, Ioannis; Brenton, James D

2015-01-01

Ovarian clear cell carcinoma is a distinct subtype of epithelial ovarian cancer, characterized by an association with endometriosis, glycogen accumulation and resistance to chemotherapy. Key driver events, including ARID1A mutations and HNF1B overexpression, have been recently identified and their functional characterization is ongoing. Additionally, the role of glycogen in promoting the malignant phenotype is coming under scrutiny. Appreciation of the notion that ovarian clear cell carcinoma is essentially an ectopic uterine cancer will hopefully lead to improved animal models of the disease, in turn paving the way for effective treatments.

Elevated osteopontin and thrombospondin expression identifies malignant human breast carcinoma but is not indicative of metastatic status

PubMed Central

Wang-Rodriguez, Jessica; Urquidi, Virginia; Rivard, Amber; Goodison, Steve

2003-01-01

Background Our previous characterization of a human breast tumor metastasis model identified several candidate metastasis genes. The expression of osteopontin (OPN) correlated with the metastatic phenotype, whereas thrombospondin-1 (TSP-1) and tyrosinase-related protein-1 (TYRP-1) correlated with the nonmetastatic phenotype of independent MDA-MB-435 cell lines implanted orthotopically into athymic mice. The aim of the present study was to examine the cellular distribution of these molecules in human breast tissue and to determine whether the relative expression level of these three genes is associated with human breast tumor metastasis. Methods Sixty-eight fresh, frozen specimens including 31 primary infiltrating ductal carcinomas, 22 nodal metastases, 10 fibroadenomas, and five normal breast tissues were evaluated for OPN expression, TSP-1 expression and TYRP-1 expression. Immunohistochemistry was performed to monitor the cellular distribution and to qualitatively assess expression. Quantitative analysis was achieved by enrichment of breast epithelial cells using laser-capture microdissection and subsequent real-time, quantitative PCR. Results The epithelial components of the breast tissue were the source of OPN and TSP-1 expression, whereas TYRP-1 was present in both the epithelial and stromal components. Both OPN and TSP-1 expression were significantly higher in malignant epithelial sources over normal and benign epithelial sources, but no difference in expression levels was evident between primary tumors with or without metastases, nor between primary and metastatic carcinomas. Conclusion Elevated expression of OPN and TSP-1 may play a role in the pathogenesis of breast cancer. The multiplex analysis of these molecules may enhance our ability to diagnose and/or prognosticate human breast malignancy. PMID:12927044

HRAS mutations in Costello syndrome: detection of constitutional activating mutations in codon 12 and 13 and loss of wild-type allele in malignancy.

PubMed

Estep, Anne L; Tidyman, William E; Teitell, Michael A; Cotter, Philip D; Rauen, Katherine A

2006-01-01

Costello syndrome (CS) is a complex developmental disorder involving characteristic craniofacial features, failure to thrive, developmental delay, cardiac and skeletal anomalies, and a predisposition to develop neoplasia. Based on similarities with other cancer syndromes, we previously hypothesized that CS is likely due to activation of signal transduction through the Ras/MAPK pathway [Tartaglia et al., 2003]. In this study, the HRAS coding region was sequenced for mutations in a large, well-characterized cohort of 36 CS patients. Heterogeneous missense point mutations predicting an amino acid substitution were identified in 33/36 (92%) patients. The majority (91%) had a 34G --> A transition in codon 12. Less frequent mutations included 35G --> C (codon 12) and 37G --> T (codon 13). Parental samples did not have an HRAS mutation supporting the hypothesis of de novo heterogeneous mutations. There is phenotypic variability among patients with a 34G --> A transition. The most consistent features included characteristic facies and skin, failure to thrive, developmental delay, musculoskeletal abnormalities, visual impairment, cardiac abnormalities, and generalized hyperpigmentation. The two patients with 35G --> C had cardiac arrhythmias whereas one patient with a 37G --> T transversion had an enlarged aortic root. Of the patients with a clinical diagnosis of CS, neoplasia was the most consistent phenotypic feature for predicating an HRAS mutation. To gain an understanding of the relationship between constitutional HRAS mutations and malignancy, HRAS was sequenced in an advanced biphasic rhabdomyosarcoma/fibrosarcoma from an individual with a 34G --> A mutation. Loss of the wild-type HRAS allele was observed, suggesting tumorigenesis in CS patients is accompanied by additional somatic changes affecting HRAS. Finally, due to phenotypic overlap between CS and cardio-facio-cutaneous (CFC) syndromes, the HRAS coding region was sequenced in a well-characterized CFC cohort. No mutations were found which support a distinct genetic etiology between CS and CFC syndromes. (c) 2005 Wiley-Liss, Inc.

Interleukin-like EMT inducer regulates partial phenotype switching in MITF-low melanoma cell lines

PubMed Central

Noguchi, Ken; Dalton, Annamarie C.; Howley, Breege V.; McCall, Buckley J.; Yoshida, Akihiro; Diehl, J. Alan

2017-01-01

ILEI (FAM3C) is a secreted factor that contributes to the epithelial-to-mesenchymal transition (EMT), a cell biological process that confers metastatic properties to a tumor cell. Initially, we found that ILEI mRNA is highly expressed in melanoma metastases but not in primary tumors, suggesting that ILEI contributes to the malignant properties of melanoma. While melanoma is not an epithelial cell-derived tumor and does not undergo a traditional EMT, melanoma undergoes a similar process known as phenotype switching in which high (micropthalmia-related transcription factor) MITF expressing (MITF-high) proliferative cells switch to a low expressing (MITF-low) invasive state. We observed that MITF-high proliferative cells express low levels of ILEI (ILEI-low) and MITF-low invasive cells express high levels of ILEI (ILEI-high). We found that inducing phenotype switching towards the MITF-low invasive state increases ILEI mRNA expression, whereas phenotype switching towards the MITF-high proliferative state decreases ILEI mRNA expression. Next, we used in vitro assays to show that knockdown of ILEI attenuates invasive potential but not MITF expression or chemoresistance. Finally, we used gene expression analysis to show that ILEI regulates several genes involved in the MITF-low invasive phenotype including JARID1B, HIF-2α, and BDNF. Gene set enrichment analysis suggested that ILEI-regulated genes are enriched for JUN signaling, a known regulator of the MITF-low invasive phenotype. In conclusion, we demonstrate that phenotype switching regulates ILEI expression, and that ILEI regulates partial phenotype switching in MITF-low melanoma cell lines. PMID:28545079

The inflammatory microenvironment in colorectal neoplasia.

PubMed

McLean, Mairi H; Murray, Graeme I; Stewart, Keith N; Norrie, Gillian; Mayer, Claus; Hold, Georgina L; Thomson, John; Fyfe, Nicky; Hope, Mairi; Mowat, N Ashley G; Drew, Janice E; El-Omar, Emad M

2011-01-07

Colorectal cancer (CRC) is a major cause of mortality and morbidity worldwide. Inflammatory activity within the stroma of invasive colorectal tumours is known to be a key predictor of disease activity with type, density and location of immune cells impacting on patient prognosis. To date, there has been no report of inflammatory phenotype within pre-malignant human colonic adenomas. Assessing the stromal microenvironment and particularly, inflammatory activity within colorectal neoplastic lesions is central to understanding early colorectal carcinogenesis. Inflammatory cell infiltrate was assessed by immunohistochemistry in paired colonic adenoma and adjacent normal colonic mucosa samples, and adenomas exhibiting increasing degrees of epithelial cell dysplasia. Macrophage phenotype was assessed using double stain immunohistochemistry incorporating expression of an intracellular enzyme of function. A targeted array of inflammatory cytokine and receptor genes, validated by RT-PCR, was used to assess inflammatory gene expression. Inflammatory cell infiltrates are a key feature of sporadic adenomatous colonic polyps with increased macrophage, neutrophil and T cell (specifically helper and activated subsets) infiltration in adenomatous colonic polyps, that increases in association with characteristics of high malignant potential, namely, increasing degree of cell dysplasia and adenoma size. Macrophages within adenomas express iNOS, suggestive of a pro-inflammatory phenotype. Several inflammatory cytokine genes (CXCL1, CXCL2, CXCL3, CCL20, IL8, CCL23, CCL19, CCL21, CCL5) are dysregulated in adenomas. This study has provided evidence of increased inflammation within pre-malignant colonic adenomas. This may allow potential mechanistic pathways in the initiation and promotion of early colorectal carcinogenesis to be identified.

Inefficient differentiation response to cell cycle stress leads to genomic instability and malignant progression of squamous carcinoma cells

PubMed Central

Alonso-Lecue, Pilar; de Pedro, Isabel; Coulon, Vincent; Molinuevo, Rut; Lorz, Corina; Segrelles, Carmen; Ceballos, Laura; López-Aventín, Daniel; García-Valtuille, Ana; Bernal, José M; Mazorra, Francisco; Pujol, Ramón M; Paramio, Jesús; Ramón Sanz, J; Freije, Ana; Toll, Agustí; Gandarillas, Alberto

2017-01-01

Squamous cell carcinoma (SCC) or epidermoid cancer is a frequent and aggressive malignancy. However in apparent paradox it retains the squamous differentiation phenotype except for very dysplastic lesions. We have shown that cell cycle stress in normal epidermal keratinocytes triggers a squamous differentiation response involving irreversible mitosis block and polyploidisation. Here we show that cutaneous SCC cells conserve a partial squamous DNA damage-induced differentiation response that allows them to overcome the cell division block. The capacity to divide in spite of drug-induced mitotic stress and DNA damage made well-differentiated SCC cells more genomically instable and more malignant in vivo. Consistently, in a series of human biopsies, non-metastatic SCCs displayed a higher degree of chromosomal alterations and higher expression of the S phase regulator Cyclin E and the DNA damage signal γH2AX than the less aggressive, non-squamous, basal cell carcinomas. However, metastatic SCCs lost the γH2AX signal and Cyclin E, or accumulated cytoplasmic Cyclin E. Conversely, inhibition of endogenous Cyclin E in well-differentiated SCC cells interfered with the squamous phenotype. The results suggest a dual role of cell cycle stress-induced differentiation in squamous cancer: the resulting mitotic blocks would impose, when irreversible, a proliferative barrier, when reversible, a source of genomic instability, thus contributing to malignancy. PMID:28661481

Increased adenosine triphosphate production by peripheral blood CD4+ cells in patients with hematologic malignancies treated with stem cell mobilization agents.

PubMed

Manga, Kiran; Serban, Geo; Schwartz, Joseph; Slotky, Ronit; Patel, Nita; Fan, Jianshe; Bai, Xiaolin; Chari, Ajai; Savage, David; Suciu-Foca, Nicole; Colovai, Adriana I

2010-07-01

Hematopoietic stem cell (HSC) transplantation is an important therapeutic option for patients with hematologic malignancies. To explore the immunomodulatory effects of HSC mobilization agents, we studied the function and phenotype of CD4(+) T cells from 16 adult patients with hematologic malignancies undergoing HSC mobilization treatment for autologous transplantation. Immune cell function was determined using the Immuknow (Cylex) assay by measuring the amount of adenosine triphosphate (ATP) produced by CD4(+) cells from whole blood. ATP activity measured in G-CSF-treated patients was significantly higher than that measured in healthy individuals or "nonmobilized" patients. In patients treated with G-CSF, CD4(+) T cells were predominantly CD25(low)FOXP3(low), consistent with an activated phenotype. However, T-cell depletion did not abrogate ATP production in blood samples from G-CSF-treated patients, indicating that CD4(+) myeloid cells contributed to the increased ATP levels observed in these patients. There was a significant correlation between ATP activity and patient survival, suggesting that efficient activation of CD4(+) cells during mobilization treatment predicts a low risk of disease relapse. Monitoring immune cell reactivity using the Immuknow assay may assist in the clinical management of patients with hematologic malignancies and optimization of HSC mobilization protocols. Copyright 2010 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.

Overexpression of nucleostemin contributes to an advanced malignant phenotype and a poor prognosis in oral squamous cell carcinoma

PubMed Central

Yoshida, R; Nakayama, H; Nagata, M; Hirosue, A; Tanaka, T; Kawahara, K; Nakagawa, Y; Matsuoka, Y; Sakata, J; Arita, H; Hiraki, A; Shinohara, M; Ito, T

2014-01-01

Background: Nucleostemin (NS) is essential for the maintenance of stem cell properties, the functions of which remain poorly understood in cancer cells. The purpose of this study was to explore the impact of NS on malignancy and its clinical significance in oral squamous cell carcinoma (OSCC) patients. Methods: We investigated the effects of NS on the proliferation and invasion of OSCC using NS-overexpressing or -knockdown OSCC cells. We assessed the activation of the STAT3 (signal transducer and activator of transcription 3) signalling pathway and the downstream targets in the cells with different expression levels of NS. An immunohistochemical analysis of NS was also performed in 54 OSCC patients who were treated with preoperative chemoradiotherapy and surgery. Results: The overexpression of NS significantly enhanced the proliferation and invasive potential of OSCC cells. On the other hand, downregulation of NS suppressed the invasiveness of the cells. The alterations of these malignant phenotypes were associated with the activation of STAT3 signalling and its downstream targets. An immunohistochemical analysis demonstrated that a high NS tumour expression level significantly correlated with an advanced T-stage and N-stage. Furthermore, a Cox regression analysis revealed that the NS status (hazard ratio, 9.09; P=0.002) was a significant progression factor for OSCC patients. Conclusions: Our results suggest that targeting NS may provide a promising treatment for highly malignant OSCC. PMID:25314067

Fibroblast Growth Factor (FGF-2) and Its Receptors FGFR-2 and FGFR-3 May Be Putative Biomarkers of Malignant Transformation of Potentially Malignant Oral Lesions into Oral Squamous Cell Carcinoma.

PubMed

Nayak, Seema; Goel, Madhu Mati; Makker, Annu; Bhatia, Vikram; Chandra, Saumya; Kumar, Sandeep; Agarwal, S P

2015-01-01

There are several factors like angiogenesis, lymphangiogenesis, genetic alterations, mutational factors that are involved in malignant transformation of potentially malignant oral lesions (PMOLs) to oral squamous cell carcinoma (OSCC). Fibroblast growth factor-2 (FGF-2) is one of the prototypes of the large family of growth factors that bind heparin. FGF-2 induces angiogenesis and its receptors may play a role in synthesis of collagen. FGFs are involved in transmission of signals between the epithelium and connective tissue, and influence growth and differentiation of a wide variety of tissue including epithelia. The present study was undertaken to analyze expression of FGF-2 and its receptors FGFR-2 and FGFR-3 in 72 PMOLs, 108 OSCC and 52 healthy controls, and their role in risk assessment for malignant transformation of Leukoplakia (LKP) and Oral submucous fibrosis (OSMF) to OSCC. Immunohistochemistry was performed using antibodies against FGF-2, FGFR-2 and FGFR-3. IHC results were validated by Real Time PCR. Expression of FGF-2, FGFR-2 and FGFR-3 was upregulated from PMOLs to OSCC. While 90% (9/10) of PMOLs which showed malignant transformation (transformed) expressed FGF-2, only 24.19% cases (15/62) of PMOLs which were not transformed (untransformed) to OSCC expressed FGF-2. Similarly, FGFR-2 expression was seen in 16/62 (25.81%) of untransformed PMOLs and 8/10 (80%) cases of transformed PMOLs. FGFR-3 expression was observed in 23/62 (37.10%) cases of untransformed PMOLs and 6/10 (60%) cases of transformed PMOLs. A significant association of FGF-2 and FGFR-2 expression with malignant transformation from PMOLs to OSCC was observed both at phenotypic and molecular level. The results suggest that FGF-2 and FGFR-2 may be useful as biomarkers of malignant transformation in patients with OSMF and LKP.

Phenotypic variability in patients with Fanconi anemia and biallelic FANCF mutations.

PubMed

Tryon, Rebecca; Zierhut, Heather; MacMillan, Margaret L; Wagner, John E

2017-01-01

Fanconi anemia is a heterogeneous genetic disorder that is characterized by progressive bone marrow failure, congenital anomalies, and markedly increased risk for malignancies. Mutations in the FANCF (FA-F) gene represent approximately 2% of affected patients. Currently, information on the phenotypic findings of patients with Fanconi anemia from biallelic mutations in FANCF is limited. Here, we report three patients who illustrate the clinical variability within the FA-F group. This analysis suggests a more severe phenotype for those with the common c.484_485delCT mutation. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Defective immunoregulatory T-cell function in chronic lymphocytic leukemia

DOE Office of Scientific and Technical Information (OSTI.GOV)

Han, T.; Ozer, H.; Henderson, E.S.

Chronic lymphocytic leukemia (CLL) of B-cell origin results in the malignant proliferation of small immunoglobulin-bearing lymphocytes. There is currently a controversy in the literature regarding both the ability of this leukemic population to differentiate into mature plasma cells, as well as the ability of apparently normal T cells from these patients to regulate allogeneic B-cell differentiation. In the present study we have examined the lymphocytes of CLL patients in various clinical stages of their disease and with different surface phenotypes of their leukemic B-cell population. Our results show that leukemic CLL B cells from all 20 patients (including one patientmore » with a monoclonal IgM paraprotein and another with a monoclonal IgG paraprotein) are incapable of further differentiation even in the absence of suppressor T cells and the presence of helper T lymphocytes. This lack of capacity to differentiate is unaffected by clinical stage, by therapy, or by the phenotype of the malignant population. Since the leukemic B population did not suppress normal allogeneic B-cell differentiation, the maturation deficit is evidently intrinsic to the leukemic clone rather than a result of activity of non-T suppressor cells. T helper function was also variably depressed in the blood of some patients with CLL, and this depression did not correlate with clinical stage, with therapy, or with the degree of lymphocytosis. Dysfunction of radiosensitive T suppressor cells was found to be the most consistent regulatory deficit of CLL T cells. Each of 11 patients whose leukemic cell population was of the ..mu..delta, ..mu cap alpha.., or ..mu.. phenotype had both helper and suppressor cell defects.« less

Inhibition of Focal Adhesion Kinase (FAK) Leads to Abrogation of the Malignant Phenotype in Aggressive Pediatric Renal Malignancies

PubMed Central

Megison, Michael L.; Gillory, Lauren A.; Stewart, Jerry E.; Nabers, Hugh C.; Mrozcek-Musulman, Elizabeth; Beierle, Elizabeth A.

2014-01-01

Despite the tremendous advances in the treatment of childhood kidney tumors, there remain subsets of pediatric renal tumors that continue to pose a therapeutic challenge, mainly malignant rhabdoid kidney tumors and non-osseous renal Ewing sarcoma. Children with advanced, metastatic or relapsed disease have a disease-free survival rate under 30%. Focal adhesion kinase (FAK) is a nonreceptor tyrosine kinase that is important in many facets of tumor development and progression. FAK has been found in other pediatric solid tumors and in adult renal cellular carcinoma, leading us to hypothesize that FAK would be present in pediatric kidney tumors and would impact their cellular survival. In the current study, we showed that FAK was present and phosphorylated in pediatric kidney tumor specimens. We also examined the effects of FAK inhibition upon G401 and SK-NEP-1 cell lines utilizing a number of parallel approaches to block FAK including RNAi and small molecule FAK inhibitors. FAK inhibition resulted in decreased cellular survival, invasion and migration, and increased apoptosis. Further, small molecule inhibition of FAK led to decreased tumor growth in a nude mouse SK-NEP-1 xenograft model. The findings from this study will help to further our understanding of the regulation of tumorigenesis in rare pediatric renal tumors, and may provide desperately needed novel therapeutic strategies and targets for these rare, but difficult to treat, malignancies. PMID:24464916

Transforming Growth Factor-β Drives the Transendothelial Migration of Hepatocellular Carcinoma Cells.

PubMed

Koudelkova, Petra; Costina, Victor; Weber, Gerhard; Dooley, Steven; Findeisen, Peter; Winter, Peter; Agarwal, Rahul; Schlangen, Karin; Mikulits, Wolfgang

2017-10-10

The entry of malignant hepatocytes into blood vessels is a key step in the dissemination and metastasis of hepatocellular carcinoma (HCC). The identification of molecular mechanisms involved in the transmigration of malignant hepatocytes through the endothelial barrier is of high relevance for therapeutic intervention and metastasis prevention. In this study, we employed a model of hepatocellular transmigration that mimics vascular invasion using hepatic sinusoidal endothelial cells and malignant hepatocytes evincing a mesenchymal-like, invasive phenotype by transforming growth factor (TGF)-β. Labelling of respective cell populations with various stable isotopes and subsequent mass spectrometry analyses allowed the "real-time" detection of molecular changes in both transmigrating hepatocytes and endothelial cells. Interestingly, the proteome profiling revealed 36 and 559 regulated proteins in hepatocytes and endothelial cells, respectively, indicating significant changes during active transmigration that mostly depends on cell-cell interaction rather than on TGF-β alone. Importantly, matching these in vitro findings with HCC patient data revealed a panel of common molecular alterations including peroxiredoxin-3, epoxide hydrolase, transgelin-2 and collectin 12 that are clinically relevant for the patient's survival. We conclude that hepatocellular plasticity induced by TGF-β is crucially involved in blood vessel invasion of HCC cells.

Transforming Growth Factor-β Drives the Transendothelial Migration of Hepatocellular Carcinoma Cells

PubMed Central

Koudelkova, Petra; Costina, Victor; Weber, Gerhard; Dooley, Steven; Findeisen, Peter; Winter, Peter; Agarwal, Rahul; Schlangen, Karin

2017-01-01

The entry of malignant hepatocytes into blood vessels is a key step in the dissemination and metastasis of hepatocellular carcinoma (HCC). The identification of molecular mechanisms involved in the transmigration of malignant hepatocytes through the endothelial barrier is of high relevance for therapeutic intervention and metastasis prevention. In this study, we employed a model of hepatocellular transmigration that mimics vascular invasion using hepatic sinusoidal endothelial cells and malignant hepatocytes evincing a mesenchymal-like, invasive phenotype by transforming growth factor (TGF)-β. Labelling of respective cell populations with various stable isotopes and subsequent mass spectrometry analyses allowed the “real-time” detection of molecular changes in both transmigrating hepatocytes and endothelial cells. Interestingly, the proteome profiling revealed 36 and 559 regulated proteins in hepatocytes and endothelial cells, respectively, indicating significant changes during active transmigration that mostly depends on cell–cell interaction rather than on TGF-β alone. Importantly, matching these in vitro findings with HCC patient data revealed a panel of common molecular alterations including peroxiredoxin-3, epoxide hydrolase, transgelin-2 and collectin 12 that are clinically relevant for the patient’s survival. We conclude that hepatocellular plasticity induced by TGF-β is crucially involved in blood vessel invasion of HCC cells. PMID:28994702

CD147/basigin promotes progression of malignant melanoma and other cancers.

PubMed

Kanekura, Takuro; Chen, Xiang

2010-03-01

CD147/basigin, a transmembrane protein belonging to the immunoglobulin super family, was originally cloned as a carrier of Lewis X carbohydrate antigen. CD147 is strongly related to cancer progression; it is highly expressed by various cancer cells including malignant melanoma (MM) cells and it plays important roles in tumor invasiveness, metastasis, cellular proliferation, and in vascular endothelial growth factor (VEGF) production, tumor cell glycolysis, and multi-drug resistance (MDR). CD147 on cancer cells induces matrix metalloproteinase expression by neighboring fibroblasts, leading to tumor cell invasion. In a nude mouse model of pulmonary metastasis from MM, the metastatic potential of CD147-expressing MM cells injected into the tail vein is abolished by CD147 silencing. CD147 enhances cellular proliferation and VEGF production by MM cells; it promotes tumor cell glycolysis by facilitating lactate transport in combination with monocarboxylate transporters, resulting in tumor progression. CD147 is responsible for the MDR phenotype via P-glycoprotein expression. These findings strongly suggest CD147 as a possible therapeutic target for overcoming metastasis and MDR, major obstacles to the effective treatment of malignant cancers. 2009 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.

Loss of heterozygosity 4q24 and TET2 mutations associated with myelodysplastic/myeloproliferative neoplasms

PubMed Central

Jankowska, Anna M.; Szpurka, Hadrian; Tiu, Ramon V.; Makishima, Hideki; Afable, Manuel; Huh, Jungwon; O'Keefe, Christine L.; Ganetzky, Rebecca; McDevitt, Michael A.

2009-01-01

Chromosomal abnormalities are frequent in myeloid malignancies, but in most cases of myelodysplasia (MDS) and myeloproliferative neoplasms (MPN), underlying pathogenic molecular lesions are unknown. We identified recurrent areas of somatic copy number–neutral loss of heterozygosity (LOH) and deletions of chromosome 4q24 in a large cohort of patients with myeloid malignancies including MDS and related mixed MDS/MPN syndromes using single nucleotide polymorphism arrays. We then investigated genes in the commonly affected area for mutations. When we sequenced TET2, we found homozygous and hemizygous mutations. Heterozygous and compound heterozygous mutations were found in patients with similar clinical phenotypes without LOH4q24. Clinical analysis showed most TET2 mutations were present in patients with MDS/MPN (58%), including CMML (6/17) or sAML (32%) evolved from MDS/MPN and typical MDS (10%), suggesting they may play a ubiquitous role in malignant evolution. TET2 mutations affected conserved domains and the N terminus. TET2 is widely expressed in hematopoietic cells but its function is unknown, and it lacks homology to other known genes. The frequency of mutations in this candidate myeloid regulatory gene suggests an important role in the pathogenesis of poor prognosis MDS/MPN and sAML and may act as a disease gene marker for these often cytogenetically normal disorders. PMID:19372255

Noonan syndrome: Severe phenotype and PTPN11 mutations.

PubMed

Carrasco Salas, Pilar; Gómez-Molina, Gertrudis; Carreto-Alba, Páxedes; Granell-Escobar, Reyes; Vázquez-Rico, Ignacio; León-Justel, Antonio

2018-04-24

Noonan syndrome (NS) is a genetic disorder characterized by a wide range of distinctive features and health problems. It caused in 50% of cases by missense mutations in PTPN11 gene. It has been postulated that it is possible to predict the disease course based into the impact of mutations on the protein. We report two cases of severe NS phenotype including hydrops fetalis. PTPN11 gene was studied in germinal cells of both patients by sequencing. Two different mutations (p.Gly503Arg and p.Met504Val) was detected in PTPN11 gene. These mutations have been reported previously, and when they were germinal variants, patients presented classic NS, NS with other malignancies and recently, p.Gly503Arg has been also observed in a patient with severe NS and hydrops fetalis, as our cases. Therefore, these observations shade light on that it is not always possibly to determine the genotype-phenotype relation based into the impact of mutations on the protein in NS patients with PTPN11 mutations. Copyright © 2018 Elsevier España, S.L.U. All rights reserved.

3-Deazaneplanocin A suppresses aggressive phenotype-related gene expression in an oral squamous cell carcinoma cell line

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hatta, Mitsutoki, E-mail: hatta@college.fdcnet.ac.jp; Naganuma, Kaori; Kato, Kenichi

In tumor tissues, alterations of gene expression caused by aberrant epigenetic modifications confer phenotypic diversity on malignant cells. Although 3-deazaneplanocin A (DZNep) has been shown to reactivate tumor suppressor genes in several cancer cells, it remains unclear whether DZNep attenuates the malignant phenotypes of oral squamous cell carcinoma (OSCC) cells. In this study, we investigated the effect of DZNep on the expression of genes related to aggressive phenotypes, such as epithelial–mesenchymal transition, in OSCC cells. We found that DZNep reduced the cellular levels of polycomb group proteins (EZH2, SUZ12, BMI1, and RING1A) and the associated trimethylation of Lys27 on histonemore » H3 and monoubiquitination of Lys119 on histone H2A in the poorly differentiated OSCC cell line SAS. Immunocytochemical staining demonstrated that DZNep induced the reorganization of filamentous actin and the membrane localization of E-cadherin associated with cell–cell adhesions. We also found an inhibitory effect of DZNep on cell proliferation using a WST assay. Finally, quantitative RT-PCR analysis demonstrated that genes involved in the aggressive phenotypes (TWIST2, EGFR, ACTA2, TGFB1, WNT5B, and APLIN) were down-regulated, whereas epithelial phenotype genes (CDH1, CLDN4, IVL, and TGM1) were up-regulated in SAS cells treated with DZNep. Collectively, our findings suggest that DZNep reverses the aggressive characteristics of OSCC cells through the dynamic regulation of epithelial plasticity via the reprogramming of gene expression patterns. - Highlights: • DZNep reduced PcG proteins and associated histone modifications in OSCC cells. • DZNep enhanced cell–cell adhesion indicative of epithelial phenotype in OSCC cells. • DZNep suppressed the aggressive phenotype-related gene expression in OSCC cells. • DZNep activated the gene expression of epithelial markers in OSCC cells.« less

On the holistic approach in cellular and cancer biology: nonlinearity, complexity, and quasi-determinism of the dynamic cellular network.

PubMed

Waliszewski, P; Molski, M; Konarski, J

1998-06-01

A keystone of the molecular reductionist approach to cellular biology is a specific deductive strategy relating genotype to phenotype-two distinct categories. This relationship is based on the assumption that the intermediary cellular network of actively transcribed genes and their regulatory elements is deterministic (i.e., a link between expression of a gene and a phenotypic trait can always be identified, and evolution of the network in time is predetermined). However, experimental data suggest that the relationship between genotype and phenotype is nonbijective (i.e., a gene can contribute to the emergence of more than just one phenotypic trait or a phenotypic trait can be determined by expression of several genes). This implies nonlinearity (i.e., lack of the proportional relationship between input and the outcome), complexity (i.e. emergence of the hierarchical network of multiple cross-interacting elements that is sensitive to initial conditions, possesses multiple equilibria, organizes spontaneously into different morphological patterns, and is controlled in dispersed rather than centralized manner), and quasi-determinism (i.e., coexistence of deterministic and nondeterministic events) of the network. Nonlinearity within the space of the cellular molecular events underlies the existence of a fractal structure within a number of metabolic processes, and patterns of tissue growth, which is measured experimentally as a fractal dimension. Because of its complexity, the same phenotype can be associated with a number of alternative sequences of cellular events. Moreover, the primary cause initiating phenotypic evolution of cells such as malignant transformation can be favored probabilistically, but not identified unequivocally. Thermodynamic fluctuations of energy rather than gene mutations, the material traits of the fluctuations alter both the molecular and informational structure of the network. Then, the interplay between deterministic chaos, complexity, self-organization, and natural selection drives formation of malignant phenotype. This concept offers a novel perspective for investigation of tumorigenesis without invalidating current molecular findings. The essay integrates the ideas of the sciences of complexity in a biological context.

Reprogramming human A375 amelanotic melanoma cells by catalase overexpression: Reversion or promotion of malignancy by inducing melanogenesis or metastasis

PubMed Central

Bracalente, Candelaria; Salguero, Noelia; Notcovich, Cintia; Müller, Carolina B.; da Motta, Leonardo L.; Klamt, Fabio; Ibañez, Irene L.; Durán, Hebe

2016-01-01

Advanced melanoma is the most aggressive form of skin cancer. It is highly metastatic and dysfunctional in melanogenesis; two processes that are induced by H2O2. This work presents a melanoma cell model with low levels of H2O2 induced by catalase overexpression to study differentiation/dedifferentiation processes. Three clones (A7, C10 and G10) of human A375 amelanotic melanoma cells with quite distinct phenotypes were obtained. These clones faced H2O2 scavenging by two main strategies. One developed by clone G10 where ROS increased. This resulted in G10 migration and metastasis associated with the increased of cofilin-1 and CAP1. The other strategy was observed in clone A7 and C10, where ROS levels were maintained reversing malignant features. Particularly, C10 was not tumorigenic, while A7 reversed the amelanotic phenotype by increasing melanin content and melanocytic differentiation markers. These clones allowed the study of potential differentiation and migration markers and its association with ROS levels in vitro and in vivo, providing a new melanoma model with different degree of malignancy. PMID:27206672

Reprogramming human A375 amelanotic melanoma cells by catalase overexpression: Reversion or promotion of malignancy by inducing melanogenesis or metastasis.

PubMed

Bracalente, Candelaria; Salguero, Noelia; Notcovich, Cintia; Müller, Carolina B; da Motta, Leonardo L; Klamt, Fabio; Ibañez, Irene L; Durán, Hebe

2016-07-05

Advanced melanoma is the most aggressive form of skin cancer. It is highly metastatic and dysfunctional in melanogenesis; two processes that are induced by H2O2. This work presents a melanoma cell model with low levels of H2O2 induced by catalase overexpression to study differentiation/dedifferentiation processes. Three clones (A7, C10 and G10) of human A375 amelanotic melanoma cells with quite distinct phenotypes were obtained. These clones faced H2O2 scavenging by two main strategies. One developed by clone G10 where ROS increased. This resulted in G10 migration and metastasis associated with the increased of cofilin-1 and CAP1. The other strategy was observed in clone A7 and C10, where ROS levels were maintained reversing malignant features. Particularly, C10 was not tumorigenic, while A7 reversed the amelanotic phenotype by increasing melanin content and melanocytic differentiation markers. These clones allowed the study of potential differentiation and migration markers and its association with ROS levels in vitro and in vivo, providing a new melanoma model with different degree of malignancy.

Utilization of nuclear structural proteins for targeted therapy and detection of proliferative and differentiation disorders

DOEpatents

Lelievre, Sophie; Bissell, Mina

2001-01-01

The localization of nuclear apparatus proteins (NUMA) is used to identify tumor cells and different stages in the tumor progression and differentiation processes. There is a characteristic organization of NuMA in tumor cells and in phenotypically normal cells. NuMA distribution patterns are significantly less diffuse in proliferating non-malignant cells compared to malignant cells. The technique encompasses cell immunostaining using a NuMA specific antibody, and microscopic analysis of NuMA distribution within each nucleus.

CD147, CD44, and the epidermal growth factor receptor (EGFR) signaling pathway cooperate to regulate breast epithelial cell invasiveness.

PubMed

Grass, G Daniel; Tolliver, Lauren B; Bratoeva, Momka; Toole, Bryan P

2013-09-06

The immunoglobulin superfamily glycoprotein CD147 (emmprin; basigin) is associated with an invasive phenotype in various types of cancers, including malignant breast cancer. We showed recently that up-regulation of CD147 in non-transformed, non-invasive breast epithelial cells is sufficient to induce an invasive phenotype characterized by membrane type-1 matrix metalloproteinase (MT1-MMP)-dependent invadopodia activity (Grass, G. D., Bratoeva, M., and Toole, B. P. (2012) Regulation of invadopodia formation and activity by CD147. J. Cell Sci. 125, 777-788). Here we found that CD147 induces breast epithelial cell invasiveness by promoting epidermal growth factor receptor (EGFR)-Ras-ERK signaling in a manner dependent on hyaluronan-CD44 interaction. Furthermore, CD147 promotes assembly of signaling complexes containing CD147, CD44, and EGFR in lipid raftlike domains. We also found that oncogenic Ras regulates CD147 expression, hyaluronan synthesis, and formation of CD147-CD44-EGFR complexes, thus forming a positive feedback loop that may amplify invasiveness. Last, we showed that malignant breast cancer cells are heterogeneous in their expression of surface-associated CD147 and that high levels of membrane CD147 correlate with cell surface EGFR and CD44 levels, activated EGFR and ERK1, and activated invadopodia. Future studies should evaluate CD147 as a potential therapeutic target and disease stratification marker in breast cancer.

Targeting the TAM Receptors in Leukemia.

PubMed

Huey, Madeline G; Minson, Katherine A; Earp, H Shelton; DeRyckere, Deborah; Graham, Douglas K

2016-11-08

Targeted inhibition of members of the TAM (TYRO-3, AXL, MERTK) family of receptor tyrosine kinases has recently been investigated as a novel strategy for treatment of hematologic malignancies. The physiologic functions of the TAM receptors in innate immune control, natural killer (NK) cell differentiation, efferocytosis, clearance of apoptotic debris, and hemostasis have previously been described and more recent data implicate TAM kinases as important regulators of erythropoiesis and megakaryopoiesis. The TAM receptors are aberrantly or ectopically expressed in many hematologic malignancies including acute myeloid leukemia, B- and T-cell acute lymphoblastic leukemia, chronic lymphocytic leukemia, and multiple myeloma. TAM receptors contribute to leukemic phenotypes through activation of pro-survival signaling pathways and interplay with other oncogenic proteins such as FLT3, LYN, and FGFR3. The TAM receptors also contribute to resistance to both cytotoxic chemotherapeutics and targeted agents, making them attractive therapeutic targets. A number of translational strategies for TAM inhibition are in development, including small molecule inhibitors, ligand traps, and monoclonal antibodies. Emerging areas of research include modulation of TAM receptors to enhance anti-tumor immunity, potential roles for TYRO-3 in leukemogenesis, and the function of the bone marrow microenvironment in mediating resistance to TAM inhibition.

Epigenetic mediated transcriptional activation of WNT5A participates in arsenical-associated malignant transformation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jensen, Taylor J.; Wozniak, Ryan J.; Arizona Cancer Center, University of Arizona, Tucson, AZ 85724

2009-02-15

Arsenic is a human carcinogen with exposure associated with cancer of the lung, skin, and bladder. Many potential mechanisms have been implicated as playing a role in the process of arsenical-induced malignancy including the perturbation of signaling pathways and aberrant epigenetic regulation. We initiated studies to examine the role of a member of the non-canonical WNT signaling pathway, WNT5A, in UROtsa cells and arsenite [URO-ASSC] and monomethylarsonous acid [URO-MSC] malignantly transformed variants. We present data herein that suggest that WNT5A is transcriptionally activated during arsenical-induced malignant transformation. This WNT5A transcriptional activation is correlated with the enrichment of permissive histone modificationsmore » and the reduction of repressive modifications in the WNT5A promoter region. The epigenetic activation of WNT5A expression and acetylation of its promoter remain after the removal of the arsenical, consistent with the maintenance of an anchorage independent growth phenotype in these cells. Additionally, treatment with epigenetic modifying drugs supports a functional role for these epigenetic marks in controlling gene expression. Reduction of WNT5A using lentiviral shRNA greatly attenuated the ability of these cells to grow in an anchorage independent fashion. Extension of our model into human bladder cancer cell lines indicates that each of the cell lines examined also express WNT5A. Taken together, these data suggest that the epigenetic remodeling of the WNT5A promoter is correlated with its transcriptional activation and this upregulation likely participates in arsenical-induced malignant transformation.« less

IDH1(R132H) mutation causes a less aggressive phenotype and radiosensitizes human malignant glioma cells independent of the oxygenation status.

PubMed

Kessler, Jacqueline; Güttler, Antje; Wichmann, Henri; Rot, Swetlana; Kappler, Matthias; Bache, Matthias; Vordermark, Dirk

2015-09-01

In malignant glioma the presence of the IDH1 mutation (IDH1(R132H)) is associated with better clinical outcome. However, it is unclear whether IDH1 mutation is associated with a less aggressive phenotype or directly linked to increased sensitivity to radiotherapy. We determined the influence of IDH1(R132H) mutant protein on proliferation and growth in 3D culture, migration, cell survival and radiosensitivity in vitro under normoxia (21% O2) and hypoxia (<1% O2) in a panel of human malignant glioma cell lines (U-251MG, U-343MG, LN-229) with stable overexpression of wild-type (IDH1(wt)) and mutated IDH1 (IDH1(R132H)). Overexpression of IDH1(R132H) in glioma cells resulted in slightly decreased cell proliferation, considerably reduced cell migration and caused differences in growth properties in 3D spheroid cultures. Furthermore, IDH1(R132H)-positive cells consistently demonstrated an increased radiosensitivity in human malignant glioma cells U-251MG (DMF10: 1.52, p<0.01 and 1.42, p<0.01), U-343MG (DMF10: 1.78, p<0.01 and 1.75, p<0.01) and LN-229 (DMF10: 1.41, p<0.05 and 1.68, p<0.01) under normoxia and hypoxia, respectively. Our data indicate that IDH1(R132H) mutation causes both a less aggressive biological behavior and direct radiosensitization of human malignant glioma cells. Targeting IDH1 appears to be an attractive approach in combination with radiotherapy. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

The Inflammatory Microenvironment in Colorectal Neoplasia

PubMed Central

McLean, Mairi H.; Murray, Graeme I.; Stewart, Keith N.; Norrie, Gillian; Mayer, Claus; Hold, Georgina L.; Thomson, John; Fyfe, Nicky; Hope, Mairi; Mowat, N. Ashley G.; Drew, Janice E.; El-Omar, Emad M.

2011-01-01

Colorectal cancer (CRC) is a major cause of mortality and morbidity worldwide. Inflammatory activity within the stroma of invasive colorectal tumours is known to be a key predictor of disease activity with type, density and location of immune cells impacting on patient prognosis. To date, there has been no report of inflammatory phenotype within pre-malignant human colonic adenomas. Assessing the stromal microenvironment and particularly, inflammatory activity within colorectal neoplastic lesions is central to understanding early colorectal carcinogenesis. Inflammatory cell infiltrate was assessed by immunohistochemistry in paired colonic adenoma and adjacent normal colonic mucosa samples, and adenomas exhibiting increasing degrees of epithelial cell dysplasia. Macrophage phenotype was assessed using double stain immunohistochemistry incorporating expression of an intracellular enzyme of function. A targeted array of inflammatory cytokine and receptor genes, validated by RT-PCR, was used to assess inflammatory gene expression. Inflammatory cell infiltrates are a key feature of sporadic adenomatous colonic polyps with increased macrophage, neutrophil and T cell (specifically helper and activated subsets) infiltration in adenomatous colonic polyps, that increases in association with characteristics of high malignant potential, namely, increasing degree of cell dysplasia and adenoma size. Macrophages within adenomas express iNOS, suggestive of a pro-inflammatory phenotype. Several inflammatory cytokine genes (CXCL1, CXCL2, CXCL3, CCL20, IL8, CCL23, CCL19, CCL21, CCL5) are dysregulated in adenomas. This study has provided evidence of increased inflammation within pre-malignant colonic adenomas. This may allow potential mechanistic pathways in the initiation and promotion of early colorectal carcinogenesis to be identified. PMID:21249124

DSE promotes aggressive glioma cell phenotypes by enhancing HB-EGF/ErbB signaling.

PubMed

Liao, Wen-Chieh; Liao, Chih-Kai; Tsai, You-Huan; Tseng, To-Jung; Chuang, Li-Ching; Lan, Chyn-Tair; Chang, Hung-Ming; Liu, Chiung-Hui

2018-01-01

Remodeling of the extracellular matrix (ECM) in the tumor microenvironment promotes glioma progression. Chondroitin sulfate (CS) proteoglycans appear in the ECM and on the cell surface, and can be catalyzed by dermatan sulfate epimerase to form chondroitin sulfate/dermatan sulfate (CS/DS) hybrid chains. Dermatan sulfate epimerase 1 (DSE) is overexpressed in many types of cancer, and CS/DS chains mediate several growth factor signals. However, the role of DSE in gliomas has never been explored. In the present study, we determined the expression of DSE in gliomas by consulting a public database and conducting immunohistochemistry on a tissue array. Our investigation revealed that DSE was upregulated in gliomas compared with normal brain tissue. Furthermore, high DSE expression was associated with advanced tumor grade and poor survival. We found high DSE expression in several glioblastoma cell lines, and DSE expression directly mediated DS chain formation in glioblastoma cells. Knockdown of DSE suppressed the proliferation, migration, and invasion of glioblastoma cells. In contrast, overexpression of DSE in GL261 cells enhanced these malignant phenotypes and in vivo tumor growth. Interestingly, we found that DSE selectively regulated heparin-binding EGF-like growth factor (HB-EGF)-induced signaling in glioblastoma cells. Inhibiting epidermal growth factor receptor (EGFR) and ErbB2 with afatinib suppressed DSE-enhanced malignant phenotypes, establishing the critical role of the ErbB pathway in regulating the effects of DSE expression. This evidence indicates that upregulation of DSE in gliomas contributes to malignant behavior in cancer cells. We provide novel insight into the significance of DS chains in ErbB signaling and glioma pathogenesis.

Syndromes that Link the Endocrine System and Genitourinary Tract.

PubMed

Özlük, Yasemin; Kılıçaslan, Işın

2015-01-01

The endocrine system and genitourinary tract unite in various syndromes. Genitourinary malignancies may cause paraneoplastic endocrine syndromes by secreting hormonal substances. These entities include Cushing`s syndrome, hypercalcemia, hyperglycemia, polycythemia, hypertension, and inappropriate ADH or HCG production. The most important syndromic scenarios that links these two systems are hereditary renal cancer syndromes with specific genotype/phenotype correlation. There are also some very rare entities in which endocrine and genitourinary systems are involved such as Carney complex, congenital adrenal hyperplasia and Beckwith-Wiedemann syndrome. We will review all the syndromes regarding manifestations present in endocrine and genitourinary organs.

Overexpression of Nrp/b (nuclear restrict protein in brain) suppresses the malignant phenotype in the C6/ST1 glioma cell line.

PubMed

Degaki, Theri Leica; Demasi, Marcos Angelo Almeida; Sogayar, Mari Cleide

2009-11-01

Upon searching for glucocorticoid-regulated cDNA sequences associated with the transformed to normal phenotypic reversion of C6/ST1 rat glioma cells, we identified Nrp/b (nuclear restrict protein in brain) as a novel rat gene. Here we report on the identification and functional characterization of the complete sequence encoding the rat NRP/B protein. The cloned cDNA presented a 1767 nucleotides open-reading frame encoding a 589 amino acids residues sequence containing a BTB/POZ (broad complex Tramtrack bric-a-brac/Pox virus and zinc finger) domain in its N-terminal region and kelch motifs in its C-terminal region. Sequence analysis indicates that the rat Nrp/b displays a high level of identity with the equivalent gene orthologs from other organisms. Among rat tissues, Nrp/b expression is more pronounced in brain tissue. We show that overexpression of the Nrp/b cDNA in C6/ST1 cells suppresses anchorage independence in vitro and tumorigenicity in vivo, altering their malignant nature towards a more benign phenotype. Therefore, Nrp/b may be postulated as a novel tumor suppressor gene, with possible relevance for glioblastoma therapy.

The inherent metastasis of leukaemia and its exploitation by sonodynamic therapy.

PubMed

Trendowski, Matthew

2015-05-01

Nearly all cancers are linked by the inexorable phenotype of metastasis as malignant growths have the capability to spread from their place of origin to distant sites throughout the body. While different cancers may have various propensities to migrate towards specific locations, they are all linked by this unifying principal. Unlike most neoplasms, leukaemia has inherent cell motility as leukocytes are required to move throughout the vascular system, suggesting that no mutations are required for anchorage independent growth. As such, it seems likely that leukaemias are inherently metastatic, endowed with the deadliest phenotype of cancer simply due to cell of origin. This article presents the biology of metastasis development and how leukaemia cells are inherently provided these phenotypic characteristics. It is then proposed how clinicians may be able to exploit the motility of leukaemia and metastatic emboli of other cancer types through an approach known as sonodynamic therapy (SDT), a treatment modality that combines chemotherapeutic agents with ultrasound to preferentially damage malignant cells. As experimental evidence has indicated, SDT is a promising therapeutic approach in need of clinical testing for further validation. Copyright © 2014 The Author. Published by Elsevier Ireland Ltd.. All rights reserved.

Methylator phenotype of malignant germ cell tumours in children identifies strong candidates for chemotherapy resistance

PubMed Central

Jeyapalan, J N; Noor, D A Mohamed; Lee, S-H; Tan, C L; Appleby, V A; Kilday, J P; Palmer, R D; Schwalbe, E C; Clifford, S C; Walker, D A; Murray, M J; Coleman, N; Nicholson, J C; Scotting, P J

2011-01-01

Background: Yolk sac tumours (YSTs) and germinomas are the two major pure histological subtypes of germ cell tumours. To date, the role of DNA methylation in the aetiology of this class of tumour has only been analysed in adult testicular forms and with respect to only a few genes. Methods: A bank of paediatric tumours was analysed for global methylation of LINE-1 repeat elements and global methylation of regulatory elements using GoldenGate methylation arrays. Results: Both germinomas and YSTs exhibited significant global hypomethylation of LINE-1 elements. However, in germinomas, methylation of gene regulatory regions differed little from control samples, whereas YSTs exhibited increased methylation at a large proportion of the loci tested, showing a ‘methylator' phenotype, including silencing of genes associated with Caspase-8-dependent apoptosis. Furthermore, we found that the methylator phenotype of YSTs was coincident with higher levels of expression of the DNA methyltransferase, DNA (cytosine-5)-methyltransferase 3B, suggesting a mechanism underlying the phenotype. Conclusion: Epigenetic silencing of a large number of potential tumour suppressor genes in YSTs might explain why they exhibit a more aggressive natural history than germinomas and silencing of genes associated with Caspase-8-dependent cell death might explain the relative resistance of YSTs to conventional therapy. PMID:21712824

Methylator phenotype of malignant germ cell tumours in children identifies strong candidates for chemotherapy resistance.

PubMed

Jeyapalan, J N; Noor, D A Mohamed; Lee, S-H; Tan, C L; Appleby, V A; Kilday, J P; Palmer, R D; Schwalbe, E C; Clifford, S C; Walker, D A; Murray, M J; Coleman, N; Nicholson, J C; Scotting, P J

2011-08-09

Yolk sac tumours (YSTs) and germinomas are the two major pure histological subtypes of germ cell tumours. To date, the role of DNA methylation in the aetiology of this class of tumour has only been analysed in adult testicular forms and with respect to only a few genes. A bank of paediatric tumours was analysed for global methylation of LINE-1 repeat elements and global methylation of regulatory elements using GoldenGate methylation arrays. Both germinomas and YSTs exhibited significant global hypomethylation of LINE-1 elements. However, in germinomas, methylation of gene regulatory regions differed little from control samples, whereas YSTs exhibited increased methylation at a large proportion of the loci tested, showing a 'methylator' phenotype, including silencing of genes associated with Caspase-8-dependent apoptosis. Furthermore, we found that the methylator phenotype of YSTs was coincident with higher levels of expression of the DNA methyltransferase, DNA (cytosine-5)-methyltransferase 3B, suggesting a mechanism underlying the phenotype. Epigenetic silencing of a large number of potential tumour suppressor genes in YSTs might explain why they exhibit a more aggressive natural history than germinomas and silencing of genes associated with Caspase-8-dependent cell death might explain the relative resistance of YSTs to conventional therapy.

Arsenic-induced malignant transformation of human keratinocytes: Involvement of Nrf2

PubMed Central

Pi, Jingbo; Diwan, Bhalchandra A.; Sun, Yang; Liu, Jie; Qu, Wei; He, Yuying; Styblo, Miroslav; Waalkes, Michael P.

2009-01-01

Arsenic is a well-known human skin carcinogen but the underlying mechanisms of carcinogenesis are unclear. Transcription factor Nrf2-mediated antioxidant response represents a critical cellular defense mechanism, and emerging data suggest that constitutive activation of Nrf2 contributes to malignant phenotype. In the present study when an immortalized, non-tumorigenic human keratinocyte cell line (HaCaT) was continuously exposed to environmentally relevant level of inorganic arsenite (100 nM) for 28 weeks, malignant transformation occurred as evidenced by the formation of highly aggressive squamous cell carcinoma after inoculation into nude mice. To investigate the mechanisms involved, a broad array of biomarkers for transformation were assessed in these arsenic-transformed cells (termed As-TM). In addition to increased secretion of matrix metalloproteinase-9 (MMP-9), a set of markers for squamous differentiation and skin keratinization, including keratin-1, keratin-10, involucrin, and loricrin, were significantly elevated in As-TM cells. Furthermore, As-TM cells showed increased intracellular glutathione, elevated expression of Nrf2 and its target genes, as well as generalized apoptotic resistance. In contrast to increased basal Nrf2 activity in As-TM cells, a diminished Nrf2-mediated antioxidant response induced by acute exposure to high dose of arsenite or tert-butyl hydroxyquinone occurred. The findings that multiple biomarkers for malignant transformation observed in As-TM cells, including MMP-9 and cytokeratins, are potentially regulated by Nrf2 suggest constitutive Nrf2 activation may be involved in arsenic carcinogenesis of skin. The weakened Nrf2 activation in response to oxidative stressors observed in As-TM cells, coupled with acquired apoptotic resistance, would potentially have increased the likelihood of transmittable oxidative DNA damage and fixation of mutational/DNA damage events. PMID:18572023

Arsenicals produce stable progressive changes in DNA methylation patterns that are linked to malignant transformation of immortalized urothelial cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jensen, Taylor J.; Arizona Cancer Center, University of Arizona, Tucson, AZ 85724; Novak, Petr

2009-12-01

Aberrant DNA methylation participates in carcinogenesis and is a molecular hallmark of a tumor cell. Tumor cells generally exhibit a redistribution of DNA methylation resulting in global hypomethylation with regional hypermethylation; however, the speed in which these changes emerge has not been fully elucidated and may depend on the temporal location of the cell in the path from normal, finite lifespan to malignant transformation. We used a model of arsenical-induced malignant transformation of immortalized human urothelial cells and DNA methylation microarrays to examine the extent and temporal nature of changes in DNA methylation that occur during the transition from immortalmore » to malignantly transformed. Our data presented herein suggest that during arsenical-induced malignant transformation, aberrant DNA methylation occurs non-randomly, progresses gradually at hundreds of gene promoters, and alters expression of the associated gene, and these changes are coincident with the acquisition of malignant properties, such as anchorage independent growth and tumor formation in immunocompromised mice. The DNA methylation changes appear stable, since malignantly transformed cells removed from the transforming arsenical exhibited no reversion in DNA methylation levels, associated gene expression, or malignant phenotype. These data suggest that arsenicals act as epimutagens and directly link their ability to induce malignant transformation to their actions on the epigenome.« less

Keratosis of unknown significance and leukoplakia: a preliminary study.

PubMed

Woo, Sook-Bin; Grammer, Rebecca L; Lerman, Mark A

2014-12-01

The objectives were to (1) determine the frequency of specific diagnoses in a series of white lesions, and (2) describe the nature of keratotic lesions that are neither reactive nor dysplastic. White lesions were analyzed and diagnosed as reactive keratoses, dysplastic/malignant, or keratoses of unknown significance (KUS). Of the 1251 specimens that were evaluated, 703 met criteria for inclusion, and approximately 75% were reactive, 10% dysplastic/malignant, and 14% KUS. Excluding reactive keratoses, 43% were dysplastic/malignant and 57% were KUS. Reactive keratoses were the most common white lesions followed by lichen planus. Dysplastic/malignant lesions constituted almost 50% of all true leukoplakias. KUS constituted the remaining cases and do not show typical reactive histopathology as well as clear dysplasia. They may represent evolving or devolving reactive keratoses but may also represent the very earliest dysplasia phenotype. Clinical findings may be helpful in differentiating the two. Copyright © 2014 Elsevier Inc. All rights reserved.

Constitutional Trisomy 8 Mosaicism with Persistent Macrocytosis.

PubMed

Altıner, Şule; Kutlay, Nüket Y; İlhan, Osman

2016-01-01

Constitutional trisomy 8 mosaicism (CT8M) is a rare chromosomal abnormality. The phenotype varies from normal features to severe malformations. CT8M increases the risk of developing leukemia and myelodysplastic syndrome. As CT8M is very rare, its diagnosis can easily be overlooked, especially in cases with mild phenotypes. Here, we report the diagnostic process of a 40-year-old female patient with CT8M and discuss the importance of follow-up in monitoring for hematological malignancies. © 2016 S. Karger AG, Basel.

[Hematopoietic stem cell transplantation. Indications, foundations and perspective].

PubMed

Buchholz, S; Ganser, A

2009-05-01

The hematopoietic stem cell transplantation (HSCT) has become a standard therapy for many inherited and acquired disorders of the bone marrow and immune system. Autologous HSCT is mainly done as part of the primary therapy in multiple myeloma and as part of relapse therapy in malignant lymphoma. In contrast, allogeneic HSCT is predominantly performed in patients with acute leukemias. The selection process for allogeneic HSCT takes disease-specific as well as patient-specific factors into account. Risk factors which can predict for poor response to chemotherapy can now be identified in acute myeloid as well as lymphoid leukemia, based on phenotype, cytogenetics, molecular genetics and response to therapy. In these patients allogeneic HSCT can improve overall survival from 0-20% to 30-60%. New conditioning protocols have now raised the upper age limit for transplantation to 70 years. In elderly patients the selection of patients based on absence of comorbidities becomes especially important. The increasing number of long-term survivors requires knowledge of organ-specific late toxicities including secondary malignancies.

Inhibitors of Rho kinase (ROCK) signaling revert the malignant phenotype of breast cancer cells in 3D context.

PubMed

Matsubara, Masahiro; Bissell, Mina J

2016-05-31

Loss of polarity and quiescence along with increased cellular invasiveness are associated with breast tumor progression. ROCK plays a central role in actin-cytoskeletal rearrangement. We used physiologically relevant 3D cultures of nonmalignant and cancer cells in gels made of laminin-rich extracellular matrix, to investigate ROCK function. Whereas expression levels of ROCK1 and ROCK2 were elevated in cancer cells compared to nonmalignant cells, this was not observed in 2D cultures. Malignant cells showed increased phosphorylation of MLC, corresponding to disorganized F-actin. Inhibition of ROCK signaling restored polarity, decreased disorganization of F-actin, and led to reduction of proliferation. Inhibition of ROCK also decreased EGFR and Integrinβ1 levels, and consequently suppressed activation of Akt, MAPK and FAK as well as GLUT3 and LDHA levels. Again, ROCK inhibition did not inhibit these molecules in 2D. A triple negative breast cancer cell line, which lacks E-cadherin, had high levels of ROCK but was less sensitive to ROCK inhibitors. Exogenous overexpression of E-cadherin, however, rendered these cells strikingly sensitive to ROCK inhibition. Our results add to the growing literature that demonstrate the importance of context and tissue architecture in determining not only regulation of normal and malignant phenotypes but also drug response.

Inhibitors of Rho kinase (ROCK) signaling revert the malignant phenotype of breast cancer cells in 3D context

PubMed Central

Matsubara, Masahiro; Bissell, Mina J.

2016-01-01

Loss of polarity and quiescence along with increased cellular invasiveness are associated with breast tumor progression. ROCK plays a central role in actin-cytoskeletal rearrangement. We used physiologically relevant 3D cultures of nonmalignant and cancer cells in gels made of laminin-rich extracellular matrix, to investigate ROCK function. Whereas expression levels of ROCK1 and ROCK2 were elevated in cancer cells compared to nonmalignant cells, this was not observed in 2D cultures. Malignant cells showed increased phosphorylation of MLC, corresponding to disorganized F-actin. Inhibition of ROCK signaling restored polarity, decreased disorganization of F-actin, and led to reduction of proliferation. Inhibition of ROCK also decreased EGFR and Integrinβ1 levels, and consequently suppressed activation of Akt, MAPK and FAK as well as GLUT3 and LDHA levels. Again, ROCK inhibition did not inhibit these molecules in 2D. A triple negative breast cancer cell line, which lacks E-cadherin, had high levels of ROCK but was less sensitive to ROCK inhibitors. Exogenous overexpression of E-cadherin, however, rendered these cells strikingly sensitive to ROCK inhibition. Our results add to the growing literature that demonstrate the importance of context and tissue architecture in determining not only regulation of normal and malignant phenotypes but also drug response. PMID:27203208

Influence of BCR/ABL fusion proteins on the course of Ph leukemias.

PubMed

Telegeev, Gennady D; Dubrovska, Anna N; Dybkov, Mykhaylo V; Maliuta, Stanislav S

2004-01-01

The hallmark of chronic myeloid leukemia (CML) and a subset of acute lymphoblastic leukemia (ALL) is the presence of the Philadelphia chromosome as a result of the t(9;22) translocation. This gene rearrangement results in the production of a novel oncoprotein, BCR/ABL, a constitutively active tyrosine kinase. There is compelling evidence that the malignant transformation by BCR/ABL is critically dependent on its Abl tyrosine kinase activity. Also the bcr part of the hybrid gene takes part in realization of the malignant phenotype. We supposed that additional mutations accumulate in this region of the BCR/ABL oncogene during the development of the malignant blast crisis in CML patients. In ALL patients having p210 fusion protein the mutations were supposed to be preexisting. Sequencing of PCR product of the BCR/ABL gene (Dbl, PH region) showed that along with single-nucleotide substitutions other mutations, mostly deletions, had occurred. In an ALL patient a deletion of the 5th exon was detected. The size of the deletions varied from 36 to 220 amino acids. For one case of blast crisis of CML changes in the character of actin organization were observed. Taking into account the functional role of these domains in the cell an etiological role of such mutations on the disease phenotype and leukemia progression is plausible.

Promotion of malignant phenotype after disruption of the three-dimensional structure of cultured spheroids from colorectal cancer.

PubMed

Piulats, Jose M; Kondo, Jumpei; Endo, Hiroko; Ono, Hiromasa; Hagihara, Takeshi; Okuyama, Hiroaki; Nishizawa, Yasuko; Tomita, Yasuhiko; Ohue, Masayuki; Okita, Kouki; Oyama, Hidejiro; Bono, Hidemasa; Masuko, Takashi; Inoue, Masahiro

2018-03-23

Individual and small clusters of cancer cells may detach from the edges of a main tumor and invade vessels, which can act as the origin of metastasis; however, the mechanism for this phenomenon is not well understood. Using cancer tissue-originated spheroids, we studied whether disturbing the 3D architecture of cancer spheroids can provoke the reformation process and progression of malignancy. We developed a mechanical disruption method to achieve homogenous disruption of the spheroids while maintaining cell-cell contact. After the disruption, 9 spheroid lines from 9 patient samples reformed within a few hours, and 3 of the 9 lines exhibited accelerated spheroid growth. Marker expression, spheroid forming capacity, and tumorigenesis indicated that stemness increased after spheroid disruption. In addition, the spheroid forming capacity increased in 6 of 11 spheroid lines. The disruption signature determined by gene expression profiling supported the incidence of remodeling and predicted the prognosis of patients with colorectal cancer. Furthermore, WNT and HER3 signaling were increased in the reformed spheroids, and suppression of these signaling pathways attenuated the increased proliferation and stemness after the disruption. Overall, the disruption and subsequent reformation of cancer spheroids promoted malignancy-related phenotypes through the activation of the WNT and ERBB pathways.

Promotion of malignant phenotype after disruption of the three-dimensional structure of cultured spheroids from colorectal cancer

PubMed Central

Endo, Hiroko; Ono, Hiromasa; Hagihara, Takeshi; Okuyama, Hiroaki; Nishizawa, Yasuko; Tomita, Yasuhiko; Ohue, Masayuki; Okita, Kouki; Oyama, Hidejiro; Bono, Hidemasa; Masuko, Takashi; Inoue, Masahiro

2018-01-01

Individual and small clusters of cancer cells may detach from the edges of a main tumor and invade vessels, which can act as the origin of metastasis; however, the mechanism for this phenomenon is not well understood. Using cancer tissue-originated spheroids, we studied whether disturbing the 3D architecture of cancer spheroids can provoke the reformation process and progression of malignancy. We developed a mechanical disruption method to achieve homogenous disruption of the spheroids while maintaining cell–cell contact. After the disruption, 9 spheroid lines from 9 patient samples reformed within a few hours, and 3 of the 9 lines exhibited accelerated spheroid growth. Marker expression, spheroid forming capacity, and tumorigenesis indicated that stemness increased after spheroid disruption. In addition, the spheroid forming capacity increased in 6 of 11 spheroid lines. The disruption signature determined by gene expression profiling supported the incidence of remodeling and predicted the prognosis of patients with colorectal cancer. Furthermore, WNT and HER3 signaling were increased in the reformed spheroids, and suppression of these signaling pathways attenuated the increased proliferation and stemness after the disruption. Overall, the disruption and subsequent reformation of cancer spheroids promoted malignancy-related phenotypes through the activation of the WNT and ERBB pathways. PMID:29662620

CHSY1 promotes aggressive phenotypes of hepatocellular carcinoma cells via activation of the hedgehog signaling pathway.

PubMed

Liu, Chiung-Hui; Lan, Chyn-Tair; Chou, Jui-Feng; Tseng, To-Jung; Liao, Wen-Chieh

2017-09-10

Abnormal expression of chondroitin sulfate has been found in many types of cancer, while its biological functions in hepatocellular carcinoma (HCC) progression remain uninvestigated. Here, we report that chondroitin sulfate synthase 1 (CHSY1), the enzyme that mediates the polymerization step of chondroitin sulfate, is a critical mediator of malignant character in HCC that acts via modulating the activity of the hedgehog signaling. CHSY1 was up-regulated frequently in HCC where these events were associated with worse histologic grade and poor survival. Enforced expression of CHSY1 was sufficient to enhance cell growth, migration, invasion, and epithelial-mesenchymal transition, whereas silencing of CHSY1 suppressed these malignant phenotypes. Mechanistic investigations revealed that the increase of cell surface chondroitin sulfate by CHSY1 promoted sonic hedgehog binding and signaling. Inhibiting hedgehog pathway with vismodegib decreased CHSY1-induced migration, invasion, and lung metastasis of HCC cells, establishing the critical role of hedgehog signaling in mediating the effects of CHSY1 expression. Together, our results indicate that CHSY1 overexpression in HCC contributes to the malignant behaviors in cancer cells, we provide novel insights into the significance of chondroitin sulfate in hedgehog signaling and HCC pathogenesis. Copyright © 2017 Elsevier B.V. All rights reserved.

Loss of Asxl1 leads to myelodysplastic syndrome-like disease in mice.

PubMed

Wang, Jiapeng; Li, Zhaomin; He, Yongzheng; Pan, Feng; Chen, Shi; Rhodes, Steven; Nguyen, Lihn; Yuan, Jin; Jiang, Li; Yang, Xianlin; Weeks, Ophelia; Liu, Ziyue; Zhou, Jiehao; Ni, Hongyu; Cai, Chen-Leng; Xu, Mingjiang; Yang, Feng-Chun

2014-01-23

ASXL1 is mutated/deleted with high frequencies in multiple forms of myeloid malignancies, and its alterations are associated with poor prognosis. De novo ASXL1 mutations cause Bohring-Opitz syndrome characterized by multiple congenital malformations. We show that Asxl1 deletion in mice led to developmental abnormalities including dwarfism, anophthalmia, and 80% embryonic lethality. Surviving Asxl1(-/-) mice lived for up to 42 days and developed features of myelodysplastic syndrome (MDS), including dysplastic neutrophils and multiple lineage cytopenia. Asxl1(-/-) mice had a reduced hematopoietic stem cell (HSC) pool, and Asxl1(-/-) HSCs exhibited decreased hematopoietic repopulating capacity, with skewed cell differentiation favoring granulocytic lineage. Asxl1(+/-) mice also developed mild MDS-like disease, which could progress to MDS/myeloproliferative neoplasm, demonstrating a haploinsufficient effect of Asxl1 in the pathogenesis of myeloid malignancies. Asxl1 loss led to an increased apoptosis and mitosis in Lineage(-)c-Kit(+) (Lin(-)c-Kit(+)) cells, consistent with human MDS. Furthermore, Asxl1(-/-) Lin(-)c-Kit(+) cells exhibited decreased global levels of H3K27me3 and H3K4me3 and altered expression of genes regulating apoptosis (Bcl2, Bcl2l12, Bcl2l13). Collectively, we report a novel ASXL1 murine model that recapitulates human myeloid malignancies, implying that Asxl1 functions as a tumor suppressor to maintain hematopoietic cell homeostasis. Future work is necessary to clarify the contribution of microenvironment to the hematopoietic phenotypes observed in the constitutional Asxl1(-/-) mice.

Immunophenotypic analysis of the Kaposi sarcoma herpesvirus (KSHV; HHV-8)-infected B cells in HIV+ multicentric Castleman disease (MCD).

PubMed

Chadburn, A; Hyjek, E M; Tam, W; Liu, Y; Rengifo, T; Cesarman, E; Knowles, D M

2008-11-01

Kaposi sarcoma herpesvirus (KSHV) is aetiologically related to Kaposi sarcoma, classical and extracavitary primary effusion lymphoma (PEL; EC-PEL) and multicentric Castleman disease (MCD), entities preferentially occurring in HIV-infected individuals. Characterization of HIV-associated PELs/EC-PELs suggests that the KSHV-infected malignant cells originate from a pre-terminal stage of B-cell differentiation. However, only limited phenotypic studies have been performed on HIV+ MCD, including for PR domain containing 1 with zinc finger domain/B lymphocyte-induced maturation protein 1 (PRDM1/BLIMP1), a key regulator of terminal B-cell differentiation. The aim was to characterize KSHV-infected cells in 17 cases of HIV+ MCD. Double immunohistochemistry and immunohistochemistry-in situ hybridization were used to characterize the KSHV-infected cells in MCD; the results were compared with the phenotypic profiles of 39 PELs/EC-PELs and seven PEL cell lines. Whereas the immunophenotype of KSHV-infected cells in MCD and malignant KSHV+ PEL cells was similar (PAX5, Bcl-6-; PRDM1/BLIMP1, IRF4/MUM1+; Ki67+), the MCD KSHV-infected cells differed, as they expressed OCT2, cytoplasmic lambda immunoglobulin; variably expressed CD27; lacked CD138; and were Epstein-Barr virus negative. Although both PEL and MCD originate from KSHV-infected pre-terminally differentiated B cells, these findings, with previously reported genetic studies, indicate HIV+ MCD may arise from extrafollicular B cells, whereas PELs may originate from cells that have traversed the germinal centre.

Senescence-Associated Secretory Phenotypes Reveal Cell-Nonautonomous Functions of Oncogenic RAS and the p53 Tumor Suppressor

DOE Office of Scientific and Technical Information (OSTI.GOV)

Coppé, Jean-Philippe; Patil, Christopher; Rodier, Francis

2008-10-24

Cellular senescence suppresses cancer by arresting cell proliferation, essentially permanently, in response to oncogenic stimuli, including genotoxic stress. We modified the use of antibody arrays to provide a quantitative assessment of factors secreted by senescent cells. We show that human cells induced to senesce by genotoxic stress secrete myriad factors associated with inflammation and malignancy. This senescence-associated secretory phenotype (SASP) developed slowly over several days and only after DNA damage of sufficient magnitude to induce senescence. Remarkably similar SASPs developed in normal fibroblasts, normal epithelial cells, and epithelial tumor cells after genotoxic stress in culture, and in epithelial tumor cellsmore » in vivo after treatment of prostate cancer patients with DNA-damaging chemotherapy. In cultured premalignant epithelial cells, SASPs induced an epithelial-mesenchyme transition and invasiveness, hallmarks of malignancy, by a paracrine mechanism that depended largely on the SASP factors interleukin (IL)-6 and IL-8. Strikingly, two manipulations markedly amplified, and accelerated development of, the SASPs: oncogenic RAS expression, which causes genotoxic stress and senescence in normal cells, and functional loss of the p53 tumor suppressor protein. Both loss of p53 and gain of oncogenic RAS also exacerbated the promalignant paracrine activities of the SASPs. Our findings define a central feature of genotoxic stress-induced senescence. Moreover, they suggest a cell-nonautonomous mechanism by which p53 can restrain, and oncogenic RAS can promote, the development of age-related cancer by altering the tissue microenvironment.« less

CD147, CD44, and the Epidermal Growth Factor Receptor (EGFR) Signaling Pathway Cooperate to Regulate Breast Epithelial Cell Invasiveness*

PubMed Central

Grass, G. Daniel; Tolliver, Lauren B.; Bratoeva, Momka; Toole, Bryan P.

2013-01-01

The immunoglobulin superfamily glycoprotein CD147 (emmprin; basigin) is associated with an invasive phenotype in various types of cancers, including malignant breast cancer. We showed recently that up-regulation of CD147 in non-transformed, non-invasive breast epithelial cells is sufficient to induce an invasive phenotype characterized by membrane type-1 matrix metalloproteinase (MT1-MMP)-dependent invadopodia activity (Grass, G. D., Bratoeva, M., and Toole, B. P. (2012) Regulation of invadopodia formation and activity by CD147. J. Cell Sci. 125, 777–788). Here we found that CD147 induces breast epithelial cell invasiveness by promoting epidermal growth factor receptor (EGFR)-Ras-ERK signaling in a manner dependent on hyaluronan-CD44 interaction. Furthermore, CD147 promotes assembly of signaling complexes containing CD147, CD44, and EGFR in lipid raftlike domains. We also found that oncogenic Ras regulates CD147 expression, hyaluronan synthesis, and formation of CD147-CD44-EGFR complexes, thus forming a positive feedback loop that may amplify invasiveness. Last, we showed that malignant breast cancer cells are heterogeneous in their expression of surface-associated CD147 and that high levels of membrane CD147 correlate with cell surface EGFR and CD44 levels, activated EGFR and ERK1, and activated invadopodia. Future studies should evaluate CD147 as a potential therapeutic target and disease stratification marker in breast cancer. PMID:23888049

Report of a patient with a constitutional missense mutation in SMARCB1, Coffin-Siris phenotype, and schwannomatosis.

PubMed

Gossai, Nathan; Biegel, Jaclyn A; Messiaen, Ludwine; Berry, Susan A; Moertel, Christopher L

2015-12-01

We report a patient with a constitutional missense mutation in SMARCB1, Coffin-Siris Syndrome (CSS), and schwannomatosis. CSS is a rare congenital syndrome with characteristic clinical findings. This thirty-three-year-old man was diagnosed early in life with the constellation of moderate intellectual disability, hypotonia, mild microcephaly, coarse facies, wide mouth with full lips, hypoplasia of the digits, and general hirsutism. At age 26, he was found to have schwannomatosis after presenting with acute spinal cord compression. Blood and tissue analysis of multiple subsequent schwannoma resections revealed a germline missense mutation of SMARCB1, acquired loss of 22q including SMARCB1 and NF2 and mutation of the remaining NF2 wild-type allele-thus completing the four-hit, three-event mechanism associated with schwannomatosis. Variations in five genes have been associated with the Coffin-Siris phenotype: ARID1A, ARID1B, SMARCA4, SMARCB1, and SMARCE1. Of these genes, SMARCB1 has a well-established association with schwannomatosis and malignancy. This is the first report of a patient with a constitutional missense mutation of SMARCB1 resulting in CSS and subsequent development of schwannomatosis. This finding demonstrates that a SMARCB1 mutation may be the initial "hit" (constitutional) for a genetic disorder with subsequent risk of developing schwannomas and other malignancies, and raises the possibility that other patients with switch/sucrose non-fermenting (SWI/SNF) mutations may be at increased risk for tumors. © 2015 Wiley Periodicals, Inc.

Hereditary Nonpolyposis Colorectal Cancer and Cancer Syndromes: Recent Basic and Clinical Discoveries

PubMed Central

Chen, Erbao; Xu, Xiaojing

2018-01-01

Approximately one-third of individuals diagnosed with colorectal cancer have a family history of cancer, suggesting that CRCs may result from a heritable component. Despite the availability of current gene-identification techniques, only 5% of all CRCs emerge from well-identifiable inherited causes for predisposition, including polyposis and nonpolyposis syndromes. Hereditary nonpolyposis colorectal cancer represents a large proportion of cases, and robustly affected patients are at increased risk for early onset, synchronous, and metachronous colorectal malignancies and extracolonic malignancies. HNPCC encompasses several cancer syndromes, such as Lynch syndrome, Lynch-like syndrome, and familial colorectal cancer type X, which have remarkable clinical presentations and overlapping genetic profiles that make clinical diagnosis a challenging task. Therefore, distinguishing between the HNPCC disorders is crucial for physicians as an approach to tailor different recommendations for patients and their at-risk family members according to the risks for colonic and extracolonic cancer associated with each syndrome. Identification of these potential patients through epidemiological characteristics and new genetic testing can estimate the individual risk, which informs appropriate cancer screening, surveillance, and/or treatment strategies. In the past three years, many appealing and important advances have been made in our understanding of the relationship between HNPCC and CRC-associated syndromes. The knowledge from the genetic profile of cancer syndromes and unique genotype-phenotype profiles in the different syndromes has changed our cognition. Therefore, this review presents and discusses HNPCC and several common nonpolyposis syndromes with respect to molecular phenotype, histopathologic features, and clinical presentation. PMID:29849630

Through the glass darkly: intraepithelial neoplasia, top-down differentiation and the road to pelvic serous cancer

PubMed Central

Crum, Christopher P; Herfs, Michael; Ning, Gang; Bijron, Jonathan G.; Howitt, Brooke E.; Jimenez, Cynthia A.; Hanamornroongruang, Suchanan; McKeon, Frank D.; Xian, Wa

2014-01-01

The origins of pelvic high grade serous cancer (HGSC) have become a subject of intense scrutiny in view of proposals to reduce the incidence of the disease via opportunistic salpingectomy in healthy women. Accumulated data implicates the fimbria as a site of origin and descriptive molecular pathology and experimental evidence strongly support a serous carcinogenic sequence in the fallopian tube. Both direct and indirect ("surrogate") precursors suggest the benign tube undergoes important biologic changes after menopause, acquiring abnormalities in gene expression that are shared with malignancy. However, the tube can be linked to only some HGSCs, recharging arguments that nearby peritoneum/ovarian surface epithelium (POSE) also hosts progenitors to this malignancy. A major sticking point is the difference in immunophenotype between POSE and Müllerian epithelium, essentially requiring mesothelial to Müllerian differentiation prior to or during malignant transformation to HGSC. However, there is emerging evidence that an embryonic or progenitor phenotype exists in the adult female genital tract with the capacity to differentiate, normally or during neoplastic transformation. Recently, a putative cell of origin to cervical cancer has been identified in the squamo-columnar (SC) junction, projecting a model whereby embryonic progenitors give rise to immuno-phenotypically distinct neoplastic progeny under stromal influences via "top down" differentiation. A similar pattern of differentiation is implied in the endometrium and the juxtaposition of disparate epithelial immuno-phenotypes (POSE and underlying Müllerian inclusions) recapitulates this in the ovary. While a sudden mesothelial-Mullerian transition remains to be proven, it would explain the rapid evolution, short asymptomatic interval, and absence of a defined epithelial starting point in many HGSCs. Resolving this question will be critical to both expectations from prophylactic salpingectomy and future approaches to pelvic serous cancer prevention. PMID:24030860

Downregulation of Bit1 expression promotes growth, anoikis resistance, and transformation of immortalized human bronchial epithelial cells via Erk activation-dependent suppression of E-cadherin.

PubMed

Yao, Xin; Gray, Selena; Pham, Tri; Delgardo, Mychael; Nguyen, An; Do, Stephen; Ireland, Shubha Kale; Chen, Renwei; Abdel-Mageed, Asim B; Biliran, Hector

2018-01-01

The mitochondrial Bit1 protein exerts tumor-suppressive function in NSCLC through induction of anoikis and inhibition of EMT. Having this dual tumor suppressive effect, its downregulation in the established human lung adenocarcinoma A549 cell line resulted in potentiation of tumorigenicity and metastasis in vivo. However, the exact role of Bit1 in regulating malignant growth and transformation of human lung epithelial cells, which are origin of most forms of human lung cancers, has not been examined. To this end, we have downregulated the endogenous Bit1 expression in the immortalized non-tumorigenic human bronchial epithelial BEAS-2B cells. Knockdown of Bit1 enhanced the growth and anoikis insensitivity of BEAS-2B cells. In line with their acquired anoikis resistance, the Bit1 knockdown BEAS-2B cells exhibited enhanced anchorage-independent growth in vitro but failed to form tumors in vivo. The loss of Bit1-induced transformed phenotypes was in part attributable to the repression of E-cadherin expression since forced exogenous E-cadherin expression attenuated the malignant phenotypes of the Bit1 knockdown cells. Importantly, we show that the loss of Bit1 expression in BEAS-2B cells resulted in increased Erk activation, which functions upstream to promote TLE1-mediated transcriptional repression of E-cadherin. These collective findings indicate that loss of Bit1 expression contributes to the acquisition of malignant phenotype of human lung epithelial cells via Erk activation-induced suppression of E-cadherin expression. Copyright © 2017 Elsevier Inc. All rights reserved.

