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

Stepwise DNA Methylation Changes Are Linked to Escape from Defined Proliferation Barriers and Mammary Epithelial Cell Immortalization

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

Novak, Petr; Jensen, Taylor J.; Garbe, James C.

The timing and progression of DNA methylation changes during carcinogenesis are not completely understood. To develop a timeline of aberrant DNA methylation events during malignant transformation, we analyzed genome-wide DNA methylation patterns in an isogenic human mammary epithelial cell (HMEC) culture model of transformation. To acquire immortality and malignancy, the cultured finite lifespan HMEC must overcome two distinct proliferation barriers. The first barrier, stasis, is mediated by the retinoblastoma protein and can be overcome by loss of p16(INK4A) expression. HMEC that escape stasis and continue to proliferate become genomically unstable before encountering a second more stringent proliferation barrier, telomere dysfunctionmore » due to telomere attrition. Rare cells that acquire telomerase expression may escape this barrier, become immortal, and develop further malignant properties. Our analysis of HMEC transitioning from finite lifespan to malignantly transformed showed that aberrant DNA methylation changes occur in a stepwise fashion early in the transformation process. The first aberrant DNA methylation step coincides with overcoming stasis, and results in few to hundreds of changes, depending on how stasis was overcome. A second step coincides with immortalization and results in hundreds of additional DNA methylation changes regardless of the immortalization pathway. A majority of these DNA methylation changes are also found in malignant breast cancer cells. These results show that large-scale epigenetic remodeling occurs in the earliest steps of mammary carcinogenesis, temporally links DNA methylation changes and overcoming cellular proliferation barriers, and provides a bank of potential epigenetic biomarkers that mayprove useful in breast cancer risk assessment.« less

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.

Some characteristics of neoplastic cell transformation in transgenic mice.

PubMed

Shvemberger, I N; Ermilov, A N

1996-01-01

The role of the expression of different cellular genes and viral oncogenes in malignant cell transformation is discussed. We pay special attention to the role of the genes for growth factors and their receptors and homeobox genes in oncogenesis. Based on both the literature and our own data, specific features of tumors developed in transgenic mice are discussed. All of these data are used to analyze current theories of multistep oncogenesis and the stochastic component in this process. We suggest that all known evidence about the mechanisms of oncogenesis be used in studying the problem at various structural and functional levels in an organism. The chapter shows that transgenic mice are a most suitable model for studying various aspects of malignant transformation from the molecular to the organismal and populational levels.

Predictive value of the combination of SMAD4 expression and lymphocyte infiltration in malignant transformation of oral leukoplakia.

PubMed

Sakata, Junki; Yoshida, Ryoji; Matsuoka, Yuichiro; Nagata, Masashi; Hirosue, Akiyuki; Kawahara, Kenta; Nakamura, Takuya; Nakamoto, Masafumi; Hirayama, Masatoshi; Takahashi, Nozomu; Nakashima, Hikaru; Arita, Hidetaka; Ogi, Hidenao; Hiraki, Akimitsu; Shinohara, Masanori; Nakayama, Hideki

2017-04-01

Oral leukoplakia (OL) is a common, potentially malignant disorder of the oral cavity. SMAD4 was initially identified as a tumor suppressor and central mediator of transforming growth factor (TGF)-β signaling. In this study, we aimed to determine the expression patterns of SMAD4 in OL, its relationship with the degree of inflammation, and its clinical implications as a biomarker for OL malignant transformation. A total of 150 patients with OL were enrolled in this study. Paraffin-embedded sections obtained from biopsy or resection specimens were subjected to immunohistochemical analysis. Associations among the status of epithelial SMAD4 expression, stromal lymphocyte infiltration, and malignant transformation of OL were examined. Malignant transformation was significantly associated with the status of SMAD4 expression (P = 0.0017) and lymphocyte infiltration status (P = 0.0054). Cox regression analysis, based on the event-free survival (EFS), revealed that a low SMAD4 expression was a significant prognostic factor in OL patients (hazard ratio, 2.632; P = 0.043). In addition, a low SMAD4 expression was closely correlated with high lymphocyte infiltration (P = 0.00035), resulting in a significant correlation between the combination of low SMAD4 expression and high lymphocyte infiltration with malignant transformation of OL (P = 0.00027). The combination of the status of epithelial SMAD4 expression and stromal lymphocyte infiltration may be a useful biomarker for predicting malignant transformation in OL patients. These results suggest that not only epithelial SMAD4 loss, but also stromal features, may regulate the risk of malignant transformation of OL. © 2017 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

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

Genetic changes in mammalian cells transformed by helium ions

NASA Astrophysics Data System (ADS)

Durante, M.; Grossi, G.; Yang, T. C.; Roots, R.

Midterm Syrian Hamster embryo (SHE) cells were employed to study high LET-radiation induced tumorigenesis. Normal SHE cells (secondary passage) were irradiated with accelerated helium ions at an incident energy of 22 MeV/u (9-10 keV/μm). Transformed clones were isolated after growth in soft agar of cells obtained from the foci of the initial monolayer plated postirradiation. To study the progression process of malignant transformation, the transformed clones were followed by monolayer subculturing for prolonged periods of time. Subsequently, neoplasia tests in nude mice were done. In this work, however, we have focused on karyotypic changes in the banding patterns of the chromosomes during the early part of the progressive process of cell transformation for helium ion-induced transformed cells.

Cadmium-induced malignant transformation of rat liver cells: Potential key role and regulatory mechanism of altered apolipoprotein E expression in enhanced invasiveness.

PubMed

Suzuki, Masayo; Takeda, Shuso; Teraoka-Nishitani, Noriko; Yamagata, Akane; Tanaka, Takahiro; Sasaki, Marika; Yasuda, Natsuki; Oda, Makiko; Okano, Tatsuji; Yamahira, Kazuhiro; Nakamura, Yuta; Kobayashi, Takanobu; Kino, Katsuhito; Miyazawa, Hiroshi; Waalkes, Michael P; Takiguchi, Masufumi

2017-05-01

Cadmium is a transition metal that is classified as human carcinogen by the International Agency for Research on Cancer (IARC) with multiple target sites. Many studies using various model systems provide evidence of cadmium-induced malignancy formation in vivo or malignant cell transformation in vitro. Nonetheless, further studies are needed to completely understand the mechanisms of cadmium carcinogenicity. Our prior studies have utilized a rat liver epithelial cell line (TRL 1215) as a model for cadmium-induced malignant transformation. In the present study, we focused on the molecular mechanisms of this malignant transformation, especially with regard to hyper-invasiveness stimulated by cadmium transformation. By performing a series of biochemical analyses on cadmium transformed cells, it was determined that cadmium had significantly down-regulated the expression of apolipoprotein E (ApoE). ApoE was recently established as a suppressor of cell invasion. A key factor in the suppression of ApoE by cadmium appeared to be that the metal evoked a 5-aza-2'-deoxycytidine-sensitive hypermethylation of the regulatory region of ApoE, coupled with interference of the action of liver X receptor α (LXRα), a transcriptional regulator for ApoE. Furthermore, the expression of LXRα itself was suppressed by cadmium-mediated epigenetic modification. Re-expression of ApoE clearly abrogated the cell invasion stimulated by cadmium-induced malignant transformation. Together, the current results suggest that the cadmium-mediated enhanced cell invasion is linked to down-regulation of ApoE during malignant transformation these liver cells. Copyright © 2017 Elsevier B.V. All rights reserved.

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.

Molecular and Cellular Determinants of Malignant Transformation in Pulmonary Premalignancy

DTIC Science & Technology

2017-07-01

AWARD NUMBER: W81XWH-16-1-0194 TITLE: Molecular and Cellular Determinants of Malignant Transformation in Pulmonary Premalignancy PRINCIPAL...2017 4. TITLE AND SUBTITLE Molecular and Cellular Determinants of Malignant Transformation in Pulmonary Premalignancy 5a. CONTRACT NUMBER 5b. GRANT...Sequenced Regions Figure 2. Intra- and inter-patient genetic heterogeneity of pulmonary lesions. A) Distribution of Jaccard indices comparing n.s

Malignant transformation of solitary spinal osteochondroma in two mature dogs.

PubMed

Green, E M; Adams, W M; Steinberg, H

1999-01-01

Canine osteochondroma is an uncommon bony tumor that arises in skeletally immature animals. Consequently, clinical signs typically occur in young dogs as a result of impingement of normal structures by the tumor. Radiographically, osteochondromas are benign in appearance. They are well circumscribed and cause no bony lysis nor periosteal proliferation. Osteochondromas may occur in two forms; solitary or multiple. Although histology and biologic behavior are identical, when in the multiple form the condition has been termed multiple cartilaginous exostoses. Malignant transformation of multiple cartilaginous exostoses has been reported in three mature dogs. We report two dogs with malignant transformation of solitary spinal osteochondromas. Both underwent transformation to osteosarcoma. Despite the benign radiographic appearance of osteochondromas and multiple cartilaginous exostoses, clinical signs should alert the clinician to the possibility of malignant transformation.

Stepwise immortalization and transformation of adult human prostate epithelial cells by a combination of HPV-18 and v-Ki-ras.

PubMed Central

Rhim, J S; Webber, M M; Bello, D; Lee, M S; Arnstein, P; Chen, L S; Jay, G

1994-01-01

Recent investigations have shown the presence of ras gene mutations and human papillomavirus (HPV) DNA in prostate carcinomas. In the present study, secondary adult human prostatic epithelial cells, upon transfection with a plasmid containing the entire HPV-18 genome, acquired an indefinite life-span in culture but did not undergo malignant conversion. Subsequent infection of these immortalized cells with the Kirsten murine sarcoma virus, which contains an activated Ki-ras oncogene, induced morphological transformation that led to the acquisition of neoplastic properties. These findings demonstrate the malignant transformation of adult human prostate epithelial cells in culture by a combination of viral oncogenes and the successive roles of HPV infection and Ki-ras activation in a multistep process responsible for prostate carcinogenesis. Images PMID:7991549

A syngeneic glioma model to assess the impact of neural progenitor target cell age on tumor malignancy

PubMed Central

Mikheev, Andrei M; Stoll, Elizabeth A; Mikheeva, Svetlana A; Maxwell, John-Patrick; Jankowski, Pawel P; Ray, Sutapa; Uo, Takuma; Morrison, Richard S; Horner, Philip J; Rostomily, Robert C

2010-01-01

Summary Human glioma incidence, malignancy and treatment resistance are directly proportional to patient age. Cell intrinsic factors are reported to contribute to human age-dependent glioma malignancy but suitable animal models to examine the role of aging are lacking. Here we developed an orthotopic syngeneic glioma model to test the hypothesis that the age of neural progenitor cells (NPCs), presumed cells of glioma origin, influences glioma malignancy. Gliomas generated from transformed donor 3-, 12-, and 18-month-old NPCs in same-aged adult hosts all formed highly invasive glial tumors that phenocopied the human disease. Survival analysis indicated increased malignancy of gliomas generated from older 12- and 18-month-old transformed NPCs compared with their 3-month counterparts (median survival of 38.5 and 42.5 vs. 77 days, respectively). This study showed for the first time that age of target cells at the time of transformation can affect malignancy and demonstrated the feasibility of a syngeneic model using transformed NPCs for future examination of the relative impacts of age-related cell intrinsic and cell-extrinsic factors in glioma malignancy. PMID:19489742

Discovering the Deregulated Molecular Functions Involved in Malignant Transformation of Endometriosis to Endometriosis-Associated Ovarian Carcinoma Using a Data-Driven, Function-Based Analysis

PubMed Central

Chang, Chia-Ming; Yang, Yi-Ping; Chuang, Jen-Hua; Chuang, Chi-Mu; Lin, Tzu-Wei; Wang, Peng-Hui; Yu, Mu-Hsien

2017-01-01

The clinical characteristics of clear cell carcinoma (CCC) and endometrioid carcinoma EC) are concomitant with endometriosis (ES), which leads to the postulation of malignant transformation of ES to endometriosis-associated ovarian carcinoma (EAOC). Different deregulated functional areas were proposed accounting for the pathogenesis of EAOC transformation, and there is still a lack of a data-driven analysis with the accumulated experimental data in publicly-available databases to incorporate the deregulated functions involved in the malignant transformation of EOAC. We used the microarray gene expression datasets of ES, CCC and EC downloaded from the National Center for Biotechnology Information Gene Expression Omnibus (NCBI GEO) database. Then, we investigated the pathogenesis of EAOC by a data-driven, function-based analytic model with the quantified molecular functions defined by 1454 Gene Ontology (GO) term gene sets. This model converts the gene expression profiles to the functionome consisting of 1454 quantified GO functions, and then, the key functions involving the malignant transformation of EOAC can be extracted by a series of filters. Our results demonstrate that the deregulated oxidoreductase activity, metabolism, hormone activity, inflammatory response, innate immune response and cell-cell signaling play the key roles in the malignant transformation of EAOC. These results provide the evidence supporting the specific molecular pathways involved in the malignant transformation of EAOC. PMID:29113136

Oral submucous fibrosis: An update on pathophysiology of malignant transformation.

PubMed

Arakeri, Gururaj; Patil, Shekar Gowda; Aljabab, Abdulsalam S; Lin, Kuan-Chou; Merkx, M A W; Gao, Shan; Brennan, Peter A

2017-07-01

Oral submucous fibrosis (OSMF) is a potentially malignant condition associated with areca nut chewing. Formerly confined to the Indian subcontinent, it is now often seen in Asian populations of the United Kingdom, USA and other developed countries, and is therefore a serious problem for global health. What makes it more sinister is the malignant transformation rate, which has been reported to be around 7.6% over a 17-year period. In this concise article, we review the current trends in the pathophysiology of malignant transformation of OSMF. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Understanding the intersections between metabolism and cancer biology

PubMed Central

Heiden, Matthew G. Vander; DeBerardinis, Ralph J.

2017-01-01

Transformed cells adapt metabolism to support tumor initiation and progression. Specific metabolic activities can participate directly in the process of transformation or support the biological processes that enable tumor growth. Exploiting cancer metabolism for clinical benefit requires defining the pathways that are limiting for cancer progression and understanding the context specificity of metabolic preferences and liabilities in malignant cells. Progress towards answering these questions is providing new insight into cancer biology and can guide the more effective targeting of metabolism to help patients. PMID:28187287

Risk of malignant transformation in patients with monoclonal gammopathy of undetermined significance.

PubMed

Pasqualetti, P; Casale, R

1997-01-01

The acturial probability of malignant transformation was analyzed in a series of 263 patients with monoclonal gammopathy of undetermined significance (MGUS) over a 15-year period and followed from 5 to 20 years. At a median follow-up of 11.5 years, 157 patients (59.7%) had died of causes unrelated to MGUS, 47 (17.9%) were still alive and presented no increase in monoclonal component, 11 (4.1%) presented an increase in monoclonal component without evidence of malignant immunoproliferative disease, and 48 (18.3%) had developed a malignant transformation of MGUS. In particular, MGUS evolved into 35 cases of multiple myeloma, two of solitary plasmacytoma of the bone, four of macroglobulinemia, three of malignant lymphoma, two of amyloidosis, one of chronic lymphocytic leukemia, and one of plasma cell leukemia. The cumulative incidence of malignant transformation was 18.3%; and the actuarial risk of malignant transformation was 6.1, 15.4, and 31.3% at 5, 10 and 20 years, respectively. The multivariate regression analysis according to Cox's proportional hazard model selected among 22 different variables established at initial diagnosis of MGUS only age as the factor significantly (P < 0.011) and negatively (b = -1.104) related to the risk of developing a malignant immunoproliferative disease. Therefore, patients with MGUS present an increased risk of developing a malignant lymphoproliferative or plasma cell proliferative disease, and MGUS could be considered a pre-neoplastic condition. Since no clinical or laboratory features are able to identify in advance the patients at high risk of disease progression, each patient must be followed up periodically and over an indefinite period.

Malignant Transformation Potentials of Human Umbilical Cord Mesenchymal Stem Cells Both Spontaneously and via 3-Methycholanthrene Induction

PubMed Central

Lai, Xiulan; Liu, Sizheng; Chen, Yezeng; Zheng, Zexin; Xie, Qingdong; Maldonado, Martin; Cai, Zhiwei; Qin, Shan; Ho, Guyu; Ma, Lian

2013-01-01

Human umbilical cord mesenchymal stem cells (HUMSCs) are highly proliferative and can be induced to differentiate into advanced derivatives of all three germ layers. Thus, HUMSCs are considered to be a promising source for cell-targeted therapies and tissue engineering. However there are reports on spontaneous transformation of mesenchymal stem cells (MSCs) derived from human bone marrows. The capacity for HUMSCs to undergo malignant transform spontaneously or via induction by chemical carcinogens is presently unknown. Therefore, we isolated HUMSCs from 10 donors and assessed their transformation potential either spontaneously or by treating them with 3-methycholanthrene (3-MCA), a DNA-damaging carcinogen. The malignant transformation of HUMSCs in vitro was evaluated by morphological changes, proliferation rates, ability to enter cell senescence, the telomerase activity, chromosomal abnormality, and the ability to form tumors in vivo. Our studies showed that HUMSCs from all 10 donors ultimately entered senescence and did not undergo spontaneous malignant transformation. However, HUMSCs from two of the 10 donors treated with 3-MCA displayed an increased proliferation rate, failed to enter senescence, and exhibited an altered cell morphology. When these cells (tHUMSCs) were injected into immunodeficient mice, they gave rise to sarcoma-like or poorly differentiated tumors. Moreover, in contrast to HUMSCs, tHUMSCs showed a positive expression of human telomerase reverse transcriptase (hTERT) and did not exhibit a shortening of the relative telomere length during the long-term culture in vitro. Our studies demonstrate that HUMSCs are not susceptible to spontaneous malignant transformation. However, the malignant transformation could be induced by chemical carcinogen 3-MCA. PMID:24339974

Characterizing and Targeting Bone Marrow-Derived Inflammatory Cells in Driving the Malignancy and Progression of Childhood Astrocytic Brain Tumors

DTIC Science & Technology

2016-11-01

importance of myeloid derived ID2/VEGFR2 signaling in low-grade to high-grade glioma transformation . 15. SUBJECT TERMS Glioma, Pediatric, bone-marrow...derived-cells, endothelial, mesenchymal, myeloid, hematopoietic, differentiation, malignant, transformation , VEGFR2, ID2. 16. SECURITY CLASSIFICATION OF...subsequent recruitment, in order to suppress the malignant transformation of gliomas. In this project, we have initiated the study of BMDCs with RCAS and

Does the immune reaction cause malignant transformation by disrupting cell-to-cell or cell-to-matrix communications?

PubMed

Prehn, Richmond T

2007-05-04

TUMOR PROGRESSION: In many (perhaps in all) tumor systems, a malignant cancer is preceded by a benign lesion. Most benign lesions do not transform to malignancy and many regress. The final transformative step to malignancy differs from the preceding steps in, among other things, that it often occurs in the absence of the original carcinogenic stimulus. Relatively low titers of specific immune reactants are known to stimulate, but cell-to-cell or cell-to-matrix interactions appear to be major inhibitors of tumor-growth. Therefore, it seems reasonable to hypothesize that the mechanism of immunostimulation may be an interference with cell-to-cell or cell-to-matrix communication by a sub-lethal immune-reaction. While the above hypothesis remains unproven, some evidence suggests that immunity may have a major facilitating effect on tumor growth especially at the time of malignant transformation. There is even some evidence suggesting that transformation in vivo may seldom occur in the absence of immunostimulation of the premalignant lesion. Positive selection by the immune reaction may be the reason that tumors are immunogenic.

Secondary Chondrosarcoma of the Upper Thoracic Costovertebral Junction with Neural Foraminal Extension and Compressing the Spinal Cord.

PubMed

Bouali, Sofiene; Bouhoula, Asma; Maatar, Nidhal; Abderrahmen, Khansa; Boubaker, Adnen; Kallel, Jalel; Jemel, Hafedh

2016-08-01

Chondrosarcoma is a rare malignant tumor of bone. This family of tumors can be primary malignant tumors or a secondary malignant transformation of an underlying benign cartilage tumor. Secondary chondrosarcoma arising from a benign solitary costal osteochondroma is extremely rare. Data show that the reported incidence of costal osteochondroma is very low and they are usually found in the anterior region at the costochondral junction. To our knowledge, however, there have been no previous reports, in English literature, describing osteochondroma malignant transformation located in the thoracic costovertebral junction. We report the case of a man with chondrosarcoma arising from the malignant degeneration of an osteochondroma at the right first thoracic costovertebral junction with neural foraminal extension and compressing the spinal cord. Although it is rare in solitary osteochondromas of rib, malignant transformation must always be considered. Copyright © 2016 Elsevier Inc. All rights reserved.

A case of McCune-Albright syndrome associated with pituitary GH adenoma: therapeutic process and autopsy.

PubMed

Liu, Fuyi; Li, Wenting; Yao, Yong; Li, Guilin; Yang, Yi; Dou, Wanchen; Zhong, Dingrong; Wang, Lin; Zhu, Xiangdong; Hu, Hua; Zhang, Jianmin; Wang, Renzhi; Chen, Gao

2011-01-01

McCune-Albright syndrome (MAS) is a clinical syndrome with low incidence, and its concurrence with pituitary GH adenoma is rare. Little of the history, treatment and outcome has been studied. Follow-up of a 37-year-old male patient of MAS associated with pituitary GH adenoma was performed continuously recording the disease development and the treatment process until death, after which an autopsy was performed. Radiation therapy (RT) efficaciously controlled GH hypersecretion, however, it may have been the cause of the malignant transformation of the dysplastic bone tissue, which eventually caused brain hernia and death; autopsy demonstrated that the cranium had significant thickening (as much as 10 cm), the pathological diagnosis was fibrous dysplasia of bone associated with chondrosarcoma; and undifferentiated chondrosarcoma with malignant fibrous histocytoma subtype in the sellar region; nodular goiter with the thyroid gland, one nodus was pathologically demonstrated as papillary carcinoma. GH adenoma, present in a patient with MAS, might be cured by RT; but the risk of malignant transformation of the dysplastic bone tissue in the field of irradiation make it controversial. Lessons from the case reported here told us that we should take great caution when recommending RT for patients like this.

Treatment and Clinical Outcomes of Patients with Teratoma with Somatic-Type Malignant Transformation: An International Collaboration.

PubMed

Giannatempo, Patrizia; Pond, Gregory R; Sonpavde, Guru; Albany, Costantine; Loriot, Yohann; Sweeney, Christopher J; Salvioni, Roberto; Colecchia, Maurizio; Nicolai, Nicola; Raggi, Daniele; Rice, Kevin R; Flack, Chandra K; El Mouallem, Nemer R; Feldman, Hope; Fizazi, Karim; Einhorn, Lawrence H; Foster, Richard S; Necchi, Andrea; Cary, Clint

2016-07-01

We assessed prognostic factors, treatments and outcomes in patients with teratoma with malignant transformation, a rare occurrence among germ cell tumors. Data on patients diagnosed with teratoma with malignant transformation between June 1981 and August 2014 were collected across 5 referral centers. Chemotherapy was dichotomized as based on germ cell tumor or teratoma with malignant transformation. Cox analyses were done to evaluate prognostic factors of overall survival, the primary end point. Each factor was evaluated in a univariable model. Forward stepwise selection was used to construct an optimal model. Among 320 patients the tumor primary site was gonadal in 287 (89.7%), retroperitoneal in 17 (5.3%) and mediastinal in 16 (5%). Teratoma with malignant transformation and germ cell tumor were diagnosed concurrently in 130 patients (40.6%). A total of 49 patients (16.8%) initially presented with clinical stage I. The remaining patients were at good (123 or 42.3%), intermediate (42 or 14.4%) and poor (77 or 26.5%) risk for metastasis according to IGCCCG (International Germ Cell Cancer Collaborative Group). First line chemotherapy was given for germ cell tumor in 159 patients (49.7%), chemotherapy for teratoma with malignant transformation was performed in 14 (4.4%) and only surgery was done in 147 (45.9%). Median followup was 25.1 months (IQR 5.4-63.8). Five-year overall survival was 83.4% (95% CI 61.3 to 93.5) in patients with clinical stage I and it was also worse than expected in those with metastasis. On multivariable analyses nonprimitive neuroectodermal tumor histology (overall p = 0.004), gonadal primary tumor (p = 0.005) and fewer prior chemotherapy regimens (p <0.001) were independent predictors of better overall survival. Chemotherapy was not independently prognostic. Less heavily pretreated teratoma with malignant transformation with a gonadal primary tumor and nonprimitive neuroectodermal tumor histology appears to be associated with longer overall survival. Generally, teratoma with malignant transformation had a worse prognosis than germ cell tumor. Uncertainties persist regarding optimal chemotherapy. Copyright © 2016 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

Evaluation of Potential Risk Factors that contribute to Malignant Transformation of Oral Lichen Planus: A Literature Review.

PubMed

Agha-Hosseini, Farzaneh; Sheykhbahaei, Nafiseh; SadrZadeh-Afshar, Maryam-Sadat

2016-08-01

Many studies have suggested that a lesion originally diagnosed as oral lichen planus (OLP) has different possibilities of undergoing malignant transformation in time, although these findings remain a controversial issue; for example, some studies reported different values of potential malignancy of OLP. World Health Organization (WHO) classifies OLP as a "potentially malignant disorder" with unspecified malignant transformation risk, and suggests that OLP patients should be closely monitored. Numerous studies have attempted to confirm the malignant transformation potential of OLP. The Cochrane Controlled Trials Register, Medline and EMBASE databases, PubMed, Google Scholar, Ovid, Up To Date, BMJ Clinical Evidence, MD Consult, and Science Direct were searched for papers published between 1997 and 2015. The medical subject heading search terms were "lichen planus," "oral lichen planus," "erosive oral lichen planus," "dysplasia," "oral precancerous condition," "oral premalignant condition," oral cancer, oral squamous cell carcinoma (OSCC), and atrophic lichen planus. A total of 120 English language abstracts were reviewed, and 50 relevant articles identified. Because of the extensive literature on the association between OLP and SCC, we have divided the data into genetic and non-genetic factors for more accurate assessment. In this evidence base, malignant transformation ranges from 0 to 37% with a mean of 4.59%. The highest rate of malignancy was noted in erythematosus and erosive lesions. In this way, follow-up of OLP patients could be carried out more efficiently and appropriately. Oral lichen planus is a premalignant lesion. All types of OLP in any site of oral mucosa must be monitored regularly.

Malignant transformation in chronic osteomyelitis: recognition and principles of management.

PubMed

Panteli, Michalis; Puttaswamaiah, Ravindra; Lowenberg, David W; Giannoudis, Peter V

2014-09-01

Malignant transformation as a result of chronic osteomyelitis represents a relatively rare and late complication with a declining incidence in the modern world. For most patients, the interval between the occurrence of the original bacterial infection and the transformation to malignant degeneration is several years. The diagnosis of malignant transformation in a chronic discharging sinus requires a high index of clinical suspicion. Wound biopsies should be obtained early, especially with the onset of new clinical signs such as increased pain, a foul smell, and changes in wound drainage. Squamous cell carcinoma is the most common presenting malignancy. Definitive treatment is amputation proximal to the tumor or wide local excision, combined with adjuvant chemotherapy and radiation therapy in selected patients. Early diagnosis may sometimes allow for treatment consisting of en bloc excision and limb salvage techniques. However, the most effective treatment is prevention with definitive treatment of the osteomyelitis, including adequate débridement, wide excision of the affected area, and early reconstruction. Copyright 2014 by the American Academy of Orthopaedic Surgeons.

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

Water Carcinogenicity and Prevalence of HPV Infection in Esophageal Cancer Patients in Huaihe River Basin, China

PubMed Central

Li, Jintao; Khodahemmati, Sara; Wang, Minglian; Wang, Yangjunqi; Zhao, Lijiao; Jia, Runqing; Chen, Su

2018-01-01

Objective The incidence of the upper gastrointestinal tumor has increased rapidly during recent decades. The relationship between local water pollution and the tumor is still not much clear, so this study was conducted to further investigate the local water pollution and its influence on the malignant cell transformation. Prevalence of human papillomavirus (HPV) in local esophageal cancer (EC) patients was also analyzed in Shenqiu County for the first time. Methods Two-step cell transformation was used to study different sources of water in the malignant cell transformation, and the existence of 3-methylcholanthrene (3-MC) in water was analyzed from the river and shallow and deep wells. HPV DNA in tissue samples of EC patients was detected by polymerase chain reaction (PCR) and HPV diagnostic kit. Results The river water has higher cytotoxicity than the shallow well water and induced significant cell malignant transformation, while deep well water has not shown the malignant cell transformation. In Huaihe River water, the 3-MC concentration was found higher than shallow and deep wells. An HPV infection rate was found high in patients with esophageal cancer. Conclusion Long-term consumption of polluted water can induce malignant cell transformation, and the presence of HPV may be an important cause of cancer. PMID:29853858

Does the immune reaction cause malignant transformation by disrupting cell-to-cell or cell-to-matrix communications?

PubMed Central

Prehn, Richmond T

2007-01-01

Tumor progression In many (perhaps in all) tumor systems, a malignant cancer is preceded by a benign lesion. Most benign lesions do not transform to malignancy and many regress. The final transformative step to malignancy differs from the preceding steps in, among other things, that it often occurs in the absence of the original carcinogenic stimulus. Mechanism of immunostimulation Relatively low titers of specific immune reactants are known to stimulate, but cell-to-cell or cell-to-matrix interactions appear to be major inhibitors of tumor-growth. Therefore, it seems reasonable to hypothesize that the mechanism of immunostimulation may be an interference with cell-to-cell or cell-to-matrix communication by a sub-lethal immune-reaction. Discussion While the above hypothesis remains unproven, some evidence suggests that immunity may have a major facilitating effect on tumor growth especially at the time of malignant transformation. There is even some evidence suggesting that transformation in vivo may seldom occur in the absence of immunostimulation of the premalignant lesion. Positive selection by the immune reaction may be the reason that tumors are immunogenic. PMID:17480231

Oxidative Stress and Antioxidant Defense in Endometriosis and Its Malignant Transformation

PubMed Central

Iwabuchi, Takuya; Yoshimoto, Chiharu; Shigetomi, Hiroshi; Kobayashi, Hiroshi

2015-01-01

The aim of this study was to investigate the role of redox status in endometriosis and its malignant transformation. A search was conducted between 1990 and 2014 through the English language literature (online MEDLINE PubMed database) using the keywords endometriosis combined with malignant transformation, oxidative stress, and antioxidant defense. In benign endometriosis, autoxidation and Fenton reaction of hemoglobin from the ferrous Fe2+ (oxyhemoglobin) state to the ferric Fe3+ (methemoglobin) state lead to production of excess reactive oxygen species (ROS) such as O2 − and ∙OH. Hemoglobin, heme, and iron derivatives in endometriotic cysts cause distortion in the homeostatic redox balance. Excess oxidative stress could trigger DNA damage and cell death. In contrast, endometriosis-associated ovarian cancer (EAOC) might be associated with an effective antioxidant defense, including heme oxygenases, cytochrome P450 family, and glutathione transferase family. The pattern of redox balance supports that enhanced antioxidants may be involved in the pathogenesis of malignant transformation. In conclusion, oxidant/antioxidant balance function is a double-edged sword, promoting cell death or carcinogenesis. Upregulation of antioxidant functions in endometriotic cyst may result in restoration of cell survival and subsequent malignant transformation. PMID:26185594

Hepatocellular carcinoma arising in a telangiectatic hepatocellular adenoma.

PubMed

González-Lara, María Fernanda; Córdova-Ramón, Juan Carlos; Gamboa-Domínguez, Armando; Cosme-Labarthe, Juan; Carrillo-Pérez, Diego Luis

2013-01-01

Telangiectatic hepatocellular adenoma is a rare, recently recognized subtype of benign liver tumor that may very rarely undergo transformation into hepatocellular carcinoma. We report an unusual case of a 75-year-old woman with no history of oral contraceptive use that underwent malignant transformation of a telangiectactic hepatocellular adenoma. No risk factors for adenoma development were identified in this otherwise healthy woman. Radiological characteristics, gross features and histopathology are herein described. In conclusion, telangiectatic hepatocellular adenoma can undergo malignant transformation. Further studies are needed to better clarify the factors associated with malignant progression.

The Snail Family in Normal and Malignant Haematopoiesis.

PubMed

Carmichael, Catherine L; Haigh, Jody J

2017-01-01

Snail family proteins are key inducers of the epithelial-mesenchymal transition (EMT), a critical process required for normal embryonic development. They have also been strongly implicated in regulating the EMT-like processes required for tumour cell invasion, migration, and metastasis. Whether these proteins also contribute to normal blood cell development, however, remains to be clearly defined. Increasing evidence supports a role for the Snail family in regulating cell survival, migration, and differentiation within the haematopoietic system, as well as potentially an oncogenic role in the malignant transformation of haematopoietic stem cells. This review will provide a broad overview of the Snail family, including key aspects of their involvement in the regulation and development of solid organ cancer, as well as a discussion on our current understanding of Snail family function during normal and malignant haematopoiesis. © 2017 S. Karger AG, Basel.

Epithelial-mesenchymal transition and cancer stem cells, mediated by a long non-coding RNA, HOTAIR, are involved in cell malignant transformation induced by cigarette smoke extract

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

Liu, Yi; Luo, Fei; Xu, Yuan

The incidence of lung diseases, including cancer, caused by cigarette smoke is increasing, but the molecular mechanisms of gene regulation induced by cigarette smoke remain unclear. This report describes a long noncoding RNA (lncRNA) that is induced by cigarette smoke extract (CSE) and experiments utilizing lncRNAs to integrate inflammation with the epithelial-mesenchymal transition (EMT) in human bronchial epithelial (HBE) cells. The present study shows that, induced by CSE, IL-6, a pro-inflammatory cytokine, leads to activation of STAT3, a transcription activator. A ChIP assay determined that the interaction of STAT3 with the promoter regions of HOX transcript antisense RNA (HOTAIR) increasedmore » levels of HOTAIR. Blocking of IL-6 with anti-IL-6 antibody, decreasing STAT3, and inhibiting STAT3 activation reduced HOTAIR expression. Moreover, for HBE cells cultured in the presence of HOTAIR siRNA for 24 h, the CSE-induced EMT, formation of cancer stem cells (CSCs), and malignant transformation were reversed. Thus, IL-6, acting on STAT3 signaling, which up-regulates HOTAIR in an autocrine manner, contributes to the EMT and to CSCs induced by CSE. These data define a link between inflammation and EMT, processes involved in the malignant transformation of cells caused by CSE. This link, mediated through lncRNAs, establishes a mechanism for CSE-induced lung carcinogenesis. - Highlights: • STAT3 directly regulates the levels of LncRNA HOTAIR. • LncRNA HOTAIR mediates the link between inflammation and EMT. • LncRNA HOTAIR is involved in the malignant transformation of cells caused by CSE.« less

The cnidarian origin of the proto-oncogenes NF-κB/STAT and WNT-like oncogenic pathway drives the ctenophores (Review)

PubMed Central

SINKOVICS, JOSEPH G.

2015-01-01

The cell survival pathways of the diploblastic early multicellular eukaryotic hosts contain and operate the molecular machinery resembling those of malignantly transformed individual cells of highly advanced multicellular hosts (including Homo). In the present review, the STAT/NF-κB pathway of the cnidarian Nematostella vectensis is compared with that of human tumors (malignant lymphomas, including Reed-Sternberg cells) pointing out similarities, including possible viral initiation in both cases. In the ctenophore genome and proteome, β-catenin gains intranuclear advantages due to a physiologically weak destructive complex in the cytoplasm, and lack of natural inhibitors (the Dickkopfs). Thus, a scenario similar to what tumor cells initiate and achieve is presented through several constitutive loss-of-function type mutations in the destructive complex and in the elimination of inhibitors. Vice versa, malignantly transformed individual cells of advanced multicellular hosts assume pheno-genotypic resemblance to cells of unicellular or early multicellular hosts, and presumably to their ancient predecessors, by returning to the semblance of immortality and to the resumption of the state of high degree of resistance to physicochemical insults. Human leukemogenic and oncogenic pathways are presented for comparisons. The supreme bioengineers RNA/DNA complex encoded both the malignantly transformed immortal cell and the human cerebral cortex. The former generates molecules for the immortality of cellular life in the Universe. The latter invents the inhibitors of the process in order to gain control over it. PMID:26239915

The cnidarian origin of the proto-oncogenes NF-κB/STAT and WNT-like oncogenic pathway drives the ctenophores (Review).

PubMed

Sinkovics, Joseph G

2015-10-01

The cell survival pathways of the diploblastic early multicellular eukaryotic hosts contain and operate the molecular machinery resembling those of malignantly transformed individual cells of highly advanced multicellular hosts (including Homo). In the present review, the STAT/NF-κB pathway of the cnidarian Nematostella vectensis is compared with that of human tumors (malignant lymphomas, including Reed-Sternberg cells) pointing out similarities, including possible viral initiation in both cases. In the ctenophore genome and proteome, β-catenin gains intranuclear advantages due to a physiologically weak destructive complex in the cytoplasm, and lack of natural inhibitors (the dickkopfs). Thus, a scenario similar to what tumor cells initiate and achieve is presented through several constitutive loss-of-function type mutations in the destructive complex and in the elimination of inhibitors. Vice versa, malignantly transformed individual cells of advanced multicellular hosts assume pheno-genotypic resemblance to cells of unicellular or early multicellular hosts, and presumably to their ancient predecessors, by returning to the semblance of immortality and to the resumption of the state of high degree of resistance to physicochemical insults. Human leukemogenic and oncogenic pathways are presented for comparisons. The supreme bioengineers RNA/DNA complex encoded both the malignantly transformed immortal cell and the human cerebral cortex. The former generates molecules for the immortality of cellular life in the Universe. The latter invents the inhibitors of the process in order to gain control over it.

Discrimination of malignant lymphomas and leukemia using Radon transform based-higher order spectra

NASA Astrophysics Data System (ADS)

Luo, Yi; Celenk, Mehmet; Bejai, Prashanth

2006-03-01

A new algorithm that can be used to automatically recognize and classify malignant lymphomas and leukemia is proposed in this paper. The algorithm utilizes the morphological watersheds to obtain boundaries of cells from cell images and isolate them from the surrounding background. The areas of cells are extracted from cell images after background subtraction. The Radon transform and higher-order spectra (HOS) analysis are utilized as an image processing tool to generate class feature vectors of different type cells and to extract testing cells' feature vectors. The testing cells' feature vectors are then compared with the known class feature vectors for a possible match by computing the Euclidean distances. The cell in question is classified as belonging to one of the existing cell classes in the least Euclidean distance sense.

Malignant Transformation and Stromal Invasion from Normal or Hyperplastic Tissues: True or False?

PubMed Central

Man, Yan-gao; Grinkemeyer, Michael; Izadjoo, Mina; Stojadinovic, Alexander

2011-01-01

Carcinogenesis is believed to be a multi-step process, progressing sequentially from normal to hyperplastic, to in situ, and to invasive stages. A number of studies, however, have detected malignancy-associated alterations in normal or hyperplastic tissues. As the molecular profile and clinical features of these tissues have not been defined, the authors invited several well-recognized pathologist, oncologists, biologist, surgeons, and molecular biologist to offer their opinion on: (1) whether these tissues belong to a previously unrevealed malignant entity or focal alterations with no significant consequence? (2) whether these alterations are linked to early onset of cancer or cancer of unknown primary site, and (3) how to further define these lesions? PMID:21811519

Modeling human endothelial cell transformation in vascular neoplasias

PubMed Central

Wen, Victoria W.; MacKenzie, Karen L.

2013-01-01

Endothelial cell (EC)-derived neoplasias range from benign hemangioma to aggressive metastatic angiosarcoma, which responds poorly to current treatments and has a very high mortality rate. The development of treatments that are more effective for these disorders will be expedited by insight into the processes that promote abnormal proliferation and malignant transformation of human ECs. The study of primary endothelial malignancy has been limited by the rarity of the disease; however, there is potential for carefully characterized EC lines and animal models to play a central role in the discovery, development and testing of molecular targeted therapies for vascular neoplasias. This review describes molecular alterations that have been identified in EC-derived neoplasias, as well as the processes that underpin the immortalization and tumorigenic conversion of ECs. Human EC lines, established through the introduction of defined genetic elements or by culture of primary tumor tissue, are catalogued and discussed in relation to their relevance as models of vascular neoplasia. PMID:24046386

Does human papilloma virus play a role in sinonasal inverted papilloma?

PubMed

Govindaraj, Satish; Wang, Hailun

2014-02-01

Inverted papillomas are a benign sinonasal tumor with a propensity for recurrence and malignant transformation. Although many investigations have been made into the nature of this disease, its etiology and causes for malignant transformation have yet to be fully elucidated. It is the authors' objective to present a review on management of the disease and evaluate the present relationship between human papilloma virus (HPV) and inverted papilloma. A causal relationship between HPV and the pathogenesis and progression of inverted papilloma has been posited since the 1980s. Although widely varied HPV detection rates have been reported, recent studies have noted a substantial increase in both recurrence and malignant transformation in HPV-infected inverted papillomas. However, exact cellular mechanisms by which infection leads to subsequent recurrence and development of carcinoma have yet to be elucidated. Evidence exists suggesting that HPV infection plays a role in the progression of inverted papilloma and confers an increased risk for recurrence and malignant transformation. PCR is the preferred detection method, and fresh or frozen specimens are the ideal source of tissue for evaluation. Although multiple studies have detected an association between HPV and inverted papilloma (both recurrent and malignant transformation), further studies are necessary to elucidate the underlying molecular pathways before an association can be changed to causation.

New knowledge and insights about the malignant transformation of endometriosis.

PubMed

Taniguchi, Fuminori

2017-07-01

Endometriosis may be a definitive risk factor for ovarian cancer, the most fatal gynecological cancer. The ability of endometriosis to transform into malignancy, first described by Dr. Sampson in 1925, is considered a rare occurrence, affecting approximately 1% of ovarian endometriomas. Recently we conducted a retrospective study regarding the malignant transformation of endometriosis in Japanese women. Many studies have reported a consistent correlation between endometriosis and ovarian cancer according to histological subtypes. However, the existing epidemiological evidence linking this association is insufficient to define the role of endometriosis as a cause of ovarian cancer and to influence changes to current clinical practice. Prospective cohort studies are therefore needed to clarify this issue. Additionally, the results of many molecular studies are conflicting, and earlier studies showing the molecular aberrations involved in genomic instability and mutation that enable malignant transformation have not been replicated in later studies. Careful long-term observation of a patient with endometrioma is required to detect possible subsequent incidence of malignant transformation. More importantly, a precise strategy should be set up for better prevention, early detection, specific diagnosis and treatment targeting molecular pathogenesis to understand the mechanisms of endometriosis-associated ovarian cancer. Clinicians need to be aware of the increased ovarian cancer risk in women with endometriosis. © 2017 Japan Society of Obstetrics and Gynecology.

The key role of extracellular vesicles in the metastatic process.

PubMed

Zhao, Hongyun; Achreja, Abhinav; Iessi, Elisabetta; Logozzi, Mariantonia; Mizzoni, Davide; Di Raimo, Rossella; Nagrath, Deepak; Fais, Stefano

2018-01-01

Extracellular vesicles (EVs), including exosomes, have a key role in the paracrine communication between organs and compartments. EVs shuttle virtually all types of biomolecules such as proteins, lipids, nucleic acids, metabolites and even pharmacological compounds. Their ability to transfer their biomolecular cargo into target cells enables EVs to play a key role in intercellular communication that can regulate cellular functions such as proliferation, apoptosis and migration. This has led to the emergence of EVs as a key player in tumor growth and metastasis through the formation of "tumor niches" in target organs. Recent data have also been shown that EVs may transform the microenvironment of primary tumors thus favoring the selection of cancer cells with a metastatic behavior. The release of EVs from resident non-malignant cells may contribute to the metastatic processes as well. However, cancer EVs may induce malignant transformation in resident mesenchymal stem cells, suggesting that the metastatic process is not exclusively due to circulating tumor cells. In this review, we outline and discuss evidence-based roles of EVs in actively regulating multiple steps of the metastatic process and how we can leverage EVs to impair metastasis. Copyright © 2017 Elsevier B.V. All rights reserved.

Overview of the biochemical and genetic processes in malignant mesothelioma*

PubMed Central

de Assis, Leonardo Vinícius Monteiro; Isoldi, Mauro César

2014-01-01

Malignant mesothelioma (MM) is a highly aggressive form of cancer, has a long latency period, and is resistant to chemotherapy. It is extremely fatal, with a mean survival of less than one year. The development of MM is strongly correlated with exposure to asbestos and erionite, as well as to simian virus 40. Although various countries have banned the use of asbestos, MM has proven to be difficult to control and there appears to be a trend toward an increase in its incidence in the years to come. In Brazil, MM has not been widely studied from a genetic or biochemical standpoint. In addition, there have been few epidemiological studies of the disease, and the profile of its incidence has yet to be well established in the Brazilian population. The objective of this study was to review the literature regarding the processes of malignant transformation, as well as the respective mechanisms of tumorigenesis, in MM. PMID:25210967

Participation of OCT3/4 and beta-catenin during dysgenetic gonadal malignant transformation.

PubMed

Palma, Icela; Peña, Rocio-Yolanda; Contreras, Alejandra; Ceballos-Reyes, Guillermo; Coyote, Ninel; Eraña, Luis; Kofman-Alfaro, Susana; Queipo, Gloria

2008-05-18

Gonadoblastoma (GB) is an in situ tumor consisting of a heterogeneous population of mature and immature germ cells, other cells resembling immature Sertoli/granulosa cells, and Leydig/lutein-like cells, may also be present. GB almost exclusively affects a subset of patients with intersex disorders and in 30% of them overgrowth of the germinal component of the tumor is observed and the lesion is term dysgerminoma/seminoma. Several pathways have been proposed to explain the malignant process, and abnormal OCT3/4 expression is the most robust risk factor for malignant transformation. Some authors have suggested that OCT3/4 and beta-catenin might both be involved in the same oncogenic pathway, as both genes are master regulators of cell differentiation and, overexpression of either gene may result in cancer development. The mechanism by which beta-catenin participates in GB transformation is not completely clear and exploration of the E-cadherin pathway did not conclusively show that this pathway participated in the molecular pathogenesis of GB. Here we analyze seven patients with mixed gonadal dysgenesis and GB, in an effort to elucidate the participation of beta-catenin and E-cadherin, as well as OCT3/4, in the oncogenic pathways involved in the transformation of GB into seminoma/dysgerminoma. We conclude that the proliferation of immature germ cells in GB may be due to an interaction between OCT3/4 and accumulated beta-catenin in the nuclei of the immature germ cells.

Cancer: a reproductive strategy of "ultra-selfish" genes?

PubMed

Schuiling, G A

2004-01-01

A hypothesis is presented in which the process of "malignant transformation" which ultimately results in the rapidly dividing tumor(s)(cells) causing "cancer", is regarded as an evolved reproductive strategy of "ultra-selfish" (proto-)(onco-) genes, already present in the genome, or introduced by a virus.

A near-infrared Fourier transform Raman spectroscopy of epidermal keratinocytes: changes in the protein?DNA structure following malignant transformation

NASA Astrophysics Data System (ADS)

Gao, Xiaoling; Butler, Ian S.; Kremer, Richard

2005-01-01

We report here the use of near-infrared (NIR) Fourier transform (FT) Raman spectroscopy to analyze normal human epidermal keratinocytes prior to and following malignant transformation. Our analysis indicates specific Raman spectral differences between immortalized (HPK1A) and malignant ras transformed (HPK1A- ras) cells. In addition, striking spectral differences are seen in the DNA isolated from these cells and particularly in the 843/810 cm -1 ratio with values of 1.6 ± 0.13 in HPK1A cells and 0.68 ± 0.09 in HPK1A- ras cells (mean ± S.D., n = 12, P < 0.001) indicating specific alterations in the backbone conformation markers following malignant transformation. Subsequently, we analysed the effect of a strong inhibitor of keratinocyte growth, the Vitamin D analog EB1089, on the Raman spectra of intact cells and on the 843/810 cm -1 ratio in the DNA isolated from both cell lines. Specific changes were observed in intact cells in the 1300-750 cm -1 region. Furthermore, the 843/810cm -1 ratio of isolated DNA from HPK1A cells was not affected by EB1089 but significantly increased in DNA isolated from HPK1A-ras cells so much that it became closer to the value observed for HPK1A cells (1.07 ± 0.10). Our data suggest that Raman analysis of DNA and in particular the 843/810cm -1 ratio can provide useful indices of malignant transformation and efficacy of anticancer agents.

Clinicopathological Profile and Malignant Transformation in Oral Lichen Planus: A Retrospective Study

PubMed Central

Bandyopadhyay, Alokenath; Behura, Shyam Sundar; Nishat, Roquaiya; Dash, Kailash Chandra; Bhuyan, Lipsa; Ramachandra, Sujatha

2017-01-01

Objectives: The aim of this study was to analyze the histopathologically diagnosed cases of oral lichen planus (OLP) in terms of age, gender, clinical variant, site, hyperpigmentation, systemic illness, grade of dysplasia, and associated malignant transformation. This study also intended to do a review of reported cases of OLP with malignant transformation. Materials and Methods: One hundred and forty-three cases of histopathologically diagnosed OLP between 2010 and 2016 were retrospectively reviewed. Demographic and clinicopathological data including malignant transformation were obtained. The data obtained were analyzed using the Statistical Package for the Social Sciences (SPSS) software for Windows version 20.0 (IBM SPSS, SPSS Inc., Chicago, IL, USA). A review of published literature on OLP with malignant transformation was also done from 1988 to 2017 and tabulated. Results: OLP in this study showed a male predilection with most of the patients in the third decade. The buccal mucosa (bilateral presentation) was the most common site (79.72%), and reticular type was the most common clinical type (79.02%) followed by erosive type (20.98%). The majority (92.31%) of cases were diagnosed with OLP without dysplasia. The rest (7.69%) of dysplastic cases were predominantly seen in the buccal mucosa of 58 years and above, female patients manifesting mainly as erosive type. Two patients (1.4%) previously diagnosed clinically and histopathologically as OLP developed oral squamous cell carcinoma. Conclusion: The present investigation revealed the predominance of OLP among middle-aged male population and the prevalence of bilateral involvement of buccal mucosa. Two of our cases showed malignant transformation over an average period of 3.5 years. The outcome of this study emphasizes the role of clinical follow-up of patients with OLP. PMID:28584781

Clinicopathological Profile and Malignant Transformation in Oral Lichen Planus: A Retrospective Study.

PubMed

Bandyopadhyay, Alokenath; Behura, Shyam Sundar; Nishat, Roquaiya; Dash, Kailash Chandra; Bhuyan, Lipsa; Ramachandra, Sujatha

2017-01-01

The aim of this study was to analyze the histopathologically diagnosed cases of oral lichen planus (OLP) in terms of age, gender, clinical variant, site, hyperpigmentation, systemic illness, grade of dysplasia, and associated malignant transformation. This study also intended to do a review of reported cases of OLP with malignant transformation. One hundred and forty-three cases of histopathologically diagnosed OLP between 2010 and 2016 were retrospectively reviewed. Demographic and clinicopathological data including malignant transformation were obtained. The data obtained were analyzed using the Statistical Package for the Social Sciences (SPSS) software for Windows version 20.0 (IBM SPSS, SPSS Inc., Chicago, IL, USA). A review of published literature on OLP with malignant transformation was also done from 1988 to 2017 and tabulated. OLP in this study showed a male predilection with most of the patients in the third decade. The buccal mucosa (bilateral presentation) was the most common site (79.72%), and reticular type was the most common clinical type (79.02%) followed by erosive type (20.98%). The majority (92.31%) of cases were diagnosed with OLP without dysplasia. The rest (7.69%) of dysplastic cases were predominantly seen in the buccal mucosa of 58 years and above, female patients manifesting mainly as erosive type. Two patients (1.4%) previously diagnosed clinically and histopathologically as OLP developed oral squamous cell carcinoma. The present investigation revealed the predominance of OLP among middle-aged male population and the prevalence of bilateral involvement of buccal mucosa. Two of our cases showed malignant transformation over an average period of 3.5 years. The outcome of this study emphasizes the role of clinical follow-up of patients with OLP.

Sequential pathological changes during malignant transformation of a craniopharyngioma: A case report and review of the literature

PubMed Central

Negoto, Tetsuya; Sakata, Kiyohiko; Aoki, Takachika; Orito, Kimihiko; Nakashima, Shinji; Hirohata, Masaru; Sugita, Yasuo; Morioka, Motohiro

2015-01-01

Background: Malignant transformation of craniopharyngiomas is quite rare, and the etiology of transformation remains unclear. The prognosis of malignantly transformed craniopharyngiomas is very poor. Case Description: A 36-year-old male had five craniotomies, five transsphenoidal surgeries, and two radiation treatments until 31 years of age after diagnosis of craniopharyngioma at 12 years of age. All serial pathological findings indicated adamantinomatous craniopharyngioma including those of a surgery performed for tumor regrowth at 31 years of age. However, when the tumor recurred approximately 5 years later, the pathological findings showed squamous metaplasia. The patient received CyberKnife surgery, but the tumor rapidly regrew within 4 months. The tumor was resected with the cavernous sinus via a dual approach: Transcranial and transsphenoidal surgery with an extracranial-intracranial bypass using the radial artery. Pathologic examination of a surgical specimen showed that it consisted primarily of squamous cells; the lamina propria was collapsed, and the tumor cells had enlarged nuclei and clarification of the nucleolus. The tumor was ultimately diagnosed as malignant transformation of craniopharyngioma. After surgery, he received combination chemotherapy (docetaxel, cisplatin, and fluorouracil). The tumor has been well controlled for more than 12 months. Conclusion: Serial pathological changes of the craniopharyngioma and a review of the 20 cases reported in the literature suggest that radiation of the squamous epithelial cell component of the craniopharyngioma led to malignant transformation via squamous metaplasia. We recommend aggressive surgical removal of craniopharyngiomas and avoidance of radiotherapy if possible. PMID:25883842

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

Inhibition of monomethylarsonous acid (MMA(III))-induced cell malignant transformation through restoring dysregulated histone acetylation.

PubMed

Ge, Yichen; Gong, Zhihong; Olson, James R; Xu, Peilin; Buck, Michael J; Ren, Xuefeng

2013-10-04

Inorganic arsenic (iAs) and its high toxic metabolite, monomethylarsonous acid (MMA(III)), are able to induce malignant transformation of human cells. Chronic exposure to these chemicals is associated with an increased risk of developing multiple cancers in human. However, the mechanisms contributing to iAs/MMA(III)-induced cell malignant transformation and carcinogenesis are not fully elucidated. We recently showed that iAs/MMA(III) exposure to human cells led to a decreased level of histone acetylation globally, which was associated with an increased sensitivity to arsenic cytotoxicity. In the current study, it demonstrated that prolonged exposure to low-level MMA(III) in human urothelial cells significantly increased the expression and activity of histone deacetylases (HDACs) with an associated reduction of histone acetylation levels both globally and lysine specifically. Administration of the HDAC inhibitor, suberoylanilide hydroxamic acid (SAHA), at 4 weeks after the initial MMA(III) treatment inhibited the MMA(III)-mediated up-regulation of the expression and activities of HDACs, leading to increase histone acetylation and prevention of MMA(III)-induced malignant transformation. These new findings suggest that histone acetylation dysregulation may be a key mechanism in MMA(III)-induced malignant transformation and carcinogenesis, and that HDAC inhibitors could be targeted to prevent or treat iAs-related cancers. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Arginine inhibits the malignant transformation induced by interferon-gamma through the NF-κB-GCN2/eIF2α signaling pathway in mammary epithelial cells in vitro and in vivo.

PubMed

Ren, Wenbo; Li, Yang; Xia, Xiaojing; Guo, Wenfei; Zhai, Taiyu; Jin, Yuting; Che, Yanyi; Gao, Haidi; Duan, Xiumei; Ma, Hongxi; Huang, Tinghao; Huang, Jing; Lei, Liancheng

2018-07-15

Breast cancer is the most common female malignant tumors in the world. It seriously affects women's physical and mental health and the leading cause of cancer death among women. Our previous study demonstrated that diet-derived IFN-γ promoted the malignant transformation of primary bovine mammary epithelial cells by accelerating arginine depletion. The current study aimed to explore whether arginine addition could inhibit the degree of malignant transformation and its molecular mechanism. The results indicate that arginine addition could alleviate the malignant transformation of mammary epithelial cells induced by IFN-γ, including reducing cell proliferation, cell migration and colony formation, through the NF-κB-GCN2/eIF2α pathway. The in vivo experiments also consistently confirmed that arginine supplementation could significantly inhibit tumor growth in tumor-bearing mice. Furthermore, the investigation of the clinical data also revealed that the plasma or tissue from human breast cancer patients owned lower arginine level and higher IFN-γ level than that from patients with benign breast disease, showing IFN-γ may be a potential control target. Our findings demonstrate that arginine supplement could antagonize the malignant transformation of mammary epithelial cells induced by IFN-γ (nutritionally induced) both in vitro and in vivo, and IFN-γ was higher in breast cancer women. This might provide a novel strategy for the prevention and treatment of breast cancer regarding to nutrition. Copyright © 2018 Elsevier Inc. All rights reserved.

Identification of Novel Prognostic Genetic Markers in Prostate Cancer

DTIC Science & Technology

2000-02-01

alterations in two normal- and three malignant-derived prostate epithelial cell lines immortalized with the E6 and E7 transforming genes of human papilloma virus (HPV...malignant-derived prostate epithelial cell lines immortalized with the E6 and E7 transforming genes of human papilloma virus (HPV) 16. These studies...transforming genes of human papilloma virus (HPV) 16 (13). The cell lines demonstrated several numerical and structural chromosomal alterations

Endometriosis, in vitro fertilisation and the risk of gynaecological malignancies, including ovarian and breast cancer.

PubMed

Vlahos, Nikos F; Economopoulos, Konstantinos P; Fotiou, Stylianos

2010-02-01

There is evidence that endometriosis as well as drugs used in the process of in vitro fertilisation appear to associate with increased risk for gynaecological cancer. In this review, we attempt to describe this relationship according to the most recent epidemiologic data and to present the possible mechanisms on the molecular level that could potentially explain this correlation. There are data to support that ovarian endometriosis could have the potential for malignant transformation. Epidemiologic and genetic studies support this notion. It seems that endometriosis is associated with specific types of ovarian cancer (endometrioid and clear cell). There is no clear association between endometriosis and breast or endometrial cancer. More studies are needed to establish the risk factors that may lead to malignant transformation of this condition and to identify predisposed individuals who may require closer surveillance. Currently, there is no proven relationship between any type of gynaecological cancer and drugs used for infertility treatment. In principle, infertile women have increased risk for gynaecologic malignancies. Nulligravidas who received treatment are at increased risk for malignancy compared with women who had conceived after treatment. There is limited evidence that clomiphene citrate use for more than six cycles or 900mg or treatment of women over the age of 40 could increase their risk for ovarian and breast cancer. More studies with the appropriate statistical power and follow-up time are required to evaluate accurately the long-term effects of these drugs and procedures.

An Investigation into the Use of Spatially-Filtered Fourier Transforms to Classify Mammary Lesions.

DTIC Science & Technology

difference in Fourier space between lesioned breast tissue which would enable accurate computer classification of benign and malignant lesions. Low...separate benign and malignant breast tissue. However, no success was achieved when using two-dimensional Fourier transform and power spectrum analysis. (Author)

Hydroquinone-induced malignant transformation of TK6 cells by facilitating SIRT1-mediated p53 degradation and up-regulating KRAS.

PubMed

Chen, Yuting; Chen, Jiajia; Yun, Lin; Xu, Longmei; Liu, Jiaxian; Xu, Yongchun; Yang, Hui; Liang, Hairong; Tang, Huanwen

2016-09-30

Hydroquinone (HQ), known as one of the metabolic products of benzene, causes a number of hematologic malignancies. The study evaluated the potential mechanism of Sirtuin 1 (SIRT1) in HQ-induced TK6 cell malignant transformation. The data of our study show that short term exposure of TK6 cells to HQ led to a decrease expression of SIRT1. Knockdown of SIRT1 sensitized to the HQ-induced apoptosis in vitro and increased the expression of p53, p21 and γ-H2AX. Furthermore, chronic HQ-treated (20μM once a week for 19 weeks) caused carcinogenic transformation and was confirmed by abnormal cell proliferation, matrix metalloproteinase 9(MMP9) and subcutaneous tumor formation in nude mice. SIRT1 increased KRAS expression, and decreased H3K9 and H3K18 acetylation, inhibited p53 signaling and the level of caspase-3 in HQ-induced transformation cells. Taken together, these data suggest that SIRT1 is involved in HQ-induced malignant transformation associated with suppressing p53 signaling and activation of KRAS. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Targeting eradication of malignant cells derived from human bone marrow mesenchymal stromal cells

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

Yang, Yingbin; School of Life Science, Southwest University, Chongqing 400715; Cai, Shaoxi, E-mail: sxcai@cqu.edu.cn

2010-12-10

Human bone marrow mesenchymal stromal cells (hBMSC) have been shown to participate in malignant transformation. However, hampered by the low frequency of malignant transformation of hBMSC, we do not yet know how to prevent malignant transformation of implanted hBMSC. In this study, in order to establish a model for the eradication of hBMSC-derived malignant cells, a gene fusion consisting of a human telomerase (hTERT) promoter modified with both c-Myc and myeloid zinc finger protein2 (MZF-2) binding elements and followed by the E. coli cytosine deaminase (CD) and luciferase genes was stably transferred into hBMSC via lentiviral transduction; n-phosphonacelyl-L-aspartic acid (PALA)more » selection was used to generate malignant cell colonies derived from transduced hBMSC after treatment with the carcinogenic reagent BPDE. Cells that were amplified after PALA selection were used for transplantation and 5-FC pro-drug cytotoxicity tests. The results showed that PALA-resistant malignant cells could be generated from hBMSC co-induced with lentiviral transduction and treatment with Benzo(a)pyrene Diol Epoxide (BPDE); the modification of c-Myc and MZF-2 binding elements could remarkably enhance the transcriptional activities of the hTERT promoter in malignant cells, whereas transcriptional activity was depressed in normal hBMSC; malignant cells stably expressing CD under the control of the modified hTERT promoter could be eliminated by 5-FC administration. This study has provided a method for targeted eradication of malignant cells derived from hBMSC.« less

Involvement of HIF-1α-regulated miR-21, acting via the Akt/NF-κB pathway, in malignant transformation of HBE cells induced by cigarette smoke extract.

PubMed

Lu, Lu; Xu, Hui; Yang, Ping; Xue, Junchao; Chen, Chao; Sun, Qian; Yang, Qianlei; Lu, Jiachun; Shi, Aimin; Liu, Qizhan

2018-06-01

Although the relationship between cigarette smoke and lung cancer has been widely studied, the molecular mechanism for cigarette smoke-induced lung cancer remains largely unclear. The present study investigated the roles of hypoxia-inducible factor (HIF)-1α and miR-21 in the malignant transformation of human bronchial epithelial (HBE) cells induced by cigarette smoke extract (CSE). In case of acute and chronic treatment of HBE cells, CSE increased the levels of HIF-1α, p-Akt, p-NF-κB, and miR-21 and decreased PTEN levels. The increased miR-21 levels induced by CSE were prevented by down-regulation of HIF-1α. Further, elevated miR-21 suppressed PTEN levels, which decreased the levels of p-Akt and p-NF-κB. However, those changes were attenuated in cells co-transfected with HIF-1α siRNA and an miR-21 mimic. Silencing of HIF-1α or NF-κB decreased colony formation and the invasion and migration capacities of CSE-transformed HBE cells; however, up-regulation of miR-21 reversed these effects. These results indicate that the oncogenic capacity of HIF-1α in regulation of miR-21-inhibited PTEN in a manner dependent on the Akt/NF-κB pathway, a process that is involved in the CSE-induced malignant transformation of HBE cells. Thus, the present research has established a new mechanism for cigarette smoke-induced lung carcinogenesis. Copyright © 2018 Elsevier B.V. All rights reserved.

[The role of microRNAs in molecular pathology of esophageal cancer and their potential usage in clinical oncology].

PubMed

Kovaříková, A; Héžová, R; Srovnal, J; Rédová-Lojová, M; Slabý, O

2014-01-01

MicroRNAs are an abundant class of noncoding RNAs (approx. 18- 25 nucleotides in length) that suppress translation through binding to their target mRNAs, eventually leading to mRNAs degradation. Sequences of these endogenous RNA molecules are highly conserved, even among unrelated species, indicating their involvement in basic bio-logical processes, such as development, differentiation, proliferation or apoptosis. MiRNAs also participate on regulation of cancer stem cell functioning, immune system and malignant transformation. This review provides a comprehensive overview of miRNAs functions in esophageal cancer, their roles in key pathogenetic pathways and disease development, as well as their potential usage in clinical routine as bio-markers improving dia-gnosis, prognosis and prediction of therapeutic response. Through regulation of signaling pathways important in malignant transformation, miRNAs present also promising therapeutic targets.

Malignant transformation of guinea pig cells after exposure to ultraviolet-irradiated guinea pig cytomegalovirus

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

Isom, H.C.; Mummaw, J.; Kreider, J.W.

1983-04-30

Guinea pig cells were malignantly transformed in vitro by ultraviolet (uv)-irradiated guinea pig cytomegalovirus (GPCMV). When guinea pig hepatocyte monolayers were infected with uv-irradiated GPCMV, three continuous epithelioid cell lines which grew in soft agarose were established. Two independently derived GPCMV-transformed liver cells and a cell line derived from a soft agarose clone of one of these lines induced invasive tumors when inoculated subcutaneously or intraperitoneally into nude mice. The tumors were sarcomas possibly derived from hepatic stroma or sinusoid. Transformed cell lines were also established after infection of guinea pig hepatocyte monolayers with human cytomegalovirus (HCMV) or simian virusmore » 40 (SV40). These cell lines also formed colonies in soft agarose and induced sarcomas in nude mice. It is concluded that (i) GPCMV can malignantly transform guinea pig cells; (ii) cloning of GPCMV-transformed cells in soft agarose produced cells that induced tumors with a shorter latency period but with no alteration in growth rate or final tumor size; and (iii) the tumors produced by GPCMV-and HCMV-transformed guinea pig cells were more similar to each other in growth rate than to those induced by SV40-transformed guinea pig cells.« less

Malignant transformation of thymoma in recipient rats by heterotopic thymus transplantation from HTLV-I transgenic rats.

PubMed

Tsuji, Takahiro; Ikeda, Hitoshi; Tsuchikawa, Takahiro; Kikuchi, Kazunori; Baba, Tomohisa; Ishizu, Akihiro; Yoshiki, Takashi

2005-07-01

Transgenic rats expressing the pX gene of human T lymphocyte virus type-I (HTLV-I) under control of the rat lymphocyte-specific protein tyrosine kinase type-I promoter (lck-pX rats) developed benign epithelial thymomas. When the thymuses of newborn lck-pX rats were transplanted into the subcapsular space of the kidney in other thymectomized lck-pX rats, similar tumors developed in the transplanted thymuses. Following the tumor growth, dissemination in the abdominal cavity and distant metastasis occurred. The tumors were histopathologically similar to the original thymomas, but prominent nuclear atypia and high mitotic activity were present. The Ki-67 index was twice as high as that in the originals. The tumors were transplantable into the subcutis of lck-pX rats, although transplantation of the originals never succeeded. All evidence indicated that malignant transformation of thymoma was induced by the heterotopic transplantation. Expression of the pX transgene in the transformed tumors were significantly reduced. Among host genes, the expression of p16ink4a/ARF, which was significantly upregulated in the originals, was never detected in the transformed tumors. Genomic Southern blots and PCR suggest that homozygous deletion of the p16ink4a/ARF gene may play important roles in malignant transformation in this model. Our model described here is a useful unique model for in vivo malignant transformation.