Correlation of tumor-infiltrating lymphocytes to histopathological features and molecular phenotypes in canine mammary carcinoma: A morphologic and immunohistochemical morphometric study.

PubMed

Kim, Jong-Hyuk; Chon, Seung-Ki; Im, Keum-Soon; Kim, Na-Hyun; Sur, Jung-Hyang

2013-04-01

Abundant lymphocyte infiltration is frequently found in canine malignant mammary tumors, but the pathological features and immunophenotypes associated with the infiltration remain to be elucidated. The aim of the present study was to evaluate the relationship between lymphocyte infiltration, histopathological features, and molecular phenotype in canine mammary carcinoma (MC). The study was done with archived formalin-fixed, paraffin-embedded samples (n = 47) by histologic and immunohistochemical methods. The degree of lymphocyte infiltration was evaluated by morphologic analysis, and the T- and B-cell populations as well as the T/B-cell ratio were evaluated by morphometric analysis; results were compared with the histologic features and molecular phenotypes. The degree of lymphocyte infiltration was significantly higher in MCs with lymphatic invasion than in those without lymphatic invasion (P < 0.0001) and in tumors of high histologic grade compared with those of lower histologic grade (P = 0.045). Morphometric analysis showed a larger amount of T-cells and B-cells in MCs with a higher histologic grade and lymphatic invasion, but the T/B ratio did not change. Lymphocyte infiltration was not associated with histologic type or molecular phenotype, as assessed from the immunohistochemical expression of epidermal growth factor receptor 2, estrogen receptor, cytokeratin 14, and p63. Since intense lymphocyte infiltration was associated with aggressive histologic features, lymphocytes may be important for tumor aggressiveness and greater malignant behavior in the tumor microenvironment.

Arylamine N-acetyltransferase (NAT2) mutations and their allelic linkage in unrelated caucasian individuals: Correlation with phenotypic activity

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cascorbi, I.; Drakoulis, N.; Brockmoeller, J.

1995-09-01

The polymorphic arylamine N-acetyltransferase (NAT2; EC2.3.1.5) is supposed to be a susceptibility factor for several drug side effects and certain malignancies. A group of 844 unrelated German subjects was genotyped for their acetylation type, and 563 of them were also phenotyped. Seven mutations of the NAT2 gene were evaluated by allele-specific PCR (mutation 341C to T) and PCR-RFLP for mutations at nt positions 191, 282, 481, 590, 803, and 857. From the mutation pattern eight different alleles, including the wild type coding for rapid acetylation and seven alleles coding for slow phenotype, were determined. Four hundred ninety-seven subjects had amore » genotype of slow acetylation (58.9%; 95% confidence limits 55.5%-62.2%). Phenotypic acetylation capacity was expressed as the ratio of 5-acetylamino-6-formylamino-3-methyluracil and 1-methylxanthine in urine after caffeine intake. Some 6.7% of the cases deviated in genotype and phenotype, but sequencing DNA of these probands revealed no new mutations. Furthermore, linkage pattern of the mutations was always confirmed, as tested in 533 subjects. In vivo acetylation capacity of homozygous wild-type subjects (NAT2{sup *}4/{sup *}4) was significantly higher than in heterozygous genotypes (P = .001). All mutant alleles showed low in vivo acetylation capacities, including the previously not-yet-defined alleles {sup *}5A, {sup *}5C, and {sup *}13. Moreover, distinct slow genotypes differed significantly among each other, as reflected in lower acetylation capacity of {sup *}6A, {sup *}7B, and {sup *}13 alleles than the group of {sup *}5 alleles. The study demonstrated differential phenotypic activity of various NAT2 genes and gives a solid basis for clinical and molecular-epidemiological investigations. 34 refs., 4 figs., 7 tabs.« less

Molecular neuro-oncology and development of targeted therapeutic strategies for brain tumors. Part 1: Growth factor and Ras signaling pathways.

PubMed

Newton, Herbert B

2003-10-01

Brain tumors are a diverse group of malignancies that remain refractory to conventional treatment approaches, including radiotherapy and cytotoxic chemotherapy. Molecular neuro-oncology has now begun to clarify the transformed phenotype of brain tumors and identify oncogenic pathways that may be amenable to targeted therapy. Growth factor signaling pathways are often upregulated in brain tumors and may contribute to oncogenesis through autocrine and paracrine mechanisms. Excessive growth factor receptor stimulation can also lead to overactivity of the Ras signaling pathway, which is frequently aberrant in brain tumors. Receptor tyrosine kinase inhibitors, antireceptor monoclonal antibodies and antisense oligonucleotides are targeted approaches under investigation as methods to regulate aberrant growth factor signaling pathways in brain tumors. Several receptor tyrosine kinase inhibitors, including imatinib mesylate (Gleevec), gefitinib (Iressa) and erlotinib (Tarceva), have entered clinical trials for high-grade glioma patients. Farnesyl transferase inhibitors, such as tipifarnib (Zarnestra), which impair processing of proRas and inhibit the Ras signaling pathway, have also entered clinical trials for patients with malignant gliomas. Further development of targeted therapies and evaluation of these new agents in clinical trials will be needed to improve survival and quality of life of patients with brain tumors.

Six1 expands the mouse mammary epithelial stem/progenitor cell pool and induces mammary tumors that undergo epithelial-mesenchymal transition

PubMed Central

McCoy, Erica L.; Iwanaga, Ritsuko; Jedlicka, Paul; Abbey, Nee-Shamo; Chodosh, Lewis A.; Heichman, Karen A.; Welm, Alana L.; Ford, Heide L.

2009-01-01

Six1 is a developmentally regulated homeoprotein with limited expression in most normal adult tissues and frequent misexpression in a variety of malignancies. Here we demonstrate, using a bitransgenic mouse model, that misexpression of human Six1 in adult mouse mammary gland epithelium induces tumors of multiple histological subtypes in a dose-dependent manner. The neoplastic lesions induced by Six1 had an in situ origin, showed diverse differentiation, and exhibited progression to aggressive malignant neoplasms, as is often observed in human carcinoma of the breast. Strikingly, the vast majority of Six1-induced tumors underwent an epithelial-mesenchymal transition (EMT) and expressed multiple targets of activated Wnt signaling, including cyclin D1. Interestingly, Six1 and cyclin D1 coexpression was found to frequently occur in human breast cancers and was strongly predictive of poor prognosis. We further show that Six1 promoted a stem/progenitor cell phenotype in the mouse mammary gland and in Six1-driven mammary tumors. Our data thus provide genetic evidence for a potent oncogenic role for Six1 in mammary epithelial neoplasia, including promotion of EMT and stem cell–like features. PMID:19726883

Tumor progression: chance and necessity in Darwinian and Lamarckian somatic (mutationless) evolution.

PubMed

Huang, Sui

2012-09-01

Current investigation of cancer progression towards increasing malignancy focuses on the molecular pathways that produce the various cancerous traits of cells. Their acquisition is explained by the somatic mutation theory: tumor progression is the result of a neo-Darwinian evolution in the tissue. Herein cells are the units of selection. Random genetic mutations permanently affecting these pathways create malignant cell phenotypes that are selected for in the disturbed tissue. However, could it be that the capacity of the genome and its gene regulatory network to generate the vast diversity of cell types during development, i.e., to produce inheritable phenotypic changes without mutations, is harnessed by tumorigenesis to propel a directional change towards malignancy? Here we take an encompassing perspective, transcending the orthodoxy of molecular carcinogenesis and review mechanisms of somatic evolution beyond the Neo-Darwinian scheme. We discuss the central concept of "cancer attractors" - the hidden stable states of gene regulatory networks normally not occupied by cells. Noise-induced transitions into such attractors provide a source for randomness (chance) and regulatory constraints (necessity) in the acquisition of novel expression profiles that can be inherited across cell divisions, and hence, can be selected for. But attractors can also be reached in response to environmental signals - thus offering the possibility for inheriting acquired traits that can also be selected for. Therefore, we face the possibility of non-genetic (mutation-independent) equivalents to both Darwinian and Lamarckian evolution which may jointly explain the arrow of change pointing toward increasing malignancy. Copyright © 2012 Elsevier Ltd. All rights reserved.

Characterizing cellular mechanical phenotypes with mechano-node-pore sensing

PubMed Central

Kim, Junghyun; Han, Sewoon; Lei, Andy; Miyano, Masaru; Bloom, Jessica; Srivastava, Vasudha; Stampfer, Martha M.; Gartner, Zev J.; LaBarge, Mark A.; Sohn, Lydia L.

2018-01-01

The mechanical properties of cells change with their differentiation, chronological age, and malignant progression. Consequently, these properties may be useful label-free biomarkers of various functional or clinically relevant cell states. Here, we demonstrate mechano-node-pore sensing (mechano-NPS), a multi-parametric single-cell-analysis method that utilizes a four-terminal measurement of the current across a microfluidic channel to quantify simultaneously cell diameter, resistance to compressive deformation, transverse deformation under constant strain, and recovery time after deformation. We define a new parameter, the whole-cell deformability index (wCDI), which provides a quantitative mechanical metric of the resistance to compressive deformation that can be used to discriminate among different cell types. The wCDI and the transverse deformation under constant strain show malignant MCF-7 and A549 cell lines are mechanically distinct from non-malignant, MCF-10A and BEAS-2B cell lines, and distinguishes between cells treated or untreated with cytoskeleton-perturbing small molecules. We categorize cell recovery time, ΔTr, as instantaneous (ΔTr ~ 0 ms), transient (ΔTr ≤ 40ms), or prolonged (ΔTr > 40ms), and show that the composition of recovery types, which is a consequence of changes in cytoskeletal organization, correlates with cellular transformation. Through the wCDI and cell-recovery time, mechano-NPS discriminates between sub-lineages of normal primary human mammary epithelial cells with accuracy comparable to flow cytometry, but without antibody labeling. Mechano-NPS identifies mechanical phenotypes that distinguishes lineage, chronological age, and stage of malignant progression in human epithelial cells. PMID:29780657

Disorders of dysregulated signal traffic through the RAS-MAPK pathway: phenotypic spectrum and molecular mechanisms.

PubMed

Tartaglia, Marco; Gelb, Bruce D

2010-12-01

RAS GTPases control a major signaling network implicated in several cellular functions, including cell fate determination, proliferation, survival, differentiation, migration, and senescence. Within this network, signal flow through the RAF-MEK-ERK pathway-the first identified mitogen-associated protein kinase (MAPK) cascade-mediates early and late developmental processes controlling morphology determination, organogenesis, synaptic plasticity, and growth. Signaling through the RAS-MAPK cascade is tightly controlled; and its enhanced activation represents a well-known event in oncogenesis. Unexpectedly, in the past few years, inherited dysregulation of this pathway has been recognized as the cause underlying a group of clinically related disorders sharing facial dysmorphism, cardiac defects, reduced postnatal growth, ectodermal anomalies, variable cognitive deficits, and susceptibility to certain malignancies as major features. These disorders are caused by heterozygosity for mutations in genes encoding RAS proteins, regulators of RAS function, modulators of RAS interaction with effectors, or downstream signal transducers. Here, we provide an overview of the phenotypic spectrum associated with germline mutations perturbing RAS-MAPK signaling, the unpredicted molecular mechanisms converging toward the dysregulation of this signaling cascade, and major genotype-phenotype correlations. © 2010 New York Academy of Sciences.

Post-transcriptional regulation in hematopoiesis: RNA binding proteins take control.

PubMed

de Rooij, Laura P M H; Chan, Derek C H; Keyvani Chahi, Ava; Hope, Kristin J

2018-06-13

Normal hematopoiesis is sustained through a carefully orchestrated balance between hematopoietic stem cell (HSC) self-renewal and differentiation. The functional importance of this axis is underscored by the severity of disease phenotypes initiated by abnormal HSC function, including myelodysplastic syndromes and hematopoietic malignancies. Major advances in the understanding of transcriptional regulation of primitive hematopoietic cells have been achieved, however, the post-transcriptional regulatory layer that may impinge on their behavior remains underexplored by comparison. Key players at this level include RNA binding proteins (RBPs), which execute precise and highly coordinated control of gene expression through modulation of RNA properties that include its splicing, polyadenylation, localization, degradation or translation. With the recent identification of RBPs having essential roles in regulating proliferation and cell fate decisions in other systems, there has been an increasing appreciation of the importance of post-transcriptional control at the stem cell level. Here we discuss our current understanding of RBP-driven post-transcriptional regulation in HSC, its implications for normal, perturbed and malignant hematopoiesis, as well as the most recent technological innovations aimed at RBP-RNA network characterization at the systems level. Emerging evidence highlights RBP-driven control as an underappreciated feature of primitive hematopoiesis, the greater understanding of which has important clinical implications.

The Queensland study of Melanoma: Environmental and Genetic Associations (Q-MEGA). Study design, baseline characteristics, and repeatability of phenotype and sun exposure measures

PubMed Central

Baxter, Amanda J.; Hughes, Maria Celia; Kvaskoff, Marina; Siskind, Victor; Shekar, Sri; Aitken, Joanne F.; Green, Adele C.; Duffy, David L.; Hayward, Nicholas K.; Martin, Nicholas G.; Whiteman, David C.

2013-01-01

Cutaneous malignant melanoma (CMM) is a major health issue in Queensland, Australia which has the world’s highest incidence. Recent molecular and epidemiologic studies suggest that CMM arises through multiple etiological pathways involving gene-environment interactions. Understanding the potential mechanisms leading to CMM requires larger studies than those previously conducted. This article describes the design and baseline characteristics of Q-MEGA, the Queensland study of Melanoma: Environmental and Genetic Associations, which followed-up four population-based samples of CMM patients in Queensland, including children, adolescents, men aged over 50, and a large sample of adult cases and their families, including twins. Q-MEGA aims to investigate the roles of genetic and environmental factors, and their interaction, in the etiology of melanoma. 3,471 participants took part in the follow-up study and were administered a computer-assisted telephone interview in 2002–2005. Updated data on environmental and phenotypic risk factors, and 2,777 blood samples were collected from interviewed participants as well as a subset of relatives. This study provides a large and well-described population-based sample of CMM cases with follow-up data. Characteristics of the cases and repeatability of sun exposure and phenotype measures between the baseline and the follow-up surveys, from six to 17 years later, are also described. PMID:18361720

miR-181d/MALT1 regulatory axis attenuates mesenchymal phenotype through NF-κB pathways in glioblastoma.

PubMed

Yang, Fan; Liu, Xing; Liu, Yanwei; Liu, Yuqing; Zhang, Chuanbao; Wang, Zheng; Jiang, Tao; Wang, Yongzhi

2017-06-28

The mesenchymal (MES) subtype of glioblastoma (GBM) indicated a more malignant phenotype and worse prognosis compared with their proneural (PN) counterpart. The plasticity between PN and MES transcriptome signatures provided an approach for clinical intervention. However, few miRNAs have been identified to participate in the shift between subtypes. Here, we utilized transcriptomic data and experimental evidences to prove that miR-181d was a novel regulator of NFκB signaling pathway by directly repressing MALT1, leading to induced PN markers and reduced MES genes. Functionally, ectopic expression of miR-181d suppressed GBM cell proliferation, colony formation and anchor-independent growth, as well as migration, invasion and tube formation. Moreover, miR-181d overexpression increased radio- and chemo-sensitivity for GBM cells. Rescue of MALT1 could partially reverse the effects of miR-181d in GBM malignant behaviors. Clinically, miR-181d could serve as a prognostic indicator for GBM patients. Taken together, we concluded that loss of miR-181d contributes to aggressive biological processes associated with MES phenotype via NFκB signaling, which broaden our insights into the underlying mechanisms in subtype transition and miRNA-based tailored medicine for GBM management. Copyright © 2017 Elsevier B.V. All rights reserved.

Differential effects of malignant mesothelioma cells on THP-1 monocytes and macrophages.

PubMed

Izzi, Valerio; Chiurchiù, Valerio; D'Aquilio, Fabiola; Palumbo, Camilla; Tresoldi, Ilaria; Modesti, Andrea; Baldini, Patrizia M

2009-02-01

Malignant mesothelioma (MM) is a highly fatal tumor arising from inner body membranes, whose extensive growth is facilitated by its week immunogenicity and by its ability to blunt the immune response which should arise from the huge mass of leukocytes typically infiltrating this tumor. It has been reported that the inflammatory infiltrate found in MM tissues is characterized by a high prevalence of macrophages. Thus, in this work we evaluated the ability of human MM cells to modulate the inflammatory phenotype of human THP-1 monocytes and macrophages, a widely used in vitro model of monocyte/macrophage differentiation. Furthermore, we tested the hypothesis that the exposure to MM cells could alter the differentiation of THP-1 monocytes favoring the development of alternatively activated, tumor-supporting macrophages. Our data prove for the first time that MM cells can polarize monocytes towards an altered inflammatory phenotype and macrophages towards an immunosuppressive phenotype. Moreover, we demonstrate that monocytes cocultivated with MM cells 'keep a memory' of their encounter with the tumor which influences their differentiation to macrophages. On the whole, we provide evidence that MM cells exert distinct, cell-specific effects on monocytes and macrophages. The thorough characterization of such effects may be of a crucial importance for the rational design of new immunotherapeutic protocols.

LncRNAs: the bridge linking RNA and colorectal cancer

PubMed Central

Yang, Qilian; Le, Xiaobing; Yang, Huiliang; Wang, Chenlu; Luo, Zhongyue; Xuan, Yu; Chen, Yi; Deng, Xiangbing; Xu, Lian; Feng, Min; Yi, Tao; Zhao, Xia; Zhou, Shengtao

2017-01-01

Long noncoding RNAs (lncRNAs) are transcribed by genomic regions (exceeding 200 nucleotides in length) that do not encode proteins. While the exquisite regulation of lncRNA transcription can provide signals of malignant transformation, lncRNAs control pleiotropic cancer phenotypes through interactions with other cellular molecules including DNA, protein, and RNA. Recent studies have demonstrated that dysregulation of lncRNAs is influential in proliferation, angiogenesis, metastasis, invasion, apoptosis, stemness, and genome instability in colorectal cancer (CRC), with consequent clinical implications. In this review, we explicate the roles of different lncRNAs in CRC, and the potential implications for their clinical application. PMID:27888635

Phenotypes and Karyotypes of Human Malignant Mesothelioma Cell Lines

PubMed Central

Relan, Vandana; Morrison, Leanne; Parsonson, Kylie; Clarke, Belinda E.; Duhig, Edwina E.; Windsor, Morgan N.; Matar, Kevin S.; Naidoo, Rishendran; Passmore, Linda; McCaul, Elizabeth; Courtney, Deborah; Yang, Ian A.; Fong, Kwun M.; Bowman, Rayleen V.

2013-01-01

Background Malignant mesothelioma is an aggressive tumour of serosal surfaces most commonly pleura. Characterised cell lines represent a valuable tool to study the biology of mesothelioma. The aim of this study was to develop and biologically characterise six malignant mesothelioma cell lines to evaluate their potential as models of human malignant mesothelioma. Methods Five lines were initiated from pleural biopsies, and one from pleural effusion of patients with histologically proven malignant mesothelioma. Mesothelial origin was assessed by standard morphology, Transmission Electron Microscopy (TEM) and immunocytochemistry. Growth characteristics were assayed using population doubling times. Spectral karyotyping was performed to assess chromosomal abnormalities. Authentication of donor specific derivation was undertaken by DNA fingerprinting using a panel of SNPs. Results Most of cell lines exhibited spindle cell shape, with some retaining stellate shapes. At passage 2 to 6 all lines stained positively for calretinin and cytokeratin 19, and demonstrated capacity for anchorage-independent growth. At passage 4 to 16, doubling times ranged from 30–72 hours, and on spectral karyotyping all lines exhibited numerical chromosomal abnormalities ranging from 41 to 113. Monosomy of chromosomes 8, 14, 22 or 17 was observed in three lines. One line displayed four different karyotypes at passage 8, but only one karyotype at passage 42, and another displayed polyploidy at passage 40 which was not present at early passages. At passages 5–17, TEM showed characteristic features of mesothelioma ultrastructure in all lines including microvilli and tight intercellular junctions. Conclusion These six cell lines exhibit varying cell morphology, a range of doubling times, and show diverse passage-dependent structural chromosomal changes observed in malignant tumours. However they retain characteristic immunocytochemical protein expression profiles of mesothelioma during maintenance in artificial culture systems. These characteristics support their potential as in vitro model systems for studying cellular, molecular and genetic aspects of mesothelioma. PMID:23516439

Pre-existing malignancy results in increased prevalence of distinct populations of CD4+ T cells during sepsis.

PubMed

Xie, Jianfeng; Robertson, Jennifer M; Chen, Ching-Wen; Zhang, Wenxiao; Coopersmith, Craig M; Ford, Mandy L

2018-01-01

The presence of pre-existing malignancy in murine hosts results in increased immune dysregulation and risk of mortality following a septic insult. Based on the known systemic immunologic changes that occur in cancer hosts, we hypothesized that the presence of pre-existing malignancy would result in phenotypic and functional changes in CD4+ T cell responses following sepsis. In order to conduct a non-biased, unsupervised analysis of phenotypic differences between CD4+ T cell compartments, cohorts of mice were injected with LLC1 tumor cells and tumors were allowed to grow for 3 weeks. These cancer hosts and age-matched non-cancer controls were then subjected to CLP. Splenocytes were harvested at 24h post CLP and flow cytometry and SPADE (Spanning-tree Progression Analysis of Density-normalized Events) were used to analyze populations of CD4+ cells most different between the two groups. Results indicated that relative to non-cancer controls, cancer mice contained more resting memory CD4+ T cells, more activated CD4+ effectors, and fewer naïve CD4+ T cells during sepsis, suggesting that the CD4+ T cell compartment in cancer septic hosts is one of increased activation and differentiation. Moreover, cancer septic animals exhibited expansion of two distinct subsets of CD4+ T cells relative to previously healthy septic controls. Specifically, we identified increases in both a PD-1hi population and a distinct 2B4hi BTLAhi LAG-3hi population in cancer septic animals. By combining phenotypic analysis of exhaustion markers with functional analysis of cytokine production, we found that PD-1+ CD4+ cells in cancer hosts failed to make any cytokines following CLP, while the 2B4+ PD-1lo cells in cancer mice secreted increased TNF during sepsis. In sum, the immunophenotypic landscape of cancer septic animals is characterized by both increased CD4+ T cell activation and exhaustion, findings that may underlie the observed increased mortality in mice with pre-existing malignancy following sepsis.

Pre-existing malignancy results in increased prevalence of distinct populations of CD4+ T cells during sepsis

PubMed Central

Xie, Jianfeng; Robertson, Jennifer M.; Chen, Ching-wen; Zhang, Wenxiao

2018-01-01

The presence of pre-existing malignancy in murine hosts results in increased immune dysregulation and risk of mortality following a septic insult. Based on the known systemic immunologic changes that occur in cancer hosts, we hypothesized that the presence of pre-existing malignancy would result in phenotypic and functional changes in CD4+ T cell responses following sepsis. In order to conduct a non-biased, unsupervised analysis of phenotypic differences between CD4+ T cell compartments, cohorts of mice were injected with LLC1 tumor cells and tumors were allowed to grow for 3 weeks. These cancer hosts and age-matched non-cancer controls were then subjected to CLP. Splenocytes were harvested at 24h post CLP and flow cytometry and SPADE (Spanning-tree Progression Analysis of Density-normalized Events) were used to analyze populations of CD4+ cells most different between the two groups. Results indicated that relative to non-cancer controls, cancer mice contained more resting memory CD4+ T cells, more activated CD4+ effectors, and fewer naïve CD4+ T cells during sepsis, suggesting that the CD4+ T cell compartment in cancer septic hosts is one of increased activation and differentiation. Moreover, cancer septic animals exhibited expansion of two distinct subsets of CD4+ T cells relative to previously healthy septic controls. Specifically, we identified increases in both a PD-1hi population and a distinct 2B4hi BTLAhi LAG-3hi population in cancer septic animals. By combining phenotypic analysis of exhaustion markers with functional analysis of cytokine production, we found that PD-1+ CD4+ cells in cancer hosts failed to make any cytokines following CLP, while the 2B4+ PD-1lo cells in cancer mice secreted increased TNF during sepsis. In sum, the immunophenotypic landscape of cancer septic animals is characterized by both increased CD4+ T cell activation and exhaustion, findings that may underlie the observed increased mortality in mice with pre-existing malignancy following sepsis. PMID:29338031

N-acetylcysteine (NAC) ameliorates Epstein-Barr virus latent membrane protein 1 induced chronic inflammation.

PubMed

Gao, Xiao; Lampraki, Eirini-Maria; Al-Khalidi, Sarwah; Qureshi, Muhammad Asif; Desai, Rhea; Wilson, Joanna Beatrice

2017-01-01

Chronic inflammation results when the immune system responds to trauma, injury or infection and the response is not resolved. It can lead to tissue damage and dysfunction and in some cases predispose to cancer. Some viruses (including Epstein-Barr virus (EBV)) can induce inflammation, which may persist even after the infection has been controlled or cleared. The damage caused by inflammation, can itself act to perpetuate the inflammatory response. The latent membrane protein 1 (LMP1) of EBV is a pro-inflammatory factor and in the skin of transgenic mice causes a phenotype of hyperplasia with chronic inflammation of increasing severity, which can progress to pre-malignant and malignant lesions. LMP1 signalling leads to persistent deregulated expression of multiple proteins throughout the mouse life span, including TGFα S100A9 and chitinase-like proteins. Additionally, as the inflammation increases, numerous chemokines and cytokines are produced which promulgate the inflammation. Deposition of IgM, IgG, IgA and IgE and complement activation form part of this process and through genetic deletion of CD40, we show that this contributes to the more tissue-destructive aspects of the phenotype. Treatment of the mice with N-acetylcysteine (NAC), an antioxidant which feeds into the body's natural redox regulatory system through glutathione synthesis, resulted in a significantly reduced leukocyte infiltrate in the inflamed tissue, amelioration of the pathological features and delay in the inflammatory signature measured by in vivo imaging. Reducing the degree of inflammation achieved through NAC treatment, had the knock on effect of reducing leukocyte recruitment to the inflamed site, thereby slowing the progression of the pathology. These data support the idea that NAC could be considered as a treatment to alleviate chronic inflammatory pathologies, including post-viral disease. Additionally, the model described can be used to effectively monitor and accurately measure therapies for chronic inflammation.

[Value of immunologic phenotyping of acute leukemias in children].

PubMed

Vannier, J P; Bene, M C

1989-10-01

Immunologic typing has demonstrated considerable heterogeneity among the acute leukemias. The most significant recent advance has been development of monoclonal antibody techniques. Some markers identified using these techniques seem to be specific for a given stage of maturation of one lymphoid or myeloid cell line. Most acute lymphoblastic leukemias (ALLs) are malignant proliferations whose differentiation appears to have become 'stuck' at one stage of maturation. Results of immunologic typing correlate well with the other clinical and biological data. For prognostic purposes, several patterns can be identified. Among B line ALLs, four varieties have been differentiated, i.e., CD10 negative ALLs, common ALLs, pre-B ALLs, and B ALLs. T ALLs include a broad spectrum of heterogeneous proliferations whose immunologic classification is made difficult by the large number of phenotypes encountered. Among acute myeloblastic leukemias (AMLs), some highly undifferentiated forms have been recognized, by means of immunologic typing, as originating in one of the myeloid cell lines. However, the nosologic and prognostic significance of these studies is less obvious than in ALLs.

Integrated single-cell genetic and transcriptional analysis suggests novel drivers of chronic lymphocytic leukemia

PubMed Central

Wang, Lili; Fan, Jean; Francis, Joshua M.; Georghiou, George; Hergert, Sarah; Li, Shuqiang; Gambe, Rutendo; Zhou, Chensheng W.; Yang, Chunxiao; Xiao, Sheng; Cin, Paola Dal; Bowden, Michaela; Kotliar, Dylan; Shukla, Sachet A.; Brown, Jennifer R.; Neuberg, Donna; Alessi, Dario R.; Zhang, Cheng-Zhong; Kharchenko, Peter V.; Livak, Kenneth J.; Wu, Catherine J.

2017-01-01

Intra-tumoral genetic heterogeneity has been characterized across cancers by genome sequencing of bulk tumors, including chronic lymphocytic leukemia (CLL). In order to more accurately identify subclones, define phylogenetic relationships, and probe genotype–phenotype relationships, we developed methods for targeted mutation detection in DNA and RNA isolated from thousands of single cells from five CLL samples. By clearly resolving phylogenic relationships, we uncovered mutated LCP1 and WNK1 as novel CLL drivers, supported by functional evidence demonstrating their impact on CLL pathways. Integrative analysis of somatic mutations with transcriptional states prompts the idea that convergent evolution generates phenotypically similar cells in distinct genetic branches, thus creating a cohesive expression profile in each CLL sample despite the presence of genetic heterogeneity. Our study highlights the potential for single-cell RNA-based targeted analysis to sensitively determine transcriptional and mutational profiles of individual cancer cells, leading to increased understanding of driving events in malignancy. PMID:28679620

[Hypertension, catecholamine hypersecretion and potential for metastasis: recent progress in the pathophysiology and genetics of pheochromocytoma and paraganglioma].

PubMed

Plouin, Pierre-François; Amar, Laurence; Gimenez-Roqueplo, Anne-paule

2015-01-01

Pheochromocytomas and paragangliomas are catecholamine-secreting tumors usually associated with arterial hypertension. They can contribute to acute cardiovascular events. Ten to 15 percent of tumors are metastatic. Autosomal dominant gene alterations are present in more than a third of cases. The secretory phenotype and the risk of malignancy are driven by the presence of gene mutations, specifically in the subunits of succinate dehydrogenase. Recent advances in genomics have clinical implications for family screening, biological follow-up, prediction of the risk of recurrence, and therapeutic options in cases with malignant recurrence.

Three dimensional cultures: a tool to study normal acinar architecture vs. malignant transformation of breast cells.

PubMed

Pal, Anupama; Kleer, Celina G

2014-04-25

Invasive breast carcinomas are a group of malignant epithelial tumors characterized by the invasion of adjacent tissues and propensity to metastasize. The interplay of signals between cancer cells and their microenvironment exerts a powerful influence on breast cancer growth and biological behavior(1). However, most of these signals from the extracellular matrix are lost or their relevance is understudied when cells are grown in two dimensional culture (2D) as a monolayer. In recent years, three dimensional (3D) culture on a reconstituted basement membrane has emerged as a method of choice to recapitulate the tissue architecture of benign and malignant breast cells. Cells grown in 3D retain the important cues from the extracellular matrix and provide a physiologically relevant ex vivo system(2,3). Of note, there is growing evidence suggesting that cells behave differently when grown in 3D as compared to 2D(4). 3D culture can be effectively used as a means to differentiate the malignant phenotype from the benign breast phenotype and for underpinning the cellular and molecular signaling involved(3). One of the distinguishing characteristics of benign epithelial cells is that they are polarized so that the apical cytoplasm is towards the lumen and the basal cytoplasm rests on the basement membrane. This apico-basal polarity is lost in invasive breast carcinomas, which are characterized by cellular disorganization and formation of anastomosing and branching tubules that haphazardly infiltrates the surrounding stroma. These histopathological differences between benign gland and invasive carcinoma can be reproduced in 3D(6,7). Using the appropriate read-outs like the quantitation of single round acinar structures, or differential expression of validated molecular markers for cell proliferation, polarity and apoptosis in combination with other molecular and cell biology techniques, 3D culture can provide an important tool to better understand the cellular changes during malignant transformation and for delineating the responsible signaling.

Protein alterations associated with temozolomide resistance in subclones of human glioblastoma cell lines.

PubMed

Sun, Stella; Wong, T S; Zhang, X Q; Pu, Jenny K S; Lee, Nikki P; Day, Philip J R; Ng, Gloria K B; Lui, W M; Leung, Gilberto K K

2012-03-01

Temozolomide (TMZ) is the standard chemotherapeutic agent for human malignant glioma, but intrinsic or acquired chemoresistance represents a major obstacle to successful treatment of this highly lethal group of tumours. Obtaining better understanding of the molecular mechanisms underlying TMZ resistance in malignant glioma is important for the development of better treatment strategies. We have successfully established a passage control line (D54-C10) and resistant variants (D54-P5 and D54-P10) from the parental TMZ-sensitive malignant glioma cell line D54-C0. The resistant sub-cell lines showed alterations in cell morphology, enhanced cell adhesion, increased migration capacities, and cell cycle arrests. Proteomic analysis identified a set of proteins that showed gradual changes in expression according to their 50% inhibitory concentration (IC(50)). Successful validation was provided by transcript profiling in another malignant glioma cell line U87-MG and its resistant counterparts. Moreover, three of the identified proteins (vimentin, cathepsin D and prolyl 4-hydroxylase, beta polypeptide) were confirmed to be upregulated in high-grade glioma. Our data suggest that acquired TMZ resistance in human malignant glioma is associated with promotion of malignant phenotypes, and our reported molecular candidates may serve not only as markers of chemoresistance but also as potential therapeutic targets in the treatment of TMZ-resistant human malignant glioma, providing a platform for future investigations.

Over-expression of FoxM1 leads to epithelial-mesenchymal transition and cancer stem cell phenotype in pancreatic cancer cells

PubMed Central

Bao, Bin; Wang, Zhiwei; Ali, Shadan; Kong, Dejuan; Banerjee, Sanjeev; Ahmad, Aamir; Li, Yiwei; Azmi, Asfar S.; Miele, Lucio; Sarkar, Fazlul H.

2011-01-01

FoxM1 is known to play important role in the development and progression of many malignancies including pancreatic cancer. Studies have shown that the acquisition of Epithelial-to-mesenchymal transition (EMT) phenotype and induction of cancer stem cell (CSC) or cancer stem-like cell phenotypes are highly inter-related, and contributes to drug resistance, tumor recurrence and metastasis. The molecular mechanism(s) by which FoxM1 contributes to the acquisition of EMT phenotype and induction of CSC self-renewal capacity is poorly understood. Therefore, we established FoxM1 over-expressing pancreatic cancer (AsPC-1) cells, which showed increased cell growth, clonogenicity and cell migration. Moreover, over-expression of FoxM1 led to the acquisition of EMT phenotype by activation of mesenchymal cell markers, ZEB1, ZEB2, Snail2, E-cadherin, and vimentin, which is consistent with increased sphere-forming (pancreatospheres) capacity and expression of CSC surface markers (CD44 and EpCAM). We also found that over-expression of FoxM1 led to decreased expression of miRNAs (let-7a, let-7b, let-7c, miR-200b and miR-200c); however, re-expression of miR-200b inhibited the expression of ZEB1, ZEB2, vimentin as well as FoxM1, and induced the expression of E-cadherin, leading to the reversal of EMT phenotype. Finally, we found that genistein, a natural chemo-preventive agent, inhibited cell growth, clonogenicity, cell migration and invasion, EMT phenotype, and formation of pancreatospheres consistent with reduced expression of CD44 and EpCAM. These results suggest, for the first time, that FoxM1 over-expression is responsible for the acquisition of EMT and CSC phenotype, which is in part mediated through the regulation of miR-200b and these processes, could be easily attenuated by genistein. PMID:21503965

Breast Cancer Methylomes Establish an Epigenomic Foundation for Metastasis

PubMed Central

Fang, Fang; Turcan, Sevin; Rimner, Andreas; Kaufman, Andrew; Giri, Dilip; Morris, Luc G. T.; Shen, Ronglai; Seshan, Venkatraman; Mo, Qianxing; Heguy, Adriana; Baylin, Stephen B.; Ahuja, Nita; Viale, Agnes; Massague, Joan; Norton, Larry; Vahdat, Linda T.; Moynahan, Mary Ellen; Chan, Timothy A.

2011-01-01

Cancer-specific alterations in DNA methylation are hallmarks of human malignancies; however, the nature of the breast cancer epigenome and its effects on metastatic behavior remain obscure. To address this issue, we used genome-wide analysis to characterize the methylomes of breast cancers with diverse metastatic behavior. Groups of breast tumors were characterized by the presence or absence of coordinate hypermethylation at a large number of genes, demonstrating a breast CpG island methylator phenotype (B-CIMP). The B-CIMP provided a distinct epigenomic profile and was a strong determinant of metastatic potential. Specifically, the presence of the B-CIMP in tumors was associated with low metastatic risk and survival, and the absence of the B-CIMP was associated with high metastatic risk and death. B-CIMP loci were highly enriched for genes that make up the metastasis transcriptome. Methylation at B-CIMP genes accounted for much of the transcriptomal diversity between breast cancers of varying prognosis, indicating a fundamental epigenomic contribution to metastasis. Comparison of the loci affected by the B-CIMP with those affected by the hypermethylator phenotype in glioma and colon cancer revealed that the CIMP signature was shared by multiple human malignancies. Our data provide a unifying epigenomic framework linking breast cancers with varying outcome and transcriptomic changes underlying metastasis. These findings significantly enhance our understanding of breast cancer oncogenesis and aid the development of new prognostic biomarkers for this common malignancy. PMID:21430268

Hypoxia signaling – license to metastasize

PubMed Central

Vanharanta, Sakari; Massagué, Joan

2013-01-01

Hypoxia-inducible transcription factors (HIFs) have long been linked to malignant tumor phenotypes in various cancer types, and several downstream mediators of HIF action have been identified in metastatic carcinomas. A new study links hypoxia-induced collagen remodeling to sarcoma progression, providing evidence for unifying mechanisms of carcinoma and sarcoma metastasis. PMID:24124230

Role of Receptor Sialylation in the Ovarian Tumor Cell Phenotype

DTIC Science & Technology

2014-08-01

Chemical Society meeting, Baton Rouge, LA, Nov 2012; (3) 19th World Congress on Advances in Oncology conference, Athens, Greece, scheduled for Oct, 2014...dehydrogenase 1 is a marker for normal and malignant human colonic stem cells (SC) and tracks SC overpopulation during colon tumorigenesis. Cancer Res 2009;69

Development of an unbiased, semi-automated approach for classifying plasma cell immunophenotype following multicolor flow cytometry of bone marrow aspirates.

PubMed

Post, Steven R; Post, Ginell R; Nikolic, Dejan; Owens, Rebecca; Insuasti-Beltran, Giovanni

2018-03-24

Despite increased usage of multiparameter flow cytometry (MFC) to assess diagnosis, prognosis, and therapeutic efficacy (minimal residual disease, MRD) in plasma cell neoplasms (PCNs), standardization of methodology and data analysis is suboptimal. We investigated the utility of using the mean and median fluorescence intensities (FI) obtained from MFC to objectively describe parameters that distinguish plasma cell (PC) phenotypes. In this retrospective study, flow cytometry results from bone marrow aspirate specimens from 570 patients referred to the Myeloma Institute at UAMS were evaluated. Mean and median FI data were obtained from 8-color MFC of non-neoplastic, malignant, and mixed PC populations using antibodies to CD38, CD138, CD19, CD20, CD27, CD45, CD56, and CD81. Of 570 cases, 252 cases showed only non-neoplastic PCs, 168 showed only malignant PCs, and 150 showed mixed PC populations. Statistical analysis of median FI data for each CD marker showed no difference in expression intensity on non-neoplastic and malignant PCs, between pure and mixed PC populations. ROC analysis of the median FI of CD expression in non-neoplastic and malignant PCs was used to develop an algorithm to convert quantitative FI values to qualitative assessments including "negative," "positive," "dim," and "heterogeneous" expression. FI data derived from 8-color MFC can be used to define marker expression on PCs. Translation of FI data from Infinicyt software to an Excel worksheet streamlines workflow and eliminates transcriptional errors when generating flow reports. © 2018 International Clinical Cytometry Society. © 2018 International Clinical Cytometry Society.

GPNMB/OA protein increases the invasiveness of human metastatic prostate cancer cell lines DU145 and PC3 through MMP-2 and MMP-9 activity

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fiorentini, Chiara; Bodei, Serena; Bedussi, Francesca

2014-04-15

Non-metastatic glycoprotein melanoma protein B (GPNMB), also known as osteoactivin (OA) is expressed in a wide array of tumors and represents an emerging target for drug development. In this study, we investigated the role of GPNMB/OA in the progression of human metastatic DU145 and PC3 prostate cancer cells. GPNMB/OA contribution in PCa malignant phenotype has been analyzed by small interfering RNA-induced GPNMB/OA silencing. We found that following GPNMB/OA silencing the migration capability of both DU145 and PC3 cells, evaluated by using in vitro invasivity assay, as well as the metalloproteinases MMP-2 and MMP-9 activity were equally strongly inhibited. By contrastmore » knocking down GPNMB/OA weakly attenuated cell proliferation rate of DU145, an effect that paralleled with an increase number of apoptotic cells. However, PC3 cell growth seems to be not affected by GPNMB/OA. Together, these data reveal that GPNMB/OA acts as a critical molecular mediator promoting the acquisition of the more aggressive, pro-metastatic phenotype distinctive of human DU145 and PC3 cell lines. - Highlights: • GPNMB/OA expression correlates with DU145 and PC3 cells malignant phenotype. • GPNMB/OA silencing affects the migration capability of both DU145 and PC3 cells. • GPNMB/OA increases invasiveness by up-regulating MMPs activity. • GPNMB/OA promotes DU145 and PC3 cells progression into a more aggressive phenotype.« less

Pigmentation Phenotype, Photosensitivity, and Skin Neoplasms in Patients with Myotonic Dystrophy

PubMed Central

Gadalla, Shahinaz M.; Hilbert, James E.; Martens, William B.; Givens, Shannon; Moxley, Richard T.; Greene, Mark H.

2017-01-01

Background Recent studies have suggested a possible excess risk of skin neoplasms in patients with myotonic dystrophy (DM). Risk factors related to this observation have not been defined. Method We collected information regarding personal history of skin tumors, pigmentation phenotype, and skin reaction to sun exposure from 266 DM patients who were enrolled in the US NIH National Registry of Myotonic Dystrophy and Facioscapulohumeral Muscular Dystrophy Patients and Family Members. Results Seventy-seven subjects reported having skin tumors that were either benign (n=31), malignant (n=32), or both (n=14). Female gender (OR=2.27, 95%CI=1.02–5.05, p=0.04), older age (OR=1.10, 95%CI=1.05–1.16, p<0.001), and DM1 subtype (OR=3.42, 95%CI=1.27–9.26, p=0.02) were associated with a malignant skin tumor. The association between malignant skin tumors and known risk factors [light eye color (OR=1.62, 95%CI=0.78–3.39, p=0.20); light skin complexion (OR=1.31, 95% CI=0.63–2.73, p=0.48), moderate/extensive face freckles (OR=1.47, 95% CI=0.50–4.34, p=0.49)] were modest. Strong, but not statistically significant, associations were noted with sunburn reactions when exposed to sunlight (OR=4.28, 95%CI=0.91–19.95, p=0.06, and 2.19, 95%CI=0.67–7.09, p=0.19 for sunburns with and without blistering, respectively). Conclusions Although our study was limited by small sample size, the risk factors for malignant skin tumors in DM strongly resemble the general population. We recommend that DM patients adhere to sun exposure protective behavior. PMID:28317292

Polymorphism of alpha-1-antitrypsin in hematological malignancies

PubMed Central

2009-01-01

Alpha-1-antitrypsin (AAT) or serine protease inhibitor A1 (SERPINA1) is an important serine protease inhibitor in humans. The main physiological role of AAT is to inhibit neutrophil elastase (NE) released from triggered neutrophils, with an additional lesser role in the defense against damage inflicted by other serine proteases, such as cathepsin G and proteinase 3. Although there is a reported association between AAT polymorphism and different types of cancer, this association with hematological malignancies (HM) is, as yet, unknown. We identified AAT phenotypes by isoelectric focusing (in the pH 4.2-4.9 range) in 151 serum samples from patients with HM (Hodgkins lymphomas, non-Hodgkins lymphomas and malignant monoclonal gammopathies). Healthy blood-donors constituted the control group (n = 272). The evaluated population of patients as well as the control group, were at Hardy-Weinberg equilibrium for the AAT gene (χ2 = 4.42, d.f.11, p = 0.96 and χ2 = 4.71, d.f.11, p = 0.97, respectively). There was no difference in the frequency of deficient AAT alleles (Pi Z and Pi S) between patients and control. However, we found a significantly higher frequency of PiM1M1 homozygote and PiM1 allele in HM patients than in control (for phenotype: f = 0.5166 and 0.4118 respectively, p = 0.037; for allele: f = 0.7020 and 0.6360 respectively, p = 0.05). In addition, PiM homozygotes in HM-patients were more numerous than in controls (59% and 48%, respectively, p = 0.044). PiM1 alleles and PiM1 homozygotes are both associated with hematological malignancies, although this is considered a functionally normal AAT variant. PMID:21637443

Dominant Suppression of β1 Integrin by Ectopic CD98-ICD Inhibits Hepatocellular Carcinoma Progression

PubMed Central

Wu, Bo; Zhou, Yang; Wang, Yu; Yang, Xiang-Min; Liu, Zhen-Yu; Li, Jiang-Hua; Feng, Fei; Chen, Zhi-Nan; Jiang, Jian-Li

2016-01-01

Hepatocellular carcinoma (HCC) is currently the third most common cause of cancer-related death in the Asia-Pacific region. Our previous work showed that knockdown of CD98 significantly inhibits malignant HCC cell phenotypes in vitro and in vivo. The level of CD98 in the membrane is tightly regulated to mediate complex processes associated with cell–cell communication and intracellular signaling. In addition, the intracellular domain of CD98 (CD98-ICD) seems to be of vital importance for recycling CD98 to the membrane after it is endocytosed. The intracellular and transmembrane domains of CD98 associate with β-integrins (primarily β1 but also β3), and this association is essential for CD98 mediation of integrin-like signaling and complements dominant suppression of β1-integrin. We speculated that isolated CD98-ICD would similarly suppress β1-integrin activation and inhibit the malignant behaviors of cancer cells. In particular, the exact role of CD98-ICD has not been studied independently in HCC. In this study, we found that ectopic expression of CD98-ICD inhibited the malignant phenotypes of HCC cells, and the mechanism possibly involves β1-integrin suppression. Moreover, the expression levels of CD98, β1-integrin-A (the activated form of β1-integrin) and Ki-67 were significantly increased in HCC tissues relative to those of normal liver tissues. Therefore, our preliminary study indicates that ectopic CD98-ICD has an inhibitory role in the malignant development of HCC, and shows that CD98-ICD acts as a dominant negative mutant of CD98 that attenuates β1-integrin activation. CD98-ICD may emerge as a promising candidate for antitumor treatment. PMID:27834933

[Pro731Ser mutation in the β-myosin heavy chain and hypertrophic cardiomyopathy in a Chinese pedigree].

PubMed

Zhao, Xintao; Wu, Yajie; Chen, Yi; Feng, Xinxing; Song, Ying; Wang, Yilu; Zou, Yubao; Wang, Jizheng; Shao, Yibing; Hui, Rutai; Song, Lei; Wang, Xu

2014-07-01

To identify the casual mutation of a Chinese pedigree with hypertrophic cardiomyopathy (HCM), and to analyze the genotype-phenotype relationship. The coding exons of 26 reported disease genes were sequenced by targeted resequencing in the proband and the identified mutation were detected with bi-directional Sanger sequencing in all family members and 307 healthy controls. The genotype-phenotype correlation was analyzed in the family. A missense mutation (c.2191C > T, p. Pro731Ser) in the 20th exon of MYH7 gene was identified. This mutation was absent in 307 healthy controls and predicted to be pathogenic by PolyPhen-HCM. Totally 13 family members carried this mutation, including 10 patients with HCM and 3 asymptomatic mutation carriers. The proband manifested severe congestive heart failure and 8 patients expressed various clinical manifestations of heart failure, including dyspnea, palpitations, chest pain, amaurosis or syncope. Five patients were diagnosed as HCM at the age of 16 or younger. One family member suffered sudden cardiac death. The Pro731Ser of MYH7 gene mutation is a causal and malignant mutation linked with familiar HCM.

Malignant perivascular epithelioid cell tumor of the retroperitoneum

PubMed Central

Wu, Ji-Hua; Zhou, Jin-Lian; Cui, Yan; Jing, Qing-Ping; Shang, Le; Zhang, Jian-Zhong

2013-01-01

Perivascular epithelioid cell tumors (PEComas) are a rare type of mesenchymal neoplasms characterized by a proliferation of perivascular cells with an epithelioid phenotype and expression of myo-melanocytic markers. The majority of PEComas seem to be benign and usually their prognosis is good. Malignant cases are extremely rare, exhibiting a malignant course with local recurrences and distant metastases. We herein report a case of a malignant PEComa arising in the retroperitoneum. The patient was a 55-year-old woman experiencing abdominal discomfort for approximately one month. Ultrasound and computer tomography (CT) scans of the abdomen revealed a solid mass arising from the retroperitoneum. Microscopically, the tumor was composed of epithelioid cells mixed with spindled cells. The nucleus had significant atypia, and the mitoses were obvious. The focal intravascular tumor embolus was visible. Immunohistochemically, the epithelioid tumor cells were positive for HMB45 and Melan-A, and the spindled tumor celLs were positive for SMA and desmin. Seven months after a surgical resection, an ultrasound revealed liver metastases. In conclusion, the malignant PEComas of the retroperitoneum is a very rare neoplasm with unique morphological and immunohistochemical characteristics. It should be differentiated from other epithelioid cell tumors of the retroperitoneum. PMID:24133607

Malignant perivascular epithelioid cell tumor of the retroperitoneum.

PubMed

Wu, Ji-Hua; Zhou, Jin-Lian; Cui, Yan; Jing, Qing-Ping; Shang, Le; Zhang, Jian-Zhong

2013-01-01

Perivascular epithelioid cell tumors (PEComas) are a rare type of mesenchymal neoplasms characterized by a proliferation of perivascular cells with an epithelioid phenotype and expression of myo-melanocytic markers. The majority of PEComas seem to be benign and usually their prognosis is good. Malignant cases are extremely rare, exhibiting a malignant course with local recurrences and distant metastases. We herein report a case of a malignant PEComa arising in the retroperitoneum. The patient was a 55-year-old woman experiencing abdominal discomfort for approximately one month. Ultrasound and computer tomography (CT) scans of the abdomen revealed a solid mass arising from the retroperitoneum. Microscopically, the tumor was composed of epithelioid cells mixed with spindled cells. The nucleus had significant atypia, and the mitoses were obvious. The focal intravascular tumor embolus was visible. Immunohistochemically, the epithelioid tumor cells were positive for HMB45 and Melan-A, and the spindled tumor celLs were positive for SMA and desmin. Seven months after a surgical resection, an ultrasound revealed liver metastases. In conclusion, the malignant PEComas of the retroperitoneum is a very rare neoplasm with unique morphological and immunohistochemical characteristics. It should be differentiated from other epithelioid cell tumors of the retroperitoneum.

Reciprocal regulation of the cholinic phenotype and epithelial-mesenchymal transition in glioblastoma cells

PubMed Central

Koch, Katharina; Hartmann, Rudolf; Schröter, Friederike; Suwala, Abigail Kora; Maciaczyk, Donata; Krüger, Andrea Caroline; Willbold, Dieter; Kahlert, Ulf Dietrich; Maciaczyk, Jaroslaw

2016-01-01

Glioblastoma (GBM) is the most malignant brain tumor with very limited therapeutic options. Standard multimodal treatments, including surgical resection and combined radio-chemotherapy do not target the most aggressive subtype of glioma cells, brain tumor stem cells (BTSCs). BTSCs are thought to be responsible for tumor initiation, progression, and relapse. Furthermore, they have been associated with the expression of mesenchymal features as a result of epithelial-mesenchymal transition (EMT) thereby inducing tumor dissemination and chemo resistance. Using high resolution proton nuclear magnetic resonance spectroscopy (1H NMR) on GBM cell cultures we provide evidence that the expression of well-known EMT activators of the ZEB, TWIST and SNAI families and EMT target genes N-cadherin and VIMENTIN is associated with aberrant choline metabolism. The cholinic phenotype is characterized by high intracellular levels of phosphocholine and total choline derivatives and was associated with malignancy in various cancers. Both genetic and pharmacological inhibition of the cardinal choline metabolism regulator choline kinase alpha (CHKα) significantly reduces the cell viability, invasiveness, clonogenicity, and expression of EMT associated genes in GBM cells. Moreover, in some cell lines synergetic cytotoxic effects were observed when combining the standard of care chemotherapeutic temozolomide with the CHKα inhibitor V-11-0711. Taken together, specific inhibition of the enzymatic activity of CHKα is a powerful strategy to suppress EMT which opens the possibility to target chemo-resistant BTSCs through impairing their mesenchymal transdifferentiation. Moreover, the newly identified EMT-oncometabolic network may be helpful to monitor the invasive properties of glioblastomas and the success of anti-EMT therapy. PMID:27705917

Monocyte-derived cells of the brain and malignant gliomas: the double face of Janus.

PubMed

Kushchayev, Sergiy V; Kushchayeva, Yevgeniya S; Wiener, Philip C; Scheck, Adrienne C; Badie, Behnam; Preul, Mark C

2014-12-01

Monocyte-derived cells of the brain (MDCB) are a diverse group of functional immune cells that are also highly abundant in gliomas. There is growing evidence that MDCB play essential roles in the pathogenesis of gliomas. The aim of this review was to collate and systematize contemporary knowledge about these cells as they relate to glioma progression and antiglioblastoma therapeutic modalities with a view toward improved effectiveness of therapy. We reviewed relevant studies to construct a summary of different MDCB subpopulations in steady state and in malignant gliomas and discuss their role in the development of malignant gliomas and potential future therapies. Current studies suggest that MDCB subsets display different phenotypes and differentiation potentials depending on their milieu in the brain and exposure to tumoral influences. MDCB possess specific and unique functions, including those that are protumoral and those that are antitumoral. Elucidating the role of mononuclear-derived cells associated with gliomas is crucial in designing novel immunotherapy strategies. Much progress is needed to characterize markers to identify cell subsets and their specific regulatory roles. Investigation of MDCB can be clinically relevant. Specific MDCB populations potentially can be used for glioma therapy as a target or as cell vehicles that might deliver cytotoxic substances or processes to the glioma microenvironment. Copyright © 2014 Elsevier Inc. All rights reserved.

Immune Escape Mechanisms in Colorectal Cancer Pathogenesis and Liver Metastasis

PubMed Central

Remo, Andrea; Febbraro, Antonio; Sabatino, Lina; Manfrin, Erminia; Ceccarelli, Michele; Colantuoni, Vittorio

2014-01-01

Over the past decade, growing evidence indicates that the tumor microenvironment (TME) contributes with genomic/epigenomic aberrations of malignant cells to enhance cancer cells survival, invasion, and dissemination. Many factors, produced or de novo synthesized by immune, stromal, or malignant cells, acting in a paracrine and autocrine fashion, remodel TME and the adaptive immune response culminating in metastasis. Taking into account the recent accomplishments in the field of immune oncology and using metastatic colorectal cancer (mCRC) as a model, we propose that the evasion of the immune surveillance and metastatic spread can be achieved through a number of mechanisms that include (a) intrinsic plasticity and adaptability of immune and malignant cells to paracrine and autocrine stimuli or genotoxic stresses; (b) alteration of positional schemes of myeloid-lineage cells, produced by factors controlling the balance between tumour-suppressing and tumour-promoting activities; (c) acquisition by cancer cells of aberrant immune-phenotypic traits (NT5E/CD73, CD68, and CD163) that enhance the interactions among TME components through the production of immune-suppressive mediators. These properties may represent the driving force of metastatic progression and thus clinically exploitable for cancer prevention and therapy. In this review we summarize results and suggest new hypotheses that favour the growing impact of tumor-infiltrating immune cells on tumour progression, metastasis, and therapy resistance. PMID:24741617

Dominant-negative mutants of platelet-derived growth factor revert the transformed phenotype of human astrocytoma cells.

PubMed Central

Shamah, S M; Stiles, C D; Guha, A

1993-01-01

Malignant astrocytoma is the most common primary human brain tumor. Most astrocytomas express a combination of platelet-derived growth factor (PDGF) and PDGF receptor which could close an autocrine loop. It is not known whether these autocrine loops contribute to the transformed phenotype of astrocytoma cells or are incidental to that phenotype. Here we show that dominant-negative mutants of the PDGF ligand break the autocrine loop and revert the phenotype of BALB/c 3T3 cells transformed by the PDGF-A or PDGF-B (c-sis) gene. Then, we show that these mutants are selective in that they do not alter the phenotype of 3T3 cells transformed by an activated Ha-ras or v-src gene or by simian virus 40. Finally, we show that these mutants revert the transformed phenotype of two independent human astrocytoma cell lines. They have no effect on the growth of human medulloblastoma, bladder carcinoma, or colon carcinoma cell lines. These observations are consistent with the view that PDGF autocrine loops contribute to the transformed phenotype of at least some human astrocytomas. Images PMID:8246942

Severe hypertension and hypokalemia as first clinical manifestations in ectopic Cushing's syndrome.

PubMed

Fernández-Rodríguez, Eva; Villar-Taibo, Rocío; Pinal-Osorio, Iria; Cabezas-Agrícola, José Manuel; Anido-Herranz, Urbano; Prieto, Alma; Casanueva, Felipe F; Araujo-Vilar, David

2008-08-01

Ectopic ACTH production occurs in about 10% of all cases of Cushing's syndrome, and about 25% of cases of ACTH-dependent Cushing's syndrome. Diverse tumor types are able to produce ACTH ectopically, including small cell lung carcinoma. Ectopic ACTH secretion by malignant neoplasm has been reported to have earlier and more aggressive metabolic effects. We report a 59-year-old male patient with severe hypertension, metabolic alkalosis and hypokalemia as the first clinical manifestations of an ACTH-secreting small cell lung carcinoma, although the typical phenotypic features of Cushing's syndrome were not present. Ectopic Cushing's syndrome should always be ruled out in patients with severe hypertension and hypokalemia.

Microglia and macrophages in malignant gliomas: recent discoveries and implications for promising therapies.

PubMed

da Fonseca, Anna Carolina Carvalho; Badie, Behnam

2013-01-01

Malignant gliomas are the most common primary brain tumors. Their deadliest manifestation, glioblastoma multiforme (GBM), accounts for 15% of all primary brain tumors and is associated with a median survival of only 15 months even after multimodal therapy. There is substantial presence of microglia and macrophages within and surrounding brain tumors. These immune cells acquire an alternatively activated phenotype with potent tumor-tropic functions that contribute to glioma growth and invasion. In this review, we briefly summarize recent data that has been reported on the interaction of microglia/macrophages with brain tumors and discuss potential application of these findings to the development of future antiglioma therapies.

A Transgenic Drosophila melanogaster Model To Study Human T-Lymphotropic Virus Oncoprotein Tax-1-Driven Transformation In Vivo

PubMed Central

Shirinian, Margret; Kambris, Zakaria; Hamadeh, Lama; Grabbe, Caroline; Journo, Chloé; Mahieux, Renaud

2015-01-01

Human T-cell lymphotropic virus type 1 (HTLV-1)-induced adult T-cell leukemia/lymphoma is an aggressive malignancy. HTLV-2 is genetically related to HTLV-1 but does not cause any malignant disease. HTLV-1 Tax transactivator (Tax-1) contributes to leukemogenesis via NF-κB. We describe transgenic Drosophila models expressing Tax in the compound eye and plasmatocytes. We demonstrate that Tax-1 but not Tax-2 induces ommatidial perturbation and increased plasmatocyte proliferation and that the eye phenotype is dependent on Kenny (IKKγ/NEMO), thus validating this new in vivo model. PMID:25995252

Carcinoma-associated fibroblasts: orchestrating the composition of malignancy

PubMed Central

Gascard, Philippe; Tlsty, Thea D.

2016-01-01

The tumor stroma is no longer seen solely as physical support for mutated epithelial cells but as an important modulator and even a driver of tumorigenicity. Within the tumor stromal milieu, heterogeneous populations of fibroblast-like cells, collectively termed carcinoma-associated fibroblasts (CAFs), are key players in the multicellular, stromal-dependent alterations that contribute to malignant initiation and progression. This review focuses on novel insights into the contributions of CAFs to disease progression, emergent events leading to the generation of CAFs, identification of CAF-specific biomarkers predictive of disease outcome, and recent therapeutic approaches aimed at blunting or reverting detrimental protumorigenic phenotypes associated with CAFs. PMID:27151975

All in the family: Clueing into the link between metabolic syndrome and hematologic malignancies.

PubMed

Karmali, Reem; Dalovisio, Andrew; Borgia, Jeffrey A; Venugopal, Parameswaran; Kim, Brian W; Grant-Szymanski, Kelly; Hari, Parameswaran; Lazarus, Hillard

2015-03-01

Metabolic syndrome constitutes a constellation of findings including central obesity, insulin resistance/type 2 diabetes mellitus (DM), dyslipidemia and hypertension. Metabolic syndrome affects 1 in 4 adults in the United States and is rapidly rising in prevalence, largely driven by the dramatic rise in obesity and insulin resistance/DM. Being central to the development of metabolic syndrome and its other related diseases, much focus has been placed on identifying the mitogenic effects of obesity and insulin resistance/DM as mechanistic clues of the link between metabolic syndrome and cancer. Pertinent mechanisms identified include altered lipid signaling, adipokine and inflammatory cytokine effects, and activation of PI3K/Akt/mTOR and RAS/RAF/MAPK/ERK pathways via dysregulated insulin/insulin-like growth factor-1 (IGF-1) signaling. Through variable activation of these multiple pathways, obesity and insulin resistance/DM pre-dispose to hematologic malignancies, imposing the aggressive and chemo-resistant phenotypes typically seen in cancer patients with underlying metabolic syndrome. Growing understanding of these pathways has identified druggable cancer targets, rationalizing the development and testing of agents like PI3K inhibitor idelalisib, mTOR inhibitors everolimus and temsirolimus, and IGF-1 receptor inhibitor linsitinib. It has also led to exploration of obesity and diabetes-directed therapies including statins and oral hypoglycemic for the management of metabolic syndrome-related hematologic neoplasms. Copyright © 2014 Elsevier Ltd. All rights reserved.

Epidermal growth factor promotes a mesenchymal over an amoeboid motility of MDA-MB-231 cells embedded within a 3D collagen matrix

NASA Astrophysics Data System (ADS)

Geum, Dongil T.; Kim, Beum Jun; Chang, Audrey E.; Hall, Matthew S.; Wu, Mingming

2016-01-01

The receptor of epidermal growth factor (EGFR) critically regulates tumor cell invasion and is a potent therapeutic target for treatment of many types of cancers, including carcinomas and glioblastomas. It is known that EGF regulates cell motility when tumor cells are embedded within a 3D biomatrix. However, roles of EGF in modulating tumor cell motility phenotype are largely unknown. In this article, we report that EGF promotes a mesenchymal over an amoeboid motility phenotype using a malignant breast tumor cell line, MDA-MB-231, embedded within a 3D collagen matrix. Amoeboid cells are rounded in shape, while mesenchymal cells are elongated, and their migrations are governed by a distinctly different set of biomolecules. Using single cell tracking analysis, we also show that EGF promotes cell dissemination through a significant increase in cell persistence along with a moderate increase of speed. The increase of persistence is correlated with the increase of the percentage of the mesenchymal cells within the population. Our work reveals a novel role of microenvironmental cue, EGF, in modulating heterogeneity and plasticity of tumor cell motility phenotype. In addition, it suggests a potential visual cue for diagnosing invasive states of breast cancer cells. This work can be easily extended beyond breast cancer cells.

On the dynamics of neutral mutations in a mathematical model for a homogeneous stem cell population.

PubMed

Traulsen, Arne; Lenaerts, Tom; Pacheco, Jorge M; Dingli, David

2013-02-01

The theory of the clonal origin of cancer states that a tumour arises from one cell that acquires mutation(s) leading to the malignant phenotype. It is the current belief that many of these mutations give a fitness advantage to the mutant population allowing it to expand, eventually leading to disease. However, mutations that lead to such a clonal expansion need not give a fitness advantage and may in fact be neutral--or almost neutral--with respect to fitness. Such mutant clones can be eliminated or expand stochastically, leading to a malignant phenotype (disease). Mutations in haematopoietic stem cells give rise to diseases such as chronic myeloid leukaemia (CML) and paroxysmal nocturnal haemoglobinuria (PNH). Although neutral drift often leads to clonal extinction, disease is still possible, and in this case, it has important implications both for the incidence of disease and for therapy, as it may be more difficult to eliminate neutral mutations with therapy. We illustrate the consequences of such dynamics, using CML and PNH as examples. These considerations have implications for many other tumours as well.

Mitochondrial and glycolytic metabolic compartmentalization in diffuse large B-cell lymphoma.

PubMed

Gooptu, Mahasweta; Whitaker-Menezes, Diana; Sprandio, John; Domingo-Vidal, Marina; Lin, Zhao; Uppal, Guldeep; Gong, Jerald; Fratamico, Roberto; Leiby, Benjamin; Dulau-Florea, Alina; Caro, Jaime; Martinez-Outschoorn, Ubaldo

2017-06-01

Metabolic heterogeneity between neoplastic cells and surrounding stroma has been described in several epithelial malignancies; however, the metabolic phenotypes of neoplastic lymphocytes and neighboring stroma in diffuse large B-cell lymphoma (DLBCL) is unknown. We investigated the metabolic phenotypes of human DLBCL tumors by using immunohistochemical markers of glycolytic and mitochondrial oxidative phosphorylation (OXPHOS) metabolism. The lactate importer MCT4 is a marker of glycolysis, whereas the lactate importer MCT1 and TOMM20 are markers of OXPHOS metabolism. Staining patterns were assessed in 33 DLBCL samples as well as 18 control samples (non-neoplastic lymph nodes). TOMM20 and MCT1 were highly expressed in neoplastic lymphocytes, indicating an OXPHOS phenotype, whereas non-neoplastic lymphocytes in the control samples did not express these markers. Stromal cells in DLBCL samples strongly expressed MCT4, displaying a glycolytic phenotype, a feature not seen in stromal elements of non-neoplastic lymphatic tissue. Furthermore, the differential expression of lactate exporters (MCT4) on tumor-associated stroma and lactate importers (MCT1) on neoplastic lymphocytes support the hypothesis that neoplastic cells are metabolically linked to the stroma likely via mutually beneficial reprogramming. MCT4 is a marker of tumor-associated stroma in neoplastic tissue. Our findings suggest that disruption of neoplastic-stromal cell metabolic heterogeneity including MCT1 and MCT4 blockade should be studied to determine if it could represent a novel treatment target in DLBCL. Copyright © 2017 Elsevier Inc. All rights reserved.

Notch-1 induces Epithelial-mesenchymal transition consistent with cancer stem cell phenotype in pancreatic cancer cells

PubMed Central

Bao, Bin; Wang, Zhiwei; Ali, Shadan; Kong, Dejuan; Li, Yiwei; Ahmad, Aamir; Banerjee, Sanjeev; Azmi, Asfar S.; Miele, Lucio; Sarkar, Fazlul H.

2011-01-01

Activation of Notch-1 is known to be associated with the development and progression of human malignancies including pancreatic cancer. Emerging evidence suggest that the acquisition of epithelial-mesenchymal transition (EMT) phenotype and induction of cancer stem cell (CSC) or cancer stem-like cell phenotype are interrelated and contributes to tumor recurrence and drug resistance. The molecular mechanism(s) by which Notch-1 contributes to the acquisition of EMT phenotype and CSC self-renewal capacity has not been fully elucidated. Here we show that forced over-expression of Notch-1 leads to increased cell growth, clonogenicity, migration and invasion of AsPC-1 cells. Moreover, over-expression of Notch-1 led to the induction of EMT phenotype by activation of mesenchymal cell markers such as ZEB1, CD44, EpCAM, and Hes 1. Here we also report, for the first time, that over-expression of Notch-1 leads to increased expression of miR-21, and decreased expression of miR-200b, miR-200c, let-7a, let-7b, and let-7c. Re-expression of miR-200b led to decreased expression of ZEB1, and vimentin, and increased expression of E-cadherin. Over-expression of Notch-1 also increased the formation of pancreatospheres consistent with expression of CSC surface markers CD44 and EpCAM. Finally, we found that genistein, a known natural anti-tumor agent inhibited cell growth, clonogenicity, migration, invasion, EMT phenotype, formation of pancreatospheres and expression of CD44 and EpCAM. These results suggest that the activation of Notch-1 signaling contributes to the acquisition of EMT phenotype, which is in part mediated through the regulation of miR-200b and CSC self-renewal capacity, and these processes could be attenuated by genistein treatment. PMID:21463919

The RET p.G533C mutation confers predisposition to multiple endocrine neoplasia type 2A in a Brazilian kindred and is able to induce a malignant phenotype in vitro and in vivo.

PubMed

Oliveira, Mariana N L; Hemerly, Jefferson P; Bastos, André U; Tamanaha, Rosana; Latini, Flavia R M; Camacho, Cléber P; Impellizzeri, Anelise; Maciel, Rui M B; Cerutti, Janete M

2011-09-01

We have previously described a p.G533C substitution in the rearranged during transfection (RET) oncogene in a large family with medullary thyroid carcinoma. Here, we explore the functional transforming potential of RET p.G533C mutation. Plasmids expressing RET mutants (p.G533C and p.C634Y) and RET wild type were stable transfected into a rat thyroid cell line (PCCL3). Biological and biochemical effects of RET p.G533C were investigated both in vitro and in vivo. Moreover, we report the first case of pheochromocytoma among the RET p.G533C-carriers in this Brazilian family and explore the RET mutational status in DNA isolated from pheochromocytoma. Ectopic expression of RET p.G533C and p.C634Y activates RET/MAPK/ERK pathway at similar levels and significantly increased cell proliferation, compared with RET wild type. We additionally show that p.G533C increased cell viability, anchorage-independent growth, and micronuclei formation while reducing apoptosis, hallmarks of the malignant phenotype. RET p.G533C down-regulates the expression of thyroid specific genes in PCCL3. Moreover, RET p.G533C-expressing cells were able to induce liver metastasis in nude mice. Finally, we described two novel RET variants (G548V and S556T) in the DNA isolated from pheochromocytoma while they were absent in the DNA isolated from blood. Our in vitro and in vivo analysis indicates that this mutation confers a malignant phenotype to PCCL3 cells. These findings, in association with the report of first case of pheochromocytoma in the Brazilian kindred, suggest that this noncysteine mutation may be more aggressive than was initially considered.

Nuclear NF-kappaB p65 phosphorylation at serine 276 by protein kinase A contributes to the malignant phenotype of head and neck cancer.

PubMed

Arun, Pattatheyil; Brown, Matthew S; Ehsanian, Reza; Chen, Zhong; Van Waes, Carter

2009-10-01

Aberrant nuclear activation and phosphorylation of the canonical NF-kappaB subunit RELA/p65 at Serine-536 by inhibitor kappaB kinase is prevalent in head and neck squamous cell carcinoma (HNSCC), but the role of other kinases in NF-kappaB activation has not been well defined. Here, we investigated the prevalence and function of p65-Ser276 phosphorylation by protein kinase A (PKA) in the malignant phenotype and gene transactivation, and studied p65-Ser276 as a potential target for therapy. Phospho and total p65 protein expression and localization were determined in HNSCC tissue array and in cell lines. The effects of the PKA inhibitor H-89 on NF-kappaB activation, downstream gene expression, cell proliferation and cell cycle were examined. Knockdown of PKA by specific siRNA confirmed the specificity. NF-kappaB p65 phosphorylated at Ser276 was prevalent in HNSCC and adjacent dysplastic mucosa, but localized to the cytoplasm in normal mucosa. In HNSCC lines, tumor necrosis factor-alpha (TNF-alpha) significantly increased, whereas H-89 inhibited constitutive and TNF-alpha-induced nuclear p65 (Ser276) phosphorylation, and significantly suppressed NF-kappaB and target gene IL-8 reporter activity. Knockdown of PKA by small interfering RNA inhibited NF-kappaB, IL-8, and BCL-XL reporter gene activities. H-89 suppressed cell proliferation, induced cell death, and blocked the cell cycle in G(1)-S phase. Consistent with its biological effects, H-89 down-modulated expression of NF-kappaB-related genes Cyclin D1, BCL2, BCL-XL, COX2, IL-8, and VEGF, as well as induced cell cycle inhibitor p21(CIP1/WAF1), while suppressing proliferative marker Ki67. NF-kappaB p65 (Ser276) phosphorylation by PKA promotes the malignant phenotype and holds potential as a therapeutic target in HNSCC.

Mesotrypsin promotes malignant growth of breast cancer cells through shedding of CD109

PubMed Central

Hockla, Alexandra; Radisky, Derek C.

2010-01-01

Serine proteases have been implicated in many stages of cancer development, facilitating tumor cell growth, invasion, and metastasis, and naturally occurring serine protease inhibitors have shown promise as potential anticancer therapeutics. Optimal design of inhibitors as potential therapeutics requires the identification of the specific serine proteases involved in disease progression and the functional targets responsible for the tumor-promoting properties. Here, we use the HMT-3522 breast cancer progression series grown in 3D organotypic culture conditions to find that serine protease inhibitors cause morphological reversion of the malignant T4-2 cells, assessed by inhibition of proliferation and formation of acinar structures with polarization of basal markers, implicating serine protease activity in their malignant growth behavior. We identify PRSS3/mesotrypsin upregulation in T4-2 cells as compared to their nonmalignant progenitors, and show that knockdown of PRSS3 attenuates, and treatment with recombinant purified mesotrypsin enhances, the malignant growth phenotype. Using proteomic methods, we identify CD109 as the functional proteolytic target of mesotrypsin. Our study identifies a new mediator and effector of breast cancer growth and progression. PMID:20035377

Molecular and Therapeutic Advances in the Diagnosis and Management of Malignant Pheochromocytomas and Paragangliomas

PubMed Central

Lowery, Aoife J.; Walsh, Siun; McDermott, Enda W.

2013-01-01

Pheochromocytomas (PCCs) and paragangliomas (PGLs) are rare catecholamine-secreting tumors derived from chromaffin cells originating in the neural crest. These tumors represent a significant diagnostic and therapeutic challenge because the diagnosis of malignancy is frequently made in retrospect by the development of metastatic or recurrent disease. Complete surgical resection offers the only potential for cure; however, recurrence can occur even after apparently successful resection of the primary tumor. The prognosis for malignant disease is poor because traditional treatment modalities have been limited. The last decade has witnessed exciting discoveries in the study of PCCs and PGLs; advances in molecular genetics have uncovered hereditary and germline mutations of at least 10 genes that contribute to the development of these tumors, and increasing knowledge of genotype-phenotype interactions has facilitated more accurate determination of malignant potential. Elucidating the molecular mechanisms responsible for malignant transformation in these tumors has opened avenues of investigation into targeted therapeutics that show promising results. There have also been significant advances in functional and radiological imaging and in the surgical approach to adrenalectomy, which remains the mainstay of treatment for PCC. In this review, we discuss the currently available diagnostic and therapeutic options for patients with malignant PCCs and PGLs and detail the molecular rationale and clinical evidence for novel and emerging diagnostic and therapeutic strategies. PMID:23576482

Monoclonal B lymphocytes with the characteristics of "indolent" chronic lymphocytic leukemia are present in 3.5% of adults with normal blood counts.

PubMed

Rawstron, Andy C; Green, Michael J; Kuzmicki, Anita; Kennedy, Ben; Fenton, James A L; Evans, Paul A S; O'Connor, Sheila J M; Richards, Stephen J; Morgan, Gareth J; Jack, Andrew S; Hillmen, Peter

2002-07-15

Molecular and cellular markers associated with malignant disease are frequently identified in healthy individuals. The relationship between these markers and clinical disease is not clear, except where a neoplastic cell population can be identified as in myeloma/monoclonal gammopathies of undetermined significance (MGUS). We have used the distinctive phenotype of chronic lymphocytic leukemia (CLL) cells to determine whether low levels of these cells can be identified in individuals with normal complete blood counts. CLL cells were identified by 4-color flow cytometric analysis of CD19/CD5/CD79b/CD20 expression in 910 outpatients over 40 years old. These outpatients were age- and sex-matched to the general population with normal hematologic parameters and no evident history of malignant disease. CLL phenotype cells were detectable in 3.5% of individuals at low level (median, 0.013; range, 0.002- 1.458 x 10(9) cells/L), and represented a minority of B lymphocytes (median, 11%; range, 3%-95%). Monoclonality was demonstrated by immunoglobulin light-chain restriction in all cases with CLL phenotype cells present and confirmed in a subset of cases by consensus-primer IgH-polymerase chain reaction. As in clinical disease, CLL phenotype cells were detected with a higher frequency in men (male-to-female ratio, 1.9:1) and elderly individuals (2.1% of 40- to 59-year-olds versus 5.0% of 60- to 89-year-olds, P =.01). The neoplastic cells were identical to good-prognosis CLL, being CD5+23+20(wk)79b(wk)11a(-)22(wk)sIg(wk)CD38-, and where assessed had a high degree (4.8%-6.6%) of IgH somatic hypermutation. The monoclonal CLL phenotype cells present in otherwise healthy individuals may represent a very early stage of indolent CLL and should be useful in elucidating the mechanisms of leukemogenesis.

Epigenetic regulation of gene expression in cancer: techniques, resources and analysis

PubMed Central

Kagohara, Luciane T; Stein-O’Brien, Genevieve L; Kelley, Dylan; Flam, Emily; Wick, Heather C; Danilova, Ludmila V; Easwaran, Hariharan; Favorov, Alexander V; Qian, Jiang; Gaykalova, Daria A; Fertig, Elana J

2018-01-01

Abstract Cancer is a complex disease, driven by aberrant activity in numerous signaling pathways in even individual malignant cells. Epigenetic changes are critical mediators of these functional changes that drive and maintain the malignant phenotype. Changes in DNA methylation, histone acetylation and methylation, noncoding RNAs, posttranslational modifications are all epigenetic drivers in cancer, independent of changes in the DNA sequence. These epigenetic alterations were once thought to be crucial only for the malignant phenotype maintenance. Now, epigenetic alterations are also recognized as critical for disrupting essential pathways that protect the cells from uncontrolled growth, longer survival and establishment in distant sites from the original tissue. In this review, we focus on DNA methylation and chromatin structure in cancer. The precise functional role of these alterations is an area of active research using emerging high-throughput approaches and bioinformatics analysis tools. Therefore, this review also describes these high-throughput measurement technologies, public domain databases for high-throughput epigenetic data in tumors and model systems and bioinformatics algorithms for their analysis. Advances in bioinformatics data that combine these epigenetic data with genomics data are essential to infer the function of specific epigenetic alterations in cancer. These integrative algorithms are also a focus of this review. Future studies using these emerging technologies will elucidate how alterations in the cancer epigenome cooperate with genetic aberrations during tumor initiation and progression. This deeper understanding is essential to future studies with epigenetics biomarkers and precision medicine using emerging epigenetic therapies. PMID:28968850

Effects of raf kinase inhibitor protein expression on metastasis and progression of human breast cancer.