The role of miR-200a in mammalian epithelial cell transformation

PubMed Central

Becker, Lindsey E.; Takwi, Apana Agha L.; Lu, Zhongxin; Li, Yong

2015-01-01

Cancer is a multistep disease that begins with malignant cell transformation and frequently culminates in metastasis. MicroRNAs (miRNAs) are small regulatory 21–25 nt RNA molecules and are frequently deregulated in cancer. miR-200a is a member of the miR-200 family, which are known inhibitors of the epithelial-to-mesenchymal transition. As such, the tumor-suppressive role of miR-200a in oncogenesis has been well documented; however, recent studies have found a proliferative role for this miRNA as well as a prometastatic role in the later steps of cancer progression. Little is known about the role of this miRNA in the early stages of cancer, namely, malignant cell transformation. Here, we show that miR-200a alone transforms an immortalized rat epithelial cell line, and miR-200a cooperates with Ras to enhance malignant transformation of an immortalized human epithelial cell line. Furthermore, miR-200a induces cell transformation and tumorigenesis in immunocompromised mice by cooperating with a Ras mutant that activates only the RalGEF effector pathway, but not Ras mutants activating PI3K or Raf effector pathways. This transformative ability is in accordance with miR-200a targeting Fog2 and p53 to activate Akt and directly repress p53 protein levels, respectively. These results demonstrate an oncogenic role for miR-200a and provide a specific cellular context where miR-200a acts as an oncomiR rather than a tumor suppressor by cooperating with an oncogene in malignant cell transformation. PMID:25239643

The Risk of Radiation-Induced Tumors or Malignant Transformation After Single-Fraction Intracranial Radiosurgery: Results Based on a 25-Year Experience

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

Pollock, Bruce E., E-mail: pollock.bruce@mayo.edu; Department of Radiation Oncology, Mayo Clinic College of Medicine, Rochester, Minnesota; Link, Michael J.

Purpose: To determine the risk of radiation-induced tumors or malignant transformation after single-fraction intracranial stereotactic radiosurgery (SRS). Methods and Materials: We performed a retrospective review of 1837 patients who received single-fraction SRS for arteriovenous malformation or benign tumor (meningioma, vestibular schwannoma, pituitary adenoma, glomus tumor) at a single center between 1990 and 2009. Patients were excluded if they refused research authorization (n=31), had a genetic predisposition to tumor development (n=84), received prior or concurrent radiation therapy (n=79), or had less than 5 years of imaging follow-up after SRS (n=501). The median imaging follow-up period for the remaining 1142 patients was 9.0 yearsmore » (range, 5-24.9 years). Results: No radiation-induced tumors were identified in 11,264 patient-years of follow-up after SRS. The risk of a radiation-induced tumor developing after SRS was 0.0% at 5 years (95% confidence interval [CI], 0.0%-0.4%), 0.0% at 10 years (95% CI, 0.0%-0.9%), and 0.0% at 15 years (95% CI, 0.0%-2.8%). Malignant transformation occurred in 7 of 316 meningioma patients (2.2%) and 1 of 358 vestibular schwannoma patients (0.3%) at a median of 4.9 years (range, 2.8-13.8 years) after SRS. No cases of malignant transformation were noted in patients with pituitary adenomas (n=188) or glomus tumors (n=47). The 5-, 10-, and 15-year risk of malignant transformation was 0.5% (95% CI, 0.0%-0.9%), 0.8% (95% CI, 0.0%-1.8%), and 2.4% (95% CI, 0.0%-5.5%), respectively. Patients who underwent prior resection (hazard ratio, 14.56; 95% CI, 1.79-118.33; P=.01) and who had meningioma pathology (hazard ratio, 11.72; 95% CI, 1.44-96.15; P=.02) were at increased risk of malignant transformation. Conclusions: The risk of radiation-induced tumors or malignant transformation after SRS is very low and should not be used as a justification for choosing alternative treatment approaches (surgical resection, observation) over SRS for appropriate patients.« less

Increased salivary aldehyde dehydrogenase 1 in non-reticular oral lichen planus.

PubMed

Mansourian, Arash; Shanbehzadeh, Najmeh; Kia, Seyed Javad; Moosavi, Mahdieh-Sadat

2017-01-01

Oral lichen planus is a potentially malignant disorder. One of the malignant transformation markers is cancer stem cells. One of the proposed marker for the detection of cancer stem cells's in head and neck cancer is aldehyde dehydrogenase. Recently it is shown that aldehyde dehydrogenase 1 expression in tissue samples is associated with oral lichen planus malignant transformation. This study evaluates salivary aldehyde dehydrogenase 1 in oral lichen planus. Thirty patients and 30 age and sex-matched healthy volunteers were recruited. Oral lichen planus was diagnosed based on the modified World Health Organization criteria. Subjects in the case group were divided into reticular and non-reticular forms. Unstimulated salivary samples were collected at 10-12 AM. Saliva concentrations of aldehyde dehydrogenase 1 were measured by ELISA. The differences between aldehyde dehydrogenase levels in the oral lichen planus group compared with the control group were not significant but aldehyde dehydrogenase in non-reticular oral lichen planus was significantly higher than that of the reticular form. This is a cross-sectional study, thus longitudinal studies in oral lichen planus may present similar or different results. The mechanism of malignant transformation in oral lichen planus is not defined. Previous analyses revealed that the aldehyde dehydrogenase 1 expression is significantly correlated with increased risk of transformation. This finding is consistent with our results because in the erosive and ulcerative forms of oral lichen planus, which have an increased risk of transformation, salivary aldehyde dehydrogenase 1 was overexpressed. A higher salivary aldehyde dehydrogenase level in non-reticular oral lichen planus can be a defensive mechanism against higher oxidative stress in these groups. Aldehyde dehydrogenase may be one of the malignant transformation markers in oral lichen planus. Further studies are needed for introducing aldehyde dehydrogenase as a prognostic indicator in certain lesions.

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

Advances in recurrence and malignant transformation of sinonasal inverted papillomas

PubMed Central

Sun, Qingjia; An, Lifeng; Zheng, Jun; Zhu, Dongdong

2017-01-01

Sinonasal inverted papilloma (SIP) is a benign tumor of the nasal cavity and sinus. SIP is characterized by aggressive malignant transformation and a high rate of recurrence. Inadequate removal of the tumor during surgery is one of the most significant contributors to SIP recurrence. A growing body of evidence suggests that molecular alteration in SIP, including human papilloma virus infections, single nucleotide polymorphisms of key genes, deregulation of signaling pathways and immunological changes, may lead to SIP occurrence and malignant transformation. However, the extent to which these molecular mechanisms contribute to SIP pathology and transformation remains unclear due to limited research. Further studies are warranted to elucidate the primary dependent factors that contribute to SIP etiology. The present article reviewed risk factors of progression and recurrence of SIP, including outdoor and industrial occupational exposure, smoking, septal deviation, SIP location, recurrent cases, stage of SIP-associated squamous cell carcinoma and choice of surgical method. PMID:28599459

Breath Alkane as an index of severity for oral submucous fibrosis: A new perspective?

PubMed

Arakeri, Gururaj; Boraks, George; Aljabab, Abdulsalam S; Patil, Shekar Gowda; Merkx, M A W; Brennan, Peter A

2017-01-01

Oral submucous fibrosis (OSMF) is a devastating disease commonly seen in the Asian subcontinent that results in significant functional morbidity for patients and has a high potential for malignant transformation. Over the last three decades, different diagnostic methods have been described to quantify and grade OSMF severity. Some methods have been used with perceived favorable outcomes although recurrence and malignant transformation remains a problem in many cases, and OSMF presents a major therapeutic challenge. We present a simple, noninvasive and less time-consuming diagnostic method which measures the severity of OSMF, helping to predict its malignant transformation and monitoring the effect of medical therapy on this disease. Copyright © 2016 Elsevier Ltd. All rights reserved.

FT-IR Spectroscopic Analysis of Normal and Malignant Human Oral Tissues

NASA Astrophysics Data System (ADS)

Krishnakumar, N.; Madhavan, R. Nirmal; Sumesh, P.; Palaniappan, Pl. Rm.; Venkatachalam, P.; Ramachandran, C. R.

2008-11-01

FT-IR spectroscopy has been used to explore the changes in the vibrational bands of normal and oral squamous cell carcinoma (OSCC) tissues in the region 4000-400 cm-1. Significant changes in the spectral features were observed. The spectral changes were the results of characteristics structural alterations at the molecular level in the malignant tissues. These alterations include structural changes of proteins and possible increase of its content, an increase in the nucleic-to-cytoplasm ratio, an increase in the relative amount of DNA, an increase in the rate of phosphorylation process induced by carcinogenesis, a loss of hydrogen bonding of the C-OH groups in the amino acid residues of proteins, a decrease in the relative amount of lipids compared to normal epithelial oral tissues. The results of the present study demonstrate that the FT-IR technique has the feasibility of discriminating malignant from normal tissues and other pathological states in a short period of time and may detect malignant transformation earlier than the standard histological examination stage.

Possible relevance of tumor-related genes mutation to malignant transformation of endometriosis.

PubMed

Ma, X; Hui, Y; Lin, L; Wu, Y; Zhang, X; Qin, X

2016-01-01

Despite studies have suggested that endometriosis has malignant potential, the molecular mechanism underlying the malignant transformation of endometriosis is poorly understood so far. Endometriosis-associated ovarian cancer (EAOC) or ovarian cancer arising from endometriosis (OCEM) may provide an ideal model for genetic studies. To investigate the genetic alterations during transformation of ovarian endometriosis into cancer, the authors analysed mutations of tumour-related genes (PTEN and p53) in EAOC cases (n=23, group 1), including 19 cases which were detected co-existence of endometriosis and cancer and four cases which fulfilled the histological criteria in malignant transformation of endometriosis (OCEMs), and in atypical hyperplasia ovarian endometriosis (aEMs) (n = 10, group 2), as well as in solitary ovarian endometriosis (EMs) (n = 20, group 3), simultaneously, to study the correlation of the two genes in the development and progression of the ovarian endometriosis malignancy. Each paraffin block was sliced into serial ten-µm-thick sections. Extracted DNA was amplified by nested PCR. Mutations of PTEN and p53 were examined by bidirectional DNA sequencing. It was acknowledged by experiments that the PTEN and p53 mutation frequency in EAOCs were significantly higher than that in aEMs and EMs. There was significant difference to compare EAOCs with EMs (p < 0.01, p < 0.05), and converse to compare with aEMs (p > 0.05), respectively. No definite involvement between the frequency of PTEN and p53 mutations in EAOCs and age difference, histological type, clinical stage, pathological grade, and whether accompanied by metastasis (p > 0.05); however, a decreasing trend of PTEN mutation with the increased age, decreased clinical stage and pathological grade, and when accompanied by metastasis was detected. Adversely, an increasing trend of p53 mutation was represented. In EAOCs group, the authors detected eight PTEN and four p53 mutation events, respectively. Moreover, one case occurred PTEN and p53 mutation simultaneously. With 23 EAOCs, two cases which fulfilled the histological criteria in malignant transformation of endometriosis, which may be a specific entity distinct from non-endometriosis-associated ovarian cancer, the authors named them the OCEMs, occurred PTEN or p53 mutation, respectively. The present study suggested that the mutation and functional incapacitation of certain tumor-related genes may be involved in malignant transformation of endometriosis. PTEN mutation is the pristine event, but p53 mutation is the late.

Management of pregnancy in woman with suspected malignant deep infiltrating endometriosis fistulised to the uterine cervix.

PubMed

Richard, Frederic; Canlorbe, Geoffroy; Bazot, Marc; Daraï, Emile

2014-06-04

Deep infiltrating endometriosis (DIE) is a well-known cause of pelvic pain and infertility. Malignant transformation of DIE is rare but can be suggested by MRI. We report a case of a spontaneous pregnancy in a woman with suspicion of malignant transformation of DIE with fistulisation to the posterior uterine isthmus through to the cervical canal. The pregnancy was closely monitored and an uneventful caesarian section was performed at 34 weeks of gestation. This case raises the issue of the relevance of imaging techniques and management of pregnancy. 2014 BMJ Publishing Group Ltd.

Differential DNA methylation profile of key genes in malignant prostate epithelial cells transformed by inorganic arsenic or cadmium.

PubMed

Pelch, Katherine E; Tokar, Erik J; Merrick, B Alex; Waalkes, Michael P

2015-08-01

Previous work shows altered methylation patterns in inorganic arsenic (iAs)- or cadmium (Cd)-transformed epithelial cells. Here, the methylation status near the transcriptional start site was assessed in the normal human prostate epithelial cell line (RWPE-1) that was malignantly transformed by 10μM Cd for 11weeks (CTPE) or 5μM iAs for 29weeks (CAsE-PE), at which time cells showed multiple markers of acquired cancer phenotype. Next generation sequencing of the transcriptome of CAsE-PE cells identified multiple dysregulated genes. Of the most highly dysregulated genes, five genes that can be relevant to the carcinogenic process (S100P, HYAL1, NTM, NES, ALDH1A1) were chosen for an in-depth analysis of the DNA methylation profile. DNA was isolated, bisulfite converted, and combined bisulfite restriction analysis was used to identify differentially methylated CpG sites, which was confirmed with bisulfite sequencing. Four of the five genes showed differential methylation in transformants relative to control cells that was inversely related to altered gene expression. Increased expression of HYAL1 (>25-fold) and S100P (>40-fold) in transformants was correlated with hypomethylation near the transcriptional start site. Decreased expression of NES (>15-fold) and NTM (>1000-fold) in transformants was correlated with hypermethylation near the transcriptional start site. ALDH1A1 expression was differentially expressed in transformed cells but was not differentially methylated relative to control. In conclusion, altered gene expression observed in Cd and iAs transformed cells may result from altered DNA methylation status. Published by Elsevier Inc.

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.

Expression of the pituitary tumor transforming gene (PTTG1) in pheochromocytoma as a potential marker for distinguishing benign versus malignant tumors.

PubMed

Haji Amousha, Mohamad Reza; Sabetkish, Nastaran; Sabet Kish, Nastaran; Heshmat, Ramin; Rajabiani, Afsaneh; Saffar, Hiva; Haghpanah, Vahid; Tavangar, Seyed Mohammad

2015-01-01

The Distinction between malignant and benign pheochromocytoma has always been a diagnostic challenge over the last decades. To date, the only reliable criterion is metastasis. The aim of the present study was to investigate the possible expression of pituitary-tumor transforming gene (PTTG1) and retinoblastoma (Rb) in benign and malignant pheochromocytoma. Paraffin blocks of 44 and 11 patients diagnosed with benign and malignant pheochromocytoma were collected. Parameters such as sex, age, tumor size, necrosis, and histological features were compared between the benign and malignant groups as well as immunohistochemical labeling using specific antibodies. PTTG1 showed negative expression in all (44) benign and 9 out of 11 (81.8%) malignant tumors with only 2 out of 11 (18.2%) malignant tumors showed positive reactivity for PTTG1 (P: 0.037) with spindle cell histological pattern in both of them (P: 0.013). Although Rb expression in malignant tumors (81.8%) was slightly more than the benign ones (52.3%), no statistically significant correlation was observed (P: 0.087). These results suggest that PTTG1 immunostaining may play a key role in distinguishing between benign and malignant phaeochromocytoma. However, larger studies are necessary to confirm the outcomes of the present study.

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

Deep-Red Fluorescent Gold Nanoclusters for Nucleoli Staining: Real-Time Monitoring of the Nucleolar Dynamics in Reverse Transformation of Malignant Cells.

PubMed

Wang, Xiaojuan; Wang, Yanan; He, Hua; Ma, Xiqi; Chen, Qi; Zhang, Shuai; Ge, Baosheng; Wang, Shengjie; Nau, Werner M; Huang, Fang

2017-05-31

Nucleoli are important subnuclear structures inside cells. We report novel fluorescent gold nanoclusters (K-AuNCs) that are able to stain the nucleoli selectively and make it possible to explore the nucleolar morphology with fluorescence imaging technique. This novel probe is prepared through an easy synthesis method by employing a tripeptide (Lys-Cys-Lys) as the surface ligand. The properties, including deep-red fluorescence emission (680 nm), large Stocks shift, broad excitation band, low cytotoxicity, and good photostability, endow this probe with potential for bioanalytical applications. Because of their small size and their positively charged surface, K-AuNCs are able to accumulate efficiently at the nucleolar regions and provide precise morphological information. K-AuNCs are also used to monitor the nucleolar dynamics along the reverse-transformation process of malignant cells, induced by the agonist of protein A, 8-chloro-cyclic adenosine monophosphate. This gives a novel approach for investigating the working mechanism of antitumor drugs.

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.

Apigenin suppresses migration and invasion of transformed cells through down-regulation of C-X-C chemokine receptor 4 expression

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

Wang, Lei; Kuang, Lisha; Hitron, John Andrew

Environmental exposure to arsenic is known to cause various cancers. There are some potential relationships between cell malignant transformation and C-X-C chemokine receptor type 4 (CXCR4) expressions. Metastasis, one of the major characteristics of malignantly transformed cells, contributes to the high mortality of cells. CXCR4 and its natural chemokine ligand C-X-C motif ligand 12 (CXCL12) play a critical role in metastasis. Therefore, identification of nutritional factors which are able to inhibit CXCR4 is important for protection from environmental arsenic-induced carcinogenesis and for abolishing metastasis of malignantly transformed cells. The present study demonstrates that apigenin (4′,5,7-trihydroxyflavone), a natural dietary flavonoid, suppressedmore » CXCR4 expression in arsenic-transformed Beas-2B cells (B-AsT) and several other types of transformed/cancer cells in a dose- and time-dependent manner. Neither proteasome nor lysosome inhibitor had any effect in reducing the apigenin-induced down-regulation of CXCR4, indicating that apigenin-induced down-regulation of CXCR4 is not due to proteolytic degradation. The down-regulation of CXCR4 is mainly due to the inhibition of nuclear factor κB (NF-κB) transcriptional activity. Apigenin also abolished migration and invasion of transformed cells induced by CXCL12. In a xenograft mouse model, apigenin down-regulated CXCR4 expression and suppressed tumor growth. Taken together, our results show that apigenin is a novel inhibitor of CXCR4 expression. This dietary flavonoid has the potential to suppress migration and invasion of transformed cells and prevent environmental arsenic-induced carcinogenesis. - Highlights: • Apigenin has a potential in preventing environmental arsenic induced carcinogenesis. • Apigenin suppresses CXCR4 in malignant transformed cells in vitro and in vivo. • The down-regulation of CXCR4 is mainly due to inhibition of NF-κB activity.« less

Leuloplakia - Review of A Potentially Malignant Disorder

PubMed Central

Abidullah, Mohammed; Gaddikeri, Kavitha; Raghoji, Swetha; Ravishankar T, Shilpa

2014-01-01

Leukoplakias are oral white lesions that have not been diagnosed as any other specific disease. They are grouped under premalignant lesions, now redesignated as potentially malignant disorders. Their significance lies in the fact that they have propensity for malignant transformation at a higher rate when compared to other oral lesions. This article reviews aetiology, epidemiology, clinical characteristics, histopathologic features, malignant potential and treatment of oral leukoplakia. PMID:25302287

Increased salivary aldehyde dehydrogenase 1 in non-reticular oral lichen planus*

PubMed Central

Mansourian, Arash; Shanbehzadeh, Najmeh; Kia, Seyed Javad; Moosavi, Mahdieh-Sadat

2017-01-01

Background Oral lichen planus is a potentially malignant disorder. One of the malignant transformation markers is cancer stem cells. One of the proposed marker for the detection of cancer stem cells's in head and neck cancer is aldehyde dehydrogenase. Recently it is shown that aldehyde dehydrogenase 1 expression in tissue samples is associated with oral lichen planus malignant transformation. Objective This study evaluates salivary aldehyde dehydrogenase 1 in oral lichen planus. Method Thirty patients and 30 age and sex-matched healthy volunteers were recruited. Oral lichen planus was diagnosed based on the modified World Health Organization criteria. Subjects in the case group were divided into reticular and non-reticular forms. Unstimulated salivary samples were collected at 10-12 AM. Saliva concentrations of aldehyde dehydrogenase 1 were measured by ELISA. Results The differences between aldehyde dehydrogenase levels in the oral lichen planus group compared with the control group were not significant but aldehyde dehydrogenase in non-reticular oral lichen planus was significantly higher than that of the reticular form. Limitations of the study This is a cross-sectional study, thus longitudinal studies in oral lichen planus may present similar or different results. Conclusions The mechanism of malignant transformation in oral lichen planus is not defined. Previous analyses revealed that the aldehyde dehydrogenase 1 expression is significantly correlated with increased risk of transformation. This finding is consistent with our results because in the erosive and ulcerative forms of oral lichen planus, which have an increased risk of transformation, salivary aldehyde dehydrogenase 1 was overexpressed. A higher salivary aldehyde dehydrogenase level in non-reticular oral lichen planus can be a defensive mechanism against higher oxidative stress in these groups. Aldehyde dehydrogenase may be one of the malignant transformation markers in oral lichen planus. Further studies are needed for introducing aldehyde dehydrogenase as a prognostic indicator in certain lesions. PMID:28538873

Continual exposure to cigarette smoke extracts induces tumor-like transformation of human nontumor bronchial epithelial cells in a microfluidic chip.

PubMed

Li, Encheng; Xu, Zhiyun; Liu, Fen; Wang, Huiling; Wen, Jiabin; Shao, Shujuan; Zhang, Lichuan; Wang, Lei; Liu, Chong; Lu, Jianxin; Wang, Wenxin; Gao, Zhancheng; Wang, Qi

2014-08-01

Heavy cigarette smoking-related chronic obstructive pulmonary disease is an independent risk factor for lung squamous carcinoma. However, the mechanisms underlying the malignant transformation of bronchial epithelial cells are unclear. In our study, human tumor-adjacent bronchial epithelial cells were obtained from 10 cases with smoking-related chronic obstructive pulmonary disease and lung squamous carcinoma and cultured in an established microfluidic chip for continual exposure to cigarette smoke extracts (CSE) to investigate the potential tumor-like transformation and mechanisms. The integrated microfluidic chip included upstream concentration gradient generator and downstream cell culture chambers supplied by flowing medium containing different concentrations of CSE. Our results showed that continual exposure to low doses of CSE promoted cell proliferation whereas to high doses of CSE triggered cell apoptosis. Continual exposure to CSE promoted reactive oxygen species production in human epithelial cells in a dose-dependent manner. More importantly, continual exposure to low dose of CSE promoted the epithelial-to-mesenchymal transition process and anchorage-independent growth, and increased chromosome instability in bronchial epithelial cells, accompanied by activating the GRP78, NF-κB, and PI3K pathways. The established microfluidic chip is suitable for primary culture of human tumor-adjacent bronchial epithelial cells to investigate the malignant transformation. Continual exposure to low doses of CSE promoted tumor-like transformation of human nontumor bronchial epithelial cells by inducing reactive oxygen species production and activating the relevant signaling.

The growth transformation of human B cells involves superinduction of hsp70 and hsp90.

PubMed

Cheung, R K; Dosch, H M

1993-04-01

Epstein-Barr virus (EBV) is a latent human herpes virus associated with a range of malignant and non-malignant disorders. EBV binds to CD21 virus receptors on B lymphocytes and growth transforms these cells; in susceptible (e.g., immunodeficient) hosts such cells rapidly expand into fatal lymphomas. Virus binding and infection trigger a cascade of cellular events which are transformation prerequisite and analogous to non-oncogenic cell activation events but which differ in several quantitative or qualitative respects. Unique trans-membrane Ca2+ currents, Na+/H+ exchange, as well as tyrosine phosphorylation and p56lck-gene induction suggest that even early on the transformation process has oncogenic specificity. In this report we describe that two additional cellular gene families, the stress proteins hsp70 and hsp90, are coordinately induced at mRNA and protein levels and, quite different from hsp induction by thermal stress, this induction is dependent on EBV-induced trans-membrane Ca2+ currents. Blockade of hsp induction prevents transformation. The kinetics and induction prerequisites set this response well apart from reported responses to thermal or viral stress protein induction. Like p56lck-, hsp induction is purely a post-receptor binding event and not dependent on expression of any viral gene. The induction kinetics, with a peak at approximately 12-16 hr and subsequent decline to control levels, considerably extend the chronological map of elements in the CD21-dependent branch of the transformation pathway and suggest a specific role of induced hsp different from the cell cycle-related functions observed in other cell systems.

Vulvar trichoblastoma: case report and literature review.

PubMed

Pina, Annick; Sauthier, Philippe; Rahimi, Kurosh

2015-01-01

Trichoblastomas are rare and benign tumors that arise from rudimentary hair follicles. Presentation varies from superficial plaques to papular or nodular lesions. Trichoblastomas usually arise on the head or neck. A few cases of other vulvar trichoblastic tumors such as trichofibromas and trichoepitheliomas have been reported to this day, but no such report of vulvar trichoblastoma exists. We report the case of a 61-year-old woman who presented with a vulvar trichoblastoma. The woman presented with a lump of the labium majus. She was managed surgically, first by wide excision of the mass followed by a second surgery consisting of a partial vulvectomy. Because surgical margins were positive and there is a potential for malignant transformation, a third surgery was performed. The margins came back negative. A literature review on trichoblastomas was performed, including its potential for malignant transformation, management, and immunohistochemistry to differentiate it from basal cell carcinoma. Trichoblastomas are benign tumors that have a potential for malignant transformation. These tumors can present aggressive characteristics. Differential diagnosis from basal cell carcinoma can be difficult but is facilitated using immunohistochemistry. This is the first case of vulvar trichoblastoma reported in the literature. Although it is a benign tumor, excision with negative margins is recommended because it can be difficult to distinguish from basal cell carcinoma and it has a potential for malignant transformation.

Differential Lectin Agglutination of Fetal, Dividing-Postnatal, and Malignant Hepatocytes

PubMed Central

Becker, F. F.

1974-01-01

Numerous studies have reported the capacity of the lectin, concanavalin A, to agglutinate selected cell-types. The finding that cells transformed in culture, embryonic cells, and malignant cells are all agglutinated by this substance, may contribute to our understanding of the oncogenic process. The present study compared the response to concanavalin A of rat hepatocytes derived from livers of differing developmental and mitotic-status as well as those derived from malignant liver tumors (hepatomas). Fetal hepatocytes and hepatoma cells were highly susceptible to agglutination while hepatocytes from post-natal livers, whether dividing or quiescent, were not. Treatment with protease(s) did not make the interphase hepatocyte agglutinable. These data emphasize the importance of examining a wide variety of cells in attempting to understand the interaction of lectins on cell surfaces, and further, demonstrate the value of obtaining cells directly from tissue(s) during differing physiologic and pathologic states. Images PMID:4373708

Management of peri-anal giant condyloma acuminatum--a case report and literature review.

PubMed

Safi, Farouk; Bekdache, Omar; Al-Salam, Suhail; Alashari, Mouied; Mazen, Taha; El-Salhat, Haytham

2013-01-01

Giant condyloma acuminatum (GCA), originally described by Buschke and Loewenstein in 1925 as a lesion of the penis, is more rarely seen in the anorectum and is characterized by clinical malignancy in the face of histologic benignity; however, malignant transformation to frankly invasive squamous-cell carcinoma has been described in about one-third of patients. In addition, malignant transformation has been reported in patients with "ordinary" condylomata acuminata. Human papillomavirus, known to cause condylomata acuminata, is also known to induce these tumors and was found in 96% of 63 cases reviewed in the last 10 years. These lesions have a propensity for recurrence and a likelihood of malignant transformation, and lead to significant mortality. Therefore, early and radical R0 excision, along with vigilant follow-up, provides the hope for cure. Conservative and/or multimodal therapy has been reported in a few cases, but its effect is not yet proved. The authors report one case of GCA; in addition, they reviewed the literature over the last 10 years and compared with previous reviews. Copyright © 2012. Published by Elsevier B.V.

Utility of positron emission tomography in schwannomatosis.

PubMed

Lieber, Bryan; Han, ByoungJun; Allen, Jeffrey; Fatterpekar, Girish; Agarwal, Nitin; Kazemi, Noojan; Zagzag, David

2016-08-01

Schwannomatosis is characterized by multiple non-intradermal schwannomas with patients often presenting with a painful mass in their extremities. In this syndrome malignant transformation of schwannomas is rare in spite of their large size at presentation. Non-invasive measures of assessing the biological behavior of plexiform neurofibromas in neurofibromatosis type 1 such as positron emission tomography (PET), CT scanning and MRI are well characterized but little information has been published on the use of PET imaging in schwannomatosis. We report a unique clinical presentation portraying the use of PET imaging in schwannomatosis. A 27-year-old woman presented with multiple, rapidly growing, large and painful schwannomas confirmed to be related to a constitutional mutation in the SMARCB1 complex. Whole body PET/MRI revealed numerous PET-avid tumors suggestive of malignant peripheral nerve sheath tumors. Surgery was performed on multiple tumors and none of them had histologic evidence of malignant transformation. Overall, PET imaging may not be a reliable predictor of malignant transformation in schwannomatosis, tempering enthusiasm for surgical interventions for tumors not producing significant clinical signs or symptoms. Copyright © 2016 Elsevier Ltd. All rights reserved.

Malignant transformation of oral epithelial dysplasia: clinicopathological risk factors and outcome analysis in a retrospective cohort of 138 cases.

PubMed

Liu, Wei; Bao, Zhe-Xuan; Shi, Lin-Jun; Tang, Guo-Yao; Zhou, Zeng-Tong

2011-10-01

To explore the usefulness of a new binary system of grading dysplasia proposed by the World Health Organization and to identify significant risk factors for malignant transformation in a long-term follow-up cohort of patients with oral epithelial dysplasia. A total of 138 patients with histologically confirmed oral dysplasia between 1978 and 2008 were reviewed retrospectively in our department. The mean follow-up period was 5.1 years. Of these dysplasias, 37 (26.8%) developed into cancer, with a mean duration of 4.6 years. Cox regression analysis revealed that high-grade dysplasia was an independent risk factor for transition, but age, gender, lesion site, diet habit, smoking and alcohol intake were not risk factors. High-grade dysplasia was associated with a 2.78-fold (95% confidence interval 1.44-5.38; P = 0.002) increased risk of transition, as compared with low-grade dysplasia. Consistently, high-grade dysplasia had a significantly higher incidence of malignancy than low-grade dysplasia by Kaplan-Meier analysis (log-rank test, P = 0.001). The utilization of high-grade dysplasia as a significant indicator for evaluating malignant transformation risk in patients with potentially malignant lesions is suggested; this may be helpful to guide treatment selection in clinical practice. 2011 Blackwell Publishing Limited.

Cryopreservation does not alter main characteristics of Good Manufacturing Process-grade human multipotent mesenchymal stromal cells including immunomodulating potential and lack of malignant transformation.

PubMed

Luetzkendorf, Jana; Nerger, Katrin; Hering, Julian; Moegel, Angelika; Hoffmann, Katrin; Hoefers, Christiane; Mueller-Tidow, Carsten; Mueller, Lutz P

2015-02-01

The immunomodulating capacity of multipotent mesenchymal stromal cells (MSCs) qualifies them as a therapeutic tool in several diseases. However, repeated transplantation with products of reproducible characteristics may be required. This could be achieved with cryopreserved aliquots of Good Manufacturing Practice (GMP)-grade MSCs. However, the impact of cryopreservation on the characteristics of GMP-MSCs is ill defined. We produced fresh and cryopreserved MSCs from human donors with a xenogen-free GMP protocol. Immunogenicity and immunomodulating capacity were tested in co-culture with putative recipient-specific peripheral blood mononuclear cells (PBMCs). Risk of malignant transformation was assessed in vitro and in vivo. Cryopreservation had no impact on viability and consensus criteria of MSCs. In co-culture with PBMCs, MSCs showed low immunogenicity and suppressed mitogen-stimulated proliferation of PBMC irrespective of cryopreservation. Cytogenetic aberrations were not observed consistently in fresh and cryopreserved products, and no signs of malignant transformation occurred in functional assays. MSC products from an elderly pretreated donor showed reduced functional quality, but imminent failure of functional criteria could be detected by an increased population doubling time in early passages. This study is the first systematic analysis on cryopreservation of xenogen-free human bone marrow-derived GMP-MSCs. The data support that cryopreservation does not alter the characteristics of the cells and thus may allow the generation of products for serial transplantation. In addition, the protocol allowed early detection of MSC products with low functional capacity. Copyright © 2015 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

Malignant Transformation of Radiotherapy-Naïve Craniopharyngioma.

PubMed

Chunhui, Liu; Chuzhong, Li; Zhenye, Li; Yilin, Sun; Yazhuo, Zhang

2016-04-01

Craniopharyngioma is a rare benign intracranial neoplasm that is successfully managed with surgery or adjuvant radiotherapy. The malignant transformation of craniopharyngioma has seldom been reported. A 30-year-old woman presented with a 5-month history of amenorrhea and was admitted to the hospital. She underwent surgical resection for three times and died at last. MRI revealed a new solid component of craniopharyngioma. Pathologic examination revealed malignant changes in the craniopharyngioma. In addition, We analyzed the expression of Ki-67, p53, VEGF, and MMP-9 in this malignant case after the third operation and in samples from 9 benign craniopharyngiomas. Immunohistochemical analysis showed that the Ki-67 index was higher in malignant craniopharyngiomas (50%) compared with benign craniopharyngiomas (3.0% ± 1.5%; range, 1.0%-6.0%). The p53, MMP-9, and VEGF protein levels were higher in the malignant craniopharyngioma compared with the benign craniopharyngiomas. Patients with a high Ki-67 index and high p53, MMP-9, and VEGF protein levels and a new solid component of craniopharyngioma on MRI may benefit from aggressive treatment and close surveillance. Copyright © 2016 Elsevier Inc. All rights reserved.

Risk prediction for malignant conversion of oral epithelial dysplasia by hypoxia related protein expression.

PubMed

Zhang, Xianglan; Han, Seonhui; Han, Hye-Yeon; Ryu, Mi Heon; Kim, Ki-Yeol; Choi, Eun-Joo; Cha, In-Ho; Kim, Jin

2013-08-01

Increased aerobic glycolysis is a unique finding in cancers and hypoxia-related proteins are associated with aerobic glycolysis. Therefore, we aimed to investigate whether hypoxia-related proteins can be predictive markers for malignant conversion of oral premalignant lesions with epithelial dysplasia (OED). Expression of HIF-1α, Glut-1 and CA9 were detected in clinical samples of eight normal oral mucosa, 85 transitional areas of oral squamous cell carcinoma (OSCC) and 28 OED with or without malignant conversion using immunohistochemistry and were also comparatively detected in immortalised human oral keratinocyte (IHOK) and OSCC cell lines under hypoxia using immunoblotting. Sequential expression of HIF-1α, Glut-1 and CA9 was found both in transitional areas of OSCC and cell lines of IHOK and OSCC under hypoxia, supporting hypoxia-aerobic glycolysis-acidosis axis. Expression of all proteins showed significant association with malignant conversion of OED and CA9 was an independent risk factor of malignant transformation of OED. But the predictability of malignant transformation was improved when all three proteins were applied together. High expression of CA9 was an independent predictive marker of malignant conversion. Moreover, the combined application of these three proteins may be useful to assess the risk of malignant conversion of OED.

Methionine restriction inhibits chemically-induced malignant transformation in the BALB/c 3T3 cell transformation assay.

PubMed

Nicken, Petra; Empl, Michael T; Gerhard, Daniel; Hausmann, Julia; Steinberg, Pablo

2016-09-01

High consumption of red meat entails a higher risk of developing colorectal cancer. Methionine, which is more frequently a component of animal proteins, and folic acid are members of the one carbon cycle and as such important players in DNA methylation and cancer development. Therefore, dietary modifications involving altered methionine and folic acid content might inhibit colon cancer development. In the present study, the BALB/c 3T3 cell transformation assay was used to investigate whether methionine and folic acid are able to influence the malignant transformation of mouse fibroblasts after treatment with the known tumour initiator 3-methylcholanthrene. Three different methionine concentrations (representing a -40%, a "normal" and a +40% cell culture medium concentration, respectively) and two different folic acid concentrations (6 and 20 μM) were thereby investigated. Methionine restriction led to a decrease of type III foci, while enhancement of both methionine and folic acid did not significantly increase the cell transformation rate. Interestingly, the focus-lowering effect of methionine was only significant in conjunction with an elevated folic acid concentration. In summary, we conclude that the malignant transformation of mouse fibroblasts is influenced by methionine levels and that methionine restriction could be a possible approach to reduce cancer development. Copyright © 2016 Elsevier Ltd. All rights reserved.

Continuous activation of Nrf2 and its target antioxidant enzymes leads to arsenite-induced malignant transformation of human bronchial epithelial cells

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

Yang, Xu; Wang, Dapeng; Department of Toxicology, School of Public Health, Guizhou Medical University, Guiyang, Guizhou

Long-term exposure to arsenite leads to human lung cancer, but the underlying mechanisms of carcinogenesis remain obscure. The transcription factor of nuclear factor-erythroid-2 p45-related factor (Nrf2)-mediated antioxidant response represents a critical cellular defense mechanism and protection against various diseases. Paradoxically, emerging data suggest that the constitutive activation of Nrf2 is associated with cancer development, progression and chemotherapy resistance. However, the role of Nrf2 in the occurrence of cancer induced by long-term arsenite exposure remains to be fully understood. By establishing transformed human bronchial epithelial (HBE) cells via chronic low-dose arsenite treatment, we showed that, in acquiring this malignant phenotype, continuousmore » low level of ROS and sustained enhancement of Nrf2 and its target antioxidant enzyme levels were observed in the later-stage of arsenite-induced cell transformation. The downregulation of Keap1 level may be responsible for the over-activation of Nrf2 and its target enzymes. To validate these observations, Nrf2 was knocked down in arsenite-transformed HBE cells by SiRNA transfection, and the levels of Nrf2 and its target antioxidant enzymes, ROS, cell proliferation, migration, and colony formation were determined following these treatments. Results showed that blocked Nrf2 expression significantly reduced Nrf2 and its target antioxidant enzyme levels, restored ROS levels, and eventually suppressed cell proliferation, migration, and colony formation of the transformed cells. In summary, the results of the study strongly suggested that the continuous activation of Nrf2 and its target antioxidant enzymes led to the over-depletion of intracellular ROS levels, which contributed to arsenite-induced HBE cell transformation. - Highlights: • Low level, long term arsenite exposure induces malignant transformation in vitro. • Long term arsenite exposure reduces ROS and MDA levels. • Long term arsenite exposure enhances Nrf2-mediated antioxidant levels. • Knockdown of Nrf2 reduces malignant degree of arsenite-transformed cells.« less

Genomic and Expression Profiling of Benign and Malignant Nerve Sheath Tumors in Neurofibromatosis Patients

DTIC Science & Technology

2008-05-01

DAMD17-03-1-0297 Title: Genomic and Expression Pr ofiling of Benign and Malignant Nerve Sheath Tumors in Neurofibromatosis Patients...have determined the gene expression signature for benign and malignant peripheral nerve sheath tumors and found that the major trend in transformation...However, EGFR data in soft tissue neoplasms is limited. Using a variety of benign and malignant spindle cell neoplasms, we assessed EGFR status by

Adenomas - Genetic factors in colorectal cancer prevention.

PubMed

Witold, Kycler; Anna, Kubiak; Maciej, Trojanowski; Jakub, Janowski

2018-01-01

Colorectal cancer is the second most common type of cancer both in Europe and Poland. During the last 30 years more than a 3-fold increase has been observed in Poland due to environmental and genetic factors. Almost all colorectal malignancies are related to the formation and malignant transformation of colorectal dysplasia and adenoma. Efforts aiming to decrease the number of colorectal cancer deaths are focused on the disease early detection. Genetic diagnosis for hereditary syndromes predisposing to colorectal cancer has been developed and is a part of the routine treatment. Most cancers are sporadic. They often develop from polyps in the colon. In addition to the genetic events described in the 1990s, showing the adenoma transformation into carcinoma that has been a prime example of malignant transformation for a long time, there are also other possibilities of neoplastic transformation. The recognition of colorectal cancer risk factors make sense as their nature is lifestyle- and diet-related. In this review paper those risk factors are presented and the prevention of colorectal cancer is discussed taking into account genetic factors.

Ovarian mature cystic teratoma with fistula formation into the rectum: a case report.

PubMed

Kizaki, Yuichiro; Nagai, Tomonori; Ohara, Ken; Gomi, Yosuke; Akahori, Taichi; Ono, Yoshihisa; Matsunaga, Shigetaka; Takai, Yasushi; Saito, Masahiro; Baba, Kazunori; Seki, Hiroyuki

2016-01-01

While ovarian mature cystic teratomas are benign ovarian germ-cell tumors and the most common type of all ovarian tumors, the formation of fistulas into surrounding organs such as the bladder and the intestinal tract is extremely rare. This report documents a case of ovarian mature cystic teratoma with a rectal fistula, thought to be caused by local inflammation. A pelvic mass was diagnosed as an ovarian mature cystic teratoma of approximately 10 cm in diameter on transvaginal ultrasound and magnetic resonance examinations. Endoscopic examination of the lower gastrointestinal tract to investigate diarrhea revealed an ulcerative lesion with hair in the rectal wall adjacent to the ovarian cyst, and formation of a fistula from the ovarian teratoma into the rectum was suspected. Laparotomy revealed extensive inflammatory adhesions between a left ovarian tumor and the rectum. Left salpingo-oophorectomy and upper anterior resection of the rectum were performed. The final pathological diagnosis was ovarian mature cystic teratoma with no malignant findings, together with severe rectal inflammation and fistula formation with no structural disorders such as diverticulitis of the colon or malignant signs. The formation of fistulas and invasion into the neighboring organs are extremely rare complications for ovarian mature cystic teratomas. The invasion of malignant cells into neighboring organs due to malignant transformation of the tumor is reported as the cause of fistula formation into the neighboring organs. A review of 17 cases including the present case revealed that fistula formation due to malignant transformation comprised only 4 cases (23.5 %), with inflammation as the actual cause in the majority of cases (13 cases, 76.5 %). Although malignancy is the first consideration when fistula formation is observed between ovarian tumors and surrounding organs, in mature cystic teratoma, local inflammation is more likely than malignant transformation.

OSTEOCHONDROMA OF THE PROXIMAL HUMERUS WITH FRICTIONAL BURSITIS AND SECONDARY SYNOVIAL OSTEOCHONDROMATOSIS.

PubMed

De Groote, J; Geerts, B; Mermuys, K; Verstraete, K

2015-01-01

We report a case of multiple hereditary exostosis in a 33-year old patient with clinical symptoms of pain and impression of a growing mass of the left shoulder alerting potential risk of malignant transformation of an osteochondroma. Imaging studies illustrated perilesional bursitis surrounding an osteochondroma of the proximal humerus. Malignant transformation was excluded with MRI. Fragments of the osteochondroma were dislocated in the inflammatory synovial bursa illustrating a case of secondary synovial osteochondromatosis.

Hospital-based epidemiological and clinical characterisation of the malignant transformation of oral leukoplakia in a Chinese population.

PubMed

Lyu, Ming-Yue; Guo, Yu-Si; Li, Shuo; Yang, Di; Hua, Hong

2017-08-01

The aim of this review was to analyse, systematically, hospital-based epidemiological information concerning the malignant transformation rate (MTR) of oral leukoplakia (OL) in a Chinese population, as well as the associated risk factors. Four electronic databases were searched for studies dealing with OL and related risk factors, including age, gender, type of lesion, site, and smoking and drinking habits. The MTR of OL in the hospital-based Chinese population ranged from 4% to 13%, based on the studies analysed. Regarding risk factors, we found that female patients had a higher MTR than male patients, and that patients older than 50 years of age also had a higher MTR. Patients who smoked had a lower MTR, while alcohol consumption seemed to have no association with MTR. Malignant transformation occurred most commonly on the tongue. Regarding lesion type, non-homogeneous OL had a higher MTR, with the granular type having the highest MTR. Our results regarding the epidemiology of OL showed a similar trend to those reported in western populations and provided preliminary epidemiological information on the Chinese population. Our findings show that female gender, age >50 years and non-homogeneous OL are risk factors for malignant transformation. It is important to develop clinical strategies to educate, diagnose and treat patients with OL and to minimise the MTR of OL. © 2017 FDI World Dental Federation.

2D-DIGE and MALDI TOF/TOF MS analysis reveal that small GTPase signaling pathways may play an important role in cadmium-induced colon cell malignant transformation

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

Lu, Jian, E-mail: lujian@ujs.edu.cn; Institute of Life Sciences, Jiangsu University, Zhenjiang 212013; Zhou, Zhongping

Cadmium is a toxic heavy metal present in the environment and in industrial materials. Cadmium has demonstrated carcinogenic activity that induces cell transformation, but how this occurs is unclear. We used 2D-DIGE and MALDI TOF/TOF MS combined with bioinformatics and immunoblotting to investigate the molecular mechanism of cadmium transformation. We found that small GTPases were critical for transformation. Additionally, proteins involved in mitochondrial transcription, DNA repair, and translation also had altered expression patterns in cadmium treated cells. Collectively, our results suggest that activation of small GTPases contributes to cadmium-induced transformation of colon cells. - Highlights: • Colon epithelial cell linemore » is firstly successfully transformed by cadmium. • 2D-DIGE is applied to visualize the differentially expressed proteins. • RhoA plays an important role in cadmium induced malignant transformation. • Bioinformatic and experimental methods are combined to explore new mechanisms.« less

Metastatic mediastinal mature teratoma with malignant transformation in a young man with an adenocarcinoma in a Klinefelter's syndrome: Case report and review of the literature.

PubMed

Le Fèvre, C; Vigneron, C; Schuster, H; Walter, A; Marcellin, L; Massard, G; Lutz, P; Noël, G

2018-05-01

Malignant transformation of mediastinal mature teratoma is extremely rare and worsens the prognosis of the disease. Transformation can appear synchronously to or several years after the initial diagnosis. Clinical and radiological signs can orientate the clinician but the definitive diagnosis is obtained thanks to histology. An 11 year-old boy presented with a mediastinal mature teratoma and bone and pulmonary metastases. He received six cycles of chemotherapy combining etoposide, ifosfamide, cisplatin, followed by resection of a 16×14×9cm mediastinal mass. Karyotype analysis revealed the presence of an additional sex chromosome X (47 XXY) pathognomonic of Klinefelter's syndrome. Ten years later, sciatalgia revealed malignant transformation of a pre-existing sacral bone metastasis into gastrointestinal adenocarcinoma. The patient received four cycles of chemotherapy combining oxaliplatin, 5-fluorouracil and cetuximab. This treatment was followed by a complete resection of the sacral metastasis and completed with adjuvant irradiation of 54Gy in 30 daily fractions. Twelve months after the diagnosis of relapse, the patient remained alive without disease. To our knowledge, this is the first case of adenocarcinoma developed in bone metastases of a mediastinal mature teratoma in a boy with a Klinefelter's syndrome. We propose a review of the literature and an analysis of 20 others published cases of mediastinal teratoma with malignant transformation into adenocarcinoma. Copyright © 2018 Société française de radiothérapie oncologique (SFRO). Published by Elsevier Masson SAS. All rights reserved.

Transforming growth factor β as regulator of cancer stemness and metastasis

PubMed Central

Bellomo, Claudia; Caja, Laia; Moustakas, Aristidis

2016-01-01

Key elements of cancer progression towards metastasis are the biological actions of cancer stem cells and stromal cells in the tumour microenvironment. Cross-communication between tumour and stromal cells is mediated by secreted cytokines, one of which, the transforming growth factor β (TGFβ), regulates essentially every cell within the malignant tissue. In this article, we focus on the actions of TGFβ on cancer stem cells, cancer-associated fibroblasts and immune cells that assist the overall process of metastatic dissemination. We aim at illustrating intricate connections made by various cells in the tumour tissue and which depend on the action of TGFβ. PMID:27537386

Giant hidradenocarcinoma: a report of malignant transformation from nodular hidradenoma.

PubMed

Lim, S C; Lee, M J; Lee, M S; Kee, K H; Suh, C H

1998-10-01

A giant hidradenocarcinoma presented by a 75-year-old female is reported. The patient had a malignant transformation within a nodular hidradenoma involving the right postauricular area, which was treated by mass removal and a right radical neck dissection with a free-flap covering. Malignant hidradenocarcinoma is the least common adnexal tumor of uncertain origin. They are usually malignant from their inception, but some develop from a benign counterpart. To the authors' knowledge, only three cases have been reported previously. Two histologically distinct components were seen in this tumor: (i) typical nodular hidradenoma, which constituted a small part of the tumor; and (ii) carcinoma with areas of transition. The secretory cells of hidradenocarcinoma showed decapitation secretion on light and electron microscopic observations, which is evidence of apocrine differentiation. Histologically, this case was concluded as a hidradenocarcinoma arising from a long-standing nodular hidradenoma. A literature review is presented and the histological, immunohistochemical and ultrastructural features are described.

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.

Histopathologic evaluation of atypical neurofibromatous tumors and their transformation into malignant peripheral nerve sheath tumor in patients with neurofibromatosis 1-a consensus overview.

PubMed

Miettinen, Markku M; Antonescu, Cristina R; Fletcher, Christopher D M; Kim, Aerang; Lazar, Alexander J; Quezado, Martha M; Reilly, Karlyne M; Stemmer-Rachamimov, Anat; Stewart, Douglas R; Viskochil, David; Widemann, Brigitte; Perry, Arie

2017-09-01

Patients with neurofibromatosis 1 (NF1) develop multiple neurofibromas, with 8% to 15% of patients experiencing malignant peripheral nerve sheath tumor (MPNST) during their lifetime. Prediction of transformation, typically from plexiform neurofibroma, is clinically and histologically challenging. In this overview, after a consensus meeting in October 2016, we outline the histopathologic features and molecular mechanisms involved in the malignant transformation of neurofibromas. Nuclear atypia alone is generally insignificant. However, with atypia, loss of neurofibroma architecture, high cellularity, and/or mitotic activity >1/50 but <3/10 high-power fields, the findings are worrisome for malignancy. We propose the term "atypical neurofibromatous neoplasms of uncertain biologic potential (ANNUBP)" for lesions displaying at least 2 of these features. This diagnosis should prompt additional sampling, clinical correlation, and possibly, expert pathology consultation. Currently, such tumors are diagnosed inconsistently as atypical neurofibroma or low-grade MPNST. Most MPNSTs arising from neurofibromas are high-grade sarcomas and pose little diagnostic difficulty, although rare nonnecrotic tumors with 3-9 mitoses/10 high-power fields can be recognized as low-grade variants. Although neurofibromas contain numerous S100 protein/SOX10-positive Schwann cells and CD34-positive fibroblasts, both components are reduced or absent in MPNST. Loss of p16/CDKN2A expression, elevated Ki67 labeling, and extensive nuclear p53 positivity are also features of MPNST that can to some degree already occur in atypical neurofibromatous neoplasms of uncertain biologic potential. Complete loss of trimethylated histone 3 lysine 27 expression is potentially more reliable, being immunohistochemically detectable in about half of MPNSTs. Correlated clinicopathological, radiologic, and genetic studies should increase our understanding of malignant transformation in neurofibromas, hopefully improving diagnosis and treatment soon. Published by Elsevier Inc.

Membrane lipid-protein interactions modify the regulatory role of adenosine-deaminase complexing protein: a phase fluorometry study of a malignancy marker

NASA Astrophysics Data System (ADS)

Parola, Abraham H.; Porat, Nurith; Caiolfa, Valeria R.; Gill, David; Kiesow, Lutz A.; Weisman, Mathew; Nemschitz, S.; Yaron, Dahlia; Singer, Karen; Solomon, Ethel

1990-05-01

The role of membrane lipid-protein interactions in malignant cell transformation was examined with adenosine deaminase (ADA) as a representative membrane protein. ADA's activity changes dramatically in transformed cells and accordingly it is a malignancy marker. Yet, the mechanisms controlling its variable activity are unknown. We undertook the spectroscopic deciphering of its interactions with its lipidic environment in normal and malignant cells. ADA exists in two interconvertible forms, small (45 KD) and large (21OKD). The large form consists of two small catalytic subunits (55-ADA) and a dimeric complexing protein ADCP. The physiological role of ADCP was not known either. Our studies were carried out at three levels.: 1. Solution enzyme kinetics, 2. The interaction of 55-ADA with ADCP reconstituted in liposomes: Effect of cholesterol and 3. Multifrequency phase modulation spectrofluorometry of pyrene-labeled 55-ADA bound to ADCP on the membranes of normal and RSV or RSV Ts68 transformed chick embryo fibroblasts. We found: 1. ADCP has an allosteric regulatory role on 55-ADA, which may be of physiological relevance: It inhibits 55-ADA activity at low physiological adenosine concentrations but accelerates deamination at high substrate concentration. 2. When reconstituted in DMPC liposomes, it retains 55-ADA activity (in its absence the activity is lost) and upon rigidification with cholesterol, a three fold increase in 55-ADA activity is attained, contrary to ADCP's regulatory activity when free of lipids. 3. The reduced ADA activity in transformed chick embryo fibroblasts is associated with increased membrane lipid fluidity (reduced order parameter), reduced accessibility of ADCP and increase rotational dynamics of the complex. We thus obtained spectroscopic deciphering of the vertical motion of ADCP, controlled by lipid-protein interaction, resulting in variable activity of this malignancy marker.

Retroperitoneal teratoma with somatic malignant transformation: a papillary renal cell carcinoma in a testicular germ cell tumour metastasis following platinum-based chemotherapy.

PubMed

Zeh, Nina; Wild, Peter J; Bode, Peter K; Kristiansen, Glen; Moch, Holger; Sulser, Tullio; Hermanns, Thomas

2013-02-12

Malignant transformation describes the phenomenon in which a somatic component of a germ cell teratoma undergoes malignant differentiation. A variety of different types of sarcoma and carcinoma, all non-germ cell, have been described as a result of malignant transformation. A 33-year-old man presented with a left testicular mass and elevated tumour markers. Staging investigations revealed retroperitoneal lymphadenopathy with obstruction of the left ureter and distant metastases. Histopathology from the left radical orchiectomy showed a mixed germ cell tumour (Stage III, poor prognosis). The ureter was stented and four cycles of cisplatin, etoposide and bleomycin chemotherapy administered. After initial remission, the patient recurred four years later with a large retroperitoneal mass involving the renal vessels and the left ureter. Left retroperitoneal lymph node dissection with en-bloc resection of the left kidney was performed.Histopathology revealed a germ cell tumour metastasis consisting mainly of mature teratoma. Additionally, within the teratoma a papillary renal cell carcinoma was found. The diagnosis was supported by immunohistochemistry showing positivity for AMACR, CD10 and focal expression of RCC and CK7. There was no radiological or histo-pathological evidence of a primary renal cell cancer. To the best of our knowledge, malignant transformation into a papillary renal cell carcinoma has not been reported in a testicular germ cell tumour metastasis following platinum-based chemotherapy. This histological diagnosis might have implications for potential future therapies. In the case of disease recurrence, renal cell cancer as origin of the recurrent tumour has to be excluded because renal cell carcinoma metastases would not respond well to the classical germ cell tumour chemotherapy regimens.

Deregulation of cell growth and malignant transformation.

PubMed

Sulić, Sanda; Panić, Linda; Dikić, Ivan; Volarević, Sinisa

2005-08-01

Cell growth and cell division are fundamental aspects of cell behavior in all organisms. Recent insights from many model organisms have shed light on the molecular mechanisms that control cell growth and cell division. A significant body of evidence has now been accumulated, showing a direct link between deregulation of components of cell cycle machinery and cancer. In addition, defects in one or more steps that control growth are important for malignant transformation, as many tumor suppressors and proto-oncogenes have been found to regulate cell growth. The importance of cell growth in tumor development is further supported by the discovery that rapamycin, an effective anticancer drug, inhibits a key regulator of protein synthetic machinery and cell growth, mammalian target of rapamycin (mTOR). In most cases, cell growth and cell division are coupled, thereby maintaining cell size within physiological limits. We believe that, in a long-term perspective, understanding how these two processes are coordinated in vivo and how their interplay is deregulated in a number of diseases, including cancer, may have a direct impact on the efficiency of modern therapeutics.

Dysregulation of mitotic machinery genes precedes genome instability during spontaneous pre-malignant transformation of mouse ovarian surface epithelial cells.

PubMed

Urzúa, Ulises; Ampuero, Sandra; Roby, Katherine F; Owens, Garrison A; Munroe, David J

2016-10-25

Based in epidemiological evidence, repetitive ovulation has been proposed to play a role in the origin of ovarian cancer by inducing an aberrant wound rupture-repair process of the ovarian surface epithelium (OSE). Accordingly, long term cultures of isolated OSE cells undergo in vitro spontaneous transformation thus developing tumorigenic capacity upon extensive subcultivation. In this work, C57BL/6 mouse OSE (MOSE) cells were cultured up to passage 28 and their RNA and DNA copy number profiles obtained at passages 2, 5, 7, 10, 14, 18, 23, 25 and 28 by means of DNA microarrays. Gene ontology, pathway and network analyses were focused in passages earlier than 20, which is a hallmark of malignancy in this model. At passage 14, 101 genes were up-regulated in absence of significant DNA copy number changes. Among these, the top-3 enriched functions (>30 fold, adj p < 0.05) comprised 7 genes coding for centralspindlin, chromosome passenger and minichromosome maintenance protein complexes. The genes Ccnb1 (Cyclin B1), Birc5 (Survivin), Nusap1 and Kif23 were the most recurrent in over a dozen GO terms related to the mitotic process. On the other hand, Pten plus the large non-coding RNAs Malat1 and Neat1 were among the 80 down-regulated genes with mRNA processing, nuclear bodies, ER-stress response and tumor suppression as relevant terms. Interestingly, the earliest discrete segmental aneuploidies arose by passage 18 in chromosomes 7, 10, 11, 13, 15, 17 and 19. By passage 23, when MOSE cells express the malignant phenotype, the dysregulated gene expression repertoire expanded, DNA imbalances enlarged in size and covered additional loci. Prior to early aneuploidies, overexpression of genes coding for the mitotic apparatus in passage-14 pre-malignant MOSE cells indicate an increased proliferation rate suggestive of replicative stress. Concomitant down-regulation of nuclear bodies and RNA processing related genes suggests altered control of nuclear RNA maturation, features recently linked to impaired DNA damage response leading to genome instability. These results, combined with cytogenetic analysis by other authors in this model, suggest that transcriptional profile at passage 14 might induce cytokinesis failure by which tetraploid cells approach a near-tetraploid stage containing primary chromosome aberrations that initiate the tumorigenic drive.

Genomic instability and tumorigenic induction in immortalized human bronchial epithelial cells by heavy ions

NASA Astrophysics Data System (ADS)

Hei, T. K.; Piao, C. Q.; Wu, L. J.; Willey, J. C.; Hall, E. J.

1998-11-01

Carcinogenesis is postulated to be a progressive multistage process characterized by an increase in genomic instability and clonal selection with each mutational event endowing a selective growth advantage. Genomic instability as manifested by the amplification of specific gene fragments is common among tumor and transformed cells. In the present study, immortalized human bronchial (BEP2D) cells were irradiated with graded doses of either 1GeV/nucleon 56Fe ions or 150 keV/μm alpha particles. Transformed cells developed through a series of successive steps before becoming tumorigenic in nude mice. Tumorigenic cells showed neither ras mutations nor deletion in the p16 tumor suppressor gene. In contrast, they harbored mutations in the p53 gene and over-expressed cyclin D1. Genomic instability among transformed cells at various stage of the carcinogenic process was examined based on frequencies of PALA resistance. Incidence of genomic instability was highest among established tumor cell lines relative to transformed, non-tumorigenic and control cell lines. Treatment of BEP2D cells with a 4 mM dose of the aminothiol WR-1065 significantly reduced their neoplastic transforming response to 56Fe particles. This model provides an opportunity to study the cellular and molecular mechanisms involved in malignant transformation of human epithelial cells by heavy ions.

Wavelet-domain de-noising of OCT images of human brain malignant glioma

NASA Astrophysics Data System (ADS)

Dolganova, I. N.; Aleksandrova, P. V.; Beshplav, S.-I. T.; Chernomyrdin, N. V.; Dubyanskaya, E. N.; Goryaynov, S. A.; Kurlov, V. N.; Reshetov, I. V.; Potapov, A. A.; Tuchin, V. V.; Zaytsev, K. I.

2018-04-01

We have proposed a wavelet-domain de-noising technique for imaging of human brain malignant glioma by optical coherence tomography (OCT). It implies OCT image decomposition using the direct fast wavelet transform, thresholding of the obtained wavelet spectrum and further inverse fast wavelet transform for image reconstruction. By selecting both wavelet basis and thresholding procedure, we have found an optimal wavelet filter, which application improves differentiation of the considered brain tissue classes - i.e. malignant glioma and normal/intact tissue. Namely, it allows reducing the scattering noise in the OCT images and retaining signal decrement for each tissue class. Therefore, the observed results reveals the wavelet-domain de-noising as a prospective tool for improved characterization of biological tissue using the OCT.

The role of hypoxia in oral cancer and potentially malignant disorders: a review.

PubMed

Kujan, Omar; Shearston, Kate; Farah, Camile S

2017-04-01

Oral and oropharyngeal cancer are major health problems globally with over 500 000 new cases diagnosed annually. Despite the fact that oral cancer is a preventable disease and has the potential for early detection, the overall survival rate remains at around 50%. Most oral cancer cases are preceded by a group of clinical lesions designated 'potentially malignant disorders'. It is difficult to predict if and when these lesions may transform to malignancy, and in turn it is difficult to agree on appropriate management strategies. Understanding underlying molecular pathways would help in predicting the malignant transformation of oral potentially malignant disorders and ultimately identifying effective methods for early detection and prevention of oral cancer. Reprogramming energy metabolism is an emerging hallmark of cancer that is predominantly controlled by hypoxia-induced genes regulating angiogenesis, tumour vascularization, invasion, drug resistance and metastasis. This review aims to highlight the role of hypoxia in oral carcinogenesis and to suggest future research implications in this arena. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Loss of autocrine endothelial-derived VEGF significantly reduces hemangiosarcoma development in conditional p53-deficient mice

PubMed Central

Farhang Ghahremani, Morvarid; Radaelli, Enrico; Haigh, Katharina; Bartunkova, Sonia; Haenebalcke, Lieven; Marine, Jean-Christophe; Goossens, Steven; Haigh, Jody J

2014-01-01

Malignant transformation of the endothelium is rare, and hemangiosarcomas comprise only 1% of all sarcomas. For this reason and due to the lack of appropriate mouse models, the genetic mechanisms of malignant endothelial transformation are poorly understood. Here, we describe a hemangiosarcoma mouse model generated by deleting p53 specifically in the endothelial and hematopoietic lineages. This strategy led to a high incidence of hemangiosarcoma, with an average latency of 25 weeks. To study the in vivo roles of autocrine or endothelial cell autonomous VEGF signaling in the initiation and/or progression of hemangiosarcomas, we genetically deleted autocrine endothelial sources of VEGF in this mouse model. We found that loss of even a single conditional VEGF allele results in substantial rescue from endothelial cell transformation. These findings highlight the important role of threshold levels of autocrine VEGF signaling in endothelial malignancies and suggest a new approach for hemangiosarcoma treatment using targeted autocrine VEGF inhibition. PMID:24626176

Loss of autocrine endothelial-derived VEGF significantly reduces hemangiosarcoma development in conditional p53-deficient mice.

PubMed

Farhang Ghahremani, Morvarid; Radaelli, Enrico; Haigh, Katharina; Bartunkova, Sonia; Haenebalcke, Lieven; Marine, Jean-Christophe; Goossens, Steven; Haigh, Jody J

2014-01-01

Malignant transformation of the endothelium is rare, and hemangiosarcomas comprise only 1% of all sarcomas. For this reason and due to the lack of appropriate mouse models, the genetic mechanisms of malignant endothelial transformation are poorly understood. Here, we describe a hemangiosarcoma mouse model generated by deleting p53 specifically in the endothelial and hematopoietic lineages. This strategy led to a high incidence of hemangiosarcoma, with an average latency of 25 weeks. To study the in vivo roles of autocrine or endothelial cell autonomous VEGF signaling in the initiation and/or progression of hemangiosarcomas, we genetically deleted autocrine endothelial sources of VEGF in this mouse model. We found that loss of even a single conditional VEGF allele results in substantial rescue from endothelial cell transformation. These findings highlight the important role of threshold levels of autocrine VEGF signaling in endothelial malignancies and suggest a new approach for hemangiosarcoma treatment using targeted autocrine VEGF inhibition.

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

A case of cervical cancer expressed three mRNA variant of Hyaluronan-mediated motility receptor

PubMed Central

Villegas-Ruíz, Vanessa; Salcedo, Mauricio; Zentella-Dehesa, Alejandro; de Oca, Edén V Montes; Román-Basaure, Edgar; Mantilla-Morales, Alejandra; Dávila-Borja, Víctor M; Juárez-Méndez, Sergio

2014-01-01

Cervical cancer is the second malignancy in Mexico, little is known about the prognostic factors associated with this disease. Several cellular components are important in their transformation and progression. Alternative mRNA splice is an important mechanism for generating protein diversity, nevertheless, in cancer unknown mRNA diversity is expressed. Hyaluronan-mediated motility receptor (HMMR, RHAMM, CD168) is a family member of proteins, hyaluronan acid dependent, and has been associated with different malignant processes such as: angiogenesis, cell invasiveness, proliferation, metastasis and poor outcome in some tumors. In the present study we identified expression of HMMR in cervical cancer by means of RT-PCR and sequencing. Our results indicate co-expression of two HMMR variants in all samples, and one case expressed three alternative HMMR splice transcripts. These results showed the heterogeneity of mRNA transcripts of HMMR that could express in cancer and the expression of HMMR could be marker of malignancy in CC. PMID:24966934

Optical diagnosis of actinic cheilitis by infrared spectroscopy.

PubMed

das Chagas E Silva de Carvalho, Luis Felipe; Pereira, Thiago Martini; Magrini, Taciana Depra; Cavalcante, Ana Sueli Rodrigues; da Silva Martinho, Herculano; Almeida, Janete Dias

2016-12-01

Actinic cheilitis (AC) is considered a potentially malignant disorder of the lip. Biomolecular markers study is important to understand malignant transformation into squamous cell carcinoma. Fourier transform infra red (FT-IR) spectroscopy was used to analyze AC in this study. The aim of the study was to evaluate if FT-IR spectral regions of nucleic acids and collagen can help in early diagnosis of malignant transformation. Tissues biopsies of 14 patients diagnosed with AC and 14 normal tissues were obtained. FT-IR spectra were measured at five different points resulting in 70 spectra of each. Analysis of Principal components analysis (PCA) and linear discrimination analysis (LDA) model were also used. In order to verify the statistical difference in the spectra, Mann-Whitney U test was performed in each variable (wavenumber) with p-value <0.05. After the Mann-Whitney U test the vibrational modes of CO (Collagen 1), PO2 (Nucleic Acids) and CO asymmetric (Triglycerides/Lipids) were observed as a possible spectral biomarker. These bands were chosen because they represent the vibrational modes related to collagen and DNA, which are supposed to be changed in AC samples. Based on the PCA-LDA results, the predictive model corresponding to the area under the curve was 0.91 for the fingerprint region and 0.83 for the high wavenumber region, showing the greater accuracy of the test. FT-IR changes in collagen and nucleic acids could be used as molecular biomarkers for malignant transformation. Copyright © 2016 Elsevier B.V. All rights reserved.

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

Determination of the transforming activities of adenovirus oncogenes.

PubMed

Nevels, Michael; Dobner, Thomas

2007-01-01

The last 50 yr of molecular biological investigations into human adenoviruses (Ads) have contributed enormously to our understanding of the basic principles of normal and malignant cell growth. Much of this knowledge stems from analyses of the Ad productive infection cycle in permissive host cells. Also, initial observations concerning the transforming potential of human Ads subsequently revealed decisive insights into the molecular mechanisms of the origins of cancer and established Ads as a model system for explaining virus-mediated transformation processes. Today it is well established that cell transformation by human Ads is a multistep process involving several gene products encoded in early transcription units 1A (E1A) and 1B (E1B). Moreover, a large body of evidence now indicates that alternative or additional mechanisms are engaged in Ad-mediated oncogenic transformation involving gene products encoded in early region 4 (E4) as well as epigenetic changes resulting from viral DNA integration. In particular, studies on the transforming potential of several E4 gene products have now revealed new pathways that point to novel general mechanisms of virus-mediated oncogenesis. In this chapter we describe in vitro and in vivo assays to determine the transforming and oncogenic activities of the E1A, E1B, and E4 oncoproteins in primary baby rat kidney cells and athymic nude mice.

Determination of the transforming activities of adenovirus oncogenes.

PubMed

Speiseder, Thomas; Nevels, Michael; Dobner, Thomas

2014-01-01

The last 50 years of molecular biological investigations into human adenoviruses (Ads) have contributed enormously to our understanding of the basic principles of normal and malignant cell growth. Much of this knowledge stems from analyses of the Ad productive infection cycle in permissive host cells. Also, initial observations concerning the transforming potential of human Ads subsequently revealed decisive insights into the molecular mechanisms of the origins of cancer and established Ads as a model system for explaining virus-mediated transformation processes. Today it is well established that cell transformation by human Ads is a multistep process involving several gene products encoded in early transcription units 1A (E1A) and 1B (E1B). Moreover, a large body of evidence now indicates that alternative or additional mechanisms are engaged in Ad-mediated oncogenic transformation involving gene products encoded in early region 4 (E4) as well as epigenetic changes resulting from viral DNA integration. In particular, studies on the transforming potential of several E4 gene products have now revealed new pathways that point to novel general mechanisms of virus-mediated oncogenesis. In this chapter we describe in vitro and in vivo assays to determine the transforming and oncogenic activities of the E1A, E1B, and E4 oncoproteins in primary baby rat kidney cells, human amniotic fluid cells and athymic nude mice.

Malignant transformation in perianal fistulas of Crohn's disease: a systematic review of literature.

PubMed

Thomas, Mathew; Bienkowski, Robert; Vandermeer, Thomas J; Trostle, Douglas; Cagir, Burt

2010-01-01

Malignant transformation of perineal fistula in Crohn's disease has rarely been reported. The aim of this study is to define the patient's characteristics and clinical presentation of this rare disease. A systematic review of case series and reports published in English language between 1950 and 2008 was conducted. All cases with malignancy in low pelvic/perineal fistula in patients with Crohn's disease were included. All selected cases were then analyzed with respect to age, gender, duration of Crohn's disease and fistula, location of fistula, presenting symptoms, method of diagnosis, delay in diagnosis, histopathology, treatment, and outcome. Data analyses were done using chi-squared or Fisher's exact test and the Mann-Whitney test. Literature review revealed 61 cases of carcinomas arising in perineal fistulas in Crohn's disease. Sixty-one percent (37) of the patients were females. Females were significantly younger than males at the time of diagnosis of cancer (47 vs. 53 years, P < 0.032). Males were also noted to have significantly longer duration of Crohn's disease compared to females (24 vs. 18 years, P = 0.005). However, females were noted to have the fistula for significantly shorter duration prior to cancer transformation when compared to males (8.3 vs. 16 years, P = 0.0035). On initial examination, malignancy was suspected and proven only in 20% of patients (n = 12). Adenocarcinoma was the most common histology (59%, n = 36), followed by squamous cell carcinoma (31%, n = 19). In most patients (59%, n = 36), the fistula was rectal in origin. A high suspicion for malignancy in chronic perineal fistulas associated with Crohn's disease should be maintained in spite of negative biopsies. Especially in women, the shorter duration of Crohn's fistulas prior to malignant degeneration necessitates an aggressive approach to rule out cancer.

Mobile phone base station radiation does not affect neoplastic transformation in BALB/3T3 cells.

PubMed

Hirose, H; Suhara, T; Kaji, N; Sakuma, N; Sekijima, M; Nojima, T; Miyakoshi, J

2008-01-01

A large-scale in vitro study focusing on low-level radiofrequency (RF) fields from mobile radio base stations employing the International Mobile Telecommunication 2000 (IMT-2000) cellular system was conducted to test the hypothesis that modulated RF fields affect malignant transformation or other cellular stress responses. Our group previously reported that DNA strand breaks were not induced in human cells exposed to 2.1425 GHz Wideband Code Division Multiple Access (W-CDMA) radiation up to 800 mW/kg from mobile radio base stations employing the IMT-2000 cellular system. In the current study, BALB/3T3 cells were continuously exposed to 2.1425 GHz W-CDMA RF fields at specific absorption rates (SARs) of 80 and 800 mW/kg for 6 weeks and malignant cell transformation was assessed. In addition, 3-methylcholanthrene (MCA)-treated cells were exposed to RF fields in a similar fashion, to assess for effects on tumor promotion. Finally, the effect of RF fields on tumor co-promotion was assessed in BALB/3T3 cells initiated with MCA and co-exposed to 12-O-tetradecanoylphorbol-13-acetate (TPA). At the end of the incubation period, transformation dishes were fixed, stained with Giemsa, and scored for morphologically transformed foci. No significant differences in transformation frequency were observed between the test groups exposed to RF signals and the sham-exposed negative controls in the non-, MCA-, or MCA plus TPA-treated cells. Our studies found no evidence to support the hypothesis that RF fields may affect malignant transformation. Our results suggest that exposure to low-level RF radiation of up to 800 mW/kg does not induce cell transformation, which causes tumor formation. (c) 2007 Wiley-Liss, Inc.

[Mediastinal teratoma with malignant transformation of the somatic component. Clinical report].

PubMed

Gerardo, Rita; Morgado, Carolina; Calvo, Dolores; Pinto, Eugénia; Bravio, Ivan; Castelão, Nelson; Martelo, Fernando

2009-01-01

Mediastinal germ cell tumours (M-GCT) are rare forms of neoplasms compared with other tumours of the same location. They are classified in seminomas, malignant non-seminomatous GCT and teratomas. The malignant transformation of the somatic component of the teratoma, with sarcomatous or carcinomatous degeneration, is even more uncommon. We report the clinical case of a 32 year old man who presented with severe chest pain on the right hemithorax. The image exams revealed the existence of a large heterogeneous lesion with a diameter of 7.7 cm, with areas of lipomatous density and a calcic image with the appearance of a tooth, in the right projection of the anterior mediastinum, in the vicinity of the large vessels, compatible with teratoma. The transthoracic biopsy (CT guided) showed morphologic aspects of sarcoma. The patient was operated on with the en bloc resection of the mediastinal mass, right lung, a segment of the pericardium and the thymus. The pathological studies showed a teratoma with malignant transformation of the mesenquimatous component, with muscular differentiation into leiomiosarcoma and rabdomiosarcoma. After surgery, the patient was treated with a scheme of doxorubicin and ifosfamide. The most prominent concepts related to this clinical entity, as well as its treatment, are debated in this article, based on the most recent publications dedicated to the subject.

Hacking cell differentiation: transcriptional rerouting in reprogramming, lineage infidelity and metaplasia

PubMed Central

Regalo, Gonçalo; Leutz, Achim

2013-01-01

Initiating neoplastic cell transformation events are of paramount importance for the comprehension of regeneration and vanguard oncogenic processes but are difficult to characterize and frequently clinically overlooked. In epithelia, pre-neoplastic transformation stages are often distinguished by the appearance of phenotypic features of another differentiated tissue, termed metaplasia. In haemato/lymphopoietic malignancies, cell lineage ambiguity is increasingly recorded. Both, metaplasia and biphenotypic leukaemia/lymphoma represent examples of dysregulated cell differentiation that reflect a history of trans-differentiation and/or epigenetic reprogramming. Here we compare the similarity between molecular events of experimental cell trans-differentiation as an emerging therapeutic concept, with lineage confusion, as in metaplasia and dysplasia forecasting tumour development. PMID:23828660

[Telangiectatic osteosarcoma secondary to a liposclerosing myxofibrous tumor: a case report].

PubMed

Illac, Claire; Delisle, Marie-Bernadette; Bonnevialle, Paul; Chiavassa-Gandois, Hélène; de Pinieux, Gonzague; Gomez-Brouchet, Anne

2012-08-01

Malignant transformation of a fibrous dysplasia into an osteosarcoma is very rare. We report the case of an 84-year-old man with telangiectatic osteosarcoma of the upper femur arising in a previous fibrous dysplasia also known as liposclerosing myxofibrous tumor. The tumor was expressing the epithelial membrane antigen. This is the first described case of a malignant transformation into an osteosarcoma arising in a liposclerosing myxofibrous tumor. We discuss the main differential diagnosis with a review. Copyright © 2012 Elsevier Masson SAS. All rights reserved.

Fourier analysis of the cell shape of paired human urothelial cell lines of the same origin but of different grades of transformation.

PubMed

Ostrowski, K; Dziedzic-Goclawska, A; Strojny, P; Grzesik, W; Kieler, J; Christensen, B; Mareel, M

1986-01-01

The rationale of the present investigation is the observations made by many authors of changes in the molecular structure of the cell surface during the multistep process of malignant transformation. These changes may influence cell-matrix and cell-cell interactions and thereby cause changes in cell adhesiveness and cell shape. The aim of the present work was to investigate whether the development of various grades of transformation in vivo and in vitro of human urothelial cells is accompanied by significant changes in cell shape as measured by Fourier analysis. The following transformation grades (TGr) have been defined (Christensen et al. 1984; Kieler 1984): TGr I = nonmalignant, mortal cell lines that grow independently of fibroblasts and have a prolonged life span. TGr II = nonmalignant cell lines with an infinite life span. TGr III = malignant and immortal cell lines that grow invasively in co-cultures with embryonic chick heart fragments and possess tumorigenic properties after s.c. injection into nude mice. Comparisons of 4 pairs of cell lines were performed; each pair was of the same origin. Two pairs--each including a TGr I cell line (Hu 961b and Hu 1703S) compared to a TGr III cell line (Hu 961a or Hu 1703He)--were derived from two transitional cell carcinomas (TCC) containing a heterogeneous cell population. Two additional cell lines classified as TGr II (HCV-29 and Hu 609) were compared to two TGr III sublines (HCV-29T and Hu 609T, respectively) which arose by "spontaneous" transformation during propagation in vitro of the respective maternal TGr II-cell lines.(ABSTRACT TRUNCATED AT 250 WORDS)

Loss of Abhd5 Promotes Colorectal Tumor Development and Progression by Inducing Aerobic Glycolysis and Epithelial-Mesenchymal Transition

PubMed Central

Ou, Juanjuan; Miao, Hongming; Ma, Yinyan; Guo, Feng; Deng, Jia; Wei, Xing; Zhou, Jie; Xie, Ganfeng; Shi, Hang; Xue, Bingzhong; Liang, Houjie; Yu, Liqing

2014-01-01

SUMMARY How cancer cells shift metabolism to aerobic glycolysis is largely unknown. Here we show that deficiency of α/β-hydrolase domain-containing-5 (Abhd5), an intracellular lipolytic activator that is also known as comparative gene identification-58 (CGI-58), promotes this metabolic shift and enhances malignancies of colorectal carcinomas (CRCs). Silencing of Abhd5 in normal fibroblasts induces malignant transformation. Intestine-specific knockout of Abhd5 in ApcMin/+ mice robustly increases tumorigenesis and malignant transformation of adenomatous polyps. In colon cancer cells, Abhd5 deficiency induces epithelial-mesenchymal transition by suppressing the AMPKα-p53 pathway, which is attributable to increased aerobic glycolysis. In human CRCs, Abhd5 expression falls substantially and correlates negatively with malignant features. Our study is the first to link Abhd5 to CRC pathogenesis. It suggests that cancer cells may develop aerobic glycolysis by suppressing Abhd5-mediated intracellular lipolysis. PMID:25482557

Mycoplasmal Infections Prevent Apoptosis and Induce Malignant Transformation of Interleukin-3-Dependent 32D Hematopoietic Cells

PubMed Central

Feng, Shaw-Huey; Tsai, Shien; Rodriguez, Jose; Lo, Shyh-Ching

1999-01-01

32D cells, a murine myeloid cell line, rapidly undergo apoptosis upon withdrawal of interleukin-3 (IL-3) supplement in culture. We found that 32D cells, if infected by several species of human mycoplasmas that rapidly activated NF-κB, would live and continue to grow in IL-3-depleted culture. Mycoplasma-infected cells showed no evidence of autocrine production of IL-3. Pyrrolidine dithiocarbamate (PDTC) blocked activation of NF-κB and led to prominent cell death. Heat-killed mycoplasmas or mycoplasmal membrane preparations alone could support continued growth of 32D cells in culture without IL-3 supplement for a substantial period of time. However, upon removal of heat-inactivated mycoplasmas, 32D cells quickly became apoptotic. In comparison, live Mycoplasma fermentans or M. penetrans infection for 4 to 5 weeks induced malignant transformation of 32D cells. Transformed 32D cells grew autonomously and no longer required support of growth-stimulating factors including IL-3 and mycoplasmas. The transformed 32D cells quickly formed tumors when injected into nude mice. Karyotyping showed that development of chromosomal changes and trisomy 19 was often associated with malignant transformation and tumorigenicity of 32D cells. Mycoplasmal infections apparently affected the fidelity of genomic transmission in cell division as well as checkpoints coordinating the progression of cell cycle events. PMID:10567525

Regulatory Control of Breast Tumor Cell Poly (ADP-Ribose) Polymerase

DTIC Science & Technology

2002-08-01

DNA replication complex (designated the DNA synthesome) from a variety of non-malignant and malignant tumor cells including breast cancer cells. We have shown that poly(ADP-ribose) polymerase PARP is among the components of the DNA synthesome. The transformation of a non-malignant human breast cell to a malignant state was accompanied by a significant alteration in the 2-D PAGE profile of specific protein components of the DNA synthesome (such as PCNA) together with a 6-8 decrease in the replication fidelity of the DNA

STAT3-regulated exosomal miR-21 promotes angiogenesis and is involved in neoplastic processes of transformed human bronchial epithelial cells.

PubMed

Liu, Yi; Luo, Fei; Wang, Bairu; Li, Huiqiao; Xu, Yuan; Liu, Xinlu; Shi, Le; Lu, Xiaolin; Xu, Wenchao; Lu, Lu; Qin, Yu; Xiang, Quanyong; Liu, Qizhan

2016-01-01

Although microRNA (miRNA) enclosed in exosomes can mediate intercellular communication, the roles of exosomal miRNA and angiogenesis in lung cancer remain unclear. We investigated functions of STAT3-regulated exosomal miR-21 derived from cigarette smoke extract (CSE)-transformed human bronchial epithelial (HBE) cells in the angiogenesis of CSE-induced carcinogenesis. miR-21 levels in serum were higher in smokers than those in non-smokers. The medium from transformed HBE cells promoted miR-21 levels in normal HBE cells and angiogenesis of human umbilical vein endothelial cells (HUVEC). Transformed cells transferred miR-21 into normal HBE cells via exosomes. Knockdown of STAT3 reduced miR-21 levels in exosomes derived from transformed HBE cells, which blocked the angiogenesis. Exosomes derived from transformed HBE cells elevated levels of vascular endothelial growth factor (VEGF) in HBE cells and thereby promoted angiogenesis in HUVEC cells. Inhibition of exosomal miR-21, however, decreased VEGF levels in recipient cells, which blocked exosome-induced angiogenesis. Thus, miR-21 in exosomes leads to STAT3 activation, which increases VEGF levels in recipient cells, a process involved in angiogenesis and malignant transformation of HBE cells. These results, demonstrating the function of exosomal miR-21 from transformed HBE cells, provide a new perspective for intervention strategies to prevent carcinogenesis of lung cancer. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Characterization of oral precancerous lesions based on higher-harmonic generation microscopy

NASA Astrophysics Data System (ADS)

Lin, Chen-Yu; Lin, Chih-Feng; Sun, Chi-Kuang

2013-03-01

It is generally accepted that oral cancer arises in the presence of oral precancerous lesions. However, the clinical courses of these lesions are quite unpredictable, and a fundamental enigma remains that when and how these lesions turn to malignant growth. Characterization of these potentially malignant lesions is thus important and could serve as early indicators of this neoplastic transformation process, potentially facilitates the treatment outcome and improves the survival rate. Higher harmonic generation microscope (HGM), providing images with a <500nm lateral resolution at a 300μm penetration depth without leaving photodamages in the tissues, was used for this purpose. Oral cavity biopsies were obtained from 18 patients with clinical suspected oral precancerous lesions scheduled for surgical biopsy. HGM images were compared with histological images to determine the results. By visualization of subtle cellular and morphological changes, the preliminary result of this HGM image discloses excellent consistency with traditional histolopathology studies, without the need for fixation, sectioning and staining. More specifically speaking, the keratin thickness was found to be increased comparing with normal adjacent controls. In some cases, variations in cell size, nuclear size and increased nuclear/cytoplasmic ratio, and increased size of nucleoli were identified, indicating different stages of malignant transformation. These results together indicated that HGM provides the capability to characterize features of oral precancerous lesions as well as oral cancer progression, and holds the greatest potential as an ideal tool for clinical screening and surveillance of suspicious oral lesions.

Deregulation of a distinct set of microRNAs is associated with transformation of gastritis into MALT lymphoma.

PubMed

Thorns, Christoph; Kuba, Johannes; Bernard, Veronica; Senft, Andrea; Szymczak, Silke; Feller, Alfred C; Bernd, Heinz-Wolfram

2012-04-01

The mechanisms underlying the transformation from chronic Helicobacter pylori gastritis to gastric extranodal marginal zone lymphoma (MALT lymphoma) are poorly understood. This study aims to identify microRNAs that might be involved in the process of neoplastic transformation. We generated microRNA signatures by RT-PCR in 68 gastric biopsy samples representing normal mucosa, gastritis, suspicious lymphoid infiltrates, and overt MALT lymphoma according to Wotherspoon criteria. Analyses revealed a total of 41 microRNAs that were significantly upregulated (n = 33) or downregulated (n = 8) in succession from normal mucosa to gastritis and to MALT lymphoma. While some of these merely reflect the presence of lymphocytes (e.g. miR-566 and miR-212) or H. pylori infection (e.g. miR-155 and let7f), a distinct set of five microRNAs (miR-150, miR-550, miR-124a, miR-518b and miR-539) was shown to be differentially expressed in gastritis as opposed to MALT lymphoma. This differential expression might therefore indicate a central role of these microRNAs in the process of malignant transformation.

[The role of developmental HOX genes in cervical cancer].

PubMed

López-Romero, Ricardo; Marrero-Rodríguez, Daniel; Romero-Morelos, Pablo; Villegas, Vanessa; Valdivia, Alejandra; Arreola, Hugo; Huerta-Padilla, Víctor; Salcedo, Mauricio

2015-01-01

Cervical cancer (CC) is a multifactorial disease associated to genetic, environmental and epigenetic factors, being the infection by human papillomavirus the main etiologic agent. Additionally, the alteration in the expression of transcription factors has been considered of importance for the development of this tumor. HOX genes encode a group of transcription factors involved in cellular proliferation and differentiation processes during the development of embryonic structures in vertebrates; their aberrant expression is associated with tumorigenesis and metastasis. A range of evidence suggests a role for HOX genes in the development of cervical neoplastic cell. Studies in CC cell lines, primary tumors and premalignant lesions have suggested the involvement of HOXA1, HOXC5, C6, C8 and C10, HOXD9 and HOXD13 in the process of cervical carcinogenesis. Also, the de novo expression of genes HOXB2, B4, B13 and HOXC11-C13 appears to be involved in the process of malignant transformation of cervical epithelial cell. These data would allow to open a field in search of new molecular markers in cervical cancer and the development of new therapeutic strategies for this malignancy.

Polyploidization of murine mesenchymal cells is associated with suppression of the long noncoding RNA H19 and reduced tumorigenicity.

PubMed

Shoshani, Ofer; Massalha, Hassan; Shani, Nir; Kagan, Sivan; Ravid, Orly; Madar, Shalom; Trakhtenbrot, Luba; Leshkowitz, Dena; Rechavi, Gideon; Zipori, Dov

2012-12-15

Mesenchymal stromal cells (MSC) are used extensively in clinical trials; however, the possibility that MSCs have a potential for malignant transformation was raised. We examined the genomic stability versus the tumor-forming capacity of multiple mouse MSCs. Murine MSCs have been shown to be less stable and more prone to malignant transformation than their human counterparts. A large series of independently isolated MSC populations exhibited low tumorigenic potential under syngeneic conditions, which increased in immunocompromised animals. Unexpectedly, higher ploidy correlated with reduced tumor-forming capacity. Furthermore, in both cultured MSCs and primary hepatocytes, polyploidization was associated with a dramatic decrease in the expression of the long noncoding RNA H19. Direct knockdown of H19 expression in diploid cells resulted in acquisition of polyploid cell traits. Moreover, artificial tetraploidization of diploid cancer cells led to a reduction of H19 levels, as well as to an attenuation of the tumorigenic potential. Polyploidy might therefore serve as a protective mechanism aimed at reducing malignant transformation through the involvement of the H19 regulatory long noncoding RNA.

The ultrastructural features of the premalignant oral lesions.

PubMed

Olinici, Doiniţa; Cotrutz, Carmen Elena; Mihali, Ciprian Valentin; Grecu, Vasile Bogdan; Botez, Emanuela Ana; Stoica, Laura; Onofrei, Pavel; Condurache, Oana; Dimitriu, Daniela Cristina

2018-01-01

Premalignant oral lesions are among the most important risk factors for the development of oral squamocellular carcinoma. Recent population studies indicate a significant rise in the prevalence of leukoplakia, erythroplakia/erythroleukoplakia, actinic cheilitis, submucous fibrosis and erosive lichen planus. Since standard histopathological examination has numerous limitations regarding the accurate appreciation of potential malignant transformation, the present study aims to aid these evaluations using the transmission electron microscopy (TEM) technique, which emphasizes ultrastructural changes pertaining to this pathology. Oral mucosa fragments collected from 43 patients that were clinically and histopathologically diagnosed with leukoplakia, erosive actinic cheilitis and erosive lichen planus have been processed through the classic technique for the examination using TEM and were examined using a Philips CM100 transmission electron microscope. The electron microscopy study has confirmed the histopathological diagnosis of the tissue samples examined using photonic microscopy and has furthermore revealed a series of ultrastructural details that on the one hand indicate the tendency for malignant transformation, and on the other reveal characteristic features of tumor development. All the details furnished by TEM complete the overall picture of morphological changes, specific to these lesions, indicating the importance of using these techniques in establishing both a correct diagnosis and prognosis.

The multifaceted functions of C/EBPα in normal and malignant haematopoiesis.

PubMed

Ohlsson, E; Schuster, M B; Hasemann, M; Porse, B T

2016-04-01

The process of blood formation, haematopoiesis, depends upon a small number of haematopoietic stem cells (HSCs) that reside in the bone marrow. Differentiation of HSCs is characterised by decreased expression of genes associated with self-renewal accompanied by a stepwise activation of genes promoting differentiation. Lineage branching is further directed by groups of cooperating and counteracting genes forming complex networks of lineage-specific transcription factors. Imbalances in such networks can result in blockage of differentiation, lineage reprogramming and malignant transformation. CCAAT/enhancer-binding protein-α (C/EBPα) was originally identified 30 years ago as a transcription factor that binds both promoter and enhancer regions. Most of the early work focused on the role of C/EBPα in regulating transcriptional processes as well as on its functions in key differentiation processes during liver, adipogenic and haematopoietic development. Specifically, C/EBPα was shown to control differentiation by its ability to coordinate transcriptional output with cell cycle progression. Later, its role as an important tumour suppressor, mainly in acute myeloid leukaemia (AML), was recognised and has been the focus of intense studies by a number of investigators. More recent work has revisited the role of C/EBPα in normal haematopoiesis, especially its function in HSCs, and also started to provide more mechanistic insights into its role in normal and malignant haematopoiesis. In particular, the differential actions of C/EBPα isoforms, as well as its importance in chromatin remodelling and cellular reprogramming, are beginning to be elucidated. Finally, recent work has also shed light on the dichotomous function of C/EBPα in AML by demonstrating its ability to act as both a tumour suppressor and promoter. In the present review, we will summarise the current knowledge on the functions of C/EBPα during normal and malignant haematopoiesis with special emphasis on the recent work.

[Morphometric indices in sarcomagenesis in the breast].

PubMed

Fiks, A F

1975-01-01

To study sarcomagenesis of the mammary gland and estimate the degree of maturity of its various stages, the author examined 45 postoperative specimens of fibroadenomatosis, fibroadenoma, leaf-shape tumor, sarcoma from the preexisting leaf-shape tumor and stromal sarcoma. Studies on the nucleus-plasma relationship, the mitotic coefficient, frequency and pathology of mitosis and quantitative-qualitative changes in sex chromatin allowed a more reliable estimation of the degree of maturity of cell elements of the fibroblastic origin in the process of malignant transformation.

Fibroblast growth factor 2 restrains Ras-driven proliferation of malignant cells by triggering RhoA-mediated senescence.

PubMed

Costa, Erico T; Forti, Fábio L; Matos, Tatiana G F; Dermargos, Alexandre; Nakano, Fábio; Salotti, Jacqueline; Rocha, Kátia M; Asprino, Paula F; Yoshihara, Celina K; Koga, Marianna M; Armelin, Hugo A

2008-08-01

Fibroblast growth factor 2 (FGF2) is considered to be a bona fide oncogenic factor, although results from our group and others call this into question. Here, we report that exogenous recombinant FGF2 irreversibly inhibits proliferation by inducing senescence in Ras-dependent malignant mouse cells, but not in immortalized nontumorigenic cell lines. We report the following findings in K-Ras-dependent malignant Y1 adrenocortical cells and H-Ras V12-transformed BALB-3T3 fibroblasts: (a) FGF2 inhibits clonal growth and tumor onset in nude and immunocompetent BALB/c mice, (b) FGF2 irreversibly blocks the cell cycle, and (c) FGF2 induces the senescence-associated beta-galactosidase with no accompanying signs of apoptosis or necrosis. The tyrosine kinase inhibitor PD173074 completely protected malignant cells from FGF2. In Y1 adrenal cells, reducing the constitutively high levels of K-Ras-GTP using the dominant-negative RasN17 mutant made cells resistant to FGF2 cytotoxicity. In addition, transfection of the dominant-negative RhoA-N19 into either Y1 or 3T3-B61 malignant cell lines yielded stable clonal transfectants that were unable to activate RhoA and were resistant to the FGF2 stress response. We conclude that in Ras-dependent malignant cells, FGF2 interacts with its cognate receptors to trigger a senescence-like process involving RhoA-GTP. Surprisingly, attempts to select FGF2-resistant cells from the Y1 and 3T3-B61 cell lines yielded only rare clones that (a) had lost the overexpressed ras oncogene, (b) were dependent on FGF2 for proliferation, and (c) were poorly tumorigenic. Thus, FGF2 exerted a strong negative selection that Ras-dependent malignant cells could rarely overcome.

Congenital neck masses.

PubMed

Rosa, Peter A; Hirsch, David L; Dierks, Eric J

2008-08-01

Congenital neck lesions reflect abnormal embryogenesis in head and neck development. A thorough knowledge of embryology and anatomy is critical in the diagnosis and treatment of these lesions. The appropriate diagnosis of these lesions is necessary to provide appropriate treatment and long-term follow up, because some of these lesions may undergo malignant transformation or be harbingers of malignant disease.

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

Orchestration of Angiogenesis by Immune Cells

PubMed Central

Bruno, Antonino; Pagani, Arianna; Pulze, Laura; Albini, Adriana; Dallaglio, Katiuscia; Noonan, Douglas M.; Mortara, Lorenzo

2014-01-01

It is widely accepted that the tumor microenvironment (TUMIC) plays a major role in cancer and is indispensable for tumor progression. The TUMIC involves many “players” going well beyond the malignant-transformed cells, including stromal, immune, and endothelial cells (ECs). The non-malignant cells can acquire tumor-promoting functions during carcinogenesis. In particular, these cells can “orchestrate” the “symphony” of the angiogenic switch, permitting the creation of new blood vessels that allows rapid expansion and progression toward malignancy. Considerable attention within the context of tumor angiogenesis should focus not only on the ECs, representing a fundamental unit, but also on immune cells and on the inflammatory tumor infiltrate. Immune cells infiltrating tumors typically show a tumor-induced polarization associated with attenuation of anti-tumor functions and generation of pro-tumor activities, among these angiogenesis. Here, we propose a scenario suggesting that the angiogenic switch is an immune switch arising from the pro-angiogenic polarization of immune cells. This view links immunity, inflammation, and angiogenesis to tumor progression. Here, we review the data in the literature and seek to identify the “conductors” of this “orchestra.” We also suggest that interrupting the immune → inflammation → angiogenesis → tumor progression process can delay or prevent tumor insurgence and malignant disease. PMID:25072019

Involvement of the antioxidative property of morusin in blocking phorbol ester-induced malignant transformation of JB6 P+ mouse epidermal cells.

PubMed

Cheng, Pai-Shan; Hu, Chao-Chin; Wang, Chau-Jong; Lee, Yean-Jang; Chung, Wei-Chia; Tseng, Tsui-Hwa

2017-02-25

Chemoprevention has been acknowledged as an important and practical strategy for managing cancer. We have previously synthesized morusin, a prenylated flavonoid that exhibits anti-cancer progression activity. In the present study, we evaluated the anti-cancer promotion potential of morusin by using the mouse epidermal JB6 P + cell model. Extensive evidence shows that tumor promotion by phorbol esters is due to the stimulation of reactive oxygen species (ROS). Therefore, the effect of morusin on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced ROS production was assessed. Noncytotoxic concentrations of morusin were found to dose-dependently reduce TPA-induced ROS production. Moreover, morusin inhibited TPA-induced activator protein-1 (AP-1) and nuclear factor-kappa B (NF-κB) activation, which can mediate cell proliferation and malignant transformation. Furthermore, morusin inhibited the TPA upregulation of cyclooxygenase 2 (COX-2), which may be regulated by AP-1 and NF-κB. In addition, noncytotoxic concentrations of morusin reduced the TPA-promoted cell growth of JB6 P + cells and inhibited TPA-induced malignant properties, such as cytoskeletal rearrangement and cell migration of JB6 P + cells. Similar to the effects of glutathione (GSH) pretreatment, morusin inhibited TPA-induced expression of N-cadeherin and vimentin, which are malignant cell surface proteins. Finally, morusin treatment dose-dependently suppressed the TPA-induced anchorage-independent cell transformation of JB6 P + cells. In conclusion, our results evidence that morusin possesses anti-cancer promotion potential because of its antioxidant property, which mediates multiple transformation-associated gene expression. Copyright © 2017 Elsevier B.V. All rights reserved.

A Case of Endometrioid Adenocarcinoma Originating from the Serous Surface of the Small Intestine.

PubMed

Makihara, Natsuko; Fujita, Ichiro; Soudaf, Hiroo; Yamamoto, Takahisa; Sashikata, Terumasa; Mukohara, Toru; Maeda, Tetsuo

2015-09-07

Malignant transformation of endometriosis has been extensively described in the literature. However, extragonadal endometrioid adenocarcinoma, either de novo or arising from malignant transformation of endometriosis, is rare. The present case report describes a patient with endometrioid adenocarcinoma on the serous surface of the small intestine. A 25-year-old female with no history of endometriosis was referred to our hospital with an intrapelvic tumor. An internal examination, ultrasound, and magnetic resonance imaging revealed a round mass approximately 80 mm in diameter; however, identification of the affected organ was difficult. Because we could not rule out malignancy based on the non-specific radiologic findings, laparotomy was performed. A mass with ileal adhesions was detected intraoperatively. In addition, the uterus and bilateral adnexa appeared normal. The tumor was resected with part of the ileum. Histopathology confirmed a diagnosis of endometrioid adenocarcinoma originating from the serous surface of the small intestine.

Inflammatory myofibroblastic tumor of maxilla showing sarcomatous change in an edentulous site with a history of tooth extraction following periodontitis: A case report with discussion.

PubMed

Biniraj, K R; Janardhanan, Mahija

2014-05-01

Inflammatory myofibroblastic tumor (IMT) is a rare tumor of uncertain origin with variable biological behavior ranging from reactive lesions to highly aggressive malignancy. Oral IMTs are extremely rare and only 25 cases had been reported so far. A case of IMT with sarcomatous transformation in an extraction site with a history of tooth extraction following tooth mobility of an upper left molar tooth is presented here. The tooth was extracted following a complaint of gingival swelling and mobility of tooth. Though malignant transformation in IMTs had been documented in the extra oral sites, wide search of associated literature suggests, this is the first case of oral IMT showing malignant change associated with gingiva. The case report attempts to highlight the variant possibilities of tooth mobility other than periodontitis and the importance of assessing the primary cause of such conditions.

Inflammatory myofibroblastic tumor of maxilla showing sarcomatous change in an edentulous site with a history of tooth extraction following periodontitis: A case report with discussion

PubMed Central

Biniraj, K. R.; Janardhanan, Mahija

2014-01-01

Inflammatory myofibroblastic tumor (IMT) is a rare tumor of uncertain origin with variable biological behavior ranging from reactive lesions to highly aggressive malignancy. Oral IMTs are extremely rare and only 25 cases had been reported so far. A case of IMT with sarcomatous transformation in an extraction site with a history of tooth extraction following tooth mobility of an upper left molar tooth is presented here. The tooth was extracted following a complaint of gingival swelling and mobility of tooth. Though malignant transformation in IMTs had been documented in the extra oral sites, wide search of associated literature suggests, this is the first case of oral IMT showing malignant change associated with gingiva. The case report attempts to highlight the variant possibilities of tooth mobility other than periodontitis and the importance of assessing the primary cause of such conditions. PMID:25024554

Revisiting the association between candidal infection and carcinoma, particularly oral squamous cell carcinoma.

PubMed

Mohd Bakri, Marina; Mohd Hussaini, Haizal; Rachel Holmes, Ann; David Cannon, Richard; Mary Rich, Alison

2010-12-21

Tobacco and alcohol are risk factors associated with cancer of the upper aerodigestive tract, but increasingly the role of infection and chronic inflammation is recognized as being significant in cancer development. Bacteria, particularly Helicobacter pylori, and viruses such as members of the human papilloma virus family and hepatitis B and C are strongly implicated as etiological factors in certain cancers. There is less evidence for an association between fungi and cancer, although it has been recognized for many years that white patches on the oral mucosa, which are infected with Candida, have a greater likelihood of undergoing malignant transformation than those that are not infected. This article reviews the association between the development of oral squamous cell carcinoma in potentially malignant oral lesions with chronic candidal infection and describes mechanisms that may be involved in Candida-associated malignant transformation.

Lactic acid alleviates stress: good for female genital tract homeostasis, bad for protection against malignancy.

PubMed

Witkin, Steven S

2018-05-01

Women are unique from all other mammals in that lactic acid is present at high levels in the vagina during their reproductive years. This dominance may have evolved in response to the unique human lifestyle and a need to optimally protect pregnant women and their fetuses from endogenous and exogenous insults. Lactic acid in the female genital tract inactivates potentially pathogenic bacteria and viruses, maximizes survival of vaginal epithelial cells, and inhibits inflammation that may be damaging to the developing fetus and maintenance of the pregnancy. In an analogous manner, lactic acid production facilitates survival of malignantly transformed cells, inhibits activation of immune cells, and prevents the release of pro-inflammatory mediators in response to tumor-specific antigens. Thus, the same stress-reducing properties of lactic acid that promote lower genital tract health facilitate malignant transformation and progression.

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

The role of Epstein–Barr virus in epithelial malignancies

PubMed Central

Tsao, Sai-Wah; Tsang, Chi Man; To, Ka-Fai; Lo, Kwok-Wai

2015-01-01

The close association of Epstein–Barr virus (EBV) infection with non-keratinizing nasopharyngeal carcinomas and a subset of gastric carcinomas suggests that EBV infection is a crucial event in these cancers. The difficulties encountered in infecting and transforming primary epithelial cells in experimental systems suggest that the role of EBV in epithelial malignancies is complex and multifactorial in nature. Genetic alterations in the premalignant epithelium may support the establishment of latent EBV infection, which is believed to be an initiation event. Oncogenic properties have been reported in multiple EBV latent genes. The BamH1 A rightwards transcripts (BARTs) and the BART-encoded microRNAs (miR-BARTs) are highly expressed in EBV-associated epithelial malignancies and may induce malignant transformation. However, enhanced proliferation may not be the crucial function of EBV infection in epithelial malignancies, at least in the early stages of cancer development. EBV-encoded gene products may confer anti-apoptotic properties and promote the survival of infected premalignant epithelial cells harbouring genetic alterations. Multiple EBV-encoded microRNAs have been reported to have immune evasion functions. Genetic alterations in host cells, as well as inflammatory stroma, could modulate the expression of EBV genes and alter the growth properties of infected premalignant epithelial cells, encouraging their selection during carcinogenesis. PMID:25251730

Surgical attitude in premalignant lesions and malignant tumors of the lower lip

PubMed Central

Calcaianu, N; Popescu, SA; Diveica, D; Lascar, I

2015-01-01

Introduction. Malignant tumors of the lower lip may have a variety of histopathology forms. The diagnosis and treatment of premalignant lesions are extremely important to avoid their malignant evolution. The lower lip tumor diagnosis is based on a series of correlations: anamnestic, clinical, laboratory and histopathological (the latter giving the certain diagnose). Material and methods. This study was carried out by selecting the cases with lower lip tumors operated between January 2012 and July 2014, in the Plastic Surgery and Reconstructive Microsurgery Clinic of Bucharest Clinical Emergency Hospital. The variables considered in the study were the following: age, gender, exposure to risk factors, diagnosis, and histopathology. Results. The histopathological examination revealed 63% squamous cell carcinoma, 30% basal cell carcinomas, 5% keratoacanthoma and 2% actinic keratosis. Men were the predominantly affected genre, with a percentage of 70%. In the group of patients studied, 66% were smokers. Discussions. The rate of the malignant transformation of premalignant lesion was 32.6% for keratoacanthoma, 16.9% for actinic cheilitis, 10% for actinic keratoses. Conclusions. There were no clinical or laboratory features to plead for the pre-malignant or malignant character of the of a lower lip tumor, consequently histopathological examination was used for the diagnosis of the lesion. Due to the high percentage of malignant transformation of precancerous lesions, particularly in the form of squamous cell carcinoma, the surgical attitude intending to eradicate a lower lip tumor from an oncological point of view was the excision with oncologic safety margins followed by a lip reconstruction. PMID:25914752

Deregulation of EZH2 expression in human spermatogenic disorders and testicular germ cell tumors.

PubMed

Hinz, Stefan; Magheli, Ahmed; Weikert, Steffen; Schulze, Wolfgang; Krause, Hans; Schrader, Mark; Miller, Kurt; Kempkensteffen, Carsten

2010-10-01

Enhancer of Zeste 2 (EZH2) is an epigenetic transcriptional repressor involved in cell cycle control and cell fate decisions. Since these processes play key roles during intact spermatogenesis, deregulation of EZH2 expression may contribute to the development and progression of benign and malignant testicular diseases. The objective of this study was to investigate the expression profile of EZH2 in testicular germ cell tumors (TGCT) and spermatogenic defects. Real-time RT-PCR was applied to quantify the m-RNA expression of EZH2 in 64 seminomas 36 non-seminomas, 4 carcinomas in situ (CIS), 40 samples harboring impaired spermatogenesis and 24 normal testicular reference biopsies. EZH2 was expressed in 99% of TGCT samples and in all biopsies with intact spermatogenesis. Its expression levels were highest in normal testicular tissue, and continuously decreased with malignant transformation to CIS and further progression to invasive TGCT (P < 0.001). EZH2 tumor levels were not related to the histological TGCT subtype or clinical tumor stage. Comparison of distinct stages of spermatogenic failure revealed an inverse association of EZH2 levels to the severity of the spermatogenic defect (P < 0.001). Our data strongly suggest that in TGCT EZH2 does not exert its often assumed oncogenic properties during malignant transformation and progression. High EZH2 levels in normal testicular tissue and the inverse association of its expression levels with the severity of spermatogenic failure point to its potential value as a molecular marker for spermatogenic defects and may indicate an important physiological role of EZH2 during intact spermatogenesis.

Retinoids and rexinoids in cancer prevention: from laboratory to clinic.

PubMed

Uray, Iván P; Dmitrovsky, Ethan; Brown, Powel H

2016-02-01

Early in the age of modern medicine the consequences of vitamin A deficiency drew attention to the fundamental link between retinoid-dependent homeostatic regulation and malignant hyperproliferative diseases. The term "retinoid" includes a handful of endogenous and a large group of synthetic derivatives of vitamin A. These multifunctional lipid-soluble compounds directly regulate target genes of specific biological functions and critical signaling pathways to orchestrate complex functions from vision to development, metabolism, and inflammation. Many of the retinoid activities on the cellular level have been well characterized and translated to the regulation of processes like differentiation and cell death, which play critical roles in the outcome of malignant transformation of tissues. In fact, retinoid-based differentiation therapy of acute promyelocytic leukemia was one of the first successful examples of molecularly targeted treatment strategies. The selectivity, high receptor binding affinity and the ability of retinoids to directly modulate gene expression programs present a distinct pharmacological opportunity for cancer treatment and prevention. However, to fully exploit their potential, the adverse effects of retinoids must be averted. In this review we provide an overview of the biology of retinoid (activated by nuclear retinoic acid receptors [RARs]) and rexinoid (engaged by nuclear retinoid X receptors [RXRs]) action concluded from a long line of preclinical studies, in relation to normal and transformed states of cells. We will also discuss the past and current uses of retinoids in the treatment of malignancies, the potential of rexinoids in the cancer prevention setting, both as single agents and in combinations. Copyright © 2016 Elsevier Inc. All rights reserved.

Cell transformation by human adenoviruses.

PubMed

Endter, C; Dobner, T

2004-01-01

The last 40 years of molecular biological investigations into human adenoviruses have contributed enormously to our understanding of the basic principles of normal and malignant cell growth. Much of this knowledge stems from analyses of their productive infection cycle in permissive host cells. Also, initial observations concerning the carcinogenic potential of human adenoviruses subsequently revealed decisive insights into the molecular mechanisms of the origins of cancer, and established adenoviruses as a model system for explaining virus-mediated transformation processes. Today it is well established that cell transformation by human adenoviruses is a multistep process involving several gene products encoded in early transcription units 1A (E1A) and 1B (E1B). Moreover, a large body of evidence now indicates that alternative or additional mechanisms are engaged in adenovirus-mediated oncogenic transformation involving gene products encoded in early region 4 (E4) as well as epigenetic changes resulting from viral DNA integration. In particular, detailed studies on the tumorigenic potential of subgroup D adenovirus type 9 (Ad9) E4 have now revealed a new pathway that points to a novel, general mechanism of virus-mediated oncogenesis. In this chapter, we summarize the current state of knowledge about the oncogenes and oncogene products of human adenoviruses, focusing particularly on recent findings concerning the transforming and oncogenic properties of viral proteins encoded in the E1B and E4 transcription units.

Hexavalent chromium induces malignant transformation of human lung bronchial epithelial cells via ROS-dependent activation of miR-21-PDCD4 signaling

PubMed Central

Divya, Sasidharan Padmaja; Turcios, Lilia; Roy, Ram Vinod; Hitron, John Andrew; Wang, Lei; Kim, Donghern; Dai, Jin; Asha, Padmaja; Zhang, Zhuo; Shi, Xianglin

2016-01-01

Hexavalent chromium [Cr(VI)] is a well-known human carcinogen associated with an increased risk of lung cancer. However, the mechanisms underlying Cr(VI)-induced carcinogenesis remain unclear. MicroRNA-21 (miR-21) is a key regulator of oncogenic processes. Studies have shown that miR-21 exerts its oncogenic activity by targeting the tumor suppressor gene programmed cell death 4 (PDCD4). The present study examined the role of miR-21-PDCD4 signaling in Cr(VI)-induced cell transformation and tumorigenesis. Results showed that Cr(VI) induces ROS generation in human bronchial epithelial (BEAS-2B) cells. Chronic exposure to Cr(VI) is able to cause malignant transformation in BEAS-2B cells. Cr(VI) caused a significant increase of miR-21 expression associated with an inhibition of PDCD4 expression. Notably, STAT3 transcriptional activation by IL-6 is crucial for the Cr(VI)-induced miR-21 elevation. Stable knockdown of miR-21 or overexpression of PDCD4 in BEAS-2B cells significantly reduced the Cr(VI)-induced cell transformation. Furthermore, the Cr(VI) induced inhibition of PDCD4 suppressed downstream E-cadherin protein expression, but promoted β-catenin/TCF-dependent transcription of uPAR and c-Myc. We also found an increased miR-21 level and decreased PDCD4 expression in xenograft tumors generated with chronic Cr(VI)-exposed BEAS-2B cells. In addition, stable knockdown of miR-21 and overexpression of PDCD4 reduced the tumorogenicity of chronic Cr(VI)-exposed BEAS-2B cells in nude mice. Taken together, these results demonstrate that the miR-21-PDCD4 signaling axis plays an important role in Cr(VI)-induced carcinogenesis. PMID:27323401

Prevalence of Human Papilloma Virus in Sinonasal Papilloma in Southern Iranian Population

PubMed Central

Valibeigi, Behnaz; Ashraf, Mohamad Javad; Kerdegari, Narges; Safai, Akbar; Abedi, Elham; Khademi, Bijan; Azarpira, Negar

2017-01-01

Statement of the Problem: Sinonasal papilloma (SNP) is a rare benign lesion characterized by high recurrence rate and malignant transformation. Purpose: This study aimed to investigate the prevalence of human papilloma virus (HPV) infection in these lesions in South of Iran. Materials and Method: In this cross sectional retrospective study, a total of 41 patients, 38 SNP and 3 SNP/Squamous cell carcinoma cases, from 2007 to 2014 were studied. Human papilloma virus (HPV) DNA detection was performed by nested PCR method and positive cases were analyzed for high risk HPV-16 and HPV-18. Results: HPV was detected in 31.7%; HPV- 16 in 4.9% and HPV 18 was not detected at all. Dysplastic epithelium was detected in 53% that was not associated with HPV. Three cases were accompanied with malignant transformation that HPV genome was detected in only one case and none of them were positive for HPV16 /18 genomic DNA. Conclusion: Current research suggests that HPV may be involved in the development of SNP. But the high risk HPV is not important in malignant transformation. More studies are needed to elucidate the possible etiologic mechanism between HPV, inverted papilloma, and squamous cell carcinoma. PMID:28620639

Prevalence of Human Papilloma Virus in Sinonasal Papilloma in Southern Iranian Population.

PubMed

Valibeigi, Behnaz; Ashraf, Mohamad Javad; Kerdegari, Narges; Safai, Akbar; Abedi, Elham; Khademi, Bijan; Azarpira, Negar

2017-06-01

Sinonasal papilloma (SNP) is a rare benign lesion characterized by high recurrence rate and malignant transformation. This study aimed to investigate the prevalence of human papilloma virus (HPV) infection in these lesions in South of Iran. In this cross sectional retrospective study, a total of 41 patients, 38 SNP and 3 SNP/Squamous cell carcinoma cases, from 2007 to 2014 were studied. Human papilloma virus (HPV) DNA detection was performed by nested PCR method and positive cases were analyzed for high risk HPV-16 and HPV-18. HPV was detected in 31.7%; HPV- 16 in 4.9% and HPV 18 was not detected at all. Dysplastic epithelium was detected in 53% that was not associated with HPV. Three cases were accompanied with malignant transformation that HPV genome was detected in only one case and none of them were positive for HPV16 /18 genomic DNA. Current research suggests that HPV may be involved in the development of SNP. But the high risk HPV is not important in malignant transformation. More studies are needed to elucidate the possible etiologic mechanism between HPV, inverted papilloma, and squamous cell carcinoma.

Role of reactive oxygen species in arsenic-induced transformation of human lung bronchial epithelial (BEAS-2B) cells

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

Zhang, Zhuo, E-mail: zhuo.zhang@uky.edu; Pratheeshkumar, Poyil; Budhraja, Amit

Highlights: • Short term exposure of cells to arsenic causes ROS generation. • Chronical exposure of cells to arsenic causes malignant cell transformation. • Inhibition of ROS generation reduces cell transformation by arsenic. • Arsenic-transformed cells exhibit reduced capacity of generating ROS. • Arsenic-transformed cells exhibit increased levels of antioxidants. - Abstract: Arsenic is an environmental carcinogen, its mechanisms of carcinogenesis remain to be investigated. Reactive oxygen species (ROS) are considered to be important. A previous study (Carpenter et al., 2011) has measured ROS level in human lung bronchial epithelial (BEAS-2B) cells and arsenic-transformed BEAS-2B cells and found that ROSmore » levels were higher in transformed cells than that in parent normal cells. Based on these observations, the authors concluded that cell transformation induced by arsenic is mediated by increased cellular levels of ROS. This conclusion is problematic because this study only measured the basal ROS levels in transformed and parent cells and did not investigate the role of ROS in the process of arsenic-induced cell transformation. The levels of ROS in arsenic-transformed cells represent the result and not the cause of cell transformation. Thus question concerning whether ROS are important in arsenic-induced cell transformation remains to be answered. In the present study, we used expressions of catalase (antioxidant against H{sub 2}O{sub 2}) and superoxide dismutase 2 (SOD2, antioxidant against O{sub 2}{sup ·−}) to decrease ROS level and investigated their role in the process of arsenic-induced cell transformation. Our results show that inhibition of ROS by antioxidant enzymes decreased arsenic-induced cell transformation, demonstrating that ROS are important in this process. We have also shown that in arsenic-transformed cells, ROS generation was lower and levels of antioxidants are higher than those in parent cells, in a disagreement with the previous report. The present study has also shown that the arsenic-transformed cells acquired apoptosis resistance. The inhibition of catalase to increase ROS level restored apoptosis capability of arsenic-transformed BEAS-2B cells, further showing that ROS levels are low in these cells. The apoptosis resistance due to the low ROS levels may increase cells proliferation, providing a favorable environment for tumorigenesis of arsenic-transformed cells.« less

Enhanced G2 chromatid radiosensitivity, an early stage in the neoplastic transformation of human epidermal keratinocytes in culture

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

Gantt, R.; Sanford, K.K.; Parshad, R.

1987-03-01

A deficiency in DNA repair, manifest as enhanced chromatid radiosensitivity during the G2 phase of the cell cycle, together with a proliferative stimulus such as that provided by active oncogenes may be necessary and sufficient for the malignant neoplastic transformation of human keratinocytes in culture. Normal epidermal keratinocytes established as continuous cell lines by transfection with pSV3-neo or infection with adeno 12-SV40 hybrid virus developed enhanced G2 chromatid radiosensitivity after 18 passages in culture. In contrast to cells from primary or secondary culture, these cells could be transformed to malignant neoplastic cells by infection with Kirsten murine sarcoma virus containingmore » the Ki-ras oncogene or in one line by the chemical carcinogen, N-methyl-N'-nitro-N-nitrosoguanidine; both of these agents produced a marked proliferative response. Cytological heterogeneity and karyotypic instability characterized the cells during their progression to neoplasia. These results are interpreted in terms of a mechanism for neoplastic transformation.« less

Intracranial solitary fibrous tumors/hemangiopericytomas: first report of malignant progression.

PubMed

Apra, Caroline; Mokhtari, Karima; Cornu, Philippe; Peyre, Matthieu; Kalamarides, Michel

2018-06-01

OBJECTIVE Meningeal solitary fibrous tumors/hemangiopericytomas (MSFTs/HPCs) are rare intracranial tumors resembling meningiomas. Their classification was redefined in 2016 by the World Health Organization (WHO) as benign Grade I fibrohyaline type, intermediate Grade II hypercellular type, and malignant highly mitotic Grade III. This grouping is based on common histological features and identification of a common NAB2-STAT6 fusion. METHODS The authors retrospectively identified 49 cases of MSFT/HPC. Clinical data were obtained from the medical records, and all cases were analyzed according to this new 2016 WHO grading classification in order to identify malignant transformations. RESULTS Recurrent surgery was performed in 18 (37%) of 49 patients. Malignant progression was identified in 5 (28%) of these 18 cases, with 3 Grade I and 2 Grade II tumors progressing to Grade III, 3-13 years after the initial surgery. Of 31 Grade III tumors treated in this case series, 16% (5/31) were proved to be malignant progressions from lower-grade tumors. CONCLUSIONS Low-grade MSFTs/HPCs can transform into higher grades as shown in this first report of such progression. This is a decisive argument in favor of a common identity for MSFT and meningeal HPC. High-grade MSFTs/HPCs tend to recur more often and be associated with reduced overall survival. Malignant progression could be one mechanism explaining some recurrences or metastases, and justifying long-term follow-up, even for patients with Grade I tumors.

Differential expression of galectin-1 and galectin-3 in thyroid tumors. Potential diagnostic implications.

PubMed Central

Xu, X. C.; el-Naggar, A. K.; Lotan, R.

1995-01-01

Carcinoma of the thyroid gland, the most frequently diagnosed endocrine malignancy, is often associated with early regional metastases. With the exception of papillary carcinoma, distinguishing benign from malignant thyroid neoplasms in the absence of metastatic disease is difficult. Recently, the vertebrate lectins galectin-1 and galectin-3 have been implicated in the regulation of cellular growth, differentiation, and malignant transformation of a variety of tissues. To determine whether these galectins have a role in thyroid neoplasia, we analyzed 32 specimens from thyroid malignancies (16 papillary, 7 follicular, 8 medullary carcinomas, and 1 metastasis to lymph node), 10 benign thyroid adenomas, 1 nodular goiter, and 33 specimens from adjacent normal thyroid tissue for the expression of galectin-1 and galectin-3 with immunohistochemical and immunoblotting techniques utilizing anti-galectin antibodies. All thyroid malignancies of epithelial origin (ie, papillary and follicular carcinomas) and a metastatic lymph node from a papillary carcinoma expressed high levels of both galectin-1 and galectin-3. The medullary thyroid carcinomas, which are of parafollicular C cell origin, showed a weaker and variable expression of these galectins. In contrast, neither benign thyroid adenomas nor adjacent normal thyroid tissue expressed galectin-1 or galectin-3. These results suggest that galectin-1 and galectin-3 may be associated with malignant transformation of thyroid epithelium and may potentially serve as markers for distinguishing benign thyroid adenomas from differentiated thyroid carcinomas. Images Figure 1 Figure 2 Figure 3 Figure 4 PMID:7677193

Proteomics-based investigation of multiple stages of OSCC development indicates that the inhibition of Trx-1 delays oral malignant transformation.

PubMed

Chen, Xijuan; Hu, Qinchao; Wu, Tong; Wang, Chunyang; Xia, Juan; Yang, Linglan; Cheng, Bin; Chen, Xiaobing

2018-03-01

The majority of cases of oral squamous cell carcinoma (OSCC) develop from oral potentially malignant disorders, which have been confirmed to be involved in chronic oxidative stimulation. However, no effective treatment approaches have been used to prevent the development of dysplasia into cancerous lesions thus far. In the present study, a well-established OSCC model was used to detect proteomics profiles at different stages during oral malignant transformation. Of the 15 proteins that were found to be upregulated in both the dysplasia and carcinoma stages, the oxidative stress-associated proteins, thioredoxin-1 (Trx-1), glutaredoxin-1 and peroxiredoxin-2 were note as the proteins with significant changes in expression Trx-1 was identified to be the most significantly upregulated protein in the precancerous stage. Validation experiments confirmed that Trx-1 was overexpressed both in dysplasia and cancerous tissue samples, and the inhibition of Trx-1 was able to promote the apoptosis of OSCC cells under hypoxic conditions. Furthermore, the experimental application of a Trx-1-specific inhibitory agent in an animal model led to a lower cancerization rate and a delay in tumor formation. The possible mechanisms were associated with the increased apoptosis via a reactive oxygen species (ROS)-dependent pathway. Taken together, our findings indicate that Trx-1 may be an important target for delaying oral malignant transformation, which provides a novel therapeutic strategy for the prevention and treatment of OSCC.

New CD20 alternative splice variants: molecular identification and differential expression within hematological B cell malignancies.

PubMed

Gamonet, Clémentine; Bole-Richard, Elodie; Delherme, Aurélia; Aubin, François; Toussirot, Eric; Garnache-Ottou, Francine; Godet, Yann; Ysebaert, Loïc; Tournilhac, Olivier; Caroline, Dartigeas; Larosa, Fabrice; Deconinck, Eric; Saas, Philippe; Borg, Christophe; Deschamps, Marina; Ferrand, Christophe

2015-01-01

CD20 is a B cell lineage-specific marker expressed by normal and leukemic B cells and targeted by several antibody immunotherapies. We have previously shown that the protein from a CD20 mRNA splice variant (D393-CD20) is expressed at various levels in leukemic B cells or lymphoma B cells but not in resting, sorted B cells from the peripheral blood of healthy donors. Western blot (WB) analysis of B malignancy primary samples showed additional CD20 signals. Deep molecular PCR analysis revealed four new sequences corresponding to in-frame CD20 splice variants (D657-CD20, D618-CD20, D480-CD20, and D177-CD20) matching the length of WB signals. We demonstrated that the cell spliceosome machinery can process ex vivo D480-, D657-, and D618-CD20 transcript variants by involving canonical sites associated with cryptic splice sites. Results of specific and quantitative RT-PCR assays showed that these CD20 splice variants are differentially expressed in B malignancies. Moreover, Epstein-Barr virus (EBV) transformation modified the CD20 splicing profile and mainly increased the D393-CD20 variant transcripts. Finally, investigation of three cohorts of chronic lymphocytic leukemia (CLL) patients showed that the total CD20 splice variant expression was higher in a stage B and C sample collection compared to routinely collected CLL samples or relapsed refractory stage A, B, or C CLL. The involvement of these newly discovered alternative CD20 transcript variants in EBV transformation makes them interesting molecular indicators, as does their association with oncogenesis rather than non-oncogenic B cell diseases, differential expression in B cell malignancies, and correlation with CLL stage and some predictive CLL markers. This potential should be investigated in further studies.

Emergence of fractal geometry on the surface of human cervical epithelial cells during progression towards cancer

NASA Astrophysics Data System (ADS)

Dokukin, M. E.; Guz, N. V.; Woodworth, C. D.; Sokolov, I.

2015-03-01

Despite considerable advances in understanding the molecular nature of cancer, many biophysical aspects of malignant development are still unclear. Here we study physical alterations of the surface of human cervical epithelial cells during stepwise in vitro development of cancer (from normal to immortal (premalignant), to malignant). We use atomic force microscopy to demonstrate that development of cancer is associated with emergence of simple fractal geometry on the cell surface. Contrary to the previously expected correlation between cancer and fractals, we find that fractal geometry occurs only at a limited period of development when immortal cells become cancerous; further cancer progression demonstrates deviation from fractal. Because of the connection between fractal behaviour and chaos (or far from equilibrium behaviour), these results suggest that chaotic behaviour coincides with the cancer transformation of the immortalization stage of cancer development, whereas further cancer progression recovers determinism of processes responsible for cell surface formation.

Human papilloma virus: a new risk factor in a subset of head and neck cancers.

PubMed

Bisht, Manisha; Bist, Sampan Singh

2011-01-01

Head and neck cancer is the sixth most common malignancy worldwide. Tobacco smoking and alcohol consumption are two well known behavioral risk factors associated with head and neck cancer. Recently, evidence is mounting that infection with human papilloma virus, most commonly human papilloma virus-16 is responsible for a subset of head and neck squamous cell carcinoma especially tumors of tonsillar origin. The molecular pathway used by human papilloma virus to trigger malignant transformation of tissue is different from that of other well known risk factors, i.e. smoking and alcohol, associated with squamous cell carcinoma. Apparently, these subsets of patients with human papilloma virus positive tumor are more likely to have a better prognosis than human papilloma virus negative tumor. Considering this fact, the human papilloma virus infection should be determined in all oropharyngeal cancers since it can have a major impact on the decision making process of the treatment.

Emerging of fractal geometry on surface of human cervical epithelial cells during progression towards cancer

PubMed Central

Dokukin, M. E.; Guz, N. V.; Woodworth, C.D.; Sokolov, I.

2015-01-01

Despite considerable advances in understanding the molecular nature of cancer, many biophysical aspects of malignant development are still unclear. Here we study physical alterations of the surface of human cervical epithelial cells during stepwise in vitro development of cancer (from normal to immortal (premalignant), to malignant). We use atomic force microscopy to demonstrate that development of cancer is associated with emergence of simple fractal geometry on the cell surface. Contrary to the previously expected correlation between cancer and fractals, we find that fractal geometry occurs only at a limited period of development when immortal cells become cancerous; further cancer progression demonstrates deviation from fractal. Because of the connection between fractal behaviour and chaos (or far from equilibrium behaviour), these results suggest that chaotic behaviour coincides with the cancer transformation of the immortalization stage of cancer development, whereas further cancer progression recovers determinism of processes responsible for cell surface formation. PMID:25844044

Chordoma: the entity.

PubMed

Yakkioui, Youssef; van Overbeeke, Jacobus J; Santegoeds, Remco; van Engeland, Manon; Temel, Yasin

2014-12-01

Chordomas are malignant tumors of the axial skeleton, characterized by their locally invasive and slow but aggressive growth. These neoplasms are presumed to be derived from notochordal remnants with a molecular alteration preceding their malignant transformation. As these tumors are most frequently observed on the skull base and sacrum, patients suffering from a chordoma present with debilitating neurological disease, and have an overall 5-year survival rate of 65%. Surgical resection with adjuvant radiotherapy is the first-choice treatment modality in these patients, since chordomas are resistant to conventional chemotherapy. Even so, management of chordomas can be challenging, as chordoma patients often present with recurrent disease. Recent advances in the understanding of the molecular events that contribute to the development of chordomas are promising; the most novel finding being the identification of brachyury in the disease process. Here we present an overview of the current paradigms and summarize relevant research findings. Copyright © 2014 Elsevier B.V. All rights reserved.

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.

Squamous cell carcinoma arising within a maxillary odontogenic keratocyst: A rare occurrence

PubMed Central

Jalali, Elnaz; Ferneini, Elie M.; Rengasamy, Kandasamy

2017-01-01

Squamous cell carcinoma (SCC) arising within the lining of an odontogenic keratocyst (OKC) is a rare occurrence. Although potentially locally destructive, OKC is a benign odontogenic process that typically presents with clinical and radiographic features characteristic of a benign intraosseous neoplasm. We present the clinical and radiographic features of a maxillary mass that demonstrated SCC arising from the lining of an OKC. Although the initial clinical and radiographic presentation suggested an infection or malignant neoplasm, biopsies revealed an infiltrative well-differentiated SCC contiguous with and arising from the focus of a pre-existing OKC. The patient subsequently underwent a type II hemi-maxillectomy with neoadjuvant chemoradiation. This report discusses the clinical and radiographic features associated with intraosseous malignancies, especially those arising from an otherwise benign odontogenic lesion. While the majority of OKCs are benign, the current report illustrates the potential for carcinomatous transformation within the lining of an OKC. PMID:28680851

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

Differential expression of mucins 1-6 in papillary thyroid carcinoma: evidence for transformation-dependent post-translational modifications of MUC1 in situ.

PubMed

Magro, Gaetano; Schiappacassi, Monica; Perissinotto, Daniela; Corsaro, Antonella; Borghese, Cinzia; Belfiore, Antonino; Colombatti, Alfonso; Grasso, Sebastiano; Botti, Carlo; Bombardieri, Emilio; Perris, Roberto

2003-07-01

Mucins are primary glycoproteins of epithelia that are known to undergo major changes in their post-translational processing during neoplastic transformation. This study has examined the expression pattern of seven primary mucins, ie mucin (MUC) 1, 2, 3, 4, 5AC, 5B and 6, in normal, hyperplastic, benign neoplastic, and papillary-type carcinoma (PTC) tissues of the thyroid. MUC1 and MUC5B were the only mucins to be widely transcribed in both benign and malignant tissues. In contrast, MUC4 transcripts were undetectable in normal thyroids, and were present in only 40% of the hyperplastic and malignant thyroid tissues. In PTC, MUC1 was identified as a single mRNA transcript, rejecting the idea that this mucin may undergo transformation-dependent alternative splicing in thyroid tumours. The tissue distribution of MUC1 and MUC4 proteins was highly heterogeneous: this largely paralleled their mRNA expression profiles and supported the conclusion that whereas MUC1 was ubiquitously expressed in PTC, MUC4 was detectable in less than 20% of the cases analysed. In order to determine whether post-translational modifications of MUC1, putatively associated with malignancy, also occurred in the mucin produced by PTC, immunohistochemistry was performed with a panel of well-characterized anti-MUC1 antibodies in conjunction with digestion of the tissue sections with deglycosylating enzymes. These experiments, which were supported by immunochemical analyses of the MUC1 and MUC4 glycoforms extracted from tissues, collectively demonstrated markedly divergent MUC1 glycosylation profiles in normal and benign thyroid tissues when compared with PTC. Characteristically, these latter neoplastic cells produced mucin molecules carrying complex poly-N-lactosamine-type glycans capped with fucose and neuraminic acid residues. The present study also found evidence in PTC for the potential presence of proteolytically processed MUC1 isoforms which differ in their post-translational traits depending on whether they are retained on the cell surface or secreted into the extracellular space. It is proposed that the observed differences in the glycosylation properties of normal and neoplastic MUC1 may be exploitable as an ancillary tool in the diagnosis of PTC. Copyright 2003 John Wiley & Sons, Ltd.

Hacking cell differentiation: transcriptional rerouting in reprogramming, lineage infidelity and metaplasia.

PubMed

Regalo, Gonçalo; Leutz, Achim

2013-08-01

Initiating neoplastic cell transformation events are of paramount importance for the comprehension of regeneration and vanguard oncogenic processes but are difficult to characterize and frequently clinically overlooked. In epithelia, pre-neoplastic transformation stages are often distinguished by the appearance of phenotypic features of another differentiated tissue, termed metaplasia. In haemato/lymphopoietic malignancies, cell lineage ambiguity is increasingly recorded. Both, metaplasia and biphenotypic leukaemia/lymphoma represent examples of dysregulated cell differentiation that reflect a history of trans-differentiation and/or epigenetic reprogramming. Here we compare the similarity between molecular events of experimental cell trans-differentiation as an emerging therapeutic concept, with lineage confusion, as in metaplasia and dysplasia forecasting tumour development. © 2013 The Authors. Published by John Wiley and Sons, Ltd on behalf of EMBO.

Distinct organization of the candidate tumor suppressor gene RFP2 in human and mouse: multiple mRNA isoforms in both species- and human-specific antisense transcript RFP2OS.

PubMed

Baranova, Ancha; Hammarsund, Marianne; Ivanov, Dmitry; Skoblov, Mikhail; Sangfelt, Olle; Corcoran, Martin; Borodina, Tatiana; Makeeva, Natalia; Pestova, Anna; Tyazhelova, Tatiana; Nazarenko, Svetlana; Gorreta, Francesco; Alsheddi, Tariq; Schlauch, Karen; Nikitin, Eugene; Kapanadze, Bagrat; Shagin, Dmitry; Poltaraus, Andrey; Ivanovich Vorobiev, Andrey; Zabarovsky, Eugene; Lukianov, Sergey; Chandhoke, Vikas; Ibbotson, Rachel; Oscier, David; Einhorn, Stefan; Grander, Dan; Yankovsky, Nick

2003-12-04

In the present study, we describe the human and mouse RFP2 gene structure, multiple RFP2 mRNA isoforms in the two species that have different 5' UTRs and a human-specific antisense transcript RFP2OS. Since the human RFP2 5' UTR is not conserved in mouse, these findings might indicate a different regulation of RFP2 in the two species. The predicted human and mouse RFP2 proteins are shown to contain a tripartite RING finger-B-box-coiled-coil domain (RBCC), also known as a TRIM domain, and therefore belong to a subgroup of RING finger proteins that are often involved in developmental and tumorigenic processes. Because homozygous deletions of chromosomal region 13q14.3 are found in a number of malignancies, including chronic lymphocytic leukemia (CLL) and multiple myeloma (MM), we suggest that RFP2 might be involved in tumor development. This study provides necessary information for evaluation of the role of RFP2 in malignant transformation and other biological processes.

A Review of the Aetiopathogenesis and Clinical and Histopathological Features of Oral Mucosal Melanoma.