PubMed

Li, Hong Zhao; Gao, Yan; Zhao, Xiu Lan; Liu, Yi Xin; Sun, Bao Cun; Yang, Jie; Yao, Zhi

2009-06-01

Raf kinase inhibitor protein (RKIP) has been shown to be a metastasis suppressor in many kinds of malignant tumors. But its function in breast cancer was not yet clarified completely. We detected RKIP expression in clinical samples of primary breast cancer, breast cancer metastases, and in different breast cancer cells. Compared with the normal breast epithelia, benign breast epithelia, or in situ ductal carcinoma, the expression level of RKIP is decreased in invasive carcinoma and significantly reduced or lost in the metastasis lymph node matched to the invasive carcinoma. To explore the potential role of RKIP in breast cancer metastasis, we studied the effect of RKIP on the malignant phenotypes of the breast cancer cells with ectopically overexpression or knockdown of RKIP. Cell proliferation, soft-agar colony formation, in vitro adhesion assay, invasion, and migation assays were done to examine the malignant phenotypes of the transfected cells. Consequently, RKIP has no effect on in vitro proliferation rate or colony-forming ability of MDA-MB-435 cells. In vitro cell invasion and migration assays indicated that the RKIP expression was inversely associated with the invasiveness of MDA-MB-435 cells. Consistent with these results, in the orthotopic murine models, we observed that overexpression of RKIP in breast cancer cells impaired invasiveness and metastasis, whereas down-regulation of RKIP expression promoted invasiveness and metastasis. These results indicate that RKIP is a metastasis suppressor gene of human breast cancer.

Chitosan-alginate 3D scaffolds as a mimic of the glioma tumor microenvironment.

PubMed

Kievit, Forrest M; Florczyk, Stephen J; Leung, Matthew C; Veiseh, Omid; Park, James O; Disis, Mary L; Zhang, Miqin

2010-08-01

Despite recent advances in the understanding of its cell biology, glioma remains highly lethal. Development of effective therapies requires a cost-effective in vitro tumor model that more accurately resembles the in vivo tumor microenvironment as standard two-dimensional (2D) tissue culture conditions do so poorly. Here we report on the use of a three-dimensional (3D) chitosan-alginate (CA) scaffold to serve as an extracellular matrix that promotes the conversion of cultured cancer cells to a more malignant in vivo-like phenotype. Human U-87 MG and U-118 MG glioma cells and rat C6 glioma cells were chosen for the study. In vitro tumor cell proliferation and secretion of factors that promote tumor malignancy, including VEGF, MMP-2, fibronectin, and laminin, were assessed. The scaffolds pre-cultured with U-87 MG and C6 cells were then implanted into nude mice to evaluate tumor growth and blood vessel recruitment compared to the standard 2D cell culture and 3D Matrigel matrix xenograft controls. Our results indicate that while the behavior of C6 cells showed minimal differences due to their highly malignant and invasive nature, U-87 MG and U-118 MG cells exhibited notably higher malignancy when cultured in CA scaffolds. CA scaffolds provide a 3D microenvironment for glioma cells that is more representative of the in vivo tumor, thus can serve as a more effective platform for development and study of anticancer therapeutics. This unique CA scaffold platform may offer a valuable alternative strategy to the time-consuming and costly animal studies for a wide variety of experimental designs. Copyright 2010 Elsevier Ltd. All rights reserved.

Is it time for a new paradigm for systemic cancer treatment? Lessons from a century of cancer chemotherapy

PubMed Central

Crawford, Sarah

2013-01-01

U.S. SEER (Surveillance Epidemiology and End Results) data for age-adjusted mortality rates for all cancers combined for all races show only a modest overall 13% decline over the past 35 years. Moreover, the greatest contributor to cancer mortality is treatment-resistant metastatic disease. The accepted therapeutic paradigm for the past half-century for the treatment of advanced cancers has involved the use of systemic chemotherapy drugs cytotoxic for cycling cells (both normal and malignant) during DNA synthesis and/or mitosis. The failure of this therapeutic modality to achieve high-level, consistent rates of disease-free survival for some of the most common cancers, including tumors of the lung, colon breast, brain, melanoma, and others is the focus of this paper. A retrospective assessment of critical milestones in cancer chemotherapy indicates that most successful therapeutic regimens use cytotoxic cell cycle inhibitors in combined, maximum tolerated, dose-dense acute treatment regimens originally developed to treat acute lymphoblastic leukemia and some lymphomas. Early clinical successes in this area led to their wholesale application to the treatment of solid tumor malignancies that, unfortunately, has not produced consistent, long-term high cure rates for many common cancers. Important differences in therapeutic sensitivity of leukemias/lymphomas versus solid tumors can be explained by key biological differences that define the treatment-resistant solid tumor phenotype. A review of these clinical outcome data in the context of recent developments in our understanding of drug resistance mechanisms characteristic of solid tumors suggests the need for a new paradigm for the treatment of chemotherapy-resistant cancers. In contrast to reductionist approaches, the systemic approach targets both microenvironmental and systemic factors that drive and sustain tumor progression. These systemic factors include dysregulated inflammatory and oxidation pathways shown to be directly implicated in the development and maintenance of the cancer phenotype. The paradigm stresses the importance of a combined preventive/therapeutic approach involving adjuvant chemotherapies that incorporate anti-inflammatory and anti-oxidant therapeutics. PMID:23805101

Gene expression profiling identifies inflammation and angiogenesis as distinguishing features of canine hemangiosarcoma.

PubMed

Tamburini, Beth A; Phang, Tzu L; Fosmire, Susan P; Scott, Milcah C; Trapp, Susan C; Duckett, Megan M; Robinson, Sally R; Slansky, Jill E; Sharkey, Leslie C; Cutter, Gary R; Wojcieszyn, John W; Bellgrau, Donald; Gemmill, Robert M; Hunter, Lawrence E; Modiano, Jaime F

2010-11-09

The etiology of hemangiosarcoma remains incompletely understood. Its common occurrence in dogs suggests predisposing factors favor its development in this species. These factors could represent a constellation of heritable characteristics that promote transformation events and/or facilitate the establishment of a microenvironment that is conducive for survival of malignant blood vessel-forming cells. The hypothesis for this study was that characteristic molecular features distinguish hemangiosarcoma from non-malignant endothelial cells, and that such features are informative for the etiology of this disease. We first investigated mutations of VHL and Ras family genes that might drive hemangiosarcoma by sequencing tumor DNA and mRNA (cDNA). Protein expression was examined using immunostaining. Next, we evaluated genome-wide gene expression profiling using the Affymetrix Canine 2.0 platform as a global approach to test the hypothesis. Data were evaluated using routine bioinformatics and validation was done using quantitative real time RT-PCR. Each of 10 tumor and four non-tumor samples analyzed had wild type sequences for these genes. At the genome wide level, hemangiosarcoma cells clustered separately from non-malignant endothelial cells based on a robust signature that included genes involved in inflammation, angiogenesis, adhesion, invasion, metabolism, cell cycle, signaling, and patterning. This signature did not simply reflect a cancer-associated angiogenic phenotype, as it also distinguished hemangiosarcoma from non-endothelial, moderately to highly angiogenic bone marrow-derived tumors (lymphoma, leukemia, osteosarcoma). The data show that inflammation and angiogenesis are important processes in the pathogenesis of vascular tumors, but a definitive ontogeny of the cells that give rise to these tumors remains to be established. The data do not yet distinguish whether functional or ontogenetic plasticity creates this phenotype, although they suggest that cells which give rise to hemangiosarcoma modulate their microenvironment to promote tumor growth and survival. We propose that the frequent occurrence of canine hemangiosarcoma in defined dog breeds, as well as its similarity to homologous tumors in humans, offers unique models to solve the dilemma of stem cell plasticity and whether angiogenic endothelial cells and hematopoietic cells originate from a single cell or from distinct progenitor cells.

Gene expression profiling identifies inflammation and angiogenesis as distinguishing features of canine hemangiosarcoma

PubMed Central

2010-01-01

Background The etiology of hemangiosarcoma remains incompletely understood. Its common occurrence in dogs suggests predisposing factors favor its development in this species. These factors could represent a constellation of heritable characteristics that promote transformation events and/or facilitate the establishment of a microenvironment that is conducive for survival of malignant blood vessel-forming cells. The hypothesis for this study was that characteristic molecular features distinguish hemangiosarcoma from non-malignant endothelial cells, and that such features are informative for the etiology of this disease. Methods We first investigated mutations of VHL and Ras family genes that might drive hemangiosarcoma by sequencing tumor DNA and mRNA (cDNA). Protein expression was examined using immunostaining. Next, we evaluated genome-wide gene expression profiling using the Affymetrix Canine 2.0 platform as a global approach to test the hypothesis. Data were evaluated using routine bioinformatics and validation was done using quantitative real time RT-PCR. Results Each of 10 tumor and four non-tumor samples analyzed had wild type sequences for these genes. At the genome wide level, hemangiosarcoma cells clustered separately from non-malignant endothelial cells based on a robust signature that included genes involved in inflammation, angiogenesis, adhesion, invasion, metabolism, cell cycle, signaling, and patterning. This signature did not simply reflect a cancer-associated angiogenic phenotype, as it also distinguished hemangiosarcoma from non-endothelial, moderately to highly angiogenic bone marrow-derived tumors (lymphoma, leukemia, osteosarcoma). Conclusions The data show that inflammation and angiogenesis are important processes in the pathogenesis of vascular tumors, but a definitive ontogeny of the cells that give rise to these tumors remains to be established. The data do not yet distinguish whether functional or ontogenetic plasticity creates this phenotype, although they suggest that cells which give rise to hemangiosarcoma modulate their microenvironment to promote tumor growth and survival. We propose that the frequent occurrence of canine hemangiosarcoma in defined dog breeds, as well as its similarity to homologous tumors in humans, offers unique models to solve the dilemma of stem cell plasticity and whether angiogenic endothelial cells and hematopoietic cells originate from a single cell or from distinct progenitor cells. PMID:21062482

Stochastic modeling and experimental analysis of phenotypic switching and survival of cancer cells under stress

NASA Astrophysics Data System (ADS)

Zamani Dahaj, Seyed Alireza; Kumar, Niraj; Sundaram, Bala; Celli, Jonathan; Kulkarni, Rahul

The phenotypic heterogeneity of cancer cells is critical to their survival under stress. A significant contribution to heterogeneity of cancer calls derives from the epithelial-mesenchymal transition (EMT), a conserved cellular program that is crucial for embryonic development. Several studies have investigated the role of EMT in growth of early stage tumors into invasive malignancies. Also, EMT has been closely associated with the acquisition of chemoresistance properties in cancer cells. Motivated by these studies, we analyze multi-phenotype stochastic models of the evolution of cancers cell populations under stress. We derive analytical results for time-dependent probability distributions that provide insights into the competing rates underlying phenotypic switching (e.g. during EMT) and the corresponding survival of cancer cells. Experimentally, we evaluate these model-based predictions by imaging human pancreatic cancer cell lines grown with and without cytotoxic agents and measure growth kinetics, survival, morphological changes and (terminal evaluation of) biomarkers with associated epithelial and mesenchymal phenotypes. The results derived suggest approaches for distinguishing between adaptation and selection scenarios for survival in the presence of external stresses.

Experimental obstructive cholestasis: the wound-like inflammatory liver response

PubMed Central

Aller, María-Angeles; Arias, Jorge-Luis; García-Domínguez, Jose; Arias, Jose-Ignacio; Durán, Manuel; Arias, Jaime

2008-01-01

Obstructive cholestasis causes hepatic cirrhosis and portal hypertension. The pathophysiological mechanisms involved in the development of liver disease are multiple and linked. We propose grouping these mechanisms according to the three phenotypes mainly expressed in the interstitial space in order to integrate them. Experimental extrahepatic cholestasis is the model most frequently used to study obstructive cholestasis. The early liver interstitial alterations described in these experimental models would produce an ischemia/reperfusion phenotype with oxidative and nitrosative stress. Then, the hyperexpression of a leukocytic phenotype, in which Kupffer cells and neutrophils participate, would induce enzymatic stress. And finally, an angiogenic phenotype, responsible for peribiliary plexus development with sinusoidal arterialization, occurs. In addition, an intense cholangiocyte proliferation, which acquires neuroendocrine abilities, stands out. This histopathological finding is also associated with fibrosis. It is proposed that the sequence of these inflammatory phenotypes, perhaps with a trophic meaning, ultimately produces a benign tumoral biliary process – although it poses severe hepatocytic insufficiency. Moreover, the persistence of this benign tumor disease would induce a higher degree of dedifferentiation and autonomy and, therefore, its malign degeneration. PMID:19014418

Tumour Cell Heterogeneity

PubMed Central

Gay, Laura; Baker, Ann-Marie; Graham, Trevor A.

2016-01-01

The population of cells that make up a cancer are manifestly heterogeneous at the genetic, epigenetic, and phenotypic levels. In this mini-review, we summarise the extent of intra-tumour heterogeneity (ITH) across human malignancies, review the mechanisms that are responsible for generating and maintaining ITH, and discuss the ramifications and opportunities that ITH presents for cancer prognostication and treatment. PMID:26973786

THE EFFECT OF A TARGETED KNOCKOUT MUTATION ON THE TRANSCRIPTIONAL PROFILE OF THE KIDNEY IN TSC2 MUTANT (EKER) RATS.

EPA Science Inventory

Renal cell carcinoma (RCC) is the most common tumor of the adult kidney, accounting for up to 80% of malignant renal neoplasms. Hereditary RCC in the Eker rat, which bear a number of cellular, molecular and phenotypic similarities to human RCC, results from an inherited insertion...

Preclinical evaluation of antiangiogenic thrombospondin-1 peptide mimetics, ABT-526 and ABT-510, in companion dogs with naturally occurring cancers.

PubMed

Rusk, Anthony; McKeegan, Evelyn; Haviv, Fortuna; Majest, Sandra; Henkin, Jack; Khanna, Chand

2006-12-15

The angiogenic phenotype of malignant cancers has been established as a target for cancer therapy. ABT-526 and ABT-510, two peptide mimetics of thrombospondin-1 (TSP-1), block angiogenesis in vitro and in vivo and slow tumor growth in mice. To guide the clinical development of these drugs, translational studies in dogs with naturally occurring cancers were initiated. A prospective open-label trial using ABT-510 or ABT-526 in pet dogs with measurable malignant spontaneously arising tumors. Endpoints included safety, pharmacokinetics, antitumor activity, and preliminary assessment of changes in circulating endothelial cell populations. Two-hundred and forty-two dogs were sequentially entered to this open-label trial. The elimination half-life for ABT-510 and ABT-526 was 0.7 and 0.8 h, respectively (range, 0.5-1 h). No dose-limiting toxicities were seen in any dogs (N = 242). Forty-two dogs receiving peptide had objective responses (>50% reduction in tumor size; n = 6) or significant disease stabilization. Most objective responses were seen after 60 days of exposure to the TSP-1 peptide. Antitumor activity was similar for both peptides and was seen in several histologies, including mammary carcinoma, head and neck carcinoma, soft tissue sarcoma, cutaneous T-cell lymphoma, and non-Hodgkin's lymphoma. Assessment of circulating endothelial cell populations in a small subset of dogs suggested that effective exposure to TSP-1 peptides may be associated with reductions in circulating endothelial cells. These results support the safety and activity of ABT-526 and ABT-510 in dogs with naturally occurring malignant cancers. Data from this preclinical trial support the development of TSP-1 mimetic peptides as anticancer agents.

Tumor malignancy is engaged to prokaryotic homolog toolbox.

PubMed

Fernandes, Janaina; Guedes, Patrícia G; Lage, Celso Luiz S; Rodrigues, Juliany Cola F; Lage, Claudia de Alencar S

2012-04-01

Cancer cells display high proliferation rates and survival provided by high glycolysis, chemoresistance and radioresistance, metabolic features that appear to be activated with malignancy, and seemed to have arisen as early in evolution as in unicellular/prokaryotic organisms. Based on these assumptions, we hypothesize that aggressive phenotypes found in malignant cells may be related to acquired unicellular behavior, launched within a tumor when viral and prokaryotic homologs are overexpressed performing likely robust functions. The ensemble of these expressed viral and prokaryotic close homologs in the proteome of a tumor tissue gives them advantage over normal cells. To assess the hypothesis validity, sequences of human proteins involved in apoptosis, energetic metabolism, cell mobility and adhesion, chemo- and radio-resistance were aligned to homologs present in other life forms, excluding all eukaryotes, using PSI-BLAST, with further corroboration from data available in the literature. The analysis revealed that selected sequences of proteins involved in apoptosis and tumor suppression (as p53 and pRB) scored non-significant (E-value>0.001) with prokaryotic homologs; on the other hand, human proteins involved in cellular chemo- and radio-resistance scored highly significant with prokaryotic and viral homologs (as catalase, E-value=zero). We inferred that such upregulated and/or functionally activated proteins in aggressive malignant cells represent a toolbox of modern human homologs evolved from a similar key set that have granted survival of ancient prokaryotes against extremely harsh environments. According to what has been discussed along this analysis, high mutation rates usually hit hotspots in important conserved protein domains, allowing uncontrolled expansion of more resistant, death-evading malignant clones. That is the case of point mutations in key viral proteins affording viruses escape to chemotherapy, and human homologs of such retroviral proteins (as Ras, Akt and EGFR) can elicit the same phenotype. Furthermore, a corollary to this hypothesis presumes that target-directed anti-cancer therapy should target human protein domains of low similarity to prokaryotic homologs for a well-succeeded anti-cancer therapy. Copyright © 2012 Elsevier Ltd. All rights reserved.

Deep sequencing of the small RNA transcriptome of normal and malignant human B cells identifies hundreds of novel microRNAs

PubMed Central

Jima, Dereje D.; Zhang, Jenny; Jacobs, Cassandra; Richards, Kristy L.; Dunphy, Cherie H.; Choi, William W. L.; Yan Au, Wing; Srivastava, Gopesh; Czader, Magdalena B.; Rizzieri, David A.; Lagoo, Anand S.; Lugar, Patricia L.; Mann, Karen P.; Flowers, Christopher R.; Bernal-Mizrachi, Leon; Naresh, Kikkeri N.; Evens, Andrew M.; Gordon, Leo I.; Luftig, Micah; Friedman, Daphne R.; Weinberg, J. Brice; Thompson, Michael A.; Gill, Javed I.; Liu, Qingquan; How, Tam; Grubor, Vladimir; Gao, Yuan; Patel, Amee; Wu, Han; Zhu, Jun; Blobe, Gerard C.; Lipsky, Peter E.; Chadburn, Amy

2010-01-01

A role for microRNA (miRNA) has been recognized in nearly every biologic system examined thus far. A complete delineation of their role must be preceded by the identification of all miRNAs present in any system. We elucidated the complete small RNA transcriptome of normal and malignant B cells through deep sequencing of 31 normal and malignant human B-cell samples that comprise the spectrum of B-cell differentiation and common malignant phenotypes. We identified the expression of 333 known miRNAs, which is more than twice the number previously recognized in any tissue type. We further identified the expression of 286 candidate novel miRNAs in normal and malignant B cells. These miRNAs were validated at a high rate (92%) using quantitative polymerase chain reaction, and we demonstrated their application in the distinction of clinically relevant subgroups of lymphoma. We further demonstrated that a novel miRNA cluster, previously annotated as a hypothetical gene LOC100130622, contains 6 novel miRNAs that regulate the transforming growth factor-β pathway. Thus, our work suggests that more than a third of the miRNAs present in most cellular types are currently unknown and that these miRNAs may regulate important cellular functions. PMID:20733160

Microglia and Macrophages in Malignant Gliomas: Recent Discoveries and Implications for Promising Therapies

PubMed Central

Carvalho da Fonseca, Anna Carolina; Badie, Behnam

2013-01-01

Malignant gliomas are the most common primary brain tumors. Their deadliest manifestation, glioblastoma multiforme (GBM), accounts for 15% of all primary brain tumors and is associated with a median survival of only 15 months even after multimodal therapy. There is substantial presence of microglia and macrophages within and surrounding brain tumors. These immune cells acquire an alternatively activated phenotype with potent tumor-tropic functions that contribute to glioma growth and invasion. In this review, we briefly summarize recent data that has been reported on the interaction of microglia/macrophages with brain tumors and discuss potential application of these findings to the development of future antiglioma therapies. PMID:23864876

A Transgenic Drosophila melanogaster Model To Study Human T-Lymphotropic Virus Oncoprotein Tax-1-Driven Transformation In Vivo.

PubMed

Shirinian, Margret; Kambris, Zakaria; Hamadeh, Lama; Grabbe, Caroline; Journo, Chloé; Mahieux, Renaud; Bazarbachi, Ali

2015-08-01

Human T-cell lymphotropic virus type 1 (HTLV-1)-induced adult T-cell leukemia/lymphoma is an aggressive malignancy. HTLV-2 is genetically related to HTLV-1 but does not cause any malignant disease. HTLV-1 Tax transactivator (Tax-1) contributes to leukemogenesis via NF-κB. We describe transgenic Drosophila models expressing Tax in the compound eye and plasmatocytes. We demonstrate that Tax-1 but not Tax-2 induces ommatidial perturbation and increased plasmatocyte proliferation and that the eye phenotype is dependent on Kenny (IKKγ/NEMO), thus validating this new in vivo model. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Cutaneous double-hit B-cell lymphoma: an aggressive form of B-cell lymphoma with a propensity for cutaneous dissemination.

PubMed

Magro, Cynthia M; Wang, Xuan; Subramaniyam, Shivakumar; Darras, Natasha; Mathew, Susan

2014-04-01

Diffuse large cell B-cell lymphoma of the skin is most commonly represented by diffuse large cell variants of primary cutaneous follicle center cell lymphoma and the leg-type lymphoma. In a minority of cases, the infiltrates are an expression of stage 4 disease of established extracutaneous B-cell lymphoma. We describe 3 patients with an aggressive form of B-cell lymphoma secondarily involving the skin. Two of the patients were in the ninth decade of life, whereas 1 patient was 34 years of age. In the elderly patients, there was an antecedent and/or concurrent history of follicular lymphoma, whereas in the younger patient, the tumor was a de novo presentation of this aggressive form of lymphoma. The elderly patients succumbed to their disease within less than a year from the time of diagnosis, whereas 1 patient is alive but with persistent and progressive disease despite chemotherapeutic intervention. The infiltrates in all 3 cases were diffuse and composed of large malignant hematopoietic cells that exhibited a round nucleus with a finely dispersed chromatin. Phenotypically, the tumor cells were Bcl-2 and CD10 positive, whereas Bcl-6 and Mum-1 showed variable positivity. One case showed combined Mum-1 positivity along with an acute lymphoblastic lymphoma phenotype, including the absence of CD20 expression. In each case, there was a c-MYC and BCL2/IGH rearrangement diagnostic of double-hit lymphoma. In one case, there was an additional BCL6 rearrangement, defining what is in essence triple-hit lymphoma. In conclusion, double-hit lymphoma is an aggressive form of B-cell neoplasia resistant to standard chemotherapy regimens, which in many but not all cases represents tumor progression in the setting of a lower grade B-cell malignancy.

Loss of One or Two PATZ1 Alleles Has a Critical Role in the Progression of Thyroid Carcinomas Induced by the RET/PTC1 Oncogene

PubMed Central

Palma, Giuseppe; Vitiello, Michela; Capiluongo, Anna; D’Andrea, Barbara; Vuttariello, Emilia; Luciano, Antonio; Cerchia, Laura; Chiappetta, Gennaro; Arra, Claudio; Fusco, Alfredo

2018-01-01

POZ/BTB and AT-hook-containing zinc finger protein 1 (PATZ1) is an emerging cancer-related gene that is downregulated in different human malignancies, including thyroid cancer, where its levels gradually decrease going from papillary thyroid carcinomas (PTC) to poorly differentiated and undifferentiated highly aggressive anaplastic carcinomas (ATC). The restoration of PATZ1 expression in thyroid cancer cells reverted their malignant phenotype by inducing mesenchymal-to-epithelial transition, thus validating a tumor suppressor role for PATZ1 and suggesting its involvement in thyroid cancer progression. Here, we investigated the consequences of the homozygous and heterozygous loss of PATZ1 in the context of a mouse modeling of PTC, represented by mice carrying the RET/PTC1 oncogene under the thyroid specific control of the thyroglobulin promoter RET/PTC1 (RET/PTC1TG). The phenotypic analysis of RET/PTC1TG mice intercrossed with Patz1-knockout mice revealed that deficiency of both Patz1 alleles enhanced thyroid cancer incidence in RET/PTC1TG mice, but not the heterozygous knockout of the Patz1 gene. However, both RET/PTC1TG;Patz1+/− and RET/PTC1TG;Patz1−/− mice developed a more aggressive thyroid cancer phenotype—characterized by higher Ki-67 expression, presence of ATCs, and increased incidence of solid variants of PTC—than that shown by RET/PTC1TG; Patz1+/+ compound mice. These results confirm that PATZ1 downregulation has a critical role in thyroid carcinogenesis, showing that it cooperates with RET/PTC1 in thyroid cancer progression. PMID:29584698

Distinct transcriptional MYCN/c-MYC activities are associated with spontaneous regression or malignant progression in neuroblastomas

PubMed Central

Westermann, Frank; Muth, Daniel; Benner, Axel; Bauer, Tobias; Henrich, Kai-Oliver; Oberthuer, André; Brors, Benedikt; Beissbarth, Tim; Vandesompele, Jo; Pattyn, Filip; Hero, Barbara; König, Rainer; Fischer, Matthias; Schwab, Manfred

2008-01-01

Background Amplified MYCN oncogene resulting in deregulated MYCN transcriptional activity is observed in 20% of neuroblastomas and identifies a highly aggressive subtype. In MYCN single-copy neuroblastomas, elevated MYCN mRNA and protein levels are paradoxically associated with a more favorable clinical phenotype, including disseminated tumors that subsequently regress spontaneously (stage 4s-non-amplified). In this study, we asked whether distinct transcriptional MYCN or c-MYC activities are associated with specific neuroblastoma phenotypes. Results We defined a core set of direct MYCN/c-MYC target genes by applying gene expression profiling and chromatin immunoprecipitation (ChIP, ChIP-chip) in neuroblastoma cells that allow conditional regulation of MYCN and c-MYC. Their transcript levels were analyzed in 251 primary neuroblastomas. Compared to localized-non-amplified neuroblastomas, MYCN/c-MYC target gene expression gradually increases from stage 4s-non-amplified through stage 4-non-amplified to MYCN amplified tumors. This was associated with MYCN activation in stage 4s-non-amplified and predominantly c-MYC activation in stage 4-non-amplified tumors. A defined set of MYCN/c-MYC target genes was induced in stage 4-non-amplified but not in stage 4s-non-amplified neuroblastomas. In line with this, high expression of a subset of MYCN/c-MYC target genes identifies a patient subtype with poor overall survival independent of the established risk markers amplified MYCN, disease stage, and age at diagnosis. Conclusions High MYCN/c-MYC target gene expression is a hallmark of malignant neuroblastoma progression, which is predominantly driven by c-MYC in stage 4-non-amplified tumors. In contrast, moderate MYCN function gain in stage 4s-non-amplified tumors induces only a restricted set of target genes that is still compatible with spontaneous regression. PMID:18851746

Sox11 expression in astrocytic gliomas: correlation with nestin/c-Met/IDH1-R132H expression phenotypes, p-Stat-3 and survival

PubMed Central

Korkolopoulou, P; Levidou, G; El-Habr, E A; Adamopoulos, C; Fragkou, P; Boviatsis, E; Themistocleous, M S; Petraki, K; Vrettakos, G; Sakalidou, M; Samaras, V; Zisakis, A; Saetta, A; Chatziandreou, I; Patsouris, E; Piperi, C

2013-01-01

Background: Sox11 is a transcription factor expressed in foetal and neoplastic brain tissue, including gliomas. It has been shown to suppress the tumourigenicity of glioma stem cells in vivo, thereby being hypothesised to function as a tumour suppressor. Methods: We investigated the expression of Sox11 in 132 diffuse astrocytomas in relation to the regulator cell marker nestin, c-Met and IDH1-R132H, which have shown to be differentially expressed among the molecular subgroups of malignant gliomas, as well as to an inducer of astrocytic differentiation, that is, signal transducer and activator of transcription (p-STAT-3), clinicopathological features and survival. Results: Sox11 immunoreactivity was identified in all tumours irrespective of grade, but being correlated with p-STAT-3. Three out of seven cases showed partial Sox11 promoter methylation. In >50% of our cases neoplastic cells coexpressed Sox11 and nestin, a finding further confirmed in primary glioblastoma cell cultures. Furthermore, nestin, c-Met and IDH1-R132H expression differed among grade categories. Cluster analysis identified four groups of patients according to c-Met, nestin and IDH1-R132H expression. The c-Met/nestin high-expressor group displayed a higher Sox11 expression. Sox11 expression was an indicator of favourable prognosis in glioblastomas, which remained in multivariate analysis and validated in an independent set of 72 cases. The c-Met/nestin high-expressor group was marginally with shorter survival in univariate analysis. Conclusions: We highlight the importance of Sox11 expression as a favourable prognosticator in glioblastomas. c-Met/nestin/IDH1-R132H expression phenotypes recapitulate the molecular subgroups of malignant glioma. PMID:23619925

Sox11 expression in astrocytic gliomas: correlation with nestin/c-Met/IDH1-R132H expression phenotypes, p-Stat-3 and survival.

PubMed

Korkolopoulou, P; Levidou, G; El-Habr, E A; Adamopoulos, C; Fragkou, P; Boviatsis, E; Themistocleous, M S; Petraki, K; Vrettakos, G; Sakalidou, M; Samaras, V; Zisakis, A; Saetta, A; Chatziandreou, I; Patsouris, E; Piperi, C

2013-05-28

Sox11 is a transcription factor expressed in foetal and neoplastic brain tissue, including gliomas. It has been shown to suppress the tumourigenicity of glioma stem cells in vivo, thereby being hypothesised to function as a tumour suppressor. We investigated the expression of Sox11 in 132 diffuse astrocytomas in relation to the regulator cell marker nestin, c-Met and IDH1-R132H, which have shown to be differentially expressed among the molecular subgroups of malignant gliomas, as well as to an inducer of astrocytic differentiation, that is, signal transducer and activator of transcription (p-STAT-3), clinicopathological features and survival. Sox11 immunoreactivity was identified in all tumours irrespective of grade, but being correlated with p-STAT-3. Three out of seven cases showed partial Sox11 promoter methylation. In >50% of our cases neoplastic cells coexpressed Sox11 and nestin, a finding further confirmed in primary glioblastoma cell cultures. Furthermore, nestin, c-Met and IDH1-R132H expression differed among grade categories. Cluster analysis identified four groups of patients according to c-Met, nestin and IDH1-R132H expression. The c-Met/nestin high-expressor group displayed a higher Sox11 expression. Sox11 expression was an indicator of favourable prognosis in glioblastomas, which remained in multivariate analysis and validated in an independent set of 72 cases. The c-Met/nestin high-expressor group was marginally with shorter survival in univariate analysis. We highlight the importance of Sox11 expression as a favourable prognosticator in glioblastomas. c-Met/nestin/IDH1-R132H expression phenotypes recapitulate the molecular subgroups of malignant glioma.

Reversing glioma malignancy: a new look at the role of antidepressant drugs as adjuvant therapy for glioblastoma multiforme.

PubMed

Bielecka-Wajdman, Anna M; Lesiak, Marta; Ludyga, Tomasz; Sieroń, Aleksander; Obuchowicz, Ewa

2017-06-01

The role of glioma stem cells (GSCs) in cancer progression is currently debated; however, it is hypothesised that this subpopulation is partially responsible for therapeutic resistance observed in glioblastoma multiforme (GBM). Recent studies have shown that the current treatments not only fail to eliminate the GSC population but even promote GSCs through reprogramming of glioma non-stem cells to stem cells. Since the standard GBM treatment often requires supplementation with adjuvant drugs such as antidepressants, their role in the regulation of the heterogeneous nature of GSCs needs evaluation. We examined the effects of imipramine, amitriptyline, fluoxetine, mirtazapine, agomelatine, escitalopram, and temozolomide on the phenotypic signature (CD44, Ki67, Nestin, Sox1, and Sox2 expression) of GSCs isolated from a human T98G cell line. These drugs were examined in several models of hypoxia (1% oxygen, 2.5% oxygen, and a hypoxia-reoxygenation model) as compared to the standard laboratory conditions (20% oxygen). We report that antidepressant drugs, particularly imipramine and amitriptyline, modulate plasticity, silence the GSC profile, and partially reverse the malignant phenotype of GBM. Moreover, we observed that, in contrast to temozolomide, these tricyclic antidepressants stimulated viability and mitochondrial activity in normal human astrocytes. The ability of phenotype switching from GSC to non-GSC as stimulated by antidepressants (primarily imipramine and amitriptyline) sheds new light on the heterogeneous nature of GSC, as well as the role of antidepressants in adjuvant GBM therapy.

Compound RYR1 heterozygosity resulting in a complex phenotype of malignant hyperthermia susceptibility and a core myopathy.

PubMed

Kraeva, N; Heytens, L; Jungbluth, H; Treves, S; Voermans, N; Kamsteeg, E; Ceuterick-de Groote, C; Baets, J; Riazi, S

2015-07-01

Malignant hyperthermia (MH) is a potentially fatal pharmacogenetic myopathy triggered by exposure to volatile anesthetics and/or depolarizing muscle relaxants. Susceptibility to MH is primarily associated with dominant mutations in the ryanodine receptor type 1 gene (RYR1). Recent genetic studies have shown that RYR1 variants are the most common cause of dominant and recessive congenital myopathies - central core and multi-minicore disease, congenital fiber type disproportion, and centronuclear myopathy. However, the MH status of many patients, especially with recessive RYR1-related myopathies, remains uncertain. We report the occurrence of a triplet of RYR1 variants, c.4711A>G (p.Ile1571Val), c.10097G>A (p.Arg3366His), c.11798A>G (p.Tyr3933Cys), found in cis in four unrelated families, one from Belgium, one from The Netherlands and two from Canada. Phenotype-genotype correlation analysis indicates that the presence of the triplet allele alone confers susceptibility to MH, and that the presence of this allele in a compound heterozygous state with the MH-associated RYR1 variant c.14545G>A (p.Val4849Ile) results in the MH susceptibility phenotype and a congenital myopathy with cores and rods. Our study underlines the notion that assigning pathogenicity to individual RYR1 variants or combination of variants, and counseling in RYR1-related myopathies may require integration of clinical, histopathological, in vitro contracture testing, MRI and genetic findings. Copyright © 2015 Elsevier B.V. All rights reserved.

Tissue Inhibitor of Metalloproteinase 1 Expression Associated with Gene Demethylation Confers Anoikis Resistance in Early Phases of Melanocyte Malignant Transformation1

PubMed Central

Ricca, Tatiana I; Liang, Gangning; Suenaga, Ana Paula M; Han, Sang W; Jones, Peter A; Jasiulionis, Miriam G

2009-01-01

Although anoikis resistance has been considered a hallmark of malignant phenotype, the causal relation between neoplastic transformation and anchorage-independent growth remains undefined. We developed an experimental model of murine melanocyte malignant transformation, where a melanocyte lineage (melan-a) was submitted to sequential cycles of anchorage blockade, resulting in progressive morphologic alterations, and malignant transformation. Throughout this process, cells corresponding to premalignant melanocytes and melanoma cell lines were established and show progressive anoikis resistance and increased expression of Timp1. In melan-a melanocytes, Timp1 expression is suppressed by DNA methylation as indicated by its reexpression after 5-aza-2′-deoxycytidine treatment. Methylation-sensitive single-nucleotide primer extension analysis showed increased demethylation in Timp1 in parallel with its expression along malignant transformation. Interestingly, TIMP1 expression has already been related with negative prognosis in some human cancers. Although described as a MMP inhibitor, this protein has been associated with apoptosis resistance in different cell types. Melan-a cells overexpressing Timp1 showed increased survival in suspension but were unable to form tumors in vivo, whereas Timp1-overexpressing melanoma cells showed reduced latency time for tumor appearance and increased metastatic potential. Here, we demonstrated for the first time an increment in Timp1 expression since the early phases of melanocyte malignant transformation, associated to a progressive gene demethylation, which confers anoikis resistance. In this way, Timp1 might be considered as a valued marker for melanocyte malignant transformation. PMID:19956395

Therapeutic Potential and Challenges of Natural Killer Cells in Treatment of Solid Tumors

PubMed Central

Gras Navarro, Andrea; Björklund, Andreas T.; Chekenya, Martha

2015-01-01

Natural killer (NK) cells are innate lymphoid cells that hold tremendous potential for effective immunotherapy for a broad range of cancers. Due to the mode of NK cell killing, requiring one-to-one target engagement and site-directed release of cytolytic granules, the therapeutic potential of NK cells has been most extensively explored in hematological malignancies. However, their ability to precisely kill antibody coated cells, cancer stem cells, and genotoxically altered cells, while maintaining tolerance to healthy cells makes them appealing therapeutic effectors for all cancer forms, including metastases. Due to their release of pro-inflammatory cytokines, NK cells may potently reverse the anti-inflammatory tumor microenvironment (TME) and augment adaptive immune responses by promoting differentiation, activation, and/or recruitment of accessory immune cells to sites of malignancy. Nevertheless, integrated and coordinated mechanisms of subversion of NK cell activity against the tumor and its microenvironment exist. Although our understanding of the receptor ligand interactions that regulate NK cell functionality has evolved remarkably, the diversity of ligands and receptors is complex, as is their mechanistic foundations in regulating NK cell function. In this article, we review the literature and highlight how the TME manipulates the NK cell phenotypes, genotypes, and tropism to evade tumor recognition and elimination. We discuss counter strategies that may be adopted to augment the efficacy of NK cell anti-tumor surveillance, the clinical trials that have been undertaken so far in solid malignancies, critically weighing the challenges and opportunities with this approach. PMID:25972872

Mitigation of arsenic-induced acquired cancer phenotype in prostate cancer stem cells by miR-143 restoration

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ngalame, Ntube N.O., E-mail: ngalamenn@niehs.nih.g

Inorganic arsenic, an environmental contaminant and a human carcinogen is associated with prostate cancer. Emerging evidence suggests that cancer stem cells (CSCs) are the driving force of carcinogenesis. Chronic arsenic exposure malignantly transforms the human normal prostate stem/progenitor cell (SC) line, WPE-stem to arsenic-cancer SCs (As-CSCs), through unknown mechanisms. MicroRNAs (miRNAs) are small, non-coding RNAs that negatively regulate gene expression at the posttranscriptional level. In prior work, miR-143 was markedly downregulated in As-CSCs, suggesting a role in arsenic-induced malignant transformation. In the present study, we investigated whether loss of miR-143 expression is important in arsenic-induced transformation of prostate SCs. Restorationmore » of miR-143 in As-CSCs was achieved by lentivirus-mediated miR-143 overexpression. Cells were assessed bi-weekly for up to 30 weeks to examine mitigation of cancer phenotype. Secreted matrix metalloproteinase (MMP) activity was increased by arsenic-induced malignant transformation, but miR-143 restoration decreased secreted MMP-2 and MMP-9 enzyme activities compared with scramble controls. Increased cell proliferation and apoptotic resistance, two hallmarks of cancer, were decreased upon miR-143 restoration. Increased apoptosis was associated with decreased BCL2 and BCL-XL expression. miR-143 restoration dysregulated the expression of SC/CSC self-renewal genes including NOTCH-1, BMI-1, OCT4 and ABCG2. The anticancer effects of miR-143 overexpression appeared to be mediated by targeting and inhibiting LIMK1 protein, and the phosphorylation of cofilin, a LIMK1 substrate. These findings clearly show that miR-143 restoration mitigated multiple cancer characteristics in the As-CSCs, suggesting a potential role in arsenic-induced transformation of prostate SCs. Thus, miR-143 is a potential biomarker and therapeutic target for arsenic-induced prostate cancer. - Highlights: • Chronic arsenic exposure malignantly transforms human prostate stem cells (SCs) to arsenic-cancer SCs via unknown mechanisms. • miR-143 was several fold downregulated in the arsenic-cancer SCs (As-CSCs), suggesting a likely role in transformation. • miR-143 restoration reduced cancer characteristics in the As-CSC, suggesting a role in arsenic-induced SC transformation. • miR-143 appears to exert its anticancer effect by inhibiting expression and activity of LIMK1, its predicted gene target. • These findings suggest miR-143 is a potential biomarker and therapeutic target for arsenic-induced prostate cancer.« less

Neurofibromatosis.

PubMed

Korf, Bruce R

2013-01-01

The "neurofibromatoses" are a set of distinct genetic disorders that have in common the occurrence of tumors of the nerve sheath. They include NF1, NF2, and schwannomatosis. All are dominantly inherited with a high rate of new mutation and variable expression. NF1 includes effects on multiple systems of the body. The major NF1-associated tumor is the neurofibroma. In addition, clinical manifestations include bone dysplasia, learning disabilities, and an increased risk of malignancy. NF2 includes schwannomas of multiple cranial and spinal nerves, especially the vestibular nerve, as well as other tumors such as meningiomas and ependymomas. The schwannomatosis phenotype is limited to multiple schwannomas, and usually presents with pain. The genes that underlie each of the disorders are known: NF1 for neurofibromatosis type 1, NF2 for neurofibromatosis type 2, and INI1/SMARCB1 for schwannomatosis. Genetic testing is possible to identify mutations. Insights into pathogenesis are beginning to suggest new treatment strategies, and therapeutic trials with several new forms of treatment are underway. Copyright © 2013 Elsevier B.V. All rights reserved.

Genotype-phenotype correlation of xeroderma pigmentosum in a Chinese Han population.

PubMed

Sun, Z; Zhang, J; Guo, Y; Ni, C; Liang, J; Cheng, R; Li, M; Yao, Z

2015-04-01

Xeroderma pigmentosum (XP) is a rare autosomal recessive disorder characterized by extreme sensitivity to sunlight, freckle-like pigmentation and a greatly increased incidence of skin cancers. Genetic mutation detection and genotype-phenotype analysis of XP are rarely reported in the Chinese Han population. To investigate the mutational spectrum of XP in a Chinese Han population, to discover any genotype-phenotype correlation and, consequently, to propose a simple and effective tool for the molecular diagnosis of XP. This study was carried out on 12 unrelated Chinese families that included 13 patients with clinically suspected XP. Genomic DNA was extracted from peripheral blood samples. Mutation screening was performed by direct sequencing of exons and flanking intron-exon boundaries for the entire coding region of eight XP genes. In 12 patients, direct sequencing of the whole coding region of eight XP genes revealed pathogenic mutations, including seven compound heterozygous mutations, three homozygous mutations and a Japanese founder mutation. Thirteen mutations have not been previously identified. This cohort was composed of four patients with XP-C (XPC), two with XP-G (ERCC5), three with XP-A (XPA) and three with XP-V (POLH). This study identified 13 novel mutations and extended the mutation spectrum of XP in the Chinese Han population. In this cohort, we found that patients with XP-G have no neurological symptoms, and patients with XP-A and XP-V have a high incidence of malignancy. Furthermore, lack of stringent protection against sunlight, late diagnosis and long duration of disease play an important role. © 2014 British Association of Dermatologists.

Nucleolus as an emerging hub in maintenance of genome stability and cancer pathogenesis.

PubMed

Lindström, Mikael S; Jurada, Deana; Bursac, Sladana; Orsolic, Ines; Bartek, Jiri; Volarevic, Sinisa

2018-05-01

The nucleolus is the major site for synthesis of ribosomes, complex molecular machines that are responsible for protein synthesis. A wealth of research over the past 20 years has clearly indicated that both quantitative and qualitative alterations in ribosome biogenesis can drive the malignant phenotype via dysregulation of protein synthesis. However, numerous recent proteomic, genomic, and functional studies have implicated the nucleolus in the regulation of processes that are unrelated to ribosome biogenesis, including DNA-damage response, maintenance of genome stability and its spatial organization, epigenetic regulation, cell-cycle control, stress responses, senescence, global gene expression, as well as assembly or maturation of various ribonucleoprotein particles. In this review, the focus will be on features of rDNA genes, which make them highly vulnerable to DNA damage and intra- and interchromosomal recombination as well as built-in mechanisms that prevent and repair rDNA damage, and how dysregulation of this interplay affects genome-wide DNA stability, gene expression and the balance between euchromatin and heterochromatin. We will also present the most recent insights into how malfunction of these cellular processes may be a central driving force of human malignancies, and propose a promising new therapeutic approach for the treatment of cancer.

Serrated Colon Polyps as Precursors to Colorectal Cancer

PubMed Central

Sweetser, Seth; Smyrk, Thomas C.; Sinicrope, Frank A.

2013-01-01

Identification of the serrated neoplasia pathway has improved our understanding of the pathogenesis of colorectal cancer (CRC). Insights have included an increased recognition of the malignant potential of different types of serrated polyps, such as sessile and traditional serrated adenomas. Sessile serrated adenomas share molecular features with colon tumors, such as microsatellite instability and a methylator phenotype, indicating that these lesions are precursors that progress via the serrated neoplasia pathway. There is evidence that the serrated pathway contributes to interval or missed cancers. These data have important implications for clinical practice and CRC prevention, since hyperplastic polyps were previously regarded as having no malignant potential. Endoscopic detection of serrated polyps is a challenge because they are often inconspicuous with indistinct margins, and are frequently covered by adherent mucus. It is important for gastroenterologists to recognize the subtle endoscopic features of serrated polyps, which would facilitate their detection and removal, to ensure a high-quality colonoscopy examination. Recognition of the role of serrated polyps in colon carcinogenesis has led to the inclusion of these lesions in post-polypectomy surveillance guidelines. However, an enhanced effort is needed to identify and completely remove serrated adenomas, with the goal of increasing the effectiveness of colonoscopy to reduce CRC incidence. PMID:23267866

ΔNp63 versatilely regulates a broad NF-κB gene program and promotes squamous epithelial proliferation, migration and inflammation

PubMed Central

Yang, Xinping; Lu, Hai; Yan, Bin; Romano, Rose-Anne; Bian, Yansong; Friedman, Jay; Duggal, Praveen; Allen, Clint; Chuang, Ryan; Ehsanian, Reza; Si, Han; Sinha, Satrajit; Van Waes, Carter; Chen, Zhong

2012-01-01

Head and neck squamous cell carcinoma (HNSCC) and many epithelial malignancies exhibit increased proliferation, invasion and inflammation, concomitant with aberrant nuclear activation of TP53 and NF-κB family members ΔNp63, c-REL and RELA. However, the mechanisms of crosstalk by which these transcription factors coordinate gene expression and the malignant phenotype remain elusive. Here we demonstrate thatΔNp63 regulates a cohort of genes involved in cell growth, survival, adhesion and inflammation, which substantially overlaps with the NF-κB transcriptome. ΔNp63 with c-REL and/or RELA are recruited to form novel binding complexes on p63 or NF-κB/REL sites of multiple target gene promoters. Overexpressed ΔNp63- or TNF-α-induced NF-κB and inflammatory cytokine IL-8 reporter activation depended upon RELA/c-REL regulatory binding sites. Depletion of RELA or ΔNp63 by siRNA significantly inhibited NF-κB-specific, or TNF-α-induced IL-8 reporter activation. ΔNp63 siRNA significantly inhibited proliferation, survival, and migration by HNSCC cells in vitro. Consistent with the above, an increase in nuclear ΔNp63 accompanied by increased proliferation (Ki67), and adhesion (β4 integrin) markers, and induced inflammatory cell infiltration was observed throughout HNSCC specimens, when compared to the basilar pattern of protein expression and minimal inflammation seen in non-malignant mucosa. Further, overexpression of ΔNp63α in squamous epithelia in transgenic mice leads to increased suprabasilar c-REL, Ki-67, and cytokine expression, together with epidermal hyperplasia and diffuse inflammation, similar to HNSCC. Our study reveals ΔNp63 as a master transcription factor that in coordination with NF-κB/RELs, orchestrates a broad gene program promoting epidermal hyperplasia, inflammation, and the malignant phenotype of HNSCC. PMID:21576089

Interaction of Epstein-Barr virus (EBV) with human B-lymphocytes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Klein, George, E-mail: Georg.Klein@ki.se; Klein, Eva; Kashuba, Elena

Epstein-Barr virus, EBV, and humans have a common history that reaches back to our primate ancestors. The virus co-evolved with man and has established a largely harmless and highly complex co-existence. It is carried as silent infection by almost all human adults. A serendipitous discovery established that it is the causative agent of infectious mononucleosis. Still, EBV became known first in 1964, in a rare, geographically prevalent malignant lymphoma of B-cell origin, Burkitt lymphoma BL. Its association with a malignancy prompted intensive studies and its capacity to immortalize B-lymphocytes in vitro was soon demonstrated. Consequently EBV was classified therefore asmore » a potentially tumorigenic virus. Despite of this property however, the virus carrier state itself does not lead to malignancies because the transformed cells are recognized by the immune response. Consequently the EBV induced proliferation of EBV carrying B-lymphocytes is manifested only under immunosuppressive conditions. The expression of EBV encoded genes is regulated by the cell phenotype. The virus genome can be found in malignancies originating from cell types other than the B-lymphocyte. Even in the EBV infected B-cell, the direct transforming capacity is restricted to a defined window of differentiation. A complex interaction between virally encoded proteins and B-cell specific cellular proteins constitute the proliferation inducing program. In this short review we touch upon aspects which are the subject of our present work. We describe the mechanisms of some of the functional interactions between EBV encoded and cellular proteins that determine the phenotype of latently infected B-cells. The growth promoting EBV encoded genes are not expressed in the virus carrying BL cells. Still, EBV seems to contribute to the etiology of this tumor by modifying events that influence cell survival and proliferation. We describe a possible growth promoting mechanism in the genesis of Burkitt lymphoma that depends on the presence of EBV.« less

Melanoma: Genetic Abnormalities, Tumor Progression, Clonal Evolution and Tumor Initiating Cells.

PubMed

Testa, Ugo; Castelli, Germana; Pelosi, Elvira

2017-11-20

Melanoma is an aggressive neoplasia issued from the malignant transformation of melanocytes, the pigment-generating cells of the skin. It is responsible for about 75% of deaths due to skin cancers. Melanoma is a phenotypically and molecularly heterogeneous disease: cutaneous, uveal, acral, and mucosal melanomas have different clinical courses, are associated with different mutational profiles, and possess distinct risk factors. The discovery of the molecular abnormalities underlying melanomas has led to the promising improvement of therapy, and further progress is expected in the near future. The study of melanoma precursor lesions has led to the suggestion that the pathway of tumor evolution implies the progression from benign naevi, to dysplastic naevi, to melanoma in situ and then to invasive and metastatic melanoma. The gene alterations characterizing melanomas tend to accumulate in these precursor lesions in a sequential order. Studies carried out in recent years have, in part, elucidated the great tumorigenic potential of melanoma tumor cells. These findings have led to speculation that the cancer stem cell model cannot be applied to melanoma because, in this malignancy, tumor cells possess an intrinsic plasticity, conferring the capacity to initiate and maintain the neoplastic process to phenotypically different tumor cells.

Wnt signaling potentiates nevogenesis

PubMed Central

Pawlikowski, Jeff S.; McBryan, Tony; van Tuyn, John; Drotar, Mark E.; Hewitt, Rachael N.; Maier, Andrea B.; King, Ayala; Blyth, Karen; Wu, Hong; Adams, Peter D.

2013-01-01

Cellular senescence is a stable proliferation arrest associated with an altered secretory pathway (senescence-associated secretory phenotype). Cellular senescence is also a tumor suppressor mechanism, to which both proliferation arrest and senescence-associated secretory phenotype are thought to contribute. The melanocytes within benign human nevi are a paradigm for tumor-suppressive senescent cells in a premalignant neoplasm. Here a comparison of proliferating and senescent melanocytes and melanoma cell lines by RNA sequencing emphasizes the importance of senescence-associated proliferation arrest in suppression of transformation. Previous studies showed that activation of the Wnt signaling pathway can delay or bypass senescence. Consistent with this, we present evidence that repression of Wnt signaling contributes to melanocyte senescence in vitro. Surprisingly, Wnt signaling is active in many senescent human melanocytes in nevi, and this is linked to histological indicators of higher proliferative and malignant potential. In a mouse, activated Wnt signaling delays senescence-associated proliferation arrest to expand the population of senescent oncogene-expressing melanocytes. These results suggest that Wnt signaling can potentiate nevogenesis in vivo by delaying senescence. Further, we suggest that activated Wnt signaling in human nevi undermines senescence-mediated tumor suppression and enhances the probability of malignancy. PMID:24043806

Wnt signaling potentiates nevogenesis.

PubMed

Pawlikowski, Jeff S; McBryan, Tony; van Tuyn, John; Drotar, Mark E; Hewitt, Rachael N; Maier, Andrea B; King, Ayala; Blyth, Karen; Wu, Hong; Adams, Peter D

2013-10-01

Cellular senescence is a stable proliferation arrest associated with an altered secretory pathway (senescence-associated secretory phenotype). Cellular senescence is also a tumor suppressor mechanism, to which both proliferation arrest and senescence-associated secretory phenotype are thought to contribute. The melanocytes within benign human nevi are a paradigm for tumor-suppressive senescent cells in a premalignant neoplasm. Here a comparison of proliferating and senescent melanocytes and melanoma cell lines by RNA sequencing emphasizes the importance of senescence-associated proliferation arrest in suppression of transformation. Previous studies showed that activation of the Wnt signaling pathway can delay or bypass senescence. Consistent with this, we present evidence that repression of Wnt signaling contributes to melanocyte senescence in vitro. Surprisingly, Wnt signaling is active in many senescent human melanocytes in nevi, and this is linked to histological indicators of higher proliferative and malignant potential. In a mouse, activated Wnt signaling delays senescence-associated proliferation arrest to expand the population of senescent oncogene-expressing melanocytes. These results suggest that Wnt signaling can potentiate nevogenesis in vivo by delaying senescence. Further, we suggest that activated Wnt signaling in human nevi undermines senescence-mediated tumor suppression and enhances the probability of malignancy.

A Distinct DNA Methylation Shift in a Subset of Glioma CpG Island Methylator Phenotypes during Tumor Recurrence.

PubMed

de Souza, Camila Ferreira; Sabedot, Thais S; Malta, Tathiane M; Stetson, Lindsay; Morozova, Olena; Sokolov, Artem; Laird, Peter W; Wiznerowicz, Maciej; Iavarone, Antonio; Snyder, James; deCarvalho, Ana; Sanborn, Zachary; McDonald, Kerrie L; Friedman, William A; Tirapelli, Daniela; Poisson, Laila; Mikkelsen, Tom; Carlotti, Carlos G; Kalkanis, Steven; Zenklusen, Jean; Salama, Sofie R; Barnholtz-Sloan, Jill S; Noushmehr, Houtan

2018-04-10

Glioma diagnosis is based on histomorphology and grading; however, such classification does not have predictive clinical outcome after glioblastomas have developed. To date, no bona fide biomarkers that significantly translate into a survival benefit to glioblastoma patients have been identified. We previously reported that the IDH mutant G-CIMP-high subtype would be a predecessor to the G-CIMP-low subtype. Here, we performed a comprehensive DNA methylation longitudinal analysis of diffuse gliomas from 77 patients (200 tumors) to enlighten the epigenome-based malignant transformation of initially lower-grade gliomas. Intra-subtype heterogeneity among G-CIMP-high primary tumors allowed us to identify predictive biomarkers for assessing the risk of malignant recurrence at early stages of disease. G-CIMP-low recurrence appeared in 9.5% of all gliomas, and these resembled IDH-wild-type primary glioblastoma. G-CIMP-low recurrence can be characterized by distinct epigenetic changes at candidate functional tissue enhancers with AP-1/SOX binding elements, mesenchymal stem cell-like epigenomic phenotype, and genomic instability. Molecular abnormalities of longitudinal G-CIMP offer possibilities to defy glioblastoma progression. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

Melanoma: Genetic Abnormalities, Tumor Progression, Clonal Evolution and Tumor Initiating Cells

PubMed Central

Castelli, Germana; Pelosi, Elvira

2017-01-01

Melanoma is an aggressive neoplasia issued from the malignant transformation of melanocytes, the pigment-generating cells of the skin. It is responsible for about 75% of deaths due to skin cancers. Melanoma is a phenotypically and molecularly heterogeneous disease: cutaneous, uveal, acral, and mucosal melanomas have different clinical courses, are associated with different mutational profiles, and possess distinct risk factors. The discovery of the molecular abnormalities underlying melanomas has led to the promising improvement of therapy, and further progress is expected in the near future. The study of melanoma precursor lesions has led to the suggestion that the pathway of tumor evolution implies the progression from benign naevi, to dysplastic naevi, to melanoma in situ and then to invasive and metastatic melanoma. The gene alterations characterizing melanomas tend to accumulate in these precursor lesions in a sequential order. Studies carried out in recent years have, in part, elucidated the great tumorigenic potential of melanoma tumor cells. These findings have led to speculation that the cancer stem cell model cannot be applied to melanoma because, in this malignancy, tumor cells possess an intrinsic plasticity, conferring the capacity to initiate and maintain the neoplastic process to phenotypically different tumor cells. PMID:29156643

DOK, a cell line established from human dysplastic oral mucosa, shows a partially transformed non-malignant phenotype.

PubMed

Chang, S E; Foster, S; Betts, D; Marnock, W E

1992-12-02

There are many reports of cell lines being established from human oral squamous-cell carcinomas but apparently none of cell lines from dysplastic or "pre-malignant" oral mucosa. We describe here the isolation and characterization of a cell line, DOK (dysplastic oral keratinocyte), from a piece of dorsal tongue showing epithelial dysplasia. The tissue was obtained from a 57-year-old man who was a heavy smoker prior to the appearance of a white patch on his tongue. Eleven years later a squamous-cell carcinoma developed at the site and was excised. Subsequently the remaining dysplasia was removed, and it was from a piece of this that the primary cell cultures which eventually gave rise to DOK were initiated. The DOK line has been single-cell cloned and is apparently immortal. It grows in the absence of 3T3 feeder cells, is anchorage-dependent for growth and is non-tumorigenic in nude mice. The keratin profile of the cells shows a striking similarity to that of the original tongue dysplasia. The karyotype of DOK is aneuploid and complex. By PCR and oligonucleotide hybridization on dot blots, codons 12, 13 and 61 of Ha-ras, Ki-ras and N-ras in DNA extracted from DOK cells were shown to be normal. Immunohistochemistry showed no abnormal, i.e., elevated expression of the onco-suppressor protein p53. Because of its origin and partially transformed phenotype, DOK presents an opportunity to study whether specific carcinogens associated with tobacco and areca nut can cause malignant transformation of oral keratinocytes in vitro.

Smad4 inactivation promotes malignancy and drug resistance of colon cancer

PubMed Central

Papageorgis, Panagiotis; Cheng, Kuanghung; Ozturk, Sait; Gong, Yi; Lambert, Arthur W.; Abdolmaleky, Hamid M.; Zhou, Jin-Rong; Thiagalingam, Sam

2010-01-01

SMAD4 is localized to chromosome 18q21, a frequent site for loss of heterozygosity (LOH) in advanced stage colon cancers. Although Smad4 is regarded as a signaling mediator of the TGFβ signaling pathway, its role as a major suppressor of colorectal cancer progression and the molecular events underlying this phenomenon, remain elusive. Here, we describe the establishment and use of colon cancer cell line model systems to dissect the functional roles of TGFβ and Smad4 inactivation in the manifestation of a malignant phenotype. We found that loss of SMAD4 and retention of intact TGFβ receptors could synergistically increase the levels of VEGF, a major pro-angiogenic factor. Pharmacological inhibition studies suggest that overactivation of the TGFβ-induced MEK-Erk and p38-MAPK auxiliary pathways are involved in the induction of VEGF expression in SMAD4 null cells. Overall, SMAD4 deficiency was responsible for the enhanced migration of colon cancer cells with a corresponding increase in MMP9, enhanced hypoxia-induced GLUT1 expression, increased aerobic glycolysis and resistance to 5′-fluoruracil-mediated apoptosis. Interestingly, Smad4 specifically interacts with HIF1α under hypoxic conditions providing a molecular basis for the differential regulation of target genes to suppress a malignant phenotype. In summary, our results define a molecular mechanism that explains how loss of the tumor suppressor Smad4 promotes colorectal cancer progression. These findings are also consistent with targeting TGFβ-induced auxiliary pathways, such as MEK-ERK, p38-MAPK and the glycolytic cascade, in SMAD4-deficient tumors as attractive strategies for therapeutic intervention. PMID:21245094

Malignancy and mortality in pediatric patients with inflammatory bowel disease: a multinational study from the porto pediatric IBD group.

PubMed

de Ridder, Lissy; Turner, Dan; Wilson, David C; Koletzko, Sibylle; Martin-de-Carpi, Javier; Fagerberg, Ulrika L; Spray, Christine; Sladek, Malgorzata; Shaoul, Ron; Roma-Giannikou, Eleftheria; Bronsky, Jiri; Serban, Daniela E; Cucchiara, Salvatore; Veres, Gabor; Ruemmele, Frank M; Hojsak, Iva; Kolho, Kaija L; Davies, Ieuan H; Aloi, Marina; Lionetti, Paolo; Veereman-Wauters, Gigi; Braegger, Christian P; Trindade, Eunice; Wewer, Anne V; Hauer, Almuthe; Levine, Arie

2014-02-01

The combination of the severity of pediatric-onset inflammatory bowel disease (IBD) phenotypes and the need for intense medical treatment may increase the risk of malignancy and mortality, but evidence regarding the extent of the problem is scarce. Therefore, the Porto Pediatric IBD working group of ESPGHAN conducted a multinational-based survey of cancer and mortality in pediatric IBD. A survey among pediatric gastroenterologists of 20 European countries and Israel on cancer and/or mortality in the pediatric patient population with IBD was undertaken. One representative from each country repeatedly contacted all pediatric gastroenterologists from each country for reporting retrospectively cancer and/or mortality of pediatric patients with IBD after IBD onset, during 2006-2011. We identified 18 cases of cancers and/or 31 deaths in 44 children (26 males) who were diagnosed with IBD (ulcerative colitis, n = 21) at a median age of 10.0 years (inter quartile range, 3.0-14.0). Causes of mortality were infectious (n = 14), cancer (n = 5), uncontrolled disease activity of IBD (n = 4), procedure-related (n = 3), other non-IBD related diseases (n = 3), and unknown (n = 2). The most common malignancies were hematopoietic tumors (n = 11), of which 3 were hepatosplenic T-cell lymphoma and 3 Ebstein-Barr virus-associated lymphomas. Cancer and mortality in pediatric IBD are rare, but cumulative rates are not insignificant. Mortality is primarily related to infections, particularly in patients with 2 or more immunosuppressive agents, followed by cancer and uncontrolled disease. At least 6 lymphomas were likely treatment-associated by virtue of their phenotype.

P21 and p27: roles in carcinogenesis and drug resistance.

PubMed

Abukhdeir, Abde M; Park, Ben Ho

2008-07-01

Human cancers arise from an imbalance of cell growth and cell death. Key proteins that govern this balance are those that mediate the cell cycle. Several different molecular effectors have been identified that tightly regulate specific phases of the cell cycle, including cyclins, cyclin-dependent kinases (CDKs) and CDK inhibitors. Notably, loss of expression or function of two G1-checkpoint CDK inhibitors - p21 (CDKN1A) and p27 (CDKN1B) - has been implicated in the genesis or progression of many human malignancies. Additionally, there is a growing body of evidence suggesting that functional loss of p21 or p27 can mediate a drug-resistance phenotype. However, reports in the literature have also suggested p21 and p27 can promote tumours, indicating a paradoxical effect. Here, we review historic and recent studies of these two CDK inhibitors, including their identification, function, importance to carcinogenesis and finally their roles in drug resistance.

Dysregulation of Wnt/β-catenin Signaling in Gastrointestinal Cancers

PubMed Central

White, Bryan D.; Chien, Andy J.; Dawson, David W.

2012-01-01

Aberrant Wnt/β-catenin signaling is widely implicated in numerous malignancies, including cancers of the gastrointestinal (GI) tract. Dysregulation of signaling is traditionally attributed to mutations in Axin, APC (adenomatous polyposis coli), and β-catenin that lead to constitutive hyperactivation of the pathway. However, Wnt/β-catenin signaling is also modulated through various other mechanisms in cancer, including crosstalk with other altered signaling pathways. A more complex view of Wnt/β-catenin signaling and its role in GI cancers is now emerging as divergent phenotypic outcomes are found to be dictated by temporospatial context and relative levels of pathway activation. This review summarizes the dysregulation of Wnt/β-catenin signaling in colorectal carcinoma, hepatocellular carcinoma, and pancreatic ductal adenocarcinoma, with particular emphasis on the latter two. We conclude by addressing some of the major challenges faced in attempting to target the pathway in the clinic. PMID:22155636

Activation of cellular death programs associated with immunosenescence-like phenotype in TPPII knockout mice

PubMed Central

Huai, Jisen; Firat, Elke; Nil, Ahmed; Million, Daniele; Gaedicke, Simone; Kanzler, Benoit; Freudenberg, Marina; van Endert, Peter; Kohler, Gabriele; Pahl, Heike L.; Aichele, Peter; Eichmann, Klaus; Niedermann, Gabriele

2008-01-01

The giant cytosolic protease tripeptidyl peptidase II (TPPII) has been implicated in the regulation of proliferation and survival of malignant cells, particularly lymphoma cells. To address its functions in normal cellular and systemic physiology we have generated TPPII-deficient mice. TPPII deficiency activates cell type-specific death programs, including proliferative apoptosis in several T lineage subsets and premature cellular senescence in fibroblasts and CD8+ T cells. This coincides with up-regulation of p53 and dysregulation of NF-κB. Prominent degenerative alterations at the organismic level were a decreased lifespan and symptoms characteristic of immunohematopoietic senescence. These symptoms include accelerated thymic involution, lymphopenia, impaired proliferative T cell responses, extramedullary hematopoiesis, and inflammation. Thus, TPPII is important for maintaining normal cellular and systemic physiology, which may be relevant for potential therapeutic applications of TPPII inhibitors. PMID:18362329

A web platform for the network analysis of high-throughput data in melanoma and its use to investigate mechanisms of resistance to anti-PD1 immunotherapy.

PubMed

Dreyer, Florian S; Cantone, Martina; Eberhardt, Martin; Jaitly, Tanushree; Walter, Lisa; Wittmann, Jürgen; Gupta, Shailendra K; Khan, Faiz M; Wolkenhauer, Olaf; Pützer, Brigitte M; Jäck, Hans-Martin; Heinzerling, Lucie; Vera, Julio

2018-06-01

Cellular phenotypes are established and controlled by complex and precisely orchestrated molecular networks. In cancer, mutations and dysregulations of multiple molecular factors perturb the regulation of these networks and lead to malignant transformation. High-throughput technologies are a valuable source of information to establish the complex molecular relationships behind the emergence of malignancy, but full exploitation of this massive amount of data requires bioinformatics tools that rely on network-based analyses. In this report we present the Virtual Melanoma Cell, an online tool developed to facilitate the mining and interpretation of high-throughput data on melanoma by biomedical researches. The platform is based on a comprehensive, manually generated and expert-validated regulatory map composed of signaling pathways important in malignant melanoma. The Virtual Melanoma Cell is a tool designed to accept, visualize and analyze user-generated datasets. It is available at: https://www.vcells.net/melanoma. To illustrate the utilization of the web platform and the regulatory map, we have analyzed a large publicly available dataset accounting for anti-PD1 immunotherapy treatment of malignant melanoma patients. Copyright © 2018 Elsevier B.V. All rights reserved.

Chest wall leiomyosarcoma after breast-conservative therapy for early-stage breast cancer in a young woman with Li-Fraumeni syndrome.

PubMed

Henry, Eve; Villalobos, Victor; Million, Lynn; Jensen, Kristin C; West, Robert; Ganjoo, Kristen; Lebensohn, Alexandra; Ford, James M; Telli, Melinda L

2012-08-01

Li-Fraumeni syndrome (LFS) is one of the most penetrant forms of familial cancer susceptibility syndromes, characterized by early age at tumor onset and a wide spectrum of malignant tumors. Identifying LFS in patients with cancer is clinically imperative because they have an increased sensitivity to ionizing radiation and are more likely to develop radiation-induced secondary malignancies. This case report describes a young woman whose initial presentation of LFS was early-onset breast cancer and whose treatment of this primary malignancy with breast conservation likely resulted in a secondary malignancy arising in her radiation field. As seen in this case, most breast cancers in patients with LFS exhibit a triple-positive phenotype (estrogen receptor-positive/progesterone receptor-positive/HER2-positive). Although this patient met classic LFS criteria based on age and personal and family history of cancer, the NCCN Clinical Practice Guidelines in Oncology for Genetic/Familial High-Risk Assessment: Breast and Ovarian Cancer endorse genetic screening for TP53 mutations in a subset of patients with early-onset breast cancer, even in the absence of a suggestive family history, because of the potential for de novo TP53 mutations.

The emerging co-regulatory role of long noncoding RNAs in epithelial-mesenchymal transition and the Warburg effect in aggressive tumors.

PubMed

Hua, Qian; Mi, Baoming; Huang, Gang

2018-06-01

Malignant tumor cells have several unique characteristics, and their ability to undergo epithelial-mesenchymal transition (EMT) is a molecular gateway to invasive behavior. Rapid proliferation and increased invasiveness during EMT enhance aberrant glucose metabolism in tumor cells. Meanwhile, aerobic glycolysis provides energy, biosynthesis precursors, and an appropriate microenvironment to facilitate EMT. Reciprocal crosstalk between the processes synergistically contributes to malignant cancer behaviors, but the regulatory mechanisms underlying this interaction remain unclear. Long non-coding RNAs (lncRNAs) are a recently recognized class of RNAs involved in multiple physiological and pathological tumor activities. Increasing evidence indicates that lncRNAs play overlapping roles in both EMT and cancer metabolism. In this review, we describe the lncRNAs reportedly involved in the two biological processes and explore the detailed mechanisms that could help elucidate this co-regulatory network and provide a theoretical basis for clinical management of EMT-related malignant phenotypes. Copyright © 2018 Elsevier B.V. All rights reserved.

Targeting the latest hallmark of cancer: another attempt at 'magic bullet' drugs targeting cancers' metabolic phenotype.

PubMed

Cuperlovic-Culf, M; Culf, A S; Touaibia, M; Lefort, N

2012-10-01

The metabolism of tumors is remarkably different from the metabolism of corresponding normal cells and tissues. Metabolic alterations are initiated by oncogenes and are required for malignant transformation, allowing cancer cells to resist some cell death signals while producing energy and fulfilling their biosynthetic needs with limiting resources. The distinct metabolic phenotype of cancers provides an interesting avenue for treatment, potentially with minimal side effects. As many cancers show similar metabolic characteristics, drugs targeting the cancer metabolic phenotype are, perhaps optimistically, expected to be 'magic bullet' treatments. Over the last few years there have been a number of potential drugs developed to specifically target cancer metabolism. Several of these drugs are currently in clinical and preclinical trials. This review outlines examples of drugs developed for different targets of significance to cancer metabolism, with a focus on small molecule leads, chemical biology and clinical results for these drugs.

HMB-45 negative multifocal malignant perivascular epithelioid cell tumor of the soft tissue responding to sirolimus: First case report from India.

PubMed

Kapoor, Akhil; Beniwal, Surender; Singhal, Mukesh Kumar; Kumar, Narender; Kumar, Vanita; Kumar, Harvindra Singh

2015-01-01

Perivascular epithelioid cell tumor (PEComa) is a group of sarcomas that exhibit a myomelanocytic phenotype and possess a unique cell type in the perivascular epithelioid cell. Traditionally HMB-45 immunoreactivity is the first criteria required to consider a tumor to be PEComa. We report a case of multifocal PEComa with negative HMB-45 marker. The patient presented with three big ulceroproliferative lesions; two over right thigh and one over the scalp in the right frontal region. The patient was prescribed with oral sirolimus to which good response was seen. To the best of our knowledge, this is the first case of HMB-45 negative multifocal malignant PEComa from India.

Loss of Canonical Smad4 Signaling Promotes KRAS Driven Malignant Transformation of Human Pancreatic Duct Epithelial Cells and Metastasis

PubMed Central

Leung, Lisa; Radulovich, Nikolina; Zhu, Chang-Qi; Wang, Dennis; To, Christine; Ibrahimov, Emin; Tsao, Ming-Sound

2013-01-01

Pancreatic ductal adenocarcinoma (PDAC) is the fourth most common cause of cancer death in North America. Activating KRAS mutations and Smad4 loss occur in approximately 90% and 55% of PDAC, respectively. While their roles in the early stages of PDAC development have been confirmed in genetically modified mouse models, their roles in the multistep malignant transformation of human pancreatic duct cells have not been directly demonstrated. Here, we report that Smad4 represents a barrier in KRAS-mediated malignant transformation of the near normal immortalized human pancreatic duct epithelial (HPDE) cell line model. Marked Smad4 downregulation by shRNA in KRAS G12V expressing HPDE cells failed to cause tumorigenic transformation. However, KRAS-mediated malignant transformation occurred in a new HPDE-TGF-β resistant (TβR) cell line that completely lacks Smad4 protein expression and is resistant to the mito-inhibitory activity of TGF-β. This transformation resulted in tumor formation and development of metastatic phenotype when the cells were implanted orthotopically into the mouse pancreas. Smad4 restoration re-established TGF-β sensitivity, markedly increased tumor latency by promoting apoptosis, and decreased metastatic potential. These results directly establish the critical combination of the KRAS oncogene and complete Smad4 inactivation in the multi-stage malignant transformation and metastatic progression of normal human HPDE cells. PMID:24386371

Metabolic Reprogramming in Glioma

PubMed Central

Strickland, Marie; Stoll, Elizabeth A.

2017-01-01

Many cancers have long been thought to primarily metabolize glucose for energy production—a phenomenon known as the Warburg Effect, after the classic studies of Otto Warburg in the early twentieth century. Yet cancer cells also utilize other substrates, such as amino acids and fatty acids, to produce raw materials for cellular maintenance and energetic currency to accomplish cellular tasks. The contribution of these substrates is increasingly appreciated in the context of glioma, the most common form of malignant brain tumor. Multiple catabolic pathways are used for energy production within glioma cells, and are linked in many ways to anabolic pathways supporting cellular function. For example: glycolysis both supports energy production and provides carbon skeletons for the synthesis of nucleic acids; meanwhile fatty acids are used both as energetic substrates and as raw materials for lipid membranes. Furthermore, bio-energetic pathways are connected to pro-oncogenic signaling within glioma cells. For example: AMPK signaling links catabolism with cell cycle progression; mTOR signaling contributes to metabolic flexibility and cancer cell survival; the electron transport chain produces ATP and reactive oxygen species (ROS) which act as signaling molecules; Hypoxia Inducible Factors (HIFs) mediate interactions with cells and vasculature within the tumor environment. Mutations in the tumor suppressor p53, and the tricarboxylic acid cycle enzymes Isocitrate Dehydrogenase 1 and 2 have been implicated in oncogenic signaling as well as establishing metabolic phenotypes in genetically-defined subsets of malignant glioma. These pathways critically contribute to tumor biology. The aim of this review is two-fold. Firstly, we present the current state of knowledge regarding the metabolic strategies employed by malignant glioma cells, including aerobic glycolysis; the pentose phosphate pathway; one-carbon metabolism; the tricarboxylic acid cycle, which is central to amino acid metabolism; oxidative phosphorylation; and fatty acid metabolism, which significantly contributes to energy production in glioma cells. Secondly, we highlight processes (including the Randle Effect, AMPK signaling, mTOR activation, etc.) which are understood to link bio-energetic pathways with oncogenic signals, thereby allowing the glioma cell to achieve a pro-malignant state. PMID:28491867

Neural Crest Migration and Survival Are Susceptible to Morpholino-Induced Artifacts

PubMed Central

Jette, Cicely A.

2016-01-01

The neural crest (NC) is a stem cell-like embryonic population that is essential for generating and patterning the vertebrate body, including the craniofacial skeleton and peripheral nervous system. Defects in NC development underlie many birth defects and contribute to formation of some of the most malignant cancers in humans, such as melanoma and neuroblastoma. For these reasons, significant research efforts have been expended to identify genes that control NC development, as it is expected to lead to a deeper understanding of the genetic mechanisms controlling vertebrate development and identify new treatments for NC-derived diseases and cancers. However, a number of inconsistencies regarding gene function during NC development have emerged from comparative analyses of gene function between mammalian and non-mammalian systems (chick, frog, zebrafish). This poses a significant barrier to identification of single genes and/or redundant pathways to target in NC diseases. Here, we determine whether technical differences, namely morpholino-based approaches used in non-mammalian systems, could contribute to these discrepancies, by examining the extent to which NC phenotypes in fascin1a (fscn1a) morphant embryos are similar to or different from fscn1a null mutants in zebrafish. Analysis of fscn1a morphants showed that they mimicked early NC phenotypes observed in fscn1a null mutants; however, these embryos also displayed NC migration and derivative phenotypes not observed in null mutants, including accumulation of p53-independent cell death. These data demonstrate that morpholinos can cause seemingly specific NC migration and derivative phenotypes, and thus have likely contributed to the inconsistencies surrounding NC gene function between species. We suggest that comparison of genetic mutants between different species is the most rigorous method for identifying conserved genetic mechanisms controlling NC development and is critical to identify new treatments for NC diseases. PMID:28005909

Is Preoperative Biochemical Testing for Pheochromocytoma Necessary for All Adrenal Incidentalomas?

PubMed Central

Jun, Joo Hyun; Ahn, Hyun Joo; Lee, Sangmin M.; Kim, Jie Ae; Park, Byung Kwan; Kim, Jee Soo; Kim, Jung Han

2015-01-01

Abstract This study examined whether imaging phenotypes obtained from computed tomography (CT) can replace biochemical tests to exclude pheochromocytoma among adrenal incidentalomas (AIs) in the preoperative setting. We retrospectively reviewed the medical records of all patients (n = 251) who were admitted for operations and underwent adrenal-protocol CT for an incidentally discovered adrenal mass from January 2011 to December 2012. Various imaging phenotypes were assessed for their screening power for pheochromocytoma. Final diagnosis was confirmed by biopsy, biochemical tests, and follow-up CT. Pheochromocytomas showed similar imaging phenotypes as malignancies, but were significantly different from adenomas. Unenhanced attenuation values ≤10 Hounsfield units (HU) showed the highest specificity (97%) for excluding pheochromocytoma as a single phenotype. A combination of size ≤3 cm, unenhanced attenuation values ≤ 10 HU, and absence of suspicious morphology showed 100% specificity for excluding pheochromocytoma. Routine noncontrast CT can be used as a screening tool for pheochromocytoma by combining 3 imaging phenotypes: size ≤3 cm, unenhanced attenuation values ≤10 HU, and absence of suspicious morphology, and may substitute for biochemical testing in the preoperative setting. PMID:26559265

Differentiating benign from malignant mediastinal lymph nodes visible at EBUS using grey-scale textural analysis.

PubMed

Edey, Anthony J; Pollentine, Adrian; Doody, Claire; Medford, Andrew R L

2015-04-01

Recent data suggest that grey-scale textural analysis on endobronchial ultrasound (EBUS) imaging can differentiate benign from malignant lymphadenopathy. The objective of studies was to evaluate grey-scale textural analysis and examine its clinical utility. Images from 135 consecutive clinically indicated EBUS procedures were evaluated retrospectively using MATLAB software (MathWorks, Natick, MA, USA). Manual node mapping was performed to obtain a region of interest and grey-scale textural features (range of pixel values and entropy) were analysed. The initial analysis involved 94 subjects and receiver operating characteristic (ROC) curves were generated. The ROC thresholds were then applied on a second cohort (41 subjects) to validate the earlier findings. A total of 371 images were evaluated. There was no difference in proportions of malignant disease (56% vs 53%, P = 0.66) in the prediction (group 1) and validation (group 2) sets. There was no difference in range of pixel values in group 1 but entropy was significantly higher in the malignant group (5.95 vs 5.77, P = 0.03). Higher entropy was seen in adenocarcinoma versus lymphoma (6.00 vs 5.50, P < 0.05). An ROC curve for entropy gave an area under the curve of 0.58 with 51% sensitivity and 71% specificity for entropy greater than 5.94 for malignancy. In group 2, the entropy threshold phenotyped only 47% of benign cases and 20% of malignant cases correctly. These findings suggest that use of EBUS grey-scale textural analysis for differentiation of malignant from benign lymphadenopathy may not be accurate. Further studies are required. © 2015 Asian Pacific Society of Respirology.