PubMed

Feller, Liviu; Khammissa, Razia A G; Lemmer, Johan

2017-01-01

Oral mucosal melanoma is an uncommon, usually heavily melanin-pigmented, but occasionally amelanotic aggressive tumour with a poor prognosis. Despite radical surgery, radiotherapy, or chemotherapy, local recurrence and distant metastasis are frequent. Microscopical examination is essential for diagnosis, and routine histological staining must be supplemented by immunohistochemical studies. The aetiology is unknown, the pathogenesis is poorly understood, and the 5-year survival rate rarely exceeds 30%. In most cases, oral mucosal melanoma arises from epithelial melanocytes in the basal layer of the epithelium and less frequently from immature melanocytes arrested in the lamina propria. In both cases the melanocytes undergo malignant transformation, invade deeper tissues, and metastasize to regional lymph nodes and to distant sites. Very rarely metastasis from skin melanoma may give rise to oral mucosal melanoma that may be mistaken for primary oral mucosal melanoma. The pathogenesis of oral mucosal melanoma is complex involving multiple interactions between cytogenetic factors including dysregulation of the cKit signalling pathways, cell cycle, apoptosis, and cell-to-cell interactions on the one hand and melanin itself, melanin intermediates, and local microenvironmental agents regulating melanogenesis on the other hand. The detailed mechanisms that initiate the malignant transformation of oral melanocytes and thereafter sustain and promote the process of melanomagenesis are unknown.

A Review of the Aetiopathogenesis and Clinical and Histopathological Features of Oral Mucosal Melanoma

PubMed Central

Lemmer, Johan

2017-01-01

Oral mucosal melanoma is an uncommon, usually heavily melanin-pigmented, but occasionally amelanotic aggressive tumour with a poor prognosis. Despite radical surgery, radiotherapy, or chemotherapy, local recurrence and distant metastasis are frequent. Microscopical examination is essential for diagnosis, and routine histological staining must be supplemented by immunohistochemical studies. The aetiology is unknown, the pathogenesis is poorly understood, and the 5-year survival rate rarely exceeds 30%. In most cases, oral mucosal melanoma arises from epithelial melanocytes in the basal layer of the epithelium and less frequently from immature melanocytes arrested in the lamina propria. In both cases the melanocytes undergo malignant transformation, invade deeper tissues, and metastasize to regional lymph nodes and to distant sites. Very rarely metastasis from skin melanoma may give rise to oral mucosal melanoma that may be mistaken for primary oral mucosal melanoma. The pathogenesis of oral mucosal melanoma is complex involving multiple interactions between cytogenetic factors including dysregulation of the cKit signalling pathways, cell cycle, apoptosis, and cell-to-cell interactions on the one hand and melanin itself, melanin intermediates, and local microenvironmental agents regulating melanogenesis on the other hand. The detailed mechanisms that initiate the malignant transformation of oral melanocytes and thereafter sustain and promote the process of melanomagenesis are unknown. PMID:28638859

Mechanisms Leading to Nonrandom, Nonhomologous Chromosomal Translocations in Leukemia

PubMed Central

Gollin, Susanne M.

2007-01-01

Nonrandom, reciprocal translocations between nonhomologous chromosomes are critical cellular events that lead to malignant transformation. Therefore, understanding the mechanisms involved in these chromosomal rearrangements is essential for understanding the process of carcinogenesis. There has been substantial discussion in the literature over the past ten years about mechanisms involved in constitutional chromosomal rearrangements, including deletions, duplications, and translocations. Yet our understanding of the mechanisms of chromosomal rearrangements in cancer is still developing. This review presents what is known about the mechanisms involved in selected nonrandom chromosomal translocations in leukemia. PMID:17157028

Autophagy in Ras-induced malignant transformation: fatal or vital?

PubMed

Mariño, Guillermo; Martins, Isabelle; Kroemer, Guido

2011-04-08

In this issue of Molecular Cell, Elgendy et al. suggest that Ras-induced autophagy may kill tumor cells on the verge of oncogenic transformation, providing a contrast to recent reports indicating that autophagy is required for optimal growth of Ras-driven cancers. Copyright © 2011 Elsevier Inc. All rights reserved.

Management of patients with metastatic teratoma with malignant somatic transformation.

PubMed

Speir, Ryan; Cary, Clint; Foster, Richard S; Masterson, Timothy A

2018-06-22

The purpose of this review is to examine the historical context alongside contemporary studies in order to provide the most current recommendations for the management of patients with metastatic teratoma with malignant somatic transformation (MST). The main themes in the recent literature covered herein include prognostic features, the management of early-stage disease, recommended chemotherapeutic and surgical strategies as well as recognized patterns of late relapse. Recent literature, combined with a significant contribution from historical studies, suggests that while MST is uncommon, its aggressive nature coupled with its resistance with traditional germ cell tumor chemotherapies makes it very difficult to manage. The key message is that surgery is recommended in all resectable MST from primary retroperitoneal lymph node dissection for clinical stage I, to radical removal of disease after chemotherapy and when chemotherapy fails. In advanced cases with documented spread of the transformed histologic subtype, systemic therapies targeted to the identified tumor type should be considered.

Expression of transforming growth factor alpha and epidermal growth factor receptor messenger RNA in neoplastic and nonneoplastic human kidney tissue.

PubMed

Mydlo, J H; Michaeli, J; Cordon-Cardo, C; Goldenberg, A S; Heston, W D; Fair, W R

1989-06-15

Using Northern blot analysis, we have demonstrated that mRNA for transforming growth factor alpha (TGF-alpha) was expressed in five malignant kidney tissue specimens but was not detected in their autologous nonneoplastic homologues. In addition, the expression of epidermal growth factor (EGF) receptor mRNA in these malignant tissues was 2- to 3-fold greater than in nontransformed tissues. In two cases examined using immunohistochemistry, we were able to correlate the increased expression of the mRNA with an increase in protein expression. Since TGF-alpha is known to bind to the EGF receptor, the finding of an increased expression of both TGF-alpha and EGF receptor mRNA in kidney tumor tissue suggests that interaction between TGF-alpha and the EGF receptor may play a role in promoting transformation and/or proliferation of kidney neoplasms, perhaps by an autocrine mechanism.

Hepatocellular carcinoma arising in a pigmented telangiectatic adenoma with nuclear β-catenin and glutamine synthetase positivity: case report and review of the literature.

PubMed

Hechtman, Jaclyn F; Raoufi, Mohammad; Fiel, M Isabel; Taouli, Bachir; Facciuto, Marcelo; Schiano, Thomas D; Blouin, Amanda G; Thung, Swan N

2011-06-01

Telangiectatic hepatocellular adenoma is a rare, recently recognized subtype of hepatocellular adenoma that is often underrecognized by pathologists. We report a case of hepatocellular carcinoma arising within a pigmented telangiectatic hepatocellular adenoma in a noncirrhotic man with diffuse glutamine synthetase and nuclear β-catenin positivity. This case highlights malignant transformation of telangiectatic adenomas, and describes a previously unreported association between pigment deposition and telangiectatic adenoma. Radiology, gross pathology, and histopathology are shown. Review of the literature with attention to β-catenin and glutamine synthetase staining, malignant transformation, patient characteristics, the presence of Dubin-Johnson-like pigment, and genetic characteristics of telangiectatic adenomas are discussed.

Pathways of tumor development and progression in drug-induced nonmelanoma skin cancer: a new hope or the next great confusion?

PubMed

Tchernev, Georgi; Wollina, Uwe

2014-07-01

The factors that lead to the clinical manifestation of the nonmelanocytic skin tumors are different. Ultraviolet radiation, infections with human papillomaviruses, and inherited or iatrogenic-induced immunosuppression (in cases of autoimmune diseases and organ transplant recipients) are considered to be some of the most important generators and/or costimulating factors supporting the appearance of "de-novo" mutations and obstruct, in one or another way, the cell cycle arrest, the programmed cell death (apoptosis), and the immunosurveillance. Preconditions are thus created for the initial persistence and subsequent proliferation of the malignant cell branch in the genome, with the simultaneous increase of the risk of nonmelanocytic skin tumor manifestation.A number of medical drugs that possess a currently well-known selective, targeting, and immunomodulating effect, like the TNF-alpha inhibitors for example, most probably possess an additional blocking action on the death receptors within the framework of the extrinsic apoptotic pathway. In this way, they seem to be one of the major factors for the clinical manifestation not only of nonmelanocytic skin but also of a number of other type of tumors with a dependency on the genetic predisposition of each separate patient.This article focuses the attention on the basic exogenic and endogenic factors that affect the regulatory processes of the cellular cycle, apoptosis, immunosurveillance, and the human inflammasome in patients with nonmelanocytic skin tumors. These processes are interwoven in a complex network and are controlled by (1) the genome regulator p53, (2) its interaction with the proapoptotic acting proteins Bak and Bax, (3) as well as the interaction with the key regulatory protein of the inflammasome-ASC/TMS1.As a process, the malignant transformation is exceptionally dynamic, plastic, and adaptive. The exterior "interferences", on the part of the clinician, in the form of a planned therapy should be targeted at the simultaneous impact on the various pathogenetic chains with the objective of bringing the tumor cells to their total collapse. This can be made possible only after the careful and simultaneous-or parallel-examination of a much greater number of markers that serve to characterize the process of the malignant transformation-a fact, which is currently being disregarded by many researchers.

Child serial murder-psychodynamics: closely watched shadows.

PubMed

Turco, R

2001-01-01

There is a malignant transformation in object relations resulting in an identification with an omnipotent and cruel object resulting in an identity transformation. If the tension, desperation, and dissociation increase, serial murder becomes spree murder. The presence of pathological narcissism and psychopathic tendencies are of diagnostic significance in understanding the murderer's personality functioning and motivation to kill. Meloy (1988) considered the degree of sadism and aggression combined with narcissistic qualities to reflect the "malignancy" of the psychopathic disturbance where gratification (of aggression) occurs in the service of narcissistic functioning--that is, cruelty toward others in the form of a triumphant victory over a rejecting object. Meloy also believes that dissociation is ubiquitious in the psychopath. The initial murder of the serial murderer may reflect a "new identity." The pathological object-relations of narcissism and the malignant narcissism are important diagnostic indicators in the personality functioning of serial killers and the occurrence of these phenomena is a significant factor in the formation of the personalities of serial killers, their inner motivations, and their pattern of commission.

High-grade malignant transformation of a radiation-naïve nasopharyngeal angiofibroma.

PubMed

Allensworth, Jordan J; Troob, Scott H; Lanciault, Christian; Andersen, Peter E

2016-04-01

Nasopharyngeal angiofibromas are typically considered benign vascular neoplasms, with descriptions of high-grade sarcomatous change found only in lesions with prior radiotherapy. We describe the first reported case of high-grade malignant change in a nasopharyngeal angiofibroma naive to radiation. A 45-year-old man presented with left-sided nasal congestion and fullness and was found to have a left-sided nasopharyngeal mass with intracranial extension on CT scan. A biopsy of the mass revealed nasopharyngeal angiofibroma. The patient opted for MRI surveillance, which revealed interval growth 3 years later. Decompression surgery revealed only angiofibroma, but resection 9 months later demonstrated high-grade sarcoma and concomitant angiofibroma. The patient had residual disease which progressed through chemoradiation, and is now pursuing clinical trial enrollment. Malignant transformation of nasopharyngeal angiofibroma is extremely rare. As highlighted by this report, high-grade undifferentiated lesions may arise in tumors without previous radiation. © 2016 Wiley Periodicals, Inc. Head Neck 38: E2425-E2427, 2016. © 2016 Wiley Periodicals, Inc.

Immunohistochemical Expression of MCM-2 in Oral Epithelial Dysplasias.

PubMed

Zakaria, Samar H; Farag, Heba A; Khater, Dina S

2016-03-17

Oral cancer is one of the most frequent cancers in the world. It arises from epithelial dysplasia. Hence, identifying these lesions in an early stage could prevent their malignant transformation. The aim of the present work was to assess the cell proliferative activity of minichromosome maintenance protein (MCM-2) in oral epithelial dysplastic lesions and to correlate the results with different grades of epithelial dysplasia in an attempt to use MCM-2 in the early detection of malignancy. MCM-2 expression was determined by the nuclear count in a total of 30 oral epithelial dysplastic specimens roughly classified into 10 cases of mild, moderate, and severe dysplasia. Five cases of early invasive squamous-cell carcinomas and 5 cases of epithelial hyperplasia were also included. The MCM-2 immunostaining was found to increase gradually from mild to moderate to severe dysplasia and reached its maximum value in early invasive squamous cell carcinoma. MCM-2 is of prognostic value in cases of oral dysplasia that have a tendency to undergo malignant transformation.

Infection and cancer in multicellular organisms

PubMed Central

Ewald, Paul W.; Swain Ewald, Holly A.

2015-01-01

Evolutionary considerations suggest that oncogenic infections should be pervasive among animal species. Infection-associated cancers are well documented in humans and domestic animals, less commonly reported in undomesticated captive animals, and rarely documented in nature. In this paper, we review the literature associating infectious agents with cancer to evaluate the reasons for this pattern. Non-malignant infectious neoplasms occur pervasively in multicellular life, but oncogenic progression to malignancy is often uncertain. Evidence from humans and domestic animals shows that non-malignant infectious neoplasms can develop into cancer, although generally with low frequency. Malignant neoplasms could be difficult to find in nature because of a low frequency of oncogenic transformation, short survival after malignancy and reduced survival prior to malignancy. Moreover, the evaluation of malignancy can be ambiguous in nature, because criteria for malignancy may be difficult to apply consistently across species. The information available in the literature therefore does not allow for a definitive assessment of the pervasiveness of infectious cancers in nature, but the presence of infectious neoplasias and knowledge about the progression of benign neoplasias to cancer is consistent with a widespread but largely undetected occurrence. PMID:26056368

Combined effects of space flight factors and radiation on humans

NASA Technical Reports Server (NTRS)

Todd, P.; Pecaut, M. J.; Fleshner, M.; Clarkson, T. W. (Principal Investigator)

1999-01-01

The probability that a dose of ionizing radiation kills a cell is about 10,000 times the probability that the cell will be transformed to malignancy. On the other hand, the number of cells killed required to significantly impact health is about 10,000 times the number that must be transformed to cause a late malignancy. If these two risks, cell killing and malignant transformation, are about equal, then the risk that occurs during a mission is more significant than the risk that occurs after a mission. The latent period for acute irradiation effects (cell killing) is about 2-4 weeks; the latent period for malignancy is 10-20 years. If these statements are approximately true, then the impact of cell killing on health in the low-gravity environment of space flight should be examined to establish an estimate of risk. The objective of this study is to synthesize data and conclusions from three areas of space biology and environmental health to arrive at rational risk assessment for radiations received by spacecraft crews: (1) the increased physiological demands of the space flight environment; (2) the effects of the space flight environment on physiological systems; and (3) the effects of radiation on physiological systems. One physiological system has been chosen: the immune response and its components, consisting of myeloid and lymphoid proliferative cell compartments. Best-case and worst-case scenarios are considered. In the worst case, a doubling of immune-function demand, accompanied by a halving of immune capacity, would reduce the endangering dose to a crew member to around 1 Gy.

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.

Genes and Proteins Differentially Expressed during In Vitro Malignant Transformation of Bovine Pancreatic Duct Cells1

PubMed Central

Jesnowski, R; Zubakov, Dmitri; Faissner, Ralf; Ringel, Jörg; Hoheisel, Jörg D; Lösel, Ralf; Schnölzer, Martina; Löhr, Matthias

2007-01-01

Abstract Pancreatic carcinoma has an extremely bad prognosis due to lack of early diagnostic markers and lack of effective therapeutic strategies. Recently, we have established an in vitro model recapitulating the first steps in the carcinogenesis of the pancreas. SV40 large T antigen-immortalized bovine pancreatic duct cells formed intrapancreatic adenocarcinoma tumors on k-rasmut transfection after orthotopic injection in the nude mouse pancreas. Here we identified genes and proteins differentially expressed in the course of malignant transformation using reciprocal suppression subtractive hybridization and 2D gel electrophoresis and mass spectrometry, respectively. We identified 34 differentially expressed genes, expressed sequence tags, and 15 unique proteins. Differential expression was verified for some of the genes or proteins in samples from pancreatic carcinoma. Among these genes and proteins, the majority had already been described either to be influenced by a mutated ras or to be differentially expressed in pancreatic adenocarcinoma, thus proving the feasibility of our model. Other genes and proteins (e.g., BBC1, GLTSCR2, and rhoGDIα), up to now, have not been implicated in pancreatic tumor development. Thus, we were able to establish an in vitro model of pancreatic carcinogenesis, which enabled us to identify genes and proteins differentially expressed during the early steps of malignant transformation. PMID:17356710

cAMP enhances Cx43 gap junction formation and function and reverses choline deficiency apoptosis.

PubMed

Albright, C D; Kuo, J; Jeong, S

2001-08-01

Previously, it had been shown that acute choline deficiency (CD) induced apoptosis in cultured rat liver epithelial cells, whereas cells that are adapted to survive in low-choline-containing medium acquire resistance to CD apoptosis and undergo malignant transformation. Thus, understanding the mechanisms of action of CD could increase our understanding of the role of choline, an essential nutrient, in the process of malignant transformation. The present experiments were designed to test the hypothesis that CD might function as a pro-apoptotic trigger by altering the localization of connexin 43 gap junction protein and gap junctional intercellular communication (GJIC). Established liver epithelial cells (WB cells; Hep3B cells) were maintained in a defined, serum-free medium control (70 microM choline) or choline deficient medium (CD, 5 microM choline) and the localization of connexin 43 protein (Cx43) was studied by immunocytochemistry and Western blotting. In nontumorigenic WB cells, CD apoptosis was associated with retention of Cx43 in the golgi/ER region of the cytoplasm and decreased GJIC as measured using a preloading fluorescent dye transfer method (calcein AM/DiIC(18)). Cells maintained in CD in the presence of 8-bromoadenosine 3':5'-cyclic monophosphate exhibited restoration of Cx43 at the plasma membrane and increased GJIC and inhibition of apoptosis. These studies show that CD apoptosis in nontumorigenic liver epithelial cells is associated with alterations to Cx43 and GJIC and that an uncoupling of Cx43 localization and GJIC is related to resistance to CD apoptosis in transformed liver epithelial cells. Copyright 2001 Academic Press.

Aberrant Huntingtin interacting protein 1 in lymphoid malignancies.

PubMed

Bradley, Sarah V; Smith, Mitchell R; Hyun, Teresa S; Lucas, Peter C; Li, Lina; Antonuk, Danielle; Joshi, Indira; Jin, Fang; Ross, Theodora S

2007-09-15

Huntingtin interacting protein 1 (HIP1) is an inositol lipid, clathrin, and actin binding protein that is overexpressed in a variety of epithelial malignancies. Here, we report for the first time that HIP1 is elevated in non-Hodgkin's and Hodgkin's lymphomas and that patients with lymphoid malignancies frequently had anti-HIP1 antibodies in their serum. Moreover, p53-deficient mice with B-cell lymphomas were 13 times more likely to have anti-HIP1 antibodies in their serum than control mice. Furthermore, transgenic overexpression of HIP1 was associated with the development of lymphoid neoplasms. The HIP1 protein was induced by activation of the nuclear factor-kappaB pathway, which is frequently activated in lymphoid malignancies. These data identify HIP1 as a new marker of lymphoid malignancies that contributes to the transformation of lymphoid cells in vivo.

ALK and TGF-Beta Resistance in Breast Cancer

DTIC Science & Technology

2017-10-01

and H.F. Lodish, Role of transforming growth factor beta in human disease. N Engl J Med, 2000. 342(18): p. 1350-8. 3. Massague, J., S.W. Blain, and... Transforming growth factor-beta signaling in normal and malignant hematopoiesis. Leukemia, 2003. 17(9): p. 1731-7. 5. Lehman, H.L., et al., Modeling and

Bowenoid transformation in seborrheic keratosis: A retrospective analysis of 429 patients

PubMed Central

Rajabi, Parvin; Adibi, Neda; Nematollahi, Pardis; Heidarpour, Mitra; Eftekhari, Mehdi; Siadat, Amir Hossein

2012-01-01

Background: Seborrheic keratosis is a common, benign skin tumor. Numerous reports have shown its possibility of malignant transformation. This study was designed to demonstrate the occurrence of concomitant seborrheic keratosis and skin cancers. Materials and Methods: Data was retrospectively reviewed from all patients with a diagnosis of seborrheic keratosis in pathology department of Alzahra Hospital and a private pathology laboratory in Isfahan, Iran over a 4-year period. We classified all demographic data and associated dysplasia or Bowen's disease and analyzed them by student-t or chi-square tests. Results: From all 429 specimens, 5 (1.2%) were found to be associated with Bowen's disease and one (0.2%) with mild dysplasia in squamous epithelium. All cases arose within the clinically, atypical seborrheic keratosis. More men were affected with lesions alone and with malignancy (230/423 (54.4%) and 5/6 (83.3%), respectively) compared to women. The average age of patients suffering from lesions with and without associated malignancy was 57 and 54 years, respectively. The common site of lesion alone was head and neck but lesions with malignancy involved lower extremities. The two lesions were significantly different in site of occurrence (p < 0.001). Conclusion: Generally, although the association between seborrheic keratosis and skin malignancy appears to be accidental, it must always be in mind. Therefore, histopathologic examination of all seborrheic keratosis should be considered, especially when seborrheic keratosis has atypical clinical manifestations. PMID:23267371

The role of miRNAs in endometrial cancer.

PubMed

Vasilatou, Diamantina; Sioulas, Vasileios D; Pappa, Vasiliki; Papageorgiou, Sotirios G; Vlahos, Nikolaos F

2015-01-01

miRNAs are small noncoding RNAs that regulate gene expression at the post-transcriptional level. Since their discovery, miRNAs have been associated with every cell function including malignant transformation and metastasis. Endometrial cancer is the most common gynecologic malignancy. However, improvement should be made in interobserver agreement on histological typing and individualized therapeutic approaches. This article summarizes the role of miRNAs in endometrial cancer pathogenesis and treatment.

Non-hematopoietic PAR-2 is essential for matriptase-driven pre-malignant progression and potentiation of ras-mediated squamous cell carcinogenesis

PubMed Central

Sales, Katiuchia Uzzun; Friis, Stine; Konkel, Joanne E.; Godiksen, Sine; Hatakeyama, Marcia; Hansen, Karina K.; Rogatto, Silvia Regina; Szabo, Roman; Vogel, Lotte K.; Chen, Wanjun; Gutkind, J. Silvio; Bugge, Thomas H.

2014-01-01

The membrane-anchored serine protease, matriptase, is consistently dysregulated in a range of human carcinomas, and high matriptase activity correlates with poor prognosis. Furthermore, matriptase is unique among tumor-associated proteases in that epithelial stem cell expression of the protease suffices to induce malignant transformation. Here, we use genetic epistasis analysis to identify proteinase-activated receptor (PAR)-2-dependent inflammatory signaling as an essential component of matriptase-mediated oncogenesis. In cell-based assays, matriptase was a potent activator of PAR-2, and PAR-2 activation by matriptase caused robust induction of NFκB through Gαi. Importantly, genetic elimination of PAR-2 from mice completely prevented matriptase-induced pre-malignant progression, including inflammatory cytokine production, inflammatory cell recruitment, epidermal hyperplasia, and dermal fibrosis. Selective ablation of PAR-2 from bone marrow-derived cells did not prevent matriptase-driven pre-malignant progression, indicating that matriptase activates keratinocyte stem cell PAR-2 to elicit its pro-inflammatory and pro-tumorigenic effects. When combined with previous studies, our data suggest that dual induction of PAR-2-NFκB inflammatory signaling and PI3K-Akt-mTor survival/proliferative signaling underlies the transforming potential of matriptase and may contribute to pro-tumorigenic signaling in human epithelial carcinogenesis. PMID:24469043

Non-hematopoietic PAR-2 is essential for matriptase-driven pre-malignant progression and potentiation of ras-mediated squamous cell carcinogenesis.

PubMed

Sales, K U; Friis, S; Konkel, J E; Godiksen, S; Hatakeyama, M; Hansen, K K; Rogatto, S R; Szabo, R; Vogel, L K; Chen, W; Gutkind, J S; Bugge, T H

2015-01-15

The membrane-anchored serine protease, matriptase, is consistently dysregulated in a range of human carcinomas, and high matriptase activity correlates with poor prognosis. Furthermore, matriptase is unique among tumor-associated proteases in that epithelial stem cell expression of the protease suffices to induce malignant transformation. Here, we use genetic epistasis analysis to identify proteinase-activated receptor (PAR)-2-dependent inflammatory signaling as an essential component of matriptase-mediated oncogenesis. In cell-based assays, matriptase was a potent activator of PAR-2, and PAR-2 activation by matriptase caused robust induction of nuclear factor (NF)κB through Gαi. Importantly, genetic elimination of PAR-2 from mice completely prevented matriptase-induced pre-malignant progression, including inflammatory cytokine production, inflammatory cell recruitment, epidermal hyperplasia and dermal fibrosis. Selective ablation of PAR-2 from bone marrow-derived cells did not prevent matriptase-driven pre-malignant progression, indicating that matriptase activates keratinocyte stem cell PAR-2 to elicit its pro-inflammatory and pro-tumorigenic effects. When combined with previous studies, our data suggest that dual induction of PAR-2-NFκB inflammatory signaling and PI3K-Akt-mTor survival/proliferative signaling underlies the transforming potential of matriptase and may contribute to pro-tumorigenic signaling in human epithelial carcinogenesis.

Transforming growth factor-beta and nitrates in epithelial ovarian cancer.

PubMed

Khalifa, A; Kassim, S K; Ahmed, M I; Fayed, S T

1999-12-01

The role of transforming growth factor-beta (TGF-beta) and nitric oxide (NO) in ovarian neoplasia is still not clear. We studied the expression of TGF-beta by enzyme immunoassay, and nitrates (as a stable end product of NO) in 127 ovarian tissues (36 normal, 37 benign, and 54 malignant). Ploidy status and synthetic phase fraction (SPF) were also assessed by flow cytometry. Mean ranks of TGF-beta, nitrate, and SPF were significant among different groups (X2 = 12.01, P = 0.0025, X2 = 67.42, P = 0.000, X2 = 9.06, P = 0.011 respectively). Nitrate mean ranks were significant among different FIGO stages of the disease (X2 = 17.6, P = 0.000). A significant correlation was shown between TGF-beta, and nitrate levels in all tissues (r = 0.24, P = 0.01), as well as in malignant tissues (r = 0.3, P = 0.026). Cutoff values were determined for both TGF-beta (290 pg/mg protein), and nitrates (310 nmole/mg non protein nitrogenous substances). At these cut-offs, nitrates showed a sensitivity of 93% and 84% specificity for malignant versus normal cases, while TGF-beta had 76% sensitivity, and 82.4% specificity for poor versus good outcome. Patients with epithelial ovarian cancer were followed up for a total of 40 months. Survival analysis showed that patients with TGF-beta above the cut-off had worse prognosis (X2 = 12.69, P = 0.004). The present results suggest that malignant transformation of ovarian tissues is associated with increased TGF-beta and NO production. NO level is related to the development and progression of epithelial ovarian cancer, while high levels of TGF-beta could be of prognostic significance.

Transforming Growth Factor-β and Nitrates in Epithelial Ovarian Cancer

PubMed Central

Khalifa, Ali; Kassim, Samar K.; Ahmed, Maha I.; Fayed, Salah T.

1999-01-01

The role of transforming growth factor-β (TGF-β) and nitric oxide (NO) in ovarian neoplasia is still not clear. We studied the expression of TGF-β by enzyme immunoassay, and nitrates (as a stable end product of NO) in 127 ovarian tissues (36 normal, 37 benign, and 54 malignant). Ploidy status and synthetic phase fraction (SPF) were also assessed by flow cytometry. Mean ranks of TGF-β, nitrate, and SPF were significant among different groups (X2 = 12.01, P = 0.0025, X2 = 67.42, P = 0.000, X2 = 9.06, P = 0.011 respectively). Nitrate mean ranks were significant among different FIGO stages of the disease (X2 = 17.6, P = 0.000). A significant correlation was shown between TGF-â, and nitrate levels in all tissues (r = 0.24, P = 0.01), as well as in malignant tissues (r = 0.3, P = 0.026). Cutoff values were determined for both TGF-β (290 pg/mg protein), and nitrates (310 nmole/mg non protein nitrogenous substances). At these cut-offs, nitrates showed a sensitivity of 93% and 84% specificity for malignant versus normal cases, while TGF-β had 76% sensitivity, and 82.4% specificity for poor versus good outcome. Patients with epithelial ovarian cancer were followed up for a total of 40 months. Survival analysis showed that patients with TGF-β above the cut-off had worse prognosis (X2 = 12.69, P = 0.004). The present results suggest that malignant transformation of ovarian tissues is associated with increased TGF-β and NO production. NO level is related to the development and progression of epithelial ovarian cancer, while high levels of TGF-β could be of prognostic significance. PMID:10689548

Adenocarcinoma arising from intracranial recurrent mature teratoma and featuring mutated KRAS and wild-type BRAF genes.

PubMed

Kim, Eun Soo; Kwon, Mi Jung; Song, Joon Ho; Kim, Dong Hoon; Park, Hye-Rim

2015-02-01

Malignant transformation or recurrence of intracranial mature teratoma is an extremely rare occurrence, compared to the usual ovarian counterpart. Previously, yolk sac tumor elements have been considered to be selective progenitors of enteric-type adenocarcinoma arising from intracranial germ cell tumors. However, the present case demonstrates the occurrence of enteric-type adenocarcinoma in recurrent intracranial mature cystic teratoma 12 years after gross total removal, a case of which has not previously been documented in the literature. The 11.5-cm long, dura mater-based tumor on the right fronto-temporal lobe displaced the brain; however, the patient had no neurologic symptoms or discomfort other than pus-like discharge on the scalp. Microscopic examinations revealed a small focus of adenocarcinoma and dysplastic colonic mucosa in the mature cystic teratoma. No immature elements were seen. The cystic wall was almost denuded and showed an exuberant xanthogranulomatous reaction with foreign-body type giant cells engulfing keratin materials and cholesterol clefts, suggesting that chronic inflammation due to repeated cyst wall rupture and the previous resection may contribute to malignant transformation. The adenocarcinoma showed strong immunohistochemical expression of CK20 and p53, but CK7 in patches. The molecular profile of the adenocarcinoma showed a mutation in KRAS and wild-type BRAF, which might be associated with malignant transformation of intracranial mature teratomas. In conclusion, the intracranial mature teratomas should require long-term follow-up, and clinicians, radiologists and pathologists should be aware of the potential for malignant progression of recurrent intracranial mature cystic teratoma despite gross total resection and no neurologic symptoms. © 2014 Japanese Society of Neuropathology.

Silencing the Snail-dependent RNA splice regulator ESRP1 drives malignant transformation of human pulmonary epithelial cells. | Office of Cancer Genomics

Cancer.gov

Epithelial-to-mesenchymal transition (EMT) is organized in cancer cells by a set of key transcription factors, but the significance of this process is still debated including in non-small cell lung cancer (NSCLC). Here we report increased expression of the EMT-inducing transcription factor Snail in premalignant pulmonary lesions, relative to histologically normal pulmonary epithelium. In immortalized human pulmonary epithelial cells and isogenic derivatives, we documented Snail-dependent anchorage-independent growth in vitro and primary tumor growth and metastatic behavior in vivo.

Cavernous Transformation of Portal Vein Secondary to Portal Vein Thrombosis: A Case Report

PubMed Central

Ramos, Radhames; Park, Yoojin; Shazad, Ghulamullah; A.Garcia, Christine; Cohen, Ronny

2012-01-01

There are few reported cases of cavernous transformation of the portal vein (CTPV) in adults. We present a case of a 58 year-old male who was found to have this complication due to portal vein thrombosis (PVT). A 58-year old African American male with chronic alcohol and tobacco use presented with a 25-day history of weakness, generalized malaise, nausea and vomiting associated with progressively worsening anorexia and weight loss. The patient was admitted for severe anemia in conjunction with abnormal liver function tests and electrolyte abnormalities, and to rule out end stage liver disease or hepatic malignancy. The work-up for anemia showed no significant colon abnormalities, cholecystitis, liver cirrhosis, or liver abnormalities but could not rule out malignancy. An esophageogastroduodenoscopy (EGD) was suspicious for a mass compressing the stomach and small bowel. After further work-up, the hepatic mass has been diagnosed as a cavernous transformation of the portal vein (CTPV), a very rare complication of portal vein thrombosis (PVT). Cavernous Transformation of the Portal Vein (CTPV) is a rare and incurable complication of portal vein thrombosis (PVT) that should be considered as one of the differential diagnoses of a hepatic mass. Keywords Cavernous transformation of the portal vein; Portal vein thrombosis; Portal hypertension; Hyperbilirubinemia; Hepatic mass PMID:22383935

Relation of epidermal growth factor receptor and estrogen receptor-independent pS2 protein to the malignant transformation of mucinous cystic neoplasms of the pancreas.

PubMed

Kirby, R E; Lewandrowski, K B; Southern, J F; Compton, C C; Warshaw, A L

1995-01-01

To evaluate the role of epidermal growth factor receptor (EGF-R) and pS2 protein in the evolution of malignancy in mucinous cystic tumors of the pancreas. Mucinous cystic tumors of the pancreas include histologically benign but premalignant mucinous cystic neoplasms and mucinous cystadenocarcinoma. The molecular events leading to transformation from a benign to a malignant mucinous tumor are not known. Overexpression of EGF-R and detection of an estrogen-induced protein (pS2) has been demonstrated in ductal adenocarcinomas of the pancreas, but these factors have not been evaluated in mucinous cystic tumors. Twenty-six mucinous tumors were examined for EGF-R, pS2 protein, and estrogen and progesterone receptors. Eight (61.2%) of 13 malignant tumors exhibited increased expression of EGF-R, whereas EGF-R was not detected in any of the 13 benign tumors (P = .002). The pS2 protein was detected in nine of 11 malignant and 11 of 11 benign tumors (P = .480). Estrogen and progesterone receptors were not detected in the epithelium of either tumor type. The median survival time of the patients with EGF-R-negative tumors was 29.0 months compared with 14.5 months for those with EGF-R-positive tumors, but this difference did not reach significance owing to the small population size. Overexpression of EGF-R in mucinous cystic tumors, as in ductal adenocarcinomas, may be an important feature associated with malignancy and may have prognostic significance. Failure to detect EGF-R in histologically benign epithelium suggests that the upregulation of EGF-R may be important in the evolution of aggressive behavior. The expression of pS2 protein appears to be independent of estrogen and may play a role in the proliferative activity of mucinous tumors. However, pS2 expression is not a feature associated exclusively with malignancy.

Wavelet-based 3D reconstruction of microcalcification clusters from two mammographic views: new evidence that fractal tumors are malignant and Euclidean tumors are benign.

PubMed

Batchelder, Kendra A; Tanenbaum, Aaron B; Albert, Seth; Guimond, Lyne; Kestener, Pierre; Arneodo, Alain; Khalil, Andre

2014-01-01

The 2D Wavelet-Transform Modulus Maxima (WTMM) method was used to detect microcalcifications (MC) in human breast tissue seen in mammograms and to characterize the fractal geometry of benign and malignant MC clusters. This was done in the context of a preliminary analysis of a small dataset, via a novel way to partition the wavelet-transform space-scale skeleton. For the first time, the estimated 3D fractal structure of a breast lesion was inferred by pairing the information from two separate 2D projected mammographic views of the same breast, i.e. the cranial-caudal (CC) and mediolateral-oblique (MLO) views. As a novelty, we define the "CC-MLO fractal dimension plot", where a "fractal zone" and "Euclidean zones" (non-fractal) are defined. 118 images (59 cases, 25 malignant and 34 benign) obtained from a digital databank of mammograms with known radiologist diagnostics were analyzed to determine which cases would be plotted in the fractal zone and which cases would fall in the Euclidean zones. 92% of malignant breast lesions studied (23 out of 25 cases) were in the fractal zone while 88% of the benign lesions were in the Euclidean zones (30 out of 34 cases). Furthermore, a Bayesian statistical analysis shows that, with 95% credibility, the probability that fractal breast lesions are malignant is between 74% and 98%. Alternatively, with 95% credibility, the probability that Euclidean breast lesions are benign is between 76% and 96%. These results support the notion that the fractal structure of malignant tumors is more likely to be associated with an invasive behavior into the surrounding tissue compared to the less invasive, Euclidean structure of benign tumors. Finally, based on indirect 3D reconstructions from the 2D views, we conjecture that all breast tumors considered in this study, benign and malignant, fractal or Euclidean, restrict their growth to 2-dimensional manifolds within the breast tissue.

Microenvironmental autophagy promotes tumour growth.

PubMed

Katheder, Nadja S; Khezri, Rojyar; O'Farrell, Fergal; Schultz, Sebastian W; Jain, Ashish; Rahman, Mohammed M; Schink, Kay O; Theodossiou, Theodossis A; Johansen, Terje; Juhász, Gábor; Bilder, David; Brech, Andreas; Stenmark, Harald; Rusten, Tor Erik

2017-01-19

As malignant tumours develop, they interact intimately with their microenvironment and can activate autophagy, a catabolic process which provides nutrients during starvation. How tumours regulate autophagy in vivo and whether autophagy affects tumour growth is controversial. Here we demonstrate, using a well characterized Drosophila melanogaster malignant tumour model, that non-cell-autonomous autophagy is induced both in the tumour microenvironment and systemically in distant tissues. Tumour growth can be pharmacologically restrained using autophagy inhibitors, and early-stage tumour growth and invasion are genetically dependent on autophagy within the local tumour microenvironment. Induction of autophagy is mediated by Drosophila tumour necrosis factor and interleukin-6-like signalling from metabolically stressed tumour cells, whereas tumour growth depends on active amino acid transport. We show that dormant growth-impaired tumours from autophagy-deficient animals reactivate tumorous growth when transplanted into autophagy-proficient hosts. We conclude that transformed cells engage surrounding normal cells as active and essential microenvironmental contributors to early tumour growth through nutrient-generating autophagy.

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

Co-occurrence of acanthosis nigricans and bladder adenocarcinoma – case report

PubMed Central

Silny, Wojciech; Żaba, Ryszard; Osmola-Mańkowska, Agnieszka; Mackiewicz-Wysocka, Małgorzata; Dańczak-Pazdrowska, Aleksandra

2013-01-01

Acanthosis nigricans (AN) is characterized by the occurrence of symmetrical velvety hyperpigmented plaques that can be observed in each location on the skin. However, the lesions are most frequently located in the axillary, inguinal and nuchal areas. Primarily, the lesions appear as hyperpigmented focuses which later transform into papillary lesions. There are two forms of the disease – benign and malignant. Malignant AN is considered to represent paraneoplastic syndrome co-occurring with advanced cancer, but as such it is not malignant. This article presents a case of a patient diagnosed with AN and coexisting bladder cancer and discusses the case in the context of available literature. PMID:24596525

A Hormonally Active Malignant Struma Ovarii

PubMed Central

Lara, Carolina; Salame, Latife; Padilla-Longoria, Rafael

2016-01-01

Struma ovarii is a rare monodermal variant of ovarian teratoma that contains at least 50% thyroid tissue. Less than 8% of struma ovarii cases present with clinical and biochemical evidence of thyrotoxicosis due to ectopic production of thyroid hormone and only 5% undergo malignant transformation into a papillary thyroid carcinoma. Only isolated cases of hormonally active papillary thyroid carcinoma developing within a struma ovarii have been reported in the literature. We report the case of a 36-year-old woman who presented with clinical signs and symptoms of hyperthyroidism as well as a left adnexal mass, which proved to be a thyroid hormone-producing, malignant struma ovarii. PMID:27882257

Decision for surgery in the management of a rare condition, childhood gallbladder polyps, and the role of ultrasonography.

PubMed

Bayram Kabaçam, Gülşah; Akbıyık, Fatih; Livanelioğlu, Ziya; Tiryaki, H Tuğrul; Karakuş, Esra; Kabaçam, Gökhan

2013-01-01

Gallbladder polyps are tumors or tumor-like protrusions of the gallbladder. They are rarely seen in the pediatric age. Most important issue about these mostly incidental lesions is the risk of malignant transformation. Size more than 10 mm is the classicalcutoff for determining this risk, but it is rarely valid in children. Ultrasonography is the method of choice for follow-up, but it rarely demonstrates change of size or malignant transformation. Hereby, we report 6 cases of childhood gallbladder polyps, none of which had a genetic risk factor. Follow-up was uneventful in 4 of them. Two patients had undergone surgery, but none of the lesions were neoplastic. In the follow-up, a single experienced radiologist should handle the patient, in order to prevent inter-observer variation. The cut-off size for deciding surgery should be 10 mm for those cases with genetic background creating malignancy risk (metachromatic leukodystrophy, pancreaticobiliary duct abnormalities, achondroplasia, Peutz-Jeghers syndrome) or with accompanying cholelithiasis, and 15 mm for those without any risk factors to prevent any unnecessary operations.

Hook1 inhibits malignancy and epithelial-mesenchymal transition in hepatocellular carcinoma.

PubMed

Sun, Xu; Zhang, Qi; Chen, Wei; Hu, Qida; Lou, Yu; Fu, Qi-Han; Zhang, Jing-Ying; Chen, Yi-Wen; Ye, Long-Yun; Wang, Yi; Xie, Shang-Zhi; Hu, Li-Qiang; Liang, Ting-Bo; Bai, Xue-Li

2017-07-01

Hook1 is a member of the hook family of coiled-coil proteins, which is recently found to be associated with malignant tumors. However, its biological function in hepatocellular carcinoma is yet unknown. Here, we evaluated the Hook1 levels in human hepatocellular carcinoma samples and matched peritumoral tissues by real-time polymerase chain reaction. Small interfering RNA knockdown and a transforming growth factor-β-induced epithelial-mesenchymal transition model were employed to investigate the biological effects of Hook1 in hepatocellular carcinoma. Our results indicated that Hook1 levels were significantly lower in hepatocellular carcinoma tissues than in the peritumoral tissues. In addition, Hook1 expression was significantly associated with hepatocellular carcinoma malignancy. Hook1 was downregulated after transforming growth factor-β-induced epithelial-mesenchymal transition. Moreover, Hook1 knockdown promoted epithelial-mesenchymal transition and attenuated the sensitivity of hepatocellular carcinoma cells to doxorubicin. In summary, our results indicate that downregulation of Hook1 plays a pivotal role in hepatocellular carcinoma progression via epithelial-mesenchymal transition. Hook1 may be used as a novel marker and therapeutic molecular target in hepatocellular carcinoma.

Integration Site and Clonal Expansion in Human Chronic Retroviral Infection and Gene Therapy

PubMed Central

Niederer, Heather A.; Bangham, Charles R. M.

2014-01-01

Retroviral vectors have been successfully used therapeutically to restore expression of genes in a range of single-gene diseases, including several primary immunodeficiency disorders. Although clinical trials have shown remarkable results, there have also been a number of severe adverse events involving malignant outgrowth of a transformed clonal population. This clonal expansion is influenced by the integration site profile of the viral integrase, the transgene expressed, and the effect of the viral promoters on the neighbouring host genome. Infection with the pathogenic human retrovirus HTLV-1 also causes clonal expansion of cells containing an integrated HTLV-1 provirus. Although the majority of HTLV-1-infected people remain asymptomatic, up to 5% develop an aggressive T cell malignancy. In this review we discuss recent findings on the role of the genomic integration site in determining the clonality and the potential for malignant transformation of cells carrying integrated HTLV-1 or gene therapy vectors, and how these results have contributed to the understanding of HTLV-1 pathogenesis and to improvements in gene therapy vector safety. PMID:25365582

A rare case report of Patellar Osteochondroma

PubMed Central

Bhatnagar, Abhinav S.; Malhan, Kaushal; Mehta, Sonu

2015-01-01

Introduction: Osteochondroma (OC) is the most common benign tumor of the skeleton. However, patellar OC is very rare. Only five case reports have been published yet and only 1 after the year 1972. OCs grow during childhood through adolescence, but usually growing ends when the epiphyseal plates close. In an adult, the growth of an OC suggests the diagnosis of malignant transformation to a chondrosarcoma. However, enlargement of a patellar OC reported as benign after skeletal maturity is present in literature. Case Report: We report the clinical and radiologic findings of a patellar OC in a 50-year-old female, with a 3-year progression of swelling, not painful, well-defined margins, normal skin, and no neurovascular deficits or functional impairment. The tumor was surgically resected, and histopathological examination did not show malignancy. After 2 years of follow-up, the patient has no complaints and no signs of recurrence. Conclusion: Patellar OCsare extremely rare with only a few reports published. It should be kept in mind that benign OCs can show symptomatic growth in skeletally mature patients without malignant transformation. PMID:27299076

The cost-effectiveness of screening for oral cancer in primary care.

PubMed

Speight, P M; Palmer, S; Moles, D R; Downer, M C; Smith, D H; Henriksson, M; Augustovski, F

2006-04-01

To use a decision-analytic model to determine the incremental costs and outcomes of alternative oral cancer screening programmes conducted in a primary care environment. The cost-effectiveness of oral cancer screening programmes in a number of primary care environments was simulated using a decision analysis model. Primary data on actual resource use and costs were collected by case note review in two hospitals. Additional data needed to inform the model were obtained from published costs, from systematic reviews and by expert opinion using the Trial Roulette approach. The value of future research was determined using expected value of perfect information (EVPI) for the decision to screen and for each of the model inputs. Hypothetical screening programmes conducted in a number of primary care settings. Eight strategies were compared: (A) no screen; (B) invitational screen--general medical practice; (C) invitational screen--general dental practice; (D) opportunistic screen--general medical practice; (E) opportunistic screen--general dental practice; (F) opportunistic high-risk screen--general medical practice; (G) opportunistic high-risk screen--general dental practice; and (H) invitational screen--specialist. A hypothetical population over the age of 40 years was studied. The main measures were mean lifetime costs and quality-adjusted life-years (QALYs) of each alternative screening scenario and incremental cost-effectiveness ratios (ICERs) to determine the additional costs and benefits of each strategy over another. No screening (strategy A) was always the cheapest option. Strategies B, C, E and H were never cost-effective and were ruled out by dominance or extended dominance. Of the remaining strategies, the ICER for the whole population (age 49-79 years) ranged from pound 15,790 to pound 25,961 per QALY. Modelling a 20% reduction in disease progression always gave the lowest ICERs. Cost-effectiveness acceptability curves showed that there is considerable uncertainty in the optimal decision identified by the ICER, depending on both the maximum amount that the NHS may be prepared to pay and the impact that treatment has on the annual malignancy transformation rate. Overall, however, high-risk opportunistic screening by a general dental or medical practitioner (strategies F and G) may be cost-effective. EVPIs were high for all parameters with population values ranging from pound 8 million to pound 462 million. However, the values were significantly higher in males than females but also varied depending on malignant transformation rate, effects of treatment and willingness to pay. Partial EVPIs showed the highest values for malignant transformation rate, disease progression, self-referral and costs of cancer treatment. Opportunistic high-risk screening, particularly in general dental practice, may be cost-effective. This screening may more effectively be targeted to younger age groups, particularly 40-60 year olds. However, there is considerable uncertainty in the parameters used in the model, particularly malignant transformation rate, disease progression, patterns of self-referral and costs. Further study is needed on malignant transformation rates of oral potentially malignant lesions and to determine the outcome of treatment of oral potentially malignant lesions. Evidence has been published to suggest that intervention has no greater benefit than 'watch and wait'. Hence a properly planned randomised controlled trial may be justified. Research is also needed into the rates of progression of oral cancer and on referral pathways from primary to secondary care and their effects on delay and stage of presentation.

SPARC Gene Expression is Repressed in Human Urothelial Cells (UROtsa) Exposed to or Malignantly Transformed by Cadmium or Arsenite

PubMed Central

Larson, Jennifer; Yasmin, Tahmina; Sens, Donald A.; Zhou, Xu Dong; Sens, Mary Ann; Garrett, Scott H.; Dunlevy, Jane R.; Cao, Ling; Somji, Seema

2010-01-01

SPARC belongs to a class of extracellular matrix-associated proteins that have counteradhesive properties. The ability of SPARC to modulate cell-cell and cell-matrix interactions provides a strong rationale for studies designed to determine its expression in cancer. The objective of this study was to determine if SPARC expression was altered in cadmium (Cd+2) and arsenite (As+3) induced bladder cancer and if these alterations were present in archival specimens of human bladder cancer. The expression of SPARC was determined in human parental UROtsa cells, their Cd+2 and As+3 transformed counterparts and derived tumors, and in archival specimens of human bladder cancer using a combination of real time reverse transcriptase polymerase chain reaction, western blotting, immunofluoresence localization and immunohistochemical staining. It was demonstrated that SPARC expression was down-regulated in Cd+2 and As+3 transformed UROtsa cells. In addition, the malignant epithelial component of tumors derived from these cell lines were also down-regulated for SPARC expression, but the stromal cells recruited to these tumors was highly reactive for SPARC. This finding was shown to translate to specimens of human bladder cancer where tumor cells were SPARC negative, but stromal cells were positive. Acute exposure of UROtsa cells to both cadmium and arsenite reduced the expression of SPARC through a mechanism that did not involve changes in DNA methylation or histone acetylation. These studies suggest that environmental exposure to As+3 or Cd+2 can alter cell-cell and cell-matrix interactions in normal urothelial cells through a reduction in the expression of SPARC. The SPARC associated loss of cell-cell and cell-matrix contacts may participate in the multi-step process of bladder carcinogenesis. PMID:20837119

Inhibition of latent membrane protein 1 impairs the growth and tumorigenesis of latency II Epstein-Barr virus-transformed T cells.

PubMed

Ndour, Papa Alioune; Brocqueville, Guillaume; Ouk, Tan-Sothéa; Goormachtigh, Gautier; Morales, Olivier; Mougel, Alexandra; Bertout, Julie; Melnyk, Oleg; Fafeur, Véronique; Feuillard, Jean; Coll, Jean; Adriaenssens, Eric

2012-04-01

Epstein-Barr virus (EBV) is a common human herpesvirus. Infection with EBV is associated with several human malignancies in which the virus expresses a set of latent proteins, among which is latent membrane protein 1 (LMP1). LMP1 is able to transform numerous cell types and is considered the main oncogenic protein of EBV. The mechanism of action is based on mimicry of activated members of the tumor necrosis factor (TNF) receptor superfamily, through the ability of LMP1 to bind similar adapters and to activate signaling pathways. We previously generated two unique models: a monocytic cell line and a lymphocytic (NC5) cell line immortalized by EBV that expresses the type II latency program. Here we generated LMP1 dominant negative forms (DNs), based on fusion between green fluorescent protein (GFP) and transformation effector site 1 (TES1) or TES2 of LMP1. Then we generated cell lines conditionally expressing these DNs. These DNs inhibit NF-κB and Akt pathways, resulting in the impairment of survival processes and increased apoptosis in these cell lines. This proapoptotic effect is due to reduced interaction of LMP1 with specific adapters and the recruitment of these adapters to DNs, which enable the generation of an apoptotic complex involving TRADD, FADD, and caspase 8. Similar results were obtained with cell lines displaying a latency III program in which LMP1-DNs decrease cell viability. Finally, we prove that synthetic peptides display similar inhibitory effects in EBV-infected cells. DNs derived from LMP1 could be used to develop therapeutic approaches for malignant diseases associated with EBV.

Inhibition of Latent Membrane Protein 1 Impairs the Growth and Tumorigenesis of Latency II Epstein-Barr Virus-Transformed T Cells

PubMed Central

Ndour, Papa Alioune; Brocqueville, Guillaume; Ouk, Tan-Sothéa; Goormachtigh, Gautier; Morales, Olivier; Mougel, Alexandra; Bertout, Julie; Melnyk, Oleg; Fafeur, Véronique; Feuillard, Jean; Coll, Jean

2012-01-01

Epstein-Barr virus (EBV) is a common human herpesvirus. Infection with EBV is associated with several human malignancies in which the virus expresses a set of latent proteins, among which is latent membrane protein 1 (LMP1). LMP1 is able to transform numerous cell types and is considered the main oncogenic protein of EBV. The mechanism of action is based on mimicry of activated members of the tumor necrosis factor (TNF) receptor superfamily, through the ability of LMP1 to bind similar adapters and to activate signaling pathways. We previously generated two unique models: a monocytic cell line and a lymphocytic (NC5) cell line immortalized by EBV that expresses the type II latency program. Here we generated LMP1 dominant negative forms (DNs), based on fusion between green fluorescent protein (GFP) and transformation effector site 1 (TES1) or TES2 of LMP1. Then we generated cell lines conditionally expressing these DNs. These DNs inhibit NF-κB and Akt pathways, resulting in the impairment of survival processes and increased apoptosis in these cell lines. This proapoptotic effect is due to reduced interaction of LMP1 with specific adapters and the recruitment of these adapters to DNs, which enable the generation of an apoptotic complex involving TRADD, FADD, and caspase 8. Similar results were obtained with cell lines displaying a latency III program in which LMP1-DNs decrease cell viability. Finally, we prove that synthetic peptides display similar inhibitory effects in EBV-infected cells. DNs derived from LMP1 could be used to develop therapeutic approaches for malignant diseases associated with EBV. PMID:22258264

Parathyroid carcinoma presenting as tertiary hyperparathyroidism.

PubMed Central

Sherlock, D. J.; Newman, J.; Holl-Allen, R. T.

1985-01-01

A case of malignant transformation in established secondary hyperparathyroidism presenting as tertiary hyperparathyroidism is reported. Although rare, this occurrence has important medical and surgical implications. Images Figure 1 PMID:3983057

Synchronous Occurrence of Chronic Myeloid Leukemia and Mantle Cell Lymphoma

PubMed Central

Li, Ying; Gray, Brian Allen; May, William Stratford

2017-01-01

Chronic myeloid leukemia (CML) and mantle cell lymphoma (MCL) are hematologic malignancies that originate from different oligopotent progenitor stem cells, namely, common myeloid and lymphoid progenitor cells, respectively. Although blastic transformation of CML can occur in the lymphoid lineage and CML has been related to non-Hodgkin lymphoma on transformation, to our knowledge, de novo and synchronous occurrence of CML and MCL has not been reported. Herein, we report the first case of synchronous CML and MCL in an otherwise healthy 38-year-old man. Potential etiologies and pathological relationships between the two malignancies are explored, including the possibility that the downstream effects of BCR-ABL may link it to an overexpression of cyclin D1, which is inherent to the etiology of MCL. PMID:28270940

Ultra-sensitive detection of tumorigenic cellular impurities in human cell-processed therapeutic products by digital analysis of soft agar colony formation.

PubMed

Kusakawa, Shinji; Yasuda, Satoshi; Kuroda, Takuya; Kawamata, Shin; Sato, Yoji

2015-12-08

Contamination with tumorigenic cellular impurities is one of the most pressing concerns for human cell-processed therapeutic products (hCTPs). The soft agar colony formation (SACF) assay, which is a well-known in vitro assay for the detection of malignant transformed cells, is applicable for the quality assessment of hCTPs. Here we established an image-based screening system for the SACF assay using a high-content cell analyzer termed the digital SACF assay. Dual fluorescence staining of formed colonies and the dissolution of soft agar led to accurate detection of transformed cells with the imaging cytometer. Partitioning a cell sample into multiple wells of culture plates enabled digital readout of the presence of colonies and elevated the sensitivity for their detection. In practice, the digital SACF assay detected impurity levels as low as 0.00001% of the hCTPs, i.e. only one HeLa cell contained in 10,000,000 human mesenchymal stem cells, within 30 days. The digital SACF assay saves time, is more sensitive than in vivo tumorigenicity tests, and would be useful for the quality control of hCTPs in the manufacturing process.

Ultra-sensitive detection of tumorigenic cellular impurities in human cell-processed therapeutic products by digital analysis of soft agar colony formation

PubMed Central

Kusakawa, Shinji; Yasuda, Satoshi; Kuroda, Takuya; Kawamata, Shin; Sato, Yoji

2015-01-01

Contamination with tumorigenic cellular impurities is one of the most pressing concerns for human cell-processed therapeutic products (hCTPs). The soft agar colony formation (SACF) assay, which is a well-known in vitro assay for the detection of malignant transformed cells, is applicable for the quality assessment of hCTPs. Here we established an image-based screening system for the SACF assay using a high-content cell analyzer termed the digital SACF assay. Dual fluorescence staining of formed colonies and the dissolution of soft agar led to accurate detection of transformed cells with the imaging cytometer. Partitioning a cell sample into multiple wells of culture plates enabled digital readout of the presence of colonies and elevated the sensitivity for their detection. In practice, the digital SACF assay detected impurity levels as low as 0.00001% of the hCTPs, i.e. only one HeLa cell contained in 10,000,000 human mesenchymal stem cells, within 30 days. The digital SACF assay saves time, is more sensitive than in vivo tumorigenicity tests, and would be useful for the quality control of hCTPs in the manufacturing process. PMID:26644244

Epigenetic Disregulation in Oral Cancer

PubMed Central

Mascolo, Massimo; Siano, Maria; Ilardi, Gennaro; Russo, Daniela; Merolla, Francesco; De Rosa, Gaetano; Staibano, Stefania

2012-01-01

Squamous cell carcinoma of the oral region (OSCC) is one of the most common and highly aggressive malignancies worldwide, despite the fact that significant results have been achieved during the last decades in its detection, prevention and treatment. Although many efforts have been made to define the molecular signatures that identify the clinical outcome of oral cancers, OSCC still lacks reliable prognostic molecular markers. Scientific evidence indicates that transition from normal epithelium to pre-malignancy, and finally to oral carcinoma, depends on the accumulation of genetic and epigenetic alterations in a multistep process. Unlike genetic alterations, epigenetic changes are heritable and potentially reversible. The most common examples of such changes are DNA methylation, histone modification, and small non-coding RNAs. Although several epigenetic changes have been currently linked to OSCC initiation and progression, they have been only partially characterized. Over the last decade, it has been demonstrated that especially aberrant DNA methylation plays a critical role in oral cancer. The major goal of the present paper is to review the recent literature about the epigenetic modifications contribution in early and later phases of OSCC malignant transformation; in particular we point out the current evidence of epigenetic marks as novel markers for early diagnosis and prognosis as well as potential therapeutic targets in oral cancer. PMID:22408457

Natural history of large regenerative nodules and dysplastic nodules in liver cirrhosis: 28-year follow-up study.

PubMed

Sato, Tsunenobu; Kondo, Fukuo; Ebara, Masaaki; Sugiura, Nobuyuki; Okabe, Shinichiro; Sunaga, Masahiko; Yoshikawa, Masaharu; Suzuki, Eiichiro; Ogasawara, Sadayuki; Shinozaki, Yusuke; Ooka, Yoshihiko; Chiba, Tetsuhiro; Kanai, Fumihiko; Kishimoto, Takashi; Nakatani, Yukio; Fukusato, Toshio; Yokosuka, Osamu

2015-04-01

Some follow-up studies of large regenerative nodules (LRNs) and dysplastic nodules (DNs) were reported previously. However, the pre-malignant potentiality of LRNs has remained controversial up to now. No LRNs showed malignant transformation in our previous study. We aimed to evaluate the pre-malignant potentiality of LRNs and DNs with a greater number of cases and longer follow-up periods. From 1982 to 2005, 1,500 consecutive nodular lesions up to 2 cm in diameter were subjected to US guided thin-needle biopsy in cirrhotic patients at Chiba University Hospital. Of these lesions, 68 LRNs in 60 cases and 20 DNs in 22 cases were followed up for more than 6 months without any anti-cancer therapy. The last US examination was in 2010. The total study period was 28 years. We analyzed the histological findings and the clinical data of all cases retrospectively. The outcome of the lesions was examined. The mean follow-up period was 38.9 (16-119) months in LRNs and 31.9 (6-101 months) in DNs. Rate of nodule enlargement was higher in DNs (8/24 nodules, 33%) than LRNs (11/68 nodules, 16 %), (p = 0.0743, not significant). Rate of malignant transformation was also higher in DNs (10/24 nodules, 42%) than LRNs (9/68 nodules, 13%), (p = 0.0040, significant). The rate of disappearance in images was similar between LRNs and DNs. We should recognize LRN as low risk pre-malignant lesions whereas DNs as high risk lesions.

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

Spontaneous Transformation of Murine Epithelial Cells Requires the Early Acquisition of Specific Chromosomal Aneuploidies and Genomic Imbalances

PubMed Central

Padilla-Nash, Hesed M.; Hathcock, Karen; McNeil, Nicole E.; Mack, David; Hoeppner, Daniel; Ravin, Rea; Knutsen, Turid; Yonescu, Raluca; Wangsa, Danny; Dorritie, Kathleen; Barenboim, Linda; Hu, Yue; Ried, Thomas

2011-01-01

Human carcinomas are defined by recurrent chromosomal aneuploidies, which result in tissue-specific distribution of genomic imbalances. In order to develop models for these genome mutations and determine their role in tumorigenesis, we generated 45 spontaneously transformed murine cell lines from normal epithelial cells derived from bladder, cervix, colon, kidney, lung, and mammary gland. Phenotypic changes, chromosomal aberrations, centrosome number, and telomerase activity were assayed in control uncultured cells and in three subsequent stages of transformation. Supernumerary centrosomes, bi-nucleate cells, and tetraploidy were observed as early as 48 hr after explantation. In addition, telomerase activity increased throughout progression. Live-cell imaging revealed that failure of cytokinesis, not cell fusion, promoted genome duplication. Spectral karyotyping demonstrated that aneuploidy preceded immortalization, consisting predominantly of whole chromosome losses (4, 9, 12, 13, 16, and Y) and gains (1, 10, 15, and 19). After transformation, focal amplifications of the oncogenes Myc and Mdm2 were frequently detected. Fifty percent of the transformed lines resulted in tumors upon injection into immuno-compromised mice. The phenotypic and genomic alterations observed in spontaneously transformed murine epithelial cells recapitulated the aberration pattern observed during human carcinogenesis. The dominant aberration of these cell lines was the presence of specific chromosomal aneuploidies. We propose that our newly derived cancer models will be useful tools to dissect the sequential steps of genome mutations during malignant transformation, and also to identify cancer-specific genes, signaling pathways, and the role of chromosomal instability in this process. PMID:22161874

Enhanced malignant transformation is accompanied by increased survival recovery after ionizing radiation in Chinese hamster embryo fibroblasts

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

Boothman, D.A.

Transformed Chinese hamster embryo fibroblasts (CHEF), which gradually increase in tumor-forming ability in nude mice, were isolated from normal diploid CHEF/18 cells. Transformed CHEF cells (i.e., T30-4 > 21-2M3 > 21-2 > normal CHEF/18) showed gradual increases in potentially lethal damage (PLD) survival recovery. {beta}-Lapachone and camptothecin, modulators of topoisomerase I (Topo I) activity, not only prevented survival recovery in normal as well as in tumor cells, but enhanced unscheduled DNA synthesis. These seemingly conflicting results are due to the fact that Topo I activity can be modulated by inhibitors to convert single-stranded DNA lesions into double-stranded breaks. Increases inmore » unscheduled DNA synthesis may result from a continual supply of free ends, on which DNA repair processes may act. Altering Topo I activity with modulators appears to increase X-ray lethality via a DNA lesion modification suicide pathway. Cells down-regulate Topo I immediately after ionizing radiation to prevent Topo I-mediated lesion modification and to enhance survival recovery. 16 refs., 3 figs., 1 tab.« less

p53 on the crossroad between regeneration and cancer.

PubMed

Charni, Meital; Aloni-Grinstein, Ronit; Molchadsky, Alina; Rotter, Varda

2017-01-01

Regeneration and tumorigenesis share common molecular pathways, nevertheless the outcome of regeneration is life, whereas tumorigenesis leads to death. Although the process of regeneration is strictly controlled, malignant transformation is unrestrained. In this review, we discuss the involvement of TP53, the major tumor-suppressor gene, in the regeneration process. We point to the role of p53 as coordinator assuring that regeneration will not shift to carcinogenesis. The fluctuation in p53 activity during the regeneration process permits a tight control. On one hand, its inhibition at the initial stages allows massive proliferation, on the other its induction at advanced steps of regeneration is essential for preservation of robustness and fidelity of the regeneration process. A better understanding of the role of p53 in regulation of regeneration may open new opportunities for implementation of TP53-based therapies, currently available for cancer patients, in regenerative medicine.

Improving the Diagnostic Specificity of CT for Early Detection of Lung Cancer: 4D CT-Based Pulmonary Nodule Elastometry

DTIC Science & Technology

2015-10-01

2012, patients who received stereotactic ablative radiotherapy ( SABR ) for early stage non-small cell lung cancer were included in this study. All...comparing the elasticities of malignant PNs treated with stereotactic ablative radiotherapy ( SABR ) with those of the lung. Methods: We analyzed...breath-hold images of 30 patients with malignant PNs who underwent SABR in our department. A parametric nonrigid transformation model based on multi

Polyostotic fibrous dysplasia with gigantism and huge pelvic tumor: a rare case of McCune-Albright syndrome.

PubMed

Sakayama, Kenshi; Sugawara, Yoshifumi; Kidani, Teruki; Fujibuchi, Taketsugu; Kito, Katsumi; Tanji, Nozomu; Nakamura, Atsushi

2011-06-01

We report a rare case of polyostotic fibrous dysplasia on endocrine hyperfunction with elevated human growth hormone and normal serum level of prolactin. There were some differential points of gender, gigantism, endocrine function, and GNAS gene from McCune-Albright syndrome. Malignant transformation was suspected in the pelvic tumor from imaging because rapid growth of the tumor by imaging was observed; however, no malignant change occurred in this case.

Piwil2 is reactivated by HPV oncoproteins and initiates cell reprogramming via epigenetic regulation during cervical cancer tumorigenesis.

PubMed

Feng, Dingqing; Yan, Keqin; Zhou, Ying; Liang, Haiyan; Liang, Jing; Zhao, Weidong; Dong, Zhongjun; Ling, Bin

2016-10-04

The human papillomavirus (HPV) oncoproteins E6 and E7 are risk factors that are primarily responsible for the initiation and progression of cervical cancer, and they play a key role in immortalization and transformation by reprogramming differentiating host epithelial cells. It is unclear how cervical epithelial cells transform into tumor-initiating cells (TICs). Here, we observed that the germ stem cell protein Piwil2 is expressed in pre-cancerous and malignant lesions of the cervix and cervical cancer cell lines with the exception of the non-HPV-infected C33a cell line. Knockdown of Piwil2 by shRNA led to a marked reduction in proliferation and colony formation, in vivo tumorigenicity, chemo-resistance, and the proportion of cancer stem-like cells. In contrast, Piwil2 overexpression induced malignant transformation of HaCaT cells and the acquisition of tumor-initiating capabilities. Gene-set enrichment analysis revealed embryonic stem cell (ESC) identity, malignant biological behavior, and specifically, activation targets of the cell reprogramming factors c-Myc, Klf4, Nanog, Oct4, and Sox2 in Piwil2-overexpressing HaCaT cells. We further confirmed that E6 and E7 reactivated Piwil2 and that E6 and E7 overexpression resulted in a similar gene-set enrichment pattern as Piwil2 overexpression in HaCaT cells. Moreover, Piwil2 overexpression or E6 and E7 activation induced H3K9 acetylation but reduced H3K9 trimethylation, which contributed to the epigenetic reprogramming and ESC signature maintenance, as predicted previously. Our study demonstrates that Piwil2, reactivated by the HPV oncoproteins E6 and E7, plays an essential role in the transformation of cervical epithelial cells to TICs via epigenetics-based cell reprogramming.

A proangiogenic signaling axis in myeloid cells promotes malignant progression of glioma.

PubMed

Huang, Yujie; Rajappa, Prajwal; Hu, Wenhuo; Hoffman, Caitlin; Cisse, Babacar; Kim, Joon-Hyung; Gorge, Emilie; Yanowitch, Rachel; Cope, William; Vartanian, Emma; Xu, Raymond; Zhang, Tuo; Pisapia, David; Xiang, Jenny; Huse, Jason; Matei, Irina; Peinado, Hector; Bromberg, Jacqueline; Holland, Eric; Ding, Bi-Sen; Rafii, Shahin; Lyden, David; Greenfield, Jeffrey

2017-05-01

Tumors are capable of coopting hematopoietic cells to create a suitable microenvironment to support malignant growth. Here, we have demonstrated that upregulation of kinase insert domain receptor (KDR), also known as VEGFR2, in a myeloid cell sublineage is necessary for malignant progression of gliomas in transgenic murine models and is associated with high-grade tumors in patients. KDR expression increased in myeloid cells as myeloid-derived suppressor cells (MDSCs) accumulated, which was associated with the transformation and progression of low-grade fibrillary astrocytoma to high-grade anaplastic gliomas. KDR deficiency in murine BM-derived cells (BMDCs) suppressed the differentiation of myeloid lineages and reduced granulocytic/monocytic populations. The depletion of myeloid-derived KDR compromised its proangiogenic function, which inhibited the angiogenic switch necessary for malignant progression of low-grade to high-grade tumors. We also identified inhibitor of DNA binding protein 2 (ID2) as a key upstream regulator of KDR activation during myeloid differentiation. Deficiency of ID2 in BMDCs led to downregulation of KDR, suppression of proangiogenic myeloid cells, and prevention of low-grade to high-grade transition. Tumor-secreted TGF-β and granulocyte-macrophage CSF (GM-CSF) enhanced the KDR/ID2 signaling axis in BMDCs. Our results suggest that modulation of KDR/ID2 signaling may restrict tumor-associated myeloid cells and could potentially be a therapeutic strategy for preventing transformation of premalignant gliomas.