Comparison of Phenotypic and Functional Characteristics Between Canine Non-B, Non-T Natural Killer Lymphocytes and CD3+CD5dimCD21- Cytotoxic Large Granular Lymphocytes.

PubMed

Lee, Soo-Hyeon; Shin, Dong-Jun; Kim, Yoseop; Kim, Cheol-Jung; Lee, Je-Jung; Yoon, Mee Sun; Uong, Tung Nguyen Thanh; Yu, Dohyeon; Jung, Ji-Youn; Cho, Duck; Jung, Bock-Gie; Kim, Sang-Ki; Suh, Guk-Hyun

2018-01-01

Natural killer (NK) cells play a pivotal role in the immune response against infections and malignant transformation, and adopted transfer of NK cells is thought to be a promising therapeutic approach for cancer patients. Previous reports describing the phenotypic features of canine NK cells have produced inconsistent results. Canine NK cells are still defined as non-B and non-T (CD3 - CD21 - ) large granular lymphocytes. However, a few reports have demonstrated that canine NK cells share the phenotypic characteristics of T lymphocytes, and that CD3 + CD5 dim CD21 - lymphocytes are putative canine NK cells. Based on our previous reports, we hypothesized that phenotypic modulation could occur between these two populations during activation. In this study, we investigated the phenotypic and functional differences between CD3 + CD5 dim CD21 - (cytotoxic large granular lymphocytes) and CD3 - CD5 - CD21 - NK lymphocytes before and after culture of peripheral blood mononuclear cells isolated from normal dogs. The results of this study show that CD3 + CD5 dim CD21 - lymphocytes can be differentiated into non-B, non-T NK (CD3 - CD5 - CD21 - TCRαβ - TCRγδ - GranzymeB + ) lymphocytes through phenotypic modulation in response to cytokine stimulation. In vitro studies of purified CD3 + CD5 dim CD21 - cells showed that CD3 - CD5 - CD21 - cells are derived from CD3 + CD5 dim CD21 - cells through phenotypic modulation. CD3 + CD5 dim CD21 - cells share more NK cell functional characteristics compared with CD3 - CD5 - CD21 - cells, including the expression of T-box transcription factors (Eomes, T-bet), the production of granzyme B and interferon-γ, and the expression of NK cell-related molecular receptors such as NKG2D and NKp30. In conclusion, the results of this study suggest that CD3 + CD5 dim CD21 - and CD3 - CD5 - CD21 - cells both contain a subset of putative NK cells, and the difference between the two populations may be due to the degree of maturation.

Rap G protein signal in normal and disordered lymphohematopoiesis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Minato, Nagahiro, E-mail: minato@imm.med.kyoto-u.ac.jp

2013-09-10

Rap proteins (Rap1, Rap2a, b, c) are small molecular weight GTPases of the Ras family. Rap G proteins mediate diverse cellular events such as cell adhesion, proliferation, and gene activation through various signaling pathways. Activation of Rap signal is regulated tightly by several specific regulatory proteins including guanine nucleotide exchange factors and GTPase-activating proteins. Beyond cell biological studies, increasing attempts have been made in the past decade to define the roles of Rap signal in specific functions of normal tissue systems as well as in cancer. In the immune and hematopoietic systems, Rap signal plays crucial roles in the developmentmore » and function of essentially all lineages of lymphocytes and hematopoietic cells, and importantly, deregulated Rap signal may lead to unique pathological conditions depending on the affected cell types, including various types of leukemia and autoimmunity. The phenotypical studies have unveiled novel, even unexpected functional aspects of Rap signal in cells from a variety of tissues, providing potentially important clues for controlling human diseases, including malignancy.« less

Battling the hematological malignancies: the 200 years' war.

PubMed

Lichtman, Marshall A

2008-02-01

The delineation of the hematological malignancies began near the end of the first third of the 19th century with the recognition of the similarity among cases with lymph node tumors and an enlarged spleen (Hodgkin's disease). Descriptions of chronic and acute leukemia and myeloma followed thereafter. In the first years of the 20th century the discovery of x-radiation permitted palliative orthovoltage radiation therapy of Hodgkin's disease. Following World War II, legitimate drug therapy for the hematological malignancies was introduced: nitrogen mustard, adrenocorticotropic hormone and cortisone acetate, and anti-folic acid derivatives, initially aminopterin. Today, about 14 classes of drugs (different mechanisms of action) and >50 individual agents are being used, with others under study. Several examples of agents targeting specific transcription factors or oncoproteins have been introduced. Despite remarkable progress, including the ability to cure acute leukemia in about 70% of children, cure several genetic variants of acute myelogenous leukemia in younger adults, cure some cases of lymphoma in children and younger adults, and induce prolonged remission in many affected persons, the majority of patients face an uncertain outcome and shortened life. Thus, we have much to do in the next several decades. The significant hurdles we must overcome include: the apparent infrequency of an exogenous cause that can be avoided, the exponential increase in incidence rates with age and the dramatic negative effect of aging on the results of treatment, the challenge of one trillion or more disseminated cancer cells among which are a smaller population of cancer stem cells, the profound genetic diversity of the hematological malignancies (apparently hundreds of unique genetic primary lesions), the redundant growth and survival pathways defining the cancer phenotype, the decreasing market for pharmaceutical companies as therapy becomes more specific (fewer target patients) and drug development costs become more expensive, and the significant negative long-term effects of current therapy on both children and adults. These challenges will be gradually overcome, if we (a) develop new models of cooperation among academia, industry, and government, (b) continue the growth of international participation in cancer research (more keen minds to the task), and (c) convince the governments of the world, including that of the U.S., that an investment in minimizing the effects of cancer is as important as defending against other threats to the welfare and longevity of their citizens.

Bacteraemia caused by Sciscionella marina in a lymphoma patient: phenotypically mimicking Nocardia.

PubMed

Sinha, M; Shivaprakash, M R; Chakrabarti, A; Shafiulla, M; Babu, K G; Jayshree, R S

2013-06-01

A 55-year-old female patient with malignant lymphoma after induction chemotherapy developed fever. Blood culture yielded an organism biochemically identified as representing Nocardia spp., but molecular identification (16S rRNA gene sequencing) later identified it as representing Sciscionella marina. This is the first report, to the best of our knowledge, of Sciscionella being isolated from a human sample.

S100A8/A9 regulates MMP-2 expression and invasion and migration by carcinoma cells

PubMed Central

Silva, Emmanuel J.; Argyris, Prokopios P.; Zou, Xianqiong; Ross, Karen F.; Herzberg, Mark C.

2014-01-01

Intracellular calprotectin (S100A8/A9) functions in the control of the cell cycle checkpoint at G2/M. Dysregulation of S100A8/A9 appears to cause loss of the checkpoint, which frequently characterizes head and neck squamous cell carcinoma (HNSCC). In the present study, we analyzed carcinoma cells for other S100A8/A9-directed changes in malignant phenotype. Using a S100A8/A9-negative human carcinoma cell line (KB), transfection to express S100A8 and S100A9 caused selective down-regulation of MMP-2 and inhibited in vitro invasion and migration. Conversely, silencing of endogenous S100A8 and S100A9 expression in TR146 cells, a well-differentiated HNSCC cell line, increased MMP-2 activity and in vitro invasion and migration. When MMP-2 expression was silenced, cells appeared to assume a less malignant phenotype. To more closely model the architecture of cell growth in vivo, cells were grown in a 3D collagen substrate, which was compared to 2D. Growth on 3D substrates caused greater MMP-2 expression. Whereas hypermethylation of CpG islands occurs frequently in HNSCC, S100A8/A9-dependent regulation of MMP-2 could not be explained by modification of the upstream promoters of MMP2 or TIMP2. Collectively, these results suggest that intracellular S100A8/A9 contributes to the cancer cell phenotype by modulating MMP-2 expression and activity to regulate cell migration and mobility. PMID:25236491

Optic pathway glioma as part of a constitutional mismatch-repair deficiency syndrome in a patient meeting the criteria for neurofibromatosis type 1.

PubMed

Yeung, Jacky T; Pollack, Ian F; Shah, Sapana; Jaffe, Ronald; Nikiforova, Marina; Jakacki, Regina I

2013-01-01

Patients with constitutional mismatch repair-deficiency (CMMR-D) caused by the biallelic deletions of mismatch repair (MMR) genes have a high likelihood of developing malignancies of the bone marrow, bowel, and brain. Affected individuals often have phenotypic features of neurofibromatosis type 1 (NF-1), including café-au-lait spots. Optic pathway gliomas (OPGs), a common manifestation of NF-1, have not been reported. We report the case of a 3-year-old male with an extensive OPG who met the diagnostic criteria for NF-1. He was subsequently found to have multiple colonic polyps and bi-allelic loss of PMS2. Testing for NF-1 was negative. Copyright © 2012 Wiley Periodicals, Inc.

Stromal-dependent tumor promotion by MIF family members.

PubMed

Mitchell, Robert A; Yaddanapudi, Kavitha

2014-12-01

Solid tumors are composed of a heterogeneous population of cells that interact with each other and with soluble and insoluble factors that, when combined, strongly influence the relative proliferation, differentiation, motility, matrix remodeling, metabolism and microvessel density of malignant lesions. One family of soluble factors that is becoming increasingly associated with pro-tumoral phenotypes within tumor microenvironments is that of the migration inhibitory factor family which includes its namesake, MIF, and its only known family member, D-dopachrome tautomerase (D-DT). This review seeks to highlight our current understanding of the relative contributions of a variety of immune and non-immune tumor stromal cell populations and, within those contexts, will summarize the literature associated with MIF and/or D-DT. Copyright © 2014 Elsevier Inc. All rights reserved.

Treatment of Ras-induced cancers by the F-actin cappers tensin and chaetoglobosin K, in combination with the caspase-1 inhibitor N1445.

PubMed

Tikoo, A; Cutler, H; Lo, S H; Chen, L B; Maruta, H

1999-01-01

For transforming normal fibroblasts to malignant cells, oncogenic Ras mutants such as v-Ha-ras require Rho family GTPases (Rho, Rac, and CDC42) that are responsible for controlling actin-cytoskeleton organization. Ras activates Rac through a PI-3 kinase-mediated pathway. Rac causes uncapping of actin filaments (F-actin) at the plus-ends, through phosphatidylinositol 4,5 bisphosphate (PIP2), and eventually induces membrane ruffling. Several distinct F-actin/PIP2-binding proteins, such as gelsolin, which severs and caps the plus-ends of actin filaments, or HS1, which cross-links actin filaments, have been shown to suppress v-Ha-Ras-induced malignant transformation when they are overexpressed. Interestingly, an F-actin cross-linking drug (photosensitizer) called MKT-077 suppresses Ras transformation. Thus, an F-actin capping/severing drug might also have an anticancer potential. This study was conducted to determine first whether Ras-induced malignant phenotype (anchorage-independent growth) is suppressed by overexpression of the gene encoding a large plus-end F-actin capping protein called tensin and second to test the anti-Ras potential of a unique fungal antibiotic (small compound) called chaetoglobosin K (CK) that also caps the plus-ends of actin filaments. DNA transfection with a retroviral vector carrying the tensin cDNA was used to overexpress tensin in v-Ha-Ras-transformed NIH 3T3 cells. All stable tensin transfectants rarely formed colonies in soft agar, indicating that tensin suppresses the anchorage-independent growth. The anti-Ras action of CK was determined by incubating the Ras-transformants in the presence of CK in soft agar. Two microM CK almost completely inhibited their colony formation, indicating that CK also suppresses the malignant phenotype. However, unlike tensin, CK causes an apoptosis of Ras-transformed NIH 3T3 cells and, less effectively, of normal NIH 3T3 cells, indicating that CK has an F-actin capping-independent side effect(s). CK-induced apoptosis is at least in part caused by CK-induced inhibition of the kinase PKB/AKT. However, a specific ICE/caspase-1 inhibitor called N1445 completely abolished the CK-induced apoptosis by reactivating PKB, but without affecting the CK-induced suppression of Ras transformation. Like the F-actin cross-linking drug MKT-077, the F-actin capping drug CK may be useful for the treatment of Ras-associated cancers if it is combined with the ICE inhibitor N1445, which abolishes the side effect of CK. Our observations that two distinct F-actin capping molecules (i.e., tensin and CK) suppress Ras-induced malignant phenotype strongly suggest, if not prove, that capping of actin filaments at the plus-ends alone is sufficient to block one of the Ras signaling pathways essential for its oncogenicity. This notion is compatible with the fact that Ras induces the uncapping of actin filaments at the plus-ends through the Rac/PIP2 pathway.

Aberrant phenotypes in peripheral T cell lymphomas.

PubMed Central

Hastrup, N; Ralfkiaer, E; Pallesen, G

1989-01-01

Seventy six peripheral T cell lymphomas were examined immunohistologically to test their reactivity with a panel of monoclonal antibodies against 11 T cell associated antigens (CD1-8, CD27, UCHL1, and the T cell antigen receptor). Sixty two (82%) lymphomas showed aberrant phenotypes, and four main categories were distinguished as follows: (i) lack of one or several pan-T cell antigens (49, 64% of the cases); (ii) loss of both the CD4 and CD8 antigens (11, 15% of the cases); (iii) coexpression of the CD4 and CD8 antigens (13, 17% of the cases); and (iv) expression of the CD1 antigen (eight, 11% of the cases). No correlation was seen between the occurrence of aberrant phenotypes and the histological subtype. It is concluded that the demonstration of an aberrant phenotype is a valuable supplement to histological assessment in the diagnosis of peripheral T cell lymphomas. It is recommended that the panel of monoclonal antibodies against T cell differentiation antigens should be fairly large, as apparently any antigen may be lost in the process of malignant transformation. Images Figure PMID:2469701

Combination Platinum-based and DNA Damage Response-targeting Cancer Therapy: Evolution and Future Directions

PubMed Central

Basourakos, Spyridon P.; Li, Likun; Aparicio, Ana M.; Corn, Paul G.; Kim, Jeri; Thompson, Timothy C.

2017-01-01

Maintenance of genomic stability is a critical determinant of cell survival and is necessary for growth and progression of malignant cells. Interstrand crosslinking (ICL) agents, including platinum-based agents, are first-line chemotherapy treatment for many solid human cancers. In malignant cells, ICL triggers the DNA damage response (DDR). When the damage burden is high and lesions cannot be repaired, malignant cells are unable to divide and ultimately undergo cell death either through mitotic catastrophe or apoptosis. The activities of ICL agents, in particular platinum-based therapies, establish a “molecular landscape,” i.e., a pattern of DNA damage that can potentially be further exploited therapeutically with DDR-targeting agents. If the molecular landscape created by platinum-based agents could be better defined at the molecular level, a systematic, mechanistic rationale(s) could be developed for the use of DDR-targeting therapies in combination/maintenance protocols for specific, clinically advanced malignancies. New therapeutic drugs such as poly(ADP-ribose) polymerase (PARP) inhibitors are examples of DDR-targeting therapies that could potentially increase the DNA damage and replication stress imposed by platinum-based agents in tumor cells and provide therapeutic benefit for patients with advanced malignancies. Recent studies have shown that the use of PARP inhibitors together with platinum-based agents is a promising therapy strategy for ovarian cancer patients with ”BRCAness”, i.e., a phenotypic characteristic of tumors that not only can involve loss-of-function mutations in either BRCA1 or BRCA2, but also encompasses the molecular features of BRCA-mutant tumors. On the basis of these promising results, additional mechanism-based studies focused on the use of various DDR-targeting therapies in combination with platinum-based agents should be considered. This review discusses, in general, (1) ICL agents, primarily platinum-based agents, that establish a molecular landscape that can be further exploited therapeutically; (2) multiple points of potential intervention after ICL agent–induced crosslinking that further predispose to cell death and can be incorporated into a systematic, therapeutic rationale for combination/maintenance therapy using DDR-targeting agents; and (3) available agents that can be considered for use in combination/maintenance clinical protocols with platinum-based agents for patients with advanced malignancies. PMID:27978798

Combination Platinum-based and DNA Damage Response-targeting Cancer Therapy: Evolution and Future Directions.

PubMed

Basourakos, Spyridon P; Li, Likun; Aparicio, Ana M; Corn, Paul G; Kim, Jeri; Thompson, Timothy C

2017-01-01

Maintenance of genomic stability is a critical determinant of cell survival and is necessary for growth and progression of malignant cells. Interstrand crosslinking (ICL) agents, including platinum-based agents, are first-line chemotherapy treatment for many solid human cancers. In malignant cells, ICL triggers the DNA damage response (DDR). When the damage burden is high and lesions cannot be repaired, malignant cells are unable to divide and ultimately undergo cell death either through mitotic catastrophe or apoptosis. The activities of ICL agents, in particular platinum-based therapies, establish a "molecular landscape," i.e., a pattern of DNA damage that can potentially be further exploited therapeutically with DDR-targeting agents. If the molecular landscape created by platinum-based agents could be better defined at the molecular level, a systematic, mechanistic rationale(s) could be developed for the use of DDR-targeting therapies in combination/maintenance protocols for specific, clinically advanced malignancies. New therapeutic drugs such as poly(ADP-ribose) polymerase (PARP) inhibitors are examples of DDR-targeting therapies that could potentially increase the DNA damage and replication stress imposed by platinum-based agents in tumor cells and provide therapeutic benefit for patients with advanced malignancies. Recent studies have shown that the use of PARP inhibitors together with platinum-based agents is a promising therapy strategy for ovarian cancer patients with "BRCAness", i.e., a phenotypic characteristic of tumors that not only can involve loss-of-function mutations in either BRCA1 or BRCA2, but also encompasses the molecular features of BRCA-mutant tumors. On the basis of these promising results, additional mechanism-based studies focused on the use of various DDR-targeting therapies in combination with platinum-based agents should be considered. This review discusses, in general, (1) ICL agents, primarily platinum-based agents, that establish a molecular landscape that can be further exploited therapeutically; (2) multiple points of potential intervention after ICL agent-induced crosslinking that further predispose to cell death and can be incorporated into a systematic, therapeutic rationale for combination/ maintenance therapy using DDR-targeting agents; and (3) available agents that can be considered for use in combination/maintenance clinical protocols with platinum-based agents for patients with advanced malignancies. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Overexpression of miR-9 in mast cells is associated with invasive behavior and spontaneous metastasis

PubMed Central

2014-01-01

Background While microRNA (miRNA) expression is known to be altered in a variety of human malignancies contributing to cancer development and progression, the potential role of miRNA dysregulation in malignant mast cell disease has not been previously explored. The purpose of this study was to investigate the potential contribution of miRNA dysregulation to the biology of canine mast cell tumors (MCTs), a well-established spontaneous model of malignant mast cell disease. Methods We evaluated the miRNA expression profiles from biologically low-grade and biologically high-grade primary canine MCTs using real-time PCR-based TaqMan Low Density miRNA Arrays and performed real-time PCR to evaluate miR-9 expression in primary canine MCTs, malignant mast cell lines, and normal bone marrow-derived mast cells (BMMCs). Mouse mast cell lines and BMMCs were transduced with empty or pre-miR-9 expressing lentiviral constructs and cell proliferation, caspase 3/7 activity, and invasion were assessed. Transcriptional profiling of cells overexpressing miR-9 was performed using Affymetrix GeneChip Mouse Gene 2.0 ST arrays and real-time PCR was performed to validate changes in mRNA expression. Results Our data demonstrate that unique miRNA expression profiles correlate with the biological behavior of primary canine MCTs and that miR-9 expression is increased in biologically high grade canine MCTs and malignant cell lines compared to biologically low grade tumors and normal canine BMMCs. In transformed mouse malignant mast cell lines expressing either wild-type (C57) or activating (P815) KIT mutations and mouse BMMCs, miR-9 overexpression significantly enhanced invasion but had no effect on cell proliferation or apoptosis. Transcriptional profiling of normal mouse BMMCs and P815 cells possessing enforced miR-9 expression demonstrated dysregulation of several genes, including upregulation of CMA1, a protease involved in activation of matrix metalloproteases and extracellular matrix remodeling. Conclusions Our findings demonstrate that unique miRNA expression profiles correlate with the biological behavior of canine MCTs. Furthermore, dysregulation of miR-9 is associated with MCT metastasis potentially through the induction of an invasive phenotype, identifying a potentially novel pathway for therapeutic intervention. PMID:24517413

The effect of IDH1 mutation on the structural connectome in malignant astrocytoma.

PubMed

Kesler, Shelli R; Noll, Kyle; Cahill, Daniel P; Rao, Ganesh; Wefel, Jeffrey S

2017-02-01

Mutation of the IDH1 gene is associated with differences in malignant astrocytoma growth characteristics that impact phenotypic severity, including cognitive impairment. We previously demonstrated greater cognitive impairment in patients with IDH1 wild type tumor compared to those with IDH1 mutant, and therefore we hypothesized that brain network organization would be lower in patients with wild type tumors. Volumetric, T1-weighted MRI scans were obtained retrospectively from 35 patients with IDH1 mutant and 32 patients with wild type malignant astrocytoma (mean age = 45 ± 14 years) and used to extract individual level, gray matter connectomes. Graph theoretical analysis was then applied to measure efficiency and other connectome properties for each patient. Cognitive performance was categorized as impaired or not and random forest classification was used to explore factors associated with cognitive impairment. Patients with wild type tumor demonstrated significantly lower network efficiency in several medial frontal, posterior parietal and subcortical regions (p < 0.05, corrected for multiple comparisons). Patients with wild type tumor also demonstrated significantly higher incidence of cognitive impairment (p = 0.03). Random forest analysis indicated that network efficiency was inversely, though nonlinearly associated with cognitive impairment in both groups (p < 0.0001). Cognitive reserve appeared to mediate this relationship in patients with mutant tumor suggesting greater neuroplasticity and/or benefit from neuroprotective factors. Tumor volume was the greatest contributor to cognitive impairment in patients with wild type tumor, supporting our hypothesis that greater lesion momentum between grades may cause more disconnection of core neurocircuitry and consequently lower efficiency of information processing.

Protocols for Migration and Invasion Studies in Prostate Cancer.

PubMed

van de Merbel, Arjanneke F; van der Horst, Geertje; Buijs, Jeroen T; van der Pluijm, Gabri

2018-01-01

Prostate cancer is the most common malignancy diagnosed in men in the western world. The development of distant metastases and therapy resistance are major clinical problems in the management of prostate cancer patients. In order for prostate cancer to metastasize to distant sites in the human body, prostate cancer cells have to migrate and invade neighboring tissue. Cancer cells can acquire a migratory and invasive phenotype in several ways, including single cell and collective migration. As a requisite for migration, epithelial prostate cancer cells often need to acquire a motile, mesenchymal-like phenotype. This way prostate cancer cells often lose polarity and epithelial characteristics (e.g., expression of E-cadherin homotypic adhesion receptor), and acquire mesenchymal phenotype (for example, cytoskeletal rearrangements, enhanced expression of proteolytic enzymes and other repertory of integrins). This process is referred to as epithelial-to-mesenchymal transition (EMT). Cellular invasion, one of the hallmarks of cancer, is characterized by the movement of cells through a three-dimensional matrix, resulting in remodeling of the cellular environment. Cellular invasion requires adhesion, proteolysis of the extracellular matrix, and migration of cells. Studying the migratory and invasive ability of cells in vitro represents a useful tool to assess the aggressiveness of solid cancers, including those of the prostate.This chapter provides a comprehensive description of the Transwell migration assay, a commonly used technique to investigate the migratory behavior of prostate cancer cells in vitro. Furthermore, we will provide an overview of the adaptations to the Transwell migration protocol to study the invasive capacity of prostate cancer cells, i.e., the Transwell invasion assay. Finally, we will present a detailed description of the procedures required to stain the Transwell filter inserts and quantify the migration and/or invasion.

Reappraisal of mesenchymal chondrosarcoma: novel morphologic observations of the hyaline cartilage and endochondral ossification and beta-catenin, Sox9, and osteocalcin immunostaining of 22 cases.

PubMed

Fanburg-Smith, Julie C; Auerbach, Aaron; Marwaha, Jayson S; Wang, Zengfeng; Rushing, Elisabeth J

2010-05-01

Mesenchymal chondrosarcoma, a rare malignant round cell and hyaline cartilage tumor, is most commonly intraosseous but can occur in extraskeletal sites. We intensively observed the morphology and applied Sox9 (master regulator of chondrogenesis), beta-catenin (involved in bone formation, thought to inhibit chondrogenesis in a Sox9-dependent manner), and osteocalcin (a marker for osteoblastic phenotype) to 22 central nervous system and musculoskeletal mesenchymal chondrosarcoma. Cases of mesenchymal chondrosarcoma were retrieved and reviewed from our files. Immunohistochemistry and follow-up were obtained on mesenchymal chondrosarcoma and tumor controls. Twenty-two mesenchymal chondrosarcomas included 5 central nervous system (all female; mean age, 30.2; mean size, 7.8 cm; in frontal lobe [n = 4] and spinal cord [n = 1]) and 17 musculoskeletal (female-male ratio, 11:6; mean age, 31.1; mean size, 6.2 cm; 3 each of humerus and vertebrae; 2 each of pelvis, rib, tibia, neck soft tissue; one each of femur, unspecified bone, and elbow soft tissue). The hyaline cartilage in most tumors revealed a consistent linear progression of chondrocyte morphology, from resting to proliferating to hypertrophic chondrocytes. Sixty-seven percent of cases demonstrated cell death and acquired osteoblastic phenotype, cells positive for osteocalcin at the site of endochondral ossification. Small round cells of mesenchymal chondrosarcoma were negative for osteocalcin. SOX9 was positive in both components of 21 of 22 cases of mesenchymal chondrosarcoma. beta-Catenin highlighted rare nuclei at the interface between round cells and hyaline cartilage in 35% cases. Control skull and central nervous system cases were compared, including chondrosarcomas and small cell osteosarcoma, the latter positive for osteocalcin in small cells. Mesenchymal chondrosarcoma demonstrates centrally located hyaline cartilage with a linear progression of chondrocytes from resting to proliferative to hypertrophic, which undergoes endochondral ossification, recapitulating growth plate cartilage and suggesting that this component of mesenchymal chondrosarcoma may be a differentiated (benign or metaplastic) component of a malignant metastasizing tumor. This hyaline cartilage component is morphologically different from cartilage of control chondrosarcoma. Mesenchymal chondrosarcoma can be separated from small cell osteosarcoma, using Sox 9 for cartilage and osteocalcin for osteoblastic phenotype. Rare nuclear beta-catenin expression at the interface between hyaline cartilage and small round cells potentially implicates the APC/Wnt pathway during endochondral ossification in morphologically benign hyaline cartilage component of mesenchymal chondrosarcoma. Published by Elsevier Inc.

Phenotypic characterization of aberrant stem and progenitor cell populations in myelodysplastic syndromes.

PubMed

Ostendorf, Benjamin N; Flenner, Eva; Flörcken, Anne; Westermann, Jörg

2018-01-01

Recent reports have revealed myelodysplastic syndromes (MDS) to arise from cancer stem cells phenotypically similar to physiological hematopoietic stem cells. Myelodysplastic hematopoiesis maintains a hierarchical organization, but the proportion of several hematopoietic compartments is skewed and multiple surface markers are aberrantly expressed. These aberrant antigen expression patterns hold diagnostic and therapeutic promise. However, eradication of MDS requires targeting of early myelodysplasia propagating stem cells. This warrants an exact assessment of the differentiation stage at which aberrant expression occurs in transformed hematopoiesis. Here, we report results on the prospective and extensive dissection of the hematopoietic hierarchy in 20 patients with either low-risk MDS or MDS with excess blasts and compare it to hematopoiesis in patients with non-malignancy-associated cytopenia or B cell lymphoma without bone marrow infiltration. We found patients with MDS with excess blasts to exhibit characteristic expansions of specific immature progenitor compartments. We also identified the aberrant expression of several markers including ALDH, CLL-1, CD44, and CD47 to be specific features of hematopoiesis in MDS with excess blasts. We show that amongst these, aberrant CLL-1 expression manifested at the early uncommitted hematopoietic stem cell level, suggesting a potential role as a therapeutic target.

The macrophage marker translocator protein (TSPO) is down-regulated on pro-inflammatory 'M1' human macrophages.

PubMed

Narayan, Nehal; Mandhair, Harpreet; Smyth, Erica; Dakin, Stephanie Georgina; Kiriakidis, Serafim; Wells, Lisa; Owen, David; Sabokbar, Afsie; Taylor, Peter

2017-01-01

The translocator protein (TSPO) is a mitochondrial membrane protein, of as yet uncertain function. Its purported high expression on activated macrophages, has lent utility to TSPO targeted molecular imaging in the form of positron emission tomography (PET), as a means to detect and quantify inflammation in vivo. However, existing literature regarding TSPO expression on human activated macrophages is lacking, mostly deriving from brain tissue studies, including studies of brain malignancy, and inflammatory diseases such as multiple sclerosis. Here, we utilized three human sources of monocyte derived macrophages (MDM), from THP-1 monocytes, healthy peripheral blood monocytes and synovial fluid monocytes from patients with rheumatoid arthritis, to undertake a detailed investigation of TSPO expression in activated macrophages. In this work, we demonstrate a consistent down-regulation of TSPO mRNA and protein in macrophages activated to a pro-inflammatory, or 'M1' phenotype. Conversely, stimulation of macrophages to an M2 phenotype with IL-4, dexamethasone or TGF-β1 did not alter TSPO expression, regardless of MDM source. The reasons for this are uncertain, but our study findings add some supporting evidence for recent investigations concluding that TSPO may be involved in negative regulation of inflammatory responses in macrophages.

Apigenin Inhibits Cancer Stem Cell-Like Phenotypes in Human Glioblastoma Cells via Suppression of c-Met Signaling.

PubMed

Kim, Boram; Jung, Narae; Lee, Sanghun; Sohng, Jae Kyung; Jung, Hye Jin

2016-11-01

Glioblastoma (GBM) is a highly malignant human brain tumor with limited treatment choices. The extremely aggressive characteristics of GBM result from GBM stem cells (GSCs), a subpopulation in tumor having self-renewal potential and resistance to chemotherapy and radiotherapy. Therefore, eliminating GSCs is an effective strategy to treat this fatal disease. In this study, we investigated the therapeutic effects of dietary flavonoids, including apigenin, quercetin, and naringenin, against cancer stem cell-like phenotypes of human GBM cell lines U87MG and U373MG. Among flavonoids studied, apigenin and quercetin significantly suppressed not only the self-renewal capacity such as cell growth and clonogenicity, but also the invasiveness of GBM stem-like cells. Notably, apigenin blocked the phosphorylation of c-Met and its downstream effectors, transducer and activator of transcription 3, AKT (Protein kinase B), and mitogen-activated protein kinase in the GSCs, thereby reducing the expression levels of GSC markers such as CD133, Nanog, and Sox2. These results suggest that the GSC inhibition effect of apigenin may be caused by downregulation of c-Met signaling pathway. Copyright © 2016 John Wiley & Sons, Ltd.

Gene expression regulation by upstream open reading frames and human disease.

PubMed

Barbosa, Cristina; Peixeiro, Isabel; Romão, Luísa

2013-01-01

Upstream open reading frames (uORFs) are major gene expression regulatory elements. In many eukaryotic mRNAs, one or more uORFs precede the initiation codon of the main coding region. Indeed, several studies have revealed that almost half of human transcripts present uORFs. Very interesting examples have shown that these uORFs can impact gene expression of the downstream main ORF by triggering mRNA decay or by regulating translation. Also, evidence from recent genetic and bioinformatic studies implicates disturbed uORF-mediated translational control in the etiology of many human diseases, including malignancies, metabolic or neurologic disorders, and inherited syndromes. In this review, we will briefly present the mechanisms through which uORFs regulate gene expression and how they can impact on the organism's response to different cell stress conditions. Then, we will emphasize the importance of these structures by illustrating, with specific examples, how disturbed uORF-mediated translational control can be involved in the etiology of human diseases, giving special importance to genotype-phenotype correlations. Identifying and studying more cases of uORF-altering mutations will help us to understand and establish genotype-phenotype associations, leading to advancements in diagnosis, prognosis, and treatment of many human disorders.

Hereditary medullary thyroid carcinoma: the management dilemma.

PubMed

Zhou, Ping; Liu, Jian; Cheng, Shao-Wen; Wang, Bing; Yang, Rong; Peng, Ling

2012-06-01

Hereditary medullary thyroid carcinoma (hereditary MTC) is a rare malignancy, accounting for 25-30% of all MTC. It occurs as part of multiple endocrine neoplasia type 2 (MEN 2). Autosomal dominant gain-of-function mutations in the RET proto-oncogene is the cause of the disease, in which the common mutations are codons 609, 611, 618, 620, 630, 634 and 918. In recent years, the spectrum of RET gene mutations has changed. The classical mutations reduced, whereas the less aggressive mutations increased. Hereditary MTC is a time-dependent disease. Stages of the disorder at diagnosis can significantly influence survival rates. Based on the genotype-phenotype, RET mutations have been classified into four risk levels by American Thyroid Association (ATA) at 2009. The classification system guides the hereditary MTC management, including risk assessment, biochemical screenings and surgical intervention. Though the application of genetic testing and codon-specific phenotypes in hereditary MTC diagnosis is effective with high accuracy, there are some difficulties in implementing RET gene testing as a routine for MTC diagnosis. And most of carriers with RET mutations did not undergo thyroidectomy at the age recommended by the ATA guidelines. The aim of the study is to review the hereditary MTC and discuss the management dilemma.

[Evaluation of three-dimensional tumor microvascular architecture phenotype heterogeneity in non-small cell carcinoma and its significance].

PubMed

Zhou, Hui; Liu, Jinkang; Chen, Shengxi; Xiong, Zeng; Zhou, Jianhua; Tong, Shiyu; Chen, Hao; Zhou, Moling

2012-06-01

To explore the degree, mechanism and clinical significance of three-dimensional tumor microvascular architecture phenotype heterogeneity (3D-TMAPH) in non-small cell carcinoma (NSCLC). Twenty-one samples of solitary pulmonary nodules were collected integrally. To establish two-dimensional tumor microvascular architecture phenotype (2D-TMAP) and three-dimensional tumor microvascular architecture phenotype (3D-TMAP), five layers of each nodule were selected and embedded in paraffin. Test indices included the expressions of vascular endothelial growth factor (VEGF), proliferating cell nuclear antigen (PCNA), EphB4, ephfinB2 and microvascular density marked by anti-CD34 (CD34-MVD). The degrees of 3D-TMAPH were evaluated by the coefficient of variation and extend of heterogeneity. Spearman rank correlation analysis was used to investigate the relationships between 2D-TMAP, 3D-TMAP and clinicopathological features. 3D-TMAPH showed that 2D-TMAP heterogeneity was expressed in the tissues of NSCLC. The heterogeneities in the malignant nodules were significantly higher than those in the active inflammatory nodules and tubercular nodules. In addition, different degrees of heterogeneity of CD34-MVD and PCNA were found in NSCLC tissues. The coefficients of variation of CD34- MVD and PCNA were positively related to the degree of differentiation (all P<0.05), but not related to the P-TNM stages, histological type or lymphatic metastasis (all P>0.05). The level of heterogeneity of various expression indexes (ephrinB2, EphB4, VEGF) in NSCLC tissues were inconsistent, but there were no significant differences in heterogeneity in NSCLC tissues with different histological types (P>0.05). 3D-TMAPH exists widely in the microenvironment during the genesis and development of NSCLC and has a significant impact on its biological complexity.

Improved Mitochondrial and Methylglyoxal-Related Metabolisms Support Hyperproliferation Induced by 50 Hz Magnetic Field in Neuroblastoma Cells.

PubMed

Falone, Stefano; Santini, Silvano; di Loreto, Silvia; Cordone, Valeria; Grannonico, Marta; Cesare, Patrizia; Cacchio, Marisa; Amicarelli, Fernanda

2016-09-01

Extremely low frequency magnetic fields (ELF-MF) are common environmental agents that are suspected to promote later stages of tumorigenesis, especially in brain-derived malignancies. Even though ELF magnetic fields have been previously linked to increased proliferation in neuroblastoma cells, no previous work has studied whether ELF-MF exposure may change key biomolecular features, such as anti-glycative defence and energy re-programming, both of which are currently considered as crucial factors involved in the phenotype and progression of many malignancies. Our study investigated whether the hyperproliferation that is induced in SH-SY5Y human neuroblastoma cells by a 50 Hz, 1 mT ELF magnetic field is supported by an improved defense towards methylglyoxal (MG), which is an endogenous cancer-static and glycating α-oxoaldehyde, and by rewiring of energy metabolism. Our findings show that not only the ELF magnetic field interfered with the biology of neuron-derived malignant cells, by de-differentiating further the cellular phenotype and by increasing the proliferative activity, but also triggered cytoprotective mechanisms through the enhancement of the defense against MG, along with a more efficient management of metabolic energy, presumably to support the rapid cell outgrowth. Intriguingly, we also revealed that the MF-induced bioeffects took place after an initial imbalance of the cellular homeostasis, which most likely created a transient unstable milieu. The biochemical pathways and molecular targets revealed in this research could be exploited for future approaches aimed at limiting or suppressing the deleterious effects of ELF magnetic fields. J. Cell. Physiol. 231: 2014-2025, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Clinical Significance of MLH1 Methylation and CpG Island Methylator Phenotype as Prognostic Markers in Patients with Gastric Cancer

PubMed Central

Shigeyasu, Kunitoshi; Nagasaka, Takeshi; Mori, Yoshiko; Yokomichi, Naosuke; Kawai, Takashi; Fuji, Tomokazu; Kimura, Keisuke; Umeda, Yuzo; Kagawa, Shunsuke; Goel, Ajay; Fujiwara, Toshiyoshi

2015-01-01

Background To improve the outcome of patients suffering from gastric cancer, a better understanding of underlying genetic and epigenetic events in this malignancy is required. Although CpG island methylator phenotype (CIMP) and microsatellite instability (MSI) have been shown to play pivotal roles in gastric cancer pathogenesis, the clinical significance of these events on survival outcomes in patients with gastric cancer remains unknown. Methods This study included a patient cohort with pathologically confirmed gastric cancer who had surgical resections. A cohort of 68 gastric cancers was analyzed. CIMP and MSI statuses were determined by analyzing promoter CpG island methylation status of 28 genes/loci, and genomic instability at 10 microsatellite markers, respectively. A Cox’s proportional hazards model was performed for multivariate analysis including age, stage, tumor differentiation, KRAS mutation status, and combined CIMP/MLH1 methylation status in relation to overall survival (OS). Results By multivariate analysis, longer OS was significantly correlated with lower pathologic stage (P = 0.0088), better tumor differentiation (P = 0.0267) and CIMP-high and MLH1 3' methylated status (P = 0.0312). Stratification of CIMP status with regards to MLH1 methylation status further enabled prediction of gastric cancer prognosis. Conclusions CIMP and/or MLH1 methylation status may have a potential to be prognostic biomarkers for patients with gastric cancer. PMID:26121593

Inherited platelet disorders: toward DNA-based diagnosis

PubMed Central

Lentaigne, Claire; Freson, Kathleen; Laffan, Michael A.; Turro, Ernest

2016-01-01

Variations in platelet number, volume, and function are largely genetically controlled, and many loci associated with platelet traits have been identified by genome-wide association studies (GWASs).1 The genome also contains a large number of rare variants, of which a tiny fraction underlies the inherited diseases of humans. Research over the last 3 decades has led to the discovery of 51 genes harboring variants responsible for inherited platelet disorders (IPDs). However, the majority of patients with an IPD still do not receive a molecular diagnosis. Alongside the scientific interest, molecular or genetic diagnosis is important for patients. There is increasing recognition that a number of IPDs are associated with severe pathologies, including an increased risk of malignancy, and a definitive diagnosis can inform prognosis and care. In this review, we give an overview of these disorders grouped according to their effect on platelet biology and their clinical characteristics. We also discuss the challenge of identifying candidate genes and causal variants therein, how IPDs have been historically diagnosed, and how this is changing with the introduction of high-throughput sequencing. Finally, we describe how integration of large genomic, epigenomic, and phenotypic datasets, including whole genome sequencing data, GWASs, epigenomic profiling, protein–protein interaction networks, and standardized clinical phenotype coding, will drive the discovery of novel mechanisms of disease in the near future to improve patient diagnosis and management. PMID:27095789

MSH-2 and MLH-1 Protein Expression in Muir Torre Syndrome-Related and Sporadic Sebaceous Neoplasms

PubMed Central

Morales-Burgos, Adisbeth; Sánchez, Jorge L.; Figueroa, Luz D.; De Jesús-Monge, Wilfredo E.; Cruz-Correa, Marcia R.; González-Keelan, Carmen; Nazario, Cruz María

2009-01-01

Background Muir-Torre Syndrome (MTS) is a rare autosomal-dominant disorder characterized by the predisposition to both sebaceous neoplasm and internal malignancies. MTS-associated sebaceous neoplasms reveal mutations in DNA mismatch repair (MMR) genes and microsatellite instability. A significant part of MTS patients represents a phenotypic variant, the hereditary nonpolyposis colorectal cancer (HNPCC). A strong correlation between microsatellite instability and immunostaining has been demonstrated. The early recognition of sebaceous neoplasm as part of MTS, and their differentiation from sporadic sebaceous neoplasm may have an important application in a clinical setting. The absence of MLH-1 or MSH-2 expression by immunostaining identifies tumors with mismatch repair deficiency. Objectives Our aim is to determine whether an immunohistochemical approach, targeting DNA repair proteins MSH-2 and MLH-1 in MTS-related sebaceous neoplasm and their sporadic counterparts, can be used for their identification. Methods We examined 15 sebaceous neoplasms (including 6 internal malignancy- associated sebaceous neoplasms and 8 sporadic sebaceous neoplasms) from 11 patients for the expression of MSH-2 and MLH-1 by immunohistochemistry. Results Four of 5 internal malignancy-associated sebaceous neoplasms showed loss of expression of MSH-2 or MLH-1. Correlation of the immunostaining pattern of the sebaceous neoplasms and the patients’ positive history of colon carcinoma was 80%. Seven of 8 sporadic sebaceous neoplasms showed a positive expression of MSH-2 and MLH-1. The prevalence for loss of expression of MMR proteins in sebaceous neoplasms was 38.5%. MMR immunostaining had 87.5% specificity and 80% sensitivity. Limitations This study is limited by a small sample size, and by bias selection due to the use of non nationwide data-base as the resource of cases. Conclusions Our findings demonstrate that immunohistochemical testing for internal malignancy-associated sebaceous neoplasms is a practical approach to confirm a suspected inherited MMR gene defect, and an accurate method to distinguish between sporadic and MTS-associated sebaceous lesions. PMID:19069357

Expression of the Intermediate Filament Nestin in Gastrointestinal Stromal Tumors and Interstitial Cells of Cajal

PubMed Central

Tsujimura, Tohru; Makiishi-Shimobayashi, Chiaki; Lundkvist, Johan; Lendahl, Urban; Nakasho, Keiji; Sugihara, Ayako; Iwasaki, Teruo; Mano, Masayuki; Yamada, Naoko; Yamashita, Kunihiro; Toyosaka, Akihiro; Terada, Nobuyuki

2001-01-01

It has recently been proposed that gastrointestinal stromal tumors (GISTs) originate from stem cells that differentiate toward a phenotype of interstitial cells of Cajal (ICCs). Nestin is a newly identified intermediate filament protein, and is predominantly expressed in immature cells, such as neuroectodermal stem cells and skeletal muscle progenitor cells, and tumors originating from these cells. In this study, we examined, using immunohistochemistry, the nestin expression in GISTs and ICCs to clarify the origin of GISTs. Strong immunoreactivity for nestin was observed in all 18 GISTs, and its expression was confirmed by Western blot and Northern blot analyses. In contrast, three leiomyomas and a schwannoma that developed in the gastrointestinal tract showed no apparent immunoreactivity for nestin. Among 17 mesenchymal tumors (seven leiomyosarcomas, five malignant peripheral nerve sheath tumors, and five fibrosarcomas) that occurred in sites other than the gastrointestinal tract, only two malignant peripheral nerve sheath tumors were moderately immunoreactive for nestin. Furthermore, with fluorescence double immunostaining of the normal small intestine, nestin expression was demonstrated in ICCs. These results show that nestin may be a useful marker for diagnosis of GISTs, and support the current hypothesis that GISTs are tumors of stem cells that differentiate toward an ICC phenotype. PMID:11238030

Protein-bound Polysaccharide-K Inhibits Hedgehog Signaling Through Down-regulation of MAML3 and RBPJ Transcription Under Hypoxia, Suppressing the Malignant Phenotype in Pancreatic Cancer.

PubMed

Yamasaki, Akio; Onishi, Hideya; Imaizumi, Akira; Kawamoto, Makoto; Fujimura, Akiko; Oyama, Yasuhiro; Katano, Mitsuo

2016-08-01

Hedgehog signaling is activated in pancreatic cancer and could be a therapeutic target. We previously demonstrated that recombination signal binding protein for immunoglobulin-kappa-J region (RBPJ) and mastermind-like 3 (MAML3) contribute to the hypoxia-induced up-regulation of Smoothened (SMO) transcription. We have also shown that protein-bound polysaccharide-K (PSK) could be effective for refractory pancreatic cancer that down-regulates SMO transcription under hypoxia. In this study, we evaluated whether the anticancer mechanism of PSK involves inhibiting RBPJ and MAML3 expression under hypoxia. PSK reduced SMO, MAML3 and RBPJ expression in pancreatic cancer cells under hypoxia. PSK also blocked RBPJ-induced invasiveness under hypoxia by inhibiting matrix metalloproteinase expression. Lastly, we showed that PSK attenuated RBPJ-induced proliferation both in vitro and in vivo. These results suggest that PSK suppresses Hedgehog signaling through down-regulation of MAML3 and RBPJ transcription under hypoxia, inhibiting the induction of a malignant phenotype in pancreatic cancer. Our results may lead to development of new treatments for refractory pancreatic cancer using PSK as a Hedgehog inhibitor. Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

Molecular and clinical significance of fibroblast growth factor 2 (FGF2 /bFGF) in malignancies of solid and hematological cancers for personalized therapies

PubMed Central

Akl, Mohamed R.; Nagpal, Poonam; Ayoub, Nehad M.; Tai, Betty; Prabhu, Sathyen A.; Capac, Catherine M.; Gliksman, Matthew; Goy, Andre; Suh, K. Stephen

2016-01-01

Fibroblast growth factor (FGF) signaling is essential for normal and cancer biology. Mammalian FGF family members participate in multiple signaling pathways by binding to heparan sulfate and FGF receptors (FGFR) with varying affinities. FGF2 is the prototype member of the FGF family and interacts with its receptor to mediate receptor dimerization, phosphorylation, and activation of signaling pathways, such as Ras-MAPK and PI3K pathways. Excessive mitogenic signaling through the FGF/FGFR axis may induce carcinogenic effects by promoting cancer progression and increasing the angiogenic potential, which can lead to metastatic tumor phenotypes. Dysregulated FGF/FGFR signaling is associated with aggressive cancer phenotypes, enhanced chemotherapy resistance and poor clinical outcomes. In vitro experimental settings have indicated that extracellular FGF2 affects proliferation, drug sensitivity, and apoptosis of cancer cells. Therapeutically targeting FGF2 and FGFR has been extensively assessed in multiple preclinical studies and numerous drugs and treatment options have been tested in clinical trials. Diagnostic assays are used to quantify FGF2, FGFRs, and downstream signaling molecules to better select a target patient population for higher efficacy of cancer therapies. This review focuses on the prognostic significance of FGF2 in cancer with emphasis on therapeutic intervention strategies for solid and hematological malignancies. PMID:27007053

Clinical utility of kallikrein-related peptidases (KLK) in urogenital malignancies.

PubMed

Dorn, J; Bayani, J; Yousef, G M; Yang, F; Magdolen, V; Kiechle, M; Diamandis, E P; Schmitt, M

2013-09-01

Kallikrein-related peptidases (KLK), which represent a major tissue-associated proteolytic system, stand for a rich source of biomarkers that may allow molecular classification, early diagnosis and prognosis of human malignancies as well as prediction of response or failure to cancer-directed drugs. International research points to an important role of certain KLKs in female and male urogenital tract malignancies, in addition to cancers of the lung, brain, skin, head and neck, and the gastrointestinal tract. Regarding the female/male urogenital tract, remarkably, all of the KLKs are expressed in the normal prostate, testis, and kidney whereas the uterus, the ovary, and the urinary bladder are expressing a limited number of KLKs only. Most of the information regarding KLK expression in tumour-affected organs is available for ovarian cancer; all of the 12 KLKs tested so far were found to be elevated in the malignant state, depicting them as valuable biomarkers to distinguish between the normal and the cancerous phenotype. In contrast, for kidney cancer, a series of KLKs was found to be downregulated, while other KLKs were not expressed. Evidently, depending on the type of cancer or cancer stage, individual KLKs may show characteristics of a Janus-faced behaviour, by either expanding or inhibiting cancer progression and metastasis.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Xu, Yuan; Zhao, Yue; Xu, Wenchao

Arsenic is a well established human carcinogen that causes diseases of the lung. Some studies have suggested a link between inflammation and lung cancer; however, it is unknown if arsenite-induced inflammation causally contributes to arsenite-caused malignant transformation of cells. In this study, we investigated the molecular mechanisms underlying inflammation during neoplastic transformation induced in human bronchial epithelial (HBE) cells by chronic exposure to arsenite. The results showed that, on acute or chronic exposure to arsenite, HBE cells over-expressed the pro-inflammatory cytokines, interleukin-6 (IL-6), interleukin-8 (IL-8), and interleukin-1β (IL-1β). The data also indicated that HIF-2α was involved in arsenite-induced inflammation. Moreover,more » IL-6 and IL-8 were essential for the malignant progression of arsenite-transformed HBE cells. Thus, these experiments show that HIF-2α mediates arsenite-induced inflammation and that such inflammation is involved in arsenite-induced malignant transformation of HBE cells. The results provide a link between the inflammatory response and the acquisition of a malignant transformed phenotype by cells chronically exposed to arsenite and thus establish a previously unknown mechanism for arsenite-induced carcinogenesis. - Highlights: • Arsenite induces inflammation. • Arsenite-induced the increases of IL-6 and IL-8 via HIF-2α. • Inflammation is involved in arsenite-induced carcinogenesis.« less

Senescence-like Phenotypes in Human Nevi

PubMed Central

Joselow, Andrew; Lynn, Darren; Terzian, Tamara; Box, Neil F.

2016-01-01

Summary Cellular senescence is an irreversible arrest of cell proliferation at the G1 stage of the cell cycle in which cells become refractory to growth stimuli. Senescence is a critical and potent defense mechanism that mammalian cells have to suppress tumors. While there are many ways to induce a senescence response, oncogene-induced senescence (OIS) remains key to inhibiting progression of cells that have acquired oncogenic mutations. In primary cells in culture, OIS induces a set of measurable phenotypic and behavioral changes, in addition to cell cycle exit. Senescence-associated β-Galactosidase (SA-β-Gal) activity is a main hallmark of senescent cells, along with morphological changes that may depend on the oncogene that is activated, or on the primary cell type. Characteristic cellular changes of senescence include increased size, flattening, multi-nucleation, and extensive vacuolation. At the molecular level, tumor suppressor genes such as p53 and p16INK4a may play a role in initiation or maintenance of OIS. Activation of a DNA damage response and a senescence-associated secretory phenotype could delineate the onset of senescence. Despite advances in our understanding of how OIS suppresses some tumor types, the in vivo role of OIS in melanocytic nevi and melanoma remains poorly understood and not validated. In an effort to stimulate research in this field, we review in this chapter the known markers of senescence and provide experimental protocols for their identification by immunofluorescent staining in melanocytic nevi and malignant melanoma. PMID:27812879

Forkhead box protein A2, a pioneer factor for hepatogenesis, is involved in the expression of hepatic phenotype of alpha-fetoprotein-producing adenocarcinoma.

PubMed

Yamamura, Nobuhisa; Fugo, Kazunori; Kishimoto, Takashi

2017-09-01

Alpha-fetoprotein (AFP)-producing adenocarcinoma is a high-malignant variant of adenocarcinoma with a hepatic or fetal-intestinal phenotype. The number of cases of AFP-producing adenocarcinomas is increasing, but the molecular mechanism underlying the aberrant production of AFP is unclear. Here we sought to assess the role of Forkhead box A (FoxA)2, which is a pioneer transcription factor in the differentiation of hepatoblasts. FoxA2 expression was investigated in five cases of AFP-producing gastric adenocarcinomas by immunohistochemistry, and all cases showed FoxA2 expression. Chromatin immunoprecipitation revealed the DNA binding of FoxA2 on the regulatory element of AFP gene in AFP-producing adenocarcinoma cells. The inhibition of FoxA2 expression with siRNA reduced the mRNA expression of liver-specific proteins, including AFP, albumin, and transferrin. The inhibition of FoxA2 also reduced the expressions of liver-enriched nuclear factors, i.e., hepatocyte nuclear factor (HNF) 4α and HNF6, although the expressions of HNF1α and HNF1β were not affected. The same effect as FoxA2 knockdown in AFP producing adenocarcinoma cells was also observed in hepatocellular carcinoma cells. Our results suggest that FoxA2 plays a key role in the expression of hepatic phenotype of AFP-producing adenocarcinomas. Copyright © 2017 Elsevier GmbH. All rights reserved.

A CpG island methylator phenotype in acute myeloid leukemia independent of IDH mutations and associated with a favorable outcome.

PubMed

Kelly, A D; Kroeger, H; Yamazaki, J; Taby, R; Neumann, F; Yu, S; Lee, J T; Patel, B; Li, Y; He, R; Liang, S; Lu, Y; Cesaroni, M; Pierce, S A; Kornblau, S M; Bueso-Ramos, C E; Ravandi, F; Kantarjian, H M; Jelinek, J; Issa, J-Pj

2017-10-01

Genetic changes are infrequent in acute myeloid leukemia (AML) compared with other malignancies and often involve epigenetic regulators, suggesting that an altered epigenome may underlie AML biology and outcomes. In 96 AML cases including 65 pilot samples selected for cured/not-cured, we found higher CpG island (CGI) promoter methylation in cured patients. Expanded genome-wide digital restriction enzyme analysis of methylation data revealed a CGI methylator phenotype independent of IDH1/2 mutations we term AML-CGI methylator phenotype (CIMP) (A-CIMP + ). A-CIMP was associated with longer overall survival (OS) in this data set (median OS, years: A-CIMP + =not reached, CIMP - =1.17; P=0.08). For validation we used 194 samples from The Cancer Genome Atlas interrogated with Illumina 450k methylation arrays where we confirmed longer OS in A-CIMP (median OS, years: A-CIMP + =2.34, A-CIMP - =1.00; P=0.01). Hypermethylation in A-CIMP + favored CGIs (OR: CGI/non-CGI=5.21), and while A-CIMP + was enriched in CEBPA (P=0.002) and WT1 mutations (P=0.02), 70% of cases lacked either mutation. Hypermethylated genes in A-CIMP + function in pluripotency maintenance, and a gene expression signature of A-CIMP was associated with outcomes in multiple data sets. We conclude that CIMP in AML cannot be explained solely by gene mutations (for example, IDH1/2, TET2), and that curability in A-CIMP + AML should be validated prospectively.

Predictive oncology: multidisciplinary, multi-scale in-silico modeling linking phenotype, morphology and growth

PubMed Central

Sanga, Sandeep; Frieboes, Hermann B.; Zheng, Xiaoming; Gatenby, Robert; Bearer, Elaine L.; Cristini, Vittorio

2007-01-01

Empirical evidence and theoretical studies suggest that the phenotype, i.e., cellular- and molecular-scale dynamics, including proliferation rate and adhesiveness due to microenvironmental factors and gene expression that govern tumor growth and invasiveness, also determine gross tumor-scale morphology. It has been difficult to quantify the relative effect of these links on disease progression and prognosis using conventional clinical and experimental methods and observables. As a result, successful individualized treatment of highly malignant and invasive cancers, such as glioblastoma, via surgical resection and chemotherapy cannot be offered and outcomes are generally poor. What is needed is a deterministic, quantifiable method to enable understanding of the connections between phenotype and tumor morphology. Here, we critically review advantages and disadvantages of recent computational modeling efforts (e.g., continuum, discrete, and cellular automata models) that have pursued this understanding. Based on this assessment, we propose and discuss a multi-scale, i.e., from the molecular to the gross tumor scale, mathematical and computational “first-principle” approach based on mass conservation and other physical laws, such as employed in reaction-diffusion systems. Model variables describe known characteristics of tumor behavior, and parameters and functional relationships across scales are informed from in vitro, in vivo and ex vivo biology. We demonstrate that this methodology, once coupled to tumor imaging and tumor biopsy or cell culture data, should enable prediction of tumor growth and therapy outcome through quantification of the relation between the underlying dynamics and morphological characteristics. In particular, morphologic stability analysis of this mathematical model reveals that tumor cell patterning at the tumor-host interface is regulated by cell proliferation, adhesion and other phenotypic characteristics: histopathology information of tumor boundary can be inputted to the mathematical model and used as phenotype-diagnostic tool and thus to predict collective and individual tumor cell invasion of surrounding host. This approach further provides a means to deterministically test effects of novel and hypothetical therapy strategies on tumor behavior. PMID:17629503

METALLOPROTEINS DURING DEVELOPMENT OF WALKER-256 CARCINOSARCOMA RESISTANT PHENOTYPE.

PubMed

Chekhun, V F; Lozovska, Yu V; Burlaka, A P; Ganusevich, I I; Shvets, Yu V; Lukianova, N Yu; Todor, I M; Demash, D V; Pavlova, A A; Naleskina, L A

2015-01-01

The study was focused on the detection of changes in serum and tumor metal-containing proteins in animals during development ofdoxorubicin-resistant phenotype in malignant cells after 12 courses of chemotherapy. We found that on every stage of resistance development there was a significant increase in content of ferritin and transferrin proteins (which take part in iron traffick and storage) in Walker-256 carc'inosarcoma tissue. We observed decreased serumferritin levels at the beginning stage of the resistance development and significant elevation of this protein levels in the cases withfully developed resistance phenotype. Transferrin content showed changes opposite to that offerritin. During the development of resistance phenotype the tumor tissue also exhibited increased 'free iron' concentration that putatively correlate with elevation of ROS generation and levels of MMP-2 and MMP-9 active forms. The tumor non-protein thiol content increases gradually as well. The serum of animals with early stages of resistance phenotype development showed high ceruloplasmin activity and its significant reduction after loss of tumor sensitivity to doxorubicin. Therefore, the development of resistance phenotype in Walker-256 carcinosarcoma is accompanied by both the deregulation of metal-containing proteins in serum and tumor tissue and by the changes in activity of antioxidant defense system. Thus, the results of this study allow us to determine the spectrum of metal-containing proteins that are involved in the development of resistant tumor phenotype and that may be targeted for methods for doxorubicin sensitivity correction therapy.

Tg737 regulates epithelial-mesenchymal transition and cancer stem cell properties via a negative feedback circuit between Snail and HNF4α during liver stem cell malignant transformation.

PubMed

Huang, Qike; Pu, Meng; Zhao, Ge; Dai, Bin; Bian, Zhenyuan; Tang, Haili; Chen, Chong; Liu, Wei; Qu, Xuan; Shen, Liangliang; Tao, Kaishan

2017-08-28

Determining the origin of liver cancer stem cells is important for treating hepatocellular carcinoma. Tg737 deficiency plays an important role in the malignant transformation of liver stem cells, but the underlying mechanism remains unclear. Here we established a chemical-induced mouse hepatoma model and found that Tg737 and hepatocyte nuclear factor 4-alpha (HNF4α) expression decreased and epithelial-mesenchymal transition (EMT)-related marker expression increased during liver cancer development. To investigate the underlying mechanism, we knocked down Tg737 in WB-F344 (WB) rat hepatic oval cells. Loss of Tg737 resulted in nuclear β-catenin accumulation and activation of the Wnt/β-catenin pathway, which further promoted EMT and the malignant phenotype. XAV939, a β-catenin inhibitor, attenuated WB cell malignant transformation due to Tg737 knockdown. To clarify the relationships of Tg737, the β-catenin pathway, and HNF4α, we inhibited Snail and overexpressed HNF4α after Tg737 knockdown in WB cells and found that Snail and HNF4α comprise a negative feedback circuit. Taken together, the results showed that Tg737 regulates a Wnt/β-catenin/Snail-HNF4α negative feedback circuit, thereby blocking EMT and the malignant transformation of liver stem cells to liver cancer stem cells. Copyright © 2017 Elsevier B.V. All rights reserved.

Angiogenesis and Vascular Architecture in Pheochromocytomas

PubMed Central

Favier, Judith; Plouin, Pierre-François; Corvol, Pierre; Gasc, Jean-Marie

2002-01-01

Angiogenesis is a critical step in tumor growth and metastatic invasion. We here report the study of the vascular status of 10 benign and 9 malignant pheochromocytomas. We examined the vascular architecture after immunostaining endothelial cells (CD34) and vascular smooth muscle cells (α-actin) and identified a vascular pattern characteristic of malignant lesions. To define a gene expression profile indicative of the invasive phenotype, we studied by in situ hybridization the expression of genes encoding several pro- and anti-angiogenic factors [hypoxia-inducible factor (HIF-1α), EPAS1, vascular endothelial growth factor (VEGF), VEGF receptors, angiopoietins and their receptor Tie2, five genes of the endothelin system, and thrombospondin 1]. A semiquantitative evaluation of the labeling revealed an induction of genes encoding EPAS1, VEGF, VEGFR-1, VEGFR-2, endothelin receptor, type B (ETB) and endothelin receptor, type A (ETA) in malignant pheochromocytomas as compared to benign tumors. These differences were observed in tumor cells, in endothelial cells, or in both. Quantification by real-time reverse-transcriptase polymerase chain reaction showed an increase of EPAS1, VEGF, and ETB transcripts of 4.5-, 3.5-, and 10-fold, respectively, in malignant versus benign tumors. Furthermore, we observed a strong correlation between the expression of EPAS1 and VEGF in tumoral tissue and between EPAS1 and ETB in endothelial cells. Altogether, our observations show that analysis of angiogenesis provides promising new criteria for the diagnosis of malignant pheochromocytomas. PMID:12368197

Regulatory T cells in the actinic cheilitis.

PubMed

Gasparoto, Thaís Helena; de Souza Malaspina, Tatiana Salles; Damante, José Humberto; de Mello, Edgard Franco; Ikoma, Maura Rosane Valério; Garlet, Gustavo Pompermaier; Costa, Maria Renata Sales Nogueira; Cavassani, Karen Angélica; da Silva, João Santana; Campanelli, Ana Paula

2014-11-01

Actinic cheilitis (AC) is an oral potentially malignant lesion which is the counterpart of actinic keratosis of the skin and has potential to develop into squamous cell carcinoma. Regulatory T cells (Tregs) have a critical role in modulating the antitumor immune responses. The presence of regulatory T cells in potentially malignant lesions has not been described. We chose investigate the involvement of regulatory T cells in potentially malignant lesions. The frequency, phenotype, and activity of CD4+CD25+ T cells isolated from blood and lesion of AC patients were analyzed by flow cytometry. Cytokines were quantified by ELISA. Data were compared with samples from healthy subjects. The frequency and suppressor activity of circulating CD4+CD25+ T cells was similar in AC patients and control subjects. However, the frequencies of IL-10-positive Tregs were higher in AC patients, and these cells inhibited interferon-gamma (IFN-γ) and increased interleukin (IL)-10 productions in co-cultures. Furthermore, CD4+CD25+ T cells accumulate in AC lesions. Lesions-derived regulatory T cells suppressed lymphocyte proliferation and pro-inflammatory cytokine production. Moreover, high levels of IL-10 and transforming growth factor-β (TGF-β), and low IFN-γ were detected in the potentially malignant lesions. Therefore, our data show that Tregs accumulate in AC lesions, and these cells could be suppressing immune responses in a potentially malignant microenvironment. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Cancer cell: using inflammation to invade the host

PubMed Central

Arias, José-Ignacio; Aller, María-Angeles; Arias, Jaime

2007-01-01

Background Inflammation is increasingly recognized as an important component of tumorigenesis, although the mechanisms involved are not fully characterized. The invasive capacity of cancers is reflected in the classic metastatic cascade: tumor (T), node (N) and metastasis (M). However, this staging system for cancer would also have a tumoral biological significance. Presentation of the hypothesis To integrate the mechanisms that control the inflammatory response in the actual staging system of cancer. It is considered that in both processes of inflammation and cancer, three successive phenotypes are presented that represent the expression of trophic functional systems of increasing metabolic complexity for using oxygen. Testing the hypothesis While a malignant tumor develops it express phenotypes that also share the inflammatory response such as: an ischemic phenotype (anoxic-hypoxic), a leukocytic phenotype with anaerobic glycolysis and migration, and an angiogenic phenotype with hyperactivity of glycolytic enzymes, tumor proliferation and metastasis, and cachexia of the host. The increasing metabolic complexity of the tumor cell to use oxygen allows for it to be released, migrate and proliferate, thus creating structures of growing complexity. Implication of the hypothesis One aim of cancer gene therapy could be the induction of oxidative phosphorylation, the last metabolic step required by inflammation in order to differentiate the tissue that it produces. PMID:17437633

Modeling microenvironmental regulation of glioblastoma stem cells: a biomaterials perspective

NASA Astrophysics Data System (ADS)

Heffernan, John M.; Sirianni, Rachael W.

2018-02-01

Following diagnosis of a glioblastoma (GBM) brain tumor, surgical resection, chemotherapy and radiation together yield a median patient survival of only 15 months. Importantly, standard treatments fail to address the dynamic regulation of the brain tumor microenvironment that actively supports tumor progression and treatment resistance. It is becoming increasingly recognized that specialized niches within the tumor microenvironment maintain a population of highly malignant glioblastoma stem-like cells (GSCs). GSCs are resistant to traditional chemotherapy and radiation therapy, suggesting that they may be responsible for the near universal rates of tumor recurrence and associated morbidity in GBM. Thus, disrupting microenvironmental support for GSCs could be critical to developing more effective GBM therapies. Three-dimensional (3D) culture models of the tumor microenvironment are powerful tools for identifying key biochemical and biophysical inputs that impact malignant behaviors. Such systems have been used effectively to identify conditions that regulate GSC proliferation, invasion, stem-specific phenotypes, and treatment resistance. Considering the significant role that GSC microenvironments play in regulating this tumorigenic sub-population, these models may be essential for uncovering mechanisms that limit GSCs malignancy.

Pulmonary artery sarcoma with angiosarcoma phenotype mimicking pleomorphic malignant fibrous histiocytoma: a case report

PubMed Central

2012-01-01

Abstract Primary sarcomas of the major blood vessels can be classified based on location in relationship to the wall or by histologic type. Angiosarcomas are malignant neoplasms that arise from the endothelial lining of the blood vessels; those arising in the intimal compartment of pulmonary artery are rare. We report a case of pulmonary artery angiosarcoma in a 36-year old female with pulmonary masses. The patient had no other primary malignant neoplasm, thus excluding a metastatic lesion. Gross examination revealed a thickened right pulmonary artery and a necrotic and hemorrhagic tumor, filling and occluding the vascular lumen. The mass extended distally, within the pulmonary vasculature of the right lung. Microscopically, an intravascular undifferentiated tumor was identified. The tumor cells showed expression for vascular markers VEGFR, VEGFR3, PDGFRa, FGF, Ulex europaeus, FVIII, FLI-1, CD31 and CD34; p53 was overexpressed and Ki67 proliferative rate was increased. Intravascular angiosarcomas are aggressive neoplasms, often associated with poor outcome. Virtual slide The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/2315906377648045. PMID:23134683

Protein kinase inhibitors against malignant lymphoma

PubMed Central

D’Cruz, Osmond J; Uckun, Fatih M

2013-01-01

Introduction Tyrosine kinases (TKs) are intimately involved in multiple signal transduction pathways regulating survival, activation, proliferation and differentiation of lymphoid cells. Deregulation or overexpression of specific oncogenic TKs is implicated in maintaining the malignant phenotype in B-lineage lymphoid malignancies. Several novel targeted TK inhibitors (TKIs) have recently emerged as active in the treatment of relapsed or refractory B-cell lymphomas that inhibit critical signaling pathways, promote apoptotic mechanisms or modulate the tumor microenvironment. Areas covered In this review, the authors summarize the clinical outcomes of newer TKIs in various B-cell lymphomas from published and ongoing clinical studies and abstracts from major cancer and hematology conferences. Expert opinion Multiple clinical trials have demonstrated that robust antitumor activity can be obtained with TKIs directed toward specific oncogenic TKs that are genetically deregulated in various subtypes of B-cell lymphomas. Clinical success of targeting TKIs is dependent upon on identifying reliable molecular and clinical markers associated with select cohorts of patients. Further understanding of the signaling pathways should stimulate the identification of novel molecular targets and expand the development of new therapeutic options and individualized therapies. PMID:23496343

Mining Gene Expression Signature for the Detection of Pre-Malignant Melanocytes and Early Melanomas with Risk for Metastasis

PubMed Central

de Souza, Camila Ferreira; Xander, Patrícia; Monteiro, Ana Carolina; Silva, Amanda Gonçalves dos Santos; da Silva, Débora Castanheira Pereira; Mai, Sabine; Bernardo, Viviane; Lopes, José Daniel; Jasiulionis, Miriam Galvonas

2012-01-01

Background Metastatic melanoma is a highly aggressive skin cancer and currently resistant to systemic therapy. Melanomas may involve genetic, epigenetic and metabolic abnormalities. Evidence is emerging that epigenetic changes might play a significant role in tumor cell plasticity and metastatic phenotype of melanoma cells. Principal findings In this study, we developed a systematic approach to identify genes implicated in melanoma progression. To do this, we used the Affymetrix GeneChip Arrays to screen 34,000 mouse transcripts in melan-a melanocytes, 4C pre-malignant melanocytes, 4C11− non-metastatic and 4C11+ metastatic melanoma cell lines. The genome-wide association studies revealed pathways commonly over-represented in the transition from immortalized to pre-malignant stage, and under-represented in the transition from non-metastatic to metastatic stage. Additionally, the treatment of cells with 10 µM 5-aza-2′-deoxycytidine (5AzaCdR) for 48 hours allowed us to identify genes differentially re-expressed at specific stages of melan-a malignant transformation. Treatment of human primary melanocytes with the demethylating agent 5AzaCdR in combination to the histone deacetylase inhibitor Trichostatin A (TSA) revealed changes on melanocyte morphology and gene expression which could be an indicator of epigenetic flexibility in normal melanocytes. Moreover, changes on gene expression recognized by affecting the melanocyte biology (NDRG2 and VDR), phenotype of metastatic melanoma cells (HSPB1 and SERPINE1) and response to cancer therapy (CTCF, NSD1 and SRC) were found when Mel-2 and/or Mel-3-derived patient metastases were exposed to 5AzaCdR plus TSA treatment. Hierarchical clustering and network analyses in a panel of five patient-derived metastatic melanoma cells showed gene interactions that have never been described in melanomas. Significance Despite the heterogeneity observed in melanomas, this study demonstrates the utility of our murine melanoma progression model to identify molecular markers commonly perturbed in metastasis. Additionally, the novel gene expression signature identified here may be useful in the future into a model more closely related to translational research. PMID:22984562

MicroRNA-9 suppresses the growth, migration, and invasion of malignant melanoma cells via targeting NRP1.

PubMed

Xu, Dan; Chen, Xiaofeng; He, Quanyong; Luo, Chengqun

2016-01-01

MicroRNAs (miRs) are a class of small noncoding RNAs that negatively regulate the gene expression by directly binding to the 3' untranslated region of their target mRNA, thus resulting in mRNA degradation or translational repression. miR-9 has recently been demonstrated to play a role in the development and progression of malignant melanoma (MM), but the regulatory mechanism of miR-9 in the malignant phenotypes of MM still remains largely unknown. In this study, a total of 73 pairs of MM tissues and adjacent normal tissues were collected. Real-time reverse transcription polymerase chain reaction and Western blot were used to detect the mRNA and protein expression of miR-9. MTT assay, wound healing assay, and transwell assay were conducted to determine the cell proliferation, migration, and invasion. Luciferase reporter assay was used to determine the targeting relationship between miR-9 and NRP1. Our data demonstrated that miR-9 expression was significantly downregulated in MM tissues compared with that in adjacent normal tissues. The decreased miR-9 level was significantly associated with the tumor stage and metastasis of MM. We also found that the expression level of miR-9 was decreased in MM cell lines (G361, B16, A375, and HME1) compared with normal skin HACAT cells. Ectopic expression of miR-9 led to a significant decrease in the ability of proliferation, migration, and invasion in A375 cells. NRP1 was further identified as a direct target gene of miR-9, and the protein expression of NRP1 was negatively regulated by miR-9 in A375 cells. Furthermore, overexpression of NRP1 reversed the suppressive effects of miR-9 on the malignant phenotypes of A375 cells. In vivo study revealed that miR-9 overexpression decreased the tumor growth, while overexpression of NRP1 increased MM growth. In summary, our findings suggest that the miR-9/NRP1 axis may serve as a potential target for the treatment of MM.

S100A8/A9 regulates MMP-2 expression and invasion and migration by carcinoma cells.

PubMed

Silva, Emmanuel J; Argyris, Prokopios P; Zou, Xianqiong; Ross, Karen F; Herzberg, Mark C

2014-10-01

Intracellular calprotectin (S100A8/A9) functions in the control of the cell cycle checkpoint at G2/M. Dysregulation of S100A8/A9 appears to cause loss of the checkpoint, which frequently characterizes head and neck squamous cell carcinoma (HNSCC). In the present study, we analyzed carcinoma cells for other S100A8/A9-directed changes in malignant phenotype. Using a S100A8/A9-negative human carcinoma cell line (KB), transfection to express S100A8 and S100A9 caused selective down-regulation of MMP-2 and inhibited in vitro invasion and migration. Conversely, silencing of endogenous S100A8 and S100A9 expression in TR146 cells, a well-differentiated HNSCC cell line, increased MMP-2 activity and in vitro invasion and migration. When MMP-2 expression was silenced, cells appeared to assume a less malignant phenotype. To more closely model the architecture of cell growth in vivo, cells were grown in a 3D collagen substrate, which was compared to 2D. Growth on 3D substrates caused greater MMP-2 expression. Whereas hypermethylation of CpG islands occurs frequently in HNSCC, S100A8/A9-dependent regulation of MMP-2 could not be explained by modification of the upstream promoters of MMP2 or TIMP2. Collectively, these results suggest that intracellular S100A8/A9 contributes to the cancer cell phenotype by modulating MMP-2 expression and activity to regulate cell migration and mobility. Published by Elsevier Ltd.

eIF4E and eIF4GI have distinct and differential imprints on multiple myeloma's proteome and signaling

PubMed Central

Attar-Schneider, Oshrat; Pasmanik-Chor, Metsada; Tartakover-Matalon, Shelly

2015-01-01

Accumulating data indicate translation plays a role in cancer biology, particularly its rate limiting stage of initiation. Despite this evolving recognition, the function and importance of specific translation initiation factors is unresolved. The eukaryotic translation initiation complex eIF4F consists of eIF4E and eIF4G at a 1:1 ratio. Although it is expected that they display interdependent functions, several publications suggest independent mechanisms. This study is the first to directly assess the relative contribution of eIF4F components to the expressed cellular proteome, transcription factors, microRNAs, and phenotype in a malignancy known for extensive protein synthesis-multiple myeloma (MM). Previously, we have shown that eIF4E/eIF4GI attenuation (siRNA/Avastin) deleteriously affected MM cells' fate and reduced levels of eIF4E/eIF4GI established targets. Here, we demonstrated that eIF4E/eIF4GI indeed have individual influences on cell proteome. We used an objective, high throughput assay of mRNA microarrays to examine the significance of eIF4E/eIF4GI silencing to several cellular facets such as transcription factors, microRNAs and phenotype. We showed different imprints for eIF4E and eIF4GI in all assayed aspects. These results promote our understanding of the relative contribution and importance of eIF4E and eIF4GI to the malignant phenotype and shed light on their function in eIF4F translation initiation complex. PMID:25717031

Automated manufacturing of chimeric antigen receptor T cells for adoptive immunotherapy using CliniMACS prodigy.

PubMed

Mock, Ulrike; Nickolay, Lauren; Philip, Brian; Cheung, Gordon Weng-Kit; Zhan, Hong; Johnston, Ian C D; Kaiser, Andrew D; Peggs, Karl; Pule, Martin; Thrasher, Adrian J; Qasim, Waseem

2016-08-01

Novel cell therapies derived from human T lymphocytes are exhibiting enormous potential in early-phase clinical trials in patients with hematologic malignancies. Ex vivo modification of T cells is currently limited to a small number of centers with the required infrastructure and expertise. The process requires isolation, activation, transduction, expansion and cryopreservation steps. To simplify procedures and widen applicability for clinical therapies, automation of these procedures is being developed. The CliniMACS Prodigy (Miltenyi Biotec) has recently been adapted for lentiviral transduction of T cells and here we analyse the feasibility of a clinically compliant T-cell engineering process for the manufacture of T cells encoding chimeric antigen receptors (CAR) for CD19 (CAR19), a widely targeted antigen in B-cell malignancies. Using a closed, single-use tubing set we processed mononuclear cells from fresh or frozen leukapheresis harvests collected from healthy volunteer donors. Cells were phenotyped and subjected to automated processing and activation using TransAct, a polymeric nanomatrix activation reagent incorporating CD3/CD28-specific antibodies. Cells were then transduced and expanded in the CentriCult-Unit of the tubing set, under stabilized culture conditions with automated feeding and media exchange. The process was continuously monitored to determine kinetics of expansion, transduction efficiency and phenotype of the engineered cells in comparison with small-scale transductions run in parallel. We found that transduction efficiencies, phenotype and function of CAR19 T cells were comparable with existing procedures and overall T-cell yields sufficient for anticipated therapeutic dosing. The automation of closed-system T-cell engineering should improve dissemination of emerging immunotherapies and greatly widen applicability. Copyright © 2016. Published by Elsevier Inc.

Red cell allo- and autoimmunisation in transfused sickle cell and cancer patients in Kenyatta National Hospital, Nairobi, Kenya

PubMed Central

Mbugua, Amos; Maturi, Peter; Rajab, Jamila; Blasczyk, Rainer; Heuft, Hans-Gert

2015-01-01

Background Currently, no data are available on the prevalence of red blood cell (RBC) antibody formation amongst Kenyan patients with multiple transfusion needs, such as patients with sickle cell disease (SCD) or haematological malignancies (HM) and solid (SM) malignancies. Objectives We determined the prevalence and specificities of RBC alloantibodies and autoantibodies in two patient groups with recurrent transfusion demands at Kenyatta National Hospital, Nairobi, Kenya. Method Between February and August 2014, 300 samples from SCD, HM and SM patients were collected and screened for alloantibodies. Samples from 51 healthy blood donors were screened for irregular antibodies and phenotyped. Results Amongst the 228 patients with viable samples (SCD, n = 137; HM, n = 48; SM, n = 43), the median transfusion frequency was two to three events per group, 38 (16.7%) were RBC immunised and 32 (14.0%) had a positive direct antiglobulin test. We identified specific alloantibodies in six patients (2.6%). Four of these six were SCD patients (2.9%) who had specific RBC alloantibodies (anti-Cw, anti-M, anti-Cob, anti-S); amongst HM patients one had anti-K and one had anti-Lea. RBC autoantibody prevalence was 3.1% (7/228). Amongst the healthy blood donors, the Ror, ccD.ee and R2r, ccD.Ee phenotypes accounted for 82% of the Rhesus phenotypes and all were Kell negative. Conclusion The numbers of transfusions and the rates of RBC alloantibodies are low and the most important RBC alloantibody-inducing blood group antigens are relatively homogeneously distributed in this population. A general change in the Kenyatta National Hospital pre-transfusion test regimen is thus not necessary. The current transfusion practice should be reconsidered if transfusion frequencies increase in the future. PMID:28879098

Functional characterisation of osteosarcoma cell lines and identification of mRNAs and miRNAs associated with aggressive cancer phenotypes

PubMed Central

Lauvrak, S U; Munthe, E; Kresse, S H; Stratford, E W; Namløs, H M; Meza-Zepeda, L A; Myklebost, O

2013-01-01

Background: Osteosarcoma is the most common primary malignant bone tumour, predominantly affecting children and adolescents. Cancer cell line models are required to understand the underlying mechanisms of tumour progression and for preclinical investigations. Methods: To identify cell lines that are well suited for studies of critical cancer-related phenotypes, such as tumour initiation, growth and metastasis, we have evaluated 22 osteosarcoma cell lines for in vivo tumorigenicity, in vitro colony-forming ability, invasive/migratory potential and proliferation capacity. Importantly, we have also identified mRNA and microRNA (miRNA) gene expression patterns associated with these phenotypes by expression profiling. Results: The cell lines exhibited a wide range of cancer-related phenotypes, from rather indolent to very aggressive. Several mRNAs were differentially expressed in highly aggressive osteosarcoma cell lines compared with non-aggressive cell lines, including RUNX2, several S100 genes, collagen genes and genes encoding proteins involved in growth factor binding, cell adhesion and extracellular matrix remodelling. Most notably, four genes—COL1A2, KYNU, ACTG2 and NPPB—were differentially expressed in high and non-aggressive cell lines for all the cancer-related phenotypes investigated, suggesting that they might have important roles in the process of osteosarcoma tumorigenesis. At the miRNA level, miR-199b-5p and mir-100-3p were downregulated in the highly aggressive cell lines, whereas miR-155-5p, miR-135b-5p and miR-146a-5p were upregulated. miR-135b-5p and miR-146a-5p were further predicted to be linked to the metastatic capacity of the disease. Interpretation: The detailed characterisation of cell line phenotypes will support the selection of models to use for specific preclinical investigations. The differentially expressed mRNAs and miRNAs identified in this study may represent good candidates for future therapeutic targets. To our knowledge, this is the first time that expression profiles are associated with functional characteristics of osteosarcoma cell lines. PMID:24064976

Kindler syndrome: extension of FERMT1 mutational spectrum and natural history.

PubMed

Has, Cristina; Castiglia, Daniele; del Rio, Marcela; Diez, Marta Garcia; Piccinni, Eugenia; Kiritsi, Dimitra; Kohlhase, Jürgen; Itin, Peter; Martin, Ludovic; Fischer, Judith; Zambruno, Giovanna; Bruckner-Tuderman, Leena

2011-11-01

Mutations in the FERMT1 gene (also known as KIND1), encoding the focal adhesion protein kindlin-1, underlie the Kindler syndrome (KS), an autosomal recessive skin disorder with an intriguing progressive phenotype comprising skin blistering, photosensitivity, progressive poikiloderma with extensive skin atrophy, and propensity to skin cancer. Herein we review the clinical and genetic data of 62 patients, and delineate the natural history of the disorder, for example, age at onset of symptoms, or risk of malignancy. Although most mutations are predicted to lead to premature termination of translation, and to loss of kindlin-1 function, significant clinical variability is observed among patients. There is an association of FERMT1 missense and in-frame deletion mutations with milder disease phenotypes, and later onset of complications. Nevertheless, the clinical variability is not fully explained by genotype-phenotype correlations. Environmental factors and yet unidentified modifiers may play a role. Better understanding of the molecular pathogenesis of KS should enable the development of prevention strategies for disease complications. © 2011 Wiley Periodicals, Inc.

Molecular mechanisms of cellular transformation by HTLV-1 Tax.

PubMed

Grassmann, Ralph; Aboud, Mordechai; Jeang, Kuan-Teh

2005-09-05

The HTLV Tax protein is crucial for viral replication and for initiating malignant transformation leading to the development of adult T-cell leukemia. Tax has been shown to be oncogenic, since it transforms and immortalizes rodent fibroblasts and human T-lymphocytes. Through CREB, NF-kappaB and SRF pathways Tax transactivates cellular promoters including those of cytokines (IL-13, IL-15), cytokine receptors (IL-2Ralpha) and costimulatory surface receptors (OX40/OX40L) leading to upregulated protein expression and activated signaling cascades (e.g. Jak/STAT, PI3Kinase, JNK). Tax also stimulates cell growth by direct binding to cyclin-dependent kinase holenzymes and/or inactivating tumor suppressors (e.g. p53, DLG). Moreover, Tax silences cellular checkpoints, which guard against DNA structural damage and chromosomal missegregation, thereby favoring the manifestation of a mutator phenotype in cells.

Possible autoimmune hepatitis induced after chronic active Epstein-Barr virus infection.

PubMed

Wada, Yoshiko; Sato, Chikako; Tomita, Kyoko; Ishii-Aso, Rika; Haga, Hiroaki; Okumoto, Kazuo; Nishise, Yuko; Watanabe, Hisayoshi; Saito, Takafumi; Ueno, Yoshiyuki

2014-02-01

Chronic active Epstein-Barr virus infection (CAEBV) can be manifested in a variety of systemic conditions, including interstitial pneumonia, malignant lymphoma, and coronary aneurysm. Sometimes it may be associated with hepatic failure, although the mechanism underlying CAEBV-related hepatotoxicity remains unclear. We encountered a case of autoimmune hepatitis (AIH) associated with CAEBV. A 61-year-old male was referred to our hospital because of abnormal liver enzyme levels after initial diagnosis of CAEBV had been made by laboratory tests and liver biopsy. On admission, positivity for anti-nuclear antibody was evident, and examination of the liver biopsy specimen showed findings compatible with AIH. Steroid administration was initiated, and the liver function parameters subsequently improved. Although phenotypic changes in liver biopsy specimens are rare in this condition, the present case could provide clues to the possible pathogenesis of AIH.

Using Human Stem Cells to Study the Role of the Stroma in the Initiation of Prostate Cancer

DTIC Science & Technology

2011-03-01

alterations in the epithelium that drives the pr ogressive transformation of nor mal human cells into highly malignant derivatives. It is evident that...of tumor initiation, we propose to use normal human prostate epithelium generated from human embryonic stem cells (hESCs) in tissue recombination...serum free conditions for 5-8 days into endoderm in vitro. Confirm endoderm phenotype using immunohistochemistry and FACs analysis . We conducted

Mechanisms of Nuclear Export in Cancer and Resistance to Chemotherapy.

PubMed

El-Tanani, Mohamed; Dakir, El-Habib; Raynor, Bethany; Morgan, Richard

2016-03-14

Tumour suppressor proteins, such as p53, BRCA1, and ABC, play key roles in preventing the development of a malignant phenotype, but those that function as transcriptional regulators need to enter the nucleus in order to function. The export of proteins between the nucleus and cytoplasm is complex. It occurs through nuclear pores and exported proteins need a nuclear export signal (NES) to bind to nuclear exportin proteins, including CRM1 (Chromosomal Region Maintenance protein 1), and the energy for this process is provided by the RanGTP/RanGDP gradient. Due to the loss of DNA repair and cell cycle checkpoints, drug resistance is a major problem in cancer treatment, and often an initially successful treatment will fail due to the development of resistance. An important mechanism underlying resistance is nuclear export, and a number of strategies that can prevent nuclear export may reverse resistance. Examples include inhibitors of CRM1, antibodies to the nuclear export signal, and alteration of nuclear pore structure. Each of these are considered in this review.

Splicing factor gene mutations in the myelodysplastic syndromes: impact on disease phenotype and therapeutic applications.

PubMed

Pellagatti, Andrea; Boultwood, Jacqueline

2017-01-01

Splicing factor gene mutations are the most frequent mutations found in patients with the myeloid malignancy myelodysplastic syndrome (MDS), suggesting that spliceosomal dysfunction plays a major role in disease pathogenesis. The aberrantly spliced target genes and deregulated cellular pathways associated with the commonly mutated splicing factor genes in MDS (SF3B1, SRSF2 and U2AF1) are being identified, illuminating the molecular mechanisms underlying MDS. Emerging data from mouse modeling studies indicate that the presence of splicing factor gene mutations can lead to bone marrow hematopoietic stem/myeloid progenitor cell expansion, impaired hematopoiesis and dysplastic differentiation that are hallmarks of MDS. Importantly, recent evidence suggests that spliceosome inhibitors and splicing modulators may have therapeutic value in the treatment of splicing factor mutant myeloid malignancies. Copyright © 2016 Elsevier Ltd. All rights reserved.

The pathobiology and mechanisms of infection of HPV.

PubMed

Wood, N H; Khammissa, R A G; Chikte, U M E; Meyerov, R; Lemmer, J; Feller, L

2010-04-01

There are more than 120 types of low-risk and high-risk human papillomaviruses, all of which are epitheliotropic. HPV infection may be latent, or active in a subclinical form or a symptomatic form, the latter manifesting as benign or malignant neoplasms. In basal cells with non-productive HPV infection some early HPV proteins are expressed independently of cell maturation: the productive cycle of HPV replication depends upon specific cellular factors of the maturation of the infected keratinocytes. In HPV-mediated oncogenesis, the combined pathobiological effects of E6 and E7 oncoproteins of high-risk HPV culminate in cellular genomic instability and transformation of persistently infected cells, that progress to the development of a malignant phenotype. In this article we provide insights into the stages of HPV infection, and into the viral genomic organization and replicative cycle.

The receptor protein tyrosine phosphatase (RPTP){beta}/{zeta} is expressed in different subtypes of human breast cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Perez-Pinera, Pablo; Garcia-Suarez, Olivia; Instituto Universitario de Oncologia del Principado de Asturias, Oviedo

2007-10-12

Increasing evidence suggests mutations in human breast cancer cells that induce inappropriate expression of the 18-kDa cytokine pleiotrophin (PTN, Ptn) initiate progression of breast cancers to a more malignant phenotype. Pleiotrophin signals through inactivating its receptor, the receptor protein tyrosine phosphatase (RPTP){beta}/{zeta}, leading to increased tyrosine phosphorylation of different substrate proteins of RPTP{beta}/{zeta}, including {beta}-catenin, {beta}-adducin, Fyn, GIT1/Cat-1, and P190RhoGAP. PTN signaling thus has wide impact on different important cellular systems. Recently, PTN was found to activate anaplastic lymphoma kinase (ALK) through the PTN/RPTP{beta}/{zeta} signaling pathway; this discovery potentially is very important, since constitutive ALK activity of nucleophosmin (NPM)-ALK fusionmore » protein is causative of anaplastic large cell lymphomas, and, activated ALK is found in other malignant cancers. Recently ALK was identified in each of 63 human breast cancers from 22 subjects. We now demonstrate that RPTP{beta}/{zeta} is expressed in each of these same 63 human breast cancers that previously were found to express ALK and in 10 additional samples of human breast cancer. RPTP{beta}/{zeta} furthermore was localized not only in its normal association with the cell membrane but also scattered in cytoplasm and in nuclei in different breast cancer cells and, in the case of infiltrating ductal carcinomas, the distribution of RPTP{beta}/{zeta} changes as the breast cancer become more malignant. The data suggest that the PTN/RPTP{beta}/{zeta} signaling pathway may be constitutively activated and potentially function to constitutively activate ALK in human breast cancer.« less

An 11-year retrospective experience of antibodies against the voltage-gated potassium channel (VGKC) complex from a tertiary neurological centre.

PubMed

Huda, S; Wong, S H; Pettingill, P; O'Connell, D; Vincent, A; Steiger, M

2015-02-01

Acquired diseases classically associated with VGKC-complex antibodies include peripheral nerve hyperexcitability (PNH), Morvan's syndrome, limbic encephalitis (LE), and epilepsy. However, not all such patients have VGKC-complex antibodies and antibodies have been reported in patients without a defined immune-mediated syndrome. To analyse the clinical relevance of positive VGKC-complex antibodies requested on the basis of initial clinical suspicion. We retrospectively analysed patients with positive VGKC-complex antibodies (>100 pM) referred to our institution between 2001 and 2011. 1,614 VGKC-complex assays were performed in 1,298 patients. Titres >100 pM were detected in 57/1,298 (4 %) patients. A classic VGKC-complex channelopathy (60 %) was associated with VGKC-complex antibody titres >400 pM (p = 0.0004). LGI1 or CASPR2 antibodies were only detected in classic VGKC-complex channelopathies (LE; n = 3/4 and PNH; n = 1/5). VGKC-complex antibody titres <400 pM were seen with PNH (n = 15/22; 68 %) but also a heterogeneous range of central and/or peripheral nervous system disorders. Electromyography was supportive of PNH in 65 % of cases and symptomatic treatment was beneficial in 46 % of patients. Irrespective of titre, the rate of malignancy in patients with VGKC-complex antibodies was higher than the age-matched national incidence of malignancy (OR 19.9, 95 % CI 8.97-44.0 p<0.0001). Clinical phenotyping and antibody titres >400 pM can help determine VGKC-complex antibody relevance. Antibody titres <400 pM are associated with PNH but also a more heterogeneous clinical spectrum. The antibody association in the latter is of doubtful clinical relevance. The rate of malignancy was significantly higher than the national incidence irrespective of titre.

Histone deacetylase inhibitors (HDACIs): multitargeted anticancer agents

PubMed Central

Ververis, Katherine; Hiong, Alison; Karagiannis, Tom C; Licciardi, Paul V

2013-01-01

Histone deacetylase (HDAC) inhibitors are an emerging class of therapeutics with potential as anticancer drugs. The rationale for developing HDAC inhibitors (and other chromatin-modifying agents) as anticancer therapies arose from the understanding that in addition to genetic mutations, epigenetic changes such as dysregulation of HDAC enzymes can alter phenotype and gene expression, disturb homeostasis, and contribute to neoplastic growth. The family of HDAC inhibitors is large and diverse. It includes a range of naturally occurring and synthetic compounds that differ in terms of structure, function, and specificity. HDAC inhibitors have multiple cell type-specific effects in vitro and in vivo, such as growth arrest, cell differentiation, and apoptosis in malignant cells. HDAC inhibitors have the potential to be used as monotherapies or in combination with other anticancer therapies. Currently, there are two HDAC inhibitors that have received approval from the US FDA for the treatment of cutaneous T-cell lymphoma: vorinostat (suberoylanilide hydroxamic acid, Zolinza) and depsipeptide (romidepsin, Istodax). More recently, depsipeptide has also gained FDA approval for the treatment of peripheral T-cell lymphoma. Many more clinical trials assessing the effects of various HDAC inhibitors on hematological and solid malignancies are currently being conducted. Despite the proven anticancer effects of particular HDAC inhibitors against certain cancers, many aspects of HDAC enzymes and HDAC inhibitors are still not fully understood. Increasing our understanding of the effects of HDAC inhibitors, their targets and mechanisms of action will be critical for the advancement of these drugs, especially to facilitate the rational design of HDAC inhibitors that are effective as antineoplastic agents. This review will discuss the use of HDAC inhibitors as multitargeted therapies for malignancy. Further, we outline the pharmacology and mechanisms of action of HDAC inhibitors while discussing the safety and efficacy of these compounds in clinical studies to date. PMID:23459471

Histone deacetylase inhibitors (HDACIs): multitargeted anticancer agents.

PubMed

Ververis, Katherine; Hiong, Alison; Karagiannis, Tom C; Licciardi, Paul V

2013-01-01

Histone deacetylase (HDAC) inhibitors are an emerging class of therapeutics with potential as anticancer drugs. The rationale for developing HDAC inhibitors (and other chromatin-modifying agents) as anticancer therapies arose from the understanding that in addition to genetic mutations, epigenetic changes such as dysregulation of HDAC enzymes can alter phenotype and gene expression, disturb homeostasis, and contribute to neoplastic growth. The family of HDAC inhibitors is large and diverse. It includes a range of naturally occurring and synthetic compounds that differ in terms of structure, function, and specificity. HDAC inhibitors have multiple cell type-specific effects in vitro and in vivo, such as growth arrest, cell differentiation, and apoptosis in malignant cells. HDAC inhibitors have the potential to be used as monotherapies or in combination with other anticancer therapies. Currently, there are two HDAC inhibitors that have received approval from the US FDA for the treatment of cutaneous T-cell lymphoma: vorinostat (suberoylanilide hydroxamic acid, Zolinza) and depsipeptide (romidepsin, Istodax). More recently, depsipeptide has also gained FDA approval for the treatment of peripheral T-cell lymphoma. Many more clinical trials assessing the effects of various HDAC inhibitors on hematological and solid malignancies are currently being conducted. Despite the proven anticancer effects of particular HDAC inhibitors against certain cancers, many aspects of HDAC enzymes and HDAC inhibitors are still not fully understood. Increasing our understanding of the effects of HDAC inhibitors, their targets and mechanisms of action will be critical for the advancement of these drugs, especially to facilitate the rational design of HDAC inhibitors that are effective as antineoplastic agents. This review will discuss the use of HDAC inhibitors as multitargeted therapies for malignancy. Further, we outline the pharmacology and mechanisms of action of HDAC inhibitors while discussing the safety and efficacy of these compounds in clinical studies to date.

Complex Determinants of Epithelial: Mesenchymal Phenotypic Plasticity in Ovarian Cancer

PubMed Central

Klymenko, Yuliya; Kim, Oleg; Stack, M. Sharon

2017-01-01

Unlike most epithelial malignancies which metastasize hematogenously, metastasis of epithelial ovarian cancer (EOC) occurs primarily via transcoelomic dissemination, characterized by exfoliation of cells from the primary tumor, avoidance of detachment-induced cell death (anoikis), movement throughout the peritoneal cavity as individual cells and multi-cellular aggregates (MCAs), adhesion to and disruption of the mesothelial lining of the peritoneum, and submesothelial matrix anchoring and proliferation to generate widely disseminated metastases. This exceptional microenvironment is highly permissive for phenotypic plasticity, enabling mesenchymal-to-epithelial (MET) and epithelial-to-mesenchymal (EMT) transitions. In this review, we summarize current knowledge on EOC heterogeneity in an EMT context, outline major regulators of EMT in ovarian cancer, address controversies in EMT and EOC chemoresistance, and highlight computational modeling approaches toward understanding EMT/MET in EOC. PMID:28792442

GBM heterogeneity characterization by radiomic analysis of phenotype anatomical planes

NASA Astrophysics Data System (ADS)

Chaddad, Ahmad; Desrosiers, Christian; Toews, Matthew

2016-03-01

Glioblastoma multiforme (GBM) is the most common malignant primary tumor of the central nervous system, characterized among other traits by rapid metastatis. Three tissue phenotypes closely associated with GBMs, namely, necrosis (N), contrast enhancement (CE), and edema/invasion (E), exhibit characteristic patterns of texture heterogeneity in magnetic resonance images (MRI). In this study, we propose a novel model to characterize GBM tissue phenotypes using gray level co-occurrence matrices (GLCM) in three anatomical planes. The GLCM encodes local image patches in terms of informative, orientation-invariant texture descriptors, which are used here to sub-classify GBM tissue phenotypes. Experiments demonstrate the model on MRI data of 41 GBM patients, obtained from the cancer genome atlas (TCGA). Intensity-based automatic image registration is applied to align corresponding pairs of fixed T1˗weighted (T1˗WI) post-contrast and fluid attenuated inversion recovery (FLAIR) images. GBM tissue regions are then segmented using the 3D Slicer tool. Texture features are computed from 12 quantifier functions operating on GLCM descriptors, that are generated from MRI intensities within segmented GBM tissue regions. Various classifier models are used to evaluate the effectiveness of texture features for discriminating between GBM phenotypes. Results based on T1-WI scans showed a phenotype classification accuracy of over 88.14%, a sensitivity of 85.37% and a specificity of 96.1%, using the linear discriminant analysis (LDA) classifier. This model has the potential to provide important characteristics of tumors, which can be used for the sub-classification of GBM phenotypes.

Epigenome remodelling in breast cancer: insights from an early in vitro model of carcinogenesis.

PubMed

Locke, Warwick J; Clark, Susan J

2012-11-15

Epigenetic gene regulation has influence over a diverse range of cellular functions, including the maintenance of pluripotency, differentiation, and cellular identity, and is deregulated in many diseases, including cancer. Whereas the involvement of epigenetic dysregulation in cancer is well documented, much of the mechanistic detail involved in triggering these changes remains unclear. In the current age of genomics, the development of new sequencing technologies has seen an influx of genomic and epigenomic data and drastic improvements in both resolution and coverage. Studies in cancer cell lines and clinical samples using next-generation sequencing are rapidly delivering spectacular insights into the nature of the cancer genome and epigenome. Despite these improvements in technology, the timing and relationship between genetic and epigenetic changes that occur during the process of carcinogenesis are still unclear. In particular, what changes to the epigenome are playing a driving role during carcinogenesis and what influence the temporal nature of these changes has on cancer progression are not known. Understanding the early epigenetic changes driving breast cancer has the exciting potential to provide a novel set of therapeutic targets or early-disease biomarkers or both. Therefore, it is important to find novel systems that permit the study of initial epigenetic events that potentially occur during the first stages of breast cancer. Non-malignant human mammary epithelial cells (HMECs) provide an exciting in vitro model of very early breast carcinogenesis. When grown in culture, HMECs are able to temporarily escape senescence and acquire a pre-malignant breast cancer-like phenotype (variant HMECs, or vHMECs). Cultured HMECs are composed mainly of cells from the basal breast epithelial layer. Therefore, vHMECs are considered to represent the basal-like subtype of breast cancer. The transition from HMECs to vHMECs in culture recapitulates the epigenomic phenomena that occur during the progression from normal breast to pre-malignancy. Therefore, the HMEC model system provides the unique opportunity to study the very earliest epigenomic aberrations occurring during breast carcinogenesis and can give insight into the sequence of epigenomic events that lead to breast malignancy. This review provides an overview of epigenomic research in breast cancer and discusses in detail the utility of the HMEC model system to discover early epigenomic changes involved in breast carcinogenesis.

Epigenome remodelling in breast cancer: insights from an early in vitro model of carcinogenesis

PubMed Central

2012-01-01

Epigenetic gene regulation has influence over a diverse range of cellular functions, including the maintenance of pluripotency, differentiation, and cellular identity, and is deregulated in many diseases, including cancer. Whereas the involvement of epigenetic dysregulation in cancer is well documented, much of the mechanistic detail involved in triggering these changes remains unclear. In the current age of genomics, the development of new sequencing technologies has seen an influx of genomic and epigenomic data and drastic improvements in both resolution and coverage. Studies in cancer cell lines and clinical samples using next-generation sequencing are rapidly delivering spectacular insights into the nature of the cancer genome and epigenome. Despite these improvements in technology, the timing and relationship between genetic and epigenetic changes that occur during the process of carcinogenesis are still unclear. In particular, what changes to the epigenome are playing a driving role during carcinogenesis and what influence the temporal nature of these changes has on cancer progression are not known. Understanding the early epigenetic changes driving breast cancer has the exciting potential to provide a novel set of therapeutic targets or early-disease biomarkers or both. Therefore, it is important to find novel systems that permit the study of initial epigenetic events that potentially occur during the first stages of breast cancer. Non-malignant human mammary epithelial cells (HMECs) provide an exciting in vitro model of very early breast carcinogenesis. When grown in culture, HMECs are able to temporarily escape senescence and acquire a pre-malignant breast cancer-like phenotype (variant HMECs, or vHMECs). Cultured HMECs are composed mainly of cells from the basal breast epithelial layer. Therefore, vHMECs are considered to represent the basal-like subtype of breast cancer. The transition from HMECs to vHMECs in culture recapitulates the epigenomic phenomena that occur during the progression from normal breast to pre-malignancy. Therefore, the HMEC model system provides the unique opportunity to study the very earliest epigenomic aberrations occurring during breast carcinogenesis and can give insight into the sequence of epigenomic events that lead to breast malignancy. This review provides an overview of epigenomic research in breast cancer and discusses in detail the utility of the HMEC model system to discover early epigenomic changes involved in breast carcinogenesis. PMID:23168266

Reversion of malignant phenotypes of human glioblastoma cells by β-elemene through β-catenin-mediated regulation of stemness-, differentiation- and epithelial-to-mesenchymal transition-related molecules.

PubMed

Zhu, Tingzhun; Li, Xiaoming; Luo, Lihan; Wang, Xiaogang; Li, Zhiqing; Xie, Peng; Gao, Xu; Song, Zhenquan; Su, Jingyuan; Liang, Guobiao

2015-11-12

Glioblastoma is the most common and lethal type of primary brain tumor. β-Elemene, a natural plant drug extracted from Curcuma wenyujin, has shown strong anti-tumor effects in various tumors with low toxicity. However, the effects of β-elemene on malignant phenotypes of human glioblastoma cells remain to be elucidated. Here we evaluated the effects of β-elemene on cell proliferation, survival, stemness, differentiation and the epithelial-to-mesenchymal transition (EMT) in vitro and in vivo, and investigated the mechanisms underlying these effects. Human primary and U87 glioblastoma cells were treated with β-elemene, cell viability was measured using a cell counting kit-8 assay, and treated cells were evaluated by flow cytometry. Western blot analysis was carried out to determine the expression levels of stemness markers, differentiation-related molecules and EMT-related effectors. Transwell assays were performed to further determine EMT of glioblastoma cells. To evaluate the effect of β-elemene on glioblastoma in vivo, we subcutaneously injected glioblastoma cells into the flank of nude mice and then intraperitoneally injected NaCl or β-elemene. The tumor xenograft volumes were measured every 3 days and the expression of stemness-, differentiation- and EMT-related effectors was determined by Western blot assays in xenografts. β-Elemene inhibited proliferation, promoted apoptosis, impaired invasiveness in glioblastoma cells and suppressed the growth of animal xenografts. The expression levels of the stemness markers CD133 and ATP-binding cassette subfamily G member 2 as well as the mesenchymal markers N-cadherin and β-catenin were significantly downregulated, whereas the expression levels of the differentiation-related effectors glial fibrillary acidic protein, Notch1, and sonic hedgehog as well as the epithelial marker E-cadherin were upregulated by β-elemene in vitro and in vivo. Interestingly, the expression of vimentin was increased by β-elemene in vitro; this result was opposite that for the in vivo procedure. Inhibiting β-catenin enhanced the anti-proliferative, EMT-inhibitory and specific marker expression-regulatory effects of β-elemene. β-Elemene reversed malignant phenotypes of human glioblastoma cells through β-catenin-involved regulation of stemness-, differentiation- and EMT-related molecules. β-Elemene represents a potentially valuable agent for glioblastoma therapy.

Treatment for Patients With Malignant Pheochromocytomas and Paragangliomas: A Perspective From the Hallmarks of Cancer

PubMed Central

Jimenez, Camilo

2018-01-01

Malignant pheochromocytomas and paragangliomas affect a very small percentage of the general population. A substantial number of these patients have a hereditary predisposition for the disease and consequently, bear the risk of developing these tumors throughout their entire lives. It is, however, unclear why some patients with no hereditary predisposition develop these tumors, which frequently share a similar molecular phenotype with their hereditary counterparts. Both hereditary and sporadic tumors usually appear at an early age, and affected people often die before reaching their expected lifespans. Unfortunately, there is currently no systemic therapy approved for patients with this orphan disease. Therefore, pheochromocytomas and paragangliomas are very challenging malignancies. The recognition of genetic and molecular abnormalities responsible for the development of these tumors as well as the identification of effective therapies for other malignancies that share a similar pathogenesis is leading to the development of exciting clinical trials. Tyrosine kinase inhibitors, radiopharmaceutical agents, and immunotherapy are currently under evaluation in prospective clinical trials. A phase 2 clinical trial of the highly specific metaiodobenzylguanidine, iobenguane 131I, has provided impressive results; this radiopharmaceutical agent may become the first approved systemic therapy for patients with malignant pheochromocytoma and paraganglioma by the United States Food and Drug Administration. Nevertheless, systemic therapies are still not able to cure the disease. This review will discuss the development of systemic therapeutic approaches using the hallmarks of cancer as a framework. This approach will help the reader to understand where research efforts currently stand and what the future for this difficult field may be.

Small Renal Masses in Close Proximity to the Collecting System and Renal Sinus Are Enriched for Malignancy and High Fuhrman Grade and Should Be Considered for Early Intervention.

PubMed

Correa, Andres F; Toussi, Amir; Amin, Milon; Hrebinko, Ronald L; Gayed, Bishoy A; Parwani, Anil V; Maranchie, Jodi K

2018-02-05

Recent reports show a correlation between renal tumor radiographic characteristics and pathologic features. We hypothesize that a more central location within the relatively hypoxic renal medulla might confer a more aggressive tumor phenotype. To test this, radiographic tumor characteristics were compared with tumor grade and histology. We retrospectively reviewed renal masses <4 cm in diameter that underwent resection between 2008 and 2013. Tumor location was recorded using standard R.E.N.A.L. Nephrometry Score. Multivariate logistic regression was performed to compare independent anatomic features with incidence of malignancy and high nuclear grade. A total of 334 renal tumors had information available for analysis. Univariate analysis showed that increasing endophycity and proximity to the collecting system (<4 mm) were predictors of malignancy and high-grade features. In multivariate analysis, proximity to the collecting system <4 mm remained the as the only anatomical variable predictive of malignancy (odds ratio [OR], 3.58; 95% confidence interval [CI], 1.06-12.05; P = .04) and high nuclear grade (OR, 2.81; 95% CI, 1.44-5.51; P = .003). Malignancy and high tumor grade occur with much greater frequency when tumors are located deep in the kidney, in close proximity to the collecting system and renal sinus. Ninety-six percent of small renal masses in this region were cancers and nearly half were Fuhrman Grade 3 or 4, suggesting that these small centrally located tumors should be targeted for early intervention. Copyright © 2018 Elsevier Inc. All rights reserved.

Gene signature associated with benign neurofibroma transformation to malignant peripheral nerve sheath tumors

PubMed Central

Sorzano, Carlos O. S.; Pascual-Montano, Alberto; Carazo, Jose M.

2017-01-01

Benign neurofibromas, the main phenotypic manifestations of the rare neurological disorder neurofibromatosis type 1, degenerate to malignant tumors associated to poor prognosis in about 10% of patients. Despite efforts in the field of (epi)genomics, the lack of prognostic biomarkers with which to predict disease evolution frustrates the adoption of appropriate early therapeutic measures. To identify potential biomarkers of malignant neurofibroma transformation, we integrated four human experimental studies and one for mouse, using a gene score-based meta-analysis method, from which we obtained a score-ranked signature of 579 genes. Genes with the highest absolute scores were classified as promising disease biomarkers. By grouping genes with similar neurofibromatosis-related profiles, we derived panels of potential biomarkers. The addition of promoter methylation data to gene profiles indicated a panel of genes probably silenced by hypermethylation. To identify possible therapeutic treatments, we used the gene signature to query drug expression databases. Trichostatin A and other histone deacetylase inhibitors, as well as cantharidin and tamoxifen, were retrieved as putative therapeutic means to reverse the aberrant regulation that drives to malignant cell proliferation and metastasis. This in silico prediction corroborated reported experimental results that suggested the inclusion of these compounds in clinical trials. This experimental validation supported the suitability of the meta-analysis method used to integrate several sources of public genomic information, and the reliability of the gene signature associated to the malignant evolution of neurofibromas to generate working hypotheses for prognostic and drug-responsive biomarkers or therapeutic measures, thus showing the potential of this in silico approach for biomarker discovery. PMID:28542306

Sarcosine influences apoptosis and growth of prostate cells via cell-type specific regulation of distinct sets of genes.

PubMed

Rodrigo, Miguel A Merlos; Strmiska, Vladislav; Horackova, Eva; Buchtelova, Hana; Michalek, Petr; Stiborova, Marie; Eckschlager, Tomas; Adam, Vojtech; Heger, Zbynek

2018-02-01

Sarcosine is a widely discussed oncometabolite of prostate cells. Although several reports described connections between sarcosine and various phenotypic changes of prostate cancer (PCa) cells, there is still a lack of insights on the complex phenomena of its effects on gene expression patterns, particularly in non-malignant and non-metastatic cells. To shed more light on this phenomenon, we performed parallel microarray profiling of RNA isolated from non-malignant (PNT1A), malignant (22Rv1), and metastatic (PC-3) prostate cell lines treated with sarcosine. Microarray results were experimentally verified using semi-quantitative-RT-PCR, clonogenic assay, through testing of the susceptibility of cells pre-incubated with sarcosine to anticancer agents with different modes of actions (inhibitors of topoisomerase II, DNA cross-linking agent, antimicrotubule agent and inhibitor of histone deacetylases) and by evaluation of activation of executioner caspases 3/7. We identified that irrespective of the cell type, sarcosine stimulates up-regulation of distinct sets of genes involved in cell cycle and mitosis, while down-regulates expression of genes driving apoptosis. Moreover, it was found that in all cell types, sarcosine had pronounced stimulatory effects on clonogenicity. Except of an inhibitor of histone deacetylase valproic acid, efficiency of all agents was significantly (P < 0.05) decreased in sarcosine pre-incubated cells. Our comparative study brings evidence that sarcosine affects not only metastatic PCa cells, but also their malignant and non-malignant counterparts and induces very similar changes in cells behavior, but via distinct cell-type specific targets. © 2017 Wiley Periodicals, Inc.

Molecular crosstalk between tumour and brain parenchyma instructs histopathological features in glioblastoma.

PubMed

Bougnaud, Sébastien; Golebiewska, Anna; Oudin, Anaïs; Keunen, Olivier; Harter, Patrick N; Mäder, Lisa; Azuaje, Francisco; Fritah, Sabrina; Stieber, Daniel; Kaoma, Tony; Vallar, Laurent; Brons, Nicolaas H C; Daubon, Thomas; Miletic, Hrvoje; Sundstrøm, Terje; Herold-Mende, Christel; Mittelbronn, Michel; Bjerkvig, Rolf; Niclou, Simone P

2016-05-31

The histopathological and molecular heterogeneity of glioblastomas represents a major obstacle for effective therapies. Glioblastomas do not develop autonomously, but evolve in a unique environment that adapts to the growing tumour mass and contributes to the malignancy of these neoplasms. Here, we show that patient-derived glioblastoma xenografts generated in the mouse brain from organotypic spheroids reproducibly give rise to three different histological phenotypes: (i) a highly invasive phenotype with an apparent normal brain vasculature, (ii) a highly angiogenic phenotype displaying microvascular proliferation and necrosis and (iii) an intermediate phenotype combining features of invasion and vessel abnormalities. These phenotypic differences were visible during early phases of tumour development suggesting an early instructive role of tumour cells on the brain parenchyma. Conversely, we found that tumour-instructed stromal cells differentially influenced tumour cell proliferation and migration in vitro, indicating a reciprocal crosstalk between neoplastic and non-neoplastic cells. We did not detect any transdifferentiation of tumour cells into endothelial cells. Cell type-specific transcriptomic analysis of tumour and endothelial cells revealed a strong phenotype-specific molecular conversion between the two cell types, suggesting co-evolution of tumour and endothelial cells. Integrative bioinformatic analysis confirmed the reciprocal crosstalk between tumour and microenvironment and suggested a key role for TGFβ1 and extracellular matrix proteins as major interaction modules that shape glioblastoma progression. These data provide novel insight into tumour-host interactions and identify novel stroma-specific targets that may play a role in combinatorial treatment strategies against glioblastoma.

Molecular crosstalk between tumour and brain parenchyma instructs histopathological features in glioblastoma

PubMed Central

Bougnaud, Sébastien; Golebiewska, Anna; Oudin, Anaïs; Keunen, Olivier; Harter, Patrick N.; Mäder, Lisa; Azuaje, Francisco; Fritah, Sabrina; Stieber, Daniel; Kaoma, Tony; Vallar, Laurent; Brons, Nicolaas H.C.; Daubon, Thomas; Miletic, Hrvoje; Sundstrøm, Terje; Herold-Mende, Christel; Mittelbronn, Michel; Bjerkvig, Rolf; Niclou, Simone P.

2016-01-01

The histopathological and molecular heterogeneity of glioblastomas represents a major obstacle for effective therapies. Glioblastomas do not develop autonomously, but evolve in a unique environment that adapts to the growing tumour mass and contributes to the malignancy of these neoplasms. Here, we show that patient-derived glioblastoma xenografts generated in the mouse brain from organotypic spheroids reproducibly give rise to three different histological phenotypes: (i) a highly invasive phenotype with an apparent normal brain vasculature, (ii) a highly angiogenic phenotype displaying microvascular proliferation and necrosis and (iii) an intermediate phenotype combining features of invasion and vessel abnormalities. These phenotypic differences were visible during early phases of tumour development suggesting an early instructive role of tumour cells on the brain parenchyma. Conversely, we found that tumour-instructed stromal cells differentially influenced tumour cell proliferation and migration in vitro, indicating a reciprocal crosstalk between neoplastic and non-neoplastic cells. We did not detect any transdifferentiation of tumour cells into endothelial cells. Cell type-specific transcriptomic analysis of tumour and endothelial cells revealed a strong phenotype-specific molecular conversion between the two cell types, suggesting co-evolution of tumour and endothelial cells. Integrative bioinformatic analysis confirmed the reciprocal crosstalk between tumour and microenvironment and suggested a key role for TGFβ1 and extracellular matrix proteins as major interaction modules that shape glioblastoma progression. These data provide novel insight into tumour-host interactions and identify novel stroma-specific targets that may play a role in combinatorial treatment strategies against glioblastoma. PMID:27049916

Towards early detection of cervical cancer: Fractal dimension of AFM images of human cervical epithelial cells at different stages of progression to cancer.

PubMed

Guz, Nataliia V; Dokukin, Maxim E; Woodworth, Craig D; Cardin, Andrew; Sokolov, Igor

2015-10-01

We used AFM HarmoniX modality to analyse the surface of individual human cervical epithelial cells at three stages of progression to cancer, normal, immortal (pre-malignant) and carcinoma cells. Primary cells from 6 normal strains, 6 cancer, and 6 immortalized lines (derived by plasmid DNA-HPV-16 transfection of cells from 6 healthy individuals) were tested. This cell model allowed for good control of the cell phenotype down to the single cell level, which is impractical to attain in clinical screening tests (ex-vivo). AFM maps of physical (nonspecific) adhesion are collected on fixed dried cells. We show that a surface parameter called fractal dimension can be used to segregate normal from both immortal pre-malignant and malignant cells with sensitivity and specificity of more than 99%. The reported method of analysis can be directly applied to cells collected in liquid cytology screening tests and identified as abnormal with regular optical methods to increase sensitivity. Despite cervical smear screening, sometimes it is very difficult to differentiate cancers cells from pre-malignant cells. By using AFM to analyze the surface properties of human cervical epithelial cells, the authors were able to accurately identify normal from abnormal cells. This method could augment existing protocols to increase diagnostic accuracy. Copyright © 2015. Published by Elsevier Inc.

A novel NF1 mutation in a Chinese patient with giant café-au-lait macule in neurofibromatosis type 1 associated with a malignant peripheral nerve sheath tumor and bone abnormality.

PubMed

Tong, H-X; Li, M; Zhang, Y; Zhu, J; Lu, W-Q

2012-08-29

Neurofibromatosis type 1 (NF1; OMIM#162200) is a common neurocutaneous disorder that is characterized by multiple café-au-lait, skinfold freckling, Lisch nodules, and neurofibromas. Mutations in the NF1 gene, which encodes the neurofibromin protein, have been identified as the pathogenic gene of NF1. In this study, we present a clinical and molecular study of a Chinese patient with giant café-au-lait in NF1. The patient showed >6 café-au-lait spots on the body, axillary freckling, and multiple subcutaneous neurofibromas. He also had a malignant peripheral nerve sheath tumor and bone abnormalities. The germline mutational analysis of the NF1 gene revealed a novel missense mutation in exon 13. It is a novel heterozygous nucleotide G>A transition at position 2241 of the NF1 gene. We found no mutation in malignant peripheral nerve sheath tumor DNA from this patient. This expands the database for NF1 gene mutations in NF1. Its absence in the normal chromosomes suggests that it is responsible for the NF1 phenotype. To our knowledge, this is the first case of giant café-au-lait macule in NF1 associated with a malignant peripheral nerve sheath tumor and bone abnormality.

ECM1 and TMPRSS4 Are Diagnostic Markers of Malignant Thyroid Neoplasms and Improve the Accuracy of Fine Needle Aspiration Biopsy

PubMed Central

Kebebew, Electron; Peng, Miao; Reiff, Emily; Duh, Quan-Yang; Clark, Orlo H.; McMillan, Alex

2005-01-01

Objective: The objective of this study was to determine whether genes that regulate cellular invasion and metastasis are differentially expressed and could serve as diagnostic markers of malignant thyroid nodules. Summary and Background Data: Patients whose thyroid nodules have indeterminate or suspicious cytologic features on fine needle aspiration (FNA) biopsy require thyroidectomy because of a 20% to 30% risk of thyroid cancer. Cell invasion and metastasis is a hallmark of malignant phenotype; therefore, genes that regulate these processes might be differentially expressed and could serve as diagnostic markers of malignancy. Methods: Differentially expressed genes (2-fold higher or lower) in malignant versus benign thyroid neoplasms were identified by extracellular matrix and adhesion molecule cDNA array analysis and confirmed by real-time quantitative polymerase chain reaction (PCR). The area under the receiver operating characteristic (AUC) curve was calculated to determine diagnostic accuracy of gene expression level cutoffs established by logistic regression analysis. Results: By cDNA array analysis, ADAMTS8, ECM1, MMP8, PLAU, SELP, and TMPRSS4 were upregulated, and by quantitative PCR, ECM1, SELP, and TMPRSS4 mRNA expression was higher in malignant (n = 57) than in benign (n = 38) thyroid neoplasms (P< 0.002). ECM1 and TMPRSS4 mRNA expression levels were independent predictors of a malignant thyroid neoplasm (P < 0.003). The AUC was 0.956 for ECM1 and 0.926 for TMPRSS4. Combining both markers improved their diagnostic use (AUC 0.985; sensitivity, 91.7%; specificity, 89.8%; positive predictive value, 85.7%; negative predictive value, 82.8%). ECM1 and TMPRSS4 expression analysis improved the diagnostic accuracy of FNA biopsy in 35 of 38 indeterminate or suspicious results. The level of ECM1 mRNA expression was higher in TNM stage I differentiated thyroid cancers than in stage II and III tumors (P ≤ 0.031). Conclusions: ECM1 and TMPRSS4 are excellent diagnostic markers of malignant thyroid nodules and may be used to improve the diagnostic accuracy of FNA biopsy. ECM1 is also a marker of the extent of disease in differentiated thyroid cancers. PMID:16135921

The Janus-faced role of ezrin in "linking" cells to either normal or metastatic phenotype.

PubMed

Brambilla, Daria; Fais, Stefano

2009-11-15

In the majority of eukaryotic cells, the ezrin, radixin and moesin (ERM) proteins are involved in many physiologic functions including regulation of actin cytoskeleton, control of cell shape, adhesion, motility and modulation of signal transduction pathways. In a previous study, we used a dominant negative ezrin-mutant to address ezrin involvement in remodeling of actin cytoskeleton and subsequently we depicted ezrin key role in melanoma cell migration and progression. Herein, we highlight recent advances on ezrin involvement in the metastatic phenomenon, including also some more neglected ezrin-related functions. Novel molecular processes driven by ezrin activation include: phagocytosis, acquisition of resistance to chemotherapeutics and triggering of programmed cell death signals. Recent data support an integrated role of ezrin also in development of tumor malignancy. On one hand, ezrin may be responsible of deranged execution of specific known functions such as adhesion and motility and on the other, it may also participate to unique metastatic determinants, through the establishment of aberrant linkages with tumor-related proteins. For instance, ezrin misslocalization, absence or deranged activity has started to be correlated with tumor progression in many tumors of different species, including humans. Concomitantly, ezrin may act simultaneously as a regulatory or deregulatory chaperon in both normal and tumor cells. It is still to be established whether this Janus-faced feature of ezrin is due to some unknown transforming Zelig-like property or to the fact that a tumor-associated molecule preferentially links to ezrin thus distracting it from its normal connections. However, the contribution of ezrin functional deregulation to the acquisition of the metastatic phenotype appears clear and ezrin or ezrin aberrant associations may represent good candidates for future anti-tumor therapies.

Pathogenesis of Germline and Somatic NF1 Rearrangements

DTIC Science & Technology

1998-10-01

skin and skeletal features consistent with a connective tissue disorder and neoplasms at a young age (7, 8, 9, 10) To test this hypothesis, patients need... myeloproliferative phenotype, these data suggest a putative role of modifying gene(s) on chromosome 17 that may contribute to the development of acute...risk for certain types of neoplasms , NF1 subjects also have an increased risk of developing a second malignancy. The risk for NF l patients is 8-20

Pax-5 is a potent regulator of E-cadherin and breast cancer malignant processes

PubMed Central

Benzina, Sami; Beauregard, Annie-Pier; Guerrette, Roxann; Jean, Stéphanie; Faye, Mame Daro; Laflamme, Mark; Maïcas, Emmanuel; Crapoulet, Nicolas; Ouellette, Rodney J.; Robichaud, Gilles A.

2017-01-01

Pax-5, an essential transcription factor for B lymphocyte development, has been linked with the development and progression of lymphoid cancers and carcinoma. In contrast to B-cell cancer lesions, the specific expression signatures and roles of Pax-5 in breast cancer progression are relatively unknown. In the present study, we set out to profile Pax-5 expression in mammary tissues and elucidate the cellular and molecular roles of Pax-5 in breast cancer processes. Using immunohistology on mammary tissue arrays, Pax-5 was detected in a total of 298/306 (97.6%) samples tested. Interestingly, our studies reveal that Pax-5 inhibits aggressive features and confers anti-proliferative effects in breast carcinoma cells in contrast to its oncogenic properties in B cell cancers. More precisely, Pax-5 suppressed breast cancer cell migration, invasion and tumor spheroid formation while concomitantly promoting cell adhesion properties. We also observed that Pax-5 inhibited and reversed breast cancer epithelial to mesenchymal phenotypic transitioning. Mechanistically, we found that the Pax-5 transcription factor binds and induces gene expression of E-cadherin, a pivotal regulator of epithelialisation. Globally, we demonstrate that Pax-5 is predominant expressed factor in mammary epithelial cells. We also present an important role for Pax-5 in the phenotypic transitioning processes and aggressive features associated with breast cancer malignancy and disease progression. PMID:28076843

EZH2 is a mediator of EWS/FLI1 driven tumor growth and metastasis blocking endothelial and neuro-ectodermal differentiation

PubMed Central

Richter, Günther H. S.; Plehm, Stephanie; Fasan, Annette; Rössler, Sabine; Unland, Rebekka; Bennani-Baiti, Idriss M.; Hotfilder, Marc; Löwel, Diana; von Luettichau, Irene; Mossbrugger, Ilona; Quintanilla-Martinez, Leticia; Kovar, Heinrich; Staege, Martin S.; Müller-Tidow, Carsten; Burdach, Stefan

2009-01-01

Ewing tumors (ET) are highly malignant, localized in bone or soft tissue, and are molecularly defined by ews/ets translocations. DNA microarray analysis revealed a relationship of ET to both endothelium and fetal neural crest. We identified expression of histone methyltransferase enhancer of Zeste, Drosophila, Homolog 2 (EZH2) to be increased in ET. Suppressive activity of EZH2 maintains stemness in normal and malignant cells. Here, we found EWS/FLI1 bound to the EZH2 promoter in vivo, and induced EZH2 expression in ET and mesenchymal stem cells. Down-regulation of EZH2 by RNA interference in ET suppressed oncogenic transformation by inhibiting clonogenicity in vitro. Similarly, tumor development and metastasis was suppressed in immunodeficient Rag2−/−γC−/− mice. EZH2-mediated gene silencing was shown to be dependent on histone deacetylase (HDAC) activity. Subsequent microarray analysis of EZH2 knock down, HDAC-inhibitor treatment and confirmation in independent assays revealed an undifferentiated phenotype maintained by EZH2 in ET. EZH2 regulated stemness genes such as nerve growth factor receptor (NGFR), as well as genes involved in neuroectodermal and endothelial differentiation (EMP1, EPHB2, GFAP, and GAP43). These data suggest that EZH2 might have a central role in ET pathology by shaping the oncogenicity and stem cell phenotype of this tumor. PMID:19289832

High-resolution telomere fluorescence in situ hybridization reveals intriguing anomalies in germ cell tumors.

PubMed

Shekhani, Mohammed Talha; Barber, John R; Bezerra, Stephania M; Heaphy, Christopher M; Gonzalez Roibon, Nilda Diana; Taheri, Diana; Reis, Leonardo O; Guner, Gunes; Joshu, Corinne E; Netto, George J; Meeker, Alan K

2016-08-01

Testicular germ cell tumor (TGCT) is the most common malignancy of young men. Most patients are completely cured, which distinguishes these from most other malignancies. Orchiectomy specimens (n=76) were evaluated using high-resolution (single-cell discriminative) telomere-specific fluorescence in situ hybridization (FISH) with simultaneous Oct4 immunofluorescence to describe telomere length phenotype in TGCT neoplastic cells. For the first time, the TGCT precursor lesion, germ cell neoplasia in situ (GCNIS) is also evaluated in depth. The intensity of the signals from cancerous cells was compared to the same patient's reference cells-namely, healthy germ cells (defined as "medium" length) and interstitial/somatic cells (defined as "short" telomere length). We observed short telomeres in most GCNIS and pure seminomas (P=.006 and P=.0005, respectively). In contrast, nonseminomas displayed longer telomeres. Lesion-specific telomere lengths were documented in mixed tumor cases. Embryonal carcinoma (EC) demonstrated the longest telomeres. A fraction of EC displays the telomerase-independent alternative lengthening of telomeres (ALT) phenotype (24% of cases). Loss of ATRX or DAXX nuclear expression was strongly associated with ALT; however, nuclear expression of both proteins was retained in half of ALT-positive ECs. The particular distribution of telomere lengths among TGCT and GCNIS precursors implicate telomeres anomalies in pathogenesis. These results may advise management decisions as well. Copyright © 2016. Published by Elsevier Inc.

Comparison among conventional and advanced MRI, 18F-FDG PET/CT, phenotype and genotype in glioblastoma.

PubMed

Valentini, Maria Consuelo; Mellai, Marta; Annovazzi, Laura; Melcarne, Antonio; Denysenko, Tetyana; Cassoni, Paola; Casalone, Cristina; Maurella, Cristiana; Grifoni, Silvia; Fania, Piercarlo; Cistaro, Angelina; Schiffer, Davide

2017-10-31

Glioblastoma (GB) is a highly heterogeneous tumor. In order to identify in vivo the most malignant tumor areas, the extent of tumor infiltration and the sites giving origin to GB stem cells (GSCs), we combined positron emission tomography/computed tomography (PET/CT) and conventional and advanced magnetic resonance imaging (MRI) with histology, immunohistochemistry and molecular genetics. Prior to dura opening and tumor resection, forty-eight biopsy specimens [23 of contrast-enhancing (CE) and 25 of non-contrast enhancing (NE) regions] from 12 GB patients were obtained by a frameless image-guided stereotactic biopsy technique. The highest values of 2-[18F]-fluoro-2-deoxy-D-glucose maximum standardized uptake value ( 18 F-FDG SUV max ), relative cerebral blood volume (rCBV), Choline/Creatine (Cho/Cr), Choline/N-acetylaspartate (Cho/NAA) and Lipids/Lactate (LL) ratio have been observed in the CE region. They corresponded to the most malignant tumor phenotype, to the greatest molecular spectrum and stem cell potential. On the contrary, apparent diffusion coefficient (ADC) and fractional anisotropy (FA) in the CE region were very variable. 18 F-FDG SUV max , Cho/Cr and Cho/NAA ratio resulted the most suitable parameters to detect tumor infiltration. In edematous areas, reactive astrocytes and microglia/macrophages were influencing variables. Combined MRI and 18 F-FDG PET/CT allowed to recognize the specific biological significance of the different identified areas of GB.

Comparison among conventional and advanced MRI, 18F-FDG PET/CT, phenotype and genotype in glioblastoma

PubMed Central

Valentini, Maria Consuelo; Mellai, Marta; Annovazzi, Laura; Melcarne, Antonio; Denysenko, Tetyana; Cassoni, Paola; Casalone, Cristina; Maurella, Cristiana; Grifoni, Silvia; Fania, Piercarlo; Cistaro, Angelina; Schiffer, Davide

2017-01-01

Glioblastoma (GB) is a highly heterogeneous tumor. In order to identify in vivo the most malignant tumor areas, the extent of tumor infiltration and the sites giving origin to GB stem cells (GSCs), we combined positron emission tomography/computed tomography (PET/CT) and conventional and advanced magnetic resonance imaging (MRI) with histology, immunohistochemistry and molecular genetics. Prior to dura opening and tumor resection, forty-eight biopsy specimens [23 of contrast-enhancing (CE) and 25 of non-contrast enhancing (NE) regions] from 12 GB patients were obtained by a frameless image-guided stereotactic biopsy technique. The highest values of 2-[18F]-fluoro-2-deoxy-D-glucose maximum standardized uptake value (18F-FDG SUVmax), relative cerebral blood volume (rCBV), Choline/Creatine (Cho/Cr), Choline/N-acetylaspartate (Cho/NAA) and Lipids/Lactate (LL) ratio have been observed in the CE region. They corresponded to the most malignant tumor phenotype, to the greatest molecular spectrum and stem cell potential. On the contrary, apparent diffusion coefficient (ADC) and fractional anisotropy (FA) in the CE region were very variable. 18F-FDG SUVmax, Cho/Cr and Cho/NAA ratio resulted the most suitable parameters to detect tumor infiltration. In edematous areas, reactive astrocytes and microglia/macrophages were influencing variables. Combined MRI and 18F-FDG PET/CT allowed to recognize the specific biological significance of the different identified areas of GB. PMID:29207673

Asbestos exposure induces alveolar epithelial cell plasticity through MAPK/Erk signaling.

PubMed

Tamminen, Jenni A; Myllärniemi, Marjukka; Hyytiäinen, Marko; Keski-Oja, Jorma; Koli, Katri

2012-07-01

The inhalation of asbestos fibers is considered to be highly harmful, and lead to fibrotic and/or malignant disease. Epithelial-to-mesenchymal transition (EMT) is a common pathogenic mechanism in asbestos associated fibrotic (asbestosis) and malignant lung diseases. The characterization of molecular pathways contributing to EMT may provide new possibilities for prognostic and therapeutic applications. The role of asbestos as an inducer of EMT has not been previously characterized. We exposed cultured human lung epithelial cells to crocidolite asbestos and analyzed alterations in the expression of epithelial and mesenchymal marker proteins and cell morphology. Asbestos was found to induce downregulation of E-cadherin protein levels in A549 lung carcinoma cells in 2-dimensional (2D) and 3D cultures. Similar findings were made in primary small airway epithelial cells cultured in 3D conditions where the cells retained alveolar type II cell phenotype. A549 cells also exhibited loss of cell-cell contacts, actin reorganization and expression of α-smooth muscle actin (α-SMA) in 2D cultures. These phenotypic changes were not associated with increased transforming growth factor (TGF)-β signaling activity. MAPK/Erk signaling pathway was found to mediate asbestos-induced downregulation of E-cadherin and alterations in cell morphology. Our results suggest that asbestos can induce epithelial plasticity, which can be interfered by blocking the MAPK/Erk kinase activity. Copyright © 2012 Wiley Periodicals, Inc.

The macrophage marker translocator protein (TSPO) is down-regulated on pro-inflammatory ‘M1’ human macrophages

PubMed Central

Mandhair, Harpreet; Smyth, Erica; Dakin, Stephanie Georgina; Kiriakidis, Serafim; Wells, Lisa; Owen, David; Sabokbar, Afsie; Taylor, Peter

2017-01-01

The translocator protein (TSPO) is a mitochondrial membrane protein, of as yet uncertain function. Its purported high expression on activated macrophages, has lent utility to TSPO targeted molecular imaging in the form of positron emission tomography (PET), as a means to detect and quantify inflammation in vivo. However, existing literature regarding TSPO expression on human activated macrophages is lacking, mostly deriving from brain tissue studies, including studies of brain malignancy, and inflammatory diseases such as multiple sclerosis. Here, we utilized three human sources of monocyte derived macrophages (MDM), from THP-1 monocytes, healthy peripheral blood monocytes and synovial fluid monocytes from patients with rheumatoid arthritis, to undertake a detailed investigation of TSPO expression in activated macrophages. In this work, we demonstrate a consistent down-regulation of TSPO mRNA and protein in macrophages activated to a pro-inflammatory, or ‘M1’ phenotype. Conversely, stimulation of macrophages to an M2 phenotype with IL-4, dexamethasone or TGF-β1 did not alter TSPO expression, regardless of MDM source. The reasons for this are uncertain, but our study findings add some supporting evidence for recent investigations concluding that TSPO may be involved in negative regulation of inflammatory responses in macrophages. PMID:28968465

Dramatically reduced surface expression of NK cell receptor KIR2DS3 is attributed to multiple residues throughout the molecule.

PubMed

VandenBussche, C J; Mulrooney, T J; Frazier, W R; Dakshanamurthy, S; Hurley, C K

2009-03-01

Using flow cytometry, fluorescent microscopy and examination of receptor glycosylation status, we demonstrate that an entire killer cell immunoglobulin-like receptor (KIR) locus (KIR2DS3)--assumed earlier to be surface expressed--appears to have little appreciable surface expression in transfected cells. This phenotype was noted for receptors encoded by three allelic variants including the common KIR2DS3*001 allele. Comparing the surface expression of KIR2DS3 with that of the better-studied KIR2DS1 molecule in two different cell lines, mutational analysis identified multiple polymorphic amino-acid residues that significantly alter the proportion of molecules present on the cell surface. A simultaneous substitution of five residues localized to the leader peptide (residues -18 and -7), second domain (residues 123 and 150) and transmembrane region (residue 234) was required to restore KIR2DS3 to the expression level of KIR2DS1. Corresponding simultaneous substitutions of KIR2DS1 to the KIR2DS3 residues resulted in a dramatically decreased surface expression. Molecular modeling was used to predict how these substitutions contribute to this phenotype. Alterations in receptor surface expression are likely to affect the balance of immune cell signaling impacting the characteristics of the response to pathogens or malignancy.

Order, Disorder, Death: Lessons from a Superorganism

PubMed Central

Amdam, Gro V.; Seehuu, Siri-Christine

2008-01-01

Animal models contribute to the understanding of molecular mechanism of cancer, revealing complex roles of altered cellular-signaling networks and deficient surveillance systems. Analogous pathologies are documented in an unconventional model organism that receives attention in research on systems theory, evolution, and aging. The honeybee (Apis mellifera) colony is an advanced integrative unit, a “superorganism” in which order is controlled via complex signaling cascades and surveillance schemes. A facultatively sterile caste, the workers, regulates patterns of growth, differentiation, homeostasis, and death. Workers differentiate into temporal phenotypes in response to dynamic social cues; chemosensory signals that can translate into dramatic physiological responses, including programmed cell death. Temporal worker forms function together, and effectively identify and terminate abnormal colony members ranging from embryos to adults. As long as this regulatory system is operational at a colony level, the unit survives and propagates. However, if the worker phenotypes that collectively govern order become too few or change into malignant forms that bypass control mechanisms to replicate aberrantly; order is replaced by disorder that ultimately leads to the destruction of the society. In this chapter we describe fundamental properties of honeybee social organization, and explore conditions that lead to states of disorder. Our hope is that this chapter will be an inspirational source for ongoing and future work in the field of cancer research. PMID:16860655

NK Cells, Tumor Cell Transition, and Tumor Progression in Solid Malignancies: New Hints for NK-Based Immunotherapy?

PubMed Central

Huergo-Zapico, Leticia; Parodi, Monica; Pedrazzi, Marco; Mingari, Maria Cristina; Sparatore, Bianca; Gonzalez, Segundo; Olive, Daniel; Bottino, Cristina

2016-01-01

Several evidences suggest that NK cells can patrol the body and eliminate tumors in their initial phases but may hardly control established solid tumors. Multiple factors, including the transition of tumor cells towards a proinvasive/prometastatic phenotype, the immunosuppressive effect of the tumor microenvironment, and the tumor structure complexity, may account for limited NK cell efficacy. Several putative mechanisms of NK cell suppression have been defined in these last years; conversely, the cross talk between NK cells and tumor cells undergoing different transitional phases remains poorly explored. Nevertheless, recent in vitro studies and immunohistochemical analyses on tumor biopsies suggest that NK cells could not only kill tumor cells but also influence their evolution. Indeed, NK cells may induce tumor cells to change the expression of HLA-I, PD-L1, or NKG2D-L and modulate their susceptibility to the immune response. Moreover, NK cells may be preferentially located in the borders of tumor masses, where, indeed, tumor cells can undergo Epithelial-to-Mesenchymal Transition (EMT) acquiring prometastatic phenotype. Finally, the recently highlighted role of HMGB1 both in EMT and in amplifying the recruitment of NK cells provides further hints on a possible effect of NK cells on tumor progression and fosters new studies on this issue. PMID:27294158

Epithelial-mesenchymal transition and tumor suppression are controlled by a reciprocal feedback loop between ZEB1 and Grainyhead-like-2

PubMed Central

Cieply, Benjamin; Farris, Joshua; Denvir, James; Ford, Heide; Frisch, Steven M.

2013-01-01

Epithelial-mesenchymal transition (EMT) in carcinoma cells enhances malignant progression by promoting invasion and survival. EMT is induced by microenvironmental factors including TGF-β and Wnt agonists, and by the E-box-binding transcription factors Twist, Snail and ZEB. Grainyhead-like-2 (GRHL2), a member of the mammalian Grainyhead family of wound healing regulatory transcription factors, suppresses EMT and restores sensitivity to anoikis by repressing ZEB1 expression and inhibiting TGF-β signaling. In this study, we elucidate the functional relationship between GRHL2 and ZEB1 in EMT/MET and tumor biology. At least three homeodomain proteins, Six1, LBX1, and HoxA5, transactivated the ZEB1 promoter, in the case of Six1, through direct protein-promoter interaction. GRHL2 altered the Six1-DNA complex, inhibiting this transactivation. Correspondingly, GRHL2 expression prevented tumor initiation in xenograft assays, sensitized breast cancer cells to paclitaxel and suppressed the emergence of CD44highCD24low cells (defining the cancer stem cell phenotype in the cell type studied). GRHL2 was down-regulated in recurrent mouse tumors that had evolved to an oncogene-independent, EMT-like state, supporting a role for GRHL2 down-regulation in this phenotypic transition, modeling disease recurrence. The combination of TGF-β and Wnt activation repressed GRHL2 expression by direct interaction of ZEB1 with the GRHL2 promoter, inducing EMT. Together, our observations indicate that a reciprocal feedback loop between GRHL2 and ZEB1 controls epithelial vs. mesenchymal phenotypes and EMT-driven tumor progression. PMID:23943797

Homozygous PMS2 deletion causes a severe colorectal cancer and multiple adenoma phenotype without extraintestinal cancer.

PubMed

Will, Olivia; Carvajal-Carmona, Luis G; Gorman, Patricia; Howarth, Kimberley M; Jones, Angela M; Polanco-Echeverry, Guadalupe M; Chinaleong, Jo-Anne; Günther, Thomas; Silver, Andrew; Clark, Susan K; Tomlinson, Ian

2007-02-01

We report a patient of Indian descent with parental consanguinity, who developed 10 carcinomas and 35 adenomatous polyps at age 23 and duodenal adenocarcinoma at age 25. He also had dysmorphic features, mental retardation, and café-au-lait spots but no brain tumor. We aimed to establish his molecular diagnosis. Germ-line screening for APC and MYH/MUTYH mutations was normal as was immunohistochemistry for MLH1 and MSH2 proteins. Investigation by array-comparative genomic hybridization revealed deletion of a small region on chromosome 7. Using polymerase chain reaction, this region was refined to a 400-kilobase deletion, which included exons 9-15 of the PMS2 gene, and all coding regions of oncomodulin, TRIAD3, and FSCN1. The deletion was confirmed as homozygous, and both parents were carriers. Immunohistochemistry showed absent PMS2 expression in all tumors and normal tissue. Most tumors showed microsatellite instability, more marked at dinucleotide than mononucleotide repeats. The tumors harbored no somatic mutations in APC, BRAF, AXIN2, or beta-catenin, but KRAS2 and TGFBR2 mutations were found. Our patient represents a novel phenotype for homozygous PMS2 mutation and perhaps the most severe colorectal cancer phenotype-in terms of numbers of malignancies at an early age-described to date. PMS2 mutations-and perhaps other homozygous mismatch repair mutations-should be considered in any patient presenting with multiple gastrointestinal tumors, since our patient could not be distinguished clinically from cases with attenuated familial adenomatous polyposis or MUTYH-associated polyposis.

Efficient Mitochondrial Glutamine Targeting Prevails Over Glioblastoma Metabolic Plasticity.

PubMed

Oizel, Kristell; Chauvin, Cynthia; Oliver, Lisa; Gratas, Catherine; Geraldo, Fanny; Jarry, Ulrich; Scotet, Emmanuel; Rabe, Marion; Alves-Guerra, Marie-Clotilde; Teusan, Raluca; Gautier, Fabien; Loussouarn, Delphine; Compan, Vincent; Martinou, Jean-Claude; Vallette, François M; Pecqueur, Claire

2017-10-15

Purpose: Glioblastoma (GBM) is the most common and malignant form of primary human brain tumor in adults, with an average survival at diagnosis of 18 months. Metabolism is a new attractive therapeutic target in cancer; however, little is known about metabolic heterogeneity and plasticity within GBM tumors. We therefore aimed to investigate metabolic phenotyping of primary cultures in the context of molecular tumor heterogeneity to provide a proof of concept for personalized metabolic targeting of GBM. Experimental Design: We have analyzed extensively several primary GBM cultures using transcriptomics, metabolic phenotyping assays, and mitochondrial respirometry. Results: We found that metabolic phenotyping clearly identifies 2 clusters, GLN High and GLN Low , mainly based on metabolic plasticity and glutamine (GLN) utilization. Inhibition of glutamine metabolism slows the in vitro and in vivo growth of GLN High GBM cultures despite metabolic adaptation to nutrient availability, in particular by increasing pyruvate shuttling into mitochondria. Furthermore, phenotypic and molecular analyses show that highly proliferative GLN High cultures are CD133 neg and display a mesenchymal signature in contrast to CD133 pos GLN Low GBM cells. Conclusions: Our results show that metabolic phenotyping identified an essential metabolic pathway in a GBM cell subtype, and provide a proof of concept for theranostic metabolic targeting. Clin Cancer Res; 23(20); 6292-304. ©2017 AACR . ©2017 American Association for Cancer Research.

The Bethesda system for reporting thyroid cytopathology: An experience of 1,382 cases in a community practice setting with the implication for risk of neoplasm and risk of malignancy.

PubMed

Wu, Howard Her-Juing; Rose, Crystal; Elsheikh, Tarik M

2012-05-01

The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) has provided a set of uniform diagnostic terminology including benign (B), atypia of undetermined significance (AUS), follicular neoplasm (FN), suspicious for malignancy (SM), malignancy (M), and nondiagnostic (ND) for the interpretation of thyroid fine-needle aspiration (FNA). We applied this terminology on our 1,382 thyroid aspirates in a community practice setting, which included 539 cases of B (39%), 376 cases of AUS (27.2%), 116 cases of FN (8.4%), 37 cases of malignant (2.7%), 36 cases of SM (2.6%), and 278 cases of ND (20.1%). Two hundred twenty-one cases (16%) of thyroid FNA had corresponding follow-up thyroidectomies. Each diagnostic category represented a unique association with risk of malignancy and risk of neoplasm. Based on histologic follow-up, the risk of neoplasm (including benign and malignant neoplasm) was B 14%, AUS 44%, FN 67%, SM 77%, and M 100% and the risk of malignancy was B 3%, AUS 6%, FN 22%, SM 56%, and M 100%. The classification and follow-up recommendation of TBSRTC are appropriate for each category. Both B and AUS are low-risk lesions with low probability of malignancy. FN predicts a higher rate for neoplasm but an intermediate rate for malignancy while SM carries a high risk for malignancy. Copyright © 2011 Wiley-Liss, Inc.

Anti-Tumor Immunity in Head and Neck Cancer: Understanding the Evidence, How Tumors Escape and Immunotherapeutic Approaches

PubMed Central

Allen, Clint T.; Clavijo, Paul E.; Van Waes, Carter; Chen, Zhong

2015-01-01

Many carcinogen- and human papilloma virus (HPV)-associated head and neck cancers (HNSCC) display a hematopoietic cell infiltrate indicative of a T-cell inflamed phenotype and an underlying anti-tumor immune response. However, by definition, these tumors have escaped immune elimination and formed a clinically significant malignancy. A number of both genetic and environmental mechanisms may allow such immune escape, including selection of poorly antigenic cancer cell subsets, tumor produced proinflammatory and immunosuppressive cytokines, recruitment of immunosuppressive immune cell subsets into the tumor and expression of checkpoint pathway components that limit T-cell responses. Here, we explore concepts of antigenicity and immunogenicity in solid tumors, summarize the scientific and clinical data that supports the use of immunotherapeutic approaches in patients with head and neck cancer, and discuss immune-based treatment approaches currently in clinical trials. PMID:26690220

Hypoxia regulates macrophage functions in inflammation.

PubMed

Murdoch, Craig; Muthana, Munitta; Lewis, Claire E

2005-11-15

The presence of areas of hypoxia is a prominent feature of various inflamed, diseased tissues, including malignant tumors, atherosclerotic plaques, myocardial infarcts, the synovia of joints with rheumatoid arthritis, healing wounds, and sites of bacterial infection. These areas form when the blood supply is occluded and/or unable to keep pace with the growth and/or infiltration of inflammatory cells in a given area. Macrophages are present in all tissues of the body where they normally assist in guarding against invading pathogens and regulate normal cell turnover and tissue remodeling. However, they are also known to accumulate in large numbers in such ischemic/hypoxic sites. Recent studies show that macrophages then respond rapidly to the hypoxia present by altering their expression of a wide array of genes. In the present study, we outline and compare the phenotypic responses of macrophages to hypoxia in different diseased states and the implications of these for their progression and treatment.

Bloom syndrome in sibs: first reports of hepatocellular carcinoma and Wilms tumor with documented anaplasia and nephrogenic rests.

PubMed

Jain, D; Hui, P; McNamara, J; Schwartz, D; German, J; Reyes-Múgica, M

2001-01-01

The triad of small body size, immunodeficiency, and sun-sensitive facial erythema characterizes the phenotype Bloom syndrome (BS), a rare autosomal recessive disorder with a striking predisposition to multiple types of cancers that arise earlier than expected in the general population. Here we report two sibs with BS. The older, a 15-year-old-girl, developed a hepatocellular carcinoma, a neoplasm not yet reported in association with BS. Her younger brother developed an anaplastic Wilms tumor (WT) associated with nephrogenic rests at the age of 31/2 years, and this was followed by a myelodysplastic syndrome. Complex cytogenetic abnormalities were identified in all three neoplasms. These examples expand the spectrum of malignancies occurring in BS to include liver cell neoplasms, and confirm the association of nephrogenic rests with WT, even in the setting of BS.

RORα, a Potential Tumor Suppressor and Therapeutic Target of Breast Cancer

PubMed Central

Du, Jun; Xu, Ren

2012-01-01

The function of the nuclear receptor (NR) in breast cancer progression has been investigated for decades. The majority of the nuclear receptors have well characterized natural ligands, but a few of them are orphan receptors for which no ligand has been identified. RORα, one member of the retinoid orphan nuclear receptor (ROR) subfamily of orphan receptors, regulates various cellular and pathological activities. RORα is commonly down-regulated and/or hypoactivated in breast cancer compared to normal mammary tissue. Expression of RORα suppresses malignant phenotypes in breast cancer cells, in vitro and in vivo. Activity of RORα can be categorized into the canonical and non-canonical nuclear receptor pathways, which in turn regulate various breast cancer cellular function, including cell proliferation, apoptosis and invasion. This information suggests that RORα is a potent tumor suppressor and a potential therapeutic target for breast cancer. PMID:23443091

Squamous cell carcinoma – similarities and differences among anatomical sites

PubMed Central

Yan, Wusheng; Wistuba, Ignacio I; Emmert-Buck, Michael R; Erickson, Heidi S

2011-01-01

Squamous cell carcinoma (SCC) is an epithelial malignancy involving many anatomical sites and is the most common cancer capable of metastatic spread. Development of early diagnosis methods and novel therapeutics are important for prevention and mortality reduction. In this effort, numerous molecular alterations have been described in SCCs. SCCs share many phenotypic and molecular characteristics, but they have not been extensively compared. This article reviews SCC as a disease, including: epidemiology, pathology, risk factors, molecular characteristics, prognostic markers, targeted therapy, and a new approach to studying SCCs. Through this comparison, several themes are apparent. For example, HPV infection is a common risk factor among the four major SCCs (NMSC, HNSC, ESCC, and NSCLC) and molecular abnormalities in cell-cycle regulation and signal transduction predominate. These data reveal that the molecular insights, new markers, and drug targets discovered in individual SCCs may shed light on this type of cancer as a whole. PMID:21938273

Breast Cancer Malignant Processes are Regulated by Pax-5 Through the Disruption of FAK Signaling Pathways

PubMed Central

Benzina, Sami; Harquail, Jason; Guerrette, Roxann; O'Brien, Pierre; Jean, Stéphanie; Crapoulet, Nicolas; Robichaud, Gilles A.

2016-01-01

The study of genetic factors regulating breast cancer malignancy is a top priority to mitigate the morbidity and mortality associated with this disease. One of these factors, Pax-5, modulates cancer aggressiveness through the regulation of various components of the epithelial to mesenchymal transitioning (EMT) process. We have previously reported that Pax-5 expression profiles in cancer tissues inversely correlate with those of the Focal Adhesion Kinase (FAK), a potent activator of breast cancer malignancy. In this study, we set out to elucidate the molecular and regulatory relationship between Pax-5 and FAK in breast cancer processes. Interestingly, we found that Pax-5 mediated suppression of breast cancer cell migration is dependent of FAK activity. Our mechanistic examination revealed that Pax-5 inhibits FAK expression and activation. We also demonstrate that Pax-5 is a potent modulator of FAK repressors (p53 and miR-135b) and activator (NFκB) which results in the overall suppression of FAK-mediated signaling cascades. Altogether, our findings bring more insight to the molecular triggers regulating phenotypic transitioning process and signaling cascades leading to breast cancer progression. PMID:28070224

Two microRNA signatures for malignancy and immune infiltration predict overall survival in advanced epithelial ovarian cancer.

PubMed

Korsunsky, Ilya; Parameswaran, Janaki; Shapira, Iuliana; Lovecchio, John; Menzin, Andrew; Whyte, Jill; Dos Santos, Lisa; Liang, Sharon; Bhuiya, Tawfiqul; Keogh, Mary; Khalili, Houman; Pond, Cassandra; Liew, Anthony; Shih, Andrew; Gregersen, Peter K; Lee, Annette T

2017-10-01

MicroRNAs have been established as key regulators of tumor gene expression and as prime biomarker candidates for clinical phenotypes in epithelial ovarian cancer (EOC). We analyzed the coexpression and regulatory structure of microRNAs and their co-localized gene targets in primary tumor tissue of 20 patients with advanced EOC in order to construct a regulatory signature for clinical prognosis. We performed an integrative analysis to identify two prognostic microRNA/mRNA coexpression modules, each enriched for consistent biological functions. One module, enriched for malignancy-related functions, was found to be upregulated in malignant versus benign samples. The second module, enriched for immune-related functions, was strongly correlated with imputed intratumoral immune infiltrates of T cells, natural killer cells, cytotoxic lymphocytes, and macrophages. We validated the prognostic relevance of the immunological module microRNAs in the publicly available The Cancer Genome Atlas data set. These findings provide novel functional roles for microRNAs in the progression of advanced EOC and possible prognostic signatures for survival. © American Federation for Medical Research (unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Alternative site of implantation affects tumor malignancy and metastatic potential in mice: its comparison to the flank model.

PubMed

Speroni, Lucia; Bustuoabad, Victoria de Los Angeles; Gasparri, Julieta; Chiaramoni, Nadia Silvia; Taira, María Cristina; Ruggiero, Raúl Alejandro; Alonso, Silvia Del Valle

2009-02-01

MC-C fibrosarcoma and B16F0 melanoma tumors were implanted intradermally in the dorsal region of the foot of mice. Tumor progression was compared to standard implantation in the flank. Although foot tumors only reached 13% (MC-C) and 25% (B16F0) of the mean volume of flank tumors, a more malignant phenotype in terms of histology and survival rate was observed in this type of tumors. Moreover, lung metastases were only detected in hosts bearing foot tumors, in contrast to MC-C and B16F0 populations with tumors growing in the flank. In addition, cellular influx and local immune reaction were higher in the dorsal region of the foot. According to our results, the dermis of the flank allows excessive tumor growth due to its low reactivity. Thus, differences in innate and adaptive immune effectors between the evaluated tumor microenvironments would account for the differences in tumor malignancy. Due to its striking differences with the standard flank inoculation, the tumor implantation model herein introduced could be a valuable tool to study the metastatic potential of different cell lines and the microenvironment components affecting tumor growth.

miR-24-3p Suppresses Malignant Behavior of Lacrimal Adenoid Cystic Carcinoma by Targeting PRKCH to Regulate p53/p21 Pathway.

PubMed

Zhang, Ming-Xue; Zhang, Jie; Zhang, Hong; Tang, Hua

2016-01-01

MicroRNA (miRNA) may function as an oncogene or a tumor suppressor in tumorigenesis. However, the mechanism of miRNAs in adenoid cystic carcinoma (ACC) is unclear. Here, we provide evidence that miR-24-3p was downreglated and functions as a tumor suppressor in human lacrimal adenoid cystic carcinoma by suppressing proliferation and migration/invasion while promoting apoptosis. miR-24-3p down-regulated protein kinase C eta (PRKCH) by binding to its untranslated region (3'UTR). PRKCH increased the of the cell growth and migration/invasion in ACC cells and suppressed the expression of p53 and p21 in both mRNA and protein level. The overexpression of miR-24-3p decreased its malignant phenotype. Ectopic expression of PRKCH counteracted the suppression of malignancy induced by miR-24-3p, as well as ectopic expression of miR-24-3p rescued the suppression of PRKCH in the p53/p21 pathway. These results suggest that miR-24-3p promotes the p53/p21 pathway by down-regulating PRKCH expression in lacrimal adenoid cystic carcinoma cells.