A proangiogenic signaling axis in myeloid cells promotes malignant progression of glioma

PubMed Central

Huang, Yujie; Rajappa, Prajwal; Hu, Wenhuo; Hoffman, Caitlin; Cisse, Babacar; Kim, Joon-Hyung; Gorge, Emilie; Yanowitch, Rachel; Cope, William; Vartanian, Emma; Xu, Raymond; Pisapia, David; Xiang, Jenny; Huse, Jason; Matei, Irina; Peinado, Hector; Bromberg, Jacqueline; Holland, Eric; Ding, Bi-sen; Rafii, Shahin; Lyden, David; Greenfield, Jeffrey

2017-01-01

Tumors are capable of coopting hematopoietic cells to create a suitable microenvironment to support malignant growth. Here, we have demonstrated that upregulation of kinase insert domain receptor (KDR), also known as VEGFR2, in a myeloid cell sublineage is necessary for malignant progression of gliomas in transgenic murine models and is associated with high-grade tumors in patients. KDR expression increased in myeloid cells as myeloid-derived suppressor cells (MDSCs) accumulated, which was associated with the transformation and progression of low-grade fibrillary astrocytoma to high-grade anaplastic gliomas. KDR deficiency in murine BM-derived cells (BMDCs) suppressed the differentiation of myeloid lineages and reduced granulocytic/monocytic populations. The depletion of myeloid-derived KDR compromised its proangiogenic function, which inhibited the angiogenic switch necessary for malignant progression of low-grade to high-grade tumors. We also identified inhibitor of DNA binding protein 2 (ID2) as a key upstream regulator of KDR activation during myeloid differentiation. Deficiency of ID2 in BMDCs led to downregulation of KDR, suppression of proangiogenic myeloid cells, and prevention of low-grade to high-grade transition. Tumor-secreted TGF-β and granulocyte-macrophage CSF (GM-CSF) enhanced the KDR/ID2 signaling axis in BMDCs. Our results suggest that modulation of KDR/ID2 signaling may restrict tumor-associated myeloid cells and could potentially be a therapeutic strategy for preventing transformation of premalignant gliomas. PMID:28394259

Immunohistochemical Expression Of Ezrin In Oral Potentially Malignant Disorders-A Descriptive Study.

PubMed

Mohanraj, Raghini; Ramani, Pratibha; Premkumar, Priya; Natesan, Anuja; Sherlin, Herald J; Sukumaran, Gheena

2017-11-01

Ezrin, also known as cytovillin, is a member of the ERM family of protein. Ezrin cross-links actin filament with the plasma membrane. They are involved in the formation of microvilli, cell-cell adhesion, maintenance of cell shape, cell motility, and membrane trafficking. Recent analysis reveals their involvement in signaling pathways. Ezrin is highly expressed in several types of human cancers, and correlation between its immunoreactivity and histopathological data as well as the patient outcome has previously been studied. The objective of the study was to analyze the immunohistochemical expression pattern of ezrin in oral potentially malignant disorders (OPMDs), namely, oral submucous fibrosis (OSMF) with different grades and clinically leucoplakia (hyperkeratosis with various degree of dysplasia) and its use as a predictive marker for malignant transformation. Sample size n = 43, histopathologically confirmed cases of OPMDs (13 cases of OSMF with different grades and 30 cases of clinically leukoplakia) were retrieved from the Department of Oral and Maxillofacial Pathology. Immunohistochemistry was done using anti-ezrin antibody, and the expression was graded in terms of proportion and intensity. There was a significant expression of ezrin in OPMDs, and its cytoplasmic shift can be used as a predictive marker for malignant transformation. The findings of the current study revealed that the expression of ezrin in OPMDs may be related to the progression of the disease.

Luteolin inhibits Cr(VI)-induced malignant cell transformation of human lung epithelial cells by targeting ROS mediated multiple cell signaling pathways

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

Pratheeshkumar, Poyil; Son, Young-Ok; Divya, Sasidharan Padmaja

Hexavalent chromium [Cr(VI)] is a well-known human carcinogen associated with the incidence of lung cancer. Inhibition of metal induced carcinogenesis by a dietary antioxidant is a novel approach. Luteolin, a natural dietary flavonoid found in fruits and vegetables, possesses potent antioxidant and anti-inflammatory activity. We found that short term exposure of human bronchial epithelial cells (BEAS-2B) to Cr(VI) (5 μM) showed a drastic increase in ROS generation, NADPH oxidase (NOX) activation, lipid peroxidation, and glutathione depletion, which were significantly inhibited by the treatment with luteolin in a dose dependent manner. Treatment with luteolin decreased AP-1, HIF-1α, COX-2, and iNOS promotermore » activity induced by Cr(VI) in BEAS-2B cells. In addition, luteolin protected BEAS-2B cells from malignant transformation induced by chronic Cr(VI) exposure. Moreover, luteolin also inhibited the production of pro-inflammatory cytokines (IL-1β, IL-6, IL-8, TNF-α) and VEGF in chronic Cr(VI) exposed BEAS-2B cells. Western blot analysis showed that luteolin inhibited multiple gene products linked to survival (Akt, Fak, Bcl-2, Bcl-xL), inflammation (MAPK, NF-κB, COX-2, STAT-3, iNOS, TNF-α) and angiogenesis (HIF-1α, VEGF, MMP-9) in chronic Cr(VI) exposed BEAS-2B cells. Nude mice injected with BEAS-2B cells chronically exposed to Cr(VI) in the presence of luteolin showed reduced tumor incidence compared to Cr(VI) alone treated group. Overexpression of catalase (CAT) or SOD2, eliminated Cr(VI)-induced malignant transformation. Overall, our results indicate that luteolin protects BEAS-2B cells from Cr(VI)-induced carcinogenesis by scavenging ROS and modulating multiple cell signaling mechanisms that are linked to ROS. Luteolin, therefore, serves as a potential chemopreventive agent against Cr(VI)-induced carcinogenesis. - Highlights: • Luteolin inhibited Cr(VI)-induced oxidative stress. • Luteolin inhibited chronic Cr(VI)-induced malignant transformation. • Luteolin inhibited chronic Cr(VI)-induced inflammation. • Luteolin inhibited chronic Cr(VI)-induced angiogenesis.« less

Autofluorescence endoscopy with "real-time" digital image processing in differential diagnostics of selected benign and malignant lesions in the oesophagus.

PubMed

Sieroń-Stołtny, Karolina; Kwiatek, Sebastian; Latos, Wojciech; Kawczyk-Krupka, Aleksandra; Cieślar, Grzegorz; Stanek, Agata; Ziaja, Damian; Bugaj, Andrzej M; Sieroń, Aleksander

2012-03-01

Oesophageal papilloma and Barrett's oesophagus are benign lesions known as risk factors of carcinoma in the oesophagus. Therefore, it is important to diagnose these early changes before neoplastic transformation. Autofluorescence endoscopy is a fast and non-invasive method of imaging of tissues based on the natural fluorescence of endogenous fluorophores. The aim of this study was to prove the diagnostic utility of autofluorescence endoscopy with digital image processing in histological diagnosis of endoscopic findings in the upper digestive tract, primarily in the imaging of oesophageal papilloma. During the retrospective analysis of about 200 endoscopic procedures in the upper digestive tract, 67 cases of benign, precancerous or cancerous changes were found. White light endoscopy (WLE) image, single-channel (red or green) autofluorescence images, as well as green and red fluorescence intensities in two modal fluorescence image and red-to-green (R/G) ratio (Numerical Colour Value, NCV) were correlated with histopathologic results. The NCV analysis in autofluorescence imaging (AFI) showed increased R/G ratio in cancerous changes in 96% vs. 85% in WLE. Simultaneous analysis with digital image processing allowed us to diagnose suspicious tissue as cancerous in all of cases. Barrett's metaplasia was confirmed in 90% vs. 79% (AFI vs. WLE), and 98% in imaging with digital image processing. In benign lesions, WLE allowed us to exclude tissue as malignant in 85%. Using autofluorescence endoscopy R/G ratio was increased in only 10% of benign changes causing the picture to be interpreted as suspicious, but when both methods were used together, 97.5% were cases excluded as malignancies. Mean R/G ratios were estimated to be 2.5 in cancers, 1.25 in Barrett's metaplasia and 0.75 in benign changes and were statistically significant (p=0.04). Autofluorescence imaging is a sensitive method to diagnose precancerous and cancerous early stages of the diseases located in oesophagus. Especially in two-modal imaging including white light endoscopy, autofluorescence imaging with digital image processing seems to be a useful modality of early diagnostics. Also in observation of papilloma changes, it facilitates differentiation between neoplastic and benign lesions and more accurate estimation of the risk of potential malignancy. Copyright © 2011 Elsevier B.V. All rights reserved.

Nonpigmented Metastatic Melanoma in a Two-Year-Old Girl: A Serious Diagnostic Dilemma

PubMed Central

Diniz, Gulden; Tosun Yildirim, Hulya; Yamaci, Selcen

2015-01-01

Although rare, malignant melanoma may occur in children. Childhood melanomas account for only 0.3–3% of all melanomas. In particular the presence of congenital melanocytic nevi is associated with an increased risk of development of melanoma. We herein report a case of malignant melanoma that developed on a giant congenital melanocytic nevus and made a metastasis to the subcutaneous tissue of neck in a two-year-old girl. The patient was hospitalized for differential diagnosis and treatment of cervical mass with a suspicion of hematological malignancy, because the malignant transformation of congenital nevus was not noticed before. In this case, we found out a nonpigmented malignant tumor of pleomorphic cells after the microscopic examination of subcutaneous lesion. Nonpigmented metastatic melanoma was diagnosed by several immunohistochemical and flow cytometric studies. She was offered palliative chemotherapy; however, her parents did not accept treatment. The patient died within 9 months of diagnosis. We emphasized here that the possibility of malignant melanoma in the differential diagnosis of childhood tumors should be kept in mind. PMID:25763285

FOXM1 upregulation is an early event in human squamous cell carcinoma and it is enhanced by nicotine during malignant transformation.

PubMed

Gemenetzidis, Emilios; Bose, Amrita; Riaz, Adeel M; Chaplin, Tracy; Young, Bryan D; Ali, Muhammad; Sugden, David; Thurlow, Johanna K; Cheong, Sok-Ching; Teo, Soo-Hwang; Wan, Hong; Waseem, Ahmad; Parkinson, Eric K; Fortune, Farida; Teh, Muy-Teck

2009-01-01

Cancer associated with smoking and drinking remains a serious health problem worldwide. The survival of patients is very poor due to the lack of effective early biomarkers. FOXM1 overexpression is linked to the majority of human cancers but its mechanism remains unclear in head and neck squamous cell carcinoma (HNSCC). FOXM1 mRNA and protein expressions were investigated in four independent cohorts (total 75 patients) consisting of normal, premalignant and HNSCC tissues and cells using quantitative PCR (qPCR), expression microarray, immunohistochemistry and immunocytochemistry. Effect of putative oral carcinogens on FOXM1 transcriptional activity was dose-dependently assayed and confirmed using a FOXM1-specific luciferase reporter system, qPCR, immunoblotting and short-hairpin RNA interference. Genome-wide single nucleotide polymorphism (SNP) array was used to 'trace' the genomic instability signature pattern in 8 clonal lines of FOXM1-induced malignant human oral keratinocytes. Furthermore, acute FOXM1 upregulation in primary oral keratinocytes directly induced genomic instability. We have shown for the first time that overexpression of FOXM1 precedes HNSCC malignancy. Screening putative carcinogens in human oral keratinocytes surprisingly showed that nicotine, which is not perceived to be a human carcinogen, directly induced FOXM1 mRNA, protein stabilisation and transcriptional activity at concentrations relevant to tobacco chewers. Importantly, nicotine also augmented FOXM1-induced transformation of human oral keratinocytes. A centrosomal protein CEP55 and a DNA helicase/putative stem cell marker HELLS, both located within a consensus loci (10q23), were found to be novel targets of FOXM1 and their expression correlated tightly with HNSCC progression. This study cautions the potential co-carcinogenic effect of nicotine in tobacco replacement therapies. We hypothesise that aberrant upregulation of FOXM1 may be inducing genomic instability through a program of malignant transformation involving the activation of CEP55 and HELLS which may facilitate aberrant mitosis and epigenetic modifications. Our finding that FOXM1 is upregulated early during oral cancer progression renders FOXM1 an attractive diagnostic biomarker for early cancer detection and its candidate mechanistic targets, CEP55 and HELLS, as indicators of malignant conversion and progression.

Decreased expression of endogenous feline leukemia virus in cat lymphomas: a case control study.

PubMed

Krunic, Milica; Ertl, Reinhard; Hagen, Benedikt; Sedlazeck, Fritz J; Hofmann-Lehmann, Regina; von Haeseler, Arndt; Klein, Dieter

2015-04-10

Cats infected with exogenous feline leukemia virus (exFeLV) have a higher chance of lymphoma development than uninfected cats. Furthermore, an increased exFeLV transcription has been detected in lymphomas compared to non-malignant tissues. The possible mechanisms of lymphoma development by exFeLV are insertional mutagenesis or persistent stimulation of host immune cells by viral antigens, bringing them at risk for malignant transformation. Vaccination of cats against exFeLV has in recent years decreased the overall infection rate in most countries. Nevertheless, an increasing number of lymphomas have been diagnosed among exFeLV-negative cats. Endogenous feline leukemia virus (enFeLV) is another retrovirus for which transcription has been observed in cat lymphomas. EnFeLV provirus elements are present in the germline of various cat species and share a high sequence similarity with exFeLV but, due to mutations, are incapable of producing infectious viral particles. However, recombination between exFeLV and enFeLV could produce infectious particles. We examined the FeLV expression in cats that have developed malignant lymphomas and discussed the possible mechanisms that could have induced malignant transformation. For expression analysis we used next-generation RNA-sequencing (RNA-Seq) and for validation reverse transcription quantitative PCR (RT-qPCR). First, we showed that there was no expression of exFeLV in all samples, which eliminates the possibility of recombination between exFeLV and enFeLV. Next, we analyzed the difference in expression of three enFeLV genes between control and lymphoma samples. Our analysis showed an average of 3.40-fold decreased viral expression for the three genes in lymphoma compared to control samples. The results were confirmed by RT-qPCR. There is a decreased expression of enFeLV genes in lymphomas versus control samples, which contradicts previous observations for the exFeLV. Our results suggest that a persistent stimulation of host immune cells is not an appropriate mechanism responsible for malignant transformation caused by feline endogenous retroviruses.

Giant melanocytic nevus with malignant melanoma: a rare disorder in a black African child.

PubMed

Katibi, Oludolapo Sherifat; Ogunbiyi, Adebola; Brown, Biobele Jotham; Adeyemi, Oyedeji Oladele

2014-10-01

Giant congenital melanocytic nevus (GCMN) is rare in babies of African descent. Unfortunately, it has an increased potential for malignant transformation. A 3-year-old female child presented with a 6-month history of multiple nodules on an existing giant congenital melanocytic nevus and swelling in the right axilla of four weeks duration. Skin biopsy of the nodular skin lesions was in keeping with a metastatic malignant melanoma (Clark stage 4). She completed a full course of chemotherapy but subsequently died four months after presentation. Patients with large GCMN should be counseled and followed up appropriately to improve and prolong life. © 2014 The International Society of Dermatology.

Epithelial to mesenchymal transition in arsenic-transformed cells promotes angiogenesis through activating β-catenin–vascular endothelial growth factor pathway

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

Wang, Zhishan; Humphries, Brock; Xiao, Hua

2013-08-15

Arsenic exposure represents a major health concern increasing cancer risks, yet the mechanism of arsenic carcinogenesis has not been elucidated. We and others recently reported that cell malignant transformation by arsenic is accompanied by epithelial to mesenchymal transition (EMT). However, the role of EMT in arsenic carcinogenesis is not well understood. Although previous studies showed that short term exposure of endothelial cells to arsenic stimulated angiogenesis, it remains to be determined whether cells that were malignantly transformed by long term arsenic exposure have a pro-angiogenic effect. The objective of this study was to investigate the effect of arsenic-transformed human bronchialmore » epithelial cells that underwent EMT on angiogenesis and the underlying mechanism. It was found that the conditioned medium from arsenic-transformed cells strongly stimulated tube formation by human umbilical vein endothelial cells (HUVECs). Moreover, enhanced angiogenesis was detected in mouse xenograft tumor tissues resulting from inoculation of arsenic-transformed cells. Mechanistic studies revealed that β-catenin was activated in arsenic-transformed cells up-regulating its target gene expression including angiogenic-stimulating vascular endothelial growth factor (VEGF). Stably expressing microRNA-200b in arsenic-transformed cells that reversed EMT inhibited β-catenin activation, decreased VEGF expression and reduced tube formation by HUVECs. SiRNA knockdown β-catenin decreased VEGF expression. Adding a VEGF neutralizing antibody into the conditioned medium from arsenic-transformed cells impaired tube formation by HUVECs. Reverse transcriptase-PCR analysis revealed that the mRNA levels of canonical Wnt ligands were not increased in arsenic-transformed cells. These findings suggest that EMT in arsenic-transformed cells promotes angiogenesis through activating β-catenin–VEGF pathway. - Highlights: • Arsenic-transformed cells that underwent EMT displayed a pro-angiogenic effect. • EMT in arsenic-transformed cells activates β-catenin. • β-Catenin activation increases VEGF expression in arsenic-transformed cells. • β-Catenin activation is likely independent of canonical Wnt signaling. • EMT in arsenic-transformed cells promotes angiogenesis via β-catenin–VEGF pathway.« less

Use of iodine 131I-tositumomab radioimmunotherapy in a patient with Waldenstrom's macroglobulinemia.

PubMed

Tsai, Donald E; Maillard, Ivan; Downs, Lisa H; Alavi, Abass; Nasta, Sunita D; Glatstein, Eli; Schuster, Stephen J

2004-03-01

Waldenstrom's macroglobulinemia is an indolent B-cell malignancy that is characterized by high levels of IgM paraprotein production and is incurable with standard chemotherapy. Iodine 131I-Tositumomab (iodine-131-labeled murine anti-CD20 monoclonal antibody; Bexxar) is a novel radioimmunotherapeutic agent that has a high response rate in relapsed or chemotherapy refractory, CD20-positive, low grade or transformed B-cell non-Hodgkin's lymphomas. There are no data on the use of radioimmunotherapy in Waldenstrom's macroglobulinemia. We report a patient with Waldenstrom's macroglobulinemia with transformation to a large B-cell lymphoma, who was treated successfully with iodine 131I-tositumomab. The patient had a complete response to the treatment, including disappearance of any detectable IgM paraprotein. This case report demonstrates the potential for radioimmunotherapy in CD20 positive B-cell malignancies.

Review of the gastrointestinal tract: from macro to micro.

PubMed

Reed, Kathleen K; Wickham, Rita

2009-02-01

To review the normal anatomy and physiology of the gastrointestinal (GI) tract, the malignant transformations in GI cancers, and the rationale for targeted therapy for these cancers. Published articles, book chapters and web sources. Oncology nurses require an understanding of normal GI anatomy and physiology, along with an understanding of malignant transformations at the cellular and molecular level, to effectively educate and care for the patient with a diagnosis of a GI cancer. Challenges for the oncology nurse include continuing education related to GI cancer, the development of effective patient education skills, ensuring safe administration of oral agents and remaining current regarding GI clinical trial opportunities. Education of nursing colleagues, development of an area of expertise through specialization, and development of leadership skills are opportunities associated with practicing in the dynamic environment of oncology nursing.

Wound Healing and Cancer Stem Cells: Inflammation as a Driver of Treatment Resistance in Breast Cancer

PubMed Central

Arnold, Kimberly M; Opdenaker, Lynn M; Flynn, Daniel; Sims-Mourtada, Jennifer

2015-01-01

The relationship between wound healing and cancer has long been recognized. The mechanisms that regulate wound healing have been shown to promote transformation and growth of malignant cells. In addition, chronic inflammation has been associated with malignant transformation in many tissues. Recently, pathways involved in inflammation and wound healing have been reported to enhance cancer stem cell (CSC) populations. These cells, which are highly resistant to current treatments, are capable of repopulating the tumor after treatment, causing local and systemic recurrences. In this review, we highlight proinflammatory cytokines and developmental pathways involved in tissue repair, whose deregulation in the tumor microenvironment may promote growth and survival of CSCs. We propose that the addition of anti-inflammatory agents to current treatment regimens may slow the growth of CSCs and improve therapeutic outcomes. PMID:25674014

Endometrioid Adenocarcinoma of Caecum Causing Intussusception

PubMed Central

Verma, Rashmi; Osborn, Sally; Horgan, Kieran

2013-01-01

Malignant transformation of endometriosis is rare and is usually seen in ovarian endometriosis. The colon and rectum are the most common sites for extragonadal endometriosis, and although serosal involvement is commonly seen, mucosal involvement is rare. Malignant transformation of endometriosis is a rare but a well-known complication of endometriosis. We report an unusual presentation of endometrioid adenocarcinoma with lymph node metastasis, arising from endometriosis in the caecal wall and causing ileocaecal intussusception. The patient presented with sudden onset of abdominal pain with features suggestive of acute appendicitis. Diagnostic laparoscopy revealed an ileocaecal intussusception. Conversion to open surgery confirmed a caecal mass causing ileocaecal intussusception, and a radical right hemicolectomy was performed. Histology revealed endometrioid adenocarcinoma arising in a focus of endometriosis in the muscularis propria and involving the mucosa, with one regional metastatic lymph node. PMID:23710407

Oral lichen planus (OLP), oral lichenoid lesions (OLL), oral dysplasia, and oral cancer: retrospective analysis of clinicopathological data from 2002-2011.

PubMed

Casparis, S; Borm, J M; Tektas, S; Kamarachev, J; Locher, M C; Damerau, G; Grätz, K W; Stadlinger, B

2015-06-01

This 10-year retrospective study analyzed the incidence of malignant transformation of oral lichen planus (OLP). The study also included dysplasia and oral lichenoid lesion (OLL) in the initial biopsy as a potential differential diagnosis. A total of 692 scalpel biopsies were taken from 542 patients (207 [38.2%] men and 335 [61.8%] women). Clinical and histopathological parameters were analyzed. The parameters gender (p = 0.022) and smoking behavior (p < 0.001) were significantly associated with the severity of diagnosis. Mucosal lesions with an ulcerative appearance (p = 0.006) and those located on the floor of the mouth (p < 0.001) showed significantly higher degrees of dysplasia or were diagnosed as oral squamous cell carcinoma (OSCC). Smoking and joint disease appeared to be significant risk factors. Treatment with tretinoin in different concentrations (0.005-0.02%) significantly improved diagnosis. Twelve patients (8 female, 4 male) showed malignant transformation to OSCC within an average period of 1.58 years. The malignant transformation rate (MTR) was higher for OLL (4.4%) than OLP (1.2%). If the first biopsy showed intraepithelial neoplasia, the risk of developing OSCC increased (by 3.5% for squamous intraepithelial neoplasia (SIN) II and by 6.7% for SIN III). Although we cannot rule out that OLP is a premalignant oral condition, we can confirm that OLP had the lowest MTR of all diagnoses.

European experience of 573 liver resections for hepatocellular adenoma: a cross-sectional study by the AFC-HCA-2013 study group.

PubMed

Laurent, Alexis; Dokmak, Safi; Nault, Jean-Charles; Pruvot, François-René; Fabre, Jean-Michel; Letoublon, Christian; Bachellier, Philippe; Capussotti, Lorenzo; Farges, Olivier; Mabrut, Jean-Yves; Le Treut, Yves-Patrice; Ayav, Ahmet; Suc, Bertrand; Soubrane, Olivier; Mentha, Gilles; Popescu, Irinel; Montorsi, Marco; Demartines, Nicolas; Belghiti, Jacques; Torzilli, Guido; Cherqui, Daniel; Hardwigsen, Jean

2016-09-01

Hepatocellular adenoma (HCA) is a benign hepatic lesion that may be complicated by bleeding and malignant transformation. The aim of the present study is to report on large series of liver resections for HCA and assess the incidence of hemorrhage and malignant transformation. A retrospective cross-sectional study, from 27 European high-volume HPB units. 573 patients were analyzed. The female: male gender ratio was 8:2, mean age: 37 ± 10 years. Of the 84 (14%) patients whose initial presentation was hemorrhagic shock (Hemorrhagic HCAs), hemostatic intervention was urgently required in 25 (30%) patients. No patients died after intervention. Tumor size was >5 cm in 74% in hemorrhagic HCAs and 64% in non-hemorrhagic HCAs (p < 0.001). In non-hemorrhagic HCAs (n = 489), 5% presented with malignant transformation. Male status and tumor size >10 cm were the two predictive factors. Liver resections included major hepatectomy in 25% and a laparoscopic approach in 37% of the patients. In non-hemorrhagic HCAs, there was no mortality and major complications occurred in 9% of patients. Liver resection for HCA is safe. Presentation with hemorrhage was associated with larger tumor size. In males with a HCA >10 cm, a HCC should be suspected. In such situation, a preoperative biopsy is preferable and an oncological liver resection should be considered. Copyright © 2016 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.

Spatial Moran models, II: cancer initiation in spatially structured tissue

PubMed Central

Foo, J; Leder, K

2016-01-01

We study the accumulation and spread of advantageous mutations in a spatial stochastic model of cancer initiation on a lattice. The parameters of this general model can be tuned to study a variety of cancer types and genetic progression pathways. This investigation contributes to an understanding of how the selective advantage of cancer cells together with the rates of mutations driving cancer, impact the process and timing of carcinogenesis. These results can be used to give insights into tumor heterogeneity and the “cancer field effect,” the observation that a malignancy is often surrounded by cells that have undergone premalignant transformation. PMID:26126947

Spectropolarimetry features of biotissue's malignant changes

NASA Astrophysics Data System (ADS)

Gruia, I.; Yermolenko, S. B.; Gavrila, C.; Ivashko, P. V.; Gruia, M. I.

2010-11-01

This paper follows to combine optical and biochemical techniques for identification the cell membrane transformation in the dynamic of growth and development of experimental solid tumour. It is researched that in all the cases the linear dichroism appears in biotissues (the human esophagus, the muscle tissue of rats, prostate tissue) with the cancer disease the magnitude of which depends on the type of the tissue and on the time of the cancer process development. As the linear dichroism is lacking for healthy tissues, then the obtained results can have diagnostic values with the purpose of detection and estimation of the stage of the cancer disease development.

Improving the Diagnostic Specificity of CT for Early Detection of Lung Cancer: 4D CT-Based Pulmonary Nodule Elastometry

DTIC Science & Technology

2015-10-01

malignant PNs treated with stereotactic ablative radiotherapy ( SABR ) with those of the lung. Methods: We analyzed breath-hold images of 30...patients with malignant PNs who underwent SABR in our department. A parametric nonrigid transformation model based on multi-level B-spline guided by Sum of...and 50 of 4D CT and deep inhale and natural exhale of breath-hold CT images of 30 MPN treated with stereotactic ablative radiotherapy ( SABR ). The

Longitudinal investigation of permeability and distribution of macromolecules in mouse malignant transformation using PET.

PubMed

Rygh, Cecilie B; Qin, Shengping; Seo, Jai W; Mahakian, Lisa M; Zhang, Hua; Adamson, Roger; Chen, Jane Q; Borowsky, Alexander D; Cardiff, Robert D; Reed, Rolf K; Curry, Fitz-Roy E; Ferrara, Katherine W

2011-02-01

We apply positron emission tomography (PET) to elucidate changes in nanocarrier extravasation during the transition from premalignant to malignant cancer, providing insight into the use of imaging to characterize early cancerous lesions and the utility of nanoparticles in early disease. Albumin and liposomes were labeled with (64)Cu (half-life 12.7 hours), and longitudinal PET and CT imaging studies were conducted in a mouse model of ductal carcinoma in situ. A pharmacokinetic model was applied to estimate the tumor vascular volume and permeability. From early time points characterized by disseminated hyperproliferation, the enhanced vascular permeability facilitated lesion detection. During disease progression, the vascular volume fraction increased 1.6-fold and the apparent vascular permeability to albumin and liposomes increased ∼2.5-fold to 6.6 × 10(-8) and 1.3 × 10(-8) cm/s, respectively, with the accumulation of albumin increasing earlier in the disease process. In the malignant tumor, both tracers reached similar mean intratumoral concentrations of ∼6% ID/cc but the distribution of liposomes was more heterogeneous, ranging from 1% to 18% ID/cc compared with 1% to 9% ID/cc for albumin. The tumor-to-muscle ratio was 17.9 ± 8.1 and 7.1 ± 0.5 for liposomes and albumin, respectively, indicating a more specific delivery of liposomes than with albumin. PET imaging of radiolabeled particles, validated by confocal imaging and histology, detected the transition from premalignant to malignant lesions and effectively quantified the associated changes in vascular permeability. ©2010 AACR.

Therapy targets in glioblastoma and cancer stem cells: lessons from haematopoietic neoplasms

PubMed Central

Cruceru, Maria Linda; Neagu, Monica; Demoulin, Jean-Baptiste; Constantinescu, Stefan N

2013-01-01

Despite intense efforts to identify cancer-initiating cells in malignant brain tumours, markers linked to the function of these cells have only very recently begun to be uncovered. The notion of cancer stem cell gained prominence, several molecules and signalling pathways becoming relevant for diagnosis and treatment. Whether a substantial fraction or only a tiny minority of cells in a tumor can initiate and perpetuate cancer, is still debated. The paradigm of cancer-initiating stem cells has initially been developed with respect to blood cancers where chronic conditions such as myeloproliferative neoplasms are due to mutations acquired in a haematopoietic stem cell (HSC), which maintains the normal hierarchy to neoplastic haematopoiesis. In contrast, acute leukaemia transformation of such blood neoplasms appears to derive not only from HSCs but also from committed progenitors that cannot differentiate. This review will focus on putative novel therapy targets represented by markers described to define cancer stem/initiating cells in malignant gliomas, which have been called ‘leukaemia of the brain’, given their rapid migration and evolution. Parallels are drawn with other cancers, especially haematopoietic, given the similar rampant proliferation and treatment resistance of glioblastoma multiforme and secondary acute leukaemias. Genes associated with the malignant conditions and especially expressed in glioma cancer stem cells are intensively searched. Although many such molecules might only coincidentally be expressed in cancer-initiating cells, some may function in the oncogenic process, and those would be the prime candidates for diagnostic and targeted therapy. For the latter, combination therapies are likely to be envisaged, given the robust and plastic signalling networks supporting malignant proliferation. PMID:23998913

Ovarian Cancer Is an Imported Disease: Fact or Fiction?

PubMed Central

Kuhn, Elisabetta; Kurman, Robert J.

2012-01-01

The cell of origin of ovarian cancer has been long debated. The current paradigm is that epithelial ovarian cancer (EOC) arises from the ovarian surface epithelium (OSE). OSE is composed of flat, nondescript cells more closely resembling the mesothelium lining the peritoneal cavity, with which it is continuous, rather than the various histologic types of ovarian carcinoma (serous, endometrioid, and clear cell carcinoma), which have a Müllerian phenotype. Accordingly, it has been argued that the OSE undergoes a process termed “metaplasia” to account for this profound morphologic transformation. Recent molecular and clinicopathologic studies not only have failed to support this hypothesis but also have provided evidence that EOC stems from Müllerian-derived extraovarian cells that involve the ovary secondarily, thereby calling into question the very existence of primary EOC. This new model of ovarian carcinogenesis proposes that fallopian tube epithelium (benign or malignant) implants on the ovary to give rise to both high-grade and low-grade serous carcinomas, and that endometrial tissue implants on the ovary and produces endometriosis, which can undergo malignant transformation into endometrioid and clear cell carcinoma. Thus, ultimately EOC is not ovarian in origin but rather is secondary, and it is logical to conclude that the only true primary ovarian neoplasms are germ cell and gonadal stromal tumors analogous to tumors in the testis. If this new model is confirmed, it has profound implications for the early detection and treatment of “ovarian cancer.” PMID:22506137

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

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

Interdependent genotoxic mechanisms of monomethylarsonous acid: Role of ROS-induced DNA damage and poly(ADP-ribose) polymerase-1 inhibition in the malignant transformation of urothelial cells

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

Wnek, Shawn M.; Kuhlman, Christopher L.; Camarillo, Jeannie M.

2011-11-15

Exposure of human bladder urothelial cells (UROtsa) to 50 nM of the arsenic metabolite, monomethylarsonous acid (MMA{sup III}), for 12 weeks results in irreversible malignant transformation. The ability of continuous, low-level MMA{sup III} exposure to cause an increase in genotoxic potential by inhibiting repair processes necessary to maintain genomic stability is unknown. Following genomic insult within cellular systems poly(ADP-ribose) polymerase-1 (PARP-1), a zinc finger protein, is rapidly activated and recruited to sites of DNA strand breaks. When UROtsa cells are continuously exposed to 50 nM MMA{sup III}, PARP-1 activity does not increase despite the increase in MMA{sup III}-induced DNA single-strandmore » breaks through 12 weeks of exposure. When UROtsa cells are removed from continuous MMA{sup III} exposure (2 weeks), PARP-1 activity increases coinciding with a subsequent decrease in DNA damage levels. Paradoxically, PARP-1 mRNA expression and protein levels are elevated in the presence of continuous MMA{sup III} indicating a possible mechanism to compensate for the inhibition of PARP-1 activity in the presence of MMA{sup III}. The zinc finger domains of PARP-1 contain vicinal sulfhydryl groups which may act as a potential site for MMA{sup III} to bind, displace zinc ion, and render PARP-1 inactive. Mass spectrometry analysis demonstrates the ability of MMA{sup III} to bind a synthetic peptide representing the zinc-finger domain of PARP-1, and displace zinc from the peptide in a dose-dependent manner. In the presence of continuous MMA{sup III} exposure, continuous 4-week zinc supplementation restored PARP-1 activity levels and reduced the genotoxicity associated with MMA{sup III}. Zinc supplementation did not produce an overall increase in PARP-1 protein levels, decrease the levels of MMA{sup III}-induced reactive oxygen species, or alter Cu-Zn superoxide dismutase levels. Overall, these results present two potential interdependent mechanisms in which MMA{sup III} may increase the susceptibility of UROtsa cells to genotoxic insult and/or malignant transformation: elevated levels of MMA{sup III}-induced DNA damage through the production of reactive oxygen species, and the direct MMA{sup III}-induced inhibition of PARP-1.« less

P16.29 Malignant craniopharyngioma

PubMed Central

Unal, E.; Kilic, K.; Ozdemir, N.; Gunver, F.; Isik, S.; Can, S.

2017-01-01

Abstract Introduction: Malignant transformation of craniopharyngioma has rarely been described. In this article, we report a case of 28th malignant craniopharyngioma ever mentioned in English literature. Materials and Methods: We performed a PUBMED, HUBMED, BAU Library Database and Ovid search on malignant craniopharyngiomas and identified 27 reported cases. CASE DESCRIPTION: 44 years old female patient was diagnosed with craniopharyngioma two years ago and underwent surgical resection of a typical craniopharyngioma, the histopathological result was adamantinomatous craniopharyngioma of Grade I. There was no malignancy. One year ago cavernous sinus invasion has been detected and gamma knife irradiation has been made. At admission she was blind in the right eye for the last six months and the vision was diminished in the left eye for a month. The MRI showed that nasal cavity was full of tumor, that the clivus was almost completely destructed and that orbita and maxillary sinus were also invaded. Firstly the ENT surgeons debulked the tumor via transmaxillary route and then the transcranial approach allowed only a subtotal removal due to a profuse bleeding. The histopatological examination showed malignant tumoral infiltration rich in cells with many mitoses. The patient died two years later. CONCLUSION: The relevant literature of malignant craniopharyngioma is reviewed and discussed. The surgeon must be aware that total removal of a malignant craniopharyngioma can be hazardous because of intractable bleedings occurring during surgery.

Dual role of the integrated stress response in medulloblastoma tumorigenesis

PubMed Central

Li, Xiting; Jamison, Stephanie; Harding, Heather P.; Ron, David; Lin, Wensheng

2016-01-01

In response to endoplasmic reticulum (ER) stress, activation of pancreatic ER kinase (PERK) coordinates an adaptive program known as the integrated stress response (ISR) by phosphorylating translation initiation factor 2α (eIF2α). Phosphorylated eIF2α is quickly dephosphorylated by the protein phosphatase 1 and growth arrest and DNA damage 34 (GADD34) complex. Data indicate that the ISR can either promote or suppress tumor development. Our previous studies showed that the ISR is activated in medulloblastoma in both human patients and animal models, and that the decreased ISR via PERK heterozygous deficiency attenuates medulloblastoma formation in Patched1 heterozygous deficient (Ptch1+/−) mice by enhancing apoptosis of pre-malignant granule cell precursors (GCPs) during cell transformation. We showed here that GADD34 heterozygous mutation moderately enhanced the ISR and noticeably increased the incidence of medulloblastoma in adult Ptch1+/− mice. Surprisingly, GADD34 homozygous mutation strongly enhanced the ISR, but significantly decreased the incidence of medulloblastoma in adult Ptch1+/− mice. Intriguingly, GADD34 homozygous mutation significantly enhanced pre-malignant GCP apoptosis in cerebellar hyperplastic lesions and reduced the lesion numbers in young Ptch1+/− mice. Nevertheless, neither GADD34 heterozygous mutation nor GADD34 homozygous mutation had a significant effect on medulloblastoma cells in adult Ptch1+/− mice. Collectively, these data imply the dual role of the ISR, promoting and inhibiting, in medulloblastoma tumorigenesis by regulating apoptosis of pre-malignant GCPs during the course of malignant transformation. PMID:27802424

Dual role of the integrated stress response in medulloblastoma tumorigenesis.

PubMed

Stone, Sarrabeth; Ho, Yeung; Li, Xiting; Jamison, Stephanie; Harding, Heather P; Ron, David; Lin, Wensheng

2016-09-27

In response to endoplasmic reticulum (ER) stress, activation of pancreatic ER kinase (PERK) coordinates an adaptive program known as the integrated stress response (ISR) by phosphorylating translation initiation factor 2α (eIF2α). Phosphorylated eIF2α is quickly dephosphorylated by the protein phosphatase 1 and growth arrest and DNA damage 34 (GADD34) complex. Data indicate that the ISR can either promote or suppress tumor development. Our previous studies showed that the ISR is activated in medulloblastoma in both human patients and animal models, and that the decreased ISR via PERK heterozygous deficiency attenuates medulloblastoma formation in Patched1 heterozygous deficient (Ptch1+/-) mice by enhancing apoptosis of pre-malignant granule cell precursors (GCPs) during cell transformation. We showed here that GADD34 heterozygous mutation moderately enhanced the ISR and noticeably increased the incidence of medulloblastoma in adult Ptch1+/- mice. Surprisingly, GADD34 homozygous mutation strongly enhanced the ISR, but significantly decreased the incidence of medulloblastoma in adult Ptch1+/- mice. Intriguingly, GADD34 homozygous mutation significantly enhanced pre-malignant GCP apoptosis in cerebellar hyperplastic lesions and reduced the lesion numbers in young Ptch1+/- mice. Nevertheless, neither GADD34 heterozygous mutation nor GADD34 homozygous mutation had a significant effect on medulloblastoma cells in adult Ptch1+/- mice. Collectively, these data imply the dual role of the ISR, promoting and inhibiting, in medulloblastoma tumorigenesis by regulating apoptosis of pre-malignant GCPs during the course of malignant transformation.

Malignant Transformation of Rat Kidney Induced by Environmental Substances and Estrogen

PubMed Central

Alfaro-Lira, Susana; Pizarro-Ortiz, María; Calaf, Gloria M.

2012-01-01

The use of organophosphorous insecticides in agricultural environments and in urban settings has increased significantly. The aim of the present study was to analyze morphological alterations induced by malathion and 17β-estradiol (estrogen) in rat kidney tissues. There were four groups of animals: control, malathion, estrogen and combination of both substances. The animals were injected for five days and sacrificed 30, 124 and 240 days after treatments. Kidney tissues were analyzed for histomorphological and immunocytochemical alterations. Morphometric analysis indicated that malathion plus estrogen-treated animals showed a significantly (p < 0.05) higher grade of glomerular hypertrophy, signs of tubular damage, atypical proliferation in cortical and hilium zone than malathion or estrogen alone-treated and control animals after 240 days. Results indicated that MFG, ER-α, ER-β, PgR, CYP1A1, Neu/ErbB2, PCNA, vimentin and Thrombospondin 1 (THB) protein expression was increased in convoluted tubules of animals treated with combination of malathion and estrogen after 240 days of 5 day treatment. Malignant proliferation was observed in the hilium zone. In summary, the combination of malathion and estrogen induced pathological lesions in glomeruli, convoluted tubules, atypical cell proliferation and malignant proliferation in hilium zone and immunocytochemical alterations in comparison to control animals or animals treated with either substance alone. It can be concluded that an increased risk of kidney malignant transformation can be induced by exposure to environmental and endogenous substances. PMID:22754462

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.

A Macro View of MicroRNAs: The Discovery of MicroRNAs and Their Role in Hematopoiesis and Hematologic Disease

PubMed Central

Weiss, Cary N.; Ito, Keisuke

2017-01-01

MicroRNAs (miRNAs) are a class of endogenously encoded ~22 nucleotide, noncoding, single-stranded RNAs that contribute to development, body planning, stem cell differentiation, and tissue identity through posttranscriptional regulation and degradation of transcripts. Given their importance, it is predictable that dysregulation of miRNAs, which target a wide variety of transcripts, can result in malignant transformation. In this review, we explore the discovery of miRNAs, their mechanism of action, and the tools that aid in their discovery and study. Strikingly, many of the studies that have expanded our understanding of the contributions of miRNAs to normal physiology and in the development of diseases have come from studies in the hematopoietic system and hematologic malignancies, with some of the earliest identified functions for mammalian miRNAs coming from observations made in leukemias. So, with a special focus on the hematologic system, we will discuss how miRNAs contribute to differentiation of stem cells and how dysregulation of miRNAs contributes to the development of malignancy, by providing examples of specific miRNAs that function as oncogenes or tumor suppressors, as well as of defects in miRNA processing. Finally, we will discuss the promise of miRNA-based therapeutics and challenges for the future study of disease-causing miRNAs. PMID:28838543

International congress on DNA damage and repair: Book of abstracts

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

Not Available

This document contains the abstracts of 105 papers presented at the Congress. Topics covered include the Escherichia coli nucleotide excision repair system, DNA repair in malignant transformations, defective DNA repair, and gene regulation. (TEM)

Mesenchymal stem cells: angels or demons?

PubMed

Wong, Rebecca S Y

2011-01-01

Mesenchymal stem cells (MSCs) have been used in cell-based therapy in various disease conditions such as graft-versus-host and heart diseases, osteogenesis imperfecta, and spinal cord injuries, and the results have been encouraging. However, as MSC therapy gains popularity among practitioners and researchers, there have been reports on the adverse effects of MSCs especially in the context of tumour modulation and malignant transformation. These cells have been found to enhance tumour growth and metastasis in some studies and have been related to anticancer-drug resistance in other instances. In addition, various studies have also reported spontaneous malignant transformation of MSCs. The mechanism of the modulatory behaviour and the tumorigenic potential of MSCs, warrant urgent exploration, and the use of MSCs in patients with cancer awaits further evaluation. However, if MSCs truly play a role in tumour modulation, they can also be potential targets of cancer treatment.

Mesenchymal Stem Cells: Angels or Demons?

PubMed Central

Wong, Rebecca S. Y.

2011-01-01

Mesenchymal stem cells (MSCs) have been used in cell-based therapy in various disease conditions such as graft-versus-host and heart diseases, osteogenesis imperfecta, and spinal cord injuries, and the results have been encouraging. However, as MSC therapy gains popularity among practitioners and researchers, there have been reports on the adverse effects of MSCs especially in the context of tumour modulation and malignant transformation. These cells have been found to enhance tumour growth and metastasis in some studies and have been related to anticancer-drug resistance in other instances. In addition, various studies have also reported spontaneous malignant transformation of MSCs. The mechanism of the modulatory behaviour and the tumorigenic potential of MSCs, warrant urgent exploration, and the use of MSCs in patients with cancer awaits further evaluation. However, if MSCs truly play a role in tumour modulation, they can also be potential targets of cancer treatment. PMID:21822372

FUNCTIONAL DEREGULATION OF KIT: LINK TO MAST CELL PROLIFERATIVE DISEASES AND OTHER NEOPLASMS

PubMed Central

Cruse, Glenn; Metcalfe, Dean D.; Olivera, Ana

2014-01-01

SYNOPSIS Signaling through the receptor tyrosine kinase KIT mediates differentiation, proliferation and survival of hematopoietic precursor cells and mast cells. Constitutive KIT signaling due to somatic point mutations in c-Kit is an important occurrence in the development of mast cell proliferation disorders and other hematological malignancies. In this review, we discuss the common gain-of-function mutations found in these malignancies, particularly in mast cell proliferation disorders, and summarize the current understanding of the molecular mechanisms by which transforming point mutations in KIT may affect KIT structure and function and lead to altered downstream signaling and cellular transformation. Drugs targeting KIT have shown mixed success in the treatment of these diseases. A brief overview of the most common KIT inhibitors currently used, the reasons for the varied clinical results of such inhibitors and a discussion of potential new strategies are provided. PMID:24745671

Low-Grade Astrocytoma within a Mature Cystic Teratoma in an Adolescent Patient.

PubMed

Yoder, Nicole; Marks, Asher; Hui, Pei; Litkouhi, Babak; Cron, Julia

2018-06-01

Mature cystic teratomas are the most common ovarian neoplasm in adolescents. They are typically benign, however, malignant transformation rarely occurs. We report a low-grade astrocytoma arising from a mature cystic teratoma in an adolescent patient. The patient was a 12-year-old girl with an asymptomatic ovarian cyst and subsequent cystectomy. Final pathology identified a solid tumor with glial tissue within the cyst, reported as low-grade astrocytoma arising in a mature cystic teratoma. There are few data on astrocytomas in the gynecologic tract. Risk factors for malignant transformation in a mature cystic teratoma include increased age, postmenopausal status, elevated carcinoma antigen 125, and large tumor size. Interestingly, this patient had a history of partial trisomy 20, which has been associated with teratoma formation in a mouse model. Copyright © 2017 North American Society for Pediatric and Adolescent Gynecology. Published by Elsevier Inc. All rights reserved.

Resistance to Fluid Shear Stress Is a Conserved Biophysical Property of Malignant Cells

PubMed Central

Henry, Michael D.

2012-01-01

During metastasis, cancer cells enter the circulation in order to gain access to distant tissues, but how this fluid microenvironment influences cancer cell biology is poorly understood. A longstanding view is that circulating cancer cells derived from solid tissues may be susceptible to damage from hemodynamic shear forces, contributing to metastatic inefficiency. Here we report that compared to non-transformed epithelial cells, transformed cells are remarkably resistant to fluid shear stress (FSS) in a microfluidic protocol, exhibiting a biphasic decrease in viability when subjected to a series of millisecond pulses of high FSS. We show that magnitude of FSS resistance is influenced by several oncogenes, is an adaptive and transient response triggered by plasma membrane damage and requires extracellular calcium and actin cytoskeletal dynamics. This novel property of malignant cancer cells may facilitate hematogenous metastasis and indicates, contrary to expectations, that cancer cells are quite resistant to destruction by hemodynamic shear forces. PMID:23226552

Regulation of Telomere Homeostasis during Epstein-Barr virus Infection and Immortalization.

PubMed

Kamranvar, Siamak A; Masucci, Maria G

2017-08-09

The acquisition of unlimited proliferative potential is dependent on the activation of mechanisms for telomere maintenance, which counteracts telomere shortening and the consequent triggering of the DNA damage response, cell cycle arrest, and apoptosis. The capacity of Epstein Barr virus (EBV) to infect B-lymphocytes in vitro and transform the infected cells into autonomously proliferating immortal cell lines underlies the association of this human gamma-herpesvirus with a broad variety of lymphoid and epithelial cell malignancies. Current evidence suggests that both telomerase-dependent and -independent pathways of telomere elongation are activated in the infected cells during the early and late phases of virus-induced immortalization. Here we review the interaction of EBV with different components of the telomere maintenance machinery and the mechanisms by which the virus regulates telomere homeostasis in proliferating cells. We also discuss how these viral strategies may contribute to malignant transformation.

Analysis of framelets for breast cancer diagnosis.

PubMed

Thivya, K S; Sakthivel, P; Venkata Sai, P M

2016-01-01

Breast cancer is the second threatening tumor among the women. The effective way of reducing breast cancer is its early detection which helps to improve the diagnosing process. Digital mammography plays a significant role in mammogram screening at earlier stage of breast carcinoma. Even though, it is very difficult to find accurate abnormality in prevalent screening by radiologists. But the possibility of precise breast cancer screening is encouraged by predicting the accurate type of abnormality through Computer Aided Diagnosis (CAD) systems. The two most important indicators of breast malignancy are microcalcifications and masses. In this study, framelet transform, a multiresolutional analysis is investigated for the classification of the above mentioned two indicators. The statistical and co-occurrence features are extracted from the framelet decomposed mammograms with different resolution levels and support vector machine is employed for classification with k-fold cross validation. This system achieves 94.82% and 100% accuracy in normal/abnormal classification (stage I) and benign/malignant classification (stage II) of mass classification system and 98.57% and 100% for microcalcification system when using the MIAS database.

NF1 truncating mutations associated to aggressive clinical phenotype with elephantiasis neuromatosa and solid malignancies.

PubMed

Ponti, Giovanni; Martorana, Davide; Pellacani, Giovanni; Ruini, Cristel; Loschi, Pietro; Baccarani, Alessio; De Santis, Giorgio; Pollio, Annamaria; Neri, Tauro Maria; Mandel, Victor Desmond; Maiorana, Antonio; Maccio, Livia; Maccaferri, Monia; Tomasi, Aldo

2014-06-01

Von Recklinghausen disease is a syndrome characterized by a wide phenotypic variability giving rise to both, cutaneous and visceral benign and malignant neoplasms. The first include cutaneous neurofibromas, subcutaneous and plexiform neurofibromas. The latter can undergo malignant transformation and/or determine elephantiasis neuromatosa. Visceral tumors may include malignant peripheral nerve sheet tumors, gastrointestinal stromal tumors, cerebral gliomas and abdominal neurofibromas. In the present study, the authors discuss the clinical and biomolecular characterization of a cohort of 20 families with a diagnosis of type 1 neurofibromatosis. Clinically, the cohort includes three probands with elephantiasis neuromatosa and a peculiarly high incidence of breast and gastrointestinal cancer. Among the 14 NF1 mutations documented, 10 encoding for a truncated protein have been associated to particularly aggressive clinical phenotypes including elephantiasis neuromatosa, malignant peripheral nerve sheet tumors, breast cancer, gastrointestinal stromal tumors. This effect on protein synthesis, rather than the type of NF1 mutation, is the key to the explanation of the genotype-phenotype correlations in the context of neurofibromatosis type 1. Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

The classification of lung cancers and their degree of malignancy by FTIR, PCA-LDA analysis, and a physics-based computational model.

PubMed

Kaznowska, E; Depciuch, J; Łach, K; Kołodziej, M; Koziorowska, A; Vongsvivut, J; Zawlik, I; Cholewa, M; Cebulski, J

2018-08-15

Lung cancer has the highest mortality rate of all malignant tumours. The current effects of cancer treatment, as well as its diagnostics, are unsatisfactory. Therefore it is very important to introduce modern diagnostic tools, which will allow for rapid classification of lung cancers and their degree of malignancy. For this purpose, the authors propose the use of Fourier Transform InfraRed (FTIR) spectroscopy combined with Principal Component Analysis-Linear Discriminant Analysis (PCA-LDA) and a physics-based computational model. The results obtained for lung cancer tissues, adenocarcinoma and squamous cell carcinoma FTIR spectra, show a shift in wavenumbers compared to control tissue FTIR spectra. Furthermore, in the FTIR spectra of adenocarcinoma there are no peaks corresponding to glutamate or phospholipid functional groups. Moreover, in the case of G2 and G3 malignancy of adenocarcinoma lung cancer, the absence of an OH groups peak was noticed. Thus, it seems that FTIR spectroscopy is a valuable tool to classify lung cancer and to determine the degree of its malignancy. Copyright © 2018 Elsevier B.V. All rights reserved.

Malignant neurocristic hamartoma: a tumor distinct from conventional melanoma and malignant blue nevus.

PubMed

Linskey, Katy R; Dias-Santagata, Dora; Nazarian, Rosalynn M; Le, Long P; Lam, Quynh; Bellucci, Kirsten S W; Robinson-Bostom, Leslie; Mihm, Martin C; Hoang, Mai P

2011-10-01

Neurocristic hamartomas are rare pigmented lesions comprised of melanocytes, Schwann cells, and pigmented dendritic spindle cells that involve the skin and soft tissue. Malignant transformation can rarely arise within neurocristic hamartomas. Up to date, there has been only 1 series of 7 cases of malignant neurocristic hamartomas (MNHs), with 3 cases that developed metastases. We present the histology and clinical course of 3 additional cases of MNH, 2 of which were metastatic. CD117 was strongly positive in all cases with available archival materials--the tumors and background neurocristic hamartoma of 3 cases, and 1 lymph node metastasis; however, KIT sequencing for exons 11, 13, 17, and 18 was negative. Mutational analyses of recurrent mutations of 17 cancer genes, including BRAF and KIT, were also negative. Although our series is small, KIT overexpression in MNH does not seem to correlate with gene mutation. The lack of BRAF, NRAS, GNAQ, and KIT mutations seems to support the notion that MNH may be distinct from conventional melanoma and from other dermal melanomas, such as malignant blue nevi and melanoma arising in congenital nevi.

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.

IR Spectroscopic signs of malignant neoplasms in the thyroid gland

NASA Astrophysics Data System (ADS)

Tolstorozhev, G. B.; Skornyakov, I. V.; Butra, V. A.

2012-03-01

We use Fourier transform IR spectroscopy to study thyroid tumor tissues which were removed during surgery. The IR spectra of the tissues with pathological foci are compared with data from histologic examination. In the region of N-H, C-H, and C = O stretching vibrations, the IR spectra of the tissues for thyroid cancer are different from the IR spectra of tissues without malignant formations. We identify the spectral signs of thyroid cancer. We show that IR analysis is promising for identification of thyroid pathology at the molecular level.

A rare case report of squamous-cell carcinoma arising from mature cystic teratoma of ovary.

PubMed

Kalampokas, E; Boutas, I; Kairi-Vasilatou, E; Salakos, N; Panoulis, K; Aravantinos, L; Damaskos, C; Kalampokas, T; Deligeoroglou, E

2014-01-01

The most frequent ovarian germ cell tumors are mature cystic teratomas (MCTs), composing 10-25% of all ovarian neoplasms. MCTs have the potential of undergoing malignant transformation, typically in postmenopausal women, with a frequency of 0.17-3%, with squamous cell carcinoma being the most common malignant tumor arising from MCT. We present the rare clinical entity of a squamous cell carcinoma arising from a mature cystic teratoma in a 56-year-old premenopausal woman as well as diagnostic and therapeutic route followed.

Induction of Crown Gall on Carrot Slices.

ERIC Educational Resources Information Center

Babich, H.; Fox, K. D.

1998-01-01

Argues that the transfer of plasmid from a bacterium to a plant cell has received little attention. Presents an experiment for studying this type of genetic transformation using the causative agent of crown gall, a malignant plant tumor. (DDR)

Human mesothelial cells are unusually susceptible to simian virus 40-mediated transformation and asbestos cocarcinogenicity

PubMed Central

Bocchetta, Maurizio; Di Resta, Ilaria; Powers, Amy; Fresco, Raoul; Tosolini, Alessandra; Testa, Joseph R.; Pass, Harvey I.; Rizzo, Paola; Carbone, Michele

2000-01-01

Mesothelioma, a malignancy associated with asbestos, has been recently linked to simian virus 40 (SV40). We found that infection of human mesothelial cells by SV40 is very different from the semipermissive infection thought to be characteristic of human cells. Mesothelial cells are uniformly infected but not lysed by SV40, a mechanism related to p53, and undergo cell transformation at an extremely high rate. Exposure of mesothelial cells to asbestos complemented SV40 mutants in transformation. Our data provide a mechanistic explanation for the ability of SV40 to transform mesothelial cells preferentially and indicate that asbestos and SV40 may be cocarcinogens. PMID:10954737

MicroRNA-150 Is up-regulated in extranodal marginal zone lymphoma of MALT type.

PubMed

Gebauer, Niklas; Kuba, Johannes; Senft, Andrea; Schillert, Arne; Bernard, Veronica; Thorns, Christoph

2014-01-01

The mechanisms promoting malignant transformation from chronic Helicobacter pylori-gastritis to gastric extranodal marginal zone lymphoma (MALT lymphoma) are insufficiently characterized. This follow-up study aimed to validate candidate microRNAs (miRs) in the process of neoplastic transformation. MicroRNA expression signatures (n=20) were generated for a total of 60 cases of gastric lesions ranging from Wotherspoon 0-5 employing a quantitative real-time polymerase chain reaction (PCR) approach. Morphological and immunohistochemical characterization of the cohort was supplemented by PCR-based immunoglobulin heavy chain recombination studies. Quantitative expression of miR-150, miR-142.3p, miR-375 and miR-494 was significantly de-regulated in samples from MALT lymphoma compared to those from gastritis. The previously reported up-regulation of miR-150 in marginal zone lymphoma of MALT type was verified in an independent cohort of lymphoma samples employing a modified methodology. This further substantiates the role of miR-150 as a potential oncomiR in MALT lymphoma.

Stromal cells can contribute oncogenic signals

NASA Technical Reports Server (NTRS)

Tlsty, T. D.

2001-01-01

The majority of studies of neoplastic transformation have focused attention on events that occur within transformed cells. These cell autonomous events result in the disruption of molecular pathways that regulate basic activities of the cells such as proliferation, death, movement and genomic integrity. Other studies have addressed the microenvironment of tumor cells and documented its importance in supporting tumor progression. Recent work has begun to expand on these initial studies of tumor microenvironment and now provide novel insights into the possible initiation and progression of malignant cells. This review will address the transforming effect of stromal cells on epithelial components. Copyright 2001 Academic Press.

FOXM1 Upregulation Is an Early Event in Human Squamous Cell Carcinoma and it Is Enhanced by Nicotine during Malignant Transformation

PubMed Central

Gemenetzidis, Emilios; Bose, Amrita; Riaz, Adeel M.; Chaplin, Tracy; Young, Bryan D.; Ali, Muhammad; Sugden, David; Thurlow, Johanna K.; Cheong, Sok-Ching; Teo, Soo-Hwang; Wan, Hong; Waseem, Ahmad; Parkinson, Eric K.; Fortune, Farida; Teh, Muy-Teck

2009-01-01

Background Cancer associated with smoking and drinking remains a serious health problem worldwide. The survival of patients is very poor due to the lack of effective early biomarkers. FOXM1 overexpression is linked to the majority of human cancers but its mechanism remains unclear in head and neck squamous cell carcinoma (HNSCC). Methodology/Principal Findings FOXM1 mRNA and protein expressions were investigated in four independent cohorts (total 75 patients) consisting of normal, premalignant and HNSCC tissues and cells using quantitative PCR (qPCR), expression microarray, immunohistochemistry and immunocytochemistry. Effect of putative oral carcinogens on FOXM1 transcriptional activity was dose-dependently assayed and confirmed using a FOXM1-specific luciferase reporter system, qPCR, immunoblotting and short-hairpin RNA interference. Genome-wide single nucleotide polymorphism (SNP) array was used to ‘trace’ the genomic instability signature pattern in 8 clonal lines of FOXM1-induced malignant human oral keratinocytes. Furthermore, acute FOXM1 upregulation in primary oral keratinocytes directly induced genomic instability. We have shown for the first time that overexpression of FOXM1 precedes HNSCC malignancy. Screening putative carcinogens in human oral keratinocytes surprisingly showed that nicotine, which is not perceived to be a human carcinogen, directly induced FOXM1 mRNA, protein stabilisation and transcriptional activity at concentrations relevant to tobacco chewers. Importantly, nicotine also augmented FOXM1-induced transformation of human oral keratinocytes. A centrosomal protein CEP55 and a DNA helicase/putative stem cell marker HELLS, both located within a consensus loci (10q23), were found to be novel targets of FOXM1 and their expression correlated tightly with HNSCC progression. Conclusions/Significance This study cautions the potential co-carcinogenic effect of nicotine in tobacco replacement therapies. We hypothesise that aberrant upregulation of FOXM1 may be inducing genomic instability through a program of malignant transformation involving the activation of CEP55 and HELLS which may facilitate aberrant mitosis and epigenetic modifications. Our finding that FOXM1 is upregulated early during oral cancer progression renders FOXM1 an attractive diagnostic biomarker for early cancer detection and its candidate mechanistic targets, CEP55 and HELLS, as indicators of malignant conversion and progression. PMID:19287496

Physiology and pathophysiology of apoptosis in epithelial cells of the liver, pancreas, and intestine.

PubMed

Jones, B A; Gores, G J

1997-12-01

Cell death of gastrointestinal epithelial cells occurs by a process referred to as apoptosis. In this review, we succinctly define apoptosis and summarize the role of apoptosis in the physiology and pathophysiology of epithelial cells in the liver, pancreas, and small and large intestine. The physiological mediators regulating apoptosis in gastrointestinal epithelial cells, when known, are discussed. Selected pathophysiological consequences of excessive apoptosis and inhibition of apoptosis are used to illustrate the significance of apoptosis in disease processes. These examples demonstrate that excessive apoptosis may result in epithelial cell atrophy, injury, and dysfunction, whereas inhibition of apoptosis results in hyperplasia and promotes malignant transformation. The specific cellular mechanisms responsible for dysregulation of epithelial cell apoptosis during pathophysiological disturbances are emphasized. Potential future areas of physiological research regarding apoptosis in gastrointestinal epithelia are highlighted when appropriate.

Location and cellular stages of NK cell development

PubMed Central

Yu, Jianhua; Freud, Aharon G.; Caligiuri, Michael A

2013-01-01

The identification of distinct tissue-specific natural killer (NK) cell populations that apparently mature from local precursor populations has brought new insight into the diversity and developmental regulation of this important lymphoid subset. NK cells provide a necessary link between the early (innate) and late (adaptive) immune responses to infection. Gaining a better understanding of the processes that govern NK cell development should allow us to better harness NK cell functions in multiple clinical settings as well as to gain further insight into how these cells undergo malignant transformation. In this review, we summarize recent advances in understanding sites and cellular stages of NK cell development in humans and mice. PMID:24055329

Role of the human papilloma virus in the development of cervical intraepithelial neoplasia and malignancy.

PubMed

Jastreboff, A M; Cymet, T

2002-04-01

Human papilloma virus (HPV) is a public health problem as a sexually transmitted disease and as a critical factor in the pathogenesis of various cancers. The clinical manifestations, epidemiology, and virology that are critical to understanding the process of cervical dysplasia and neoplasia are reviewed. A discussion of the cervical transformation zone and the classification of cervical dysplasia and neoplasia leads into the importance of the Papanicolaou smear in prevention of potentially devastating sequelae of this virus. The role of the immune system in the progression of the disease and how it relates to vaccines, as well as treatment and prevention of HPV, are reviewed.

Role of the human papilloma virus in the development of cervical intraepithelial neoplasia and malignancy

PubMed Central

Jastreboff, A; Cymet, T

2002-01-01

Human papilloma virus (HPV) is a public health problem as a sexually transmitted disease and as a critical factor in the pathogenesis of various cancers. The clinical manifestations, epidemiology, and virology that are critical to understanding the process of cervical dysplasia and neoplasia are reviewed. A discussion of the cervical transformation zone and the classification of cervical dysplasia and neoplasia leads into the importance of the Papanicolaou smear in prevention of potentially devastating sequelae of this virus. The role of the immune system in the progression of the disease and how it relates to vaccines, as well as treatment and prevention of HPV, are reviewed. PMID:11930025

Interleukin-8 (IL-8) over-production and autocrine cell activation are key factors in monomethylarsonous acid [MMA(III)]-induced malignant transformation of urothelial cells

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

Escudero-Lourdes, C., E-mail: cescuder@uaslp.mx; Wu, T.; Camarillo, J.M.

2012-01-01

The association between chronic human exposure to arsenicals and bladder cancer development is well recognized; however, the underlying molecular mechanisms have not been fully determined. We propose that inflammatory responses can play a pathogenic role in arsenic-related bladder carcinogenesis. In previous studies, it was demonstrated that chronic exposure to 50 nM monomethylarsenous acid [MMA(III)] leads to malignant transformation of an immortalized model of urothelial cells (UROtsa), with only 3 mo of exposure necessary to trigger the transformation-related changes. In the three-month window of exposure, the cells over-expressed pro-inflammatory cytokines (IL-1β, IL-6 and IL-8), consistent with the sustained activation of NFKβmore » and AP1/c-jun, ERK2, and STAT3. IL-8 was over-expressed within hours after exposure to MMA(III), and sustained over-expression was observed during chronic exposure. In this study, we profiled IL-8 expression in UROtsa cells exposed to 50 nM MMA(III) for 1 to 5 mo. IL-8 expression was increased mainly in cells after 3 mo MMA(III) exposure, and its production was also found increased in tumors derived from these cells after heterotransplantation in SCID mice. UROtsa cells do express both receptors, CXCR1 and CXCR2, suggesting that autocrine cell activation could be important in cell transformation. Supporting this observation and consistent with IL-8 over-expression, CXCR1 internalization was significantly increased after three months of exposure to MMA(III). The expression of MMP-9, cyclin D1, bcl-2, and VGEF was significantly increased in cells exposed to MMA(III) for 3 mo, but these mitogen-activated kinases were significantly decreased after IL-8 gene silencing, together with a decrease in cell proliferation rate and in anchorage-independent colony formation. These results suggest a relevant role of IL-8 in MMA(III)-induced UROtsa cell transformation. -- Highlights: ► IL-8 is over-expressed in human MMA(III)-exposed urothelial cells. ► Internal CXCR1 and tumor progression markers are also increased. ► IL-8 silencing decreased malignant transformation markers in MMA(III)-exposed cells.« less

Glioma Invasiveness Responds Variably to Irradiation in a Co-Culture Model

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

Nakamura, Jean L.; Haas-Kogan, Daphne A.; Department of Neurological Surgery, University of California-San Francisco, San Francisco, CA

2007-11-01

Purpose: We developed a co-culture system to quantitate the growth and invasion of human malignant gliomas into a background of confluent normal human astrocytes, then used this assay to assess independently the effects of irradiating both cell types on glioma invasion. Methods and Materials: Enhanced green fluorescent protein (EGFP)-labeled immortalized human astrocytes, human malignant glioma cells, or transformed human astrocytes were focally plated onto a confluent layer of normal human astrocytes, and the invasiveness of EGFP-labeled cells was scored after 96 h. To address the consequences of irradiation on glioma invasion, the invasiveness of irradiated glioma cell lines and irradiatedmore » astrocytic backgrounds was assessed. Fluorescence-activated cell sorting was used to quantitate the total number of EGFP-labeled cells. Results: Growth in the co-culture assay consistently reflected transformation states of the plated cells. Immortalized, but untransformed human astrocytes failed even to establish growth on confluent normal human astrocytes. In contrast, all malignant human glioma cell lines and transformed human astrocytes demonstrated various degrees of infiltration into the astrocytic bed. Irradiation failed to alter the invasiveness of U87, A172, and U373. A 1-Gy dose slightly reduced the invasiveness of U251 MG by 75% (p < 0.05 by one-way analysis of variance and post hoc Neuman-Keuls), without reducing total cell numbers. Independently irradiating the human astrocytic bed did not alter the invasiveness of nonirradiated U251, whereas the matrix metalloproteinase (MMP) inhibitor GM6001 reduced U251 invasiveness in the co-culture assay. Conclusions: Growth in the co-culture assay reflects the transformation status and provides a useful in vitro model for assessing invasiveness. Human glioma invasiveness in the co-culture model responds variably to single low-dose fractions. MMP activity promotes invasiveness in the co-culture model. Reduced invasiveness in irradiated U251 appears to be mediated by MMP-independent mechanisms.« less

Comparative Multifractal Analysis of Dynamic Infrared Thermograms and X-Ray Mammograms Enlightens Changes in the Environment of Malignant Tumors.