Cancer Stem-Like Cells Enriched in Panc-1 Spheres Possess Increased Migration Ability and Resistance to Gemcitabine

PubMed Central

Yin, Tao; Wei, Hongji; Gou, Shanmiao; Shi, Pengfei; Yang, Zhiyong; Zhao, Gang; Wang, Chunyou

2011-01-01

Pancreatic cancer is one of the most lethal malignancies with poor prognosis. Previously, we found that a subpopulation of cancer stem cells (CSCs) in the Panc-1 pancreatic cancer cell line could propagate to form spheres. Here we characterized the malignant phenotypes of the pancreatic cancer stem CD44+/CD24+ cells, which were enriched under sphere forming conditions as analyzed by flow cytometry. These cells demonstrated increased resistance to gemcitabine and increased migration ability. Moreover, these cells exhibited epithelial to mesenchymal transition characterized by a decreased level of the epithelial marker E-cadherin and an increased level of the mesenchymal marker vimentin. Notably, abnormal expression of Bmi-1, ABCG2, Cyclin D1 and p16 were found in Panc-1 CSCs. Our results suggest that targeted inhibition of CSCs represents a novel therapeutic approach to overcome chemoresistance and metastasis of pancreatic cancer. PMID:21673909

Viruses and oral cancer. Is there a link?

PubMed

Sand, Lars; Jalouli, Jamshid

2014-05-01

Oral squamous cell carcinoma (OSCC) is the most common malignant tumour of the oral cavity. The aetiology of epithelial cancer of the head and neck is considered to be a multifactorial, sequential process. DNA viruses are found in many different cancers and are also capable of transforming cells to a malignant phenotype. Human Papilloma Virus (HPV) has been proposed as risk factors in OSCC development and HPV type 16 is the most important subtype. Other oncogenic virus species i.e., Epstein-Barr Virus and Herpes Simplex Virus Type 1 have been proposed to be involved in oral carcinogenesis. However, no convincing evidence exist that they are an established risk factor in OSCC. Therefore more studies are needed in order to clarify the different aspects of virus involvement. Here, we review the existing literature on viral involvement in oral cancer. Copyright © 2014 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.

Short Chain Fatty Acids (SCFA) Reprogram Gene Expression in Human Malignant Epithelial and Lymphoid Cells

PubMed Central

Astakhova, Lidiia; Ngara, Mtakai; Babich, Olga; Prosekov, Aleksandr; Asyakina, Lyudmila; Dyshlyuk, Lyubov; Midtvedt, Tore; Zhou, Xiaoying; Ernberg, Ingemar; Matskova, Liudmila

2016-01-01

The effect of short chain fatty acids (SCFAs) on gene expression in human, malignant cell lines was investigated, with a focus on signaling pathways. The commensal microbial flora produce high levels of SCFAs with established physiologic effects in humans. The most abundant SCFA metabolite in the human microflora is n-butyric acid. It is well known to activate endogenous latent Epstein-Barr virus (EBV), that was used as a reference read out system and extended to EBV+ epithelial cancer cell lines. N-butyric acid and its salt induced inflammatory and apoptotic responses in tumor cells of epithelial and lymphoid origin. Epithelial cell migration was inhibited. The n-butyric gene activation was reduced by knock-down of the cell membrane transporters MCT-1 and -4 by siRNA. N-butyric acid show biologically significant effects on several important cellular functions, also with relevance for tumor cell phenotype. PMID:27441625

The hitchhikers guide to cancer stem cell theory: markers, pathways and therapy.

PubMed

Fábián, Ákos; Vereb, György; Szöllősi, János

2013-01-01

Cancer stem cell (CSC) biology is a rapidly developing field within cancer research. CSCs are postulated to be a unique cell population exclusively capable of infinite self renewal, multilineage differentiation and with ability to evade conventional cytotoxic cancer therapy. These traits distinguish CSCs from their more differentiated counterparts, which possess only limited or no potential for self renewal and tumor initiation. Therefore, CSCs would be the driving motor of malignant growth and therapy resistance. Accordingly, successful cancer treatment would need to eliminate this highly potent group of cells, since even small residual numbers would suffice to recapitulate the disease after therapy. Putative CSCs has been identified in a broad range of human malignancies and several cell surface markers have been associated with their stem cell phenotype. Despite all efforts, a pure CSC population has not been isolated and often in vitro clonogenic and in vivo tumorigenic potential is found in several cell populations with occasionally contradictory surface marker signatures. Here, we give a brief overview of recent advances in CSC theory, including the signaling pathways in CSCs that also appear crucial for stem cells homeostasis in normal tissues. We discuss evidence for the interaction of CSCs with the stromal tumor environment. Finally, we review the emerging potentially effective CSC-targeted treatment strategies and their future role in therapy. Copyright © 2012 International Society for Advancement of Cytometry.

Aberrant Expression of Retinoic Acid Signaling Molecules Influences Patient Survival in Astrocytic Gliomas

PubMed Central

Campos, Benito; Centner, Franz-Simon; Bermejo, Justo Lorenzo; Ali, Ramadan; Dorsch, Katharina; Wan, Feng; Felsberg, Jörg; Ahmadi, Rezvan; Grabe, Niels; Reifenberger, Guido; Unterberg, Andreas; Burhenne, Jürgen; Herold-Mende, Christel

2011-01-01

Undifferentiated cell populations may influence tumor growth in malignant glioma. We investigated potential disruptions in the retinoic acid (RA) differentiation pathway that could lead to a loss of differentiation capacity, influencing patient prognosis. Expression of key molecules belonging to the RA differentiation pathway was analyzed in 283 astrocytic gliomas and was correlated with tumor proliferation, tumor differentiation, and patient survival. In addition, in situ concentrations of retinoids were measured in tumors, and RA signaling events were studied in vitro. Unlike other tumors, in gliomas expression of most RA signaling molecules increased with malignancy and was associated with augmented intratumoral retinoid levels in high-grade gliomas. Aberrantly expressed RA signaling molecules included i) the retinol-binding protein CRBP1, which facilitates cellular retinoid uptake; ii) ALDH1A1, capable of activating RA precursors; iii) the RA-degrading enzyme CYP26B1; and iv) the RA-binding protein FABP5, which can inhibit RA-induced differentiation. In contrast, expression of the RA-binding protein CRABP2, which fosters differentiation, was decreased in high-grade tumors. Moreover, expression of CRBP1 correlated with tumor proliferation, and FABP5 expression correlated with an undifferentiated tumor phenotype. CRBP1 and ALDH1A1 were independent prognostic markers for adverse patient survival. Our data indicate a complex and clinically relevant deregulation of RA signaling, which seems to be a central event in glioma pathogenesis. PMID:21514413

Probing HER2-PUMA and EGFR-PUMA Crosstalks in Aggressive Breast Cancer

DTIC Science & Technology

2013-09-01

malignant biology and drug-resistant phenotype of EGFR- and/or HER2-overexpressing breast cancer and to use the acquired knowledge for the development...with PUMA, we first assessed whether HER2 can physically interact with PUMA using immunoprecipitation/western blotting (IP/WB). We used SK-BR3 and BT...activate HER2. We subjected the cell lysates to IP/WB using a PUMA antibody for IP and immunoblotted with anti-phospho-tyrosine antibodies. As shown

Genetic predisposition to neuroblastoma mediated by a LMO1 super-enhancer polymorphism | Office of Cancer Genomics

Cancer.gov

Neuroblastoma is a paediatric malignancy that typically arises in early childhood, and is derived from the developing sympathetic nervous system. Clinical phenotypes range from localized tumours with excellent outcomes to widely metastatic disease in which long-term survival is approximately 40% despite intensive therapy. A previous genome-wide association study identified common polymorphisms at the LMO1 gene locus that are highly associated with neuroblastoma susceptibility and oncogenic addiction to LMO1 in the tumour cells.

New KRAS Antibodies Available | Office of Cancer Clinical Proteomics Research

Cancer.gov

Researchers estimate that approximately 30% of all human cancers are driven by RAS oncogenes. Mutated RAS genes are responsible for making RAS proteins that support cancer development. While anti-RAS therapies may have potential clinical benefit, researchers yet do not understand how the four RAS protein isoforms, KRAS4A, KRAS4B, HRAS, and NRAS, drive malignant phenotypes. Well-characterized and defined reagents like antibodies are central to reproducibility in biomedical research and necessary for future RAS studies.

Breast Tissue Stromal Cells Preferentially Promote Generation of M2 Macrophages: A Novel Mechanism for Tumor Supportive Properties of Breast Microenvironment

DTIC Science & Technology

2011-08-01

macrophages (MQs), on growth of breast tumor cells, and (2) to test the hypothesis that MSCs of non -breast adipose tissues, in contrast to MSCs of...macrophages in normal and malignant tissues. In contrast to all studies focused on the role of breast tissue microenvironment in growth of primary breast...the phenotype of macrophages, provide an immune environment suitable for growth of breast cancer cells, but MSCs present in non -breast adipose

The t(14;18) translocation is absent from endothelial and follicular dendritic cells of follicular lymphoma (FL) and shows heterogeneous presence in preserved FL mantle zones.

PubMed

Kosmidis, Perikles; Mankel, Barbara; Fend, Falko; Adam, Patrick

2018-05-02

The translocation t(14;18)(q32;q21) is the genetic hallmark of follicular lymphoma (FL) and can be observed in 85-90% of cases. Whether the translocation is restricted to cells with germinal center B-cell phenotype or can be observed in other cell types of the microenvironment remains debated. Of interest, cases of associated histiocytic and dendritic cell sarcomas arising in the background of FL have been shown to be clonally related and carry the t(14;18), suggesting a "transdifferentiation" of the malignant FL clone into a neoplasm of a different hematopoietic lineage. We analyzed the presence of the t(14;18)(q32;q21) as a surrogate marker of the malignant clone in cells of the FL microenvironment using combined fluorescence immunophenotyping and interphase cytogenetics targeting the BCL2 gene locus. In addition to non-lymphoid cells in FL, we analysed FL with preserved IgD+ mantle zones and cases of in situ follicular neoplasia (ISFN) to investigate whether cells of non-germinal center B-cell phenotype are part of the malignant clone. Six (40%) of 15 manifest FL cases with preserved IgD+ mantle zones did not harbour the t(14;18)(q32;q21) translocation. In all t(14;18) + FL cases, follicular dendritic cells and endothelial cells lacked the t(14;18) translocation. 2/9 FL revealed t(14;18)- IgD+ mantle zone B-cells. In the seven ISFN cases, the t(14;18) translocation was strictly confined to germinal center cells. The t(14;18) translocation in follicular lymphoma is limited to B-cells. The origin of IgD+ mantle cells is heterogeneous, in the majority of cases belonging to the neoplastic clone, whereas a minority of cases of manifest FL show nonneoplastic mantle zones, similar to ISFN.

Acquisition of Epithelial-Mesenchymal Transition phenotype of gemcitabine-resistant pancreatic cancer cells is linked with activation of Notch signaling pathway

PubMed Central

Wang, Zhiwei; Li, Yiwei; Kong, Dejuan; Banerjee, Sanjeev; Ahmad, Aamir; Azmi, Asfar Sohail; Ali, Shadan; Abbruzzese, James L.; Gallick, Gary E.; Sarkar, Fazlul H

2009-01-01

Despite rapid advances in many fronts, pancreatic cancer (PC) remains one of the most difficult human malignancies to treat, in part due to de novo and acquired chemo- and radio-resistance. Gemcitabine alone or in combination with other conventional therapeutics is the standard of care for the treatment of advanced PC without any significant improvement in the overall survival of patients diagnosed with this deadly disease. Previous studies have shown that PC cells that are gemcitabine-resistant (GR) acquired epithelial-mesenchymal transition (EMT) phenotype which is reminiscent of “cancer stem-like cells (CSC)”; however the molecular mechanism that led to EMT phenotype has not been fully investigated. The present study demonstrates that Notch-2 and its ligand Jagged-1 are highly up-regulated in GR cells, which is consistent with the role of Notch signaling pathway in the acquisition of EMT and CSC phenotype. We also found that the down-regulation of Notch signaling was associated with decreased invasive behavior of GR cells. Moreover, down-regulation of Notch signaling by siRNA approach led to partial reversal of the EMT phenotype, resulting in the mesenchymal-epithelial transition (MET), which was associated with decreased expression of vimentin, ZEB1, Slug, Snail and NF-κB. These results provide molecular evidence showing that the activation of Notch signaling is mechanistically linked with chemo-resistance phenotype (EMT phenotype) of PC cells, suggesting that the inactivation of Notch signaling by novel strategies could be a potential targeted therapeutic approach for overcoming chemo-resistance toward the prevention of tumor progression and/or treatment of metastatic PC. PMID:19276344

Macrophage phenotypic subtypes diametrically regulate epithelial-mesenchymal plasticity in breast cancer cells.

PubMed

Yang, Min; Ma, Bo; Shao, Hanshuang; Clark, Amanda M; Wells, Alan

2016-07-07

Metastatic progression of breast cancer involves phenotypic plasticity of the carcinoma cells moving between epithelial and mesenchymal behaviors. During metastatic seeding and dormancy, even highly aggressive carcinoma cells take on an E-cadherin-positive epithelial phenotype that is absent from the emergent, lethal metastatic outgrowths. These phenotypes are linked to the metastatic microenvironment, though the specific cells and induction signals are still to be deciphered. Recent evidence suggests that macrophages impact tumor progression, and may alter the balance between cancer cell EMT and MErT in the metastatic microenvironment. Here we explore the role of M1/M2 macrophages in epithelial-mesenchymal plasticity of breast cancer cells by coculturing epithelial and mesenchymal cells lines with macrophages. We found that after polarizing the THP-1 human monocyte cell line, the M1 and M2-types were stable and maintained when co-cultured with breast cancer cells. Surprisingly, M2 macrophages may conferred a growth advantage to the epithelial MCF-7 cells, with these cells being driven to a partial mesenchymal phenotypic as indicated by spindle morphology. Notably, E-cadherin protein expression is significantly decreased in MCF-7 cells co-cultured with M2 macrophages. M0 and M1 macrophages had no effect on the MCF-7 epithelial phenotype. However, the M1 macrophages impacted the highly aggressive mesenchymal-like MDA-MB-231 breast cancer cells to take on a quiescent, epithelial phenotype with re-expression of E-cadherin. The M2 macrophages if anything exacerbated the mesenchymal phenotype of the MDA-MB-231 cells. Our findings demonstrate M2 macrophages might impart outgrowth and M1 macrophages may contribute to dormancy behaviors in metastatic breast cancer cells. Thus EMT and MErT are regulated by selected macrophage phenotype in the liver metastatic microenvironment. These results indicate macrophage could be a potential therapeutic target for limiting death due to malignant metastases in breast cancer.

Adrenal Gland Cancer

MedlinePlus

... either benign or malignant. Benign tumors aren't cancer. Malignant ones are. Most adrenal gland tumors are ... and may not require treatment. Malignant adrenal gland cancers are uncommon. Types of tumors include Adrenocortical carcinoma - ...

Stage-Specific Human Induced Pluripotent Stem Cells Map the Progression of Myeloid Transformation to Transplantable Leukemia.

PubMed

Kotini, Andriana G; Chang, Chan-Jung; Chow, Arthur; Yuan, Han; Ho, Tzu-Chieh; Wang, Tiansu; Vora, Shailee; Solovyov, Alexander; Husser, Chrystel; Olszewska, Malgorzata; Teruya-Feldstein, Julie; Perumal, Deepak; Klimek, Virginia M; Spyridonidis, Alexandros; Rampal, Raajit K; Silverman, Lewis; Reddy, E Premkumar; Papaemmanuil, Elli; Parekh, Samir; Greenbaum, Benjamin D; Leslie, Christina S; Kharas, Michael G; Papapetrou, Eirini P

2017-03-02

Myeloid malignancy is increasingly viewed as a disease spectrum, comprising hematopoietic disorders that extend across a phenotypic continuum ranging from clonal hematopoiesis to myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). In this study, we derived a collection of induced pluripotent stem cell (iPSC) lines capturing a range of disease stages encompassing preleukemia, low-risk MDS, high-risk MDS, and secondary AML. Upon their differentiation, we found hematopoietic phenotypes of graded severity and/or stage specificity that together delineate a phenotypic roadmap of disease progression culminating in serially transplantable leukemia. We also show that disease stage transitions, both reversal and progression, can be modeled in this system using genetic correction or introduction of mutations via CRISPR/Cas9 and that this iPSC-based approach can be used to uncover disease-stage-specific responses to drugs. Our study therefore provides insight into the cellular events demarcating the initiation and progression of myeloid transformation and a new platform for testing genetic and pharmacological interventions. Copyright © 2017 Elsevier Inc. All rights reserved.

Genetic and phenotypic heterogeneity of human malignancies: finding order in chaos.

PubMed

Shackney, S E; Shankey, T V

1995-09-01

The presence of cellular heterogeneity within human tumors has been recognized for many years. Current concepts regarding the clonal origin of human neoplasms, and recent advances in the study of successive genetic changes that occur during tumor evolution may now make it possible to understand in greater depth the biological and clinical implications of intra-tumor heterogeneity at both the phenotypic and genotypic levels. In order to explore these concepts further, and to better identify the potential contributions that flow and image cytometry can make to our understanding of tumor heterogeneity, a session of the 1994 ISAC Congress was dedicated to plenary presentations on human cancer cell heterogeneity. Here, we provide a brief overview of the genetic evolutionary progression of human cancers, some considerations of clinically important phenotypic and genotypic markers, and an outline that might serve as a basis for framing relevant issues that are ammenable to further study. All Nature is but Art, unknown to thee; All Chance, Direction, which thou canst not see; All Discord, Harmony not understood: All partial Evil, universal Good. (Alexander Pope, Essay on Man, end of Epistle 1).

Transketolase-like 1 ectopic expression is associated with DNA hypomethylation and induces the Warburg effect in melanoma cells.

PubMed

Jayachandran, Aparna; Lo, Pu-Han; Chueh, Anderly C; Prithviraj, Prashanth; Molania, Ramyar; Davalos-Salas, Mercedes; Anaka, Matthew; Walkiewicz, Marzena; Cebon, Jonathan; Behren, Andreas

2016-02-22

The metabolism of cancer cells is often reprogrammed by dysregulation of metabolic enzymes. Transketolase-like 1 (TKTL1) is a homodimeric transketolase linking the pentose-phosphate pathway with the glycolytic pathway. It is generally silenced at a transcriptional level in somatic tissues. However, in human cancers its expression is associated with the acquisition of a glycolytic phenotype (the Warburg effect) by cancer cells that contributes to the progression of malignant tumors. In melanoma, defective promoter methylation results in the expression of genes and their products that can affect the tumor cell's phenotype including the modification of immune and functional characteristics. The present study evaluates the role of TKTL1 as a mediator of disease progression in melanoma associated with a defective methylation phenotype. The expression of TKTL1 in metastatic melanoma tumors and cell lines was analysed by qRT-PCR and immunohistochemistry. The promoter methylation status of TKTL1 in melanoma cells was evaluated by quantitative methylation specific PCR. Using qRT-PCR, the effect of a DNA demethylating agent 5-aza-2'-deoxycytidine (5aza) on the expression of TKTL1 was examined. Biochemical and molecular analyses such as glucose consumption, lactate production, invasion, proliferation and cell cycle progression together with ectopic expression and siRNA mediated knockdown were used to investigate the role of TKTL1 in melanoma cells. Expression of TKTL1 was highly restricted in normal adult tissues and was overexpressed in a subset of metastatic melanoma tumors and derived cell lines. The TKTL1 promoter was activated by hypomethylation and treatment with 5aza induced TKTL1 expression in melanoma cells. Augmented expression of TKTL1 in melanoma cells was associated with a glycolytic phenotype. Loss and gain of function studies revealed that TKTL1 contributed to enhanced invasion of melanoma cells. Our data provide evidence for an important role of TKTL1 in aerobic glycolysis and tumor promotion in melanoma that may result from defective promoter methylation. This epigenetic change may enable the natural selection of tumor cells with a metabolic phenotype and thereby provide a potential therapeutic target for a subset of melanoma tumors with elevated TKTL1 expression.

Malignant Mesothelioma Treatment (PDQ®)—Health Professional Version

Cancer.gov

Malignant mesothelioma treatment may include surgery, radiation therapy, and chemotherapy. Get detailed information about the diagnosis and treatment of newly diagnosed and recurrent malignant mesothelioma in this summary for clinicians.

MicroRNA-9 enhances sensitivity to cetuximab in epithelial phenotype hepatocellular carcinoma cells through regulation of the eukaryotic translation initiation factor 5A-2.

PubMed

Xue, Fei; Liang, Yuntian; Li, Zhenrong; Liu, Yanhui; Zhang, Hongwei; Wen, Yu; Yan, Lei; Tang, Qiang; Xiao, Erhui; Zhang, Dongyi

2018-01-01

Hepatocellular carcinoma (HCC) is one of the most widespread malignant human tumors worldwide. Treatment options include radiotherapy, surgical intervention and chemotherapy; however, drug resistance is an ongoing treatment concern. In the present study, the effects of a microRNA (miR/miRNA), miR-9, on the sensitivity of HCC cell lines to the epidermal growth factor receptor inhibitor, cetuximab, were examined. miR-9 has been proposed to serve a role in tumorigenesis and tumor progression. In the present study, bioinformatics analyses identified the eukaryotic translation initiation factor 5A2 (eIF-5A-2) as a target of miR-9. The expression levels of miR-9 and eIF-5A-2 were examined by reverse transcription-quantitative polymerase chain reaction and HCC cell lines were transfected with miR-9 mimics and inhibitors to determine the effects of the miRNA on cell proliferation and viability. The miR-9 mimic was revealed to significantly increase the sensitivity of epithelial phenotype HCC cells (Hep3B and Huh7) to cetuximab, while the miR-9 inhibitor triggered the opposite effect. There were no significant differences in sensitivity to cetuximab observed in mesenchymal phenotype HCC cells (SNU387 and SNU449). Cells lines displaying high expression levels of eIF-5A-2 were more resistant to cetuximab. Transfection of cells with a miR-9 mimic resulted in downregulation of the expression of eIF-5A-2 mRNA, while an miR-9 inhibitor increased expression. When expression of eIF-5A-2 was knocked down with siRNA, the effects of miR-9 on cetuximab sensitivity were no longer observed. Taken together, these data support a role for miR-9 in enhancing the sensitivity of epithelial phenotype HCC cells to cetuximab through regulation of eIF-5A-2.

Mutations in KCNT1 cause a spectrum of focal epilepsies

PubMed Central

Møller, Rikke S.; Heron, Sarah E.; Larsen, Line H. G.; Lim, Chiao Xin; Ricos, Michael G.; Bayly, Marta A.; van Kempen, Marjan J. A.; Klinkenberg, Sylvia; Andrews, Ian; Kelley, Kent; Ronen, Gabriel M.; Callen, David; McMahon, Jacinta M.; Yendle, Simone C.; Carvill, Gemma L.; Mefford, Heather C.; Nabbout, Rima; Poduri, Annapurna; Striano, Pasquale; Baglietto, Maria G.; Zara, Federico; Smith, Nicholas J.; Pridmore, Clair; Gardella, Elena; Nikanorova, Marina; Dahl, Hans Atli; Gellert, Pia; Scheffer, Ingrid E.; Gunning, Boudewijn; Kragh-Olsen, Bente; Dibbens, Leanne M.

2018-01-01

Summary Autosomal dominant mutations in the sodium-gated potassium channel subunit gene KCNT1 have been associated with two distinct seizure syndromes, nocturnal frontal lobe epilepsy (NFLE) and malignant migrating focal seizures of infancy (MMFSI). To further explore the phenotypic spectrum associated with KCNT1, we examined individuals affected with focal epilepsy or an epileptic encephalopathy for mutations in the gene. We identified KCNT1 mutations in 12 previously unreported patients with focal epilepsy, multifocal epilepsy, cardiac arrhythmia, and in a family with sudden unexpected death in epilepsy (SUDEP), in addition to patients with NFLE and MMFSI. In contrast to the 100% penetrance so far reported for KCNT1 mutations, we observed incomplete penetrance. It is notable that we report that the one KCNT1 mutation, p.Arg398Gln, can lead to either of the two distinct phenotypes, ADNFLE or MMFSI, even within the same family. This indicates that genotype–phenotype relationships for KCNT1 mutations are not straightforward. We demonstrate that KCNT1 mutations are highly pleiotropic and are associated with phenotypes other than ADNFLE and MMFSI. KCNT1 mutations are now associated with Ohtahara syndrome, MMFSI, and nocturnal focal epilepsy. They may also be associated with multifocal epilepsy and cardiac disturbances. PMID:26122718

Microsatellite instability as a predictive factor for immunotherapy in malignant melanoma.

PubMed

Kubecek, Ondrej; Trojanova, Petronela; Molnarova, Veronika; Kopecky, Jindrich

2016-08-01

Immunotherapy has attracted attention as a novel treatment modality for malignant melanoma. Although the use of immunotherapy in metastatic melanoma has shown promising results, there remains a lack of predictive biomarkers indicating treatment benefit from immunotherapy. There is growing evidence suggesting that microsatellite instability (MSI) as a product of DNA mismatch repair deficiency, may be one of possible predictive markers in malignant melanoma. It has been proposed that the immunogenicity of some tumors might be determined by mutational heterogeneity and could be the key to the success of immune therapies. This is also supported by the fact that tumors with the highest amount of somatic mutations, such as malignant melanoma have showed positive results with immune checkpoint inhibitors. There are promising data regarding the association between MSI status and immunogenicity from studies with colorectal cancer, where MSI is linked to improved prognosis compared to microsatellite stable cancers. MSI in colon cancer is linked to a significant increase of immunocompetent cells responsible for the antitumor activity - CD3(+), CD8(+), CD45RO(+), and T-bet(+) lymphocytes and decrease of inhibition factors such as Foxp3, IL-6, IL-17, and TGF-β. On the other hand, taking into account the progression-dependent accumulation of somatic mutations in MSI tumors and consequent high levels of neo-antigens, the possible drug resistance of MSI tumors to traditional treatment, and the presence of inhibition checkpoints within the MSI tumors, there is a solid rationale for the use of novel therapeutic strategies such as immunotherapy in MSI melanomas. We presume that the MSI phenotype in malignant melanoma might be helpful to identify patients, who would be more likely to profit from immunotherapy than from conventional therapy. Copyright © 2016 Elsevier Ltd. All rights reserved.

Long-term low-dose α-particle enhanced the potential of malignant transformation in human bronchial epithelial cells through MAPK/Akt pathway

DOE Office of Scientific and Technical Information (OSTI.GOV)

Liu, Weili; Xiao, Linlin; Dong, Chen

2014-05-09

Highlights: • Multi-exposures of 25 mGy α-ray enhanced cell proliferation, adhesion, and invasion. • MAPK/Akt but not JNK/P66 was positively correlated with cell invasive phenotypes. • LDR of α-irradiation triggers cell malignant transformation through MAPK/Akt. - Abstract: Since the wide usage of ionizing radiation, the cancer risk of low dose radiation (LDR) (<0.1 Gy) has become attractive for a long time. However, most results are derived from epidemiologic studies on atomic-bomb survivors and nuclear accidents surrounding population, and the molecular mechanism of this risk is elusive. To explore the potential of a long-term LDR-induced malignant transformation, human bronchial epithelial cellsmore » Beas-2B were fractionally irradiated with 0.025 Gy α-particles for 8 times in total and then further cultured for 1–2 months. It was found that the cell proliferation, the abilities of adhesion and invasion, and the protein expressions of p-ERK, p-Akt, especially p-P38 were not only increased in the multiply-irradiated cells but also in their offspring 1–2 months after the final exposure, indicating high potentiality of cell malignant transformation. On opposite, the expressions of p-JNK and p-P66 were diminished in the subcultures of irradiated cells and thus may play a role of negative regulation in canceration. When the cells were transferred with p38 siRNA, the LDR-induced enhancements of cell adhesion and invasion were significantly reduced. These findings suggest that long-term LDR of α-particles could enhance the potential of malignant transformation incidence in human bronchial epithelial cells through MAPK/Akt pathway.« less

Epithelial-type and neural-type cadherin expression in malignant noncarcinomatous neoplasms with epithelioid features that involve the soft tissues.

PubMed

Laskin, William B; Miettinen, Markku

2002-04-01

Transmembrane adhesion molecules, epithelial-type cadherin (ECAD) and neural-type cadherin (NCAD), help in regulating transformations between epithelial and mesenchymal cells in the developing embryo and in maintaining the epithelioid phenotype. Consequently, the presence of epithelioid cells in certain malignant noncarcinomatous neoplasms raises speculation that the expression of ECAD and NCAD in these neoplasms may have diagnostic significance. To investigate the utility of ECAD and NCAD immunoexpression in distinguishing malignant (noncarcinomatous) neoplasms with epithelioid features that involve the soft tissues. Membranous immunoreactivity of anti-ECAD and anti-NCAD was evaluated on archived cases selected from the files of the Armed Forces Institute of Pathology. Epithelial-type cadherin was found in biphasic synovial sarcoma (35 of 35 cases), malignant melanoma (13/21), monophasic fibrous synovial sarcoma (13/26), clear cell sarcoma (4/9), poorly differentiated synovial sarcoma (3/13), diffuse mesothelioma (4/20), malignant epithelioid peripheral nerve sheath tumor (1/6), and epithelioid sarcoma (5/62). Neural-type cadherin was observed in chordoma (11/11), biphasic synovial sarcoma (30/35), diffuse mesothelioma (14/20), malignant melanoma (14/25), epithelioid sarcoma (24/63), epithelioid angiosarcoma (1/4), poorly differentiated synovial sarcoma (2/13), clear cell sarcoma (1/10), and monophasic fibrous synovial sarcoma (1/26). Eighteen cases of primary cutaneous squamous cell carcinomas all tested positive for ECAD, whereas NCAD was focally observed in 5 cases. No expression of either molecule was observed in cases of epithelioid hemangioendothelioma (n = 9), alveolar soft part sarcoma (n = 8), and extraskeletal myxoid chondrosarcoma (n = 7). Epithelial-type and neural-type cadherins are found in a variety of noncarcinomatous neoplasms with epithelioid features that involve the soft tissues and can be utilized, in association with other immunomarkers, in distinguishing chordoma (100% NCAD) from extraskeletal myxoid chondrosarcoma and conventional chondrosarcoma of bone (0% NCAD), squamous cell carcinoma (100% ECAD) from epithelioid sarcoma (8% ECAD), and biphasic synovial sarcoma (100% ECAD) from diffuse mesothelioma (20% ECAD).

Untargeted mass spectrometry-based metabolomic profiling of pleural effusions: fatty acids as novel cancer biomarkers for malignant pleural effusions.

PubMed

Lam, Ching-Wan; Law, Chun-Yiu

2014-09-05

Untargeted mass spectrometry-based metabolomic profiling is a powerful analytical method used for broad-spectrum identification and quantification of metabolites in biofluids in human health and disease states. In this study, we exploit metabolomic profiling for cancer biomarker discovery for diagnosis of malignant pleural effusions. We envisage the result will be clinically useful since currently there are no cancer biomarkers that are accurate enough for the diagnosis of malignant pleural effusions. Metabolomes of 32 malignant pleural effusions from lung cancer patients and 18 benign effusions from patients with pulmonary tuberculosis were analyzed using reversed-phase liquid chromatography tandem mass spectrometry (LC-MS/MS) using AB SCIEX TripleTOF 5600. MS spectra were analyzed using XCMS, PeakView, and LipidView. Metabolome-Wide Association Study (MWAS) was performed by Receiver Operating Characteristic Curve Explorer and Tester (ROCCET). Insignificant markers were filtered out using a metabolome-wide significance level (MWSL) with p-value < 2 × 10(-5) for t test. Only compounds in Human Metabolome Database (HMDB) will be used as cancer biomarkers. ROCCET analysis of ESI positive and negative MS spectra revealed free fatty acid (FFA) 18:1 (oleic acid) had the largest area-under-ROC of 0.96 (95% CI = 0.87-1.00) in malignant pleural effusions. Using a ratio of FFA 18:1-to-ceramide (d18:1/16:0), the area-under-ROC was further increased to 0.99 (95% CI = 0.91-1.00) with sensitivity 93.8% and specificity 100.0%. Using untargeted metabolomic profiling, the diagnostic cancer biomarker with the largest area-under-ROC can be determined objectively. This lipogenic phenotype could be explained by overexpression of fatty acid synthase (FASN) in cancer cells. The diagnostic performance of FFA 18:1-to-ceramide (d18:1/16:0) ratio supports its use for diagnosis of malignant pleural effusions.

Patterns of Invasive Growth in Malignant Gliomas-The Hippocampus Emerges as an Invasion-Spared Brain Region.

PubMed

Mughal, Awais A; Zhang, Lili; Fayzullin, Artem; Server, Andres; Li, Yuping; Wu, Yingxi; Glass, Rainer; Meling, Torstein; Langmoen, Iver A; Leergaard, Trygve B; Vik-Mo, Einar O

2018-05-21

Widespread infiltration of tumor cells into surrounding brain parenchyma is a hallmark of malignant gliomas, but little data exist on the overall invasion pattern of tumor cells throughout the brain. We have studied the invasive phenotype of malignant gliomas in two invasive mouse models and patients. Tumor invasion patterns were characterized in a patient-derived xenograft mouse model using brain-wide histological analysis and magnetic resonance (MR) imaging. Findings were histologically validated in a cdkn2a-/- PDGF-β lentivirus-induced mouse glioblastoma model. Clinical verification of the results was obtained by analysis of MR images of malignant gliomas. Histological analysis using human-specific cellular markers revealed invasive tumors with a non-radial invasion pattern. Tumors cells accumulated in structures located far from the transplant site, such as the optic white matter and pons, whereas certain adjacent regions were spared. As such, the hippocampus was remarkably free of infiltrating tumor cells despite the extensive invasion of surrounding regions. Similarly, MR images of xenografted mouse brains displayed tumors with bihemispheric pathology, while the hippocampi appeared relatively normal. In patients, most malignant temporal lobe gliomas were located lateral to the collateral sulcus. Despite widespread pathological fluid-attenuated inversion recovery signal in the temporal lobe, 74% of the "lateral tumors" did not show signs of involvement of the amygdalo-hippocampal complex. Our data provide clear evidence for a compartmental pattern of invasive growth in malignant gliomas. The observed invasion patterns suggest the presence of preferred migratory paths, as well as intra-parenchymal boundaries that may be difficult for glioma cells to traverse supporting the notion of compartmental growth. In both mice and human patients, the hippocampus appears to be a brain region that is less prone to tumor invasion. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Proposed Terminology and Classification of Pre-Malignant Neoplastic Conditions: A Consensus Proposal.

PubMed

Valent, Peter; Akin, Cem; Arock, Michel; Bock, Christoph; George, Tracy I; Galli, Stephen J; Gotlib, Jason; Haferlach, Torsten; Hoermann, Gregor; Hermine, Olivier; Jäger, Ulrich; Kenner, Lukas; Kreipe, Hans; Majeti, Ravindra; Metcalfe, Dean D; Orfao, Alberto; Reiter, Andreas; Sperr, Wolfgang R; Staber, Philipp B; Sotlar, Karl; Schiffer, Charles; Superti-Furga, Giulio; Horny, Hans-Peter

2017-12-01

Cancer evolution is a step-wise non-linear process that may start early in life or later in adulthood, and includes pre-malignant (indolent) and malignant phases. Early somatic changes may not be detectable or are found by chance in apparently healthy individuals. The same lesions may be detected in pre-malignant clonal conditions. In some patients, these lesions may never become relevant clinically whereas in others, they act together with additional pro-oncogenic hits and thereby contribute to the formation of an overt malignancy. Although some pre-malignant stages of a malignancy have been characterized, no global system to define and to classify these conditions is available. To discuss open issues related to pre-malignant phases of neoplastic disorders, a working conference was organized in Vienna in August 2015. The outcomes of this conference are summarized herein and include a basic proposal for a nomenclature and classification of pre-malignant conditions. This proposal should assist in the communication among patients, physicians and scientists, which is critical as genome-sequencing will soon be offered widely for early cancer-detection. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

DNMT3A and TET2 in the Pre-Leukemic Phase of Hematopoietic Disorders

PubMed Central

Sato, Hanae; Wheat, Justin C.; Steidl, Ulrich; Ito, Keisuke

2016-01-01

In recent years, advances in next-generation sequencing (NGS) technology have provided the opportunity to detect putative genetic drivers of disease, particularly cancers, with very high sensitivity. This knowledge has substantially improved our understanding of tumor pathogenesis. In hematological malignancies such as acute myeloid leukemia and myelodysplastic syndromes, pioneering work combining multi-parameter flow cytometry and targeted resequencing in leukemia have clearly shown that different classes of mutations appear to be acquired in particular sequences along the hematopoietic differentiation hierarchy. Moreover, as these mutations can be found in “normal” cells recovered during remission and can be detected at relapse, there is strong evidence for the existence of “pre-leukemic” stem cells (pre-LSC). These cells, while phenotypically normal by flow cytometry, morphology, and functional studies, are speculated to be molecularly poised to transform owing to a limited number of predisposing mutations. Identifying these “pre-leukemic” mutations and how they propagate a pre-malignant state has important implications for understanding the etiology of these disorders and for the development of novel therapeutics. NGS studies have found a substantial enrichment for mutations in epigenetic/chromatin remodeling regulators in pre-LSC, and elegant genetic models have confirmed that these mutations can predispose to a variety of hematological malignancies. In this review, we will discuss the current understanding of pre-leukemic biology in myeloid malignancies, and how mutations in two key epigenetic regulators, DNMT3A and TET2, may contribute to disease pathogenesis. PMID:27597933

Benign and malignant tumors in the UK myotonic dystrophy patient registry.

PubMed

Alsaggaf, Rotana; Wang, Youjin; Marini-Bettolo, Chiara; Wood, Libby; Nikolenko, Nikoletta; Lochmüller, Hanns; Greene, Mark H; Gadalla, Shahinaz M

2018-02-01

In light of recent evidence indicating that cancer is part of the myotonic dystrophy (DM) phenotype, we assessed the prevalence of benign and malignant tumors among 220 patients enrolled in the UK Myotonic Dystrophy Patient Registry and evaluated factors associated with their development. A survey was distributed to collect tumor history and lifestyle information. We used multinomial logistic regression for the analysis. Thirty-nine benign (30 patients), and 16 malignant (15 patients) tumors were reported. Increasing age (odds ratio [OR] = 1.13, 95% confidence interval [CI] = 1.05-1.21, P = 0.001) and earlier age at DM diagnosis (OR = 1.06, 95% CI = 1.00-1.13, P = 0.04) were associated with benign and malignant tumors (OR = 1.20, 95% CI = 1.10-1.30, P < 0.001 and OR = 1.08, 95% CI = 1.01-1.15, P = 0.02, respectively). Female gender was associated with benign tumors only (OR = 6.43, 95% CI = 1.79-23.04, P = 0.004). No associations were observed between tumors and smoking (P = 0.24), alcohol consumption (P = 0.50), or body mass index (P = 0.21). Our results confirm previous findings suggesting a limited role for common lifestyle factors and a potential genetic contribution in DM tumor predisposition. Muscle Nerve 57: 316-320, 2018. © 2017 Wiley Periodicals, Inc.

Pre-emptive and therapeutic adoptive immunotherapy for nasopharyngeal carcinoma: Phenotype and effector function of T cells impact on clinical response.

PubMed

Smith, Corey; Lee, Victor; Schuessler, Andrea; Beagley, Leone; Rehan, Sweera; Tsang, Janice; Li, Vivian; Tiu, Randal; Smith, David; A Neller, Michelle; Matthews, Katherine K; Gostick, Emma; Price, David A; Burrows, Jacqueline; Boyle, Glen M; Chua, Daniel; Panizza, Benedict; Porceddu, Sandro V; Nicholls, John; Kwong, Dora; Khanna, Rajiv

2017-01-01

Adoptive T cell therapy has emerged as a powerful strategy to treat human cancers especially haematological malignancies. Extension of these therapies to solid cancers remains a significant challenge especially in the context of defining immunological correlates of clinical responses. Here we describe results from a clinical study investigating autologous Epstein-Barr virus (EBV)-specific T cells generated using a novel AdE1-LMPpoly vector to treat patients with nasopharyngeal carcinoma (NPC) either pre-emptively in at-risk patients with no or minimal residual disease (N/MRD) or therapeutically in patients with active recurrent/metastatic disease (ARMD). Tolerability, safety and efficacy, including progression-free survival (PFS) and overall survival (OS), were evaluated following adoptive T-cell immunotherapy. Twenty-nine patients, including 20 with ARMD and nine with N/MRD, successfully completed T-cell therapy. After a median follow-up of 18.5 months, the median PFS was 5.5 months (95% CI 2.1 to 9.0 months) and the median OS was 38.1 months (95% CI 17.2 months to not reached). Post-immunotherapy analyses revealed that disease stabilization in ARMD patients was significantly associated with the functional and phenotypic composition of in vitro -expanded T cell immunotherapy. These included a higher proportion of effector CD8 + T-cells and an increased number of EBV-specific T-cells with broader antigen specificity. These observations indicate that adoptive immunotherapy with AdE1-LMPpoly-expanded T cells stabilizes relapsed, refractory NPC without significant toxicity. Promising clinical outcomes in N/MRD patients further suggest a potential role for this approach as a consolidation treatment following first-line chemotherapy.

Periocular Skin Cancer in Solid Organ Transplant Recipients.

PubMed

Perry, Julian D; Polito, Sara C; Chundury, Rao V; Singh, Arun D; Fritz, Michael A; Vidimos, Allison T; Gastman, Brian R; Koyfman, Shlomo A

2016-01-01

To determine the proportion of solid organ transplant recipients developing periocular nonmelanoma skin cancer and to describe the morbidity of these cancers in transplant recipients. Cohort study. Consecutive patients undergoing solid organ transplantation at the Cleveland Clinic between 1990 and 2008. The charts of all patients receiving a solid organ transplant from 1990-2008 evaluated in the dermatology department for a subsequent biopsy-proven head and neck malignancy through April 2015 were reviewed. Patients with a periocular region nonmelanoma skin cancer (NMSC) or a nonperiocular NMSC causing a complication requiring eyelid surgery were included. Charts were reviewed for demographic data; transplant date, type, and source; immunosuppressive agents received at diagnosis; and type of NMSC, number of nonperiocular NMSCs, ophthalmologic findings, and periocular sequelae after the repair. Primary outcome measures included the type, location, final defect size, tumor-node-metastasis classification, presence of perineural invasion, and reconstruction technique(s) used for each periocular NMSC. Secondary outcome measures included the type and treatment of ocular sequelae due to nonperiocular facial NMSC. A total of 3489 patients underwent solid organ transplantation between 1990 and 2008. Of these, 420 patients were evaluated in the dermatology clinic for biopsy-proven NMSC of the head and neck during the study period, and 11 patients (15 malignancies) met inclusion criteria. Nine patients developed 12 periocular malignancies and 3 patients required eyelid surgery for facial malignancies outside the periocular zone. All 11 patients developed a squamous cell carcinoma (14 malignancies), and 1 patient (1 malignancy) also developed a periocular basal cell carcinoma. There was orbital invasion in 4 cases and paranasal and/or cavernous sinus invasion in 3 cases. Two patients underwent exenteration. Seven cases required reconstruction with a free flap or graft. Periocular sequelae included lower eyelid ectropion (6 malignancies), dry eye and/or exposure symptoms (8 malignancies), unilateral vision loss (3 malignancies), and facial nerve paresis (5 malignancies). Squamous cell carcinoma affecting the periocular region represents a risk of solid organ transplantation and may produce significant ocular morbidity, including the need for major eyelid reconstruction, globe loss, and disfiguring surgery. Copyright © 2016 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.

MAME Models for 4D Live-cell Imaging of Tumor: Microenvironment Interactions that Impact Malignant Progression

PubMed Central

Sameni, Mansoureh; Anbalagan, Arulselvi; Olive, Mary B.; Moin, Kamiar; Mattingly, Raymond R.; Sloane, Bonnie F.

2012-01-01

We have developed 3D coculture models, which we term MAME (mammary architecture and microenvironment engineering), and used them for live-cell imaging in real-time of cell:cell interactions. Our overall goal was to develop models that recapitulate the architecture of preinvasive breast lesions to study their progression to an invasive phenotype. Specifically, we developed models to analyze interactions among pre-malignant breast epithelial cell variants and other cell types of the tumor microenvironment that have been implicated in enhancing or reducing the progression of preinvasive breast epithelial cells to invasive ductal carcinomas. Other cell types studied to date are myoepithelial cells, fibroblasts, macrophages and blood and lymphatic microvascular endothelial cells. In addition to the MAME models, which are designed to recapitulate the cellular interactions within the breast during cancer progression, we have developed comparable models for the progression of prostate cancers. Here we illustrate the procedures for establishing the 3D cocultures along with the use of live-cell imaging and a functional proteolysis assay to follow the transition of cocultures of breast ductal carcinoma in situ (DCIS) cells and fibroblasts to an invasive phenotype over time, in this case over twenty-three days in culture. The MAME cocultures consist of multiple layers. Fibroblasts are embedded in the bottom layer of type I collagen. On that is placed a layer of reconstituted basement membrane (rBM) on which DCIS cells are seeded. A final top layer of 2% rBM is included and replenished with every change of media. To image proteolysis associated with the progression to an invasive phenotype, we use dye-quenched (DQ) fluorescent matrix proteins (DQ-collagen I mixed with the layer of collagen I and DQ-collagen IV mixed with the middle layer of rBM) and observe live cultures using confocal microscopy. Optical sections are captured, processed and reconstructed in 3D with Volocity visualization software. Over the course of 23 days in MAME cocultures, the DCIS cells proliferate and coalesce into large invasive structures. Fibroblasts migrate and become incorporated into these invasive structures. Fluorescent proteolytic fragments of the collagens are found in association with the surface of DCIS structures, intracellularly, and also dispersed throughout the surrounding matrix. Drugs that target proteolytic, chemokine/cytokine and kinase pathways or modifications in the cellular composition of the cocultures can reduce the invasiveness, suggesting that MAME models can be used as preclinical screens for novel therapeutic approaches. PMID:22371028

MAME models for 4D live-cell imaging of tumor: microenvironment interactions that impact malignant progression.

PubMed

Sameni, Mansoureh; Anbalagan, Arulselvi; Olive, Mary B; Moin, Kamiar; Mattingly, Raymond R; Sloane, Bonnie F

2012-02-17

We have developed 3D coculture models, which we term MAME (mammary architecture and microenvironment engineering), and used them for live-cell imaging in real-time of cell:cell interactions. Our overall goal was to develop models that recapitulate the architecture of preinvasive breast lesions to study their progression to an invasive phenotype. Specifically, we developed models to analyze interactions among pre-malignant breast epithelial cell variants and other cell types of the tumor microenvironment that have been implicated in enhancing or reducing the progression of preinvasive breast epithelial cells to invasive ductal carcinomas. Other cell types studied to date are myoepithelial cells, fibroblasts, macrophages and blood and lymphatic microvascular endothelial cells. In addition to the MAME models, which are designed to recapitulate the cellular interactions within the breast during cancer progression, we have developed comparable models for the progression of prostate cancers. Here we illustrate the procedures for establishing the 3D cocultures along with the use of live-cell imaging and a functional proteolysis assay to follow the transition of cocultures of breast ductal carcinoma in situ (DCIS) cells and fibroblasts to an invasive phenotype over time, in this case over twenty-three days in culture. The MAME cocultures consist of multiple layers. Fibroblasts are embedded in the bottom layer of type I collagen. On that is placed a layer of reconstituted basement membrane (rBM) on which DCIS cells are seeded. A final top layer of 2% rBM is included and replenished with every change of media. To image proteolysis associated with the progression to an invasive phenotype, we use dye-quenched (DQ) fluorescent matrix proteins (DQ-collagen I mixed with the layer of collagen I and DQ-collagen IV mixed with the middle layer of rBM) and observe live cultures using confocal microscopy. Optical sections are captured, processed and reconstructed in 3D with Volocity visualization software. Over the course of 23 days in MAME cocultures, the DCIS cells proliferate and coalesce into large invasive structures. Fibroblasts migrate and become incorporated into these invasive structures. Fluorescent proteolytic fragments of the collagens are found in association with the surface of DCIS structures, intracellularly, and also dispersed throughout the surrounding matrix. Drugs that target proteolytic, chemokine/cytokine and kinase pathways or modifications in the cellular composition of the cocultures can reduce the invasiveness, suggesting that MAME models can be used as preclinical screens for novel therapeutic approaches.

β-Myosin heavy chain variant Val606Met causes very mild hypertrophic cardiomyopathy in mice, but exacerbates HCM phenotypes in mice carrying other HCM mutations.

PubMed

Blankenburg, Robert; Hackert, Katarzyna; Wurster, Sebastian; Deenen, René; Seidman, J G; Seidman, Christine E; Lohse, Martin J; Schmitt, Joachim P

2014-07-07

Approximately 40% of hypertrophic cardiomyopathy (HCM) is caused by heterozygous missense mutations in β-cardiac myosin heavy chain (β-MHC). Associating disease phenotype with mutation is confounded by extensive background genetic and lifestyle/environmental differences between subjects even from the same family. To characterize disease caused by β-cardiac myosin heavy chain Val606Met substitution (VM) that has been identified in several HCM families with wide variation of clinical outcomes, in mice. Unlike 2 mouse lines bearing the malignant myosin mutations Arg453Cys (RC/+) or Arg719Trp (RW/+), VM/+ mice with an identical inbred genetic background lacked hallmarks of HCM such as left ventricular hypertrophy, disarray of myofibers, and interstitial fibrosis. Even homozygous VM/VM mice were indistinguishable from wild-type animals, whereas RC/RC- and RW/RW-mutant mice died within 9 days after birth. However, hypertrophic effects of the VM mutation were observed both in mice treated with cyclosporine, a known stimulator of the HCM response, and compound VM/RC heterozygous mice, which developed a severe HCM phenotype. In contrast to all heterozygous mutants, both systolic and diastolic function of VM/RC hearts was severely impaired already before the onset of cardiac remodeling. The VM mutation per se causes mild HCM-related phenotypes; however, in combination with other HCM activators it exacerbates the HCM phenotype. Double-mutant mice are suitable for assessing the severity of benign mutations. © 2014 American Heart Association, Inc.

Inhibition of long non-coding RNA UCA1 by CRISPR/Cas9 attenuated malignant phenotypes of bladder cancer.

PubMed

Zhen, Shuai; Hua, Ling; Liu, Yun-Hui; Sun, Xiao-Min; Jiang, Meng-Meng; Chen, Wei; Zhao, Le; Li, Xu

2017-02-07

CRISPR/Cas9 is a novel and effective genome editing technique, but its application is not widely expanded to manipulate long non-coding RNA (lncRNA) expression. The lncRNA urothelial carcinoma-associated 1 (UCA1) is upregulated in bladder cancer and promotes the progression of bladder cancer. Here, we design gRNAs specific to UCA1 and construct CRISPR/Cas9 systems targeting UCA1. Single CRISPR/Cas9-UCA1 can effectively inhibit UCA1 expression when transfected into 5637 and T24 bladder cancer cells, while the combined transfection of the two most effective CRISPR/Cas9-UCA1s can generate more satisfied inhibitory effect. CRISPR/Cas9-UCA1s attenuate UCA1 expression via targeted genome-specific DNA cleavage, resulting in the significant inhibition of cell proliferation, migration and invasion in vitro and in vivo. The mechanisms associated with the inhibitory effect of CRISPR/Cas9-UCA1 on malignant phenotypes of bladder cancer are attributed to the induction of cell cycle arrest at G1 phase, a substantial increase of apoptosis, and an enhanced activity of MMPs. Additionally, urinary UCA1 can be used as a non-invasive diagnostic marker for bladder cancer as revealed by a meta-analysis. Collectively, our data suggest that CRISPR/Cas9 technique can be used to down-modulate lncRNA expression, and urinary UCA1 may be used as a non-invasive marker for diagnosis of bladder cancer.

Towards a systemic paradigm in carcinogenesis: linking epigenetics and genetics.

PubMed

Burgio, Ernesto; Migliore, Lucia

2015-04-01

For at least 30 years cancer has been defined as a genetic disease and explained by the so-called somatic mutation theory (SMT), which has dominated the carcinogenesis field. Criticism of the SMT has recently greatly increased, although still not enough to force all SMT supporters to recognize its limits. Various researchers point out that cancer appears to be a complex process concerning a whole tissue; and that genomic mutations, although variably deleterious and unpredictably important in determining the establishment of the neoplastic phenotype, are not the primary origin for a malignant neoplasia. We attempt to describe the inadequacies of the SMT and demonstrate that epigenetics is a more logical cause of carcinogenesis. Many previous models of carcinogenesis fall into two classes: (i) in which some biological changes inside cells alone lead to malignancy; and (ii) requiring changes in stroma/extracellular matrix. We try to make clear that in the (ii) model genomic instability is induced by persistent signals coming from the microenvironment, provoking epigenetic and genetic modifications in tissue stem cells that can lead to cancer. In this perspective, stochastic mutations of DNA are a critical by-product rather then the primary cause of cancer. Indirect support for such model of carcinogenesis comes from the in vitro and vivo experiments showing apparent 'reversion' of cancer phenotypes obtained via physiological factors of cellular differentiation (cytokines and other signaling molecules) or drugs, even if the key mutations are not 'reversed'.

IQ-domain GTPase-activating protein 1 promotes the malignant phenotype of invasive ductal breast carcinoma via canonical Wnt pathway.

PubMed

Zhao, Huan-Yu; Han, Yang; Wang, Jian; Yang, Lian-He; Zheng, Xiao-Ying; Du, Jiang; Wu, Guang-Ping; Wang, En-Hua

2017-06-01

IQ-domain GTPase-activating protein 1 is a scaffolding protein with multidomain which plays a role in modulating dishevelled (Dvl) nuclear translocation in canonical Wnt pathway. However, the biological function and mechanism of IQ-domain GTPase-activating protein 1 in invasive ductal carcinoma (IDC) remain unknown. In this study, we found that IQ-domain GTPase-activating protein 1 expression was elevated in invasive ductal carcinoma, which was positively correlated with tumor grade, lymphatic metastasis, and poor prognosis. Coexpression of IQ-domain GTPase-activating protein 1 and Dvl in the nucleus and cytoplasm of invasive ductal carcinoma was significantly correlated but not in the membrane. Postoperative survival in the patients with their coexpression in the nucleus and cytoplasm was obviously lower than that without coexpression. The positive expression rates of c-myc and cyclin D1 were significantly higher in the patients with nuclear coexpression of Dvl and IQ-domain GTPase-activating protein 1 than that with cytoplasmic coexpression, correlating with poor prognosis. IQ-domain GTPase-activating protein 1 significantly enhanced cell proliferation and invasion in invasive ductal carcinoma cell lines by interacting with Dvl in cytoplasm to promote Dvl nuclear translocation so as to upregulate the expression of c-myc and cyclin D1. Collectively, our data suggest that IQ-domain GTPase-activating protein 1 may promote the malignant phenotype of invasive ductal carcinoma via canonical Wnt signaling, and it could be used as a potential prognostic biomarker for breast cancer patients.

Cancer biomarker discovery: the entropic hallmark.

PubMed

Berretta, Regina; Moscato, Pablo

2010-08-18

It is a commonly accepted belief that cancer cells modify their transcriptional state during the progression of the disease. We propose that the progression of cancer cells towards malignant phenotypes can be efficiently tracked using high-throughput technologies that follow the gradual changes observed in the gene expression profiles by employing Shannon's mathematical theory of communication. Methods based on Information Theory can then quantify the divergence of cancer cells' transcriptional profiles from those of normally appearing cells of the originating tissues. The relevance of the proposed methods can be evaluated using microarray datasets available in the public domain but the method is in principle applicable to other high-throughput methods. Using melanoma and prostate cancer datasets we illustrate how it is possible to employ Shannon Entropy and the Jensen-Shannon divergence to trace the transcriptional changes progression of the disease. We establish how the variations of these two measures correlate with established biomarkers of cancer progression. The Information Theory measures allow us to identify novel biomarkers for both progressive and relatively more sudden transcriptional changes leading to malignant phenotypes. At the same time, the methodology was able to validate a large number of genes and processes that seem to be implicated in the progression of melanoma and prostate cancer. We thus present a quantitative guiding rule, a new unifying hallmark of cancer: the cancer cell's transcriptome changes lead to measurable observed transitions of Normalized Shannon Entropy values (as measured by high-throughput technologies). At the same time, tumor cells increment their divergence from the normal tissue profile increasing their disorder via creation of states that we might not directly measure. This unifying hallmark allows, via the the Jensen-Shannon divergence, to identify the arrow of time of the processes from the gene expression profiles, and helps to map the phenotypical and molecular hallmarks of specific cancer subtypes. The deep mathematical basis of the approach allows us to suggest that this principle is, hopefully, of general applicability for other diseases.

Giant Malignant Pheochromocytoma with Palpable Rib Metastases

PubMed Central

Gokce, Gokhan; Kilicli, Fatih; Elagoz, Sahande; Ayan, Semih; Gultekin, Emin Yener

2014-01-01

Pheochromocytoma is a rare and usually benign neuroendocrine neoplasm. Only 10% of all these tumors are malignant and there are no definitive histological or cytological criteria of malignancy. Single malignancy criteria are the presence of advanced locoregional disease or metastases. We report a case, with a giant retroperitoneal tumor having multiple metastases including palpable rib metastases, who was diagnosed as a malignant pheochromocytoma. The patient was treated with surgery. The literature was reviewed to evaluate tumor features and current diagnostic and therapeutic approaches for patients with metastatic or potentially malignant pheochromocytoma. PMID:25152826

Exosomes isolated from cancer patients' sera transfer malignant traits and confer the same phenotype of primary tumors to oncosuppressor-mutated cells.

PubMed

Abdouh, Mohamed; Hamam, Dana; Gao, Zu-Hua; Arena, Vincenzo; Arena, Manuel; Arena, Goffredo Orazio

2017-08-30

Horizontal transfer of malignant traits from the primary tumor to distant organs, through blood circulating factors, has recently become a thoroughly studied metastatic pathway to explain cancer dissemination. Recently, we reported that oncosuppressor gene-mutated human cells undergo malignant transformation when exposed to cancer patients' sera. We also observed that oncosuppressor mutated cells would show an increased uptake of cancer-derived exosomes and we suggested that oncosuppressor genes might protect the integrity of the cell genome by blocking integration of cancer-derived exosomes. In the present study, we tested the hypothesis that cancer patients' sera-derived exosomes might be responsible for the malignant transformation of target cells and that oncosuppressor mutation would promote their increased uptake. We also sought to unveil the mechanisms behind the hypothesized phenomena. We used human BRCA1 knockout (BRCA1-KO) fibroblasts as target cells. Cells were treated in vitro with cancer patients' sera or cancer patients' sera-derived exosomes. Treated cells were injected into NOD-SCID mice. Immunohistochemical analyses were performed to determine the differentiation state of the xenotransplants. Mass spectrometry analyses of proteins from cancer exosomes and the BRCA1-KO fibroblasts' membrane were performed to investigate possible de novo expression of molecules involved in vesicles uptake. Blocking of the identified molecules in vitro was performed and in vivo experiments were conducted to confirm the role of these molecules in the malignant transformation carried out by cancer-derived exosomes. Cells treated with exosomes isolated from cancer patients' sera underwent malignant transformation and formed tumors when transplanted into immunodeficient mice. Histological analyses showed that the tumors were carcinomas that differentiated into the same lineage of the primary tumors of blood donors. Oncosuppressor mutation promoted the de novo expression, on the plasma membrane of target cells, of receptors, responsible for the increased uptake of cancer-derived exosomes. The selective blocking of these receptors inhibited the horizontal transfer of malignant traits. These findings strengthen the hypothesis that oncogenic factors transferred via circulating cancer exosomes, induce malignant transformation of target cells even at distance. Oncosuppressor genes might protect the integrity of the cell genome by inhibiting the uptake of cancer-derived exosomes.

Lgr5High/DCLK1High phenotype is more common in early stage and intestinal subtypes of gastric carcinomas.

PubMed

Kalantari, Elham; Asadi Lari, Mohammad Hossein; Roudi, Raheleh; Korourian, Alireza; Madjd, Zahra

2017-12-06

Gastric carcinoma is the third most common malignancy and is one of the main causes of cancer deaths worldwide. Cancer stem cells (CSCs) are a subpopulation of tumour cells capable of self-renewal and differentiation, likely responsible for the initiation, recurrence, metastasis and chemo/radio-resistance. This study was conducted to evaluate the expression patterns and clinicopathologic significance of putative CSC markers, Lgr5 and DCLK1, in gastric carcinoma. The expression levels of Lgr5 and DCLK1 were examined in a well-defined series of gastric carcinoma tissues, including 75 (80%) from intestinal and 19 (20%) from diffuse subtypes, using tissue microarray (TMA). In addition, the correlation of the expression of these markers with clinicopathological factors was explored. Higher expressions of Lgr5 and DCLK1 were mainly detected in intestinal subtypes of gastric carcinomas compared to diffuse subtypes (P= 0.005 and P= 0.050, respectively). We also found a higher expression of Lgr5 and DCLK1 more frequently in well-differentiated gastric carcinoma cases (P< 0.001 and P= 0.007). The combined analysis demonstrated that the co-expression of Lgr5 and DCLK1 (Lgr5High/DCLK1High) was more common in intestinal subtypes (P= 0.025) and well-differentiated gastric carcinoma samples (P< 0.001). Interestingly, there was a significant correlation between Lgr5High/DCLK1High phenotype and early-stage gastric carcinoma specimens (P= 0.045). Our findings indicated that the Lgr5High/DCLK1High expression pattern may be considered as a signature phenotype for intestinal subtypes of gastric carcinoma.

Variable Expression of PIK3R3 and PTEN in Ewing Sarcoma Impacts Oncogenic Phenotypes

PubMed Central

Niemeyer, Brian F.; Parrish, Janet K.; Spoelstra, Nicole S.; Joyal, Teresa; Richer, Jennifer K.; Jedlicka, Paul

2015-01-01

Ewing Sarcoma is an aggressive malignancy of bone and soft tissue affecting children and young adults. Ewing Sarcoma is driven by EWS/Ets fusion oncoproteins, which cause widespread alterations in gene expression in the cell. Dysregulation of receptor tyrosine kinase signaling, particularly involving IGF-1R, also plays an important role in Ewing Sarcoma pathogenesis. However, the basis of this dysregulation, including the relative contribution of EWS/Ets-dependent and independent mechanisms, is not well understood. In the present study, we identify variable expression of two modifiers of PI3K signaling activity, PIK3R3 and PTEN, in Ewing Sarcoma, and examine the consequences of this on PI3K pathway regulation and oncogenic phenotypes. Our findings indicate that PIK3R3 plays a growth-promotional role in Ewing Sarcoma, but suggest that this role is not strictly dependent on regulation of PI3K pathway activity. We further show that expression of PTEN, a well-established, potent tumor suppressor, is lost in a subset of Ewing Sarcomas, and that this loss strongly correlates with high baseline PI3K pathway activity in cell lines. In support of functional importance of PTEN loss in Ewing Sarcoma, we show that re-introduction of PTEN into two different PTEN-negative Ewing Sarcoma cell lines results in downregulation of PI3K pathway activity, and sensitization to the IGF-1R small molecule inhibitor OSI-906. Our findings also suggest that PTEN levels may contribute to sensitivity of Ewing Sarcoma cells to the microtubule inhibitor vincristine, a relevant chemotherapeutic agent in this cancer. Our studies thus identify PIK3R3 and PTEN as modifiers of oncogenic phenotypes in Ewing Sarcoma, with potential clinical implications. PMID:25603314

Mechanisms of Nuclear Export in Cancer and Resistance to Chemotherapy

PubMed Central

El-Tanani, Mohamed; Dakir, El-Habib; Raynor, Bethany; Morgan, Richard

2016-01-01

Tumour suppressor proteins, such as p53, BRCA1, and ABC, play key roles in preventing the development of a malignant phenotype, but those that function as transcriptional regulators need to enter the nucleus in order to function. The export of proteins between the nucleus and cytoplasm is complex. It occurs through nuclear pores and exported proteins need a nuclear export signal (NES) to bind to nuclear exportin proteins, including CRM1 (Chromosomal Region Maintenance protein 1), and the energy for this process is provided by the RanGTP/RanGDP gradient. Due to the loss of DNA repair and cell cycle checkpoints, drug resistance is a major problem in cancer treatment, and often an initially successful treatment will fail due to the development of resistance. An important mechanism underlying resistance is nuclear export, and a number of strategies that can prevent nuclear export may reverse resistance. Examples include inhibitors of CRM1, antibodies to the nuclear export signal, and alteration of nuclear pore structure. Each of these are considered in this review. PMID:26985906

Serrated pathway in colorectal carcinogenesis

PubMed Central

Yamane, Letícia; Scapulatempo-Neto, Cristovam; Reis, Rui Manuel; Guimarães, Denise Peixoto

2014-01-01

Serrated adenocarcinoma is a recently described subset of colorectal cancer (CRC), which account for about 10% of all CRCs and follows an alternative pathway in which serrated polyps replace the traditional adenoma as the precursor lesion to CRC. Serrated polyps form a heterogeneous group of colorectal lesions that includes hyperplastic polyps (HPs), sessile serrated adenoma (SSA), traditional serrated adenoma (TSA) and mixed polyps. HPs are the most common serrated polyp followed by SSA and TSA. This distinct histogenesis is believed to have a major influence in prevention strategies, patient prognosis and therapeutic impact. Genetically, serrated polyps exhibited also a distinct pattern, with KRAS and BRAF having an important contribution to its development. Two other molecular changes that have been implicated in the serrated pathway include microsatellite instability and the CpG island methylator phenotype. In the present review we will address the current knowledge of serrated polyps, clinical pathological features and will update the most recent findings of its molecular pathways. The understanding of their biology and malignancy potential is imperative to implement a surveillance approach in order to prevent colorectal cancer development. PMID:24627599

Multiple metastatic malignant melanoma presenting intraluminal gallbladder bleeding.

PubMed

Onozawa, Hisashi; Saito, Motonobu; Yoshida, Sayaka; Sakuma, Takeshi; Matsuzaki, Masami; Katagata, Naoto; Watanabe, Fumiaki; Yamaguchi, Yoshiko; Takenoshita, Seiichi; Nomizu, Tadashi

2014-01-01

We report a case of malignant melanoma of unknown primary origin presenting metastasis in various organs as well as intraluminal gallbladder bleeding due to gallbladder metastasis. A 58-year-old woman was diagnosed with stage IV metastatic malignant melanoma. Because she exhibited acute cholecystitis and hemobilia due to malignant melanoma of the gallbladder, laparoscopic cholecystectomy was performed to relieve the symptoms. The resected gallbladder specimen showed a pedunculated black mass indicating malignant melanoma. Pathologic examination and immunohistochemical analysis revealed malignant melanoma of the gallbladder. Only a few cases of gallbladder malignant melanoma presenting hemobilia have been reported; here we present our case, including the experience of multidisciplinary treatment.

Diagnosis of Fanconi Anemia by Diepoxybutane Analysis

PubMed Central

Auerbach, Arleen D.

2015-01-01

Fanconi anemia (FA) is a genetically and phenotypically heterogeneous disorder characterized by congenital malformations, progressive bone marrow failure, and predisposition to cancer, particularly hematological malignancies and solid tumors of the head and neck. The main role of FA proteins is in the repair of DNA interstrand crosslinks (ICLs). FA results from pathogenic variants in at least 16 distinct genes, causing genomic instability. Although the highly variable phenotype makes accurate diagnosis on the basis of clinical manifestations difficult in some patients, diagnosis based on a profound sensitivity to DNA crosslinking agents can be used to identify the pre-anemia patient as well as patients with aplastic anemia or leukemia who may or may not have the physical stigmata associated with the syndrome. Diepoxybutane (DEB) analysis is the preferred test for FA because other agents have higher rates of false-positive and false-negative results. PMID:25827349

The neuropathological basis to the functional role of microglia/macrophages in gliomas.

PubMed

Schiffer, Davide; Mellai, Marta; Bovio, Enrica; Annovazzi, Laura

2017-09-01

The paper wants to be a tracking shot of the main recent acquisitions on the function and significance of microglia/macrophages in gliomas. The observations have been principally carried out on in vitro cultures and on tumor transplants in animals. Contrary to what is deduced from microglia in non-neoplastic pathologic conditions of central nervous system (CNS), most conclusions indicate that microglia acts favoring tumor proliferation through an immunosuppression induced by glioma cells. By immunohistochemistry, different microglia phenotypes are recognized in gliomas, from ramified microglia to frank macrophagic aspect. One wonders whether the functional conclusions drawn from many microglia studies, but not in conditions of human pathology, apply to all the phenotypes recognizable in them. It is difficult to verify in human pathology a prognostic significance of microglia. Only CD163-positive microglia/macrophages inversely correlate with glioma patients' survival, whereas the total number of microglia does not change with the malignancy grade.

Ultrasound-Based Risk Stratification for Malignancy in Thyroid Nodules: A Four-Tier Categorization System.

PubMed

Seo, Hyobin; Na, Dong Gyu; Kim, Ji-Hoon; Kim, Kyung Won; Yoon, Ji Won

2015-07-01

The purpose of this study was to stratify the malignancy risk of US features, with an emphasis on nodule echogenicity. A total of 1,058 nodules of 824 consecutive patients (236 malignant and 822 benign) were included in this study. Malignancy risk of each nodule was analyzed according to US features, with an emphasis on nodule echogenecity, and was stratified into 4-tier categories. In multivariate analysis, isoechogenicity, indistinct margin, non-solid internal content, and parallel orientation were predictive of benign nodules (P < 0.002), while hypoechogenicity, marked hypoechogenicity, spiculated/microlobulated margin, solid content, nonparallel orientation (taller than wide), microcalcification, and macrocalcification were predictive of malignancy (P ≤ 0.037). Although the presence of US features associated with malignancy was significantly predictive of malignancy in hypoechoic and markedly hypoechoic nodules (P ≤ 0.004), it was not associated with malignancy in isoechoic or hyperechoic nodules. Thyroid nodules could be stratified into four categories according to the malignancy risk: benign (risk 0%), probably benign (risk ≤ 5%), indeterminate (risk > 5 and < 50%), and suspicion of malignancy (risk > 50%). The US-based four-tier categorization system will be useful for predicting the risk of malignancy and decisions regarding FNA for thyroid nodules. • No US feature was predictive of malignancy in isoechoic nodules. • Isoechoic nodules without calcification can be included in the probably benign category. • We suggest a four-tier categorization stratified primarily by nodule echogenecity. • The four-tier categorization of thyroid nodules will be useful for FNA decisions.

The epidemiology of glioma in adults: a “state of the science” review

PubMed Central

Ostrom, Quinn T.; Bauchet, Luc; Davis, Faith G.; Deltour, Isabelle; Fisher, James L.; Langer, Chelsea Eastman; Pekmezci, Melike; Schwartzbaum, Judith A.; Turner, Michelle C.; Walsh, Kyle M.; Wrensch, Margaret R.; Barnholtz-Sloan, Jill S.

2014-01-01

Gliomas are the most common primary intracranial tumor, representing 81% of malignant brain tumors. Although relatively rare, they cause significant mortality and morbidity. Glioblastoma, the most common glioma histology (∼45% of all gliomas), has a 5-year relative survival of ∼5%. A small portion of these tumors are caused by Mendelian disorders, including neurofibromatosis, tuberous sclerosis, and Li-Fraumeni syndrome. Genomic analyses of glioma have also produced new evidence about risk and prognosis. Recently discovered biomarkers that indicate improved survival include O6-methylguanine-DNA methyltransferase methylation, isocitrate dehydrogenase mutation, and a glioma cytosine–phosphate–guanine island methylator phenotype. Genome-wide association studies have identified heritable risk alleles within 7 genes that are associated with increased risk of glioma. Many risk factors have been examined as potential contributors to glioma risk. Most significantly, these include an increase in risk by exposure to ionizing radiation and a decrease in risk by history of allergies or atopic disease(s). The potential influence of occupational exposures and cellular phones has also been examined, with inconclusive results. We provide a “state of the science” review of current research into causes and risk factors for gliomas in adults. PMID:24842956

Suppression of Aurora-A-FLJ10540 signaling axis prohibits the malignant state of head and neck cancer.

PubMed

Chen, Chang-Han; Chang, Alice Y W; Li, Shau-Hsuan; Tsai, Hsin-Ting; Shiu, Li-Yen; Su, Li-Jen; Wang, Wen-Lung; Chiu, Tai-Jen; Luo, Sheng-Dean; Huang, Tai-Lin; Chien, Chih-Yen

2015-04-12

Head and neck cancer (HNC) is a highly invasive cancer. Aurora-A has been reported for a number of malignancies. However, the identity of downstream effectors responsible for its aggressive phenotype in HNC remains underinvestigated. The mRNA and protein expression levels of Aurora-A and FLJ10540 were assessed in HNC specimens and cell lines using RT-qPCR, western blot, Oncomine, and microarray database analysis. The downstream molecular mechanisms of Aurora-A were confirmed by RT-qPCR, western blot, luciferase reporter, confocal microscopy analyses, immunoprecipitation, colony formation, cell viability, and xenograft model. Cellular functions in response to Aurora-A-modulated downstream targets such as FLJ10540 and MMPs were examined in vitro and in vivo, including cell growth, motility and chemosensitivity. Aurora-A/FLJ10540/MMPs expression was determined in cancer and adjacent normal tissues from HNC patients by immunohistochemistry approach. In the current study, Aurora-A exhibited similar gene expression profiles with FLJ10540 by using accessibly public microarray and Oncomine database analysis, raising the possibility that these molecules might coordinately participate in cancer progression and metastasis of HNC. These two molecules connection were also examined in cell lines and tissues of HNC. Aurora-A overexpression could not only bind to the promoter of FLJ10540 to induce FLJ10540 expression, but also increase both mRNA and protein levels of MMP-7 and MMP-10 in HNC cells. Conversely, depletion of Aurora-A expression by using siRNA or Aurora-A kinase inhibitor, MLN8237, suppressed FLJ10540, MMP-7 and MMP-10 mRNA and protein expressions in vitro and in vivo. In addition, the FLJ10540-PI3K complex was destroyed by inhibition the Aurora-A kinase activity. Forced overexpression of FLJ10540 in Aurora-A-depleted or in MLN8237-treated HNC cells attenuated the effect on cytotoxicity to cisplatin. Elevated Aurora-A expression in HNC cells led to the characteristics of more aggressive malignancy, including enhanced chemoresistance and increased the abilities of proliferation, migration and invasion, which was required for FLJ10540/MMP-7 or FLJ10540/MMP-10 expressions. Finally, immunohistochemical analysis of human HNC specimens showed a significant positively correlation among Aurora-A, FLJ10540, MMP-7 and MMP-10 expressions. Together, our findings define a novel mechanism by which Aurora-A promotes cell malignancy, with potential implications for understanding the clinical action of Aurora-A.

Epigenetics markers of metastasis and HPV-induced tumorigenesis in penile cancer.

PubMed

Feber, Andrew; Arya, Manit; de Winter, Patricia; Saqib, Muhammad; Nigam, Raj; Malone, Peter R; Tan, Wei Shen; Rodney, Simon; Lechner, Matthias; Freeman, Alex; Jameson, Charles; Muneer, Asif; Beck, Stephan; Kelly, John D

2015-03-01

Penile cancer is a rare malignancy in the developed world with just more than 1,600 new cases diagnosed in the United States per year; however, the incidence is much higher in developing countries. Although HPV is known to contribute to tumorigenesis, little is known about the genetic or epigenetic alterations defining penile cancer. Using high-density genome-wide methylation arrays, we have identified epigenetic alterations associated with penile cancer. Q-MSP was used to validate lymph node metastasis markers in 50 cases. A total of 446 head and neck squamous cell carcinoma (HNSCC) and cervical squamous cell carcinoma (CESCC) samples were used to validate HPV-associated epigenetic alterations. We defined 6,933 methylation variable positions (MVP) between normal and tumor tissue, which includes 997 hypermethylated differentially methylated regions associated with tumor supressor genes, including CDO1, AR1, and WT1. Analysis of penile cancer tumors identified a 4 gene epi-signature which accurately predicted lymph node metastasis in an independent cohort (AUC of 89%). Finally, we explored the epigenetic alterations associated with penile cancer HPV infection and defined a 30 loci lineage-independent HPV specific epi-signature which predicts HPV status and survival in independent HNSCC, CESC cohorts. Epi-signature-negative patients have a significantly worse overall survival [HNSCC P = 0.00073; 95% confidence interval (CI), 0.021-0.78; CESC P = 0.0094; HR = 3.91, 95% CI = 0.13-0.78], HPV epi-signature is a better predictor of survival than HPV status alone. These data demonstrate for the first time genome-wide epigenetic events involved in an aggressive penile cancer phenotype and define the epigenetic alterations common across multiple HPV-driven malignancies. ©2014 American Association for Cancer Research.

Epigenetics markers of metastasis and HPV induced tumourigenesis in Penile cancer

PubMed Central

Feber, Andrew; Arya, Manit; de Winter, Patricia; Saqib, Muhammad; Nigam, Raj; Malone, Peter R; Tan, Wei Shen; Rodney, Simon; Lechner, Matthias; Freeman, Alex; Jameson, Charles; Muneer, Asif; Beck, Stephan; Kelly, John D

2015-01-01

Purpose Penile cancer is a rare malignancy in the developed world, with just over 1600 new cases diagnosed in the USA per year, however, the incidence is much higher in developing countries. Although HPV is known to contribute to tumourigenesis, little is known about the genetic or epigenetic alterations defining penile cancer (PeCa). Experimental Design Using high-density genome-wide methylation arrays we have identified epigenetic alterations associated with PeCa. Q-MSP was used to validate lymph node metastasis markers in 50 cases. 446 HNSCC and CESCC (head and neck squamous cell carcinoma and cervical squamous cell carcinoma) samples were used to validate HPV associated epigenetic alterations. Results We defined 6933 methylation variable positions (MVPs) between normal and tumour tissue, which include 997 hypermethylated differentially methylated regions associated with tumour supressor genes including CDO1, AR1 and WT1. Analysis of PeCa tumours identified a 4 gene epi-signature which accurately predicted lymph node metastasis in an independent cohort (AUC of 89%). Finally, we explored the epigenetic alterations associated with PeCa HPV infection and defined a 30 loci lineage independent HPV specific epi-signature which predicts HPV status and survival in independent HNSCC, CESC cohorts. Epi-signature negative patients have a significantly worse overall survival (HNSCC p=0.00073, CI 0.021-0.78, CESC p= 0.0094, HR=3.91, 95% CI =0.13-0.78), HPV epi-signature is a better predictor of survival than HPV status alone. Conclusion These data demonstrate for the first time genome-wide epigenetic events involved in an aggressive penile cancer phenotype and define the epigenetic alterations common across multiple HPV driven malignancies. PMID:25538261

Oceans of opportunity: exploring vertebrate hematopoiesis in zebrafish.

PubMed

Carroll, Kelli J; North, Trista E

2014-08-01

Exploitation of the zebrafish model in hematology research has surged in recent years, becoming one of the most useful and tractable systems for understanding regulation of hematopoietic development, homeostasis, and malignancy. Despite the evolutionary distance between zebrafish and humans, remarkable genetic and phenotypic conservation in the hematopoietic system has enabled significant advancements in our understanding of blood stem and progenitor cell biology. The strengths of zebrafish in hematology research lie in the ability to perform real-time in vivo observations of hematopoietic stem, progenitor, and effector cell emergence, expansion, and function, as well as the ease with which novel genetic and chemical modifiers of specific hematopoietic processes or cell types can be identified and characterized. Further, myriad transgenic lines have been developed including fluorescent reporter systems to aid in the visualization and quantification of specified cell types of interest and cell-lineage relationships, as well as effector lines that can be used to implement a wide range of experimental manipulations. As our understanding of the complex nature of blood stem and progenitor cell biology during development, in response to infection or injury, or in the setting of hematologic malignancy continues to deepen, zebrafish will remain essential for exploring the spatiotemporal organization and integration of these fundamental processes, as well as the identification of efficacious small molecule modifiers of hematopoietic activity. In this review, we discuss the biology of the zebrafish hematopoietic system, including similarities and differences from mammals, and highlight important tools currently utilized in zebrafish embryos and adults to enhance our understanding of vertebrate hematology, with emphasis on findings that have impacted our understanding of the onset or treatment of human hematologic disorders and disease. Copyright © 2014 ISEH - International Society for Experimental Hematology. Published by Elsevier Inc. All rights reserved.

Oceans of Opportunity: Exploring Vertebrate Hematopoiesis in Zebrafish

PubMed Central

Carroll, Kelli J.; North, Trista E.

2015-01-01

Exploitation of the zebrafish model in hematology research has surged in recent years, becoming one of the most useful and tractable systems for understanding regulation of hematopoietic development, homeostasis, and malignancy. Despite the evolutionary distance between zebrafish and humans, remarkable genetic and phenotypic conservation in the hematopoietic system has enabled significant advancements in our understanding of blood stem and progenitor cell (HSPC) biology. The strengths of zebrafish in hematology research lie in the ability to perform real-time in vivo observations of hematopoietic stem, progenitor and effector cell emergence, expansion and function, as well as the ease with which novel genetic and chemical modifiers of specific hematopoietic processes or cell-types can be identified and characterized. Further, a myriad of transgenic lines have been developed including fluorescent reporter systems to aid in the visualization and quantification of specified cell types of interest and cell-lineage relationships, as well as effector lines that can be used to implement a wide range of experimental manipulations. As our understanding of the complex nature of HSPC biology during development, in response to infection or injury, or in the setting of hematological malignancy, continues to deepen, zebrafish will remain essential for exploring the spatio-temporal organization and integration of these fundamental processes, as well as the identification of efficacious small molecule modifiers of hematopoietic activity. In this review, we discuss the biology of the zebrafish hematopoietic system, including similarities and differences from mammals, and highlight important tools currently utilized in zebrafish embryos and adults to enhance our understanding of vertebrate hematology, with emphasis on findings that have impacted our understanding of the onset or treatment of human hematologic disorders and disease. PMID:24816275

Epigenetic Alterations in Epstein-Barr Virus-Associated Diseases.

PubMed

Niller, Hans Helmut; Banati, Ferenc; Salamon, Daniel; Minarovits, Janos

2016-01-01

Latent Epstein-Bar virus genomes undergo epigenetic modifications which are dependent on the respective tissue type and cellular phenotype. These define distinct viral epigenotypes corresponding with latent viral gene expression profiles. Viral Latent Membrane Proteins 1 and 2A can induce cellular DNA methyltransferases, thereby influencing the methylation status of the viral and cellular genomes. Therefore, not only the viral genomes carry epigenetic modifications, but also the cellular genomes adopt major epigenetic alterations upon EBV infection. The distinct cellular epigenotypes of EBV-infected cells differ from the epigenotypes of their normal counterparts. In Burkitt lymphoma (BL), nasopharyngeal carcinoma (NPC) and EBV-associated gastric carcinoma (EBVaGC) significant changes in the host cell methylome with a strong tendency towards CpG island hypermethylation are observed. Hypermethylated genes unique for EBVaGC suggest the existence of an EBV-specific "epigenetic signature". Contrary to the primary malignancies carrying latent EBV genomes, lymphoblastoid cells (LCs) established by EBV infection of peripheral B cells in vitro are characterized by a massive genome-wide demethylation and a significant decrease and redistribution of heterochromatic histone marks. Establishing complete epigenomes of the diverse EBV-associated malignancies shall clarify their similarities and differences and further clarify the contribution of EBV to the pathogenesis, especially for the epithelial malignancies, NPC and EBVaGC.

Perhexiline maleate enhances antitumor efficacy of cisplatin in neuroblastoma by inducing over-expression of NDM29 ncRNA

PubMed Central

Vella, Serena; Penna, Ilaria; Longo, Luca; Pioggia, Giulia; Garbati, Patrizia; Florio, Tullio; Rossi, Fabio; Pagano, Aldo

2015-01-01

High Risk Neuroblastoma (HR-NB) is a pediatric cancer characterized by high malignancy and remarkable cell heterogeneity within the tumour nodules. In a recent study, we demonstrated that in vitro and in vivo over-expression of the non-coding RNA NDM29 (neuroblastoma differentiation marker 29) induces NB cell differentiation, dramatically reducing their malignancy. Among gene expression changes, differentiated phenotype induced by NDM29 is characterized by decrease of the expression of ABC transporters responsible for anticancer drug resistance. Thus, the pharmacological induction of NDM29, in principle, might represent a possible novel strategy to increase cytotoxic drug responses. In this work, we identify a small molecule able to induce the expression of NDM29 in NB cells, conferring to malignant cells increased susceptibility to cisplatin cytotoxic effects. We demonstrate that the pharmacological induction of NDM29 expression in vivo enhances the antitumoral effects of chemotherapy specifically on tumour initiating/cancer stem cells sub-population, usually refractory to therapies and responsible for tumour relapse. In summary, we suggest a novel therapeutical approach possibly useful to treat very aggressive NB cases with poor prognosis. This novel pharmacological strategy aims to promote differentiation of “stem-like” cells to render them more susceptible to the killing action of cytotoxic anticancer drugs. PMID:26674674

Perhexiline maleate enhances antitumor efficacy of cisplatin in neuroblastoma by inducing over-expression of NDM29 ncRNA.

PubMed

Vella, Serena; Penna, Ilaria; Longo, Luca; Pioggia, Giulia; Garbati, Patrizia; Florio, Tullio; Rossi, Fabio; Pagano, Aldo

2015-12-17

High Risk Neuroblastoma (HR-NB) is a pediatric cancer characterized by high malignancy and remarkable cell heterogeneity within the tumour nodules. In a recent study, we demonstrated that in vitro and in vivo over-expression of the non-coding RNA NDM29 (neuroblastoma differentiation marker 29) induces NB cell differentiation, dramatically reducing their malignancy. Among gene expression changes, differentiated phenotype induced by NDM29 is characterized by decrease of the expression of ABC transporters responsible for anticancer drug resistance. Thus, the pharmacological induction of NDM29, in principle, might represent a possible novel strategy to increase cytotoxic drug responses. In this work, we identify a small molecule able to induce the expression of NDM29 in NB cells, conferring to malignant cells increased susceptibility to cisplatin cytotoxic effects. We demonstrate that the pharmacological induction of NDM29 expression in vivo enhances the antitumoral effects of chemotherapy specifically on tumour initiating/cancer stem cells sub-population, usually refractory to therapies and responsible for tumour relapse. In summary, we suggest a novel therapeutical approach possibly useful to treat very aggressive NB cases with poor prognosis. This novel pharmacological strategy aims to promote differentiation of "stem-like" cells to render them more susceptible to the killing action of cytotoxic anticancer drugs.

Antitumor immunity and cancer stem cells.

PubMed

Schatton, Tobias; Frank, Markus H

2009-09-01

Self-renewing cancer stem cells (CSC) capable of spawning more differentiated tumor cell progeny are required for tumorigenesis and neoplastic progression of leukemias and several solid cancers. The mechanisms by which CSC cause tumor initiation and growth are currently unknown. Recent findings that suggest a negative correlation between degrees of host immunocompetence and rates of cancer development raise the possibility that only a restricted minority of malignant cells, namely CSC, may possess the phenotypic and functional characteristics to evade host antitumor immunity. In human malignant melanoma, a highly immunogenic cancer, we recently identified malignant melanoma initiating cells (MMIC), a novel type of CSC, based on selective expression of the chemoresistance mediator ABCB5. Here we present evidence of a relative immune privilege of ABCB5(+) MMIC, suggesting refractoriness to current immunotherapeutic treatment strategies. We discuss our findings in the context of established immunomodulatory functions of physiologic stem cells and in relation to mechanisms responsible for the downregulation of immune responses against tumors. We propose that the MMIC subset might be responsible for melanoma immune evasion and that immunomodulation might represent one mechanism by which CSC advance tumorigenic growth and resistance to immunotherapy. Accordingly, the possibility of an MMIC-driven tumor escape from immune-mediated rejection has important implications for current melanoma immunotherapy.

Antitumor Immunity and Cancer Stem Cells

PubMed Central

Schatton, Tobias; Frank, Markus H.

2010-01-01

Self-renewing cancer stem cells (CSC) capable of spawning more differentiated tumor cell progeny are required for tumorigenesis and neoplastic progression of leukemias and several solid cancers. The mechanisms by which CSC cause tumor initiation and growth are currently unknown. Recent findings that suggest a negative correlation between degrees of host immunocompetence and rates of cancer development raise the possibility that only a restricted minority of malignant cells, namely CSC, may possess the phenotypic and functional characteristics to evade host antitumor immunity. In human malignant melanoma, a highly immunogenic cancer, we recently identified malignant melanoma initiating cells (MMIC), a novel type of CSC, based on selective expression of the chemoresistance mediator ABCB5. Here we present evidence of a relative immune privilege of ABCB5+ MMIC, suggesting refractoriness to current immunotherapeutic treatment strategies. We discuss our findings in the context of established immunomodulatory functions of physiologic stem cells and in relation to mechanisms responsible for the downregulation of immune responses against tumors. We propose that the MMIC subset might be responsible for melanoma immune evasion and that immunomodulation might represent one mechanism by which CSC advance tumorigenic growth and resistance to immunotherapy. Accordingly, the possibility of an MMIC-driven tumor escape from immune-mediated rejection has important implications for current melanoma immunotherapy. PMID:19796244

Xenopatients 2.0

PubMed Central

Menendez, Javier A; Alarcón, Tomás; Corominas-Faja, Bruna; Cuyàs, Elisabet; López-Bonet, Eugeni; Martin, Ángel G; Vellon, Luciano

2014-01-01

In the science-fiction thriller film Minority Report, a specialized police department called “PreCrime” apprehends criminals identified in advance based on foreknowledge provided by 3 genetically altered humans called “PreCogs”. We propose that Yamanaka stem cell technology can be similarly used to (epi)genetically reprogram tumor cells obtained directly from cancer patients and create self-evolving personalized translational platforms to foresee the evolutionary trajectory of individual tumors. This strategy yields a large stem cell population and captures the cancer genome of an affected individual, i.e., the PreCog-induced pluripotent stem (iPS) cancer cells, which are immediately available for experimental manipulation, including pharmacological screening for personalized “stemotoxic” cancer drugs. The PreCog-iPS cancer cells will re-differentiate upon orthotopic injection into the corresponding target tissues of immunodeficient mice (i.e., the PreCrime-iPS mouse avatars), and this in vivo model will run through specific cancer stages to directly explore their biological properties for drug screening, diagnosis, and personalized treatment in individual patients. The PreCog/PreCrime-iPS approach can perform sets of comparisons to directly observe changes in the cancer-iPS cell line vs. a normal iPS cell line derived from the same human genetic background. Genome editing of PreCog-iPS cells could create translational platforms to directly investigate the link between genomic expression changes and cellular malignization that is largely free from genetic and epigenetic noise and provide proof-of-principle evidence for cutting-edge “chromosome therapies” aimed against cancer aneuploidy. We might infer the epigenetic marks that correct the tumorigenic nature of the reprogrammed cancer cell population and normalize the malignant phenotype in vivo. Genetically engineered models of conditionally reprogrammable mice to transiently express the Yamanaka stemness factors following the activation of phenotypic copies of specific cancer diseases might crucially evaluate a “reprogramming cure” for cancer. A new era of xenopatients 2.0 generated via nuclear reprogramming of the epigenetic landscapes of patient-derived cancer genomes might revolutionize the current personalized translational platforms in cancer research. PMID:24406535

Xenopatients 2.0: reprogramming the epigenetic landscapes of patient-derived cancer genomes.

PubMed

Menendez, Javier A; Alarcón, Tomás; Corominas-Faja, Bruna; Cuyàs, Elisabet; López-Bonet, Eugeni; Martin, Angel G; Vellon, Luciano

2014-01-01

In the science-fiction thriller film Minority Report, a specialized police department called "PreCrime" apprehends criminals identified in advance based on foreknowledge provided by 3 genetically altered humans called "PreCogs". We propose that Yamanaka stem cell technology can be similarly used to (epi)genetically reprogram tumor cells obtained directly from cancer patients and create self-evolving personalized translational platforms to foresee the evolutionary trajectory of individual tumors. This strategy yields a large stem cell population and captures the cancer genome of an affected individual, i.e., the PreCog-induced pluripotent stem (iPS) cancer cells, which are immediately available for experimental manipulation, including pharmacological screening for personalized "stemotoxic" cancer drugs. The PreCog-iPS cancer cells will re-differentiate upon orthotopic injection into the corresponding target tissues of immunodeficient mice (i.e., the PreCrime-iPS mouse avatars), and this in vivo model will run through specific cancer stages to directly explore their biological properties for drug screening, diagnosis, and personalized treatment in individual patients. The PreCog/PreCrime-iPS approach can perform sets of comparisons to directly observe changes in the cancer-iPS cell line vs. a normal iPS cell line derived from the same human genetic background. Genome editing of PreCog-iPS cells could create translational platforms to directly investigate the link between genomic expression changes and cellular malignization that is largely free from genetic and epigenetic noise and provide proof-of-principle evidence for cutting-edge "chromosome therapies" aimed against cancer aneuploidy. We might infer the epigenetic marks that correct the tumorigenic nature of the reprogrammed cancer cell population and normalize the malignant phenotype in vivo. Genetically engineered models of conditionally reprogrammable mice to transiently express the Yamanaka stemness factors following the activation of phenotypic copies of specific cancer diseases might crucially evaluate a "reprogramming cure" for cancer. A new era of xenopatients 2.0 generated via nuclear reprogramming of the epigenetic landscapes of patient-derived cancer genomes might revolutionize the current personalized translational platforms in cancer research.

Genetic heterogeneity in families with non-epidermolytic palmar plantar keratosis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Spurr, N.K.; Kelshell, D.P.; Stevens, H.

1994-09-01

Following reports of linkage close to the keratin gene cluster in families with tylosis and the detection of mutations in the keratin 9 gene cosegregating in families with epidermolytic palmar plantar keratoderma (EPPK, and EPPK associated with breast and ovarian cancer), we have identified families with three phenotypically distinct forms of non-epidermolytic keratosis with either punctate, diffuse or focal keratoderma, one with diffuse lesions and one with punctate and malignancies. Initially we typed these families with 17q markers close to the keratin gene cluster; this included a dinucleotide repeat marker within the keratin 9 gene. Two point linkage analysis ofmore » the focal keratoderma family showed a positive lod score of 3.2 at a theta of 0 from the marker D17S855. The lod score for the diffuse family was -6.0 at a theta of 0.05 from the marker D17S776. The second focal keratoderma family showed a haplotype consistent with linkage to 17q close to the keratin gene cluster. A second keratin gene cluster has been mapped in humans on 12q, and we decided to test the unlinked diffuse and punctate keratoderma families with markers in that region. We used the markers: D12S87-D12S85-D12S368-D12S96-D12S90. Linkage analysis of the diffuse family gave a lod score of 3.1 at a theta of 0 from the marker D12S368. Currently studies are underway to look for mutations in specific keratin genes in the clusters on 17q and 12q that segregate with the observed phenotypes. The punctate keratoderma family gave lod scores of -3.9 at a theta of 0.55 with D17S855 and -6.0 at a theta of 0.05 with D12S90/D12S83. This would lead us to the conclusion that a separate susceptibility locus must exist for the punctate family associated with malignancy. Investigations of candidate regions are in progress.« less

miR-489 inhibits proliferation, cell cycle progression and induces apoptosis of glioma cells via targeting SPIN1-mediated PI3K/AKT pathway.

PubMed

Li, Yan; Ma, Xiaolin; Wang, Yanpeng; Li, Guohua

2017-09-01

microRNA-489 (miR-489), a newly identified tumor-related miRNA, functions as an oncogene or tumor suppressor via regulating growth and metastasis of human cancers. But, the clinical significance, biological function and underlying mechanisms of miR-489 in glioma remain rarely known. Here, we showed that the levels of miR-489 in glioma tissues were notably underexpressed compared to corresponding non-tumor tissues. In accordance, the relative levels of miR-489 were decreased in glioma cell lines compared with NHA cells. Kaplan-Meier plots indicated that miR-489 low expressing glioma patients showed a prominent shorter overall survival. In addition, miR-489 overexpression prohibited proliferation and cell cycle progression, and promoted apoptosis in U251 cells. While, miR-489 knockdown showed opposite effects on these cellular processes of U87 cells. In vivo experiments demonstrated that miR-489 restoration reduced the tumor volume and weight of subcutaneous glioma xenografts in nude mice. Notably, Spindlin 1 (SPIN1) was inversely and directly regulated by miR-489 in glioma cells. A negative correlation between the expression of miR-489 and SPIN1 mRNA was confirmed in glioma tissues. Interestingly, miR-489 inversely modulated activation of PI3K/AKT pathway and expression of downstream targets including p-mTOR, Cyclin D1 and BCL-XL. SPIN1 re-expression abolished the effects of miR-489 on U251 cells with enhanced activation of PI3K/AKT pathway and malignant phenotype. Meanwhile, AKT inhibitor MK-2206 blocked activation of PI3K/AKT pathway and resulted in reduced proliferation, cell cycle arrest and increased apoptosis in miR-489 down-regulating U87 cells. Altogether, our data support that miR-489 loss facilitates malignant phenotype of glioma cells probably via SPIN1-mediated PI3K/AKT pathway. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

The Cancer Genome Atlas Clinical Explorer: a web and mobile interface for identifying clinical-genomic driver associations.

PubMed

Lee, HoJoon; Palm, Jennifer; Grimes, Susan M; Ji, Hanlee P

2015-10-27

The Cancer Genome Atlas (TCGA) project has generated genomic data sets covering over 20 malignancies. These data provide valuable insights into the underlying genetic and genomic basis of cancer. However, exploring the relationship among TCGA genomic results and clinical phenotype remains a challenge, particularly for individuals lacking formal bioinformatics training. Overcoming this hurdle is an important step toward the wider clinical translation of cancer genomic/proteomic data and implementation of precision cancer medicine. Several websites such as the cBio portal or University of California Santa Cruz genome browser make TCGA data accessible but lack interactive features for querying clinically relevant phenotypic associations with cancer drivers. To enable exploration of the clinical-genomic driver associations from TCGA data, we developed the Cancer Genome Atlas Clinical Explorer. The Cancer Genome Atlas Clinical Explorer interface provides a straightforward platform to query TCGA data using one of the following methods: (1) searching for clinically relevant genes, micro RNAs, and proteins by name, cancer types, or clinical parameters; (2) searching for genomic/proteomic profile changes by clinical parameters in a cancer type; or (3) testing two-hit hypotheses. SQL queries run in the background and results are displayed on our portal in an easy-to-navigate interface according to user's input. To derive these associations, we relied on elastic-net estimates of optimal multiple linear regularized regression and clinical parameters in the space of multiple genomic/proteomic features provided by TCGA data. Moreover, we identified and ranked gene/micro RNA/protein predictors of each clinical parameter for each cancer. The robustness of the results was estimated by bootstrapping. Overall, we identify associations of potential clinical relevance among genes/micro RNAs/proteins using our statistical analysis from 25 cancer types and 18 clinical parameters that include clinical stage or smoking history. The Cancer Genome Atlas Clinical Explorer enables the cancer research community and others to explore clinically relevant associations inferred from TCGA data. With its accessible web and mobile interface, users can examine queries and test hypothesis regarding genomic/proteomic alterations across a broad spectrum of malignancies.

Malignant Mesothelioma Treatment (PDQ®)—Patient Version

Cancer.gov

Treatment for malignant mesothelioma may include surgery, radiation therapy, and chemotherapy, as well as targeted therapy. The type of treatment you receive depends on where the cancer is found and at what stage. Find out about treatment options for malignant mesothelioma.

Irregular echogenic foci representing coagulation necrosis: a useful but perhaps under-recognized EUS echo feature of malignant lymph node invasion.

PubMed

Bhutani, Manoop S; Saftoiu, Adrian; Chaya, Charles; Gupta, Parantap; Markowitz, Avi B; Willis, Maurice; Kessel, Ivan; Sharma, Gulshan; Zwischenberger, Joseph B

2009-06-01

Coagulation necrosis has been described in malignant lymph nodes. Our aim was to determine if coagulation necrosis in mediastinal lymph nodes imaged by EUS could be used as a useful echo feature for predicting malignant invasion. Patients with known or suspected lung cancer who had undergone mediastinal lymph node staging by EUS. Tertiary Care university hospital. An expert endosonographer blinded to the final diagnosis, reviewed the archived digital EUS images of lymph nodes prior to being sampled by FNA. LNs positive for malignancy by FNA were included. The benign group included lymph node images with either negative EUS-FNA or lymph nodes imaged by EUS but not subjected to EUS-FNA, with surgical correlation of their benign nature. 24 patients were included. 8 patients were found to have coagulation necrosis. 7/8 patients had positive result for malignancy by EUS-FNA. One patient determined to have coagulation necrosis had a non-malignant diagnosis indicating a false positive result. 16 patients had no coagulation necrosis. In 6 patients with no coagulation necrosis, the final diagnosis was malignant and in the remaining 10 cases, the final diagnosis was benign. For coagulation necrosis as an echo feature for malignant invasion, sensitivity was 54%, specificity was 91%, positive predictive value was 88%, negative predictive value was 63% and accuracy was 71%. Coagulation necrosis is a useful echo feature for mediastinal lymph node staging by EUS.

The Role of the EGF Receptor and Vitamins A and D in Development and Progression of Breast Cancer to More Malignant Hormones Independent Phenotypes

DTIC Science & Technology

1999-09-01

parathyroid hormone (46) and rat bone sialoprotein (47) genes are perhaps the most frequently cited examples of negative transcriptional regulation...specific to BT549 cells. A similar mechanism has been postulated to explain the vitamin D mediated suppression of the rat bone sialoprotein gene through a...Yamauchi M, Freedman LP, Sodek J 1996 Identification of a vitamin D3-response element that overlaps a unique inverted TATA box in the rat bone sialoprotein

Population Based Assessment of MHC Class I Antigens Down Regulation as Markers of Increased Risk for Development and Progression of Breast Cancer from Benign Breast Lesions

DTIC Science & Technology

2007-01-01

cancer. Int J Cancer. 1992;51:379-385. 10. Cabrera T, Collado A, Fernandez MA, et al. 1998. High frequency of altered HLA class I phenotypes in invasive...head and neck squamous cell carcinomas. Human Immunology. 1999;60:697-706. 12. Cabrera T, Salinero J, Fernandez MA, Garrido F. High frequency of...Solano, R., Romero, J., Alonso , C., Pena J. MHC class I antigen expression is inversely related with tumor malignancy and ras oncogene products

Control of Metastatic Progression by microRNA Regulatory Networks

PubMed Central

Pencheva, Nora; Tavazoie, Sohail F.

2015-01-01

Aberrant microRNA (miRNA) expression is a defining feature of human malignancy. Specific miRNAs have been identified as promoters or suppressors of metastatic progression. These miRNAs control metastasis through divergent or convergent regulation of metastatic gene pathways. Some miRNA regulatory networks govern cell-autonomous cancer phenotypes, while others modulate the cell-extrinsic composition of the metastatic microenvironment. The use of small RNAs as probes into the molecular and cellular underpinnings of metastasis holds promise for the identification of candidate genes for potential therapeutic intervention. PMID:23728460

Revving up Natural Killer Cells and Cytokine-Induced Killer Cells Against Hematological Malignancies.

PubMed

Pittari, Gianfranco; Filippini, Perla; Gentilcore, Giusy; Grivel, Jean-Charles; Rutella, Sergio

2015-01-01

Natural killer (NK) cells belong to innate immunity and exhibit cytolytic activity against infectious pathogens and tumor cells. NK-cell function is finely tuned by receptors that transduce inhibitory or activating signals, such as killer immunoglobulin-like receptors, NK Group 2 member D (NKG2D), NKG2A/CD94, NKp46, and others, and recognize both foreign and self-antigens expressed by NK-susceptible targets. Recent insights into NK-cell developmental intermediates have translated into a more accurate definition of culture conditions for the in vitro generation and propagation of human NK cells. In this respect, interleukin (IL)-15 and IL-21 are instrumental in driving NK-cell differentiation and maturation, and hold great promise for the design of optimal NK-cell culture protocols. Cytokine-induced killer (CIK) cells possess phenotypic and functional hallmarks of both T cells and NK cells. Similar to T cells, they express CD3 and are expandable in culture, while not requiring functional priming for in vivo activity, like NK cells. CIK cells may offer some advantages over other cell therapy products, including ease of in vitro propagation and no need for exogenous administration of IL-2 for in vivo priming. NK cells and CIK cells can be expanded using a variety of clinical-grade approaches, before their infusion into patients with cancer. Herein, we discuss GMP-compliant strategies to isolate and expand human NK and CIK cells for immunotherapy purposes, focusing on clinical trials of adoptive transfer to patients with hematological malignancies.

Hypoxia modulates CCR7 expression in head and neck cancers.

PubMed

Basheer, Haneen A; Pakanavicius, Edvinas; Cooper, Patricia A; Shnyder, Steven D; Martin, Lisette; Hunter, Keith D; Vinader, Victoria; Afarinkia, Kamyar

2018-05-01

The chemokine receptor CCR7 is expressed on lymphocytes and dendritic cells and is responsible for trafficking of these cells in and out of secondary lymphoid organs. It has recently been shown that CCR7 expression is elevated in a number of cancers, including head and neck cancers, and that its expression correlates to lymph node (LN) metastasis. However, little is known about the factors that can induce CCR7 expression in head and neck cancers. We compared the protein expression and functional responses of CCR7 under normoxia and hypoxia in head and neck cancer cell lines OSC-19, FaDu, SCC-4, A-253 and Detroit-562 cultured as monolayers, spheroids, and grown in vivo as xenografts in balb/c mice. In addition, we analysed the correlation between hypoxia marker HIF-1α and CCR7 expression in a tissue microarray comprising 80 clinical samples with various stages and grades of malignant tumour and normal tissue. Under hypoxia, the expression of CCR7 is elevated in both in vitro and in vivo models. Furthermore, in malignant tissue, a correlation is observed between hypoxia marker HIF-1α and CCR7 across all clinical stages. This correlation is also strong in early histological grade of tumours. Hypoxia plays a role in the regulation of the expression of CCR7 and it may contribute to the development of a metastatic phenotype in head and neck cancers through this axis. Copyright © 2018. Published by Elsevier Ltd.

Acquired RhD mosaicism identifies fibrotic transformation of thrombopoietin receptor-mutated essential thrombocythemia.

PubMed

Montemayor-Garcia, Celina; Coward, Rebecca; Albitar, Maher; Udani, Rupa; Jain, Prachi; Koklanaris, Eleftheria; Battiwalla, Minoo; Keel, Siobán; Klein, Harvey G; Barrett, A John; Ito, Sawa

2017-09-01

Acquired copy-neutral loss of heterozygosity has been described in myeloid malignant progression with an otherwise normal karyotype. A 65-year-old woman with MPL-mutated essential thrombocythemia and progression to myelofibrosis was noted upon routine pretransplant testing to have mixed field reactivity with anti-D and an historic discrepancy in RhD type. The patient had never received transfusions or transplantation. Gel immunoagglutination revealed group A red blood cells and a mixed-field reaction for the D phenotype, with a predominant D-negative population and a small subset of circulating red blood cells carrying the D antigen. Subsequent genomic microarray single nucleotide polymorphism profiling revealed copy-neutral loss of heterozygosity of chromosome 1 p36.33-p34.2, a known molecular mechanism underlying fibrotic progression of MPL-mutated essential thrombocythemia. The chromosomal region affected by this copy-neutral loss of heterozygosity encompassed the RHD, RHCE, and MPL genes. We propose a model of chronological molecular events that is supported by RHD zygosity assays in peripheral lymphoid and myeloid-derived cells. Copy-neutral loss of heterozygosity events that lead to clonal selection and myeloid malignant progression may also affect the expression of adjacent unrelated genes, including those encoding for blood group antigens. Detection of mixed-field reactions and investigation of discrepant blood typing results are important for proper transfusion support of these patients and can provide useful surrogate markers of myeloproliferative disease progression. © 2017 AABB.

Overgrowth syndromes with vascular anomalies.

PubMed

Blei, Francine

2015-04-01

Overgrowth syndromes with vascular anomalies encompass entities with a vascular anomaly as the predominant feature vs those syndromes with predominant somatic overgrowth and a vascular anomaly as a more minor component. The focus of this article is to categorize these syndromes phenotypically, including updated clinical criteria, radiologic features, evaluation, management issues, pathophysiology, and genetic information. A literature review was conducted in PubMed using key words "overgrowth syndromes and vascular anomalies" as well as specific literature reviews for each entity and supportive genetic information (e.g., somatic mosaicism). Additional searches in OMIM and Gene Reviews were conducted for each syndrome. Disease entities were categorized by predominant clinical features, known genetic information, and putative affected signaling pathway. Overgrowth syndromes with vascular anomalies are a heterogeneous group of disorders, often with variable clinical expression, due to germline or somatic mutations. Overgrowth can be focal (e.g., macrocephaly) or generalized, often asymmetrically (and/or mosaically) distributed. All germ layers may be affected, and the abnormalities may be progressive. Patients with overgrowth syndromes may be at an increased risk for malignancies. Practitioners should be attentive to patients having syndromes with overgrowth and vascular defects. These patients require proactive evaluation, referral to appropriate specialists, and in some cases, early monitoring for potential malignancies. Progress in identifying vascular anomaly-related overgrowth syndromes and their genetic etiology has been robust in the past decade and is contributing to genetically based prenatal diagnosis and new therapies targeting the putative causative genetic mutations. Copyright © 2015 Mosby, Inc. All rights reserved.

Mapping the cellular and molecular heterogeneity of normal and malignant breast tissues and cultured cell lines

PubMed Central

2010-01-01

Introduction Normal and neoplastic breast tissues are comprised of heterogeneous populations of epithelial cells exhibiting various degrees of maturation and differentiation. While cultured cell lines have been derived from both normal and malignant tissues, it remains unclear to what extent they retain similar levels of differentiation and heterogeneity as that found within breast tissues. Methods We used 12 reduction mammoplasty tissues, 15 primary breast cancer tissues, and 20 human breast epithelial cell lines (16 cancer lines, 4 normal lines) to perform flow cytometry for CD44, CD24, epithelial cell adhesion molecule (EpCAM), and CD49f expression, as well as immunohistochemistry, and in vivo tumor xenograft formation studies to extensively analyze the molecular and cellular characteristics of breast epithelial cell lineages. Results Human breast tissues contain four distinguishable epithelial differentiation states (two luminal phenotypes and two basal phenotypes) that differ on the basis of CD24, EpCAM and CD49f expression. Primary human breast cancer tissues also contain these four cellular states, but in altered proportions compared to normal tissues. In contrast, cultured cancer cell lines are enriched for rare basal and mesenchymal epithelial phenotypes, which are normally present in small numbers within human tissues. Similarly, cultured normal human mammary epithelial cell lines are enriched for rare basal and mesenchymal phenotypes that represent a minor fraction of cells within reduction mammoplasty tissues. Furthermore, although normal human mammary epithelial cell lines exhibit features of bi-potent progenitor cells they are unable to differentiate into mature luminal breast epithelial cells under standard culture conditions. Conclusions As a group breast cancer cell lines represent the heterogeneity of human breast tumors, but individually they exhibit increased lineage-restricted profiles that fall short of truly representing the intratumoral heterogeneity of individual breast tumors. Additionally, normal human mammary epithelial cell lines fail to retain much of the cellular diversity found in human breast tissues and are enriched for differentiation states that are a minority in breast tissues, although they do exhibit features of bi-potent basal progenitor cells. These findings suggest that collections of cell lines representing multiple cell types can be used to model the cellular heterogeneity of tissues. PMID:20964822

Complementary roles of tumour specific PET tracer ¹⁸F-FAMT to ¹⁸F-FDG PET/CT for the assessment of bone metastasis.

PubMed

Morita, Motoho; Higuchi, Tetsuya; Achmad, Arifudin; Tokue, Azusa; Arisaka, Yukiko; Tsushima, Yoshito

2013-10-01

The usefulness of (18)F-FDG PET/CT for bone metastasis evaluation has already been established. The amino acid PET tracer [(18)F]-3-fluoro-alpha-methyl tyrosine ((18)F-FAMT) has been reported to be highly specific for malignancy. We evaluated the additional value of (18)F-FAMT PET/CT to complement (18)F-FDG PET/CT in the evaluation of bone metastasis. This retrospective study included 21 patients with bone metastases of various cancers who had undergone both (18)F-FDG and (18)F-FAMT PET/CT within 1 month of each other. (18)F-FDG-avid bone lesions suspicious for malignancy were carefully selected based on the cut-off value for malignancy, and the SUVmax of the (18)F-FAMT in the corresponding lesions were evaluated. A total of 72 (18)F-FDG-positive bone lesions suspected to be metastases in the 21 patients were used as the reference standard. (18)F-FAMT uptake was found in 87.5 % of the lesions. In the lesions of lung cancer origin, the uptake of the two tracers showed a good correlation (40 lesions, r = 0.68, P < 0.01). Bone metastatic lesions of oesophageal cancer showed the highest average of (18)F-FAMT uptake. Bone metastatic lesions of squamous cell carcinoma showed higher (18)F-FAMT uptake than those of adenocarcinoma. No significant difference in (18)F-FAMT uptake was seen between osteoblastic and osteolytic bone metastatic lesions. The usefulness of (18)F-FAMT PET/CT for bone metastasis detection regardless of the lesion phenotype was demonstrated. The fact that (18)F-FAMT uptake was confirmed by (18)F-FDG uptake suggests that (18)F-FAMT PET/CT has the potential to complement (18)F-FDG PET/CT for the detection of bone metastases.

MicroRNA profiling in intraocular medulloepitheliomas.

PubMed

Edward, Deepak P; Alkatan, Hind; Rafiq, Qundeel; Eberhart, Charles; Al Mesfer, Saleh; Ghazi, Nicola; Al Safieh, Leen; Kondkar, Altaf A; Abu Amero, Khaled K

2015-01-01

To study the differential expression of microRNA (miRNA) profiles between intraocular medulloepithelioma (ME) and normal control tissue (CT). Total RNA was extracted from formalin fixed paraffin embedded (FFPE) intraocular ME (n=7) and from age matched ciliary body controls (n=8). The clinical history and phenotype was recorded. MiRNA profiles were determined using the Affymetrix GeneChip miRNA Arrays analyzed using expression console 1.3 software. Validation of significantly dysregulated miRNA was confirmed by quantitative real-time PCR. The web-based DNA Intelligent Analysis (DIANA)-miRPath v2.0 was used to perform enrichment analysis of differentially expressed (DE) miRNA gene targets in Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway. The pathologic evaluation revealed one benign (benign non-teratoid, n=1) and six malignant tumors (malignant teratoid, n=2; malignant non-teratoid, n = 4). A total of 88 miRNAs were upregulated and 43 miRNAs were downregulated significantly (P<0.05) in the tumor specimens. Many of these significantly dysregulated miRNAs were known to play various roles in carcinogenesis and tumor behavior. RT-PCR validated three significantly upregulated miRNAs and three significantly downregulated miRNAs namely miR-217, miR-216a, miR-216b, miR-146a, miR-509-3p and miR-211. Many DE miRNAs that were significant in ME tumors showed dysregulation in retinoblastoma, glioblastoma, and precursor, normal and reactive human cartilage. Enriched pathway analysis suggested a significant association of upregulated miRNAs with 15 pathways involved in prion disease and several types of cancer. The pathways involving significantly downregulated miRNAs included the toll-like receptor (TLR) (p<4.36E-16) and Nuclear Factor kappa B (NF-κB) signaling pathways (p<9.00E-06). We report significantly dysregulated miRNAs in intraocular ME tumors, which exhibited abnormal profiles in other cancers as well such as retinoblastoma and glioblastoma. Pathway analysis of all dysregulated miRNAs shared commonalities with other cancer pathways.

Arsenic transformation predisposes human skin keratinocytes to UV-induced DNA damage yet enhances their survival apparently by diminishing oxidant response

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sun Yang; Kojima, Chikara; Chignell, Colin

2011-09-15

Inorganic arsenic and UV, both human skin carcinogens, may act together as skin co-carcinogens. We find human skin keratinocytes (HaCaT cells) are malignantly transformed by low-level arsenite (100 nM, 30 weeks; termed As-TM cells) and with transformation concurrently undergo full adaptation to arsenic toxicity involving reduced apoptosis and oxidative stress response to high arsenite concentrations. Oxidative DNA damage (ODD) is a possible mechanism in arsenic carcinogenesis and a hallmark of UV-induced skin cancer. In the current work, inorganic arsenite exposure (100 nM) did not induce ODD during the 30 weeks required for malignant transformation. Although acute UV-treatment (UVA, 25 J/cm{supmore » 2}) increased ODD in passage-matched control cells, once transformed by arsenic to As-TM cells, acute UV actually further increased ODD (> 50%). Despite enhanced ODD, As-TM cells were resistant to UV-induced apoptosis. The response of apoptotic factors and oxidative stress genes was strongly mitigated in As-TM cells after UV exposure including increased Bcl2/Bax ratio and reduced Caspase-3, Nrf2, and Keap1 expression. Several Nrf2-related genes (HO-1, GCLs, SOD) showed diminished responses in As-TM cells after UV exposure consistent with reduced oxidant stress response. UV-exposed As-TM cells showed increased expression of cyclin D1 (proliferation gene) and decreased p16 (tumor suppressor). UV exposure enhanced the malignant phenotype of As-TM cells. Thus, the co-carcinogenicity between UV and arsenic in skin cancer might involve adaptation to chronic arsenic exposure generally mitigating the oxidative stress response, allowing apoptotic by-pass after UV and enhanced cell survival even in the face of increased UV-induced oxidative stress and increased ODD. - Highlights: > Arsenic transformation adapted to UV-induced apoptosis. > Arsenic transformation diminished oxidant response. > Arsenic transformation enhanced UV-induced DNA damage.« less

Cryopreservation has no effect on function of natural killer cells differentiated in vitro from umbilical cord blood CD34(+) cells.

PubMed

Domogala, Anna; Madrigal, J Alejandro; Saudemont, Aurore

2016-06-01

Natural killer (NK) cells offer the potential for a powerful cellular immunotherapy because they can target malignant cells without being direct effectors of graft-versus-host disease. We have previously shown that high numbers of functional NK cells can be differentiated in vitro from umbilical cord blood (CB) CD34(+) cells. To develop a readily available, off-the-shelf cellular product, it is essential that NK cells differentiated in vitro can be frozen and thawed while maintaining the same phenotype and functions. We evaluated the phenotype and function of fresh and frozen NK cells differentiated in vitro. We also assessed whether the concentration of NK cells at the time of freezing had an impact on cell viability. We found that cell concentration of NK cells at the time of freezing did not have an impact on their viability and on cell recovery post-thaw. Moreover, freezing of differentiated NK cells in vitro did not affect their phenotype, cytotoxicity and degranulation capacity toward K562 cells, cytokine production and proliferation. We are therefore able to generate large numbers of functional NK cells from CB CD34(+) cells that maintain the same phenotype and function post-cryopreservation, which will allow for multiple infusions of a highly cytotoxic NK cell product. Copyright © 2016 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

Risk Factors for De Novo Malignancies in Women After Kidney Transplantation: A Multicenter Transversal Study.

PubMed

Helmy, Samir; Marschalek, Julian; Bader, Yvonne; Koch, Marianne; Schmidt, Alice; Kanzler, Marina; Gyoeri, Georg; Polterauer, Stephan; Reinthaller, Alexander; Grimm, Christoph

2016-06-01

Transplantation results in a 5-time elevated risk for a variety of malignancies (Kaposi sarcoma, skin, liver, lung, gastrointestinal cancer). A patient's risk for malignancies could be of particular interest for the follow-up programs of patients and risk adaption after kidney transplantation. The aim of this study was to identify independent risk factors for de novo malignancies in women after renal transplantation. This is a multicenter transversal study, conducted at the Medical University of Vienna and Hospital Rudolfstiftung, Vienna, Austria. We included female kidney graft recipients who were transplanted between 1980 and 2012 and followed-up at our institutions (N = 280). Clinical data of patients were extracted from hospital charts and electronic patient files. Patients were interviewed using a standardized questionnaire regarding their medical history, history of transplantation, and malignant diseases. Detailed information about present and past immunosuppressive regimens, rejection episodes and therapies, renal graft function, and information about primary disease was obtained. Diagnostic work-up and/or surgical exploration was performed if any presence of malignancy was suspected during routine follow-up. Histological specimens were obtained from all patients. the presence of de novo malignancy after kidney transplantation. Two hundred sixty-two women were included for statistical analysis. Median (interquartile range) follow-up period after transplantation was 101.1 (27.3-190.7) months. Thirty-two patients (12.2%) developed a malignancy: dermatologic malignancies (5.7%), breast cancer (3.4%), cervical cancer (0.8%), lung cancer (0.4%), gastrointestinal malignancies (1.5%), vulvar cancer (0.4%), and unclassified malignancies (1.9%). Median (interquartile range) time to malignancy after transplantation was 185.9 (92.0-257.6) months. Cumulative cancer rates were 4.9% (1 year), 14.4% (3 years), 16.4% (5 years), and 21.8% (10 years). Second transplantations were identified as independent risk factor for development of malignancy after transplantation. Long-term risk of developing a malignancy after kidney transplantation is high, which might justify a follow-up of more than 10 years.

Mechanisms of resistance to imatinib in CML patients: a paradigm for the advantages and pitfalls of molecularly targeted therapy.

PubMed

Ritchie, E; Nichols, G

2006-12-01

One of the challenges of cancer therapeutics is to discover targets unique to the tumor cell population. Constitutively activated tyrosine kinases play a role in the malignant phenotype in a number of different cancers. While the kinases may be present in the normal cell, the cancer cell is often dependent upon the activation of the kinase for the maintenance of malignant growth. Inhibition of kinase activation may therefore selectively inhibit malignant proliferation. In the case of chronic myelogenous leukemia (CML), the activated tyrosine kinase (BCR-ABL) is due to a chromosomal translocation that defines this disease, and is necessary for malignant transformation. Imatinib mesylate (Gleevec, Novartis) is a small molecule tyrosine kinase inhibitor, developed through the chemical modification to be selected for a small number of tyrosine kinases present in human cells. This agent is also orally bioavailable and has been found to be effective in clinical trials. We have learned much through the clinical use of this agent. 1) Specific targeting of activated signal transduction pathways may be effective in inhibiting cancer cells. 2) Cancer cells may not only be inherently resistant to small molecule inhibitors, but may also develop resistance after exposure to the inhibitor. 3) Increased knowledge regarding critical signal transduction pathways, the structure of the molecules that are being targeted and the inhibitors themselves, will allow us to understand resistance as it develops and create new molecules to bypass resistance. We will discuss imatinib as an important example of the success and pitfalls of targeted therapeutics for cancer.

Carcinoma in gastric hyperplastic polyps: A phenotypic study

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zea-Iriarte, W.L.; Sekine, Ichiro; Itsuno, Minoru

1996-02-01

One-hundred twelve hyperplastic polyps were analyzed. The aim was to study their malignant transformation. Among them, four hyperplastic polyps harbored adenocarcinoma; two were from our own institution (1.8%). The majority were pedunculated and located in the antrum with an average of 14.5 mm in diameter. The four polyps bore well-differentiated adenocarcinoma. Dysplasia and intestinal metaplasia were detected in two and three polyps, respectively. The cancer and dysplastic foci shared the same type of neutral and acid mucosubstances. p53 oncoprotein was positive in three cancer foci and in the dysplastic areas, and nucleolar organizer region counts were higher in the cancermore » foci. In conclusion, hyperplastic polyps have malignant potential. Such possibility increases in polyps larger than 14.5 mm. In our cases, the carcinoma foci may have arisen from dysplastic areas. Once the neoplastic changes occur, the cancer cells proliferate and behave as other adenocarcinomas of the stomach. 40 refs., 7 figs., 5 tabs.« less

The morphologies of breast cancer cell lines in three-dimensionalassays correlate with their profiles of gene expression

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kenny, Paraic A.; Lee, Genee Y.; Myers, Connie A.

2007-01-31

3D cell cultures are rapidly becoming the method of choice for the physiologically relevant modeling of many aspects of non-malignant and malignant cell behavior ex vivo. Nevertheless, only a limited number of distinct cell types have been evaluated in this assay to date. Here we report the first large scale comparison of the transcriptional profiles and 3D cell culture phenotypes of a substantial panel of human breast cancer cell lines. Each cell line adopts a colony morphology of one of four main classes in 3D culture. These morphologies reflect, at least in part, the underlying gene expression profile and proteinmore » expression patterns of the cell lines, and distinct morphologies were also associated with tumor cell invasiveness and with cell lines originating from metastases. We further demonstrate that consistent differences in genes encoding signal transduction proteins emerge when even tumor cells are cultured in 3D microenvironments.« less

Pre-Cancerous Lesions in the Oral and Maxillofacial Region: A Literature Review with Special Focus on Etiopathogenesis

PubMed Central

Irani, Soussan

2016-01-01

Many types of cancers develop in the oral and maxillofacial region. Squamous cell carcinoma is the most common cancer and constitutes over 90 percent of these tumors. Malignant transformation is a genetic process, which later makes a phenotyping change at the cellular level. Some cancers such as oral squamous cell carcinomas (OSCCs) develop from pre-malignant lesions and conditions. Despite advances in the treatment of OSCC, the 5-year survival rate remains approximately 50% due to inability of early detection of OSCC and precursor lesions. Early detection of oral cancer, especially in the premalignant stage, can decrease mortality and morbidity significantly. This article reviews some clinical, histopathological features and etiopathogenesis of pre-cancerous lesions of the oral cavity and skin of face and lip vermilion. A relevant English literature search in Pubmed, Science Direct, and Google Scholar was performed from 1930 to 2015. Full text of 191 articles met the specific inclusion criteria for this review. PMID:28855922

[Malignant melanoma of the skin in Denmark--epidemiology, diagnosis and treatment].

PubMed

von der Maase, H; Osterlind, A; Drzewiecki, K T; Dahlstrøm, K K; Geertsen, P F; Gjedde, S B; Hastrup, N C; Holmberg, S B; Krag, C; Lock-Andersen, J

1992-07-06

About 700 new cases of malignant melanoma of the skin are registered annually in Denmark. The incidence is increasing rapidly and the number of new cases increases by more than 5% per annum. The most important phenotypical risk factors are the number of acquired pigmented naevi and exposure to sunlight is the most important risk factor in the external environment so that severe sunburn in children and intermittent intense exposure to sunlight increase the risk of melanoma. The thickness of the tumour at the time of the diagnosis is the most important prognostic factor. The prognosis deteriorates with increasing thickness. Treatment is primarily surgical. In cases of inoperable local melanoma and regional recurrences, irradiation may be administered. Chemotherapy and/or immunotherapy are of experimental character. In the light of the rapidly increasing incidence, it is important that knowledge of risk factors for development of the disease and the clinical characteristics of early melanoma is spread to not only the medical profession but also to the general public.

A regulatory circuit of miR-125b/miR-20b and Wnt signalling controls glioblastoma phenotypes through FZD6-modulated pathways

PubMed Central

Huang, Tianzhi; Alvarez, Angel A.; Pangeni, Rajendra P.; M. Horbinski, Craig; Lu, Songjian; Kim, Sung-Hak; James, C. David; J. Raizer, Jeffery; A. Kessler, John; Brenann, Cameron W.; Sulman, Erik P.; Finocchiaro, Gaetano; Tan, Ming; Nishikawa, Ryo; Lu, Xinghua; Nakano, Ichiro; Hu, Bo; Cheng, Shi-Yuan

2016-01-01

Molecularly defined subclassification is associated with phenotypic malignancy of glioblastoma (GBM). However, current understanding of the molecular basis of subclass conversion that is often involved in GBM recurrence remain rudimentary at best. Here we report that canonical Wnt signalling that is active in proneural (PN) but inactive in mesenchymal (MES) GBM, along with miR-125b and miR-20b that are expressed at high levels in PN compared with MES GBM, comprise a regulatory circuit involving TCF4-miR-125b/miR-20b-FZD6. FZD6 acts as a negative regulator of this circuit by activating CaMKII–TAK1–NLK signalling, which, in turn, attenuates Wnt pathway activity while promoting STAT3 and NF-κB signalling that are important regulators of the MES-associated phenotype. These findings are confirmed by targeting differentially enriched pathways in PN versus MES GBM that results in inhibition of distinct GBM subtypes. Correlative expressions of the components of this circuit are prognostic relevant for clinical GBM. Our findings provide insights for understanding GBM pathogenesis and for improving treatment of GBM. PMID:27698350

Discovering cancer vulnerabilities using high-throughput micro-RNA screening.

PubMed

Nikolic, Iva; Elsworth, Benjamin; Dodson, Eoin; Wu, Sunny Z; Gould, Cathryn M; Mestdagh, Pieter; Marshall, Glenn M; Horvath, Lisa G; Simpson, Kaylene J; Swarbrick, Alexander

2017-12-15

Micro-RNAs (miRNAs) are potent regulators of gene expression and cellular phenotype. Each miRNA has the potential to target hundreds of transcripts within the cell thus controlling fundamental cellular processes such as survival and proliferation. Here, we exploit this important feature of miRNA networks to discover vulnerabilities in cancer phenotype, and map miRNA-target relationships across different cancer types. More specifically, we report the results of a functional genomics screen of 1280 miRNA mimics and inhibitors in eight cancer cell lines, and its presentation in a sophisticated interactive data portal. This resource represents the most comprehensive survey of miRNA function in oncology, incorporating breast cancer, prostate cancer and neuroblastoma. A user-friendly web portal couples this experimental data with multiple tools for miRNA target prediction, pathway enrichment analysis and visualization. In addition, the database integrates publicly available gene expression and perturbation data enabling tailored and context-specific analysis of miRNA function in a particular disease. As a proof-of-principle, we use the database and its innovative features to uncover novel determinants of the neuroblastoma malignant phenotype. © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.

The function of cancer-shed gangliosides in macrophage phenotype: involvement with angiogenesis.

PubMed

Chung, Tae-Wook; Choi, Hee-Jung; Park, Mi-Ju; Choi, Hee-Jin; Lee, Syng-Ook; Kim, Keuk-Jun; Kim, Cheorl-Ho; Hong, Changwan; Kim, Kyun-Ha; Joo, Myungsoo; Ha, Ki-Tae

2017-01-17

Tumor-derived gangliosides in the tumor microenvironment are involved in the malignant progression of cancer. However, the molecular mechanisms underlying the effects of gangliosides shed from tumors on macrophage phenotype remain unknown. Here, we showed that ganglioside GM1 highly induced the activity and expression of arginase-1 (Arg-1), a major M2 macrophage marker, compared to various gangliosides in bone marrow-derived macrophages (BMDM), peritoneal macrophages and Raw264.7 macrophage cells. We found that GM1 bound to macrophage mannose receptor (MMR/CD206) and common gamma chain (γc). In addition, GM1 increased Arg-1 expression through CD206 and γc-mediated activation of Janus kinase 3 (JAK3) and signal transducer and activator of transcription- 6 (STAT-6). Interestingly, GM1-stimulated macrophages secreted monocyte chemoattractant protein-1 (MCP-1/CCL2) through a CD206/γc/STAT6-mediated signaling pathway and induced angiogenesis. Moreover, the angiogenic effect of GM1-treated macrophages was diminished by RS102895, an MCP-1 receptor (CCR2) antagonist. From these results we suggest that tumor-shed ganglioside is a secretory factor regulating the phenotype of macrophages and consequently enhancing angiogenesis.

Malignant transformation of actinic cheilitis: A systematic review of observational studies.

PubMed

Dancyger, Alex; Heard, Victoria; Huang, Baikai; Suley, Cameron; Tang, Dorothy; Ariyawardana, Anura

2018-06-04

The aim of the present systematic review was to determine the malignant transformation rate of actinic cheilitis (AC). A comprehensive literature search was conducted using Medline/PubMed, Cumulative Index of Nursing and Allied Health Literature, Scopus, OvidSP, and Google Scholar. The inclusion criteria comprised of observational human studies involving the malignant transformation of AC and publications in English. Studies included in this review were clinical follow-up, cohort, retrospective, or prospective investigations. The search yielded 1126 articles, and after exclusion, 34 full-text articles were eligible for full-text analysis. Only one article met the inclusion criteria. Based on the included article, it was determined that the malignant transformation rate of AC to squamous cell carcinoma (SCC) was 3.07%. Excluded articles focused on the clinicopathological characteristics and treatment efficacies of AC, and no malignant transformation rate was assessed. There is a need for more clinical studies on the malignant transformation of AC, as lip cancer is a public health concern. High-risk populations, including those living in tropical regions, have excessive exposure to UV radiation, and have older aged males, fair-skinned people, and smokers should be identified to prevent AC and its malignant change. Health practitioners should facilitate early intervention to prevent the progression of AC to SCC of the lip. © 2018 John Wiley & Sons Australia, Ltd.

Rationale and design of the LURIC study--a resource for functional genomics, pharmacogenomics and long-term prognosis of cardiovascular disease.

PubMed

Winkelmann, B R; März, W; Boehm, B O; Zotz, R; Hager, J; Hellstern, P; Senges, J

2001-02-01

Coronary artery disease (CAD), arterial hypertension and Type 2 diabetes mellitus are common polygenetic disorders which have a major impact on public health. Disease prevalence and progression to cardiovascular complications, such as myocardial infarction (MI), stroke or heart failure, are the product of environment and gene interaction. The LUdwigshafen RIsk and Cardiovascular Health (LURIC) study aims to provide a well-defined resource for the study of environmental and genetic risk factors, and their interactions, and the study of functional relationships between gene variation and biochemical phenotype (functional genomics) or response to medication (pharmacogenomics). Long-term follow-up on clinical events will allow us to study the prognostic importance of common genetic variants (polymorphisms) and plasma biomarkers. Cardiology unit in tertiary care medical centre in south-west Germany. Prospective cohort study of individuals with and without cardiovascular disease at baseline. LURIC is an ongoing prospective study of currently > 3300 individuals in whom the cardiovascular and metabolic phenotypes CAD, MI, dyslipidaemia, hypertension, metabolic syndrome and diabetes mellitus have been defined or ruled out using standardised methodologies in all study participants. Inclusion criteria for LURIC were: German ancestry (limitation of genetic heterogeneity) clinical stability (except for acute coronary syndromes [ACSs]) availability of a coronary angiogram (this inclusion criterium was waived for family members provided that they met all other inclusion and exclusion criteria) Exclusion criteria were: any acute illness other than ACSs any chronic disease where non-cardiac disease predominated a history of malignancy within the past five years. Exclusion criteria were pre-specified in order to minimise the impact of concomitant non-cardiovascular disease on intermediate biochemical phenotypes or on clinical prognosis (limitation of clinical heterogeneity). A standardised personal and family history questionnaire and an extensive laboratory work-up (including glucose tolerance testing in non-diabetics and objective assessment of smoking exposure by determination of cotinine plasma levels) was obtained from all individuals after informed consent. A total of 115 ml of fasting venous blood was sampled for the determination of a pre-specified wide range of intermediate biochemical phenotypes in serum, plasma or whole blood, for leukocyte DNA extraction and immortalisation of B-lymphocytes. Biochemical phenotypes measured included markers of endothelial dysfunction, inflammation, oxidative status, coagulation, lipid metabolism and flow cytometric surface receptor expression of lympho-, mono- and thrombocytes. In addition, multiple aliquots of blood samples were stored for future analyses. A total of 3500 LURIC baseline measurements were performed in 3316 individuals between July 1997 and January 2000. The baseline examination was repeated within a median of 35 days in 5% of study participants (n = 166, including a third examination in 18 after a median of 69 days) for pharmacogenomic assessment of lipid-lowering therapy and for quality control purposes. A five-year follow-up on major clinical events (death, any cardiovascular event including MI, stroke and revascularisation, malignancy and any hospitalisation) is ongoing. The clinical phenotypes prevalent at baseline in the cohort of 2309 men (70%) with a mean age of 62 +/- 11 years and 1007 women (30%), mean age 65 +/- 10 years, were angiographically-documented CAD in 2567 (79%), MI in 1368 (41%), dyslipidaemia in 2050 (62%) with hypercholesterolaemia > or = 240 mg/dl (27%), hypertriglyceridaemia > or = 150 mg/dl (44%) and HDL-cholesterol < or = 35 mg/dl (38%) in individuals not treated with lipid-lowering agents, systemic hypertension in 1921 (58%), metabolic syndrome in 1591 (48%), Type 2 diabetes in 1063 (32%) and obesity defined by body mass index > or = 30 kg/m2 in 770 (23%). Control patients in whom CAD had been ruled out angiographically were five years younger than those with CAD (59 +/- 12 and 64 +/- 10 years, respectively; p < 0.001), twice as often females (48% compared to 25% females in the CAD group, p < 0.001) and had significantly less cardiovascular risk factors than individuals with CAD. The prevalence of specific cardiovascular risk subsets in LURIC, such as the elderly (> or = 75 years), was 375 (11%), while 213 (6%) were young adults (< 45 years) and 904 (27%) were postmenopausal women (90% of all females). A low risk status (< or = 1 out of the four traditional risk factors: dyslipidaemia, smoking, hypertension and diabetes mellitus) was identified in 314 (9%) individuals of the entire cohort (5% in CAD and 26% in controls, p < 0.001) and 97 (3%) carried none of the four risk factors (1% in CAD and 9% in controls, p < 0.001). (ABSTRACT TRUNCATED)

Malignant gastric lymphoma with spontaneous perforation.

PubMed

Shimada, Satoko; Gen, Tokichi; Okamoto, Hiroyuki

2013-01-17

Malignant gastric lymphoma, accounting only for 1% of primary gastric carcinoma, is usually a diffuse large B-cell lymphoma. Toyota et al reported that 37% of gastric perforations involved malignancy, generally gastric carcinoma. Fukuda et al found that less than 5% of malignant gastric lymphomas perforate. While it is relatively well known that perforations often take place during chemotherapy, they are rare in patients not receiving chemotherapy. To our knowledge, spontaneous perforation is rare in gastric malignant lymphoma, having been reported in the Japanese literature only 26 times, including this case, in the last 25 years.

Malignant transformation of a residual cerebellopontine angle epidermoid cyst.

PubMed

Pikis, Stylianos; Margolin, Emil

2016-11-01

Malignant transformation is a rare but devastating complication following partial resection of an intracranial epidermoid cyst (EC). Time to malignant transformation is highly variable and optimal management is unclear. A literature search from 1965 to January 2016 identified manuscripts discussing clinical presentation, management, and outcome of malignant transformation of a remnant intracranial EC. One male patient diagnosed with malignant transformation of a remnant intracranial EC in our institution was also included in the study. There were 21 patients with malignant transformation of a remnant intracranial EC, including the current patient. Mean age was 51.4years (range 36 to 77) and there was a female predominance (12 women, 9 men, ratio 1.33:1). The mean time interval from partial resection of a benign intracranial EC to malignant transformation was 7.74years (range from 3months to 33years). Surgical resection of the tumor alone was the treatment of choice in 10 patients with one of them requiring a second operation and radiotherapy 2months following the first operation. Adjuvant treatment modalities were employed in 11 patients and included radiotherapy (n=4), stereotactic radiosurgery (SRS) (n=3), chemotherapy (n=1), chemotherapy combined with SRS (n=1) and with radiotherapy (n=1) and radiotherapy combined with SRS and followed by a second tumor resection (n=1). Follow-up period ranged from 1 day to 5years and 11/19 patients (57.8%) were reported dead on follow-up. Prospective studies are required to define the optimal management of malignant transformation of remnant intracranial EC. Copyright © 2016 Elsevier Ltd. All rights reserved.

dNTP pool levels modulate mutator phenotypes of error-prone DNA polymerase ε variants.

PubMed

Williams, Lindsey N; Marjavaara, Lisette; Knowels, Gary M; Schultz, Eric M; Fox, Edward J; Chabes, Andrei; Herr, Alan J

2015-05-12

Mutator phenotypes create genetic diversity that fuels tumor evolution. DNA polymerase (Pol) ε mediates leading strand DNA replication. Proofreading defects in this enzyme drive a number of human malignancies. Here, using budding yeast, we show that mutator variants of Pol ε depend on damage uninducible (Dun)1, an S-phase checkpoint kinase that maintains dNTP levels during a normal cell cycle and up-regulates dNTP synthesis upon checkpoint activation. Deletion of DUN1 (dun1Δ) suppresses the mutator phenotype of pol2-4 (encoding Pol ε proofreading deficiency) and is synthetically lethal with pol2-M644G (encoding altered Pol ε base selectivity). Although pol2-4 cells cycle normally, pol2-M644G cells progress slowly through S-phase. The pol2-M644G cells tolerate deletions of mediator of the replication checkpoint (MRC) 1 (mrc1Δ) and radiation sensitive (Rad) 9 (rad9Δ), which encode mediators of checkpoint responses to replication stress and DNA damage, respectively. The pol2-M644G mutator phenotype is partially suppressed by mrc1Δ but not rad9Δ; neither deletion suppresses the pol2-4 mutator phenotype. Thus, checkpoint activation augments the Dun1 effect on replication fidelity but is not required for it. Deletions of genes encoding key Dun1 targets that negatively regulate dNTP synthesis, suppress the dun1Δ pol2-M644G synthetic lethality and restore the mutator phenotype of pol2-4 in dun1Δ cells. DUN1 pol2-M644G cells have constitutively high dNTP levels, consistent with checkpoint activation. In contrast, pol2-4 and POL2 cells have similar dNTP levels, which decline in the absence of Dun1 and rise in the absence of the negative regulators of dNTP synthesis. Thus, dNTP pool levels correlate with Pol ε mutator severity, suggesting that treatments targeting dNTP pools could modulate mutator phenotypes for therapy.

ECT2 and RASAL2 mediate mesenchymal-amoeboid transition in human astrocytoma cells.

PubMed

Weeks, Adrienne; Okolowsky, Nadia; Golbourn, Brian; Ivanchuk, Stacey; Smith, Christian; Rutka, James T

2012-08-01

Malignant astrocytomas are highly invasive brain tumors. The Rho family of cytoskeletal GTPases are key regulators of astrocytoma migration and invasion; expression of the guanine nucleotide exchange factor ECT2 is elevated in primary astrocytomas and predicts both survival and malignancy. Mice bearing orthotopically implanted astrocytoma cells with diminished ECT2 levels following ECT2 knockdown exhibit longer survival. Although ECT2 is normally expressed in the nucleus, we show that ECT2 is aberrantly localized to the cytoplasm in both astrocytoma cell lines and primary human astrocytomas, and colocalizes with RAC1 and CDC42 at the leading edge of migrating astrocytoma cells. Inhibition of ECT2 expression by RNA interference resulted in decreased RAC1 and CDC42 activity, but no change in RHO activity, suggesting that ECT2 is capable of activating these pro-migratory Rho family members. ECT2 overexpression in astrocytoma cells resulted in a transition to an amoeboid phenotype that was abolished with the ROCK inhibitor, Y-27632. Cytoplasmic fractionation of astrocytoma cells followed by ECT2 immunoprecipitation and mass spectrometry were used to identify protein-binding partners that modulate the activity of ECT2 toward RAC1 and RHO/ROCK. We identified RASAL2 as an ECT2-interacting protein that regulates RHO activity in astrocytoma cells. RASAL2 knockdown leads to a conversion to an amoeboid phenotype. Our studies reveal that ECT2 has a novel role in mesenchymal-amoeboid transition in human astrocytoma cells. Copyright © 2012 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Epithelial Mesenchymal Transition in Cancer Progression: Prev entive Phytochemicals.

PubMed

Illam, Soorya P; Narayanankutty, Arunaksharan; Mathew, Shaji E; Valsalakumari, Remya; Jacob, Rosemol M; Raghavamenon, Achuthan C

2017-01-01

Epithelial-Mesenchymal Transition (EMT) is the conversion of epithelial cells into mesenchymal phenotype generally observed during embryogenesis and wound healing as well as in malignant transformation. Several signaling pathways and transcription factors associated with EMT have been explored. Dietary phytochemicals that are multi-targeted agents which interfere with these pathways, assume preventive potential against pathologic EMT. The present review aims to provide a detailed description of the nature and characteristics of EMT in physiological and pathophysiological conditions and the scope of phytochemicals in its prevention. Details regarding the initiation, progression as well as prevention of pathologic EMT and metastasis and recent patents on preventive phytochemicals were obtained from PubMed literatures and patent databases. The phenotypic changes during EMT are regulated by transcription factors like Snail, Slug, Twist and Zeb, which are activated through diverse signaling pathways of TGF-β, NF-kB, Wnt and Notch. s phytocompounds that are potent enough to interfere with these signaling pathways, which in turn prevent pathological implications of EMT. Present review also discusses 28 recent patents on those phytocompounds. EMT is a significant pharmacological target for developing preventive agents to combat pathological conditions like malignancy. Many of the phytochemicals cited in this review are being enrolled for different phases of clinical trials for their efficacy. In spite of the major limitations regarding bioavailability, sensitivity and tolerance of these compounds, their synthetic analogs, formulations and efficient drug delivery systems are also being attempted which will hopefully generate productive and promising results in near future. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Zinc finger X-chromosomal protein (ZFX) promotes solid agar colony growth of osteosarcoma cells.

PubMed

Jiang, Rui; Wang, Jin-cheng; Sun, Mei; Zhang, Xing-yi; Wu, Han

2012-01-01

Zinc finger X-chromosomal protein (ZFX) is a member of the zinc finger family of proteins. The importance of ZFX in several cancer types, including prostate cancer, laryngeal squamous cell carcinoma, and glioma, has been addressed. However, the role of ZFX in human osteosarcoma remains unknown. Here we investigated the phenotype of ZFX knockdown on cell proliferation and in vitro tumorigenesis using lentivirus-mediated loss-of-function strategy. The results demonstrated that the proliferation and colony formation ability of human osteosarcoma Saos-2 and MG63 cells was impaired by ZFX small interfering RNA (siRNA)-expressing lentivirus. Moreover, loss of ZFX led to G0/G1 phase cell cycle arrest and a significant increase of cells in the sub-G1 fraction, indicating that ZFX functions as an oncogene in the malignant proliferation process in osteosarcoma. Furthermore, ZFX siRNA may have an antitumorigenic effect on osteosarcoma cells. Our findings hold important significance for RNA interference-mediated cancer gene therapy for human osteosarcoma.

TEAD1 mediates the oncogenic activities of Hippo-YAP1 signaling in osteosarcoma.

PubMed

Chai, Jiwei; Xu, Shijie; Guo, Fengbo

2017-06-24

Hippo signaling pathway is an evolutionarily conserved developmental network that governs the downstream transcriptional co-activators, YAP and TAZ, which bind to and activate the output of TEADs that responsible for cell proliferation, apoptosis, and stem cell self renewal. Emerging evidence has shown the tumor suppressor properties of Hippo signaling. However, limited knowledge is available concerning the downstream transcription factors of Hippo pathway in osteosarcoma (OS). In this study, we demonstrated that TEAD1 was the major transcription factor of Hippo signaling pathway in OS. Genetic silencing of TEAD1 suppressed multiple malignant phenotypes of OS cells including cell proliferation, apoptosis resistance, and invasive potential. Mechanistically, we showed that TEAD1 largely exerted its transcriptional control of its functional targets, PTGS2 and CYR61. Collectively, this work identifies the YAP1/TEAD1 complex as the representative dysregulated profile of Hippo signaling in OS and provides proof-of-principle that targeting TEAD1 may be a therapeutic strategy of osteosarcoma. Copyright © 2017. Published by Elsevier Inc.

Single cell analysis of normal and leukemic hematopoiesis.

PubMed

Povinelli, Benjamin J; Rodriguez-Meira, Alba; Mead, Adam J

2018-02-01

The hematopoietic system is well established as a paradigm for the study of cellular hierarchies, their disruption in disease and therapeutic use in regenerative medicine. Traditional approaches to study hematopoiesis involve purification of cell populations based on a small number of surface markers. However, such population-based analysis obscures underlying heterogeneity contained within any phenotypically defined cell population. This heterogeneity can only be resolved through single cell analysis. Recent advances in single cell techniques allow analysis of the genome, transcriptome, epigenome and proteome in single cells at an unprecedented scale. The application of these new single cell methods to investigate the hematopoietic system has led to paradigm shifts in our understanding of cellular heterogeneity in hematopoiesis and how this is disrupted in disease. In this review, we summarize how single cell techniques have been applied to the analysis of hematopoietic stem/progenitor cells in normal and malignant hematopoiesis, with a particular focus on recent advances in single-cell genomics, including how these might be utilized for clinical application. Copyright © 2017. Published by Elsevier Ltd.

Multidrug Resistance and Cancer Stem Cells in Neuroblastoma and Hepatoblastoma

PubMed Central

Alisi, Anna; Cho, William C.; Locatelli, Franco; Fruci, Doriana

2013-01-01

Chemotherapy is one of the major modalities in treating cancers. However, its effectiveness is limited by the acquisition of multidrug resistance (MDR). Several mechanisms could explain the up-regulation of MDR genes/proteins in cancer after chemotherapy. It is known that cancer stem cells (CSCs) play a role as master regulators. Therefore, understanding the mechanisms that regulate some traits of CSCs may help design efficient strategies to overcome chemoresistance. Different CSC phenotypes have been identified, including those found in some pediatric malignancies. As solid tumors in children significantly differ from those observed in adults, this review aims at providing an overview of the mechanistic relationship between MDR and CSCs in common solid tumors, and, in particular, focuses on clinical as well as experimental evidence of the relations between CSCs and MDR in neuroblastoma and hepatoblastoma. Finally, some novel approaches, such as concomitant targeting of multiple key transcription factors governing the stemness of CSCs, as well as nanoparticle-based approaches will also be briefly addressed. PMID:24351843

An RNAi-based chemical genetic screen identifies three small-molecule inhibitors of the Wnt/wingless signaling pathway

PubMed Central

Gonsalves, Foster C.; Klein, Keren; Carson, Brittany B.; Katz, Shauna; Ekas, Laura A.; Evans, Steve; Nagourney, Robert; Cardozo, Timothy; Brown, Anthony M. C.; DasGupta, Ramanuj

2011-01-01

Misregulated β-catenin responsive transcription (CRT) has been implicated in the genesis of various malignancies, including colorectal carcinomas, and it is a key therapeutic target in combating various cancers. Despite significant effort, successful clinical implementation of CRT inhibitory therapeutics remains a challenging goal. This is, in part, because of the challenge of identifying inhibitory compounds that specifically modulate the nuclear transcriptional activity of β-catenin while not affecting its cytoskeletal function in stabilizing adherens junctions at the cell membrane. Here, we report an RNAi-based modifier screening strategy for the identification of CRT inhibitors. Our data provide support for the specificity of these inhibitory compounds in antagonizing the transcriptional function of nuclear β-catenin. We show that these inhibitors efficiently block Wnt/β-catenin–induced target genes and phenotypes in various mammalian and cancer cell lines. Importantly, these Wnt inhibitors are specifically cytotoxic to human colon tumor biopsy cultures as well as colon cancer cell lines that exhibit deregulated Wnt signaling. PMID:21393571

Chemokine Function in Periodontal Disease and Oral Cavity Cancer

PubMed Central

Sahingur, Sinem Esra; Yeudall, W. Andrew

2015-01-01

The chemotactic cytokines, or chemokines, comprise a superfamily of polypeptides with a wide range of activities that include recruitment of immune cells to sites of infection and inflammation, as well as stimulation of cell proliferation. As such, they function as antimicrobial molecules and play a central role in host defenses against pathogen challenge. However, their ability to recruit leukocytes and potentiate or prolong the inflammatory response may have profound implications for the progression of oral diseases such as chronic periodontitis, where tissue destruction may be widespread. Moreover, it is increasingly recognized that chronic inflammation is a key component of tumor progression. Interaction between cancer cells and their microenvironment is mediated in large part by secreted factors such as chemokines, and serves to enhance the malignant phenotype in oral and other cancers. In this article, we will outline the biological and biochemical mechanisms of chemokine action in host–microbiome interactions in periodontal disease and in oral cancer, and how these may overlap and contribute to pathogenesis. PMID:25999952

Thromboembolic complications following aminocaproic acid use in patients with hematologic malignancies.

PubMed

Juhl, Rebecca C; Roddy, Julianna V F; Wang, Tzu-Fei; Li, Junan; Elefritz, Jessica L

2018-02-09

Aminocaproic acid is frequently used in patients with hematologic malignancy that present with thrombocytopenia with or without hemorrhage. We conducted a retrospective study to evaluate the safety of aminocaproic acid in 109 patients with hematologic malignancies. Patients were included if aminocaproic acid had been administered for at least 24 hours for the prevention or treatment of thrombocytopenic hemorrhage. Our primary outcome was thromboembolic complications defined as arterial or venous thrombotic events objectively confirmed by imaging studies. Thromboembolic complications occurred in five patients (4.6%) and all were venous thromboses. Other than the underlying malignancy, these patients also had many concurrent risk factors including indwelling central venous catheters, which could have contributed to thromboses. In conclusion, in our population of patients with a variety of hematological malignancies, aminocaproic acid does not appear to be associated with a high incidence of thromboembolic complications.

Cause-Specific Mortality Due to Malignant and Non-Malignant Disease in Korean Foundry Workers

PubMed Central

Yoon, Jin-Ha; Ahn, Yeon-Soon

2014-01-01

Background Foundry work is associated with serious occupational hazards. Although several studies have investigated the health risks associated with foundry work, the results of these studies have been inconsistent with the exception of an increased lung cancer risk. The current study evaluated the mortality of Korean foundry workers due to malignant and non-malignant diseases. Methods This study is part of an ongoing investigation of Korean foundry workers. To date, we have observed more than 150,000 person-years in male foundry production workers. In the current study, we stratified mortality ratios by the following job categories: melting-pouring, molding-coremaking, fettling, and uncategorized production work. We calculated standard mortality ratios (SMR) of foundry workers compare to general Korean men and relative risk (RR) of mortality of foundry production workers reference to non-production worker, respectively. Results Korean foundry production workers had a significantly higher risk of mortality due to malignant disease, including stomach (RR: 3.96; 95% CI: 1.41–11.06) and lung cancer (RR: 2.08; 95% CI: 1.01–4.30), compared with non-production workers. High mortality ratios were also observed for non-malignant diseases, including diseases of the circulatory (RR: 1.92; 95% CI: 1.18–3.14), respiratory (RR: 1.71; 95% CI: 1.52–21.42 for uncategorized production worker), and digestive (RR: 2.27; 95% CI: 1.22–4.24) systems, as well as for injuries (RR: 2.36; 95% CI: 1.52–3.66) including suicide (RR: 3.64; 95% CI: 1.32–10.01). Conclusion This study suggests that foundry production work significantly increases the risk of mortality due to some kinds of malignant and non-malignant diseases compared with non-production work. PMID:24505454

Tenure Eligible/Tenure Track Investigator | Center for Cancer Research

Cancer.gov

The HIV and AIDS Malignancy Branch (HAMB), Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), is a national leader in research in the cancers associated with HIV/AIDS, in the development of therapies for HIV infection, and in oncogenic viruses.  We are seeking a tenure-eligible or tenure-track investigator in the field of HIV–related malignancies or viral oncogenesis.  It is anticipated that the investigator will establish an independent translational research program targeted to the study of the treatment, pathogenesis, and/or prevention of viral-induced or other HIV-associated tumors. The program can be primarily clinical, laboratory-based, or a combination of the two, and can also include animal model studies.  There is the potential to interface with a strong existing clinical research program. Potential areas of focus may include, but are not limited to, therapies for HIV malignancies, including novel immunologic approaches; viral oncogenesis; pathogenesis of HIV-associated malignancies; and virus host interactions, including immunologic interactions. 

Nuclear factor κB and cyclooxygenase-2 immunoexpression in oral dysplasia and oral squamous cell carcinoma.

PubMed

Pontes, Hélder Antônio Rebelo; Pontes, Flávia Sirotheau Corrêa; Fonseca, Felipe Paiva; de Carvalho, Pedro Luiz; Pereira, Erika Martins; de Abreu, Michelle Carvalho; de Freitas Silva, Brunno Santos; dos Santos Pinto, Décio

2013-02-01

Oral leukoplakia is the main potentially malignant oral lesion, and oral squamous cell carcinoma accounts for more than 95% of all malignant neoplasms in the oral cavity. Therefore, the aim of this study was to verify the immunoexpression of nuclear factor κB (NF-κB) and cyclooxygenase-2 (COX-2) proteins in dysplastic oral lesions and oral squamous cell carcinoma. Immunohistochemical reactions were performed on 6 inflammatory fibrous hyperplasia, 28 oral leukoplakia, and 15 oral squamous cell carcinoma paraffin-embedded samples. Immunoperoxidase reaction for NF-κB and COX-2 was applied on the specimens, and the positivity of the reactions was calculated for 1000 epithelial cells. Using the analysis of variance and the Tukey post hoc statistical analyses, a significantly increased immunoexpression for NF-κB was observed when oral squamous cell carcinoma samples were compared with the other groups studied. However, using the Kruskal-Wallis and the Dunn post hoc tests, a statistically significant result for COX-2 expression was obtained only when the moderate dysplasia group was compared with the inflammatory fibrous hyperplasia group. Nuclear factor κB may participate in the malignant phenotype acquisition process of the oral squamous cell carcinoma in its late stages, whereas COX-2 may be involved in the early stages of oral carcinogenesis process. Copyright © 2013 Elsevier Inc. All rights reserved.

The human homologue of Dictyostelium discoideum phg1A is expressed by human metastatic melanoma cells.

PubMed

Lozupone, Francesco; Perdicchio, Maurizio; Brambilla, Daria; Borghi, Martina; Meschini, Stefania; Barca, Stefano; Marino, Maria Lucia; Logozzi, Mariantonia; Federici, Cristina; Iessi, Elisabetta; de Milito, Angelo; Fais, Stefano

2009-12-01

Tumour cannibalism is a characteristic of malignancy and metastatic behaviour. This atypical phagocytic activity is a crucial survival option for tumours in conditions of low nutrient supply, and has some similarities to the phagocytic activity of unicellular microorganisms. In fact, Dictyostelium discoideum has been used widely as a model to study phagocytosis. Recently, phg1A has been described as a protein that is primarily involved in the phagocytic process of this microorganism. The closest human homologue to phg1A is transmembrane 9 superfamily protein member 4 (TM9SF4). Here, we report that TM9SF4 is highly expressed in human malignant melanoma cells deriving from metastatic lesions, whereas it is undetectable in healthy human tissues and cells. TM9SF4 is predominantly expressed in acidic vesicles of melanoma cells, in which it co-localizes with the early endosome antigens Rab5 and early endosome antigen 1. TM9SF4 silencing induced marked inhibition of cannibal activity, which is consistent with a derangement of intracellular pH gradients, with alkalinization of acidic vesicles and acidification of the cell cytosol. We propose TM9SF4 as a new marker of malignancy, representing a potential new target for anti-tumour strategies with a specific role in tumour cannibalism and in the establishment of a metastatic phenotype.