PubMed

Gerasimova-Chechkina, Evgeniya; Toner, Brian; Marin, Zach; Audit, Benjamin; Roux, Stephane G; Argoul, Francoise; Khalil, Andre; Gileva, Olga; Naimark, Oleg; Arneodo, Alain

2016-01-01

There is growing evidence that the microenvironment surrounding a tumor plays a special role in cancer development and cancer therapeutic resistance. Tumors arise from the dysregulation and alteration of both the malignant cells and their environment. By providing tumor-repressing signals, the microenvironment can impose and sustain normal tissue architecture. Once tissue homeostasis is lost, the altered microenvironment can create a niche favoring the tumorigenic transformation process. A major challenge in early breast cancer diagnosis is thus to show that these physiological and architectural alterations can be detected with currently used screening techniques. In a recent study, we used a 1D wavelet-based multi-scale method to analyze breast skin temperature temporal fluctuations collected with an IR thermography camera in patients with breast cancer. This study reveals that the multifractal complexity of temperature fluctuations superimposed on cardiogenic and vasomotor perfusion oscillations observed in healthy breasts is lost in malignant tumor foci in cancerous breasts. Here we use a 2D wavelet-based multifractal method to analyze the spatial fluctuations of breast density in the X-ray mammograms of the same panel of patients. As compared to the long-range correlations and anti-correlations in roughness fluctuations, respectively observed in dense and fatty breast areas, some significant change in the nature of breast density fluctuations with some clear loss of correlations is detected in the neighborhood of malignant tumors. This attests to some architectural disorganization that may deeply affect heat transfer and related thermomechanics in breast tissues, corroborating the change to homogeneous monofractal temperature fluctuations recorded in cancerous breasts with the IR camera. These results open new perspectives in computer-aided methods to assist in early breast cancer diagnosis.

Comparative Multifractal Analysis of Dynamic Infrared Thermograms and X-Ray Mammograms Enlightens Changes in the Environment of Malignant Tumors

PubMed Central

Gerasimova-Chechkina, Evgeniya; Toner, Brian; Marin, Zach; Audit, Benjamin; Roux, Stephane G.; Argoul, Francoise; Khalil, Andre; Gileva, Olga; Naimark, Oleg; Arneodo, Alain

2016-01-01

There is growing evidence that the microenvironment surrounding a tumor plays a special role in cancer development and cancer therapeutic resistance. Tumors arise from the dysregulation and alteration of both the malignant cells and their environment. By providing tumor-repressing signals, the microenvironment can impose and sustain normal tissue architecture. Once tissue homeostasis is lost, the altered microenvironment can create a niche favoring the tumorigenic transformation process. A major challenge in early breast cancer diagnosis is thus to show that these physiological and architectural alterations can be detected with currently used screening techniques. In a recent study, we used a 1D wavelet-based multi-scale method to analyze breast skin temperature temporal fluctuations collected with an IR thermography camera in patients with breast cancer. This study reveals that the multifractal complexity of temperature fluctuations superimposed on cardiogenic and vasomotor perfusion oscillations observed in healthy breasts is lost in malignant tumor foci in cancerous breasts. Here we use a 2D wavelet-based multifractal method to analyze the spatial fluctuations of breast density in the X-ray mammograms of the same panel of patients. As compared to the long-range correlations and anti-correlations in roughness fluctuations, respectively observed in dense and fatty breast areas, some significant change in the nature of breast density fluctuations with some clear loss of correlations is detected in the neighborhood of malignant tumors. This attests to some architectural disorganization that may deeply affect heat transfer and related thermomechanics in breast tissues, corroborating the change to homogeneous monofractal temperature fluctuations recorded in cancerous breasts with the IR camera. These results open new perspectives in computer-aided methods to assist in early breast cancer diagnosis. PMID:27555823

Therapy targets in glioblastoma and cancer stem cells: lessons from haematopoietic neoplasms.

PubMed

Cruceru, Maria Linda; Neagu, Monica; Demoulin, Jean-Baptiste; Constantinescu, Stefan N

2013-10-01

Despite intense efforts to identify cancer-initiating cells in malignant brain tumours, markers linked to the function of these cells have only very recently begun to be uncovered. The notion of cancer stem cell gained prominence, several molecules and signalling pathways becoming relevant for diagnosis and treatment. Whether a substantial fraction or only a tiny minority of cells in a tumor can initiate and perpetuate cancer, is still debated. The paradigm of cancer-initiating stem cells has initially been developed with respect to blood cancers where chronic conditions such as myeloproliferative neoplasms are due to mutations acquired in a haematopoietic stem cell (HSC), which maintains the normal hierarchy to neoplastic haematopoiesis. In contrast, acute leukaemia transformation of such blood neoplasms appears to derive not only from HSCs but also from committed progenitors that cannot differentiate. This review will focus on putative novel therapy targets represented by markers described to define cancer stem/initiating cells in malignant gliomas, which have been called 'leukaemia of the brain', given their rapid migration and evolution. Parallels are drawn with other cancers, especially haematopoietic, given the similar rampant proliferation and treatment resistance of glioblastoma multiforme and secondary acute leukaemias. Genes associated with the malignant conditions and especially expressed in glioma cancer stem cells are intensively searched. Although many such molecules might only coincidentally be expressed in cancer-initiating cells, some may function in the oncogenic process, and those would be the prime candidates for diagnostic and targeted therapy. For the latter, combination therapies are likely to be envisaged, given the robust and plastic signalling networks supporting malignant proliferation. © 2013 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

Differentiation of Normal and Malignant Breast Tissues using Infrared Spectroscopy

NASA Astrophysics Data System (ADS)

Mehrotra, Ranjana; Jangir, Deepak Kumar; Gupta, Alka; Kandpal, H. C.

2008-11-01

Infrared spectra of carcinomatous and their normal fore bearing tissues were collected in the 600 cm-1 to 4000 cm-1 region. Fourier Transform Infrared (FTIR) data of infiltrating ductal carcinoma of breast with different grades of malignancy from patients of different age groups were analyzed. Infrared spectra demonstrate significant spectral differences between the tumor sections of normal and the malignant breast tissues. In particular, changes in frequency and intensity in the spectra of protein, nucleic acid and glycogen were observed. This allows to make a qualitative and semi quantitative evaluation of the changes in proliferation activities from normal to diseased tissue. The findings establish a framework for additional studies, which may enable us to establish a relation of the diseased state with its infrared spectra.

Molecular markers associated with development and progression of potentially premalignant oral epithelial lesions: Current knowledge and future implications.

PubMed

Nikitakis, Nikolaos G; Pentenero, Monica; Georgaki, Maria; Poh, Catherine F; Peterson, Douglas E; Edwards, Paul; Lingen, Mark; Sauk, John J

2018-06-01

Identification and management of potentially premalignant oral epithelial lesions (PPOELs) at highest risk of malignant transformation holds great promise for successful secondary prevention of oral squamous cell carcinoma, potentially reducing oral cancer morbidity and mortality. However, to date, neither clinical nor histopathologic validated risk predictors that can reliably predict which PPOELs will definitively progress to malignancy have been identified. In addition, the management of PPOELs remains a major challenge. Arguably, progress in the prevention and treatment of oral premalignancy and cancer will require improved understanding of the underlying molecular mechanisms, facilitating the discovery of diagnostic, prognostic, and predictive markers, as well as the identification of novel targeted therapeutics. This review provides a synopsis of the molecular biomarkers that have been studied in PPOELs and have been correlated with the presence and grade of dysplasia and/or their propensity to undergo malignant transformation to oral squamous cell carcinoma. The emphasis is on highlighting new emerging research fields, particularly epigenetic events, including methylation and micro-RNA regulation. Several promising biomarkers are highlighted. Current limitations and challenges are discussed. Recommendations for future focused research areas, to validate and promote clinically useful applications, are offered. Copyright © 2018 Elsevier Inc. All rights reserved.

Viral Carcinogenesis Beyond Malignant Transformation: EBV in the Progression of Human Cancers

PubMed Central

Müller-Coan, Bárbara G.; Pagano, Joseph S.

2017-01-01

Cancer progression begins when malignant cells colonize adjacent sites, and it is characterized by increasing tumor heterogeneity, invasion and dissemination of cancer cells. Clinically, progression is the most relevant stage in the natural history of cancers. A given virus is usually regarded as oncogenic because of its ability to induce malignant transformation of cells. Nonetheless, oncogenic viruses may also be important for the progression of infection-associated cancers. Recently this hypothesis has been addressed because of studies on the contribution of the Epstein–Barr virus (EBV) to the aggressiveness of nasopharyngeal carcinoma (NPC). Several EBV products modulate cancer progression phenomena, such as the epithelial–mesenchymal transition, cell motility, invasiveness, angiogenesis, and metastasis. In this regard, there are compelling data about the effects of EBV latent membrane proteins (LMPs) and EBV nuclear antigens (EBNAs), as well as nontranslated viral RNAs, such as the EBV-encoded small nonpolyadenylated RNAs (EBERs) and viral microRNAs, notably EBV miR-BARTs. The available data on the mechanisms and players involved in the contribution of EBV infection to the aggressiveness of NPC are discussed in this review. Overall, this conceptual framework may be valuable for the understanding of the contribution of some infectious agents in the progression of cancers. PMID:27068530

MALDI imaging reveals NCOA7 as a potential biomarker in oral squamous cell carcinoma arising from oral submucous fibrosis.

PubMed

Xie, Xiaoyan; Jiang, Yuchen; Yuan, Yao; Wang, Peiqi; Li, Xinyi; Chen, Fangman; Sun, Chongkui; Zhao, Hang; Zeng, Xin; Jiang, Lu; Zhou, Yu; Dan, Hongxia; Feng, Mingye; Liu, Rui; Chen, Qianming

2016-09-13

Oral squamous cell carcinoma (OSCC) ranks among the most common cancer worldwide, and is associated with severe morbidity and high mortality. Oral submucous fibrosis (OSF), characterized by fibrosis of the mucosa of the upper digestive tract, is a pre-malignant lesion, but the molecular mechanisms underlying this malignant transformation remains to be elucidated. In this study, matrix-assisted laser desorption ionization imaging mass spectrometry (MALDI-IMS)-based proteomic strategy was employed to profile the differentially expressed peptides/proteins between OSCC tissues and the corresponding adjacent non-cancerous OSF tissues. Sixty-five unique peptide peaks and nine proteins were identified with altered expression levels. Of them, expression of NCOA7 was found to be up-regulated in OSCC tissues by immunohistochemistry staining and western blotting, and correlated with a pan of clinicopathologic parameters, including lesion site, tumor differentiation status and lymph node metastasis. Further, we show that overexpression of NCOA7 promotes OSCC cell proliferation in either in vitro or in vivo models. Mechanistic study demonstrates that NCOA7 induces OSCC cell proliferation probably by activating aryl hydrocarbon receptor (AHR). The present study suggests that NCOA7 is a potential biomarker for early diagnosis of OSF malignant transformation, and leads to a better understanding of the molecular mechanisms responsible for OSCC development.

Mena, a new available marker in tumors of salivary glands?

PubMed

Gurzu, S; Krause, M; Ember, I; Azamfirei, L; Gobel, G; Feher, K; Jung, I

2012-02-07

Mena (mammalian Ena) is an actin regulatory protein involved in cell motility and adhesion. Based on its potential role in malignant transformation revealed in other organs, we analyzed the Mena expression in normal salivary glands (SG) and salivary tumors. Mena expression was determined in normal SG (n=10) and also benign (n=20) and malignant (n=35) lesions of SG. For the immunohistochemical staining we used the anti-Mena antibody. All normal SG and the benign lesions (10 pleomorphic adenomas, 10 Warthin's tumors) were Mena negative. Salivary duct carcinomas (n=5), carcinomas in pleomorphic adenoma (n=5), acinic cell carcinomas (n=5), squamous cell carcinomas (n=10) and high-grade mucoepidermoid carcinomas (n=2) were positive. The lymphomas (n=5) and low-grade mucoepidermoid carcinomas (n=1) were Mena negative. In one case the lymphoblastic cells stained positive for Mena. Some of the endothelial cells, in the peritumoral vessels, were Mena positive. To the best of our knowledge, this is the first study in the literature about Mena expression in salivary tumors. Our study suggests that Mena protein seems to play a role in malignant transformation and its intensity is correlated with the type and grade of tumor and also with vascular invasion. Its positivity in endothelial cells may suggest its potential role in tumor angiogenesis.

‘Trained immunity’: consequences for lymphoid malignancies

PubMed Central

Stevens, Wendy B.C.; Netea, Mihai G.; Kater, Arnon P.; van der Velden, Walter J.F.M.

2016-01-01

In hematological malignancies complex interactions exist between the immune system, microorganisms and malignant cells. On one hand, microorganisms can induce cancer, as illustrated by specific infection-induced lymphoproliferative diseases such as Helicobacter pylori-associated gastric mucosa-associated lymphoid tissue lymphoma. On the other hand, malignant cells create an immunosuppressive environment for their own benefit, but this also results in an increased risk of infections. Disrupted innate immunity contributes to the neoplastic transformation of blood cells by several mechanisms, including the uncontrolled clearance of microbial and autoantigens resulting in chronic immune stimulation and proliferation, chronic inflammation, and defective immune surveillance and anti-cancer immunity. Restoring dysfunction or enhancing responsiveness of the innate immune system might therefore represent a new angle for the prevention and treatment of hematological malignancies, in particular lymphoid malignancies and associated infections. Recently, it has been shown that cells of the innate immune system, such as monocytes/macrophages and natural killer cells, harbor features of immunological memory and display enhanced functionality long-term after stimulation with certain microorganisms and vaccines. These functional changes rely on epigenetic reprogramming and have been termed ‘trained immunity’. In this review the concept of ‘trained immunity’ is discussed in the setting of lymphoid malignancies. Amelioration of infectious complications and hematological disease progression can be envisioned to result from the induction of trained immunity, but future studies are required to prove this exciting new hypothesis. PMID:27903713

Diagnosis and treatment of concurrent dermal malignant melanoma and melanocytomas in a pygmy hippopotamus (Choeropsis liberiensis).

PubMed

Saunders, Richard A; Killick, Rowena S; Barrows, Michelle G; Bowlt, Kelly A; Denk, Daniella

2017-10-01

Dermal melanocytic neoplasms are common in some even-toed ungulates (Artiodactyla), yet this entity has not been reported in the pygmy hippopotamus to date. Concurrent occurrence of multiple benign and malignant melanocytic neoplasms is unusual. Malignant transformation occurs in a small percentage of benign melanocytic tumours in people but this phenomenon has not been well documented in animals. To report the diagnosis and treatment of concurrent dermal melanocytomas and malignant melanomas in a pygmy hippopotamus. A 36-year-old intact male pygmy hippopotamus, part of a zoological collection, housed with a 10-year-old female of the same species, presented with multiple raised and pigmented skin masses. Initial impression smears of one ulcerated lesion were consistent with inflammation; subsequent histopathological findings from a skin biopsy revealed an underlying malignant melanoma. The animal was anaesthetised, ultrasonographic imaging of the local lymph nodes indicated no local involvement and all skin lesions were removed. Recovery from anaesthesia was unremarkable, skin healing was within normal limits for the species. There was no sign of recurrence 34 months post-surgery. A diagnosis of malignant melanomas and concurrent melanocytomas was made on histopathological evaluation. To the best of the authors' knowledge, this is the first reported case of melanocytic neoplasia in the pygmy hippopotamus. The occurrence of both benign and malignant melanocytic skin tumours should be considered in this species. © 2017 ESVD and ACVD.

Multistep carcinogenesis of normal human fibroblasts. Human fibroblasts immortalized by repeated treatment with Co-60 gamma rays were transformed into tumorigenic cells with Ha-ras oncogenes.

PubMed

Namba, M; Nishitani, K; Fukushima, F; Kimoto, T

1988-01-01

Two normal mortal human fibroblast cell strains were transformed into immortal cell lines, SUSM-1 and KMST-6, by treatment with 4-nitroquinoline 1-oxide (4NQO) and Co-60 gamma rays, respectively. These immortalized cell lines showed morphological changes of cells and remarkable chromosome aberrations, but neither of them grew in soft agar or formed tumors in nude mice. The immortal cell line, KMST-6, was then converted into neoplastic cells by treatment with Harvey murine sarcoma virus (Ha-MSV) or the c-Ha-ras oncogene derived from a human lung carcinoma. These neoplastically transformed cells acquired anchorage-independent growth potential and developed tumors when transplanted into nude mice. All the tumors grew progressively without regression until the animals died of tumors. In addition, the tumors were transplantable into other nude mice. Normal human fibroblasts, on the other hand, were not transformed into either immortal or tumorigenic cells by treatment with Ha-MSV or c-Ha-ras alone. Our present data indicate that (1) the chemical carcinogen, 4NQO, or gamma rays worked as an initiator of carcinogenesis in normal human cells, giving rise to immortality, and (2) the ras gene played a role in the progression of the immortally transformed cells to more malignant cells showing anchorage-independent growth and tumorigenicity. In other words, the immortalization process of human cells seems to be a pivotal or rate-limiting step in the carcinogenesis of human cells.

Beclin-1 Expression in Normal Bladder and in Cd+2 and As+3 Exposed and Transformed Human Urothelial Cells (UROtsa)

PubMed Central

Larson, Jennifer L.; Somji, Seema; Zhou, Xu Dong; Sens, Mary Ann; Garrett, Scott H.; Sens, Donald A.; Dunlevy, Jane R.

2010-01-01

The expression of beclin-1 in normal human bladder and in Cd+2 and As+3 exposed and transformed urothelial cells (UROtsa) was examined in this study. It was shown using a combination of real time PCR, western analysis and immunohistochemistry that beclin-1 was expressed in the urothelial cells of the normal bladder. It was also demonstrated that the parental UROtsa cell line expressed beclin-1 mRNA and protein at levels similar to that of the in situ urothelium. The level of beclin-1 expression underwent only modest alterations when the UROtsa cells were malignantly transformed by Cd+2 or As+3 or when the parental cells were exposed acutely to Cd+2 or As+3. While there were instances of significant alterations at individual time points and within cell line-to-cell line comparisons there was no evidence of a dose response relationship or correlations to the phenotypic properties of the cell lines. Similar results were obtained for the expression of the Atg-5, Atg-7, Atg-12 and LC3B autophagy-related proteins. The findings provide initial evidence for beclin-1 expression in normal bladder and that large alterations in the expression of beclin-1 and associated proteins do not occur when human urothelial cells are malignantly transformed with, or exposed to, either Cd+2 or As+3. PMID:20206246

Schneiderian papillomas: Comparative review of exophytic, oncocytic, and inverted types

PubMed Central

Vira, Darshni; Suh, Jeffrey D.; Bhuta, Sunita; Wang, Marilene B.

2013-01-01

Background: Sinonasal papillomas are benign epithelial neoplasms arising from Schneiderian mucosa. The three subtypes, exophytic, oncocytic, and inverted (inverted papilloma [IP]), should be distinguished from one another histopathologically. This study (1) highlights the histopathological and clinical differences between the Schneiderian papilloma subtypes and (2) identifies clinical features that potentially predict papilloma subtypes. Methods: A retrospective review was performed of patients with Schneiderian papillomas over an 11-year period. Results: Seventy patients with sinonasal papillomas who underwent sinus surgery were identified. There were 50 (71%) male and 20 (29%) female subjects diagnosed at an average age of 53 years (range, 13–80 years). Exophytic (n = 25), oncocytic (n = 9), and IP (n = 37) were identified. IP was associated with transformation into squamous cell carcinoma in three (8%) cases and dysplasia in three (8%) cases. Neither oncocytic nor exophytic subtypes were associated with dysplasia or malignancy. On multivariate analysis of potential predictors of papilloma subtype, history of chronic rhinosinusitis (CRS) and location of papilloma were significantly associated with papilloma subtype. Using classification and regression tree model, papilloma subtypes can be predicted based on presence or absence of CRS and papilloma location with nominal 82.4% accuracy. Conclusion: The inverted and exophytic type are the most common sinonasal papillomas, with the inverted type having an 8% rate of malignant transformation in this study. In contrast, the oncocytic type was not associated with dysplasia or malignancy in our series despite reports in the literature indicating malignant potential. History of CRS and papilloma location can provide clues to the histological subtype, which is important for surgical planning and patient counseling. PMID:23883810

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

Oncogenic signalling pathways in benign odontogenic cysts and tumours.

PubMed

Diniz, Marina Gonçalves; Gomes, Carolina Cavalieri; de Sousa, Sílvia Ferreira; Xavier, Guilherme Machado; Gomez, Ricardo Santiago

2017-09-01

The first step towards the prevention of cancer is to develop an in-depth understanding of tumourigenesis and the molecular basis of malignant transformation. What drives tumour initiation? Why do most benign tumours fail to metastasize? Oncogenic mutations, previously considered to be the hallmark drivers of cancers, are reported in benign cysts and tumours, including those that have an odontogenic origin. Despite the presence of such alterations, the vast majority of odontogenic lesions are benign and never progress to the stage of malignant transformation. As these lesions are likely to develop due to developmental defects, it is possible that they harbour quiet genomes. Now the question arises - do they result from DNA replication errors? Specific candidate genes have been sequenced in odontogenic lesions, revealing recurrent BRAF mutation in the case of ameloblastoma, KRAS mutation in adenomatoid odontogenic tumours, PTCH1 mutation in odontogenic keratocysts, and CTNNB1 (Beta-catenin) mutation in calcifying odontogenic cysts. Studies on these benign and rare entities might reveal important information about the tumorigenic process and the mechanisms that hinder/halt neoplastic progression. This is because the role of relatively common oncogenic mutations seems to be context dependent. In this review, each mutation signature of the odontogenic lesion and the affected signalling pathways are discussed in the context of tooth development and tumorigenesis. Furthermore, behavioural differences between different types of odontogenic lesions are explored and discussed based on the molecular alteration described. This review also includes the employment of molecular results for guiding therapeutic approaches towards odontogenic lesions. Copyright © 2017 Elsevier Ltd. All rights reserved.

Pattern of galectins expression in actinic cheilitis with different risks of malignant transformation.

PubMed

Lopes, Maria Luiza Diniz de Sousa; Nonaka, Cassiano Francisco Weege; Queiroz, Lélia Maria Guedes; de Souza, Lélia Batista; Miguel, Márcia Cristina da Costa; da Silveira, Éricka Janine Dantas

2016-09-01

Actinic cheilitis (AC) is a chronic inflammatory lesion that in some situations can turn into squamous cell carcinoma of the lip. The molecular mechanisms involved in this process are not yet completely understood. This study aimed to investigate the expression pattern of galectins in actinic cheilitis according to the histopathological grading. Immunoexpression of galectin-1, galectin-3, galectin-7, and galectin-9 was semiquantitatively analyzed in 65 cases of actinic cheilitis graded as low risk (n = 40) or high risk (n = 25) of malignant transformation. Association between the location of the galectins in the cellular compartments and histopathological grading was analyzed. Galectin-1 was mainly observed in the cell cytoplasm, and was elevated (score 3) in 60% of cases, regardless of the histopathological grade (P > 0.05). Galectin-3 expression was higher in high-risk group than in the low-risk group (P < 0.05), with a predominant expression in the cytoplasm and nucleus of low-risk (67.5%), and only in the cytoplasm of high-risk cases (60%) (P < 0.05). Galectin-7 expression did not show significant differences between low-risk and high-risk groups (P > 0.05). With respect to galectin-9, 89.2% of cases were positive, showing decrease in median of scores as there was an increase in histological grade (P < 0.001), with predominant expression in the nucleus and cytoplasm. This study is the first indication of galectins involvement in the pathogenesis and morphologic progression of actinic cheilitis, particularly galectin-3 and galectin-9. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Cadherin-11 in poor prognosis malignancies and rheumatoid arthritis: common target, common therapies

PubMed Central

Hampel, Constanze; Anastasiadis, Panos Z.; Kallakury, Bhaskar; Uren, Aykut; Foley, David W; Brown, Milton L.; Shapiro, Lawrence; Brenner, Michael; Haigh, David; Byers, Stephen W.

2014-01-01

Cadherin-11 (CDH11), associated with epithelial to mesenchymal transformation in development, poor prognosis malignancies and cancer stem cells, is also a major therapeutic target in rheumatoid arthritis (RA). CDH11 expressing basal-like breast carcinomas and other CDH11 expressing malignancies exhibit poor prognosis. We show that CDH11 is increased early in breast cancer and ductal carcinoma in-situ. CDH11 knockdown and antibodies effective in RA slowed the growth of basal-like breast tumors and decreased proliferation and colony formation of breast, glioblastoma and prostate cancer cells. The repurposed arthritis drug celecoxib, which binds to CDH11, and other small molecules designed to bind CDH11 without inhibiting COX-2 preferentially affect the growth of CDH11 positive cancer cells in vitro and in animals. These data suggest that CDH11 is important for malignant progression, and is a therapeutic target in arthritis and cancer with the potential for rapid clinical translation PMID:24681547

Transformation of Epithelial Ovarian Cancer Stemlike Cells into Mesenchymal Lineage via EMT Results in Cellular Heterogeneity and Supports Tumor Engraftment

PubMed Central

Jiang, Hua; Lin, Xiaolong; Liu, Yingtao; Gong, Wenjia; Ma, Xiaoling; Yu, Yinhua; Xie, Yi; Sun, Xiaoxi; Feng, Youji; Janzen, Viktor; Chen, Tong

2012-01-01

Ovarian cancers are heterogeneous and contain stemlike cells that are able to self-renew and are responsible for sustained tumor growth. Metastasis in the peritoneal cavity occurs more frequently in ovarian cancer than in other malignancies, but the underlying mechanism remains largely unknown. We have identified that ovarian cancer stemlike cells (CSCs), which were defined as side population (SP) cells, were present in patients’ ascitic fluid and mesenchymally transformed cell lines, ES-2 and HO-8910PM. SP cells, which were sorted from both cell lines and implanted into immunocompromised mice, were localized to the xenografted tumor boundary. In addition, SP cells exhibited an epithelial phenotype and showed a distinct gene expression profile with reduced expression of cell adhesion molecules (CAMs), indicating that SP cells exert an important role in ovarian cancer progression on the basis of their delicate interaction with the surrounding microenvironment and anatomical localization in tumors. In contrast, non-SP cells exhibited a more mesenchymal phenotype and showed more increased invasive potential than SP cells. This heterogeneity was observed as an endogenous transformation via the epithelial–mesenchymal transition (EMT) process. Inhibition of the EMT process by Snail1 silencing reduced the SP cell frequency, and affected their invasive capacity and engraftment. These findings illustrate the interplay between epithelial ovarian CSCs and the EMT, and exert a link to explain tumor heterogeneity and its necessity for ovarian cancer maintenance, metastasis and progression. PMID:22801793

Exome sequencing of bilateral testicular germ cell tumors suggests independent development lineages.

PubMed

Brabrand, Sigmund; Johannessen, Bjarne; Axcrona, Ulrika; Kraggerud, Sigrid M; Berg, Kaja G; Bakken, Anne C; Bruun, Jarle; Fosså, Sophie D; Lothe, Ragnhild A; Lehne, Gustav; Skotheim, Rolf I

2015-02-01

Intratubular germ cell neoplasia, the precursor of testicular germ cell tumors (TGCTs), is hypothesized to arise during embryogenesis from developmentally arrested primordial germ cells (PGCs) or gonocytes. In early embryonal life, the PGCs migrate from the yolk sac to the dorsal body wall where the cell population separates before colonizing the genital ridges. However, whether the malignant transformation takes place before or after this separation is controversial. We have explored the somatic exome-wide mutational spectra of bilateral TGCT to provide novel insight into the in utero critical time frame of malignant transformation and TGCT pathogenesis. Exome sequencing was performed in five patients with bilateral TGCT (eight tumors), of these three patients in whom both tumors were available (six tumors) and two patients each with only one available tumor (two tumors). Selected loci were explored by Sanger sequencing in 71 patients with bilateral TGCT. From the exome-wide mutational spectra, no identical mutations in any of the three bilateral tumor pairs were identified. Exome sequencing of all eight tumors revealed 87 somatic non-synonymous mutations (median 10 per tumor; range 5-21), some in already known cancer genes such as CIITA, NEB, platelet-derived growth factor receptor α (PDGFRA), and WHSC1. SUPT6H was found recurrently mutated in two tumors. We suggest independent development lineages of bilateral TGCT. Thus, malignant transformation into intratubular germ cell neoplasia is likely to occur after the migration of PGCs. We reveal possible drivers of TGCT pathogenesis, such as mutated PDGFRA, potentially with therapeutic implications for TGCT patients. Copyright © 2014 Neoplasia Press, Inc. Published by Elsevier Inc. All rights reserved.

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.

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.

Cytomics - importance of multimodal analysis of cell function and proliferation in oncology.

PubMed

Tárnok, A; Bocsi, J; Brockhoff, G

2006-12-01

Cancer is a highly complex and heterogeneous disease involving a succession of genetic changes (frequently caused or accompanied by exogenous trauma), and resulting in a molecular phenotype that in turn results in a malignant specification. The development of malignancy has been described as a multistep process involving self-sufficiency in growth signals, insensitivity to antigrowth signals, evasion of apoptosis, limitless replicative potential, sustained angiogenesis, and finally tissue invasion and metastasis. The quantitative analysis of networking molecules within the cells might be applied to understand native-state tissue signalling biology, complex drug actions and dysfunctional signalling in transformed cells, that is, in cancer cells. High-content and high-throughput single-cell analysis can lead to systems biology and cytomics. The application of cytomics in cancer research and diagnostics is very broad, ranging from the better understanding of the tumour cell biology to the identification of residual tumour cells after treatment, to drug discovery. The ultimate goal is to pinpoint in detail these processes on the molecular, cellular and tissue level. A comprehensive knowledge of these will require tissue analysis, which is multiplex and functional; thus, vast amounts of data are being collected from current genomic and proteomic platforms for integration and interpretation as well as for new varieties of updated cytomics technology. This overview will briefly highlight the most important aspects of this continuously developing field.

Choline metabolism in malignant transformation

PubMed Central

Glunde, Kristine; Bhujwalla, Zaver M.; Ronen, Sabrina M.

2015-01-01

Abnormal choline metabolism is emerging as a metabolic hallmark that is associated with oncogenesis and tumour progression. Following transformation, the modulation of enzymes that control anabolic and catabolic pathways causes increased levels of choline-containing precursors and breakdown products of membrane phospholipids. These increased levels are associated with proliferation, and recent studies emphasize the complex reciprocal interactions between oncogenic signalling and choline metabolism. Because choline-containing compounds are detected by non-invasive magnetic resonance spectroscopy (MRS), increased levels of these compounds provide a non-invasive biomarker of transformation, staging and response to therapy. Furthermore, enzymes of choline metabolism, such as choline kinase, present novel targets for image-guided cancer therapy. PMID:22089420

Chronic myeloid leukemia among patients with a history of prior malignancies: A tale of dual survivorship.

PubMed

Koller, Paul B; Kantarjian, Hagop M; Nogueras-Gonzalez, Graciela M; Jabbour, Elias; Verstovsek, Srdan; Borthakur, Gautam; Estrov, Zeev; Wierda, William G; Garcia-Manero, Guillermo; Ferrajoli, Alessandra; Ravandi, Farhad; O'Brien, Susan M; Cortes, Jorge E

2017-02-15

Some patients with chronic myeloid leukemia (CML) have a history of previous malignancies. To the authors' knowledge, outcomes for CML diagnosed in these patients have not been well described. The current study was conducted to determine the outcome of patients with CML and a history of prior malignancies. The current study included patients who were enrolled in clinical trials of tyrosine kinase inhibitors as initial therapy for CML in chronic phase from July 2000 to January 2014. Of the 630 patients with CML who were treated with frontline tyrosine kinase inhibitors, 626 had a known prior malignancy status. Of these, 45 patients (7%) had a prior malignancy other than nonmelanoma skin cancer whereas 17 patients (3%) had a history of nonmelanoma skin cancers alone. Characteristics of CML were similar between the patients with no prior malignancy, those with a prior malignancy, and those with nonmelanoma skin cancer. Patients with a prior malignancy were found to have an older median age compared with the other 2 groups. The most common prior malignancies were nonmelanoma skin cancer in 20 patients, breast cancer in 11 patients, melanoma in 7 patients, prostate cancer in 6 patients, and colorectal cancer in 5 patients. With regard to CML, the event-free survival, transformation-free survival, and failure-free survival rates were found to be similar between the groups. There was a statistically significantly decreased survival in the group with a prior malignancy versus the group with no prior malignancy versus the group with nonmelanoma skin cancer. In a multivariate analysis, advanced age and an elevated creatinine level were found to be associated with worse survival after a diagnosis of CML. Patients with CML with a history of prior malignancies appear to have the same excellent outcome as patients with no prior malignancies. In the few instances in which concomitant therapy for other malignancies was required during therapy with tyrosine kinase inhibitors, this was able to be accomplished without significant toxicity. Cancer 2017;123:609-616. © 2016 American Cancer Society. © 2016 American Cancer Society.

Computerized lung cancer malignancy level analysis using 3D texture features

NASA Astrophysics Data System (ADS)

Sun, Wenqing; Huang, Xia; Tseng, Tzu-Liang; Zhang, Jianying; Qian, Wei

2016-03-01

Based on the likelihood of malignancy, the nodules are classified into five different levels in Lung Image Database Consortium (LIDC) database. In this study, we tested the possibility of using threedimensional (3D) texture features to identify the malignancy level of each nodule. Five groups of features were implemented and tested on 172 nodules with confident malignancy levels from four radiologists. These five feature groups are: grey level co-occurrence matrix (GLCM) features, local binary pattern (LBP) features, scale-invariant feature transform (SIFT) features, steerable features, and wavelet features. Because of the high dimensionality of our proposed features, multidimensional scaling (MDS) was used for dimension reduction. RUSBoost was applied for our extracted features for classification, due to its advantages in handling imbalanced dataset. Each group of features and the final combined features were used to classify nodules highly suspicious for cancer (level 5) and moderately suspicious (level 4). The results showed that the area under the curve (AUC) and accuracy are 0.7659 and 0.8365 when using the finalized features. These features were also tested on differentiating benign and malignant cases, and the reported AUC and accuracy were 0.8901 and 0.9353.

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.

Malignant transformation of a 5-mm gallbladder polyp over 2 years: a case report and review of current literature.

PubMed

Lu, Darren; Radin, Randall; Yung, Evan; Tchelepi, Hisham

2015-03-01

Gallbladder polyps (GBPs) are incidentally seen in 4% to 7% of adults on abdominal ultrasounds. Most GBPs are benign cholesterol polyps, adenomyomatosis, or inflammatory polyps. Currently, cholecystectomy is widely accepted as appropriate care for polyps 10 mm or larger as they present a higher risk for malignancy. However, the management of small polyps smaller than 10 mm has continued to be a dilemma to clinicians and radiologists. Many authors support a nonoperative approach with imaging follow-up for polyps smaller than 10 mm, as most have been shown to be benign. However, small polyps do have the potential to be neoplastic adenomas and become malignant. In this report, we will describe a case of a tiny GBP that subsequently developed into a 20-mm carcinoma over a period of 2 years.

The association of mammalian DREAM complex and HPV16 E7 proteins

PubMed Central

Rashid, Nurshamimi Nor; Rothan, Hussin A; Yusoff, Mohd Shahrizal Mohd

2015-01-01

The mammalian DREAM (Drosophila, RB, E2F, and Myb) complex was discovered in 2004 by several research groups. It was initially identified in Drosophila followed by Caenorhaditis elegans and later in mammalian cells. The composition of DREAM is temporally regulated during cell cycle; being associated with E2F-4 and either p107 or p130 in G0/G1 (repressive DREAM complexes) and with B-myb transcription factor in S/G2 (activator DREAM complex). High risk human papillomavirus (HPV) E6 and E7 oncoproteins expression are important for malignant transformation of cervical cancer cells. In particular, the E7 of high risk HPV binds to pRB family members (pRB, p107 and p130) for degradation. It has recently been discovered that the p107 and p130 ‘pocket proteins’ are members of mammalian DREAM complexes. With this understanding, we would like to hypothesise the mammalian DREAM complex could plays a critical role for malignant transformation in cervical cancer cells. PMID:26885443

Risk Factors of Recurrence and Malignant Transformation of Sinonasal Inverted Papilloma

PubMed Central

Ścierski, Wojciech; Misiołek, Maciej

2017-01-01

Sinonasal inverted papilloma is a relatively rare disease; however, it is prevalent enough for every ENT practitioner to encounter it several times throughout medical routines. Despite the developments in experimental and clinical medicine as well as surgical techniques, our knowledge of this disease is still inadequate. With improved imaging and better diagnostic techniques, proper diagnosis and qualification for surgical approaches leave no doubt. Although the endoscopic approach seems to be the gold standard for such condition, some cases may additionally require an external approach. Regardless of the type of surgery, postoperative management is crucial for both healing and long-term follow-up. Unfortunately, the procedures are still lacking in explicit and standardized postoperative management guidelines. Moreover, an important issue is still the need for a biomarker indicative of inverted papilloma and its malignant transformation. Several particles, within the spotlight of the researchers, have been SCCA, Ki-67, Bcl-2, Wnt proteins, and many more. Nevertheless, the topic requires further investigations. PMID:29250552

Mazabraud syndrome associated with McCune-Albright syndrome: a case report and review of the literature.

PubMed

Biazzo, Alessio; Di Bernardo, Andrea; Parafioriti, Antonina; Confalonieri, Norberto

2017-08-23

Mazabraud syndrome is a very rare benign disorder characterized by the association of monostotic or polyostotic fibrous dysplasia and one or multiple intramuscular myxomas. McCune -Albright syndrome is a rare benign disorder characterized by the association of polyostotic fibrous dysplasia, cafè-au-lait skin pigmentations and endocrine dysfunction, such as precocious puberty, diabetes mellitus, goiter and breast fibroadenomatosis. The association of Mazabraud syndrome and McCune-Albright in the same patient is an anecdotal event. We report the case of a 28-year-old girl with Mazabraud syndrome associated with McCune-Albright syndrome. Our literature review shows that in these patients there is a higher risk of malignant transformation of fibrous dysplasia into osteosarcoma, confirming previous reports. Conversely, no malignant transformation has been reported for myxomas in isolated Mazabraud syndrome or in the association with McCune-Albright syndrome. We conclude that these patients should be scheduled to a close and long-term follow-up.

Clinicopathological study of 13 cases of squamous cell carcinoma complicating hidradenitis suppurativa.

PubMed

Lavogiez, C; Delaporte, E; Darras-Vercambre, S; Martin De Lassalle, E; Castillo, C; Mirabel, X; Laurent, F; Patenotre, P; Gheit, T; Talmant, J C; Beylot-Barry, M; Martinot, V; Piette, F; Aubin, F; Mortier, L

2010-01-01

To the best of our knowledge, only 52 cases of squamous cell carcinoma (SCC) complicating hidradenitis suppurativa (HS) have been reported since 1958. We describe 13 new cases. We propose a clinical and histological analysis of our cases. We include these results in a review of previously reported cases to analyze a total of 65 patients. In our series of 13 cases, we also investigate the presence of human papillomavirus (HPV) in tumor samples, by polymerase chain reaction (PCR) on paraffin-embedded material. Malignant transformation affects mainly men with a long-term history of genitoanal HS. Although our cases were 7 well-differentiated carcinomas and 6 verrucous carcinomas, lymphatic and visceral metastasis occurred in 2 and 3 cases, respectively. With PCR, we demonstrated presence of HPV in genitoanal tumoral lesions, principally HPV-16. SCC complicating HS evolves poorly, despite a good histological prognosis. Our results sustain the implication of HPV in the malignant transformation of HS.

[MALIGNANT TUMORS IN OVARIAN MATURE CYSTIC TERATOMAS INTRAOPERATIVE DIAGNOSTIC BASIS].

PubMed

Khachatryan, A

2016-11-01

Extremely rare ovarian primary tumors formed in a mature cystic teratomaare described in the literature. This research work studies the frequency of malignant mature cystic teratoma, as well as their clinical and morphological features and necessity of intraoperative histological examination of all teratomas. Cases histories of 56 patients, suffering from ovarian mature cystic teratomahave been studied in MC Shengavit in the period of 2003 - 2015. Among them 4 patients with the somatic malignancies were identified. Morphological methods, which are considered to be "gold standard" of tumor investigation, were used in staining the slides with hematoxylin - eosin. According to the literature the secondary malignant transformation rarely occurs and is typical in postmenopausal women, with a frequency of 0.17-3%. According to the results of our study, malignant tumors in mature cystic teratomas were observed in 4 (7,14%) from the total number of mature cystic teratomas (n=56). There was not revealed a correlation between the duration of the complaints, age of the patients, sizes of ovarian mature teratoma and malignization degree. Thus, the greatest difficulties of clinical diagnosis of malignant tumors in the ovarian mature cystic teratomas were in the early stage of the disease, because of a variety of clinical manifestations, not pathognomonic for malignization. All mentioned symptoms may be observed in the patients with usual mature cystic teratomas. Тhis cases confirm the necessity to take tissue samples from the other ovary for intraoperative histopathological evaluation in each case of mature cystic teratomas. It is necessary to examine a large number of tumor sites, to prevent errors in the assessment of the maturity degree of teratoma.

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

Pelch, Katherine E.; Tokar, Erik J.; Merrick, B. Alex

Previous work shows altered methylation patterns in inorganic arsenic (iAs)- or cadmium (Cd)-transformed epithelial cells. Here, the methylation status near the transcriptional start site was assessed in the normal human prostate epithelial cell line (RWPE-1) that was malignantly transformed by 10 μM Cd for 11 weeks (CTPE) or 5 μM iAs for 29 weeks (CAsE-PE), at which time cells showed multiple markers of acquired cancer phenotype. Next generation sequencing of the transcriptome of CAsE-PE cells identified multiple dysregulated genes. Of the most highly dysregulated genes, five genes that can be relevant to the carcinogenic process (S100P, HYAL1, NTM, NES, ALDH1A1)more » were chosen for an in-depth analysis of the DNA methylation profile. DNA was isolated, bisulfite converted, and combined bisulfite restriction analysis was used to identify differentially methylated CpG sites, which was confirmed with bisulfite sequencing. Four of the five genes showed differential methylation in transformants relative to control cells that was inversely related to altered gene expression. Increased expression of HYAL1 (> 25-fold) and S100P (> 40-fold) in transformants was correlated with hypomethylation near the transcriptional start site. Decreased expression of NES (> 15-fold) and NTM (> 1000-fold) in transformants was correlated with hypermethylation near the transcriptional start site. ALDH1A1 expression was differentially expressed in transformed cells but was not differentially methylated relative to control. In conclusion, altered gene expression observed in Cd and iAs transformed cells may result from altered DNA methylation status. - Highlights: • Cd and iAs are known human carcinogens, yet neither appears directly mutagenic. • Prior data suggest epigenetic modification plays a role in Cd or iAs induced cancer. • Altered methylation of four misregulated genes was found in Cd or iAs transformants. • The resulting altered gene expression may be relevant to cellular transformation.« less

Phenytoin Induced Cutaneous B Cell Pseudolymphoma

PubMed Central

Riyaz, Najeeba; Sasidharanpillai, Sarita; Aravindan, Karumathil P; Nobin, Babu K; Raghavan, Nisha T; Nikhila, Pappinissery K

2015-01-01

Cutaneous pseudolymphomas are benign lymphoproliferative processes mimicking lymphomas clinically and histologically. One of the precipitating factors for pseudolymphoma is drugs like anticonvulsants, antidepressants and angiotensin-converting enzyme inhibitors. According to existing literature phenytoin-induced cutaneous pseudolymphomas are usually T-cell predominant. Most often withdrawal of the drug with or without short-course systemic steroids can attain a cure. Rarely malignant transformation has been reported years later despite withdrawal of the offending drug, which necessitates a long-term follow up of the affected. We report an 80-year-old male patient who was receiving phenytoin sodium and who presented with diffuse erythema and infiltrated skin lesions which histologically resembled cutaneous B-cell lymphoma. Substituting phenytoin with levetiracetam achieved resolution of symptoms. Further evaluation was suggestive of a reactive process. A detailed drug history is of paramount importance in differentiating drug-induced pseudolymphoma from lymphoma. Searching literature we could not find any previous reports of phenytoin-induced cutaneous B-cell pseudolymphoma. PMID:26538730

High mobility group box associated with cell proliferation appears to play an important role in hepatocellular carcinogenesis in rats and humans.

PubMed

Suzuki, Shugo; Takeshita, Kentaro; Asamoto, Makoto; Takahashi, Satoru; Kandori, Hitoshi; Tsujimura, Kazunari; Saito, Fumiyo; Masuko, Kazuo; Shirai, Tomoyuki

2009-01-31

To identify genes important in hepatocellular carcinogenesis, especially processes involved in malignant transformation, we focused on differences in gene expression between adenomas and carcinomas by DNA microarray. Eighty-one genes for which expression was specific in carcinomas were analyzed using Ingenuity Pathway Analysis software and Gene Ontology, and found to be associated with TP53 and regulators of cell proliferation. In the genes associated with TP53, we selected high mobility group box (HMGB) for detailed analysis. Immunohistochemistry revealed expression of HMGBs in carcinomas to be significantly higher than in other lesions among both human and rat liver, and a positive correlation between HMGBs and TP53 was detected in rat carcinomas. Knock-down of HMGB 2 expression in a rat hepatocellular carcinoma cell line by RNAi resulted in inhibition of cell growth, although no effects on invasion were evident in vitro. These results suggest that acquisition of malignant potential in the liver requires specific signaling pathways related to high cell proliferation associated with TP53. In particular, HMGBs appear to have an important role for progression and cell proliferation associated with loss of TP53 function in rat and in human hepatocarcinogenesis.

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.

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.

Targeting the nucleolus for cancer intervention.

PubMed

Quin, Jaclyn E; Devlin, Jennifer R; Cameron, Donald; Hannan, Kate M; Pearson, Richard B; Hannan, Ross D

2014-06-01

The contribution of the nucleolus to cancer is well established with respect to its traditional role in facilitating ribosome biogenesis and proliferative capacity. More contemporary studies however, infer that nucleoli contribute a much broader role in malignant transformation. Specifically, extra-ribosomal functions of the nucleolus position it as a central integrator of cellular proliferation and stress signaling, and are emerging as important mechanisms for modulating how oncogenes and tumor suppressors operate in normal and malignant cells. The dependence of certain tumor cells to co-opt nucleolar processes to maintain their cancer phenotypes has now clearly been demonstrated by the application of small molecule inhibitors of RNA Polymerase I to block ribosomal DNA transcription and disrupt nucleolar function (Bywater et al., 2012 [1]). These drugs, which selectively kill tumor cells in vivo while sparing normal cells, have now progressed to clinical trials. It is likely that we have only just begun to scratch the surface of the potential of the nucleolus as a new target for cancer therapy, with "suppression of nucleolar stress" representing an emerging "hallmark" of cancer. This article is part of a Special Issue entitled: Role of the Nucleolus in Human Disease. Copyright © 2013 Elsevier B.V. All rights reserved.

Ideal-observer analysis of lesion detectability in planar, conventional SPECT, and dedicated SPECT scintimammography using effective multi-dimensional smoothing

NASA Astrophysics Data System (ADS)

La Riviere, P. J.; Pan, X.; Penney, B. C.

1998-06-01

Scintimammography, a nuclear-medicine imaging technique that relies on the preferential uptake of Tc-99m-sestamibi and other radionuclides in breast malignancies, has the potential to provide differentiation of mammographically suspicious lesions, as well as outright detection of malignancies in women with radiographically dense breasts. In this work we use the ideal-observer framework to quantify the detectability of a 1-cm lesion using three different imaging geometries: the planar technique that is the current clinical standard, conventional single-photon emission computed tomography (SPECT), in which the scintillation cameras rotate around the entire torso, and dedicated breast SPECT, in which the cameras rotate around the breast alone. We also introduce an adaptive smoothing technique for the processing of planar images and of sinograms that exploits Fourier transforms to achieve effective multidimensional smoothing at a reasonable computational cost. For the detection of a 1-cm lesion with a clinically typical 6:1 tumor-background ratio, we find ideal-observer signal-to-noise ratios (SNR) that suggest that the dedicated breast SPECT geometry is the most effective of the three, and that the adaptive, two-dimensional smoothing technique should enhance lesion detectability in the tomographic reconstructions.

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

A Rare Case of Multiple Segmental Eccrine Spiradenomas

PubMed Central

Englander, Laura; McClain, Danielle; Amin, Bijal; Turner, Ryan B.

2011-01-01

Eccrine spiradenoma is a benign adnexal neoplasm that has been historically designated as a tumor of eccrine differentiation, although current reconsideration indicates an apocrine process. It usually presents on the trunk and extremities as a tender dermal or subcutaneous papule or nodule frequently with a pink or blue hue. The clinical picture is often not distinct and biopsy is required for diagnosis. Eccrine spiradenoma can present in a variety of ways, including as tumors arranged in zosteriform/dermatomal and/or blaschkoid distributions, often precluding a straightforward diagnosis. Proper diagnosis of eccrine spiradenoma is important due to the occurrence of potentially life-threatening malignant transformation. This article illustrates a rare presentation of eccrine spiradenoma with a concise review for the dermatologist. PMID:21532877

The epigenetic landscape of aneuploidy: constitutional mosaicism leading the way?

PubMed

Davidsson, Josef

2014-02-01

The role of structural genetic changes in human disease has received substantial attention in recent decades, but surprisingly little is known about numerical chromosomal abnormalities, even though they have been recognized since the days of Boveri as partaking in different cellular pathophysiological processes such as cancer and genomic disorders. The current knowledge of the genetic and epigenetic consequences of aneuploidy is reviewed herein, with a special focus on using mosaic genetic syndromes to study the DNA methylation footprints and expressional effects associated with whole-chromosomal gains. Recent progress in understanding the debated role of aneuploidy as a driver or passenger in malignant transformation, as well as how the cell responds to and regulates excess genetic material in experimental settings, is also discussed in detail.

Ion Channels in Brain Metastasis

PubMed Central

Klumpp, Lukas; Sezgin, Efe C.; Eckert, Franziska; Huber, Stephan M.

2016-01-01

Breast cancer, lung cancer and melanoma exhibit a high metastatic tropism to the brain. Development of brain metastases severely worsens the prognosis of cancer patients and constrains curative treatment options. Metastasizing to the brain by cancer cells can be dissected in consecutive processes including epithelial–mesenchymal transition, evasion from the primary tumor, intravasation and circulation in the blood, extravasation across the blood–brain barrier, formation of metastatic niches, and colonization in the brain. Ion channels have been demonstrated to be aberrantly expressed in tumor cells where they regulate neoplastic transformation, malignant progression or therapy resistance. Moreover, many ion channel modulators are FDA-approved drugs and in clinical use proposing ion channels as druggable targets for future anti-cancer therapy. The present review article aims to summarize the current knowledge on the function of ion channels in the different processes of brain metastasis. The data suggest that certain channel types involving voltage-gated sodium channels, ATP-release channels, ionotropic neurotransmitter receptors and gap junction-generating connexins interfere with distinct processes of brain metastazation. PMID:27618016

Endorsing cellular competitiveness in aberrant epithelium of oral submucous fibrosis progression: neighbourhood analysis of immunohistochemical attributes.

PubMed

Anura, Anji; Kazi, Anees; Pal, Mousumi; Paul, Ranjan Rashmi; Sengupta, Sanghamitra; Chatterjee, Jyotirmoy

2018-04-23

Epithelial abnormality during the transformation of oral submucous fibrosis (OSF) into oral squamous cell carcinoma has been well studied and documented. However, the differential contribution of atrophy and hyperplasia for malignant potentiality of OSF is yet to be resolved. Existing diagnostic conjectures lack precise diagnostic attributes which may be effectively resolved by substantiation of specific molecular pathology signatures. Present study elucidates existence of cellular competitiveness in OSF conditions using computer-assisted neighbourhood analysis in quantitative immunohistochemistry (IHC) framework. The concept of field cancerization was contributory in finding correspondence among neighbouring cells of epithelial layers with reference to differential expression of cardinal cancer-related genes [c-Myc (oncogene), p53 (tumour suppressor), and HIF-1α (hypoxia regulator)] which are known to be important sensors in recognizing cellular competitive interface. Our analyses indicate that different states of OSF condition may be associated with different forms of competitiveness within epithelial neighbouring cells which might be responsible to shape the present and future of the pre-malignant condition. Analytical findings indicated association of atrophic epithelium with stress-driven competitive environment having low c-Myc, high-p53, and stable HIF-1α (the looser cells) which undergo apoptosis. Whereas, the cells with high c-Myc + (winner cells) give rise to hyperplastic epithelium via possible mutation in p53. The epithelial dysplasia plausibly occurs due to clonal expansion of c-Myc and p53 positive supercompetitor cells. Present study proposes quantitative IHC along with neighbourhood analysis which might help us to dig deeper on to the interaction among epithelial cell population to provide a better understanding of field cancerization and malignant transformation of pre-malignancy.

Bilateral primary malignant lymphoma of the breast.

PubMed

Shpitz, B; Witz, M; Kaufman, Z; Griffel, B; Manor, Y; Dinbar, A

1985-08-01

A rare case of bilateral primary malignant lymphoma of breast in a 76 year old woman is presented. The lesion was examined by electron microscopy and immunochemistry. The diagnosis of primary malignant lymphoma remains a diagnosis by exclusion and requires extensive work-up to exclude widespread malignant process. The behaviour of this malignancy tends to be an aggressive one and the prognosis is generally poor.

The management of menopause in women with a history of endometriosis: a systematic review

PubMed Central

Gemmell, L.C.; Webster, K.E.; Kirtley, S.; Vincent, K.; Zondervan, K.T.; Becker, C.M.

2017-01-01

Abstract BACKGROUND Endometriosis is typically regarded as a premenopausal disease, resolving after natural or iatrogenic menopause due to declining oestrogen levels. Nonetheless, case reports over the years have highlighted the incidence of recurrent postmenopausal endometriosis. It is now clear that both recurrence and malignant transformation of endometriotic foci can occur in the postmenopausal period. Postmenopausal women are commonly treated with hormone replacement therapy (HRT) to treat climacteric symptoms and prevent bone loss; however, HRT may reactivate endometriosis and stimulate malignant transformation in women with a history of endometriosis. Given the uncertain risks of initiating HRT, it is difficult to determine the best menopausal management for this group of women. OBJECTIVE AND RATIONAL The aim of this study was to systematically review the existing literature on management of menopausal symptoms in women with a history of endometriosis. We also aimed to evaluate the published literature on the risks associated with HRT in these women, and details regarding optimal formulations and timing (i.e. initiation and duration) of HRT. SEARCH METHODS Four electronic databases (MEDLINE via OVID, Embase via OVID, PsycINFO via OVID and CINAHL via EbscoHost) were searched from database inception until June 2016, using a combination of relevant controlled vocabulary terms and free-text terms related to ‘menopause’ and ‘endometriosis’. Inclusion criteria were: menopausal women with a history of endometriosis and menopausal treatment including HRT or other preparations. Case reports/series, observational studies and clinical trials were included. Narrative review articles, organizational guidelines and conference abstracts were excluded, as were studies that did not report on any form of menopausal management. Articles were assessed for risk of bias and quality using GRADE criteria. OUTCOMES We present a synthesis of the existing case reports of endometriosis recurrence or malignant transformation in women undergoing treatment for menopausal symptoms. We highlight common presenting symptoms, potential risk factors and outcomes amongst the studies. Sparse high-quality evidence was identified, with few observational studies and only two randomized controlled trials. Given this paucity of data, no definitive conclusions can be drawn concerning risk. WIDER IMPLICATIONS Due to the lack of high-quality studies, it remains unclear how to advise women with a history of endometriosis regarding the management of menopausal symptoms. The absolute risk of disease recurrence and malignant transformation cannot be quantified, and the impact of HRT use on these outcomes is not known. Multicentre randomized trials or large observational studies are urgently needed to inform clinicians and patients alike. PMID:28498913

The management of menopause in women with a history of endometriosis: a systematic review.

PubMed

Gemmell, L C; Webster, K E; Kirtley, S; Vincent, K; Zondervan, K T; Becker, C M

2017-07-01

Endometriosis is typically regarded as a premenopausal disease, resolving after natural or iatrogenic menopause due to declining oestrogen levels. Nonetheless, case reports over the years have highlighted the incidence of recurrent postmenopausal endometriosis. It is now clear that both recurrence and malignant transformation of endometriotic foci can occur in the postmenopausal period. Postmenopausal women are commonly treated with hormone replacement therapy (HRT) to treat climacteric symptoms and prevent bone loss; however, HRT may reactivate endometriosis and stimulate malignant transformation in women with a history of endometriosis. Given the uncertain risks of initiating HRT, it is difficult to determine the best menopausal management for this group of women. The aim of this study was to systematically review the existing literature on management of menopausal symptoms in women with a history of endometriosis. We also aimed to evaluate the published literature on the risks associated with HRT in these women, and details regarding optimal formulations and timing (i.e. initiation and duration) of HRT. Four electronic databases (MEDLINE via OVID, Embase via OVID, PsycINFO via OVID and CINAHL via EbscoHost) were searched from database inception until June 2016, using a combination of relevant controlled vocabulary terms and free-text terms related to 'menopause' and 'endometriosis'. Inclusion criteria were: menopausal women with a history of endometriosis and menopausal treatment including HRT or other preparations. Case reports/series, observational studies and clinical trials were included. Narrative review articles, organizational guidelines and conference abstracts were excluded, as were studies that did not report on any form of menopausal management. Articles were assessed for risk of bias and quality using GRADE criteria. We present a synthesis of the existing case reports of endometriosis recurrence or malignant transformation in women undergoing treatment for menopausal symptoms. We highlight common presenting symptoms, potential risk factors and outcomes amongst the studies. Sparse high-quality evidence was identified, with few observational studies and only two randomized controlled trials. Given this paucity of data, no definitive conclusions can be drawn concerning risk. Due to the lack of high-quality studies, it remains unclear how to advise women with a history of endometriosis regarding the management of menopausal symptoms. The absolute risk of disease recurrence and malignant transformation cannot be quantified, and the impact of HRT use on these outcomes is not known. Multicentre randomized trials or large observational studies are urgently needed to inform clinicians and patients alike. © The Author 2017. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology.

Active and passive immunization for cancer.

PubMed

Baxter, David

2014-01-01

Vaccination started around the 10th century AD as a means of preventing smallpox. By the end of the 19th century such therapeutic vaccines were well established with both active and passive preparations being used in clinical practice. Active immunization involved administering an immunogen that might be live/ attenuated, killed/ inactivated, toxoid or subunit in origin. Passive immunization involved giving pre-formed antibodies, usually to very recently exposed individuals. At about the same time such approaches were also tried to treat a variety of cancers - proof of principle for the protective role of the immune response against malignancy was established by the observation that tumors transplanted into syngeneic hosts were rejected by the host innate and adaptive responses. The impact of these therapeutic vaccination has taken a considerable time to become established - in part because target antigens against which an adaptive response can be directed do not appear to be uniquely expressed on malignant transformed cells; and also because tumor cells are able to manipulate their environment to downregulate the host immune response. Therapeutic cancer vaccines are also divided into active and passive types - the latter being subdivided into specific and non-specific vaccines. Active immunization utilizes an immunogen to generate a host response designed to eliminate the malignant cells, whereas in passive immunization preformed antibodies or cells are administered to directly eliminate the transformed cells - examples of each are considered in this review.

Active and passive immunization for cancer

PubMed Central

Baxter, David

2014-01-01

Vaccination started around the 10th century AD as a means of preventing smallpox. By the end of the 19th century such therapeutic vaccines were well established with both active and passive preparations being used in clinical practice. Active immunization involved administering an immunogen that might be live/ attenuated, killed/ inactivated, toxoid or subunit in origin. Passive immunization involved giving pre-formed antibodies, usually to very recently exposed individuals. At about the same time such approaches were also tried to treat a variety of cancers – proof of principle for the protective role of the immune response against malignancy was established by the observation that tumors transplanted into syngeneic hosts were rejected by the host innate and adaptive responses. The impact of these therapeutic vaccination has taken a considerable time to become established - in part because target antigens against which an adaptive response can be directed do not appear to be uniquely expressed on malignant transformed cells; and also because tumor cells are able to manipulate their environment to downregulate the host immune response. Therapeutic cancer vaccines are also divided into active and passive types – the latter being subdivided into specific and non-specific vaccines. Active immunization utilizes an immunogen to generate a host response designed to eliminate the malignant cells, whereas in passive immunization preformed antibodies or cells are administered to directly eliminate the transformed cells - examples of each are considered in this review. PMID:25424829

Myofibrillogenesis regulator 1 (MR-1): a potential therapeutic target for cancer and PNKD.

PubMed

Wang, Junxia; Zhao, Wuli; Liu, Hong; He, Hongwei; Shao, Rongguang

2017-11-15

Human myofibrillogenesis regulator 1 (MR-1) is a functional gene also known as paroxysmal nonkinesigenic dyskinesia (PNKD). It is localised on human chromosome 2q35 and three different isomers, MR-1L, MR-1M and MR-1S, are formed by alternative splicing. MR-1S promotes cardiac hypertrophy and is closely related to cancer. MR-1S is overexpressed in haematologic and solid malignancies, such as hepatoma, breast cancer and chronic myelogenous leukaemia. MR-1S causes disordered cell differentiation, initiates malignant transformation and accelerates metastasis. MR-1S directly phosphorylates and activates the MEK-ERK-RSK pathway to accelerate cancer growth and facilitates metastasis by activating the MLC2-FAK-AKT pathway. Silencing MR-1 inhibits cancer cell proliferation and metastasis. MR-1S causes disordered cell differentiation, initiates malignant transformation and accelerates metastasis. MR-1 interacts with eukaryotic translation initiation factors and MRIP-1, which contains Ras GTPase, PH and zinc-containing ArfGap domains, as well as three ankyrin repeats. Mutations in the N-terminal region of MR-1L and MR-1S are the main causes of PNKD (a hereditary disease characterised by paroxysmal dystonic choreoathetosis) and targeting the mutated protein could provide symptomatic relief. These findings provide compelling evidence that MR-1 might be a diagnostic marker and therapeutic target for solid tumours, myelogenous leukaemia and PNKD.

Low level exposure to monomethyl arsonous acid-induced the over-production of inflammation-related cytokines and the activation of cell signals associated with tumor progression in a urothelial cell model

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

Escudero-Lourdes, C., E-mail: cescuder@uaslp.m; Medeiros, M.K.; Cardenas-Gonzalez, M.C.

2010-04-15

Human bladder cancer has been associated with chronic exposure to arsenic. Chronic exposure of an immortalized non-tumorigenic urothelial cell line (UROtsa cells) to arsenicals has transformed these cells to a malignant phenotype, but the involved mechanisms are not fully understood. Chronic inflammation has been linked with cancer development mainly because many pro-inflammatory cytokines, growth factors as well as angiogenic chemokines have been found in tumors. In this study the chronology of inflammatory cytokines production was profiled in UROtsa cells chronically exposed to the toxic arsenic metabolite, monomethylarsonous acid [50 nM MMA(III)] to know the role of inflammation in cell transformation.more » Acute 50 nM MMA(III) exposure induced over-production of many pro-inflammatory cytokines as soon as 12 h after acute exposure. The same cytokines remain over-regulated after chronic exposure to 50 nM MMA(III), especially after 3 mo exposure. At 3 mo exposure the sustained production of cytokines like IL-1, IL-6, IL-8 and TNF is coincident with the appearance of characteristics associated with cell transformation seen in other arsenic-UROtsa studies. The sustained and increased activation of NFkappaB and c-Jun is also present along the transformation process and the phosphorylated proteins p38 MAPK and ERK 1/2 are increased also through the time line. Taken together these results support the notion that chronic inflammation is associated within MMA(III)-induced cell transformation and may act as a promoting factor in UROtsa cell transformation.« less

Mesenchymal stromal cells of osteosarcoma patients do not show evidence of neoplastic changes during long-term culture.

PubMed

Buddingh, Emilie P; Ruslan, S Eriaty N; Reijnders, Christianne M A; Szuhai, Karoly; Kuijjer, Marieke L; Roelofs, Helene; Hogendoorn, Pancras C W; Maarten Egeler, R; Cleton-Jansen, Anne-Marie; Lankester, Arjan C

2015-01-01

In vitro expanded mesenchymal stromal cells (MSCs) are increasingly used as experimental cellular therapy. However, there have been concerns regarding the safety of their use, particularly with regard to possible oncogenic transformation. MSCs are the hypothesized precursor cells of high-grade osteosarcoma, a tumor with often complex karyotypes occurring mainly in adolescents and young adults. To determine if MSCs from osteosarcoma patients could be predisposed to malignant transformation we cultured MSCs of nine osteosarcoma patients and five healthy donors for an average of 649 days (range 601-679 days). Also, we compared MSCs derived from osteosarcoma patients at diagnosis and from healthy donors using genome wide gene expression profiling. Upon increasing passage, increasing frequencies of binucleate cells were detected, but no increase in proliferation suggestive of malignant transformation occurred in MSCs from either patients or donors. Hematopoietic cell specific Lyn substrate 1 (HLCS1) was differentially expressed (fold change 0.25, P value 0.0005) between MSCs of osteosarcoma patients (n = 14) and healthy donors (n = 9). This study shows that although HCLS1 expression was downregulated in MSCs of osteosarcoma patients and binucleate cells were present in both patient and donor derived MSCs, there was no evidence of neoplastic changes to occur during long-term culture.

HTLV-1 Tax protects against CD95-mediated apoptosis by induction of the cellular FLICE-inhibitory protein (c-FLIP).

PubMed

Krueger, Andreas; Fas, Stefanie C; Giaisi, Marco; Bleumink, Marc; Merling, Anette; Stumpf, Christine; Baumann, Sven; Holtkotte, Denise; Bosch, Valerie; Krammer, Peter H; Li-Weber, Min

2006-05-15

The HTLV-1 transactivator protein Tax is essential for malignant transformation of CD4 T cells, ultimately leading to adult T-cell leukemia/lymphoma (ATL). Malignant transformation may involve development of apoptosis resistance. In this study we investigated the molecular mechanisms by which HTLV-1 Tax confers resistance toward CD95-mediated apoptosis. We show that Tax-expressing T-cell lines derived from HTLV-1-infected patients express elevated levels of c-FLIP(L) and c-FLIP(S). The levels of c-FLIP correlated with resistance toward CD95-mediated apoptosis. Using an inducible system we demonstrated that both resistance toward CD95-mediated apoptosis and induction of c-FLIP are dependent on Tax. In addition, analysis of early cleavage of the BH3-only Bcl-2 family member Bid, a direct caspase-8 substrate, revealed that apoptosis is inhibited at a CD95 death receptor proximal level in Tax-expressing cells. Finally, using siRNA we directly showed that c-FLIP confers Tax-mediated resistance toward CD95-mediated apoptosis. In conclusion, our data suggest an important mechanism by which expression of HTLV-1 Tax may lead to immune escape of infected T cells and, thus, to persistent infection and transformation.

Spectral karyotyping (SKY) analysis of heritable effects of radiation-induced malignant transformation

NASA Astrophysics Data System (ADS)

Zitzelsberger, Horst; Fung, Jingly; Janish, C.; McNamara, George; Bryant, P. E.; Riches, A. C.; Weier, Heinz-Ulli G.