Salivary gland carcinosarcoma: oligonucleotide array CGH reveals similar genomic profiles in epithelial and mesenchymal components.

PubMed

Vékony, Hedy; Leemans, C René; Ylstra, Bauke; Meijer, Gerrit A; van der Waal, Isaäc; Bloemena, Elisabeth

2009-03-01

In this study, we present a case of parotid gland de novo carcinosarcoma. Salivary gland carcinosarcoma (or true malignant mixed tumor) is a rare biphasic neoplasm, composed of both malignant epithelial and malignant mesenchymal components. It is yet unclear whether these two phenotypes occur by collision of two independent tumors or if they are of clonal origin. To analyze the clonality of the different morphologic tumor components, oligonucleotide microarray-based comparative genomic hybridization (oaCGH) was performed on the carcinoma and the sarcoma entity separately. This technique enables a high-resolution, genome-wide overview of the chromosomal alterations in the distinct tumor elements. Analysis of both fractions showed a high number of DNA copy number changes. Losses were more prevalent than gains (82 and 49, respectively). The carcinomatous element displayed more chromosomal aberrations than the sarcomatous component. Specific amplifications of MUC20 (in mesenchymal element) and BMI-1 (in both elements) loci were observed. Overall homology between the two genomic profiles was 75%. DNA copy number profiles of the epithelial and mesenchymal components in this salivary gland carcinosarcoma displayed extensive overlap, indicating a monoclonal origin. Since losses are shared to a larger extent than gains, they seem to be more essential for initial oncogenic events. Furthermore, specific amplifications of a mucin and a Polycomb group gene imply these proteins in the tumorigenesis of carcinosarcomas.

Surface receptors on human haematopoietic cell lines.

PubMed Central

Huber, C; Sundström, C; Nilsson, K; Wigzell, H

1976-01-01

The expression of complement receptors, of Fc receptors, of SRBC receptors and of S-Ig was investigated on human haematopoietic cell lines of proved malignant derivation. According to their origin and to a panel of phenotypic markers these lines have been classified into lymphoma lines, myeloma lines and leukemia lines. Results were compared with those obtained on non-malignant EBV carrying lymphoblastoid cell lines (LCL). Among the lymphoid cell lines the LCL showed a pattern of B-lymphocyte surface markers, i.e. surface immunoglobulins, C3 receptors but low density of Fc receptors. The non-Burkitt lymphoma lines bore in varying degree these B-lymphocyte markers. The lines U-698 M and DG-75 were exceptional in having only surface immunoglobulin. The Burkitt lymphoma lines had all B-lymphocyte markers. The myeloma lines differed from the lymphoid lines in lacking C3 and Fc receptors and showed only trace amounts of surface immunoglobulins. In contrast to lymphoid and myeloma lines, the leukaemia lines were completely lacking surface immunoglobulins, but showed C3 and Fc receptors in variable densities. On line, the ALL derived line MOLT-3 showed the capacity to spontaneous rosette formation with SRBC. The findings that LCL presented a homogeneous pattern of B-lymphocyte surface markers may be of value in order to discriminate between these lines and lines derived from haematopoietic malignancies other than Burkitt lymphomas. PMID:963908

Prevalence and Physical Distribution of SRY in the Gonads of a Woman with Turner Syndrome: Phenotypic Presentation, Tubal Formation, and Malignancy Risk.

PubMed

Baer, Tamar G; Freeman, Christopher E; Cujar, Claudia; Mansukhani, Mahesh; Singh, Bahadur; Chen, Xiaowei; Abellar, Rosanna; Oberfield, Sharon E; Levy, Brynn

2017-01-01

Although monosomy X is the most common karyotype in patients with Turner syndrome, the presence of Y chromosome material has been observed in about 10% of patients. Y chromosome material in patients with Turner syndrome poses an increased risk of gonadoblastoma and malignant transformation. We report a woman with a diagnosis of Turner syndrome at 12 years of age, without signs of virilization, and karyotype reported as 46,X,del(X)(q13). At 26 years, cytogenetic studies indicated the patient to be mosaic for monosomy X and a cell line that contained a du-plicated Yq chromosome. Bilateral gonadectomy was performed and revealed streak gonads, without evidence of gonadoblastoma. Histological analysis showed ovarian stromal cells with few primordial tubal structures. FISH performed on streak gonadal tissue showed a heterogeneous distribution of SRY, with exclusive localization to the primordial tubal structures. DNA extraction from the gonadal tissue showed a 6.5% prevalence of SRY by microarray analysis, contrasting the 86% prevalence in the peripheral blood sample. This indicates that the overall gonadal sex appears to be determined by the majority gonosome complement in gonadal tissue in cases of sex chromosome mosaicism. This case also raises questions regarding malignancy risk associated with Y prevalence and tubal structures in gonadal tissue. © 2017 S. Karger AG, Basel.

N-acetylcysteine negatively regulates Notch3 and its malignant signaling

PubMed Central

Zhu, Juan-Juan; Liu, Xue-Xia; You, Hui; Gong, Mei-Ying; Zou, Ming; Cheng, Wen-Hsing; Zhu, Jian-Hong

2016-01-01

Notch3 receptor is expressed in a variety of cancers and the excised active intracellular domain (N3ICD) initiates its signaling cascade. N-acetylcysteine (NAC) as an antioxidant has been implicated in cancer prevention and therapy. In this study, we demonstrated a negative regulation of Notch3 by NAC in cancer cells. HeLa cells treated with NAC exhibited a time- and concentration-dependent decrease in Notch3 levels and its downstream effectors Hes1 and HRT1 in a manner independent of f-secretase or glutathione. In contrast, NAC did not affect protein levels of Notch1, the full length Notch3 precursor, or ectopically expressed N3ICD. Although SOD, catalase and NAC suppressed reactive oxygen species in HeLa cells, the first two antioxidants did not impact on Notch3 levels. While the mRNA expression of Notch3 was not altered by NAC, functional inhibition of lysosome, but not proteasome, blocked the NAC-dependent reduction of Notch3 levels. Furthermore, results from Notch3 silencing and N3ICD overexpression demonstrated that NAC prevented malignant phenotypes through down-regulation of Notch3 protein in multiple cancer cells. In summary, NAC reduces Notch3 levels through lysosome-dependent protein degradation, thereby negatively regulates Notch3 malignant signaling in cancer cells. These results implicate a novel NAC treatment in sensitizing Notch3-expressing tumors. PMID:27102435

N-acetylcysteine negatively regulates Notch3 and its malignant signaling.

PubMed

Zhang, Xiong; Wang, Ya-Nan; Zhu, Juan-Juan; Liu, Xue-Xia; You, Hui; Gong, Mei-Ying; Zou, Ming; Cheng, Wen-Hsing; Zhu, Jian-Hong

2016-05-24

Notch3 receptor is expressed in a variety of cancers and the excised active intracellular domain (N3ICD) initiates its signaling cascade. N-acetylcysteine (NAC) as an antioxidant has been implicated in cancer prevention and therapy. In this study, we demonstrated a negative regulation of Notch3 by NAC in cancer cells. HeLa cells treated with NAC exhibited a time- and concentration-dependent decrease in Notch3 levels and its downstream effectors Hes1 and HRT1 in a manner independent of f-secretase or glutathione. In contrast, NAC did not affect protein levels of Notch1, the full length Notch3 precursor, or ectopically expressed N3ICD. Although SOD, catalase and NAC suppressed reactive oxygen species in HeLa cells, the first two antioxidants did not impact on Notch3 levels. While the mRNA expression of Notch3 was not altered by NAC, functional inhibition of lysosome, but not proteasome, blocked the NAC-dependent reduction of Notch3 levels. Furthermore, results from Notch3 silencing and N3ICD overexpression demonstrated that NAC prevented malignant phenotypes through down-regulation of Notch3 protein in multiple cancer cells. In summary, NAC reduces Notch3 levels through lysosome-dependent protein degradation, thereby negatively regulates Notch3 malignant signaling in cancer cells. These results implicate a novel NAC treatment in sensitizing Notch3-expressing tumors.

Role of stents and laser therapy in biliary strictures

NASA Astrophysics Data System (ADS)

Chennupati, Raja S.; Trowers, Eugene A.

2001-05-01

The most frequent primary cancers causing malignant obstructive jaundice were pancreatic cancer (57%), hilar biliary cancer (19% including metastatic disease), nonhilar biliary cancer (14%) and papillary cancer (10%). Endoscopic stenting has widely replaced palliative surgery for malignant biliary obstruction because of its lower risk and cost. Self-expandable metal stents are the preferred mode of palliation for hilar malignancies. Plastic stents have a major role in benign biliary strictures. Major complications and disadvantages associated with metallic stents include high cost, cholangitis. malposition, migration, unextractability, and breakage of the stents, pancreatitis and stent dysfunction. Dysfunction due to tumor ingrowth can be relieved by thermal methods (argon plasma coagulator therapy). We present a concise review of the efficacy of metallic stents for palliation of malignant strictures.

Glial tumors with neuronal differentiation.

PubMed

Park, Chul-Kee; Phi, Ji Hoon; Park, Sung-Hye

2015-01-01

Immunohistochemical studies for neuronal differentiation in glial tumors revealed subsets of tumors having both characteristics of glial and neuronal lineages. Glial tumors with neuronal differentiation can be observed with diverse phenotypes and histologic grades. The rosette-forming glioneuronal tumor of the fourth ventricle and papillary glioneuronal tumor have been newly classified as distinct disease entities. There are other candidates for classification, such as the glioneuronal tumor without pseudopapillary architecture, glioneuronal tumor with neuropil-like islands, and the malignant glioneuronal tumor. The clinical significance of these previously unclassified tumors should be confirmed. Copyright © 2015 Elsevier Inc. All rights reserved.

Primary B cell lymphoma of the tongue base: a case report

PubMed Central

Bechir, Achour; Asma, Achour; Haifa, Regaieg; Nesrine, Abdessayed; Yosra, Ben Youssef; Badreddine, Sriha; Abderrahim, Khelif

2016-01-01

Primary non-Hodgkin’s lymphoma’s of the tongue is very rare and accounts for 1% of all malignant tumor of the oral cavity. Clinical features are non-specific ulcerative lesions that do not heal. In the literature, the majority of cases are diffuse large B cell type however, T cell phenotype also may occur. We describe a 77 years old man, who presented with an ulcerative mass in the left margin of the tongue the diagnosis diffuse large B cell lymphoma was confirmed. The patient is actually on treatment R-mini CEOP and has favorable evolution. PMID:28292136

Treatment of unilateral zone I cytomegalovirus retinitis in acute lymphoblastic leukemia with oral valganciclovir and intravitreal ganciclovir

PubMed Central

Tripathy, Koushik; Mittal, Kanhaiya; Venkatesh, Pradeep; Bakhshi, Sameer; Chawla, Rohan

2017-01-01

Cytomegalovirus retinitis (CMVR) is an opportunistic infection seen in immunocompromised patients, especially suffering from acquired immune deficiency syndrome. It is uncommonly seen in hematological malignancies and in patients on immunosuppressants. The authors present a 12-year-old girl with unilateral CMVR who was on maintenance phase therapy for mixed phenotype (B/myeloid) leukemia. Serology for human immunodeficiency virus was negative. The child was successfully treated with oral valganciclovir and repeated intravitreal ganciclovir injections. CMVR in pediatric population with leukemia can be successfully treated with oral valganciclovir and intravitreal ganciclovir injections. PMID:29118508

Familial association of specific histologic types of ovarian malignancy with other malignancies.

PubMed

Lorenzo Bermejo, Justo; Rawal, Rajesh; Hemminki, Kari

2004-04-01

Population-based data on the familial association of specific histologic types of ovarian malignancy with other malignancies are limited. Such data may help to elucidate etiologic differences among histologic types of ovarian malignancy. The nationwide Swedish Family-Cancer Database, which includes 10.3 million individuals and 20,974 ovarian carcinomas, was used to calculate standardized incidence ratios and 95% confidence intervals for age- and histology-specific ovarian malignancies in women whose parents or siblings were affected with malignancies at the most common disease sites. Ovarian malignancy was found to be associated with ovarian, laryngeal, breast, endometrial, liver, and colon carcinoma, as well as myeloma; epithelial ovarian malignancy was found to be associated with ovarian, endometrial, and skin malignancies and with melanoma and myeloma; papillary serous cystadenocarcinoma was found to be associated with ovarian and skin malignancies and with myeloma; and endometrioid carcinoma was found to be associated with endometrial, ovarian, and prostate malignancies and with melanoma. For younger women (ages 40-45 years) whose mothers were affected with endometrial malignancies, the risk of developing endometrioid carcinoma was slightly greater than the risk of developing papillary serous cystadenocarcinoma. Specific types of ovarian malignancy may be associated with specific familial disease sites, with such associations depending on age at diagnosis; the strength of the observed associations varied according to histology. Associations were found between endometrioid carcinoma and endometrial malignancy and between serous carcinoma and Hodgkin disease. Copyright 2004 American Cancer Society.

Differentiation of Benign and Malignant Head and Neck Lesions With Diffusion Tensor Imaging and DWI.

PubMed

Koontz, Nicholas A; Wiggins, Richard H

2017-05-01

The purpose of this study was to determine whether diffusion tensor imaging (DTI) can be used to differentiate between benign and malignant head and neck lesions. This retrospective study included patients with head and neck lesions who underwent clinical MRI at 1.5 or 3 T with DWI or DTI parameters. ROI analysis was performed, with lesion-to-medulla apparent diffusion coefficient (ADC) ratios generated. Sixty-five patients with head and neck lesions were included (71 benign, 40 malignant). Twenty-one patients had multiple lesions. Statistically significant differences (p < 0.001) were seen in the mean ADC values ± SD of malignant and benign lesions (0.55 × 10 -3 ± 0.14 × 10 -3 mm 2 /s vs 0.89 × 10 -3 ± 0.29 × 10 -3 mm 2 /s, respectively) and in the mean ADC ratios of malignant and benign lesions (0.88 ± 0.21 vs 1.40 ± 0.44, respectively) with DTI parameters. DTI and DWI parameters produced similar mean ADC ratio values for malignant (0.88 ± 0.21 and 0.92 ± 0.54, respectively) and benign lesions (1.40 ± 0.44 and 1.79 ± 0.52, respectively). ADC ratio thresholds for predicting malignancy for DTI (ADC ratio ≤ 1) and DWI (ADC ratio ≤ 0.94) were also similar. DTI is a useful predictor of malignancy for head and neck lesions, with ADC values of malignant lesions significantly lower than those of benign lesions. DTI ADC values were lower than DWI ADC values for all head and neck lesions in our study group, often below reported malignant DWI threshold values. Normalization of ADC values to an internal control resulted in similar ADC ratios on DWI and DTI.

Altered interactions between unicellular and multicellular genes drive hallmarks of transformation in a diverse range of solid tumors.

PubMed

Trigos, Anna S; Pearson, Richard B; Papenfuss, Anthony T; Goode, David L

2017-06-13

Tumors of distinct tissues of origin and genetic makeup display common hallmark cellular phenotypes, including sustained proliferation, suppression of cell death, and altered metabolism. These phenotypic commonalities have been proposed to stem from disruption of conserved regulatory mechanisms evolved during the transition to multicellularity to control fundamental cellular processes such as growth and replication. Dating the evolutionary emergence of human genes through phylostratigraphy uncovered close association between gene age and expression level in RNA sequencing data from The Cancer Genome Atlas for seven solid cancers. Genes conserved with unicellular organisms were strongly up-regulated, whereas genes of metazoan origin were primarily inactivated. These patterns were most consistent for processes known to be important in cancer, implicating both selection and active regulation during malignant transformation. The coordinated expression of strongly interacting multicellularity and unicellularity processes was lost in tumors. This separation of unicellular and multicellular functions appeared to be mediated by 12 highly connected genes, marking them as important general drivers of tumorigenesis. Our findings suggest common principles closely tied to the evolutionary history of genes underlie convergent changes at the cellular process level across a range of solid cancers. We propose altered activity of genes at the interfaces between multicellular and unicellular regions of human gene regulatory networks activate primitive transcriptional programs, driving common hallmark features of cancer. Manipulation of cross-talk between biological processes of different evolutionary origins may thus present powerful and broadly applicable treatment strategies for cancer.

Altered interactions between unicellular and multicellular genes drive hallmarks of transformation in a diverse range of solid tumors

PubMed Central

Trigos, Anna S.; Pearson, Richard B.; Papenfuss, Anthony T.; Goode, David L.

2017-01-01

Tumors of distinct tissues of origin and genetic makeup display common hallmark cellular phenotypes, including sustained proliferation, suppression of cell death, and altered metabolism. These phenotypic commonalities have been proposed to stem from disruption of conserved regulatory mechanisms evolved during the transition to multicellularity to control fundamental cellular processes such as growth and replication. Dating the evolutionary emergence of human genes through phylostratigraphy uncovered close association between gene age and expression level in RNA sequencing data from The Cancer Genome Atlas for seven solid cancers. Genes conserved with unicellular organisms were strongly up-regulated, whereas genes of metazoan origin were primarily inactivated. These patterns were most consistent for processes known to be important in cancer, implicating both selection and active regulation during malignant transformation. The coordinated expression of strongly interacting multicellularity and unicellularity processes was lost in tumors. This separation of unicellular and multicellular functions appeared to be mediated by 12 highly connected genes, marking them as important general drivers of tumorigenesis. Our findings suggest common principles closely tied to the evolutionary history of genes underlie convergent changes at the cellular process level across a range of solid cancers. We propose altered activity of genes at the interfaces between multicellular and unicellular regions of human gene regulatory networks activate primitive transcriptional programs, driving common hallmark features of cancer. Manipulation of cross-talk between biological processes of different evolutionary origins may thus present powerful and broadly applicable treatment strategies for cancer. PMID:28484005

Chemical Library Screening and Structure-Function Relationship Studies Identify Bisacodyl as a Potent and Selective Cytotoxic Agent Towards Quiescent Human Glioblastoma Tumor Stem-Like Cells

PubMed Central

Mameri, Samir; Dong, Jihu; Salomé, Christophe; Chen, Wanyin; El-Habr, Elias A.; Bousson, Fanny; Sy, Mohamadou; Obszynski, Julie; Boh, Alexandre; Villa, Pascal; Assad Kahn, Suzana; Didier, Bruno; Bagnard, Dominique; Junier, Marie-Pierre; Chneiweiss, Hervé; Haiech, Jacques; Hibert, Marcel; Kilhoffer, Marie-Claude

2015-01-01

Cancer stem-like cells reside in hypoxic and slightly acidic tumor niches. Such microenvironments favor more aggressive undifferentiated phenotypes and a slow growing "quiescent state" which preserves them from chemotherapeutic agents that essentially target proliferating cells. Our objective was to identify compounds active on glioblastoma stem-like cells, including under conditions that mimick those found in vivo within this most severe and incurable form of brain malignancy. We screened the Prestwick Library to identify cytotoxic compounds towards glioblastoma stem-like cells, either in a proliferating state or in more slow-growing "quiescent" phenotype resulting from non-renewal of the culture medium in vitro. Compound effects were assessed by ATP-level determination using a cell-based assay. Twenty active molecules belonging to different pharmacological classes have thus been identified. Among those, the stimulant laxative drug bisacodyl was the sole to inhibit in a potent and specific manner the survival of quiescent glioblastoma stem-like cells. Subsequent structure-function relationship studies led to identification of 4,4'-dihydroxydiphenyl-2-pyridyl-methane (DDPM), the deacetylated form of bisacodyl, as the pharmacophore. To our knowledge, bisacodyl is currently the only known compound targeting glioblastoma cancer stem-like cells in their quiescent, more resistant state. Due to its known non-toxicity in humans, bisacodyl appears as a new potential anti-tumor agent that may, in association with classical chemotherapeutic compounds, participate in tumor eradication. PMID:26270679

A CpG island methylator phenotype in acute myeloid leukemia independent of IDH mutations and associated with a favorable outcome

PubMed Central

Kelly, Andrew D.; Kroeger, Heike; Yamazaki, Jumpei; Taby, Rodolphe; Neumann, Frank; Yu, Sijia; Lee, Justin T.; Patel, Bela; Li, Yuesheng; He, Rong; Liang, Shoudan; Lu, Yue; Cesaroni, Matteo; Pierce, Sherry A.; Kornblau, Steven M.; Bueso-Ramos, Carlos E.; Ravandi, Farhad; Kantarjian, Hagop M.; Jelinek, Jaroslav; Issa, Jean-Pierre J.

2016-01-01

Genetic changes are infrequent in acute myeloid leukemia (AML) compared to other malignancies and often involve epigenetic regulators, suggesting that an altered epigenome may underlie AML biology and outcomes. In 96 AML cases including 65 pilot samples selected for cured/not-cured, we found higher CpG island (CGI) promoter methylation in cured patients. Expanded genome-wide digital restriction enzyme analysis of methylation (DREAM) data revealed a CGI methylator phenotype independent of IDH1/2 mutations we term AML-CIMP (A-CIMP+). A-CIMP was associated with longer overall survival (OS) in this dataset (median OS, years: A-CIMP+ = Not reached, A-CIMP− =1.17; P=0.08). For validation we used 194 samples from The Cancer Genome Atlas interrogated with Illumina 450k methylation arrays where we confirmed longer OS in A-CIMP (median OS, years: A-CIMP+ =2.34, A-CIMP− =1.00; P=0.01). Hypermethylation in A-CIMP favored CGIs (OR: CGI/non-CGI=5.21), and while A-CIMP was enriched in CEBPA (P=0.002) and WT1 mutations (P=0.02), 70% of cases lacked either mutation. Hypermethylated genes in A-CIMP function in pluripotency maintenance, and a gene expression signature of A-CIMP was associated with outcomes in multiple datasets. We conclude that CIMP in AML cannot be explained solely by gene mutations (e.g. IDH1/2, TET2), and that curability in A-CIMP+ AML should be validated prospectively. PMID:28074068

Mutational profiles of Brenner tumors show distinctive features uncoupling urothelial carcinomas and ovarian carcinoma with transitional cell histology.

PubMed

Pfarr, Nicole; Darb-Esfahani, Silvia; Leichsenring, Jonas; Taube, Eliane; Boxberg, Melanie; Braicu, Ioana; Jesinghaus, Moritz; Penzel, Roland; Endris, Volker; Noske, Aurelia; Weichert, Wilko; Schirmacher, Peter; Denkert, Carsten; Stenzinger, Albrecht

2017-10-01

Brenner tumors (BT) are rare ovarian tumors encompassing benign, borderline, and malignant variants. While the histopathology of BTs and their clinical course is well described, little is known about the underlying genetic defects. We employed targeted next generation sequencing to analyze the mutational landscape in a cohort of 23 BT cases (17 benign, 2 borderline, and 4 malignant) and 3 ovarian carcinomas with transitional cell histology (TCC). Copy number variations (CNV) were validated by fluorescence in-situ hybridization (FISH) and quantitative PCR-based copy number assays. Additionally, we analyzed the TERT promotor region by conventional Sanger sequencing. We identified 25 different point mutations in 23 of the analyzed genes in BTs and 10 mutations in 8 genes in TCCs. About 57% percent of mutations occurred in genes involved in cell cycle control, DNA repair, and epigenetic regulation processes. All TCC cases harbored TP53 mutations whereas all BTs were negative and none of the mutations observed in BTs were present in TCCs. CNV analysis revealed recurrent MDM2 amplifications in 3 out of 4 of the malignant BT cases with one case harboring a concomitant amplification of CCND1. No mutations were observed in the TERT promoter region in BTs and TCCs, which is mutated in about 50%-75% of urothelial carcinoma and in 16% of ovarian clear-cell carcinomas. In conclusion, our study highlights distinct genetic features of BTs, and detection of the triplet phenotype MDM2 amplification/TP53 wt/TERT wt may aid diagnosis of malignant BT in difficult cases. Moreover, selected genetic lesions may be clinically exploitable in a metastatic setting. © 2017 Wiley Periodicals, Inc.

Modulation of T Cell Activation by Malignant Melanoma Initiating Cells

PubMed Central

Schatton, Tobias; Schütte, Ute; Frank, Natasha Y.; Zhan, Qian; Hoerning, André; Robles, Susanne C.; Zhou, Jun; Hodi, F. Stephen; Spagnoli, Giulio C.; Murphy, George F.; Frank, Markus H.

2010-01-01

Highly immunogenic cancers such as malignant melanoma are capable of inexorable tumor growth despite the presence of antitumor immunity. This raises the possibility that only a restricted minority of tumorigenic malignant cells might possess the phenotypic and functional characteristics to modulate tumor-directed immune activation. Here we provide evidence supporting this hypothesis, by demonstrating that tumorigenic ABCB5+ malignant melanoma-initiating cells (MMICs) possess the capacity to preferentially inhibit interleukin (IL)-2-dependent T cell activation and to support, in a B7.2-dependent manner, regulatory T (Treg) cell induction. Compared to melanoma bulk populations, ABCB5+ MMICs expressed lower levels of the major histocompatibility complex (MHC) class I, showed aberrant positivity for MHC class II, and exhibited lower expression levels of the melanoma-associated antigens (MAAs) MART-1, ML-IAP, NY-ESO-1, and MAGE-A. In addition, tumorigenic ABCB5+ subpopulations preferentially expressed the costimulatory molecules B7.2 and PD-1 in both established melanoma xenografts and clinical tumor specimens in vivo. In immune activation assays, ABCB5+ melanoma cells inhibited mitogen-dependent human peripheral blood mononuclear cell (PBMC) proliferation and IL-2 production more efficiently than ABCB5− populations. Moreover, coculture with ABCB5+ MMICs increased, in a B7.2 signalling-dependent manner, CD4+CD25+FoxP3+ Treg cell abundance and IL-10 production by mitogen-activated PBMCs. Consistent with these findings, ABCB5+ melanoma subsets also preferentially inhibited IL-2 production and induced IL-10 secretion by cocultured patient-derived, syngeneic PBMCs. Our findings identify novel T cell-modulatory functions of ABCB5+ melanoma subpopulations and suggest specific roles for MMICs in the evasion of antitumor immunity and in cancer immunotherapeutic resistance. PMID:20068175

Correlations between Transmembrane 4 L6 Family Member 5 (TM4SF5), CD151, and CD63 in Liver Fibrotic Phenotypes and Hepatic Migration and Invasive Capacities

PubMed Central

Kang, Minkyung; Ryu, Jihye; Lee, Doohyung; Lee, Mi-Sook; Kim, Hye-Jin; Nam, Seo Hee; Song, Haeng Eun; Choi, Jungeun; Lee, Gyu-Ho; Kim, Tai Young; Lee, Hansoo; Kim, Sang Jick; Ye, Sang-Kyu; Kim, Semi; Lee, Jung Weon

2014-01-01

Transmembrane 4 L6 family member 5 (TM4SF5) is overexpressed during CCl4-mediated murine liver fibrosis and in human hepatocellular carcinomas. The tetraspanins form tetraspanin-enriched microdomains (TEMs) consisting of large membrane protein complexes on the cell surface. Thus, TM4SF5 may be involved in the signal coordination that controls liver malignancy. We investigated the relationship between TM4SF5-positive TEMs with liver fibrosis and tumorigenesis, using normal Chang hepatocytes that lack TM4SF5 expression and chronically TGFβ1-treated Chang cells that express TM4SF5. TM4SF5 expression is positively correlated with tumorigenic CD151 expression, but is negatively correlated with tumor-suppressive CD63 expression in mouse fibrotic and human hepatic carcinoma tissues, indicating cooperative roles of the tetraspanins in liver malignancies. Although CD151 did not control the expression of TM4SF5, TM4SF5 appeared to control the expression levels of CD151 and CD63. TM4SF5 interacted with CD151, and caused the internalization of CD63 from the cell surface into late lysosomal membranes, presumably leading to terminating the tumor-suppressive functions of CD63. TM4SF5 could overcome the tumorigenic effects of CD151, especially cell migration and extracellular matrix (ECM)-degradation. Taken together, TM4SF5 appears to play a role in liver malignancy by controlling the levels of tetraspanins on the cell surface, and could provide a promising therapeutic target for the treatment of liver malignancies. PMID:25033048

In vitro characterization of cancer cell morphology, chemokinesis, and matrix invasion using a novel microfabricated system

NASA Astrophysics Data System (ADS)

Blaha, Laura

A diagnosis of metastatic cancer reduces a patient's 5-year survival rate by nearly 80% compared to a primary tumor diagnosed at an early stage. While gene expression arrays have revealed unique gene signatures for metastatic cancer cells, we are lacking an understanding of the tangible physical changes that distinguish metastatic tumor cells from each other and from their related primary tumors. At the fundamental level, this translates into first characterizing the phenotype of metastatic cancer cells in vitro both in 2D - looking at morphology and migration - and in 3D - focusing on matrix invasion. While 2D in vitro studies have provided insight into the effects of specific environmental conditions on specific cancer cell lines, the unique details included in each experimental design make it challenging to compare cell phenotype across different in vitro platforms as well as between laboratories and disciplines that share the goal of understanding cancer. While 3D phenotype studies have employed more standardized and ubiquitous assays, most available tools lack the imaging capability and geometry to effectively characterize all factors driving 3D matrix invasion. In this work, we present protocols and platforms aimed at addressing the problems identified in the tools currently available for studying metastatic cancer in vitro. First, we present a 2D study of morphology and migration using widely accepted protocols. The study is applied to characterizing phenotypes of three breast cancer cell lines with different metastatic organ tropisms. The results show that general populations of cells from each of the 3 lines are unique in shape and motility despite being derived from the same tumor line and that the observed phenotype differences may be related to differences in focal adhesion assembly. More broadly, these studies suggest that standardizing phenotype studies using commonly available techniques may provide a platform by which to compare phenotypic studies across cancer cell types and between research groups to investigate tropism-specific cancer phenotypes. We conclude our investigation of phenotype with a study of 3D matrix invasion using a novel microfluidic platform. The results show that invasion of metastatic breast cancer cells into a 3D type I collagen gel is significantly enhanced in the presence of live endothelial cells. In applying the model to study cell-cell and cell-matrix interactions driving invasion, our platform revealed that, while the fibronectin-rich matrix deposited by endothelial cells was not sufficient to drive invasion alone, metastatic breast cancer cells were able to exploit a structural or secreted component of energetically inactivated endothelial cell to gain entry into the underlying matrix. These findings have important implications for designing drugs targeted at preventing cancer metastasis. The findings in this dissertation reveal significant phenotypic differences in metastatic breast cancer cells with different preferences in metastatic target organ. In addition, the microfluidic platform reveals novel cell-cell interactions driving a key step in the seeding and colonization of a metastatic tumor. Collectively, these results reveal important characteristics of metastatic cancer cells and their interactions with other cell types during metastasis. These studies also provide platforms on which to target or prevent malignant phenotypes and cellular interactions in the future.

Glutathione S-transferase gene polymorphisms in celiac disease and their correlation with genomic instability phenotype.

PubMed

Fundia, Ariela F; Weich, Natalia; Crivelli, Adriana; La Motta, Graciela; Larripa, Irene B; Slavutsky, Irma

2014-06-01

Genomic instability and reduced glutathione S-transferase (GST) activity have been identified as potential risk factors for malignant complications in celiac disease (CD). In this study, we assessed the possible influence of GST polymorphisms on genome instability phenotypes in a genetically characterised group of celiac patients from previous studies. The deletion polymorphisms in GSTM1 and GSTT1 genes and the single-nucleotide polymorphism GSTP1 c.313A>G were genotyped using PCR in a set of 20 untreated adult patients with a known genomic instability phenotype and 69 age- and sex-matched healthy individuals. The frequencies of variant genotypes in patients were GSTM1-null (30%), GSTT1-null (5%), GSTP1-AG (60%) and GSTP1-GG (15%), and they showed no differences from controls. No significant differences were found in the genotype distribution based on telomere length. Cases with GSTM1-null genotype (83%) and microsatellite stability were more frequent than those with genomic instability. Moreover, carriers of GSTP1-variant genotype (73%) and stable phenotype were significantly increased compared to unstable patients (27%) (P=0.031). No differences were found according to the clinical-pathological characteristics of celiac cases. No association between GST polymorphic variants and celiac-associated genomic instability was proven in our cohort. Future studies should explore the usefulness of other biomarkers to distinguish celiac patients who are susceptible to cancer development. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Deregulation of protein methylation in melanoma.

PubMed

Limm, Katharina; Ott, Corinna; Wallner, Susanne; Mueller, Daniel W; Oefner, Peter; Hellerbrand, Claus; Bosserhoff, Anja-Katrin

2013-04-01

Loss of methylthioadenosine phosphorylase (MTAP) expression and a concomitant accumulation of 5'-methyl-thioadenosine (MTA) characterise several tumour entities including malignant melanoma. MTA affects cellular signalling, proliferation and migration not only of cancer but also surrounding cells including lymphocytes and stromal fibroblasts. The mode of action of MTA is still not known. Interestingly, MTA is a known potent inhibitor of protein arginine methyltransferases (PRMTs) and is used as a tool in studying activity and impact of PRMTs. This study aimed at analysing PRMTs in melanoma and the potential impact of MTA on tumourigenesis. Our findings demonstrate that expression of PRMT4/CARM1 and PRMT6 is deregulated in melanoma, whereas expression of the remaining PRMTs stays unchanged. General PRMT activity and, consequently, symmetric and asymmetric protein methylation are reduced significantly in melanoma cells and tissues. This is due to a loss of MTAP expression and accumulation of MTA. Reduction of protein methylation by MTA affects cell signalling and leads, for example, to an activation of extracellular signal-regulated kinase (ERK) activity. The effects of endogeneous MTA on PRMTs as presented in this study can strongly support the migratory and invasive phenotype of melanoma cells. Copyright © 2012 Elsevier Ltd. All rights reserved.

Dendritic cells for active immunotherapy: optimizing design and manufacture in order to develop commercially and clinically viable products.

PubMed

Nicolette, C A; Healey, D; Tcherepanova, I; Whelton, P; Monesmith, T; Coombs, L; Finke, L H; Whiteside, T; Miesowicz, F

2007-09-27

Dendritic cell (DC) active immunotherapy is potentially efficacious in a broad array of malignant disease settings. However, challenges remain in optimizing DC-based therapy for maximum clinical efficacy within manufacturing processes that permit quality control and scale-up of consistent products. In this review we discuss the critical issues that must be addressed in order to optimize DC-based product design and manufacture, and highlight the DC based platforms currently addressing these issues. Variables in DC-based product design include the type of antigenic payload used, DC maturation steps and activation processes, and functional assays. Issues to consider in development include: (a) minimizing the invasiveness of patient biological material collection; (b) minimizing handling and manipulations of tissue at the clinical site; (c) centralized product manufacturing and standardized processing and capacity for commercial-scale production; (d) rapid product release turnaround time; (e) the ability to manufacture sufficient product from limited starting material; and (f) standardized release criteria for DC phenotype and function. Improvements in the design and manufacture of DC products have resulted in a handful of promising leads currently in clinical development.

Long non-coding RNA CRYBG3 blocks cytokinesis by directly binding G-actin.

PubMed

Pei, Hailong; Hu, Wentao; Guo, Ziyang; Chen, Huaiyuan; Ma, Ji; Mao, Weidong; Li, Bingyan; Wang, Aiqing; Wan, Jianmei; Zhang, Jian; Nie, Jing; Zhou, Guangming; Hei, Tom K

2018-06-22

The dynamic interchange between monomeric globular actin (G-actin) and polymeric filamentous actin filaments (F-actin) is fundamental and essential to many cellular processes including cytokinesis and maintenance of genomic stability. Here we report that the long non-coding RNA LNC CRYBG3 directly binds G-actin to inhibit its polymerization and formation of contractile rings, resulting in M-Phase cell arrest. Knockdown of LNC CRYBG3 in tumor cells enhanced their malignant phenotypes. Nucleotide sequence 228-237 of the full-length LNC CRYBG3 and the ser14 domain of beta-actin are essential for their interaction, and mutation of either of these sites abrogated binding of LNC CRYBG3 to G-actin. Binding of LNC CRYBG3 to G-actin blocked nuclear localization of MAL, which consequently kept serum response factor (SRF) away from the promoter region of several immediate early genes, including JUNB and Arp3, which are necessary for cellular proliferation, tumor growth, adhesion, movement, and metastasis. These findings reveal a novel lncRNA-actin-MAL-SRF pathway and highlight LNC CRYBG3 as a means to block cytokinesis and treat cancer by targeting the actin cytoskeleton. Copyright ©2018, American Association for Cancer Research.

Cartilage-hair hypoplasia with normal height in childhood-4 patients with a unique genotype.

PubMed

Klemetti, P; Valta, H; Kostjukovits, S; Taskinen, M; Toiviainen-Salo, S; Mäkitie, O

2017-08-01

The manifestations of cartilage-hair hypoplasia (CHH), a metaphyseal chondrodysplasia caused by RMRP mutations, include short stature, hypoplastic hair, immunodeficiency and increased risk of malignancies. Clinical features show significant variability. We report a patient with normal height until age 12.5 years (-1.6 SDS at 11 years) who was diagnosed with CHH at 14 years. RMRP sequencing revealed compound heterozygosity for g.70A>G mutation and a 10-nucleotide duplication at position -13 (TACTCTGTGA). Through the Finnish Skeletal Dysplasia Register, we identified 3 additional patients with identical genotype. Two of them also showed unusually mild growth failure (height SDS -1.6 at 14 years and -3.0 at 12 years, respectively). Three of the 4 patients suffered from recurrent infections; 1 developed progressive bronchiectasis and another died from aggressive lymphoma. Our findings expand the phenotypic variability in CHH to include normal childhood height. The milder growth retardation related to this particular genotype was not associated with less severe extra-skeletal manifestations, emphasizing the need for careful follow-up also in CHH patients with mild-skeletal manifestations. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Ethanol inhibits B16-BL6 melanoma metastasis and cell phenotypes associated with metastasis.

PubMed

Kushiro, Kyoko; Núñez, Nomelí P

2012-01-01

Every year, approximately 68,000 new cases of malignant melanoma are diagnosed in the US. Ethanol consumption inhibits metastasis of melanoma in mice, but the mechanism is not well understood. C57BL/6J ob/+ mice, given either water or 20% ethanol, were injected intravenously with B16-BL6 melanoma cells to determine pulmonary metastasis. The effects of ethanol on cell phenotypes and markers of the epithelial-to-mesenchymal transition were determined in cell culture. In mice, ethanol consumption inhibited experimental pulmonary metastasis. This inhibition was associated with decreased body weight, and levels of systemic leptin, and insulin. In cell culture, ethanol inhibited B16-BL6 cell motility, invasion, and anchorage-independent growth. Additionally, ethanol reduced Snai1 expression and increased E-cadherin expression. Lastly, ethanol increased the expression of Kiss1 metastasis-suppressor and the metastasis suppressor Nm23/nucleoside diphosphate kinase. In both animal and in cell culture conditions, ethanol inhibited the metastatic ability of B16-BL6 melanoma cells.

JPO2/CDCA7L and LEDGF/p75 Are Novel Mediators of PI3K/AKT Signaling and Aggressive Phenotypes in Medulloblastoma.

PubMed

Chan, Tiffany Sin Yu; Hawkins, Cynthia; Krieger, Jonathan R; McGlade, C Jane; Huang, Annie

2016-05-01

Substantial evidence links Myc-PI3K/AKT signaling to the most aggressive subtype of medulloblastoma and this axis in medulloblastoma therapy. In this study, we advance understanding of how Myc-PI3K/AKT signaling contributes to this malignancy, specifically, in identifying the Myc-interacting protein JPO2 and its partner binding protein LEDGF/p75 as critical modulators of PI3K/AKT signaling and metastasis in medulloblastoma. JPO2 overexpression induced metastatic medulloblastoma in vivo through two synergistic feed-forward regulatory circuits involving LEDGF/p75 and AKT that promote metastatic phenotypes in this setting. Overall, our findings highlight two novel prometastatic loci in medulloblastoma and point to the JPO2:LEDGF/p75 protein complex as a potentially new targetable component of PI3K/AKT signaling in medulloblastoma. Cancer Res; 76(9); 2802-12. ©2016 AACR. ©2016 American Association for Cancer Research.

Hereditary familial polyposis and Gardner's syndrome: contribution of the odonto-stomatology examination in its diagnosis and a case description.

PubMed

Chimenos-Küstner, Eduardo; Pascual, Montserrat; Blanco, Ignacio; Finestres, Fernando

2005-01-01

Familial Adenomatous Polyposis (FAP) and its phenotype variant, Gardner's syndrome, constitute a rare autosomal dominant inherited disorder. They are characterised by the development, generally during the second and third decades of life, of multiple adenomatous polyps in the colon and rectum. These polyps have a high risk of subsequently becoming malignant, which normally occurs in the third and fourth decades of life. The phenotypical features of FAP can be very variable. As well as colorectal polyps, these individuals can present with extra-colonic symptoms, among which are particularly: gastro-duodenal polyps, dermoid and epidermoid cysts, desmoid tumours, congenital hypertrophy of the retinal pigment epithelium, disorders of the maxillary and skeletal bones and dental anomalies. In this paper the most important aspects of this syndrome are reviewed, showing an example based on a well documented clinical case. The importance of odonto-stomatological examinations should be pointed out, among others, as a means of reaching a presumptive diagnosis, whose confirmation is vital to the patient.

Epigenomic alterations define lethal CIMP-positive ependymomas of infancy

PubMed Central

Mack, S. C.; Witt, H.; Piro, R. M.; Gu, L.; Zuyderduyn, S.; Stütz, A. M.; Wang, X.; Gallo, M.; Garzia, L.; Zayne, K.; Zhang, X.; Ramaswamy, V.; Jäger, N.; Jones, D. T. W.; Sill, M.; Pugh, T. J.; Ryzhova, M.; Wani, K. M.; Shih, D. J. H.; Head, R.; Remke, M.; Bailey, S. D.; Zichner, T.; Faria, C. C.; Barszczyk, M.; Stark, S.; Seker-Cin, H.; Hutter, S.; Johann, P.; Bender, S.; Hovestadt, V.; Tzaridis, T.; Dubuc, A. M.; Northcott, P. A.; Peacock, J.; Bertrand, K. C.; Agnihotri, S.; Cavalli, F. M. G.; Clarke, I.; Nethery-Brokx, K.; Creasy, C. L.; Verma, S. K.; Koster, J.; Wu, X.; Yao, Y.; Milde, T.; Sin-Chan, P.; Zuccaro, J.; Lau, L.; Pereira, S.; Castelo-Branco, P.; Hirst, M.; Marra, M. A.; Roberts, S. S.; Fults, D.; Massimi, L.; Cho, Y. J.; Van Meter, T.; Grajkowska, W.; Lach, B.; Kulozik, A. E.; von Deimling, A.; Witt, O.; Scherer, S. W.; Fan, X.; Muraszko, K. M.; Kool, M.; Pomeroy, S. L.; Gupta, N.; Phillips, J.; Huang, A.; Tabori, U.; Hawkins, C.; Malkin, D.; Kongkham, P. N.; Weiss, W. A.; Jabado, N.; Rutka, J. T.; Bouffet, E.; Korbel, J. O.; Lupien, M.; Aldape, K. D.; Bader, G. D.; Eils, R.; Lichter, P.; Dirks, P. B.; Pfister, S. M.; Korshunov, A.; Taylor, M. D.

2014-01-01

Ependymomas are common childhood brain tumours that occur throughout the nervous system, but are most common in the paediatric hindbrain. Current standard therapy comprises surgery and radiation, but not cytotoxic chemotherapy as it does not further increase survival. Whole-genome and whole-exome sequencing of 47 hindbrain ependymomas reveals an extremely low mutation rate, and zero significant recurrent somatic single nucleotide variants. Although devoid of recurrent single nucleotide variants and focal copy number aberrations, poor-prognosis hindbrain ependymomas exhibit a CpG island methylator phenotype. Transcriptional silencing driven by CpG methylation converges exclusively on targets of the Polycomb repressive complex 2 which represses expression of differentiation genes through trimethylation of H3K27. CpG island methylator phenotype-positive hindbrain ependymomas are responsive to clinical drugs that target either DNA or H3K27 methylation both in vitro and in vivo. We conclude that epigenetic modifiers are the first rational therapeutic candidates for this deadly malignancy, which is epigenetically deregulated but genetically bland. PMID:24553142

Epigenomic alterations define lethal CIMP-positive ependymomas of infancy.

PubMed

Mack, S C; Witt, H; Piro, R M; Gu, L; Zuyderduyn, S; Stütz, A M; Wang, X; Gallo, M; Garzia, L; Zayne, K; Zhang, X; Ramaswamy, V; Jäger, N; Jones, D T W; Sill, M; Pugh, T J; Ryzhova, M; Wani, K M; Shih, D J H; Head, R; Remke, M; Bailey, S D; Zichner, T; Faria, C C; Barszczyk, M; Stark, S; Seker-Cin, H; Hutter, S; Johann, P; Bender, S; Hovestadt, V; Tzaridis, T; Dubuc, A M; Northcott, P A; Peacock, J; Bertrand, K C; Agnihotri, S; Cavalli, F M G; Clarke, I; Nethery-Brokx, K; Creasy, C L; Verma, S K; Koster, J; Wu, X; Yao, Y; Milde, T; Sin-Chan, P; Zuccaro, J; Lau, L; Pereira, S; Castelo-Branco, P; Hirst, M; Marra, M A; Roberts, S S; Fults, D; Massimi, L; Cho, Y J; Van Meter, T; Grajkowska, W; Lach, B; Kulozik, A E; von Deimling, A; Witt, O; Scherer, S W; Fan, X; Muraszko, K M; Kool, M; Pomeroy, S L; Gupta, N; Phillips, J; Huang, A; Tabori, U; Hawkins, C; Malkin, D; Kongkham, P N; Weiss, W A; Jabado, N; Rutka, J T; Bouffet, E; Korbel, J O; Lupien, M; Aldape, K D; Bader, G D; Eils, R; Lichter, P; Dirks, P B; Pfister, S M; Korshunov, A; Taylor, M D

2014-02-27

Ependymomas are common childhood brain tumours that occur throughout the nervous system, but are most common in the paediatric hindbrain. Current standard therapy comprises surgery and radiation, but not cytotoxic chemotherapy as it does not further increase survival. Whole-genome and whole-exome sequencing of 47 hindbrain ependymomas reveals an extremely low mutation rate, and zero significant recurrent somatic single nucleotide variants. Although devoid of recurrent single nucleotide variants and focal copy number aberrations, poor-prognosis hindbrain ependymomas exhibit a CpG island methylator phenotype. Transcriptional silencing driven by CpG methylation converges exclusively on targets of the Polycomb repressive complex 2 which represses expression of differentiation genes through trimethylation of H3K27. CpG island methylator phenotype-positive hindbrain ependymomas are responsive to clinical drugs that target either DNA or H3K27 methylation both in vitro and in vivo. We conclude that epigenetic modifiers are the first rational therapeutic candidates for this deadly malignancy, which is epigenetically deregulated but genetically bland.

Recent studies on the developing human hepatocellular carcinoma.

PubMed

Gerber, M A

1986-01-01

From our knowledge of characteristic phenotypic changes of the preneoplastic lesions during the stepwise evolution of hepatocellular carcinoma (HCC) in experimental models, we are now beginning to define the structural, histochemical, biochemical, antigenic and molecular properties of early HCC and of the putative preneoplastic changes in human liver. Histological, ultrastructural, morphometric and immunohistochemical studies suggest that adenomatous nodules of regenerating and hyperplastic hepatocytes are more likely to represent direct precursors of HCC than dysplastic hepatocytes. Histochemical and immunomorphological investigations show appreciable functional and phenotypic heterogeneity of human HCC as previously recognized in experimental hepatocarcinogenesis. Studies of altered expression of oncogenes in the regenerating liver and HCC are beginning to define the molecular mechanisms in cell growth and malignant transformation. Although integration of Hepadna viral DNA sequences frequently occurs during persistent infection in man and animals, the exact mechanism of viral oncogenesis remains to be elucidated. It is likely that the development of monoclonal antibodies to surface antigens on transformed hepatocytes will be useful for exploring lineage relationships between the cell populations involved in hepatocarcinogenesis.

The role of IDH1 mutated tumour cells in secondary glioblastomas: an evolutionary game theoretical view

NASA Astrophysics Data System (ADS)

Basanta, David; Scott, Jacob G.; Rockne, Russ; Swanson, Kristin R.; Anderson, Alexander R. A.

2011-02-01

Recent advances in clinical medicine have elucidated two significantly different subtypes of glioblastoma which carry very different prognoses, both defined by mutations in isocitrate dehydrogenase-1 (IDH-1). The mechanistic consequences of this mutation have not yet been fully clarified, with conflicting opinions existing in the literature; however, IDH-1 mutation may be used as a surrogate marker to distinguish between primary and secondary glioblastoma multiforme (sGBM) from malignant progression of a lower grade glioma. We develop a mathematical model of IDH-1 mutated secondary glioblastoma using evolutionary game theory to investigate the interactions between four different phenotypic populations within the tumor: autonomous growth, invasive, glycolytic, and the hybrid invasive/glycolytic cells. Our model recapitulates glioblastoma behavior well and is able to reproduce two recent experimental findings, as well as make novel predictions concerning the rate of invasive growth as a function of vascularity, and fluctuations in the proportions of phenotypic populations that a glioblastoma will experience under different microenvironmental constraints.

Inhibition of GPR158 by microRNA-449a suppresses neural lineage of glioma stem/progenitor cells and correlates with higher glioma grades.

PubMed

Li, Ningning; Zhang, Ying; Sidlauskas, Kastytis; Ellis, Matthew; Evans, Ian; Frankel, Paul; Lau, Joanne; El-Hassan, Tedani; Guglielmi, Loredana; Broni, Jessica; Richard-Loendt, Angela; Brandner, Sebastian

2018-05-03

To identify biomarkers for glioma growth, invasion and progression, we used a candidate gene approach in mouse models with two complementary brain tumour phenotypes, developing either slow-growing, diffusely infiltrating gliomas or highly proliferative, non-invasive primitive neural tumours. In a microRNA screen we first identified microRNA-449a as most significantly differentially expressed between these two tumour types. miR-449a has a target dependent effect, inhibiting cell growth and migration by downregulation of CCND1 and suppressing neural phenotypes by inhibition of G protein coupled-receptor (GPR) 158. GPR158 promotes glioma stem cell differentiation and induces apoptosis and is highest expressed in the cerebral cortex and in oligodendrogliomas, lower in IDH mutant astrocytomas and lowest in the most malignant form of glioma, IDH wild-type glioblastoma. The correlation of GPR158 expression with molecular subtypes, patient survival and therapy response suggests a possible role of GPR158 as prognostic biomarker in human gliomas.

Secondary malignancy following radiotherapy for thyroid eye disease.

PubMed

Gillis, Christopher C; Chang, Eun Hae; Al-Kharazi, Khalid; Pickles, Tom

2016-01-01

To describe the first case of a secondary meningioma in a patient after radiation treatment for thyroid eye disease (TED). Secondarily to identify any additional cases of secondary malignancy resulting from radiotherapy for thyroid eye disease from our institutional experience. Thyroid eye disease (TED) is a self-limiting auto-immune disorder causing expansion of orbital soft tissue from deposition of glycosaminoglycans and collagen, leading to significant cosmetic and functional morbidity. Established management options for TED include: glucocorticosteroids, orbital radiotherapy, and surgical orbital decompression. Two large series on radiotherapy for TED have been reported without any cases of secondary malignancy. The case of a patient with visual failure, found to have a sphenoid wing meningioma after previous TED radiotherapy is described. We then reviewed 575 patients with at least 3-year follow-up receiving radiotherapy for TED at British Columbia Cancer Agency to identify other possible secondary malignancies. The patient had postoperative improvement in her vision without any identified complications. Three additional cases of hematologic malignancy were identified. The calculated risk in our population of developing a radiation-induced meningioma after TED with at least 3 years of follow-up of is 0.17% (1/575); with hematopoetic malignancies the risk for secondary malignancy is 0.7% (4/575). Our calculated risk for secondary malignancy (0.17%, 0.7%) is similar to the reported theoretical risk published in the literature (0.3-1.2%). There is real risk for the development of a secondary malignancy after radiotherapy treatment of TED and treatment options should include consideration for this potential.

Economic burden of non-malignant blood disorders across Europe: a population-based cost study.

PubMed

Luengo-Fernandez, Ramon; Burns, Richeal; Leal, Jose

2016-08-01

Blood disorders comprise a wide range of diseases including anaemia, malignant blood disorders, and haemorrhagic disorders. Although they are a common cause of disease, no systematic cost-of-illness studies have been done to assess the economic effect of non-malignant blood disorders in Europe. We aimed to assess the economic burden of non-malignant blood disorders across the 28 countries of the European Union (EU), Iceland, Norway, and Switzerland. Non-malignant blood disorder-related costs (WHO International Classification of Diseases, 10th revision [ICD] D50-89) were estimated for 28 EU countries, Iceland, Norway, and Switzerland for 2012. Country-specific costs were estimated with aggregate data on morbidity, mortality, and health-care resource use obtained from international and national sources. Health-care costs were estimated from expenditure on primary care, outpatient care, emergency care, hospital inpatient care, and drugs. Costs of informal care and productivity losses due to morbidity and early death were also included. To these costs we added those due to malignant blood disorders (ICD-10 C81-96 and D47) as estimated in a Burns and colleagues' companion Article to obtain the total costs of blood disorders. Non-malignant disorders of the blood cost the 31 European countries €11 billion in 2012. Health-care costs accounted for €8 billion (75% of total costs), productivity losses for €2 billion (19%), and informal care for less than €1 billion (6%). Averaged across the European population studied, non-malignant disorders of the blood represented an annual health-care cost of €159 per ten citizens. Combining malignant and non-malignant blood disorders, the total cost of blood disorders was €23 billion in 2012. Our study highlights the economic burden that non-malignant blood disorders place on European health-care systems and societies. Our study also shows that blood disorder costs were evenly distributed between malignant and non-malignant blood disorders. Our results should be of use to decision makers and research-funding authorities charged with allocating health-care resources and research funds. European Hematology Association. Copyright © 2016 Elsevier Ltd. All rights reserved.

Genotype-Phenotype Correlation in NF1: Evidence for a More Severe Phenotype Associated with Missense Mutations Affecting NF1 Codons 844-848.

PubMed

Koczkowska, Magdalena; Chen, Yunjia; Callens, Tom; Gomes, Alicia; Sharp, Angela; Johnson, Sherrell; Hsiao, Meng-Chang; Chen, Zhenbin; Balasubramanian, Meena; Barnett, Christopher P; Becker, Troy A; Ben-Shachar, Shay; Bertola, Debora R; Blakeley, Jaishri O; Burkitt-Wright, Emma M M; Callaway, Alison; Crenshaw, Melissa; Cunha, Karin S; Cunningham, Mitch; D'Agostino, Maria D; Dahan, Karin; De Luca, Alessandro; Destrée, Anne; Dhamija, Radhika; Eoli, Marica; Evans, D Gareth R; Galvin-Parton, Patricia; George-Abraham, Jaya K; Gripp, Karen W; Guevara-Campos, Jose; Hanchard, Neil A; Hernández-Chico, Concepcion; Immken, LaDonna; Janssens, Sandra; Jones, Kristi J; Keena, Beth A; Kochhar, Aaina; Liebelt, Jan; Martir-Negron, Arelis; Mahoney, Maurice J; Maystadt, Isabelle; McDougall, Carey; McEntagart, Meriel; Mendelsohn, Nancy; Miller, David T; Mortier, Geert; Morton, Jenny; Pappas, John; Plotkin, Scott R; Pond, Dinel; Rosenbaum, Kenneth; Rubin, Karol; Russell, Laura; Rutledge, Lane S; Saletti, Veronica; Schonberg, Rhonda; Schreiber, Allison; Seidel, Meredith; Siqveland, Elizabeth; Stockton, David W; Trevisson, Eva; Ullrich, Nicole J; Upadhyaya, Meena; van Minkelen, Rick; Verhelst, Helene; Wallace, Margaret R; Yap, Yoon-Sim; Zackai, Elaine; Zonana, Jonathan; Zurcher, Vickie; Claes, Kathleen; Martin, Yolanda; Korf, Bruce R; Legius, Eric; Messiaen, Ludwine M

2018-01-04

Neurofibromatosis type 1 (NF1), a common genetic disorder with a birth incidence of 1:2,000-3,000, is characterized by a highly variable clinical presentation. To date, only two clinically relevant intragenic genotype-phenotype correlations have been reported for NF1 missense mutations affecting p.Arg1809 and a single amino acid deletion p.Met922del. Both variants predispose to a distinct mild NF1 phenotype with neither externally visible cutaneous/plexiform neurofibromas nor other tumors. Here, we report 162 individuals (129 unrelated probands and 33 affected relatives) heterozygous for a constitutional missense mutation affecting one of five neighboring NF1 codons-Leu844, Cys845, Ala846, Leu847, and Gly848-located in the cysteine-serine-rich domain (CSRD). Collectively, these recurrent missense mutations affect ∼0.8% of unrelated NF1 mutation-positive probands in the University of Alabama at Birmingham (UAB) cohort. Major superficial plexiform neurofibromas and symptomatic spinal neurofibromas were more prevalent in these individuals compared with classic NF1-affected cohorts (both p < 0.0001). Nearly half of the individuals had symptomatic or asymptomatic optic pathway gliomas and/or skeletal abnormalities. Additionally, variants in this region seem to confer a high predisposition to develop malignancies compared with the general NF1-affected population (p = 0.0061). Our results demonstrate that these NF1 missense mutations, although located outside the GAP-related domain, may be an important risk factor for a severe presentation. A genotype-phenotype correlation at the NF1 region 844-848 exists and will be valuable in the management and genetic counseling of a significant number of individuals. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Paediatric and adult soft tissue sarcomas with NTRK1 gene fusions: a subset of spindle cell sarcomas unified by a prominent myopericytic/haemangiopericytic pattern.

PubMed

Haller, Florian; Knopf, Jasmin; Ackermann, Anne; Bieg, Matthias; Kleinheinz, Kortine; Schlesner, Matthias; Moskalev, Evgeny A; Will, Rainer; Satir, Ali Abdel; Abdelmagid, Ibtihalat E; Giedl, Johannes; Carbon, Roman; Rompel, Oliver; Hartmann, Arndt; Wiemann, Stefan; Metzler, Markus; Agaimy, Abbas

2016-04-01

Neoplasms with a myopericytomatous pattern represent a morphological spectrum of lesions encompassing myopericytoma of the skin and soft tissue, angioleiomyoma, myofibromatosis/infantile haemangiopericytoma and putative neoplasms reported as malignant myopericytoma. Lack of reproducible phenotypic and genetic features of malignant myopericytic neoplasms have prevented the establishment of myopericytic sarcoma as an acceptable diagnostic category. Following detection of a LMNA-NTRK1 gene fusion in an index case of paediatric haemangiopericytoma-like sarcoma by combined whole-genome and RNA sequencing, we identified three additional sarcomas harbouring NTRK1 gene fusions, termed 'spindle cell sarcoma, NOS with myo/haemangiopericytic growth pattern'. The patients were two children aged 11 months and 2 years and two adults aged 51 and 80 years. While the tumours of the adults were strikingly myopericytoma-like, but with clear-cut atypical features, the paediatric cases were more akin to infantile myofibromatosis/haemangiopericytoma. All cases contained numerous thick-walled dysplastic-like vessels with segmental or diffuse nodular myxohyaline myo-intimal proliferations of smooth muscle actin-positive cells, occasionally associated with thrombosis. Immunohistochemistry showed variable expression of smooth muscle actin and CD34, but other mesenchymal markers, including STAT6, were negative. This study showed a novel variant of myo/haemangiopericytic sarcoma with recurrent NTRK1 gene fusions. Given the recent introduction of a novel therapeutic approach targeting NTRK fusion-positive neoplasms, recognition of this rare but likely under-reported sarcoma variant is strongly encouraged. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Potential Role of Natural Compounds as Anti-Angiogenic Agents in Cancer.

PubMed

Shanmugam, Muthu K; Warrier, Sudha; Kumar, Alan P; Sethi, Gautam; Arfuso, Frank

2017-01-01

Neovascularization, also known as angiogenesis, is the process of capillary sprouting from pre-existing blood vessels. This physiological process is a hallmark event in normal embryonic development as blood vessels generally supply both oxygen and nutrients to the cells of the body. Any disruption in this process can lead to the development of various chronic diseases, including cancer. In cancer, aberrant angiogenesis plays a prominent role in maintaining sustained tumor growth to malignant phenotypes and promoting metastasis. The leakiness in the tumor microvasculature is attributed to the tumor cells migrating to distal site organs and forming colonies. In this article, we briefly review the various mediators involved in the angiogenic process and the anti-angiogenic potential of selected natural compounds against various malignancies. Several growth factors and their receptors such as vascular endothelial growth factor and receptor (VEGF/VEGFR), basic fibroblast growth factor and receptor (bFGF/FGFR), angiopoietins, and hypoxia inducible factors facilitate the development of angiogenesis and are attractive anti-cancer targets. Natural products represent a rich diversity of compounds for drug discovery and are currently being actively exploited to target tumor angiogenesis. Agents such as curcumin, artemisinin, EGCG, resveratrol, emodin, celastrol, thymoquinone and tocotrienols all have shown prominent anti-angiogenic effects in the preclinical models of tumor angiogenesis. Several semi-synthetic derivatives and novel nano-formulations of these natural compounds have also exhibited excellent anti-angiogenic activity by increasing bioavailability and delivering the drugs to the sites of tumor angiogenesis. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

The serrated neoplasia pathway of colorectal tumors: Identification of MUC5AC hypomethylation as an early marker of polyps with malignant potential.

PubMed

Renaud, Florence; Mariette, Christophe; Vincent, Audrey; Wacrenier, Agnès; Maunoury, Vincent; Leclerc, Julie; Coppin, Lucie; Crépin, Michel; Van Seuningen, Isabelle; Leteurtre, Emmanuelle; Buisine, Marie-Pierre

2016-03-15

The serrated neoplasia pathway accounts for 20-30% of colorectal cancers (CRC), which are characterized by extensive methylation (CpG island methylation phenotype, CIMP), frequent BRAF mutation and high microsatellite instability (MSI). We recently identified MUC5AC mucin gene hypomethylation as a specific marker of MSI CRC. The early identification of preneoplastic lesions among serrated polyps is currently challenging. Here, we performed a detailed pathological and molecular analysis of a large series of colorectal serrated polyps and evaluated the usefulness of mucin genes MUC2 and MUC5AC to differentiate serrated polyps and to identify lesions with malignant potential. A series of 330 colorectal polyps including 218 serrated polyps [42 goblet cell-rich hyperplastic polyps (GCHP), 68 microvesicular hyperplastic polyps (MVHP), 100 sessile serrated adenoma (SSA) and eight traditional serrated adenoma (TSA)] and 112 conventional adenomas was analyzed for BRAF/KRAS mutations, MSI, CIMP, MLH1 and MGMT methylation, and MUC2 and MUC5AC expression and methylation. We show that MUC5AC hypomethylation is an early event in the serrated neoplasia pathway, and specifically detects MVHP and SSA, arguing for a filiation between MVHP, SSA and CIMP-H/MSI CRC, whereas GCHP and TSA arise from a distinct pathway. Moreover, MUC5AC hypomethylation specifically identified serrated lesions with BRAF mutation, CIMP-H or MSI, suggesting that it may be useful to identify serrated neoplasia pathway-related precursor lesions. Our data suggest that MVHP should be recognized among HP and require particular attention. © 2015 UICC.

Immunohistochemical features of giant cell ependymoma of the filum terminale with unusual clinical and radiological presentation.

PubMed

Candanedo-Gonzalez, Fernando; Ortiz-Arce, Cindy Sharon; Rosales-Perez, Samuel; Remirez-Castellanos, Ana Lilia; Cordova-Uscanga, Candelaria; Gamboa-Dominguez, Armando

2017-01-14

Giant cell ependymoma of the filum terminale is a rare variant, generally manifested as a well-circunscribed intradural mass with an indolent biological behavior. We describe the case of a 48-year-old Mexican female who non-relevant past medical history, that developed a GCE of the filum terminale. Magnetic resonance imaging and computed tomography revealed the presence of an intra-axial tumor extending from L3 to L5 with extra-medullary invasion. Therefore the tumor was considered unresectable and only incisional biopsy was obtained, establishing the tentative diagnosis of a poorly differentiated neoplasia. A second evaluation of the case revealed the presence of numerous non-cohesive pleomorphic giant cells with intranuclear inclusions and broad eosinophilic cytoplasm, alternating with intermediate size cells with round, hyperchromatic nuclei and forming a perivascular pseudo-rosettes pattern. The ependymal phenotype was supported by light microscopy and corroborated by immunohistochemistry analysis. The patient was subsequently treated with radiotherapy 54Gy. She is alive after a 27-month follow-up, with residual disease, difficulty ambulating and pain. GCE of filum terminale may have an atypical clinical and radiological presentation, albeit with invasive characteristics and anaplasia on histologic analysis. However, its biological behavior is indolent and associated to longer survival. Due to the presence of giant cells, the differential diagnosis of other primary neoplasias at that site were considered, including paraganglioma, malignant peripheral nerve sheath tumors as well as metastatic malignant melanoma, adrenal carcinoma, thyroid gland carcinoma and urothelial carcinoma, that may all harbor giant cells.

Delocalized Claudin-1 promotes metastasis of human osteosarcoma cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jian, Yuekui; Chen, Changqiong; Li, Bo

2015-10-23

Tight junction proteins (TJPs) including Claudins, Occludin and tight junction associated protein Zonula occludens-1 (ZO-1), are the most apical component of junctional complex that mediates cell–cell adhesion in epithelial and endothelial cells. In human malignancies, TJPs are often deregulated and affect cellular behaviors of tumor cells. In this study, we investigated alternations of TJPs and related biological characteristics in human osteosarcoma (OS). Claudin1 was increased in the metastatic OS cells (KRIB and KHOS) compared with the normal osteoblast cells (hFOB1.19) or primary tumor cells (HOS and U2OS), whereas no significant difference was found in Occludin and ZO-1. Immunohistochemistry, immunofluorescence andmore » Western blotting revealed that Claudin1 was initially localized at cell junctions of normal osteoblasts, but substantially delocalized to the nucleus of metastatic OS cells. Phenotypically, inhibition of the nucleus Claudin1 expression compromised the metastatic potential of KRIB and KHOS cells. Moreover, we found that protein kinase C (PKC) but not PKA phosphorylation influenced Claudin1 expression and cellular functions, as PKC inhibitor (Go 6983 and Staurosporine) or genetic silencing of PKC reduced Claudin1 expression and decreased the motility of KRIB and KHOS cells. Taken together, our study implied that delocalization of claudin-1 induced by PKC phosphorylation contributes to metastatic capacity of OS cells. - Highlights: • Claudin1 is increased during the malignant transformation of human OS. • Delocalization of Claudin1 in metastatic OS cells. • Silencing nuclear Claudin1 expression inhibits cell invasion of OS. • Deregulated Claudin1 is regulated by PKC.« less

Mouse papillomavirus infections spread to cutaneous sites with progression to malignancy

PubMed Central

Cladel, Nancy M.; Budgeon, Lynn R.; Cooper, Timothy K.; Balogh, Karla K.; Christensen, Neil D.; Myers, Roland; Majerciak, Vladimir; Gotte, Deanna; Zheng, Zhi-Ming; Hu, Jiafen

2017-01-01

We report secondary cutaneous infections in the mouse papillomavirus (MmuPV1)/mouse model. Our previous study demonstrated that cutaneous MmuPV1 infection could spread to mucosal sites. Recently, we observed that mucosal infections could also spread to various cutaneous sites including the back, tail, muzzle and mammary tissues. The secondary site lesions were positive for viral DNA, viral capsid protein and viral particles as determined by in situ hybridization, immunohistochemistry and transmission electron microscopy analyses, respectively. We also demonstrated differential viral production and tumour growth at different secondarily infected skin sites. For example, fewer viral particles were detected in the least susceptible back tissues when compared with those in the infected muzzle and tail, although similar amounts of viral DNA were detected. Follow-up studies demonstrated that significantly lower amounts of viral DNA were packaged in the back lesions. Lavages harvested from the oral cavity and lower genital tracts were equally infectious at both cutaneous and mucosal sites, supporting the broad tissue tropism of this papillomavirus. Importantly, two secondary skin lesions on the forearms of two mice displayed a malignant phenotype at about 9.5 months post-primary infection. Therefore, MmuPV1 induces not only dysplasia at mucosal sites such as the vagina, anus and oral cavity but also skin carcinoma at cutaneous sites. These findings demonstrate that MmuPV1 mucosal infection can be spread to cutaneous sites and suggest that the model could serve a useful role in the study of the viral life cycle and pathogenesis of papillomavirus. PMID:28942760

Mouse papillomavirus infections spread to cutaneous sites with progression to malignancy.

PubMed

Cladel, Nancy M; Budgeon, Lynn R; Cooper, Timothy K; Balogh, Karla K; Christensen, Neil D; Myers, Roland; Majerciak, Vladimir; Gotte, Deanna; Zheng, Zhi-Ming; Hu, Jiafen

2017-09-25

We report secondary cutaneous infections in the mouse papillomavirus (MmuPV1)/mouse model. Our previous study demonstrated that cutaneous MmuPV1 infection could spread to mucosal sites. Recently, we observed that mucosal infections could also spread to various cutaneous sites including the back, tail, muzzle and mammary tissues. The secondary site lesions were positive for viral DNA, viral capsid protein and viral particles as determined by in situ hybridization, immunohistochemistry and transmission electron microscopy analyses, respectively. We also demonstrated differential viral production and tumour growth at different secondarily infected skin sites. For example, fewer viral particles were detected in the least susceptible back tissues when compared with those in the infected muzzle and tail, although similar amounts of viral DNA were detected. Follow-up studies demonstrated that significantly lower amounts of viral DNA were packaged in the back lesions. Lavages harvested from the oral cavity and lower genital tracts were equally infectious at both cutaneous and mucosal sites, supporting the broad tissue tropism of this papillomavirus. Importantly, two secondary skin lesions on the forearms of two mice displayed a malignant phenotype at about 9.5 months post-primary infection. Therefore, MmuPV1 induces not only dysplasia at mucosal sites such as the vagina, anus and oral cavity but also skin carcinoma at cutaneous sites. These findings demonstrate that MmuPV1 mucosal infection can be spread to cutaneous sites and suggest that the model could serve a useful role in the study of the viral life cycle and pathogenesis of papillomavirus.

Changing presentation of cutaneous malignant melanoma.

PubMed

Klit, Anders; Lassen, Cecilie Brandt; Olsen, Caroline Holkmann; Lock-Andersen, Jørgen

2015-10-01

The incidence of cutaneous malignant melanoma is rapidly increasing in Denmark like in other Northern and Western European countries. Our objective was to investigate the characteristics of current patients suffering from cutaneous malignant melanoma. We evaluated patient and tumour characteristics in a cross-sectional study based on data from the Danish Melanoma Register. We included all patients diagnosed with cutaneous malignant melanoma in Healthcare Region Zealand in 2012 and 2013. We identified 520 patients with invasive cutaneous malignant melanoma. More females than males suffered from cutaneous malignant melanoma. Furthermore, females were younger than males, and the anatomical distribution of malignant melanoma varied between the genders. Outcome of sentinel lymph node biopsy was associated with tumour thickness. When comparing findings in our study with earlier Danish studies, we see a trend towards an increase in age at diagnosis. Furthermore, tumour thickness is decreasing and the topical distribution of cutaneous malignant melanoma in females changes towards a male pattern. none. The study has been approved by the Danish National Data Protection Agency.

Malignancy in solitary thyroid nodule: A clinicoradiopathological evaluation.

PubMed

Jena, Amitabh; Patnayak, Rashmi; Prakash, Jaya; Sachan, Alok; Suresh, V; Lakshmi, Amarchala Yadagiri

2015-01-01

Thyroid nodules are common. They can be either benign or malignant. Solitary thyroid nodules (STN) have a high likelihood of being malignant. They should be characterized properly for optimum management. In this study, we have analyzed our departmental data over a period of 5 years. All the patients who presented to the outpatient department with a clinically detected STN were included in the study group. Our approach was individualized. Preoperative ultrasonography (USG) and fine-needle aspiration cytology were planned in all these patients. Hemi thyroidectomy and total thyroidectomy with and without neck dissection were performed wherever appropriate. There were 162 cases of clinically detected STN. USG findings were available in 146 cases. Postoperative histopathology was reported as malignant in 58 cases. Malignant STN was more likely in males. Ultrasonographically detected solid STN were more prone for malignancy as compared to multinodular goiter (P = 0.000) Presence of micro calcification and cervical lymphadenopathy were more commonly noted in malignant thyroid swellings. Solitary thyroid nodules do have a high likelihood of harboring a malignancy. Solid echogenicity, micro calcification and cervical lymphadenopathy on USG were seen more frequently in malignant nodules.

Computational Trials: Unraveling Motility Phenotypes, Progression Patterns, and Treatment Options for Glioblastoma Multiforme

PubMed Central

Raman, Fabio; Scribner, Elizabeth; Saut, Olivier; Wenger, Cornelia; Colin, Thierry; Fathallah-Shaykh, Hassan M.

2016-01-01

Glioblastoma multiforme is a malignant brain tumor with poor prognosis and high morbidity due to its invasiveness. Hypoxia-driven motility and concentration-driven motility are two mechanisms of glioblastoma multiforme invasion in the brain. The use of anti-angiogenic drugs has uncovered new progression patterns of glioblastoma multiforme associated with significant differences in overall survival. Here, we apply a mathematical model of glioblastoma multiforme growth and invasion in humans and design computational trials using agents that target angiogenesis, tumor replication rates, or motility. The findings link highly-dispersive, moderately-dispersive, and hypoxia-driven tumors to the patterns observed in glioblastoma multiforme treated by anti-angiogenesis, consisting of progression by Expanding FLAIR, Expanding FLAIR + Necrosis, and Expanding Necrosis, respectively. Furthermore, replication rate-reducing strategies (e.g. Tumor Treating Fields) appear to be effective in highly-dispersive and moderately-dispersive tumors but not in hypoxia-driven tumors. The latter may respond to motility-reducing agents. In a population computational trial, with all three phenotypes, a correlation was observed between the efficacy of the rate-reducing agent and the prolongation of overall survival times. This research highlights the potential applications of computational trials and supports new hypotheses on glioblastoma multiforme phenotypes and treatment options. PMID:26756205

Elevated phospholipase D activity in androgen-insensitive prostate cancer cells promotes both survival and metastatic phenotypes.

PubMed

Utter, Matthew; Chakraborty, Sohag; Goren, Limor; Feuser, Lucas; Zhu, Yuan-Shan; Foster, David A

2018-06-01

Prostate cells are hormonally driven to grow and divide. Typical treatments for prostate cancer involve blocking activation of the androgen receptor by androgens. Androgen deprivation therapy can lead to the selection of cancer cells that grow and divide independently of androgen receptor activation. Prostate cancer cells that are insensitive to androgens commonly display metastatic phenotypes and reduced long-term survival of patients. In this study we provide evidence that androgen-insensitive prostate cancer cells have elevated PLD activity relative to the androgen-sensitive prostate cancer cells. PLD activity has been linked with promoting survival in many human cancer cell lines; and consistent with the previous studies, suppression of PLD activity in the prostate cancer cells resulted in apoptotic cell death. Of significance, suppressing the elevated PLD activity in androgen resistant prostate cancer lines also blocked the ability of these cells to migrate and invade Matrigel™. Since survival signals are generally an early event in tumorigenesis, the apparent coupling of survival and metastatic phenotypes implies that metastasis is an earlier event in malignant prostate cancer than generally thought. This finding has implications for screening strategies designed to identify prostate cancers before dissemination. Copyright © 2018 Elsevier B.V. All rights reserved.

Classification and clinical behavior of blastic plasmacytoid dendritic cell neoplasms according to their maturation-associated immunophenotypic profile

PubMed Central

Martín-Martín, Lourdes; López, Antonio; Vidriales, Belén; Caballero, María Dolores; Rodrigues, António Silva; Ferreira, Silvia Inês; Lima, Margarida; Almeida, Sérgio; Valverde, Berta; Martínez, Pilar; Ferrer, Ana; Candeias, Jorge; Ruíz-Cabello, Francisco; Buadesa, Josefa Marco; Sempere, Amparo; Villamor, Neus

2015-01-01

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare subtype of leukemia/lymphoma, whose diagnosis can be difficult to achieve due to its clinical and biological heterogeneity, as well as its overlapping features with other hematologic malignancies. In this study we investigated whether the association between the maturational stage of tumor cells and the clinico-biological and prognostic features of the disease, based on the analysis of 46 BPDCN cases classified into three maturation-associated subgroups on immunophenotypic grounds. Our results show that blasts from cases with an immature plasmacytoid dendritic cell (pDC) phenotype exhibit an uncommon CD56− phenotype, coexisting with CD34+ non-pDC tumor cells, typically in the absence of extramedullary (e.g. skin) disease at presentation. Conversely, patients with a more mature blast cell phenotype more frequently displayed skin/extramedullary involvement and spread into secondary lymphoid tissues. Despite the dismal outcome, acute lymphoblastic leukemia-type therapy (with central nervous system prophylaxis) and/or allogeneic stem cell transplantation appeared to be the only effective therapies. Overall, our findings indicate that the maturational profile of pDC blasts in BPDCN is highly heterogeneous and translates into a wide clinical spectrum -from acute leukemia to mature lymphoma-like behavior-, which may also lead to variable diagnosis and treatment. PMID:26056082

The diagnostic performance of shear wave elastography for malignant cervical lymph nodes: A systematic review and meta-analysis.

PubMed

Suh, Chong Hyun; Choi, Young Jun; Baek, Jung Hwan; Lee, Jeong Hyun

2017-01-01

To evaluate the diagnostic performance of shear wave elastography for malignant cervical lymph nodes. We searched the Ovid-MEDLINE and EMBASE databases for published studies regarding the use of shear wave elastography for diagnosing malignant cervical lymph nodes. The diagnostic performance of shear wave elastography was assessed using bivariate modelling and hierarchical summary receiver operating characteristic modelling. Meta-regression analysis and subgroup analysis according to acoustic radiation force impulse imaging (ARFI) and Supersonic shear imaging (SSI) were also performed. Eight eligible studies which included a total sample size of 481 patients with 647 cervical lymph nodes, were included. Shear wave elastography showed a summary sensitivity of 81 % (95 % CI: 72-88 %) and specificity of 85 % (95 % CI: 70-93 %). The results of meta-regression analysis revealed that the prevalence of malignant lymph nodes was a significant factor affecting study heterogeneity (p < .01). According to the subgroup analysis, the summary estimates of the sensitivity and specificity did not differ between ARFI and SSI (p = .93). Shear wave elastography is an acceptable imaging modality for diagnosing malignant cervical lymph nodes. We believe that both ARFI and SSI may have a complementary role for diagnosing malignant cervical lymph nodes. • Shear wave elastography is acceptable modality for diagnosing malignant cervical lymph nodes. • Shear wave elastography demonstrated summary sensitivity of 81 % and specificity of 85 %. • ARFI and SSI have complementary roles for diagnosing malignant cervical lymph nodes.