1999-05-01

Radiocarcinogenesis is widely recognized as occupational, environmental and therapeutical hazard, but the underlying mechanisms and cellular targets have not yet been identified. We applied SKY to study chromosomal rearrangements leading to malignant transformation of irradiated thyroid epithelial cells. SKY is a recently developed technique to detect translocations involving non-homologous based on unique staining of all 24 human chromosomes by hybridization with a mixture of whole chromosome painting probes. A tuneable interferometer mounted on a fluorescence microscope in front of a CCD camera allows to record the 400 nm - 1000 nm fluorescence spectrum for each pixel in the image. After background correction, spectra recorded for each pixel are compared to reference spectra stored previously for each chromosome-specific probe. Thus, pixel spectra can be associated with specific chromosomes and displayed in 'classification' colors, which are defined so that even small translocations become readily discernible. SKY analysis was performed on several radiation-transformed cell lines. Line S48T was generated from a primary tumor of a child exposed to elevated levels of radiation following the Chernobyl nuclear accident. Subclones were generated from the human thyroid epithelial cell line (HTori-3) by exposure to gamma or alpha irradiation. SKY analysis revealed multiple translocations and, combined with G-banding, allowed the definition of targets for positional cloning of tumor related genes.

Nickel-smelting fumes increased the expression of HIF-1α through PI3K/ERK pathway in NIH/3T3 cells

PubMed Central

Han, Dan; Yang, Yue; Zhang, Lin; Wang, Chao; Wang, Yue; Tan, Wen-Qiao; Hu, Xue-Ying; Wu, Yong-Hui

2016-01-01

Objective: The purpose of this study was to investigate the effects of Nickel (Ni) -smelting fumes on oncogenic proteins in vivo and in vitro. Methods: Ni fallout beside a Ni smelting furnace in a factory was sampled to study its toxic effect. The effects of Ni-smelting fumes on the regulation of PI3K and ERK signaling pathways and the important downstream hypoxia inducible factor, HIF-1α, were studied both in NIH/3T3 cells and in the lung tissue of rats. NIH/3T3 cell transformation induced by Ni-smelting fumes was also observed. Results: Ni-smelting fumes activated PI3K, p-AKT, p70S6K1, and ERK proteins and increased HIF-1α expression in a time- and dose-dependent manner. However, activation was suppressed when NIH/3T3 cells were pretreated with PI3K/AKT or ERK inhibitors. Ni-smelting fumes caused malignant transformation of NIH/3T3 cells. Conclusions: Ni-smelting fumes increased the expression of HIF-1α through the PI3K/ERK pathway in NIH/3T3 cells and induced malignant transformation in these cells indicating that Ni-smelting fumes may be a potential carcinogen in mammalian cells. PMID:27488040

Induction of Dlk1 by PTTG1 inhibits adipocyte differentiation and correlates with malignant transformation.

PubMed

Espina, Agueda G; Méndez-Vidal, Cristina; Moreno-Mateos, Miguel A; Sáez, Carmen; Romero-Franco, Ana; Japón, Miguel A; Pintor-Toro, José A

2009-07-01

Pituitary tumor-transforming gene-1 (PTTG1) is an oncogene highly expressed in a variety of endocrine, as well as nonendocrine-related cancers. Several tumorigenic mechanisms for PTTG1 have been proposed, one of the best characterized being its capacity to act as a transcriptional activator. To identify novel downstream target genes, we have established cell lines with inducible expression of PTTG1 and a differential display approach to analyze gene expression changes after PTTG1 induction. We identified dlk1 (also known as pref-1) as one of the most abundantly expressed PTTG1 targets. Dlk1 is known to participate in several differentiation processes, including adipogenesis, adrenal gland development, and wound healing. Dlk1 is also highly expressed in neuroendocrine tumors. Here, we show that PTTG1 overexpression inhibits adipogenesis in 3T3-L1 cells and that this effect is accomplished by promoting the stability and accumulation of Dlk1 mRNA, supporting a role for PTTG1 in posttranscriptional regulation. Moreover, both pttg1 and dlk1 genes show concomitant expression in fetal liver and placenta, as well as in pituitary adenomas, breast adenocarcinomas, and neuroblastomas, suggesting that PTTG1 and DLK1 are involved in cell differentiation and transformation.

Induction of Dlk1 by PTTG1 Inhibits Adipocyte Differentiation and Correlates with Malignant Transformation

PubMed Central

Espina, Águeda G.; Méndez-Vidal, Cristina; Moreno-Mateos, Miguel A.; Sáez, Carmen; Romero-Franco, Ana; Japón, Miguel A.

2009-01-01

Pituitary tumor-transforming gene-1 (PTTG1) is an oncogene highly expressed in a variety of endocrine, as well as nonendocrine-related cancers. Several tumorigenic mechanisms for PTTG1 have been proposed, one of the best characterized being its capacity to act as a transcriptional activator. To identify novel downstream target genes, we have established cell lines with inducible expression of PTTG1 and a differential display approach to analyze gene expression changes after PTTG1 induction. We identified dlk1 (also known as pref-1) as one of the most abundantly expressed PTTG1 targets. Dlk1 is known to participate in several differentiation processes, including adipogenesis, adrenal gland development, and wound healing. Dlk1 is also highly expressed in neuroendocrine tumors. Here, we show that PTTG1 overexpression inhibits adipogenesis in 3T3-L1 cells and that this effect is accomplished by promoting the stability and accumulation of Dlk1 mRNA, supporting a role for PTTG1 in posttranscriptional regulation. Moreover, both pttg1 and dlk1 genes show concomitant expression in fetal liver and placenta, as well as in pituitary adenomas, breast adenocarcinomas, and neuroblastomas, suggesting that PTTG1 and DLK1 are involved in cell differentiation and transformation. PMID:19477929

Recognition algorithm for assisting ovarian cancer diagnosis from coregistered ultrasound and photoacoustic images: ex vivo study

NASA Astrophysics Data System (ADS)

Alqasemi, Umar; Kumavor, Patrick; Aguirre, Andres; Zhu, Quing

2012-12-01

Unique features and the underlining hypotheses of how these features may relate to the tumor physiology in coregistered ultrasound and photoacoustic images of ex vivo ovarian tissue are introduced. The images were first compressed with wavelet transform. The mean Radon transform of photoacoustic images was then computed and fitted with a Gaussian function to find the centroid of a suspicious area for shift-invariant recognition process. Twenty-four features were extracted from a training set by several methods, including Fourier transform, image statistics, and different composite filters. The features were chosen from more than 400 training images obtained from 33 ex vivo ovaries of 24 patients, and used to train three classifiers, including generalized linear model, neural network, and support vector machine (SVM). The SVM achieved the best training performance and was able to exclusively separate cancerous from non-cancerous cases with 100% sensitivity and specificity. At the end, the classifiers were used to test 95 new images obtained from 37 ovaries of 20 additional patients. The SVM classifier achieved 76.92% sensitivity and 95.12% specificity. Furthermore, if we assume that recognizing one image as a cancer is sufficient to consider an ovary as malignant, the SVM classifier achieves 100% sensitivity and 87.88% specificity.

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

Potentially malignant oral lesions: clinicopathological correlations

PubMed Central

Maia, Haline Cunha de Medeiros; Pinto, Najara Alcântara Sampaio; Pereira, Joabe dos Santos; de Medeiros, Ana Miryam Costa; da Silveira, Éricka Janine Dantas; Miguel, Márcia Cristina da Costa

2016-01-01

ABSTRACT Objective To determine the incidence of potentially malignant oral lesions, and evaluate and correlate their clinical and pathological aspects. Methods The sample consisted of cases clinically diagnosed as oral leukoplakia, oral erythroplakia, erythroleukoplakia, actinic cheilitis, and oral lichen planus treated at a diagnostic center, between May 2012 and July 2013. Statistical tests were conducted adopting a significance level of 5% (p≤0.05). Results Out of 340 patients, 106 (31.2%) had potentially malignant oral lesions; and 61 of these (17.9%) were submitted to biopsy. Actinic cheilitis was the most frequent lesion (37.5%) and the lower lip was the most affected site (49.6%). Among 106 patients in the sample, 48 (45.3%) reported nicotine consumption, 35 (33%) reported alcohol intake and 34 (32.1%) sun exposure while working. When clinical and histopathological diagnoses were compared, oral erythroplakia and atypical ulcer were the lesions that exhibited greater compatibility (100% each). Conclusion In most cases, clinical and histopathological diagnoses were compatible. An association between the occurrence of erythroplakia, leukoplakia and erythroleukoplakia with smoking was observed. Similarly, an association between actinic cheilitis and sun exposure was noted. Erythroleukoplakia presented the highest malignancy grade in this study. Finally, dental surgeons should draw special attention to diagnosis of potentially malignant oral lesions, choose the best management, and control the lesions to avoid their malignant transformation. PMID:27074232

Bilateral primary malignant lymphoma of the breast.

PubMed Central

Shpitz, B.; Witz, M.; Kaufman, Z.; Griffel, B.; Manor, Y.; Dinbar, A.

1985-01-01

A rare case of bilateral primary malignant lymphoma of breast in a 76 year old woman is presented. The lesion was examined by electron microscopy and immunochemistry. The diagnosis of primary malignant lymphoma remains a diagnosis by exclusion and requires extensive work-up to exclude widespread malignant process. The behaviour of this malignancy tends to be an aggressive one and the prognosis is generally poor. Images Figure 1 Figure 2 PMID:4034464

Clinicopathological factors relating malignant lymphoma with Sjögren's syndrome.

PubMed

Anaya, J M; McGuff, H S; Banks, P M; Talal, N

1996-04-01

This study was undertaken to summarize the current status of the clinicopathologic factors related to non-Hodgkin's lymphoma (NHL) development in patients with Sjögren's syndrome (SS). Through a MEDLINE search, pertinent articles on SS, monoclonality, and NHL were found and reviewed. Malignant lymphoma description was based on the International Lymphoma Study Group classification. Patients with SS are known to have an increased risk for developing B-cell NHL (B-NHL). However, such a complication occurs in less than 10% of patients, being reported mainly in those with primary SS. Extranodal low-grade B-NHL are observed most frequently. Persistent enlargement of parotid glands, adenopathy, monoclonal gammopathy, and cross-reactive idiotypes are all signs suggesting possible lymphoma evolution. Although monoclonality does not mean malignancy unequivocally, it is considered to be a precursor for NHL development in SS. Factors implicated into lymphomagenesis in SS include dysregulation in the mechanisms leading to apoptosis, hyperstimulation of B-1 cells, and an infectious agent. Polyclonal lymphoproliferation characterizing SS might in some instances transform into monoclonal, and then to malignancy. Further studies on the mechanism whereby NHL develops in SS are warranted.

Carcinoma ex pleomorphic adenoma, with particular emphasis on early lesions.

PubMed

Di Palma, Silvana

2013-07-01

Carcinoma ex pleomorphic adenoma (CXPA) is a broad category of carcinomas of the salivary glands which includes at least 2 clinically relevant categories; one is referred here as early CXPA (ECXPA), the other as widely invasive CXPA. The former includes several histological patterns ranging from non-invasive/in situ/intraductal/intratubular, early invasive/extratubular/intracapsular and extracapsular (up to 6 mm). The latter includes any CXPA with invasion of >6 mm. The clinical behaviour of ECXPA is not aggressive and tends to overlap that of a pleomorphic adenoma (PA) which makes the histological report of carcinoma contradictory. These early malignant changes in PA are known since the 1970s but it has been the use of immunohistochemical and molecular genetic analysis for HER-2 and TP53 gene in the last decade that has clarified the genuine malignant nature of the cells. HER-2 and TP53 gene and protein are involved in the early stages of malignant transformation of PA. Moreover the immunohistochemical over-expression HER-2, p53 protein and Mib-1 proliferation marker may be useful markers to identify malignant areas in PA.

Loss of c-KIT expression in thyroid cancer cells.

PubMed

Franceschi, Sara; Lessi, Francesca; Panebianco, Federica; Tantillo, Elena; La Ferla, Marco; Menicagli, Michele; Aretini, Paolo; Apollo, Alessandro; Naccarato, Antonio Giuseppe; Marchetti, Ivo; Mazzanti, Chiara Maria

2017-01-01

Papillary thyroid carcinoma is the most frequent histologic type of thyroid tumor. Few studies investigated the role of c-KIT expression in thyroid tumors, suggesting a role for this receptor and its ligand in differentiation and growth control of thyroid epithelium and a receptor loss following malignant transformation. We investigated and correlated c-KIT expression levels and two known markers of thyrocytes differentiation, PAX8 and TTF-1, in malignant and benign cytological thyroid samples. Moreover, we performed functional studies on human papillary thyroid carcinoma cell line to associated c-KIT expression to thyrocytes differentiation and tumor proliferation. c-KIT and PAX8 expression resulted higher in benign samples compared to the malignant ones, and the expression levels of these two genes were significantly correlated to each other. We also observed that c-KIT overexpression led to an increase of PAX8 expression level together with a decrease of proliferation. Furthermore, c-KIT overexpressing cells showed a regression of typical morphological features of malignancy. Taken together these results suggest that c-KIT could be involved in the differentiation of thyroid cells and in tumor progression.

Loss of c-KIT expression in thyroid cancer cells

PubMed Central

Panebianco, Federica; Tantillo, Elena; La Ferla, Marco; Menicagli, Michele; Aretini, Paolo; Apollo, Alessandro; Naccarato, Antonio Giuseppe; Marchetti, Ivo; Mazzanti, Chiara Maria

2017-01-01

Papillary thyroid carcinoma is the most frequent histologic type of thyroid tumor. Few studies investigated the role of c-KIT expression in thyroid tumors, suggesting a role for this receptor and its ligand in differentiation and growth control of thyroid epithelium and a receptor loss following malignant transformation. We investigated and correlated c-KIT expression levels and two known markers of thyrocytes differentiation, PAX8 and TTF-1, in malignant and benign cytological thyroid samples. Moreover, we performed functional studies on human papillary thyroid carcinoma cell line to associated c-KIT expression to thyrocytes differentiation and tumor proliferation. c-KIT and PAX8 expression resulted higher in benign samples compared to the malignant ones, and the expression levels of these two genes were significantly correlated to each other. We also observed that c-KIT overexpression led to an increase of PAX8 expression level together with a decrease of proliferation. Furthermore, c-KIT overexpressing cells showed a regression of typical morphological features of malignancy. Taken together these results suggest that c-KIT could be involved in the differentiation of thyroid cells and in tumor progression. PMID:28301608

Haemangiosarcoma of breast

PubMed Central

Kessler, E.; Kozenitzky, I. L.

1971-01-01

This is a report of a haemangiosarcoma involving the breast, spleen, liver, lungs, and subcutaneous tissue. There appears to be evidence that the tumour arose in the breast with the other sites representing metastases rather than a malignant transformation of multiple haemangiomatoses. Histologically the primary breast tumour appeared deceptively innocuous. Images PMID:5106732

Cooperativity Between Oncogenic PKC Epsilon and Pten Loss in Prostate Cancer Progression

DTIC Science & Technology

2016-10-01

objective of our studies is to elucidate the mechanisms by which PKCε, in conjunction with Pten loss, lead to malignant transformation and metastasis...ligand for the G-protein-coupled receptor CXCR5. This led us to hypothesize that PKCε in conjunction Pten deficienty activate an autonomous autocrine

Mitochondria in cancer: not just innocent bystanders.

PubMed

Frezza, Christian; Gottlieb, Eyal

2009-02-01

The first half of the 20th century produced substantial breakthroughs in bioenergetics and mitochondria research. During that time, Otto Warburg observed abnormally high glycolysis and lactate production in oxygenated cancer cells, leading him to suggest that defects in mitochondrial functions are at the heart of malignant cell transformation. Warburg's hypothesis profoundly influenced the present perception of cancer metabolism, positioning what is termed aerobic glycolysis in the mainstream of clinical oncology. While some of his ideas stood the test of time, they also frequently generated misconceptions regarding the biochemical mechanisms of cell transformation. This review examines experimental evidence which supports or refutes the Warburg effect and discusses the possible advantages conferred on cancer cells by 'metabolic transformation'.

Multiparametric Determination of Radiation Risk

NASA Technical Reports Server (NTRS)

Richmond, Robert C.

2003-01-01

Predicting risk of human cancer following exposure to ionizing space radiation is challenging in part because of uncertainties of low-dose distribution amongst cells, of unknown potentially synergistic effects of microgravity upon cellular protein-expression, and of processing dose-related damage within cells to produce rare and late-appearing malignant transformation, degrade the confidence of cancer risk-estimates. The NASA- specific responsibility to estimate the risks of radiogenic cancer in a limited number of astronauts is not amenable to epidemiologic study, thereby increasing this challenge. Developing adequately sensitive cellular biodosimeters that simultaneously report 1) the quantity of absorbed close after exposure to ionizing radiation, 2) the quality of radiation delivering that dose, and 3) the risk of developing malignant transformation by the cells absorbing that dose could be useful for resolving these challenges. Use of a multiparametric cellular biodosimeter is suggested using analyses of gene-expression and protein-expression whereby large datasets of cellular response to radiation-induced damage are obtained and analyzed for expression-profiles correlated with established end points and molecular markers predictive for cancer-risk. Analytical techniques of genomics and proteomics may be used to establish dose-dependency of multiple gene- and protein- expressions resulting from radiation-induced cellular damage. Furthermore, gene- and protein-expression from cells in microgravity are known to be altered relative to cells grown on the ground at 1g. Therefore, hypotheses are proposed that 1) macromolecular expression caused by radiation-induced damage in cells in microgravity may be different than on the ground, and 2) different patterns of macromolecular expression in microgravity may alter human radiogenic cancer risk relative to radiation exposure on Earth. A new paradigm is accordingly suggested as a national database wherein genomic and proteomic datasets are registered and interrogated in order to provide statistically significant dose-dependent risk estimation of radiogenic cancer in astronauts.

Radiomics Evaluation of Histological Heterogeneity Using Multiscale Textures Derived From 3D Wavelet Transformation of Multispectral Images.

PubMed

Chaddad, Ahmad; Daniel, Paul; Niazi, Tamim

2018-01-01

Colorectal cancer (CRC) is markedly heterogeneous and develops progressively toward malignancy through several stages which include stroma (ST), benign hyperplasia (BH), intraepithelial neoplasia (IN) or precursor cancerous lesion, and carcinoma (CA). Identification of the malignancy stage of CRC pathology tissues (PT) allows the most appropriate therapeutic intervention. This study investigates multiscale texture features extracted from CRC pathology sections using 3D wavelet transform (3D-WT) filter. Multiscale features were extracted from digital whole slide images of 39 patients that were segmented in a pre-processing step using an active contour model. The capacity for multiscale texture to compare and classify between PTs was investigated using ANOVA significance test and random forest classifier models, respectively. 12 significant features derived from the multiscale texture (i.e., variance, entropy, and energy) were found to discriminate between CRC grades at a significance value of p  < 0.01 after correction. Combining multiscale texture features lead to a better predictive capacity compared to prediction models based on individual scale features with an average (±SD) classification accuracy of 93.33 (±3.52)%, sensitivity of 88.33 (± 4.12)%, and specificity of 96.89 (± 3.88)%. Entropy was found to be the best classifier feature across all the PT grades with an average of the area under the curve (AUC) value of 91.17, 94.21, 97.70, 100% for ST, BH, IN, and CA, respectively. Our results suggest that multiscale texture features based on 3D-WT are sensitive enough to discriminate between CRC grades with the entropy feature, the best predictor of pathology grade.

[Abnormal expression of genes that regulate retinoid metabolism and signaling in non-small-cell lung cancer].

PubMed

Kuznetsova, E S; Zinovieva, O L; Oparina, N Yu; Prokofjeva, M M; Spirin, P V; Favorskaya, I A; Zborovskaya, I B; Lisitsyn, N A; Prassolov, V S; Mashkova, T D

2016-01-01

Retinoids are signaling molecules that control a wide variety of cellular processes and possess antitumor activity. This work presents a comprehensive description of changes in the expression of 23 genes that regulate retinoid metabolism and signaling in non-small-cell lung cancer tumors compared to adjacent normal tissues obtained using RT-PCR. Even at early stages of malignant transformation, a significant decrease in ADH1B, ADH3, RDHL, and RALDH1 mRNA levels was observed in 82, 79, 73, and 64% of tumor specimens, respectively, and a considerable increase in AKR1B10 mRNA content was observed in 80% of tumors. Dramatic changes in the levels of these mRNAs can impair the synthesis of all-trans retinoic acid, a key natural regulatory retinoid. Apart from that, it was found that mRNA levels of nuclear retinoid receptor genes RXRγ, RARα, RXRα, and gene RDH11 were significantly decreased in 80, 67, 57, and 66% of tumor specimens, respectively. Thus, neoplastic transformation of lung tissue cells is accompanied with deregulated expression of key genes of retinoid metabolism and function.

Are blood group isoantigens lost from malignant prostatic epithelium? Immunohistochemical support for the preservation of the H isoantigen.

PubMed Central

Vowden, P.; Lowe, A. D.; Lennox, E. S.; Bleehen, N. M.

1986-01-01

Previous studies while demonstrating the presence of blood group isoantigens on normal prostatic epithelium have failed to identify such antigens on malignant prostatic tissue. Using a series of blood group specific monoclonal antibodies directed towards the A, B, H and Y antigens we have reinvestigated blood group isoantigen expression in both benign prostatic hypertrophy and prostatic adenocarcinoma. Results obtained from areas of benign prostatic hypertrophy are in broad agreement with those published however though we were unable to detect either A or B blood group isoantigens Type 2H and Y isoantigens were identified in 10 of the 12 tumours. These findings, while differing from previously reported results, lend support to the suggested connection between ontogenesis, oncogenesis and blood group isoantigen expression and also support the proposed link between Type 2 structures and malignant transformation. Images Figure 1 Figure 2 PMID:2421753

Cell Survival Signaling in Neuroblastoma

PubMed Central

Megison, Michael L.; Gillory, Lauren A.; Beierle, Elizabeth A.

2013-01-01

Neuroblastoma is the most common extracranial solid tumor of childhood and is responsible for over 15% of pediatric cancer deaths. Neuroblastoma tumorigenesis and malignant transformation is driven by overexpression and dominance of cell survival pathways and a lack of normal cellular senescence or apoptosis. Therefore, manipulation of cell survival pathways may decrease the malignant potential of these tumors and provide avenues for the development of novel therapeutics. This review focuses on several facets of cell survival pathways including protein kinases (PI3K, AKT, ALK, and FAK), transcription factors (NF-κB, MYCN and p53), and growth factors (IGF, EGF, PDGF, and VEGF). Modulation of each of these factors decreases the growth or otherwise hinders the malignant potential of neuroblastoma, and many therapeutics targeting these pathways are already in the clinical trial phase of development. Continued research and discovery of effective modulators of these pathways will revolutionize the treatment of neuroblastoma. PMID:22934706

Bilateral fungiform papilloma with synchronous verrucous carcinoma of the nasal septum: a rare presentation and a literature review.

PubMed

Maithani, T; Dey, D; Pandey, A; Chawla, N

2012-04-01

Fungiform papillomas are benign mucosal neoplasms presenting as a unilateral exophytic mass involving the anterior portion of the nasal septum. In this study, we present an exceptional case of a bilateral fungiform papilloma with a synchronous verrucous carcinoma of the nasal septum. A case study with a review of the literature concerning malignant changes in fungiform papilloma. The general consensus in most of the literature is that malignant change in fungiform papilloma is exceptional. Our patient is probably the third reported case of verrucous carcinoma of the nasal septum, and the first report of a bilateral fungiform papilloma with a synchronous verrucous carcinoma. The tumour was subjected to complete surgical removal in the first instance. There was no recurrence at follow up seven months after surgery. Although fungiform papillomas are generally not premalignant, occasional malignant transformation may occur. Thus, they must be managed with the utmost cautiousness.

Progranulin and its biological effects in cancer.

PubMed

Arechavaleta-Velasco, Fabian; Perez-Juarez, Carlos Eduardo; Gerton, George L; Diaz-Cueto, Laura

2017-11-07

Cancer cells have defects in regulatory mechanisms that usually control cell proliferation and homeostasis. Different cancer cells share crucial alterations in cell physiology, which lead to malignant growth. Tumorigenesis or tumor growth requires a series of events that include constant cell proliferation, promotion of metastasis and invasion, stimulation of angiogenesis, evasion of tumor suppressor factors, and avoidance of cell death pathways. All these events in tumor progression may be regulated by growth factors produced by normal or malignant cells. The growth factor progranulin has significant biological effects in different types of cancer. This protein is a regulator of tumorigenesis because it stimulates cell proliferation, migration, invasion, angiogenesis, malignant transformation, resistance to anticancer drugs, and immune evasion. This review focuses on the biological effects of progranulin in several cancer models and provides evidence that this growth factor should be considered as a potential biomarker and target in cancer treatment.

Granulocyte colony-stimulating factor receptor signaling in severe congenital neutropenia, chronic neutrophilic leukemia, and related malignancies.

PubMed

Dwivedi, Pankaj; Greis, Kenneth D

2017-02-01

Granulocyte colony-stimulating factor is a hematopoietic cytokine that stimulates neutrophil production and hematopoietic stem cell mobilization by initiating the dimerization of homodimeric granulocyte colony-stimulating factor receptor. Different mutations of CSF3R have been linked to a unique spectrum of myeloid disorders and related malignancies. Myeloid disorders caused by the CSF3R mutations include severe congenital neutropenia, chronic neutrophilic leukemia, and atypical chronic myeloid leukemia. In this review, we provide an analysis of granulocyte colony-stimulating factor receptor, various mutations, and their roles in the severe congenital neutropenia, chronic neutrophilic leukemia, and malignant transformation, as well as the clinical implications and some perspective on approaches that could expand our knowledge with respect to the normal signaling mechanisms and those associated with mutations in the receptor. Copyright © 2016 ISEH - International Society for Experimental Hematology. Published by Elsevier Inc. All rights reserved.

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

Immunohistochemical detection of p53 protein in ameloblastoma types.

PubMed

el-Sissy, N A

1999-05-01

Overexpression of p53 protein in unicystic ameloblastoma (uAB) is denser than in the conventional ameloblastoma (cAB) type, indicating increased wild type p53--suppressing the growth potential of uAB and denoting the early event of neoplastic transformation, probably of a previous odontogenic cyst. Overexpression of p53 in borderline cAB and malignant ameloblastoma (mAB) types might reflect a mutational p53 protein playing an oncogenic role, promoting tumour growth. Overexpression of p53 protein could be a valid screening method for predicting underlying malignant genetic changes in AB types, through increased frequency of immunoreactive cells or increased staining density.

Unique presentation of giant metastatic microcystic serous adenocarcinoma of the pancreas.

PubMed

Philips, Cyriac Abby; Kalal, Chetan Ramesh; Bihari, Chhagan; Sahney, Amrish; Kumar, Kn Chandan; Rastogi, Archana

2014-01-01

Tumors of the pancreas that contain substantial cystic components include mainly mucinous cystic neoplasm, intraductal papillary mucinous neoplasm, solid pseudopapillary tumor, and cystadenomas (which encompass microcystic, macrocystic/oligocystic, and rare solid serous adenomas). Microcystic adenoma of the pancreas is a tumor that is benign in nature. Malignant transformation in the tumor with metastases is rare and only about 26 cases have been reported so far. Here we present a giant microcystic adenoma of the pancreas, possibly the largest ever malignant type in this group ever reported in the literature with extensive metastases to the liver and causing extensive compression and encasement on surrounding structures.

Unique Presentation of Giant Metastatic Microcystic Serous Adenocarcinoma of the Pancreas

PubMed Central

Kalal, Chetan Ramesh; Bihari, Chhagan; Sahney, Amrish; Kumar, KN Chandan; Rastogi, Archana

2014-01-01

Tumors of the pancreas that contain substantial cystic components include mainly mucinous cystic neoplasm, intraductal papillary mucinous neoplasm, solid pseudopapillary tumor, and cystadenomas (which encompass microcystic, macrocystic/oligocystic, and rare solid serous adenomas). Microcystic adenoma of the pancreas is a tumor that is benign in nature. Malignant transformation in the tumor with metastases is rare and only about 26 cases have been reported so far. Here we present a giant microcystic adenoma of the pancreas, possibly the largest ever malignant type in this group ever reported in the literature with extensive metastases to the liver and causing extensive compression and encasement on surrounding structures. PMID:24782930

Atezolizumab in urothelial bladder carcinoma.

PubMed

Hamilou, Zineb; Lavaud, Pernelle; Loriot, Yohann

2018-02-01

Metastatic bladder cancer is an aggressive malignancy with a poor prognosis when presenting with advanced stage. Cisplatin-based therapy has been the mainstay of first-line treatment but therapy in second-line setting has been an unmet medical need for decades. Moreover, many patients are unable to receive cisplatin-based therapy. Recently, immune-checkpoint inhibitors transformed the management and prognosis of many malignancies and will certainly redefine the standard of care for bladder cancer. Atezolizumab, an anti-PD-L1 antibody, was the first immune-checkpoint inhibitor to be approved by the US FDA in May 2016 for patients with urothelial carcinoma. In this review, we discuss the evidence behind this promising drug.

Thyroid C-Cell Biology and Oncogenic Transformation

PubMed Central

Cote, Gilbert J.; Grubbs, Elizabeth G.; Hofmann, Marie-Claude

2017-01-01

The thyroid parafollicular cell, or commonly named “C-cell,” functions in serum calcium homeostasis. Elevations in serum calcium trigger release of calcitonin from the C-cell, which in turn functions to inhibit absorption of calcium by the intestine, resorption of bone by the osteoclast, and reabsorption of calcium by renal tubular cells. Oncogenic transformation of the thyroid C-cell is thought to progress through a hyperplastic process prior to malignancy with increasing levels of serum calcitonin serving as a biomarker for tumor burden. The discovery that Multiple Endocrine Neoplasia, type 2 is caused by activating mutations of the RET gene serves to highlight the RET-RAS-MAPK signaling pathway in both initiation and progression of medullary thyroid carcinoma. Thyroid C-cells are known to express RET at high levels relative to most cell types, therefore aberrant activation of this receptor is targeted primarily to the C-cell, providing one possible cause of tissue-specific oncogenesis. The role of RET signaling in normal C-cell function is unknown though calcitonin gene transcription appears to be sensitive to RET activation. Beyond RET the modeling of oncogenesis in animals and screening of human tumors for candidate gene mutations has uncovered mutation of RAS family members and inactivation of Rb1 regulatory pathway as potential mediators of C-cell transformation. A growing understanding of how RET interacts with these pathways, both in normal C-cell function and during oncogenic transformation will help in the development of novel molecular targeted therapies. PMID:26494382

Lysine-specific demethylase 1 (LSD1) destabilizes p62 and inhibits autophagy in gynecologic malignancies.

PubMed

Chao, Angel; Lin, Chiao-Yun; Chao, An-Ning; Tsai, Chia-Lung; Chen, Ming-Yu; Lee, Li-Yu; Chang, Ting-Chang; Wang, Tzu-Hao; Lai, Chyong-Huey; Wang, Hsin-Shih

2017-09-26

Lysine-specific demethylase 1 (LSD1) - also known as KDM1A - is the first identified histone demethylase. LSD1 is highly expressed in numerous human malignancies and has recently emerged as a target for anticancer drugs. Owing to the presence of several functional domains, we speculated that LSD1 could have additional functions other than histone demethylation. P62 - also termed sequestasome 1 (SQSTM1) - plays a key role in malignant transformation, apoptosis, and autophagy. Here, we show that a high LSD1 expression promotes tumorigenesis in gynecologic malignancies. Notably, LSD1 inhibition with either siRNA or pharmacological agents activates autophagy. Mechanistically, LSD1 decreases p62 protein stability in a demethylation-independent manner. Inhibition of LSD1 reduces both tumor growth and p62 protein degradation in vivo . The combination of LSD1 inhibition and p62 knockdown exerts additive anticancer effects. We conclude that LSD1 destabilizes p62 and inhibits autophagy in gynecologic cancers. LSD1 inhibition reduces malignant cell growth and activates autophagy. The combinations of LSD1 inhibition and autophagy blockade display additive inhibitory effect on cancer cell viability. A better understanding of the role played by p62 will shed more light on the anticancer effects of LSD1 inhibitors.

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

Malignant changes developing from odontogenic cysts: A systematic review.

PubMed

Borrás-Ferreres, Jordi; Sánchez-Torres, Alba; Gay-Escoda, Cosme

2016-12-01

The aim of this study was to systematically review scientific literature in orderto describe the characteristics and prognosis of malignant entities developing from odontogenic cysts. A search in Pubmed (MEDLINE) and Cochrane databases was conducted. The inclusion criteria were articles published in English related to the malignisation of odontogenic cysts in humans. The exclusion criteria were articles that do not specify the type of odontogenic cyst, malignisation of parakeratinised keratocysts, the presence of an ameloblastic carcinoma and metastasis from distant primary tumours. The selected articles were classified according to Strength of Recommendation Taxonomy criteria. Statistical analysis of the data was carried out using statistical package software SPSS version 22.0. From the 1,237 articles initially obtained, the authors included 3 case series and 45 case reports in the end. Descriptive analysis showed that men have a disposition for malignisation from odontogenic cysts and they frequently appear at the posterior mandible, with pain and swelling being the most frequent signs and symptoms. Follicular cysts were the entities that underwent the most malignant changes with well differentiated squamous cell carcinomas being the most prevalent type of malignancy. The real prognosis of this malignancy is not known because of the heterogeneity of available studies. Key words: Odontogenic cysts, squamous cell carcinoma, neoplastic cell transformation, oral cancer.

Development and validation of a nomogram to estimate the pretest probability of cancer in Chinese patients with solid solitary pulmonary nodules: A multi-institutional study.

PubMed

She, Yunlang; Zhao, Lilan; Dai, Chenyang; Ren, Yijiu; Jiang, Gening; Xie, Huikang; Zhu, Huiyuan; Sun, Xiwen; Yang, Ping; Chen, Yongbing; Shi, Shunbin; Shi, Weirong; Yu, Bing; Xie, Dong; Chen, Chang

2017-11-01

To develop and validate a nomogram to estimate the pretest probability of malignancy in Chinese patients with solid solitary pulmonary nodule (SPN). A primary cohort of 1798 patients with pathologically confirmed solid SPNs after surgery was retrospectively studied at five institutions from January 2014 to December 2015. A nomogram based on independent prediction factors of malignant solid SPN was developed. Predictive performance also was evaluated using the calibration curve and the area under the receiver operating characteristic curve (AUC). The mean age of the cohort was 58.9 ± 10.7 years. In univariate and multivariate analysis, age; history of cancer; the log base 10 transformations of serum carcinoembryonic antigen value; nodule diameter; the presence of spiculation, pleural indentation, and calcification remained the predictive factors of malignancy. A nomogram was developed, and the AUC value (0.85; 95%CI, 0.83-0.88) was significantly higher than other three models. The calibration cure showed optimal agreement between the malignant probability as predicted by nomogram and the actual probability. We developed and validated a nomogram that can estimate the pretest probability of malignant solid SPNs, which can assist clinical physicians to select and interpret the results of subsequent diagnostic tests. © 2017 Wiley Periodicals, Inc.

Differences in the epigenetic regulation of MT-3 gene expression between parental and Cd+2 or As+3 transformed human urothelial cells

PubMed Central

2011-01-01

Background Studies have shown that metallothionein 3 (MT-3) is not expressed in normal urothelium or in the UROtsa cell line, but is expressed in urothelial cancer and in tumors generated from the UROtsa cells that have been transformed by cadmium (Cd+2) or arsenite (As+3).The present study had two major goals. One, to determine if epigenetic modifications control urothelial MT-3 gene expression and if regulation is altered by malignant transformation by Cd+2 or As+3. Two, to determine if MT-3 expression might translate clinically as a biomarker for malignant urothelial cells released into the urine. Results The histone deacetylase inhibitor MS-275 induced MT-3 mRNA expression in both parental UROtsa cells and their transformed counterparts. The demethylating agent, 5-Aza-2'-deoxycytidine (5-AZC) had no effect on MT-3 mRNA expression. ChIP analysis showed that metal-responsive transformation factor-1 (MTF-1) binding to metal response elements (MRE) elements of the MT-3 promoter was restricted in parental UROtsa cells, but MTF-1 binding to the MREs was unrestricted in the transformed cell lines. Histone modifications at acetyl H4, trimethyl H3K4, trimethyl H3K27, and trimethyl H3K9 were compared between the parental and transformed cell lines in the presence and absence of MS-275. The pattern of histone modifications suggested that the MT-3 promoter in the Cd+2 and As+3 transformed cells has gained bivalent chromatin structure, having elements of being "transcriptionally repressed" and "transcription ready", when compared to parental cells. An analysis of MT-3 staining in urinary cytologies showed that a subset of both active and non-active patients with urothelial cancer shed positive cells in their urine, but that control patients only rarely shed MT-3 positive cells. Conclusion The MT-3 gene is silenced in non-transformed urothelial cells by a mechanism involving histone modification of the MT-3 promoter. In contrast, transformation of the urothelial cells with either Cd+2 or As+3 modified the chromatin of the MT-3 promoter to a bivalent state of promoter readiness. Urinary cytology for MT-3 positive cells would not improve the diagnosis of urothelial cancer, but might have potential as a biomarker for tumor progression. PMID:21303554

Differentiation of EL4 lymphoma cells by tumoral environment is associated with inappropriate expression of the large chondroitin sulfate proteoglycan PG-M and the tumor-associated antigen HTgp-175.

PubMed

Rottiers, P; Verfaillie, T; Contreras, R; Revets, H; Desmedt, M; Dooms, H; Fiers, W; Grooten, J

1998-11-09

Progression to malignancy of transformed cells involves complex genetic alterations and aberrant gene expression patterns. While aberrant gene expression is often caused by alterations in individual genes, the contribution of the tumoral environment to the triggering of this gene expression is less well established. The stable but heterogeneous expression in cultured EL4/13 cells of a novel tumor-associated antigen, designated as HTgp-175, was chosen for the investigation of gene expression during tumor formation. Homogeneously HTgp-175-negative EL4/13 cells, isolated by cell sorting or obtained by subcloning, acquired HTgp-175 expression as a result of tumor formation. The tumorigenicity of HTgp-175-negative vs. HTgp-175-positive EL4 variants was identical, indicating that induction but not selection accounted for the phenotypic switch from HTgp-175-negative to HTgp-175-positive. Although mutagenesis experiments showed that the protein was not essential for tumor establishment, tumor-derived cells showed increased malignancy, linking HTgp-175 expression with genetic changes accompanying tumor progression. This novel gene expression was not an isolated event, since it was accompanied by ectopic expression of the large chondroitin sulfate proteoglycan PG-M and of normal differentiation antigens. We conclude that signals derived from the tumoral microenvironment contribute significantly to the aberrant gene expression pattern of malignant cells, apparently by fortuitous activation of differentiation processes and cause expression of novel differentiation antigens as well as of inappropriate tumor-associated and ectopic antigens.

Malignant human cell transformation of Marcellus Shale gas drilling flow back water

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

Yao, Yixin; Department of Environmental Medicine, New York University School of Medicine, Tuxedo, NY 10987; Chen, Tingting

The rapid development of high-volume horizontal hydraulic fracturing for mining natural gas from shale has posed potential impacts on human health and biodiversity. The produced flow back waters after hydraulic stimulation are known to carry high levels of saline and total dissolved solids. To understand the toxicity and potential carcinogenic effects of these wastewaters, flow back waters from five Marcellus hydraulic fracturing oil and gas wells were analyzed. The physicochemical nature of these samples was analyzed by inductively coupled plasma mass spectrometry and scanning electron microscopy/energy dispersive X-ray spectroscopy. A cytotoxicity study using colony formation as the endpoint was carriedmore » out to define the LC{sub 50} values of test samples using human bronchial epithelial cells (BEAS-2B). The BEAS-2B cell transformation assay was employed to assess the carcinogenic potential of the samples. Barium and strontium were among the most abundant metals in these samples and the same metals were found to be elevated in BEAS-2B cells after long-term treatment. BEAS-2B cells treated for 6 weeks with flow back waters produced colony formation in soft agar that was concentration dependent. In addition, flow back water-transformed BEAS-2B cells show better migration capability when compared to control cells. This study provides information needed to assess the potential health impact of post-hydraulic fracturing flow back waters from Marcellus Shale natural gas mining. - Highlights: • This is the first report of potential cytotoxicity and transforming activity of Marcellus shale gas mining flow back to mammalian cells. • Barium and Strontium were elevated in flow back water exposed cells. • Flow back water malignantly transformed cells and formed tumor in athymic nude mice. • Flow back transformed cells exhibited altered transcriptome with dysregulated cell migration pathway and adherent junction pathway.« less

[Bladder pseudotumor in childhood].

PubMed

Fernández Arjona, M; Muñoz-Delgado Salmerón, J; Shihadei, S; Colomar, P J; García Estevez, J A

1997-01-01

Case report of a 10 year-old male with vesical mass suggestive of a rabdomiosarcoma based on the radiologic studies performed. The existence of an inflammatory process with no signs of malignancy was confirmed by transurethral resection. The serological studies were negative and the absence of malignant disease in further substantiated by immunohistochemistry. We want to emphasize that certain vesical masses. which appear to be malignant on the radiological study (Pseudotumours), may be just inflammatory processes.

Concomitant endometriosis in malignant and borderline ovarian tumours.

PubMed

Oral, Engin; Aydin, Ovgu; Kumbak, Banu Aygun; İlvan, Sennur; Yilmaz, Handan; Tustas, Esra; Bese, Tugan; Demirkiran, Fuat; Arvas, Macit

2018-06-08

The aim of the study was to reveal the prevalence of concomitant endometriosis in malignant and borderline ovarian tumours. A retrospective analysis was performed of 530 patients with malignant ovarian tumours and 131 with borderline ovarian tumours, who underwent surgery in our hospital between 1995 and 2011. Forty-eight (7.3%) of 661 patients with malignant and borderline ovarian tumours were associated with endometriosis. Of the 48 endometriosis cases, 73% of those were atypical. Infertility was noted in 38% of patients with endometriosis-associated ovarian tumours. The most frequently endometriosis-associated subtypes were endometrioid (33%) and clear cell (18%) histologies. Of endometriosis-associated endometrioid and clear cell ovarian tumours, 70% were early stage and 60% were premenopausal. The prevalence of concomitant endometriosis in borderline tumours (12%) was found to be significantly higher than that found in the malignant ones (6%; p = .02). Of 32 endometriosis-associated malignant ovarian tumours, 69% were FIGO stages I and II. In conclusion, ovarian endometriosis is seen with both malignant and borderline ovarian tumours, the association being significant with borderline tumours. Fortunately, the endometriosis-associated malignant ovarian tumours are mostly early stage. Impact statement What is already known on this subject? Epidemiologic data suggest that endometriosis has malignant potential. However, a subgroup of women with endometriosis at a high risk for ovarian cancer is yet to be clarified. Currently, endometriosis and ovarian cancer association does not seem to have a clinical implication. What do the results of this study add? The findings of this study revealed that nearly 75% of endometriosis-associated ovarian tumours were of atypical endometriosis. Half of endometriosis-associated ovarian tumour cases were of endometrioid/clear cell histology and 70% were early-stage. Endometriosis was significantly associated with borderline ovarian tumours and the endometriosis-associated malignant ovarian tumours were mostly early stage. What are the implications of these findings for clinical practice and/or further research? Additional studies need to be conducted to develop screening approaches for malignant transformation or an association in women with endometriosis. Till that time, a change of current clinical practices cannot be justified. However, counselling and treating women with endometriosis who are at high risk for cancer coexistence or conversion is encouraged.

Folliculotropic T-cell infiltrates associated with B-cell chronic lymphocytic leukaemia or MALT lymphoma may reveal either true mycosis fungoides or pseudolymphomatous reaction: seven cases and review of the literature.

PubMed

Ingen-Housz-Oro, S; Franck, N; Beneton, N; Fauconneau, A; Do-Pham, G; Carlotti, A; Petit, T; Liolios, I; Bara, C; Carpentier, H; Storelli, D; Prophette, B; Garderet, L; Haioun, C; Petit, E; Delfau-Larue, M-H; Vergier, B; Chosidow, O; Beylot-Barry, M; Ortonne, N

2015-01-01

Mycosis fungoides (MF) and pseudo-MF (or MF simulant) can be associated with B-cell malignancies, but distinction between a true neoplasm and a reactive process may be difficult. To report seven patients with B-cell malignancy and folliculotropic MF or pseudo-MF and emphasize on criteria allowing distinction between the two conditions. We retrospectively and prospectively included seven patients with B-cell malignancy who presented skin lesions histologically consisting in a folliculotropic T-cell infiltrate and reviewed the literature on the topic. Four men and three women had a chronic lymphocytic leukaemia (n = 6) or a MALT-type lymphoma (n = 1). Five patients had localized papules, and two had patches and plaques. Histological examination showed in all cases a diffuse dermal T-cell infiltrate with folliculotropic involvement and follicular mucinosis associated with clusters of the B-cell lymphoma, without significant expression of follicular helper T-cell markers. T-cell rearrangement studies showed a polyclonal pattern in the patients with papules and a monoclonal pattern in the cases of patches and plaques. Papular lesions had an indolent evolution, whereas patches and plaques persisted or worsened into transformed MF. Folliculotropic T-cell infiltrates associated with B-cell malignancies can be either a true folliculotropic MF or a pseudo-MF. The distinction between both conditions cannot rely only on the histopathological aspect, but needs both a clinical pathological correlation and the search for a dominant T-cell clone. Whether the neoplastic T and B cells derive from a common ancestor or the T-cell proliferation is promoted by the underlying B-cell lymphoma remains unsolved, but interaction between B and T cell in the skin does not appear to be dependent on a TFH differentiation of the T-cell infiltrate. © 2014 European Academy of Dermatology and Venereology.

Biological Significance of Prolactin in Gynecological Cancers

PubMed Central

Levina, Vera V; Nolen, Brian; Su, YunYun; Godwin, Andrew K.; Fishman, David; Liu, Jinsong; Mor, Gil; Maxwell, Larry G.; Herberman, Ronald B.; Szczepanski, Miroslaw J.; Szajnik, Marta E.; Gorelik, Elieser; Lokshin, Anna E

2010-01-01

There is increasing evidence that Prolactin (PRL), a hormone/cytokine, plays a role in breast, prostate and colorectal cancers via local production or accumulation. Elevated levels of serum PRL in ovarian and endometrial cancers have been reported indicating a potential role for prolactin in endometrial and ovarian carcinogenesis. In this study, we demonstrate that serum PRL levels are significantly elevated in women with a strong family history of ovarian cancer. We demonstrate dramatically increased expression of PRL receptor (PRLR) in ovarian and endometrial tumors as well as in endometrial hyperplasia signifying the importance of PRL signaling in malignant and premalignant conditions. PRL mRNA was expressed in ovarian and endometrial tumors indicating the presence of an autocrine loop. PRL potently induced proliferation in several ovarian and endometrial cancer cell lines. Binding of PRL to its receptor was followed by rapid phosphorylation of ERK1/2, MEK-1, STAT3, CREB, ATF-2, and p53, and activation of 37 transcription factors in ovarian and endometrial carcinoma cells. PRL also activated Ras oncogene in these cells. When human immortalized normal ovarian epithelial (NOE) cells were chronically exposed to PRL a malignant transformation occurred manifested by the acquired ability of transformed cells to form clones, grow in soft agar, and form tumors in SCID-beige mice. Transformation efficiency was diminished by a Ras inhibitor providing proof that PRL-induced transformation utilizes the Ras pathway. In summary, we present findings that indicate an important role for PRL in ovarian and endometrial tumorigenesis. PRL may represent a risk factor for ovarian and endometrial cancers. PMID:19491263

Spectrum of Kaposi's Sarcoma-Associated Herpesvirus, or Human Herpesvirus 8, Diseases

PubMed Central

Ablashi, Dharam V.; Chatlynne, Louise G.; Whitman, Jr., James E.; Cesarman, Ethel

2002-01-01

Human herpesvirus 8 (HHV-8), also known as Kaposi's sarcoma-associated herpesvirus (KSHV), discovered in 1994, is a human rhadinovirus (gamma-2 herpesvirus). Unlike other human herpesviruses (herpes simplex virus, Epstein-Barr virus, varicella-zoster virus, cytomegalovirus, HHV-6, and HHV-7), it is not widespread in the general population and has many unique proteins. HHV-8 is strongly associated with all subtypes of Kaposi's sarcoma (KS), multicentric Castleman's disease, and a rare form of B-cell lymphoma, primary effusion lymphoma. In addition, HHV-8 DNA sequences have been found in association with other diseases, but the role of the virus in these diseases is largely unconfirmed and remains controversial. The seroprevalence of HHV-8, based on detection of latent and lytic proteins, is 2 to 5% in healthy donors except in certain geographic areas where the virus is endemic, 80 to 95% in classic KS patients, and 40 to 50% in HIV-1 patients without KS. This virus can be transmitted both sexually and through body fluids (e.g., saliva and blood). HHV-8 is a transforming virus, as evidenced by its presence in human malignancies, by the in vitro transforming properties of several of its viral genes, and by its ability to transform some primary cells in culture. It is not, however, sufficient for transformation, and other cofactors such as immunosuppressive cytokines are involved in the development of HHV-8-associated malignancies. In this article, we review the biology, molecular virology, epidemiology, transmission, detection methods, pathogenesis, and antiviral therapy of this newly discovered human herpesvirus. PMID:12097251

Enhanced CT images by the wavelet transform improving diagnostic accuracy of chest nodules.

PubMed

Guo, Xiuhua; Liu, Xiangye; Wang, Huan; Liang, Zhigang; Wu, Wei; He, Qian; Li, Kuncheng; Wang, Wei

2011-02-01

The objective of this study was to compare the diagnostic accuracy in the interpretation of chest nodules using original CT images versus enhanced CT images based on the wavelet transform. The CT images of 118 patients with cancers and 60 with benign nodules were used in this study. All images were enhanced through an algorithm based on the wavelet transform. Two experienced radiologists interpreted all the images in two reading sessions. The reading sessions were separated by a minimum of 1 month in order to minimize the effect of observer's recall. The Mann-Whitney U nonparametric test was used to analyze the interpretation results between original and enhanced images. The Kruskal-Wallis H nonparametric test of K independent samples was used to investigate the related factors which could affect the diagnostic accuracy of observers. The area under the ROC curves for the original and enhanced images was 0.681 and 0.736, respectively. There is significant difference in diagnosing the malignant nodules between the original and enhanced images (z = 7.122, P < 0.001), whereas there is no significant difference in diagnosing the benign nodules (z = 0.894, P = 0.371). The results showed that there is significant difference between original and enhancement images when the size of nodules was larger than 2 cm (Z = -2.509, P = 0.012, indicating the size of the nodules is a critical evaluating factor of the diagnostic accuracy of observers). This study indicated that the image enhancement based on wavelet transform could improve the diagnostic accuracy of radiologists for the malignant chest nodules.

Differential effects of human papillomavirus type 6, 16, and 18 DNAs on immortalization and transformation of human cervical epithelial cells

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

Pecoraro, G.; Morgan, D.; Defendi, V.

1989-01-01

The human papillomaviruses (HPVs) are associated with specific benign and malignant lesions of the skin and mucosal epithelia. Cloned viral DNAs from HPV types 6b, 16, and 18 associated with different pathological manifestations of genital neoplasia in vivo were introduced into primary human cervical epithelial cells by electroporation. Cells transfected with HPV16 or HPV18 DNA acquired indefinite lifespans, distinct morphological alterations, and anchorage-independent growth (HPV18), and contain integrated transcriptionally active viral genomes. HPV6b or plasmid electroporated cells senesced at low passage. The alterations in growth and differentiation of the cells appear to reflect the progressive oncogenic processes that result inmore » cervical carcinoma in vivo.« less

The Role of the EGF Receptor First Intron in Its Regulation in Breast Canceer.

DTIC Science & Technology

1997-08-01

of EGFR, to malignantly transform mammary glands in transgenic mice (46). Future work could determine if these putative oncogene factor binding sites...general transcription factors, and the use or overuse of one promoter could monopolize the abundance of these transcription factors within a cell. The ideal

Problem-Solving Test: The Mechanism of Action of a Human Papilloma Virus Oncoprotein

ERIC Educational Resources Information Center

Szeberenyi, Jozsef

2009-01-01

Terms to be familiar with before you start to solve the test: human papilloma virus; cervical cancer; oncoproteins; malignant transformation; retinoblastoma protein; cell cycle; quiescent and cycling cells; cyclin/cyclin-dependent kinase (Cdk) complexes; E2F; S-phase genes; enhancer element; proto-oncogenes; tumor suppressor genes; radioactive…

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.

Schneiderian-Type Papilloma of the Middle Ear: A Review of the Literature

PubMed Central

Schaefer, Nathan; Chong, Jessica; Griffin, Aaron; Little, Andrew; Gochee, Peter; Dixon, Natalie

2015-01-01

Schneiderian-type papilloma of the middle ear is a rare finding. We present a 46-year-old Aboriginal man with a large tympanic membrane perforation and a Schneiderian-type papilloma filling the middle ear. The aim of this study is to familiarize clinicians with this uncommon disease through discussion of its clinical presentation, diagnostic considerations and management. A search of English-language peer-reviewed literature was undertaken using the key words “Schneiderian-type papilloma,” “inverted papilloma,” and “middle ear.” A total of 29 cases (including the present case) of Schneiderian-type papilloma involving the middle ear were reviewed. Common presenting symptoms include hearing loss, otalgia, and otorrhea. Middle ear disease is associated with higher rates of recurrence and malignant transformation than its sinonasal counterpart. Radical surgical resection is the only curative treatment. Schneiderian-type papilloma is a benign, but locally aggressive, epithelial neoplasm most commonly arising in the sinonasal tract. Whilst involvement of the middle ear is extremely rare, knowledge of this condition is important due to its propensity to recur and the high rate of malignant transformation. PMID:25564042

Very early stage adenocarcinoma arising from adenomyosis in the uterus.

PubMed

Hsu, Ming-I; Chou, Szu-Yuan; Lin, Sey-En; Liang, So-Jung; Chiu, Hsiao-Chen; Hsu, Chun-Sen

2006-12-01

Malignant transformations of adenomyosis in premenopausal women with normal endometrium are extremely rare. We report a case of adenocarcinoma arising from an adenomyotic focus in the uterus, which was found unexpectedly in a woman undergoing myomectomy for adenomyosis. A 47-year-old premenopausal woman presented with massive vaginal bleeding and anemia. She was admitted and underwent myomectomy under the initial diagnosis of uterine leiomyoma. Microscopic studies revealed endometrioid adenocarcinoma, which was a malignant transformation of a focus of adenomyosis in the surgical specimen. A total hysterectomy and bilateral salpingo-oophorectomy with pelvic and para-aortic lymphadenectomy was then performed. Pathologic studies showed no residual tumors in the entire resected specimen except for the previous lesion. The endometrium had normal thickness with mild proliferative activity throughout the cavity. There was no atrophic or hyperplastic change in the whole endometrium. The adenocarcinoma was present exclusively in the myometrium, and a transition between the carcinoma and the adenomyotic glands was observed. This case report presents evidence that adenocarcinoma may a rise de novo from an adenomyotic lesion in the uterus.

Oral lichen planus patients exhibit consistent chromosomal numerical aberrations: A follow-up analysis.

PubMed

Yahalom, Ran; Yarom, Noam; Shani, Tali; Amariglio, Ninet; Kaplan, Ilana; Trakhtenbrot, Luba; Hirshberg, Abraham

2016-04-01

Oral lichen planus (OLP) carries an increased risk for malignant transformation with aneuploid cells (ACs) being found in brush samples of a quarter of patients with OLP. Patients with OLP were followed and repeated brush samples were simultaneously analyzed for morphology and fluorescent in situ hybridization (FISH) using centromeric probes for chromosomes 2 and 8. Three patients with a high proportion of ACs developed oral cancer. Fifteen patients had ≥1% ACs (13 in affected sites and 2 in nonaffected sites), whereas only 2 of the 15 patients with <1% ACs in the first sample had ≥1% ACs in the second sample. A strong positive correlation between the results of the initial and repeated samples was found. High proportion of ACs in brush samples from patients with OLP may imply an impending malignant transformation. As FISH analysis is consistent over time, it can be used to identify a subgroup of patients who would require close follow-up. © 2015 Wiley Periodicals, Inc. Head Neck 38: E741-E746, 2016. © 2015 Wiley Periodicals, Inc.

Countermeasures for space radiation induced adverse biologic effects

NASA Astrophysics Data System (ADS)

Kennedy, A. R.; Wan, X. S.

2011-11-01

Radiation exposure in space is expected to increase the risk of cancer and other adverse biological effects in astronauts. The types of space radiation of particular concern for astronaut health are protons and heavy ions known as high atomic number and high energy (HZE) particles. Recent studies have indicated that carcinogenesis induced by protons and HZE particles may be modifiable. We have been evaluating the effects of proton and HZE particle radiation in cultured human cells and animals for nearly a decade. Our results indicate that exposure to proton and HZE particle radiation increases oxidative stress, cytotoxicity, cataract development and malignant transformation in in vivo and/or in vitro experimental systems. We have also shown that these adverse biological effects can be prevented, at least partially, by treatment with antioxidants and some dietary supplements that are readily available and have favorable safety profiles. Some of the antioxidants and dietary supplements are effective in preventing radiation induced malignant transformation in vitro even when applied several days after the radiation exposure. Our recent progress is reviewed and discussed in the context of the relevant literature.

Primary intraosseous squamous cell carcinoma arising in an odontogenic keratocyst previously treated with marsupialization: case report and immunohistochemical study.

PubMed

Martínez-Martínez, Marisol; Mosqueda-Taylor, Adalberto; Delgado-Azañero, Wilson; Rumayor-Piña, Alicia; de Almeida, Oslei Paes

2016-04-01

A rare case of primary intraosseous squamous cell carcinoma arising in an odontogenic keratocyst (OKC) is presented here, with the clinical and histologic features of the first biopsy showing characteristics of OKC and the second biopsy disclosing a squamous cell carcinoma. Immunoprofile of this case was compared with five cases of classical OKC by using cytokeratins CK5, CK14, and CK19, CD138, p63, Ki-67, p53, and bcl-2. Classic OKCs showed expected positivity, mainly in the basal and/or suprabasal layers with most antibodies, except for p53, which was negative, whereas the present case showed irregular positivity in all layers, indicating that this can be useful for differential diagnosis and suggesting a possible role in malignant transformation into primary intraosseous squamous cell carcinoma. In conclusion, immunohistochemical differences between the first biopsy of the present case and classic OKC suggest that immunohistochemistry can be helpful in cases with areas of subtle initial malignant transformation. Copyright © 2016 Elsevier Inc. All rights reserved.

Schneiderian-Type Papilloma of the Middle Ear: A Review of the Literature.

PubMed

Schaefer, Nathan; Chong, Jessica; Griffin, Aaron; Little, Andrew; Gochee, Peter; Dixon, Natalie

2015-06-01

Schneiderian-type papilloma of the middle ear is a rare finding. We present a 46-year-old Aboriginal man with a large tympanic membrane perforation and a Schneiderian-type papilloma filling the middle ear. The aim of this study is to familiarize clinicians with this uncommon disease through discussion of its clinical presentation, diagnostic considerations and management. A search of English-language peer-reviewed literature was undertaken using the key words "Schneiderian-type papilloma," "inverted papilloma," and "middle ear." A total of 29 cases (including the present case) of Schneiderian-type papilloma involving the middle ear were reviewed. Common presenting symptoms include hearing loss, otalgia, and otorrhea. Middle ear disease is associated with higher rates of recurrence and malignant transformation than its sinonasal counterpart. Radical surgical resection is the only curative treatment. Schneiderian-type papilloma is a benign, but locally aggressive, epithelial neoplasm most commonly arising in the sinonasal tract. Whilst involvement of the middle ear is extremely rare, knowledge of this condition is important due to its propensity to recur and the high rate of malignant transformation.

[Papilloma of the lacrimal sac].

PubMed

Burduk, Paweł K; Seredyka-Burduk, Małgorzata; Kaźmierczak, Wojciech; Dalke, Krzysztof; Marszałek, Andrzej

2013-01-01

The benign lesions of the lacrimal sac are very rare. The most typical epithelial tumor is squamous papilloma. This tumors often present with symptoms of dacryostenosis and dacriocystitis. Human papillomavirus (HPV) infection is known to be causative agent in the development of epithelial tumor. Lacrimal sac tumors could transform to malignant neoplasms, especially if they are developed of coexisting HPV infection. We present a patient with a squamous papilloma of the lacrimal sac and discussed the method of treatment. The patient was suffered from epiphora and recurrent dacriocystitis. An endoscopic surgery with dacriocystorhinostomy and local resection of the tumor could be an effective method of choice. The usage of a shaver for wide removal of the lacrimal sac wall is recommended to prevent local recurrence. The histopathology examination showed squamous papilloma. The patient is free of the disease over 8 months of follow up. Primary lacrimal sac papilloma require long term follow up for recurrence or malignant transformation. HPV infection could be associated with the development of lacrimal sac papillomas. Copyright © 2012 Polish Otorhinolaryngology - Head and Neck Surgery Society. Published by Elsevier Urban & Partner Sp. z.o.o. All rights reserved.

[Congenital "kissing" lesions: Nevus or "café au lait" spot?

PubMed

Durazzo, A; Boccara, O; Fraitag, S; Fusade, T; Picard, A; Kadlub, N

2016-12-01

"Café au lait" spots (CLS) are pigmented skin lesions principally located at the trunk and the limbs. Histologically, CLSs consist in an excessive pigmentation of the epidermis, with no risk of malignant transformation. The "kissing" nevus is a rare pigmented congenital nevus affecting both lower and upper eyelids in a mirror layout. As other nevi, it presents a theoretical risk of malignant transformation. These two pigmented lesions are responsible for aesthetic discomfort when affecting the face. Three patients presenting with a congenital pigmented lesion affecting the two eyelids in a mirror layout are presented. In two cases, the lesions, initially considered as "kissing" nevi, were classified as CLSs. The diagnosis of CLS was made on a biopsy in one patient and after surgery in the other one. Pigmented mirror layout lesions, called "kissing" lesions, are exclusively described for the nevi. We describe two cases of CLSs affecting the eyelids in a mirror layout. Difficulties in diagnostic are exposed and the possible treatments are discussed. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Human papilloma virus positive oropharyngeal squamous cell carcinoma: a growing epidemic.

PubMed

Panwar, Aru; Batra, Rishi; Lydiatt, William M; Ganti, Apar Kishor

2014-03-01

The incidence of oropharyngeal squamous cell carcinoma (OPSCC) is increasing despite a decrease in tobacco use. Almost 20-30% of patients with OPSCC do not have the traditional risk factors of smoking and alcohol use and in a vast majority of these patients, the human papilloma virus (HPV) appears to drive the malignant transformation. HPV induced malignant transformation is attributed to two viral oncogenes and their non-structural protein products (E6 and E7). These two proteins appear to affect carcinogenesis by their inhibitory effects on p53 and retinoblastoma proteins (Rb). Patients with HPV mediated OPSCC seem to have a better prognosis compared to their non-HPV counterparts. However, in the absence of strong evidence, standard of care at this time for OPSCC does not differ based on HPV status. Current research is focused on the role of de-escalation of treatment and elucidation of prognostic markers in this unique population. This review focuses on the pathogenesis of HPV mediated OPSCC and details the current evidence in the management of these patients. Published by Elsevier Ltd.

[Oral squamous cell carcinoma and lichen planus vs. lichenoid lesions. Case report].

PubMed

Esquivel-Pedraza, Lilly; Fernández-Cuevas, Laura; Ruelas-Villavicencio, Ana Lilia; Guerrero-Ramos, Brenda; Hernández-Salazar, Amparo; Milke-García, María Pilar; Méndez-Flores, Silvia

2016-01-01

The development of squamous cell carcinoma from oral lichen planus is controversial. We report a case of intraoral squamous cell carcinoma, which presents together with lesions of oral lichen planus. The aim of this report was to analyze the problem to distinguish between the incipient changes of squamous cell carcinoma from the features described in oral lichen planus, in order to establish an accurate diagnosis of both entities. A 57-year old man with a history of smoking and chronic alcohol intake, who had an ulcerated tumor mass located in the tongue, and bilateral white reticular patches on buccal mucosa and borders of the tongue. The histopathological report was moderately differentiated invasive squamous cell carcinoma and lichen planus respectively. The premalignant nature of OLP is still indeterminate and controversial, this is primarily due to inconsistency in the clinical and histological diagnostic criteria used to differentiate cases of oral lichen planus from lichenoid reactions or other lesions causing intraepithelial dysplasia with high potentially malignant transformation. Oral lichenoid reactions are possibly most likely to develop malignant transformation as compared to the classic OLP lesions.

IKKε-mediated tumorigenesis requires K63-linked polyubiquitination by a cIAP1/cIAP2/TRAF2 E3 ubiquitin ligase complex

PubMed Central

Zhou, Alicia Y.; Shen, Rhine R.; Kim, Eejung; Lock, Ying J.; Xu, Ming; Chen, Zhijian J.; Hahn, William C.

2014-01-01

SUMMARY IκB kinase ε (IKKε, IKBKE) is a key regulator of innate immunity and a breast cancer oncogene, amplified in ~30% of breast cancers, that promotes malignant transformation through NF-κB activation. Here we show that IKKε is modified and regulated by K63-linked polyubiquitination at Lysine 30 and Lysine 401. TNFα and IL-1β stimulation induces IKKε K63-linked polyubiquitination over baseline levels in both macrophages and breast cancer cell lines, and this modification is essential for IKKε kinase activity, IKKε-mediated NF-κB activation and IKKε-induced malignant transformation. Disruption of K63-linked ubiquitination of IKKε does not affect its overall structure but impairs the recruitment of canonical NF-κB proteins. A cIAP1/cIAP2/TRAF2 E3 ligase complex binds to and ubiquitinates IKKε. Together, these observations demonstrate that K63-linked polyubiquitination regulates IKKε activity in both inflammatory and oncogenic contexts and suggests an alterative approach to target this breast cancer oncogene. PMID:23453969

PREDICTION OF MALIGNANT BREAST LESIONS FROM MRI FEATURES: A COMPARISON OF ARTIFICIAL NEURAL NETWORK AND LOGISTIC REGRESSION TECHNIQUES

PubMed Central

McLaren, Christine E.; Chen, Wen-Pin; Nie, Ke; Su, Min-Ying

2009-01-01

Rationale and Objectives Dynamic contrast enhanced MRI (DCE-MRI) is a clinical imaging modality for detection and diagnosis of breast lesions. Analytical methods were compared for diagnostic feature selection and performance of lesion classification to differentiate between malignant and benign lesions in patients. Materials and Methods The study included 43 malignant and 28 benign histologically-proven lesions. Eight morphological parameters, ten gray level co-occurrence matrices (GLCM) texture features, and fourteen Laws’ texture features were obtained using automated lesion segmentation and quantitative feature extraction. Artificial neural network (ANN) and logistic regression analysis were compared for selection of the best predictors of malignant lesions among the normalized features. Results Using ANN, the final four selected features were compactness, energy, homogeneity, and Law_LS, with area under the receiver operating characteristic curve (AUC) = 0.82, and accuracy = 0.76. The diagnostic performance of these 4-features computed on the basis of logistic regression yielded AUC = 0.80 (95% CI, 0.688 to 0.905), similar to that of ANN. The analysis also shows that the odds of a malignant lesion decreased by 48% (95% CI, 25% to 92%) for every increase of 1 SD in the Law_LS feature, adjusted for differences in compactness, energy, and homogeneity. Using logistic regression with z-score transformation, a model comprised of compactness, NRL entropy, and gray level sum average was selected, and it had the highest overall accuracy of 0.75 among all models, with AUC = 0.77 (95% CI, 0.660 to 0.880). When logistic modeling of transformations using the Box-Cox method was performed, the most parsimonious model with predictors, compactness and Law_LS, had an AUC of 0.79 (95% CI, 0.672 to 0.898). Conclusion The diagnostic performance of models selected by ANN and logistic regression was similar. The analytic methods were found to be roughly equivalent in terms of predictive ability when a small number of variables were chosen. The robust ANN methodology utilizes a sophisticated non-linear model, while logistic regression analysis provides insightful information to enhance interpretation of the model features. PMID:19409817

ABERRANT SPLICING OF A BRAIN-ENRICHED ALTERNATIVE EXON ELIMINATES TUMOR SUPPRESSOR FUNCTION AND PROMOTES ONCOGENE FUNCTION DURING BRAIN TUMORIGENESIS

PubMed Central

Bredel, Markus; Ferrarese, Roberto; Harsh, Griffith R.; Yadav, Ajay K.; Bug, Eva; Maticzka, Daniel; Reichardt, Wilfried; Masilamani, Anie P.; Dai, Fangping; Kim, Hyunsoo; Hadler, Michael; Scholtens, Denise M.; Yu, Irene L.Y.; Beck, Jürgen; Srinivasasainagendra, Vinodh; Costa, Fabrizio; Baxan, Nicoleta; Pfeifer, Dietmar; Elverfeldt, Dominik v.; Backofen, Rolf; Weyerbrock, Astrid; Duarte, Christine W.; He, Xiaolin; Prinz, Marco; Chandler, James P.; Vogel, Hannes; Chakravarti, Arnab; Rich, Jeremy N.; Carro, Maria S.

2014-01-01

BACKGROUND: Tissue-specific alternative splicing is known to be critical to emergence of tissue identity during development, yet its role in malignant transformation is undefined. Tissue-specific splicing involves evolutionary-conserved, alternative exons, which represent only a minority of total alternative exons. Many, however, have functional features that influence activity in signaling pathways to profound biological effect. Given that tissue-specific splicing has a determinative role in brain development and the enrichment of genes containing tissue-specific exons for proteins with roles in signaling and development, it is thus plausible that changes in such exons could rewire normal neurogenesis towards malignant transformation. METHODS: We used integrated molecular genetic and cell biology analyses, computational biology, animal modeling, and clinical patient profiles to characterize the effect of aberrant splicing of a brain-enriched alternative exon in the membrane-binding tumor suppressor Annexin A7 (ANXA7) on oncogene regulation and brain tumorigenesis. RESULTS: We show that aberrant splicing of a tissue-specific cassette exon in ANXA7 diminishes endosomal targeting and consequent termination of the signal of the EGFR oncoprotein during brain tumorigenesis. Splicing of this exon is mediated by the ribonucleoprotein Polypyrimidine Tract-Binding Protein 1 (PTBP1), which is normally repressed during brain development but, we find, is excessively expressed in glioblastomas through either gene amplification or loss of a neuron-specific microRNA, miR-124. Silencing of PTBP1 attenuates both malignancy and angiogenesis in a stem cell-derived glioblastoma animal model characterized by a high native propensity to generate tumor endothelium or vascular pericytes to support tumor growth. We show that EGFR amplification and PTBP1 overexpression portend a similarly poor clinical outcome, further highlighting the importance of PTBP1-mediated activation of EGFR. CONCLUSIONS: Our data illustrate how anomalous splicing of a tissue-regulated exon in a constituent of an oncogenic signaling pathway eliminates its tumor suppressor function and promotes tumorigenesis. This paradigm of malignant glial transformation as a consequence of tissue-specific alternative exon splicing in a tumor suppressor, may have widespread applicability in explaining how changes in critical tissue-specific regulatory mechanisms reprogram normal development to oncogenesis. SECONDARY CATEGORY: n/a.

The role of chemicals and radiation in the etiology of cancer

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

Huberman, E.; Barr, S.H.

In this volume, investigators consider the mechanisms of oncogenesis, cell transformation, and carcinogen metabolism and present new findings on chemical and radiation carcinogenesis and chemically induced mutagenesis and chromosomal changes. As background to the studies of chemical and radiation carcinogenesis, the book surveys knowledge of cell transformation and carcinogen metabolism. Among the topics reviewed are the transforming genes involved in human malignancy, the genetics and epigenetics of neoplasia, and the single-hit and multi-hit concepts of hepatocarcinogenesis. Also examined are organ, species, and interindividual differences in carcinogen metabolism; chemical and biochemical dosimetry of genotoxic chemical exposure; and the role of pharmacokineticsmore » and DNA dosimetry in relating in vitro to in vivo actions of N-nitroso compounds.« less

Folate restriction and methylenetetrahydrofolate reductase 677T polymorphism decreases adoMet synthesis via folate-dependent remethylation in human-transformed lymphoblasts.

PubMed

Chiang, E-P; Wang, Y-C; Tang, F-Y

2007-04-01

The homozygous mutation (677TT) in the methylenetetrahydrofolate reductase (MTHFR) gene reduces enzyme activity and alters cellular folate composition. Previous epidemiological studies reported a potential protective effect of MTHFR677C --> T against acute lymphocytic leukemia and malignant lymphoma, but the mechanism remains to be determined. We investigated the biochemical impacts of MTHFR677C --> T on cellular S-adenosyl methionine (adoMet) synthesis, global DNA methylation, and de novo purine synthesis, all of which are potential regulatory pathways involved in tumorigenesis. Metabolic fluxes of homocysteine remethylation and de novo purine synthesis were compared between Epstein-Barr virus-transformed lymphoblasts expressing MTHFR 677C and MTHFR 677T using stable isotopic tracers and GCMS. MTHFR TT genotype significantly reduced folate-dependent remethylation under folate restriction, reflecting limited methylated folates under folate restriction. Data also suggested increased formylated folate pool and increased purine synthesis when folate is adequate. The impacts of MTHFR 677T polymorphism appeared closely related to folate status, and such alterations may modulate metabolic pathways involved in cancer onset/progression. The advantage of de novo purine synthesis found in the MTHFR TT genotype may account for the protective effect of MTHFR in hematological malignancies. These transformed cells are potential models for studying the consequences of human genetic variation and cancer pathogenesis.

Aid is a key regulator of myeloid/erythroid differentiation and DNA methylation in hematopoietic stem/progenitor cells

PubMed Central

Kunimoto, Hiroyoshi; McKenney, Anna Sophia; Meydan, Cem; Shank, Kaitlyn; Nazir, Abbas; Rapaport, Franck; Durham, Benjamin; Garrett-Bakelman, Francine E.; Pronier, Elodie; Shih, Alan H.; Melnick, Ari; Chaudhuri, Jayanta

2017-01-01

Recent studies have reported that activation-induced cytidine deaminase (AID) and ten-eleven-translocation (TET) family members regulate active DNA demethylation. Genetic alterations of TET2 occur in myeloid malignancies, and hematopoietic-specific loss of Tet2 induces aberrant hematopoietic stem cell (HSC) self-renewal/differentiation, implicating TET2 as a master regulator of normal and malignant hematopoiesis. Despite the functional link between AID and TET in epigenetic gene regulation, the role of AID loss in hematopoiesis and myeloid transformation remains to be investigated. Here, we show that Aid loss in mice leads to expansion of myeloid cells and reduced erythroid progenitors resulting in anemia, with dysregulated expression of Cebpa and Gata1, myeloid/erythroid lineage-specific transcription factors. Consistent with data in the murine context, silencing of AID in human bone marrow cells skews differentiation toward myelomonocytic lineage. However, in contrast to Tet2 loss, Aid loss does not contribute to enhanced HSC self-renewal or cooperate with Flt3-ITD to induce myeloid transformation. Genome-wide transcription and differential methylation analysis uncover the critical role of Aid as a key epigenetic regulator. These results indicate that AID and TET2 share common effects on myeloid and erythroid lineage differentiation, however, their role is nonredundant in regulating HSC self-renewal and in myeloid transformation. PMID:28077417

A novel inhibitor of STAT3 homodimerization selectively suppresses STAT3 activity and malignant transformation.

PubMed

Zhang, Xiaolei; Sun, Ying; Pireddu, Roberta; Yang, Hua; Urlam, Murali K; Lawrence, Harshani R; Guida, Wayne C; Lawrence, Nicholas J; Sebti, Saïd M

2013-03-15

STAT3-STAT3 dimerization, which involves reciprocal binding of the STAT3-SH2 domain to phosphorylated tyrosine-705 (Y-705), is required for STAT3 nuclear translocation, DNA binding, and transcriptional regulation of downstream target genes. Here, we describe a small molecule S3I-1757 capable of disrupting STAT3-STAT3 dimerization, activation, and malignant transforming activity. Fluorescence polarization assay and molecular modeling suggest that S3I-1757 interacts with the phospho-Y-705-binding site in the SH2 domain and displaces fluorescein-labeled GpYLPQTV phosphotyrosine peptide from binding to STAT3. We generated hemagglutinin (HA)-tagged STAT3 and FLAG-tagged STAT3 and showed using coimmunoprecipitation and colocalization studies that S3I-1757 inhibits STAT3 dimerization and STAT3-EGF receptor (EGFR) binding in intact cells. Treatment of human cancer cells with S3I-1757 (but not a closely related analog, S3I-1756, which does not inhibit STAT3 dimerization), inhibits selectively the phosphorylation of STAT3 over AKT1 and ERK1/2 (MAPK3/1), nuclear accumulation of P-Y705-STAT3, STAT3-DNA binding, and transcriptional activation and suppresses the expression levels of STAT3 target genes, such as Bcl-xL (BCL2L1), survivin (BIRC5), cyclin D1 (CCND1), and matrix metalloproteinase (MMP)-9. Furthermore, S3I-1757, but not S3I-1756, inhibits anchorage-dependent and -independent growth, migration, and invasion of human cancer cells, which depend on STAT3. Finally, STAT3-C, a genetically engineered mutant of STAT3 that forms a constitutively dimerized STAT3, rescues cells from the effects of S3I-1757 inhibition. Thus, we have developed S3I-1757 as a STAT3-STAT3 dimerization inhibitor capable of blocking hyperactivated STAT3 and suppressing malignant transformation in human cancer cells that depend on STAT3.

A novel inhibitor of STAT3 homodimerization selectively suppresses STAT3 activity and malignant transformation

PubMed Central

Zhang, Xiaolei; Sun, Ying; Pireddu, Roberta; Yang, Hua; Urlam, Murali K.; Lawrence, Harshani R.; Guida, Wayne C.; Lawrence, Nicholas J.; Sebti, Saïd M.

2014-01-01

STAT3-STAT3 dimerization, which involves reciprocal binding of the STAT3-SH2 domain to phosphorylated tyrosine-705 (Y-705), is required for STAT3 nuclear translocation, DNA binding and transcriptional regulation of downstream target genes. Here we describe a small molecule S3I-1757 capable of disrupting STAT3-STAT3 dimerization, activation and malignant transforming activity. Fluorescence polarization assays and molecular modeling suggest that S3I-1757 interacts with the Y-705 binding site in the SH2 domain and displaces fluorescein-labelled GpYLPQTV phosphotyrosine peptide from binding to STAT3. We generated HA-tagged STAT3 and FLAG-tagged STAT3 and showed using co-immunoprecipitation and co-localization studies that S3I-1757 inhibits STAT3 dimerization and STAT3-EGF receptor binding in intact cells. Treatment of human cancer cells with S3I-1757 (but not a closely related analogue, S3I-1756, that does not inhibit STAT3 dimerization), inhibits selectively the phosphorylation of STAT3 over AKT1 and ERK1/2 (MAPK3/1), nuclear accumulation of P-Y705-STAT3, STAT3-DNA binding and transcriptional activation and suppresses the expression levels of STAT3 target genes such as Bcl-xL (BCL2L1), survivin (BIRC5), cyclin D1 (CCND1) and MMP9. Furthermore, S3I-1757 but not S3I-1756 inhibits anchorage-dependent and -independent growth, migration and invasion of human cancer cells which depend on STAT3. Finally, STAT3-C, a genetically engineered mutant of STAT3 that forms a constitutively dimerized STAT3, rescues cells from the effects of S3I-1757 inhibition. Thus, we have developed S3I-1757 as a STAT3-STAT3 dimerization inhibitor capable of blocking hyper activated STAT3 and suppressing malignant transformation in human cancer cells that depend on STAT3. PMID:23322008

Overexpression of insulin-like growth factor-I receptor as a pertinent biomarker for hepatocytes malignant transformation

PubMed Central

Yan, Xiao-Di; Yao, Min; Wang, Li; Zhang, Hai-Jian; Yan, Mei-Juan; Gu, Xing; Shi, Yun; Chen, Jie; Dong, Zhi-Zhen; Yao, Deng-Fu

2013-01-01

AIM: To investigate the dynamic features of insulin-like growth factor-I receptor (IGF-IR) expression in rat hepatocarcinogenesis, and the relationship between IGF-IR and hepatocytes malignant transformation at mRNA or protein level. METHODS: Hepatoma models were made by inducing with 2-fluorenylacetamide (2-FAA) on male Sprague-Dawley rats. Morphological changes of hepatocytes were observed by pathological Hematoxylin and eosin staining, the dynamic expressions of liver and serum IGF-IR were quantitatively analyzed by an enzyme-linked immunosorbent assay. The distribution of hepatic IGF-IR was located by immunohistochemistry. The fragments of IGF-IR gene were amplified by reverse transcription-polymerase chain reaction, and confirmed by sequencing. RESULTS: Rat hepatocytes after induced by 2-FAA were changed dynamically from granule-like degeneration, precancerous to hepatoma formation with the progressing increasing of hepatic mRNA or IGF-IR expression. The incidences of liver IGF-IR, IGF-IR mRNA, specific IGF-IR concentration (ng/mg wet liver), and serum IGF-IR level (ng/mL) were 0.0%, 0.0%, 0.63 ± 0.17, and 1.33 ± 0.47 in the control; 50.0%, 61.1%, 0.65 ± 0.2, and 1.51 ± 0.46 in the degeneration; 88.9%, 100%, 0.66 ± 0.14, and 1.92 ± 0.29 in the precancerosis; and 100%, 100%, 0.96 ± 0.09, and 2.43 ± 0.57 in the cancerous group, respectively. IGF-IR expression in the cancerous group was significantly higher (P < 0.01) than that in any of other groups at mRNA or protein level. The closely positive IGF-IR relationship was found between livers and sera (r = 0.91, t = 14.222, P < 0.01), respectively. CONCLUSION: IGF-IR expression may participate in rat hepatocarcinogenesis and its abnormality should be an early marker for hepatocytes malignant transformation. PMID:24106410

Women with HIV are more commonly infected with non-16 and -18 high-risk HPV types.

PubMed

McKenzie, Nathalie Dauphin; Kobetz, Erin N; Hnatyszyn, James; Twiggs, Leo B; Lucci, Joseph A

2010-03-01

To review and summarize evidence from clinical, translational and epidemiologic studies which have examined the clinically relevant aspects of HPV type prevalence and cervical dysplasia in HIV-infected women. Relevant studies were identified through a MEDLINE search. References of identified reports were also used to identify additional published articles for review. HIV-infected women in different geographic regions (such as Zambia, Brazil, Rochester NY) appear to be infected with less prevalent types of HR-HPV as compared to the general population who, across all continents, are more commonly infected with types 16 and 18. Secondly, integration of HPV DNA into the host genome is no longer thought to be a necessary cause of malignant transformation of cervical cells. However, rate of integration appears to differ by the type of HPV. In fact, the types of HPV which appear to be more common in cervical dysplasia of HIV-infected women are the same types which are more likely to require integration for malignant transformation. Finally, HPV types found in HIV-infected women are relatively common and likely to persist. The most common among these types belong to the alpha-9 and -7 species which are the most carcinogenic species. Given that current vaccines target HR-HPV-16/18, the findings from the above mentioned studies may have important implications for the design of HPV vaccines that target the types of HPV associated with disease risk in HIV-infected women. HPV typing and assessment of the physical state (whether it is integrated or episomal) appear to be two valuable parameters for the prognostic evaluation of dysplastic lesions of the uterine cervix. This, however, has not yet been assessed in HIV-infected women. Recent data about the immune response in HPV/HIV co-infection may lead to understanding potential mechanisms for less virulent HPV causing malignant transformation in HIV-infected women.

Enchondromas of the hand: factors affecting recurrence, healing, motion, and malignant transformation.

PubMed

Sassoon, Adam A; Fitz-Gibbon, Patrick D; Harmsen, William S; Moran, Steven L

2012-06-01

Enchondromas represent the most common primary bone tumor in the hand. Despite their frequency, a standardized treatment protocol is lacking. This study examines the outcome of surgically treated enchondromas of the hand with regard to tumor location, graft choice, and presence or absence of fracture. We retrospectively reviewed 102 enchondromas in 80 patients, identified between 1991 and 2008, with a mean clinical follow-up of 38 months. We assessed the effects of age, tumor location, and graft choice on outcomes for all lesions. Patients presenting with Ollier disease, Maffucci syndrome, pathologic fractures, or recurrent disease were separated for additional analysis. Of the 102 lesions, 62 (61%) achieved complete radiographic healing in a median time of 6 months. Full range of motion was achieved following treatment of 68 lesions (67%) in a median time of 3 months. A total of 95 lesions (93%) remained recurrence free following surgery. One case of malignant transformation occurred in a patient with Maffucci syndrome. Tumor location and graft choice did not affect healing grade, time to healing, range of motion, or recurrence rate. Age at presentation greater than 30 was associated with more rapid healing. Monocentric, nonexpanding lesions were associated with improved postoperative range of motion. Patients with a diagnosis of multiple enchondromas had a higher rate of recurrence following surgery, and patients presenting with a recurrent lesion had a higher rate of complications. Following pathologic fracture, no differences in outcomes were observed when enchondromas were treated primarily or following fracture healing. Following surgical treatment of enchondromas in the hand, the majority of patients achieve complete bony healing and full range of motion, regardless of the graft material used. Malignant transformation is rare, and aggressive follow-up measures should be reserved for patients with a diagnosis of multiple enchondromas. Therapeutic IV. Copyright © 2012 American Society for Surgery of the Hand. All rights reserved.

The cancer paradigms of mammalian regeneration: can mammals regenerate as amphibians?

PubMed

Sarig, Rachel; Tzahor, Eldad

2017-04-01

Regeneration in mammals is restricted to distinct tissues and occurs mainly by expansion and maturation of resident stem cells. During regeneration, even subtle mutations in the proliferating cells may cause a detrimental effect by eliciting abnormal differentiation or malignant transformation. Indeed, cancer in mammals has been shown to arise through deregulation of stem cells maturation, which often leads to a differentiation block and cell transformation. In contrast, lower organisms such as amphibians retain a remarkable regenerative capacity in various organs, which occurs via de- and re-differentiation of mature cells. Interestingly, regenerating amphibian cells are highly resistant to oncogenic transformation. Therapeutic approaches to improve mammalian regeneration mainly include stem-cell transplantations; but, these have proved unsuccessful in non-regenerating organs such as the heart. A recently developed approach is to induce de-differentiation of mature cardiomyocytes using factors that trigger their re-entry into the cell cycle. This novel approach raises numerous questions regarding the balance between transformation and regeneration induced by de-differentiation of mature mammalian somatic cells. Can this balance be controlled artificially? Do de-differentiated cells acquire the protection mechanisms seen in regenerating cells of lower organisms? Is this model unique to the cardiac tissue, which rarely develops tumors? This review describes regeneration processes in both mammals and lower organisms and, particularly, the ability of regenerating cells to avoid transformation. By comparing the characteristics of mammalian embryonic and somatic cells, we discuss therapeutic strategies of using various cell populations for regeneration. Finally, we describe a novel cardiac regeneration approach and its implications for regenerative medicine. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Epstein–Barr virus latent genes

PubMed Central

Kang, Myung-Soo; Kieff, Elliott

2015-01-01

Latent Epstein–Barr virus (EBV) infection has a substantial role in causing many human disorders. The persistence of these viral genomes in all malignant cells, yet with the expression of limited latent genes, is consistent with the notion that EBV latent genes are important for malignant cell growth. While the EBV-encoded nuclear antigen-1 (EBNA-1) and latent membrane protein-2A (LMP-2A) are critical, the EBNA-leader proteins, EBNA-2, EBNA-3A, EBNA-3C and LMP-1, are individually essential for in vitro transformation of primary B cells to lymphoblastoid cell lines. EBV-encoded RNAs and EBNA-3Bs are dispensable. In this review, the roles of EBV latent genes are summarized. PMID:25613728

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.

Osteochondroma of the Scapula with Accessory Nerve (XI) Compression.

PubMed

Beauchamp-Chalifour, Philippe; Pelet, Stéphane

2018-01-01

Osteochondroma is the most common benign bone tumor and is characterized as a cartilage-capped bony stalk. This lesion usually develops from the growth plate of long bones. Most osteochondromas are asymptomatic. Neurovascular compressions or cosmetic issues can occur in specific locations. Malignant transformation is extremely rare, and MRI can help evaluate these lesions. Symptomatic mass and malignancy features are the main surgical indications. Uncommonly, an osteochondroma can develop from flat bones. We present the case of a 25-year-old patient with a right scapula osteochondroma causing an accessory nerve compression. The mass was surgically removed, and the diagnosis was confirmed. The patient fully recovered at the latest 3-year follow-up visit.

Understanding the Role of Non-Coding RNAs in Bladder Cancer: From Dark Matter to Valuable Therapeutic Targets

PubMed Central

Pop-Bica, Cecilia; Gulei, Diana; Cojocneanu-Petric, Roxana; Braicu, Cornelia; Petrut, Bogdan; Berindan-Neagoe, Ioana

2017-01-01

The mortality and morbidity that characterize bladder cancer compel this malignancy into the category of hot topics in terms of biomolecular research. Therefore, a better knowledge of the specific molecular mechanisms that underlie the development and progression of bladder cancer is demanded. Tumor heterogeneity among patients with similar diagnosis, as well as intratumor heterogeneity, generates difficulties in terms of targeted therapy. Furthermore, late diagnosis represents an ongoing issue, significantly reducing the response to therapy and, inevitably, the overall survival. The role of non-coding RNAs in bladder cancer emerged in the last decade, revealing that microRNAs (miRNAs) may act as tumor suppressor genes, respectively oncogenes, but also as biomarkers for early diagnosis. Regarding other types of non-coding RNAs, especially long non-coding RNAs (lncRNAs) which are extensively reviewed in this article, their exact roles in tumorigenesis are—for the time being—not as evident as in the case of miRNAs, but, still, clearly suggested. Therefore, this review covers the non-coding RNA expression profile of bladder cancer patients and their validated target genes in bladder cancer cell lines, with repercussions on processes such as proliferation, invasiveness, apoptosis, cell cycle arrest, and other molecular pathways which are specific for the malignant transformation of cells. PMID:28703782

Understanding the Role of Non-Coding RNAs in Bladder Cancer: From Dark Matter to Valuable Therapeutic Targets.

PubMed

Pop-Bica, Cecilia; Gulei, Diana; Cojocneanu-Petric, Roxana; Braicu, Cornelia; Petrut, Bogdan; Berindan-Neagoe, Ioana

2017-07-13

The mortality and morbidity that characterize bladder cancer compel this malignancy into the category of hot topics in terms of biomolecular research. Therefore, a better knowledge of the specific molecular mechanisms that underlie the development and progression of bladder cancer is demanded. Tumor heterogeneity among patients with similar diagnosis, as well as intratumor heterogeneity, generates difficulties in terms of targeted therapy. Furthermore, late diagnosis represents an ongoing issue, significantly reducing the response to therapy and, inevitably, the overall survival. The role of non-coding RNAs in bladder cancer emerged in the last decade, revealing that microRNAs (miRNAs) may act as tumor suppressor genes, respectively oncogenes, but also as biomarkers for early diagnosis. Regarding other types of non-coding RNAs, especially long non-coding RNAs (lncRNAs) which are extensively reviewed in this article, their exact roles in tumorigenesis are-for the time being-not as evident as in the case of miRNAs, but, still, clearly suggested. Therefore, this review covers the non-coding RNA expression profile of bladder cancer patients and their validated target genes in bladder cancer cell lines, with repercussions on processes such as proliferation, invasiveness, apoptosis, cell cycle arrest, and other molecular pathways which are specific for the malignant transformation of cells.

Evaluation of AgNORs in Oral Potentially Malignant Lesions.

PubMed

Tomazelli, Karin Berria; Modolo, Filipe; Rivero, Elena Riet Correa

2015-01-01

Oral squamous cell carcinoma (OSCC) is usually preceded by detectable mucosal changes, as leukoplakias and erythroplakia. Histologically, these lesions can range from hyperkeratosis and acanthosis to epithelial dysplasia and even OSCC. The aim of this study was to investigate the proliferative activity, using AgNORs quantification proteins, in low- and high-risk oral epithelial dysplasia, OSCC, and nondysplastic epithelium (inflammatory fibrous hyperplasia). The sample was divided into 4 groups: G1: 10 cases of inflammatory fibrous hyperplasia (IFH), G2: 11 cases of low-risk epithelial dysplasia (LD), G3: 10 cases of high-risk epithelial dysplasia (HD), and G4: 11 cases of OSCC. The quantitative analysis was performed using an image processing software in photomicrographs at 1000x magnification. The one-way ANOVA was used for comparison of the mean AgNORs counts between the study groups. The mean AgNORs count was significantly higher (P ≤ 0.01) in OSCC when compared to IFH and the LD; however, it was not statistically different from HD. The mean number of LD was significantly lower than the HD and OSCC, with no difference related to IFH. AgNORs quantification can be an important and cheap method to help in the determination of the degree of epithelial dysplasia and, consequently, in the analysis of their potential for malignant transformation.

Expression signatures of early-stage and advanced medaka melanomas.

PubMed

Klotz, Barbara; Kneitz, Susanne; Regensburger, Martina; Hahn, Lena; Dannemann, Michael; Kelso, Janet; Nickel, Birgit; Lu, Yuan; Boswell, William; Postlethwait, John; Warren, Wesley; Kunz, Manfred; Walter, Ronald B; Schartl, Manfred

2018-06-01

Melanoma is one of the most aggressive tumors with a very low survival rate once metastasized. The incidence of newly detected cases increases every year suggesting the necessity of development and application of innovative treatment strategies. Human melanoma develops from melanocytes localized in the epidermis of the skin to malignant tumors because of deregulated effectors influencing several molecular pathways. Despite many advances in describing the molecular changes accompanying melanoma formation, many critical and clinically relevant molecular features of the transformed pigment cells and the underlying mechanisms are largely unknown. To contribute to a better understanding of the molecular processes of melanoma formation, we use a transgenic medaka melanoma model that is well suited for the investigation of melanoma tumor development because fish and human melanocytes are both localized in the epidermis. The purpose of our study was to gain insights into melanoma development from the first steps of tumor formation up to melanoma progression and to identify gene expression patterns that will be useful for monitoring treatment effects in drug screening approaches. Comparing transcriptomes from juvenile fish at the tumor initiating stage with nevi and advanced melanoma of adults, we identified stage specific expression signatures and pathways that are characteristic for the development of medaka melanoma, and are also found in human malignancies. Copyright © 2017 Elsevier Inc. All rights reserved.

Chronic exposure to the cytolethal distending toxins of Gram-negative bacteria promotes genomic instability and altered DNA damage response

PubMed Central

Guidi, Riccardo; Guerra, Lina; Levi, Laura; Stenerlöw, Bo; Fox, James G.; Josenhans, Christine; Masucci, Maria G.; Frisan, Teresa

2014-01-01

Summary Epidemiological evidence links chronic bacterial infections to the increased incidence of certain types of cancer but the molecular mechanisms by which bacteria contribute to tumour initiation and progression are still poorly characterized. Here we show that chronic exposure to the genotoxin cytolethal distending toxin (CDT) of Gram-negative bacteria promotes genomic instability and acquisition of phenotypic properties of malignancy in fibroblasts and colon epithelial cells. Cells grown for more than 30 weeks in the presence of sublethal doses of CDT showed increased mutation frequency, and accumulation of chromatin and chromosomal aberrations in the absence of significant alterations of cell cycle distribution, decreased viability or senescence. Cell survival was dependent on sustained activity of the p38 MAP kinase. The ongoing genomic instability was associated with impaired activation of the DNA damage response and failure to efficiently activate cell cycle checkpoints upon exposure to genotoxic stress. Independently selected sublines showed enhanced anchorage-independent growth as assessed by the formation of colonies in semisolid agarose. These findings support the notion that chronic infection by CDT-producing bacteria may promote malignant transformation, and point to the impairment of cellular control mechanisms associated with the detection and repair of DNA damage as critical events in the process. PMID:22998585

Enhancing the discrimination accuracy between metastases, gliomas and meningiomas on brain MRI by volumetric textural features and ensemble pattern recognition methods.

PubMed

Georgiadis, Pantelis; Cavouras, Dionisis; Kalatzis, Ioannis; Glotsos, Dimitris; Athanasiadis, Emmanouil; Kostopoulos, Spiros; Sifaki, Koralia; Malamas, Menelaos; Nikiforidis, George; Solomou, Ekaterini

2009-01-01

Three-dimensional (3D) texture analysis of volumetric brain magnetic resonance (MR) images has been identified as an important indicator for discriminating among different brain pathologies. The purpose of this study was to evaluate the efficiency of 3D textural features using a pattern recognition system in the task of discriminating benign, malignant and metastatic brain tissues on T1 postcontrast MR imaging (MRI) series. The dataset consisted of 67 brain MRI series obtained from patients with verified and untreated intracranial tumors. The pattern recognition system was designed as an ensemble classification scheme employing a support vector machine classifier, specially modified in order to integrate the least squares features transformation logic in its kernel function. The latter, in conjunction with using 3D textural features, enabled boosting up the performance of the system in discriminating metastatic, malignant and benign brain tumors with 77.14%, 89.19% and 93.33% accuracy, respectively. The method was evaluated using an external cross-validation process; thus, results might be considered indicative of the generalization performance of the system to "unseen" cases. The proposed system might be used as an assisting tool for brain tumor characterization on volumetric MRI series.

Fidelity of DNA Replication in Normal and Malignant Human Breast Cells

DTIC Science & Technology

1998-07-01

synthesome has been extensively demonstrated to carry out full length DNA replication in vitro, and to accurately depict the DNA replication process as it...occurs in the intact cell. By examining the fidelity of the DNA replication process carried out by the DNA synthesome from a number of breast cell types...we have demonstrated for the first time, that the cellular DNA replication machinery of malignant human breast cells is significantly more error-prone than that of non- malignant human breast cells.

Spectroscopic diagnosis of laryngeal carcinoma using near-infrared Raman spectroscopy and random recursive partitioning ensemble techniques.

PubMed

Teh, Seng Khoon; Zheng, Wei; Lau, David P; Huang, Zhiwei

2009-06-01

In this work, we evaluated the diagnostic ability of near-infrared (NIR) Raman spectroscopy associated with the ensemble recursive partitioning algorithm based on random forests for identifying cancer from normal tissue in the larynx. A rapid-acquisition NIR Raman system was utilized for tissue Raman measurements at 785 nm excitation, and 50 human laryngeal tissue specimens (20 normal; 30 malignant tumors) were used for NIR Raman studies. The random forests method was introduced to develop effective diagnostic algorithms for classification of Raman spectra of different laryngeal tissues. High-quality Raman spectra in the range of 800-1800 cm(-1) can be acquired from laryngeal tissue within 5 seconds. Raman spectra differed significantly between normal and malignant laryngeal tissues. Classification results obtained from the random forests algorithm on tissue Raman spectra yielded a diagnostic sensitivity of 88.0% and specificity of 91.4% for laryngeal malignancy identification. The random forests technique also provided variables importance that facilitates correlation of significant Raman spectral features with cancer transformation. This study shows that NIR Raman spectroscopy in conjunction with random forests algorithm has a great potential for the rapid diagnosis and detection of malignant tumors in the larynx.

Targeting the Tumor Microenvironment with Immunotherapy for Genitourinary Malignancies.

PubMed

Marciscano, Ariel E; Madan, Ravi A

2018-03-08

Bacillus Calmette-Guérin in urothelial carcinoma, high-dose interleukin-2 in renal cell carcinoma, and sipuleucel-T in prostate cancer serve as enduring examples that the host immune response can be harnessed to promote effective anti-tumor immunity in genitourinary malignancies. Recently, cancer immunotherapy with immune checkpoint inhibitors has transformed the prognostic landscape leading to durable responses in a subset of urothelial carcinoma and renal cell carcinoma patients with traditionally poor prognosis. Despite this success, many patients fail to respond to immune checkpoint inhibitors and progression/relapse remains common. Furthermore, modest clinical activity has been observed with ICIs as a monotherapy in advanced PCa. As such, novel treatment approaches are warranted and improved biomarkers for patient selection and treatment response are desperately needed. Future efforts should focus on exploring synergistic and rational combinations that safely and effectively boost response rates and survival in genitourinary malignancies. Specific areas of interest include (1) evaluating the optimal sequencing, disease burden, and timing of immuno-oncology agents with other anti-cancer therapeutics and (2) validating novel biomarkers of response to immunotherapy to optimize patient selection and to identify individuals most likely to benefit from immunotherapy across the heterogenous spectrum of genitourinary malignancies.

Nanomelatonin triggers superior anticancer functionality in a human malignant glioblastoma cell line

NASA Astrophysics Data System (ADS)

Yadav, Sanjeev Kumar; Srivastava, Anup Kumar; Dev, Atul; Kaundal, Babita; Choudhury, Subhasree Roy; Karmakar, Surajit

2017-09-01

Melatonin (MEL) has promising medicinal value as an anticancer agent in a variety of malignancies, but there are difficulties in achieving a therapeutic dose due to its short half-life, low bioavailability, poor solubility and extensive first-pass metabolism. In this study chitosan/tripolyphosphate (TPP) nanoparticles were prepared by an ionic gelation method to overcome the therapeutic challenges of melatonin and to improve its anticancer efficacy. Characterization of the melatonin-loaded chitosan (MEL-CS) nanoformulation was performed using transmission and scanning electron microscopies, dynamic light scattering, Fourier transform infrared spectroscopy, Raman spectroscopy and x-ray diffraction. In vitro release, cellular uptake and efficacy studies were tested for their enhanced anticancer potential in human U87MG glioblastoma cells. Confocal studies revealed higher cellular uptake of MEL-CS nanoparticles and enhanced anticancer efficacy in human malignant glioblastoma cancer cells than in healthy non-malignant human HEK293T cells in mono- and co-culture models. Our study has shown for the first time that MEL-CS nanocomposites are therapeutically more effective as compared to free MEL at inducing functional anticancer efficacy in the human brain tumour U87MG cell line.

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.

Development of the Bruton's tyrosine kinase inhibitor ibrutinib for B cell malignancies.

PubMed

Gayko, Urte; Fung, Mann; Clow, Fong; Sun, Steven; Faust, Elizabeth; Price, Samiyeh; James, Danelle; Doyle, Margaret; Bari, Samina; Zhuang, Sen Hong

2015-11-01

Ibrutinib is a first-in-class oral covalent inhibitor of Bruton's tyrosine kinase that has demonstrated clinical benefit for many patients with B cell malignancies. Positive results in initial trials led the U.S. Food and Drug Administration to grant ibrutinib three breakthrough therapy designations for mantle cell lymphoma (MCL), del17p chronic lymphocytic leukemia (CLL), and Waldenström's macroglobulinemia (WM). Ibrutinib was approved for these three cancers within 14 months of the original U.S. approval. Additionally, ibrutinib is approved for patient subsets with MCL and/or CLL in >45 other countries. Via a unique mechanism of action, ibrutinib inhibits B cell signaling pathways that regulate the survival, proliferation, adhesion, and homing of cancerous cells. This marks a paradigm shift from the conventional cytotoxic chemotherapy approach to treating B cell malignancies. Ibrutinib continues to be evaluated across a range of B cell malignancies, either as single-agent therapy or in combination with other therapies, and continues to transform the lives of these patients. © 2015 The Authors. Annals of the New York Academy of Sciences published by Wiley Periodicals Inc. on behalf of The New York Academy of Sciences.

Three-Class Mammogram Classification Based on Descriptive CNN Features

PubMed Central

Zhang, Qianni; Jadoon, Adeel

2017-01-01

In this paper, a novel classification technique for large data set of mammograms using a deep learning method is proposed. The proposed model targets a three-class classification study (normal, malignant, and benign cases). In our model we have presented two methods, namely, convolutional neural network-discrete wavelet (CNN-DW) and convolutional neural network-curvelet transform (CNN-CT). An augmented data set is generated by using mammogram patches. To enhance the contrast of mammogram images, the data set is filtered by contrast limited adaptive histogram equalization (CLAHE). In the CNN-DW method, enhanced mammogram images are decomposed as its four subbands by means of two-dimensional discrete wavelet transform (2D-DWT), while in the second method discrete curvelet transform (DCT) is used. In both methods, dense scale invariant feature (DSIFT) for all subbands is extracted. Input data matrix containing these subband features of all the mammogram patches is created that is processed as input to convolutional neural network (CNN). Softmax layer and support vector machine (SVM) layer are used to train CNN for classification. Proposed methods have been compared with existing methods in terms of accuracy rate, error rate, and various validation assessment measures. CNN-DW and CNN-CT have achieved accuracy rate of 81.83% and 83.74%, respectively. Simulation results clearly validate the significance and impact of our proposed model as compared to other well-known existing techniques. PMID:28191461

Three-Class Mammogram Classification Based on Descriptive CNN Features.

PubMed

Jadoon, M Mohsin; Zhang, Qianni; Haq, Ihsan Ul; Butt, Sharjeel; Jadoon, Adeel

2017-01-01

In this paper, a novel classification technique for large data set of mammograms using a deep learning method is proposed. The proposed model targets a three-class classification study (normal, malignant, and benign cases). In our model we have presented two methods, namely, convolutional neural network-discrete wavelet (CNN-DW) and convolutional neural network-curvelet transform (CNN-CT). An augmented data set is generated by using mammogram patches. To enhance the contrast of mammogram images, the data set is filtered by contrast limited adaptive histogram equalization (CLAHE). In the CNN-DW method, enhanced mammogram images are decomposed as its four subbands by means of two-dimensional discrete wavelet transform (2D-DWT), while in the second method discrete curvelet transform (DCT) is used. In both methods, dense scale invariant feature (DSIFT) for all subbands is extracted. Input data matrix containing these subband features of all the mammogram patches is created that is processed as input to convolutional neural network (CNN). Softmax layer and support vector machine (SVM) layer are used to train CNN for classification. Proposed methods have been compared with existing methods in terms of accuracy rate, error rate, and various validation assessment measures. CNN-DW and CNN-CT have achieved accuracy rate of 81.83% and 83.74%, respectively. Simulation results clearly validate the significance and impact of our proposed model as compared to other well-known existing techniques.

Epigenetic dysregulation of epstein-barr virus latency and development of autoimmune disease.

PubMed

Niller, Hans Helmut; Wolf, Hans; Ay, Eva; Minarovits, Janos

2011-01-01

Epstein-Barr virus (EBV) is ahumanherpesvirus thatpersists in the memory B-cells of the majority of the world population in a latent form. Primary EBV infection is asymptomatic or causes a self-limiting disease, infectious mononucleosis. Virus latency is associated with a wide variety of neoplasms whereof some occur in immune suppressed individuals. Virus production does not occur in strict latency. The expression of latent viral oncoproteins and nontranslated RNAs is under epigenetic control via DNA methylation and histone modifications that results either in a complete silencing of the EBV genome in memory B cells, or in a cell-type dependent usage of a couple of latency promoters in tumor cells, germinal center B cells and lymphoblastoid cells (LCL, transformed by EBV in vitro). Both, latent and lytic EBV proteins elicit a strong immune response. In immune suppressed and infectious mononucleosis patients, an increased viral load can be detected in the blood. Enhanced lytic replication may result in new infection- and transformation-events and thus is a risk factor both for malignant transformation and the development of autoimmune diseases. An increased viral load or a changed presentation of a subset of lytic or latent EBV proteins that cross-react with cellular antigens may trigger pathogenic processes through molecular mimicry that result in multiple sclerosis (MS), systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA).

Anaplastic transformation of an atypical intraventricular meningioma with metastases to the liver: case report.

PubMed

Garcia-Conde, M; Roldan-Delgado, H; Martel-Barth-Hansen, D; Manzano-Sanz, C

2009-12-01

Malignant intraventricular meningiomas are very rare. To the best of our knowledge, only eleven cases have been reported thus far. Seven of them developed cerebrospinal fluid (CSF) metastases. We present herein the first case of a malignant intraventricular meningioma with extraneural metastases. We report a 44 year-old-man with a history of progressive headache and disorientation. Magnetic resonance imaging (MRI) revealed a 5-cm homogeneously-enhancing mass in the right trigone. The lesion was totally resected via a parietooccipital transcortical approach. Histological examination demonstrated an atypical meningioma. Thereafter, the tumor recurred twice. At first recurrence, the tumor was completely removed again and external radiotherapy was administered. At surgery at second recurrence, the tumor was more aggressive, invading the brain parenchyma. Histological examination showed anaplastic meningioma. The patient was readmitted to hospital with fever and pain in right hypochondrium. Abdominal ultrasound examination disclosed multiple hypoechoic liver lesions. Biopsy was consistent with liver metastases of a malignant meningioma. The patient died of acute liver failure seven months after initial diagnosis. Malignant intraventricular meningiomas are prone to recur and develop metastases, mainly through the CSF. Nevertheless, our case shows that extraneural metastases are also possible. Therefore, when systemic deterioration occurs in a patient with a malignant intraventricular meningioma, metastases to extraneural organs such as the liver must be ruled out.

Induction of morphological transformation in mouse C3H/10T1/2 clone 8 cells and chromosomal damage in hamster A(T1)C1-3 cells by cancer chemotherapeutic agents.

PubMed

Benedict, W F; Banerjee, A; Gardner, A; Jones, P A

1977-07-01

Various cancer chemotherapeutic agents including alkylating agents, antimetabolites, and antibiotics or natural products were studied for their ability to produce morphological transformation in the C3H/10T1/2 clone 8 mouse cell line and chromosomal damage in the A(T1)C1-3 hamster cell line following a 24-hr exposure of each agent at different concentrations. Those drugs that were known to be carcinogenic in vivo also produced morphological transformation and chromosomal damage, whereas those agents that have not been shown to be carcinogenic in vivo produced neither transformation nor chromosomal lesions. The concentrations used for these studies were in general similar to those actually reached in the plasma of patients treated with these same drugs for malignant, as well as certain nonmalignant, conditions.

Cell Cycle Control by PTEN.

PubMed

Brandmaier, Andrew; Hou, Sheng-Qi; Shen, Wen H

2017-07-21

Continuous and error-free chromosome inheritance through the cell cycle is essential for genomic stability and tumor suppression. However, accumulation of aberrant genetic materials often causes the cell cycle to go awry, leading to malignant transformation. In response to genotoxic stress, cells employ diverse adaptive mechanisms to halt or exit the cell cycle temporarily or permanently. The intrinsic machinery of cycling, resting, and exiting shapes the cellular response to extrinsic stimuli, whereas prevalent disruption of the cell cycle machinery in tumor cells often confers resistance to anticancer therapy. Phosphatase and tensin homolog (PTEN) is a tumor suppressor and a guardian of the genome that is frequently mutated or deleted in human cancer. Moreover, it is increasingly evident that PTEN deficiency disrupts the fundamental processes of genetic transmission. Cells lacking PTEN exhibit cell cycle deregulation and cell fate reprogramming. Here, we review the role of PTEN in regulating the key processes in and out of cell cycle to optimize genomic integrity. Copyright © 2017 Elsevier Ltd. All rights reserved.

Urine metabolic profiling for the pathogenesis research of erosive oral lichen planus.

PubMed

Li, Xu-Zhao; Yang, Xu-Yan; Wang, Yu; Zhang, Shuai-Nan; Zou, Wei; Wang, Yan; Li, Xiao-Nan; Wang, Ling-Shu; Zhang, Zhi-Gang; Xie, Liang-Zhen

2017-01-01

Oral lichen planus (OLP) is a relatively common chronic immune-pathological and inflammatory disease and potentially oral precancerous lesion. Erosive OLP patients show the higher rate of malignant transformation than patients with non-erosive OLP. Identifying the potential biomarkers related to erosive OLP may help to understand the pathogenesis of the diseases. Metabolic profiles were compared in control and patient subjects with erosive OLP by using ultra-performance liquid chromatography-quadrupole time-of-flight-mass spectrometry (UPLC-QTOF-MS) coupled with pattern recognition methods An integrative analysis was used to identify the perturbed metabolic pathways and pathological processes that may be associated with the disease. In total, 12 modulated metabolites were identified and considered as the potential biomarkers of erosive OLP. Multiple metabolic pathways and pathological processes were involved in erosive OLP. The dysregulations of these metabolites could be used to explain the pathogenesis of the disease, which could also be the potential therapeutic targets for the disease. Copyright © 2016 Elsevier Ltd. All rights reserved.

Pituitary adenylate cyclase-activating polypeptide: a novel peptide with protean implications.

PubMed

Pisegna, Joseph R; Oh, David S

2007-02-01

The purpose of this review is to highlight the importance of pituitary adenylate cyclase-activating polypeptide in physiological processes and to describe how this peptide is becoming increasingly recognized as having a major role in the body. Since its discovery in 1989, investigators have sought to determine the site of biological activity and the function of pituitary adenylate cyclase-activating polypeptide in maintaining homeostasis. Since its discovery, pituitary adenylate cyclase-activating polypeptide appears to play an important role in the regulation of processes within the central nervous system and gastrointestinal tract, as well in reproductive biology. Pituitary adenylate cyclase-activating polypeptide has been shown to regulate tumor cell growth and to regulate immune function through its effects on T lympocytes. These discoveries suggest the importance of pituitary adenylate cyclase-activating polypeptide in neuronal development, neuronal function, gastrointestinal tract function and reproduction. Future studies will examine more closely the role of pituitary adenylate cyclase-activating polypeptide in regulation of malignantly transformed cells, as well as in regulation of immune function.

Amino acid-dependent signaling via S6K1 and MYC is essential for regulation of rDNA transcription

PubMed Central

Kang, Jian; Kusnadi, Eric P.; Ogden, Allison J.; Hicks, Rodney J.; Bammert, Lukas; Kutay, Ulrike; Hung, Sandy; Sanij, Elaine; Hannan, Ross D.; Hannan, Katherine M.; Pearson, Richard B.

2016-01-01

Dysregulation of RNA polymerase I (Pol I)-dependent ribosomal DNA (rDNA) transcription is a consistent feature of malignant transformation that can be targeted to treat cancer. Understanding how rDNA transcription is coupled to the availability of growth factors and nutrients will provide insight into how ribosome biogenesis is maintained in a tumour environment characterised by limiting nutrients. We demonstrate that modulation of rDNA transcription initiation, elongation and rRNA processing is an immediate, co-regulated response to altered amino acid abundance, dependent on both mTORC1 activation of S6K1 and MYC activity. Growth factors regulate rDNA transcription initiation while amino acids modulate growth factor-dependent rDNA transcription by primarily regulating S6K1-dependent rDNA transcription elongation and processing. Thus, we show for the first time amino acids regulate rRNA synthesis by a distinct, post-initiation mechanism, providing a novel model for integrated control of ribosome biogenesis that has implications for understanding how this process is dysregulated in cancer. PMID:27385002

Keloid in the gray reef shark, Carcharhinus amblyrhynchos

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

Smith, A.C.; Hartley, F.K.

1976-04-01

A gray reef shark, Carcharhinus amblyrhynchos, was captured at Enewetak Atoll, the Marshall Islands, in 1972. Near the right pectoral fin was a large fungating tumor. Microscopically, no evidence of microorganisms or definite malignant transformation was observed, and inflammation and necrosis were minimal. However, the tumor appeared to be a keloid, the first to be reported in sharks.

Photobiomodulation therapy in the management of oral mucositis: search for the optimal clinical treatment parameters.

PubMed

Elad, Sharon; Arany, Praveen; Bensadoun, Rene-Jean; Epstein, Joel B; Barasch, Andrei; Raber-Durlacher, Judith

2018-05-22

This commentary attempts to clarify the setting of photobiomodulation (BPM) therapy in the management of oral mucositis. The suggested dose range balances efficacy data with our current understanding about PBM safety. The literature about the molecular basis of photobiomodulation and its controversial relationship to malignant transformation is briefly presented.

Laparoscopic Finding of Ectopic Adrenocortical Tissue in a 2-Year-Old Boy with Vanishing Testis

PubMed Central

Marte, Antonio

2018-01-01

Ectopic adrenocortical tissue (EAT) along the spermatic cord is an unusual condition in children. The author reports on a 2-year-old boy with impalpable testis. On laparoscopy, EAT was detected along the hypotrophic spermatic vessels and excised. These remnants should be removed to prevent hormone production or malignant transformation. PMID:29326864

Laparoscopic Finding of Ectopic Adrenocortical Tissue in a 2-Year-Old Boy with Vanishing Testis.

PubMed

Marte, Antonio

2018-01-01

Ectopic adrenocortical tissue (EAT) along the spermatic cord is an unusual condition in children. The author reports on a 2-year-old boy with impalpable testis. On laparoscopy, EAT was detected along the hypotrophic spermatic vessels and excised. These remnants should be removed to prevent hormone production or malignant transformation.

Cancer Incidence among Persons with Fragile X Syndrome in Finland: A Population-Based Study

ERIC Educational Resources Information Center

Sund, Reijo; Pukkala, E.; Patja, K.

2009-01-01

Background: Fragile X syndrome is a common inheritable cause of intellectual disability (ID) and is characterised by a large number of CGG repeats at the gene "FMR1" located on the X-chromosome. It has been reported that this genetic mechanism may protect against malignant transformations. Methods: We extracted from the Finnish registry…

Homodimerization of Marek's disease virus encoded Meq protein is not sufficient for transformation of lymphocytes in chicken

USDA-ARS?s Scientific Manuscript database

Marek’s disease virus (MDV), the etiologic agent of Marek’s disease, is a potent oncogenic herpesvirus. MDV is highly contagious and elicits a rapid onset of malignant T-cell lymphomas in chickens within several weeks after infection. MDV codes for an oncoprotein, Meq, which shares resemblance wit...

Homotypic gap junctional communication associated with metastasis increases suppression increases with PKA kinase activity and is unaffected by P13K inhibition

USDA-ARS?s Scientific Manuscript database

Loss of gap junctional intercellular communication (GJIC) between cancer cells is a common characteristic of malignant transformation. This communication is mediated by connexin proteins that make up the functional units of gap junctions. Connexins are highly regulated at the protein level and phosp...

Nanotechnology applications in hematological malignancies (Review).

PubMed

Samir, Ahmed; Elgamal, Basma M; Gabr, Hala; Sabaawy, Hatem E

2015-09-01

A major limitation to current cancer therapies is the development of therapy-related side-effects and dose limiting complications. Moreover, a better understanding of the biology of cancer cells and the mechanisms of resistance to therapy is rapidly developing. The translation of advanced knowledge and discoveries achieved at the molecular level must be supported by advanced diagnostic, therapeutic and delivery technologies to translate these discoveries into useful tools that are essential in achieving progress in the war against cancer. Nanotechnology can play an essential role in this aspect providing a transforming technology that can translate the basic and clinical findings into novel diagnostic, therapeutic and preventive tools useful in different types of cancer. Hematological malignancies represent a specific class of cancer, which attracts special attention in the applications of nanotechnology for cancer diagnosis and treatment. The aim of the present review is to elucidate the emerging applications of nanotechnology in cancer management and describe the potentials of nanotechnology in changing the key fundamental aspects of hematological malignancy diagnosis, treatment and follow-up.

Pigmented well-differentiated hepatocellular neoplasm with beta-catenin mutation.

PubMed

Souza, Lara Neves; de Martino, Rodrigo Bronze; Thompson, Richard; Strautnieks, Sandra; Heaton, Nigel D; Quaglia, Alberto

2015-12-01

According to the most recent WHO classification of hepatocellular adenomas, a small percentage of inflammatory hepatocellular adenomas presents with mutation in the beta-catenin gene and are at higher risk of malignant transformation. It has been recognized that adenoma-like hepatocellular neoplasms with focal atypia, or in unusual clinical context present with similar cytogenetic and immunohistochemistry characteristics to well-differentiated hepatocellular carcinomas. We report a case of a well-differentiated hepatocellular neoplasm with Dubin-Johnson-like pigment displaying histological features overlapping with a beta-catenin mutated inflammatory adenoma and a well-differentiated hepatocellular carcinoma in a non-cirrhotic liver. The patient was a 48-year-old woman, who was asymptomatic, and had a clinical history of intra-uterine exposure to diethylstilbestrol, previous cancers and past oral contraceptive use. The recently proposed term "well-differentiated hepatocellular neoplasm of uncertain malignant potential" should be applied in such cases to highlight the different pathogenesis and risk of malignancy compared to the typical adenomas, and to suggest a careful and customized clinical management.

Nanotechnology applications in hematological malignancies (Review)

PubMed Central

SAMIR, AHMED; ELGAMAL, BASMA M; GABR, HALA; SABAAWY, HATEM E

2015-01-01

A major limitation to current cancer therapies is the development of therapy-related side-effects and dose limiting complications. Moreover, a better understanding of the biology of cancer cells and the mechanisms of resistance to therapy is rapidly developing. The translation of advanced knowledge and discoveries achieved at the molecular level must be supported by advanced diagnostic, therapeutic and delivery technologies to translate these discoveries into useful tools that are essential in achieving progress in the war against cancer. Nanotechnology can play an essential role in this aspect providing a transforming technology that can translate the basic and clinical findings into novel diagnostic, therapeutic and preventive tools useful in different types of cancer. Hematological malignancies represent a specific class of cancer, which attracts special attention in the applications of nanotechnology for cancer diagnosis and treatment. The aim of the present review is to elucidate the emerging applications of nanotechnology in cancer management and describe the potentials of nanotechnology in changing the key fundamental aspects of hematological malignancy diagnosis, treatment and follow-up. PMID:26134389

Chemotherapy-Induced Depletion of OCT4-Positive Cancer Stem Cells in a Mouse Model of Malignant Testicular Cancer.

PubMed

Pierpont, Timothy M; Lyndaker, Amy M; Anderson, Claire M; Jin, Qiming; Moore, Elizabeth S; Roden, Jamie L; Braxton, Alicia; Bagepalli, Lina; Kataria, Nandita; Hu, Hilary Zhaoxu; Garness, Jason; Cook, Matthew S; Capel, Blanche; Schlafer, Donald H; Southard, Teresa; Weiss, Robert S

2017-11-14

Testicular germ cell tumors (TGCTs) are among the most responsive solid cancers to conventional chemotherapy. To elucidate the underlying mechanisms, we developed a mouse TGCT model featuring germ cell-specific Kras activation and Pten inactivation. The resulting mice developed malignant, metastatic TGCTs composed of teratoma and embryonal carcinoma, the latter of which exhibited stem cell characteristics, including expression of the pluripotency factor OCT4. Consistent with epidemiological data linking human testicular cancer risk to in utero exposures, embryonic germ cells were susceptible to malignant transformation, whereas adult germ cells underwent apoptosis in response to the same oncogenic events. Treatment of tumor-bearing mice with genotoxic chemotherapy not only prolonged survival and reduced tumor size but also selectively eliminated the OCT4-positive cancer stem cells. We conclude that the chemosensitivity of TGCTs derives from the sensitivity of their cancer stem cells to DNA-damaging chemotherapy. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

Causes of Death in HIV Patients and the Evolution of an AIDS Hospice: 1988–2008

PubMed Central

Stewart, Ann; Chan Carusone, Soo; To, Kent; Schaefer-McDaniel, Nicole; Halman, Mark; Grimes, Richard

2012-01-01

This paper reports on the transformation that has occurred in the care of people living with HIV/AIDS in a Toronto Hospice. Casey House opened in the pre-HAART era to care exclusively for people with HIV/AIDS, an incurable disease. At the time, all patients were admitted for palliative care and all deaths were due to AIDS-defining conditions. AIDS-defining malignancies accounted for 22 percent of deaths, mainly, Kaposi sarcoma and lymphoma. In the post-HAART era, AIDS-defining malignancies dropped dramatically and non-AIDS-defining malignancies became a significant cause of death, including liver cancer, lung cancer and gastric cancers. In the post-HAART era, people living with HIV/AIDS served at Casey House have changed considerably, with increasing numbers of patients facing homelessness and mental health issues, including substance use. Casey House offers a picture of the evolving epidemic and provides insight into changes and improvements made in the care of these patients. PMID:22666562

Adenovirus-mediated suppression of HMGI(Y) protein synthesis as potential therapy of human malignant neoplasias

PubMed Central

Scala, Stefania; Portella, Giuseppe; Fedele, Monica; Chiappetta, Gennaro; Fusco, Alfredo

2000-01-01

High mobility group I (HMGI) proteins are overexpressed in several human malignant tumors. We previously demonstrated that inhibition of HMGI synthesis prevents thyroid cell transformation. Here, we report that an adenovirus carrying the HMGI(Y) gene in an antisense orientation (Ad-Yas) induced programmed cell death of two human thyroid anaplastic carcinoma cell lines (ARO and FB-1), but not normal thyroid cells. The Ad-Yas virus led to death of lung, colon, and breast carcinoma cells. A control adenovirus carrying the lacZ gene did not inhibit the growth of either normal or neoplastic cells. Ad-Yas treatment of tumors induced in athymic mice by ARO cells caused a drastic reduction in tumor size. Therefore, suppression of HMGI(Y) protein synthesis by an HMGI(Y) antisense adenoviral vector may be a useful treatment strategy in a variety of human malignant neoplasias, in which HMGI(Y) gene overexpression is a general event. PMID:10759549

Early loss of Crebbp confers malignant stem cell properties on lymphoid progenitors.

PubMed

Horton, Sarah J; Giotopoulos, George; Yun, Haiyang; Vohra, Shabana; Sheppard, Olivia; Bashford-Rogers, Rachael; Rashid, Mamunur; Clipson, Alexandra; Chan, Wai-In; Sasca, Daniel; Yiangou, Loukia; Osaki, Hikari; Basheer, Faisal; Gallipoli, Paolo; Burrows, Natalie; Erdem, Ayşegül; Sybirna, Anastasiya; Foerster, Sarah; Zhao, Wanfeng; Sustic, Tonci; Petrunkina Harrison, Anna; Laurenti, Elisa; Okosun, Jessica; Hodson, Daniel; Wright, Penny; Smith, Ken G; Maxwell, Patrick; Fitzgibbon, Jude; Du, Ming Q; Adams, David J; Huntly, Brian J P

2017-09-01

Loss-of-function mutations of cyclic-AMP response element binding protein, binding protein (CREBBP) are prevalent in lymphoid malignancies. However, the tumour suppressor functions of CREBBP remain unclear. We demonstrate that loss of Crebbp in murine haematopoietic stem and progenitor cells (HSPCs) leads to increased development of B-cell lymphomas. This is preceded by accumulation of hyperproliferative lymphoid progenitors with a defective DNA damage response (DDR) due to a failure to acetylate p53. We identify a premalignant lymphoma stem cell population with decreased H3K27ac, which undergoes transcriptional and genetic evolution due to the altered DDR, resulting in lymphomagenesis. Importantly, when Crebbp is lost later in lymphopoiesis, cellular abnormalities are lost and tumour generation is attenuated. We also document that CREBBP mutations may occur in HSPCs from patients with CREBBP-mutated lymphoma. These data suggest that earlier loss of Crebbp is advantageous for lymphoid transformation and inform the cellular origins and subsequent evolution of lymphoid malignancies.

CXCR4 expression in feline mammary carcinoma cells: evidence of a proliferative role for the SDF-1/CXCR4 axis.

PubMed

Ferrari, Angelo; Petterino, Claudio; Ratto, Alessandra; Campanella, Chiara; Wurth, Roberto; Thellung, Stefano; Vito, Guendalina; Barbieri, Federica; Florio, Tullio

2012-03-14

Mammary tumours frequently develop in female domestic cats being highly malignant in a large percentage of cases. Chemokines regulate many physiological and pathological processes including organogenesis, chemotaxis of inflammatory cells, as well as tumour progression and metastasization. In particular, the chemokine/receptor pair SDF-1/CXCR4 has been involved in the regulation of metastatic potential of neoplastic cells, including breast cancer. The aim of this study was the immunohistochemical defininition of the expression profile of CXCR4 in primary and metastatic feline mammary carcinomas and the evaluation of the role of SDF-1 in feline mammary tumour cell proliferation. A total of 45 mammary surgical samples, including 33 primary tumours (31 carcinomas and 2 adenomas), 6 metastases, and 4 normal mammary tissues were anlyzed. Tumor samples were collected from a total number of 26 animals, as in some cases concurrent occurrence of neoplasm in more than one mammary gland was observed. Tissues were processed for standard histological examination, and all lesions were classified according to the World Health Organization criteria. CXCR4 expression in neoplastic cells was evaluated by immunohistochemistry. The level of CXCR4 immunoreactivity was semi-quantitatively estimated as CXCR4 score evaluating both the number of positive cells and the intensity of staining. Six primary, fibroblast-free primary cultures were obtained from fresh feline mammary carcinomas and characterized by immunofluorescence for CXCR4 and malignant mammary cell marker expression. SDF-1-dependent in vitro proliferative effects were also assayed. CXCR4 expression was observed in 29 out of 31 malignant tissues with a higher CXCR4 score observed in 4 out of 6 metastatic lesions than in the respective primary tumours. In 2 benign lesions analyzed, only the single basaloid adenoma showed a mild positive immunostaining against CXCR4. Normal tissue did not show CXCR4 immunoreactivity. CXCR4 score was statistically significantly associated with the histological features of the samples, showing an increase accordingly with the degree of neoplastic transformation (from normal tissue to metastatic lesions). Finally, in the primary cultures obtained from 6 primary feline mammary carcinomas CXCR4 expression was detected in all cells and its activation by SDF-1 in vitro treatment caused a significant increase in the proliferation rate in 5 out of 6 tumours. These results indicate that malignant feline mammary tumours commonly express CXCR4, with a higher level in malignant tumours, and, in most of the cases analysed, metastatic cells display stronger immunoreactivity for CXCR4 than the corresponding primary tumours. Moreover, CXCR4 activation in primary cultures of feline mammary carcinomas causes increase in the proliferative rate. Thus, SDF-1/CXCR4 system seems to play a tumorigenic in feline mammary gland malignancy and in vitro cultures from these tumour samples may represent an experimental model to investigate the biological and pharmacological role of this chemokinergic axis.

CXCR4 expression in feline mammary carcinoma cells: evidence of a proliferative role for the SDF-1/CXCR4 axis

PubMed Central

2012-01-01

Background Mammary tumours frequently develop in female domestic cats being highly malignant in a large percentage of cases. Chemokines regulate many physiological and pathological processes including organogenesis, chemotaxis of inflammatory cells, as well as tumour progression and metastasization. In particular, the chemokine/receptor pair SDF-1/CXCR4 has been involved in the regulation of metastatic potential of neoplastic cells, including breast cancer. The aim of this study was the immunohistochemical defininition of the expression profile of CXCR4 in primary and metastatic feline mammary carcinomas and the evaluation of the role of SDF-1 in feline mammary tumour cell proliferation. Results A total of 45 mammary surgical samples, including 33 primary tumours (31 carcinomas and 2 adenomas), 6 metastases, and 4 normal mammary tissues were anlyzed. Tumor samples were collected from a total number of 26 animals, as in some cases concurrent occurrence of neoplasm in more than one mammary gland was observed. Tissues were processed for standard histological examination, and all lesions were classified according to the World Health Organization criteria. CXCR4 expression in neoplastic cells was evaluated by immunohistochemistry. The level of CXCR4 immunoreactivity was semi-quantitatively estimated as CXCR4 score evaluating both the number of positive cells and the intensity of staining. Six primary, fibroblast-free primary cultures were obtained from fresh feline mammary carcinomas and characterized by immunofluorescence for CXCR4 and malignant mammary cell marker expression. SDF-1-dependent in vitro proliferative effects were also assayed. CXCR4 expression was observed in 29 out of 31 malignant tissues with a higher CXCR4 score observed in 4 out of 6 metastatic lesions than in the respective primary tumours. In 2 benign lesions analyzed, only the single basaloid adenoma showed a mild positive immunostaining against CXCR4. Normal tissue did not show CXCR4 immunoreactivity. CXCR4 score was statistically significantly associated with the histological features of the samples, showing an increase accordingly with the degree of neoplastic transformation (from normal tissue to metastatic lesions). Finally, in the primary cultures obtained from 6 primary feline mammary carcinomas CXCR4 expression was detected in all cells and its activation by SDF-1 in vitro treatment caused a significant increase in the proliferation rate in 5 out of 6 tumours. Conclusions These results indicate that malignant feline mammary tumours commonly express CXCR4, with a higher level in malignant tumours, and, in most of the cases analysed, metastatic cells display stronger immunoreactivity for CXCR4 than the corresponding primary tumours. Moreover, CXCR4 activation in primary cultures of feline mammary carcinomas causes increase in the proliferative rate. Thus, SDF-1/CXCR4 system seems to play a tumorigenic in feline mammary gland malignancy and in vitro cultures from these tumour samples may represent an experimental model to investigate the biological and pharmacological role of this chemokinergic axis. PMID:22417013

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

Type of surgical treatment and recurrence of oral leukoplakia: A retrospective clinical study

PubMed Central

Barbieri, Cinzia; Warnakulasuriya, Saman; Martins, Marco; Salazar, Filomena; Pacheco, José-Júlio; Vescovi, Paolo; Meleti, Marco

2017-01-01

Background Oral leukoplakia (OL) is the most typical potentially malignant disorder of the oral mucosa. We aimed to evaluate the clinical outcome of oral leukoplakia treated with several types of lasers and with the use of quantic molecular resonance (QMR) lancet, in terms of recurrence rate. Material and Methods Eighty-seven previously untreated OL (52 occurring in females and 35 in males, mean age of 59.4 ± 13.9 years) were consecutively submitted to surgical treatment at University Hospital of Parma, Italy, and Hospital de Valongo, Portugal, (1999 to 2012). Interventions were subclassified into 5 groups according to the instrument used for the surgical removal of OL (cold blade – 17; Nd:YAG 1064nm laser – 14; Er:YAG 2940nm laser - 33; CO2 10600nm laser – 15; and QMR scalpel – 8). The mean follow-up period after treatment was 21.6 months (range 1-151 months). The outcome of treatment was scored through the same clinical protocol in the two participating units. Statistical analysis were carried by univariate analysis using chi-square test (or Pearson´s test when appropriate). Results Recurrences were observed in 24 cases of OL (27.6%). Malignant transformation occurred in one patient (1.1%) after a period of 35 months. Statistical comparison of the 5 surgical treatment modalities showed no differences in clinical outcomes nor in the recurrence rate of OL. However, when Er:YAG laser group was compared with traditional scalpel, a significantly better outcome in cases treated with Er:YAG laser (P = 0.015) was highlighted. Conclusions Our results suggests that Er:YAG laser could be a promising option for the treatment of OL. Key words:Oral leukoplakia; Potentially malignant disorders; Er:YAG Laser; CO2 Laser; Nd:YAG Laser; Quantic molecular resonance scalpel; malignant transformation rate. PMID:28809365

A Drosophila Model of HPV E6-Induced Malignancy Reveals Essential Roles for Magi and the Insulin Receptor

PubMed Central

Padash Barmchi, Mojgan; Gilbert, Mary; Thomas, Miranda; Banks, Lawrence; Zhang, Bing; Auld, Vanessa J.

2016-01-01

Cervical cancer is one of the leading causes of cancer death in women worldwide. The causative agents of cervical cancers, high-risk human papillomaviruses (HPVs), cause cancer through the action of two oncoproteins, E6 and E7. The E6 oncoprotein cooperates with an E3 ubiquitin ligase (UBE3A) to target the p53 tumour suppressor and important polarity and junctional PDZ proteins for proteasomal degradation, activities that are believed to contribute towards malignancy. However, the causative link between degradation of PDZ proteins and E6-mediated malignancy is largely unknown. We have developed an in vivo model of HPV E6-mediated cellular transformation using the genetic model organism, Drosophila melanogaster. Co-expression of E6 and human UBE3A in wing and eye epithelia results in severe morphological abnormalities. Furthermore, E6, via its PDZ-binding motif and in cooperation with UBE3A, targets a suite of PDZ proteins that are conserved in human and Drosophila, including Magi, Dlg and Scribble. Similar to human epithelia, Drosophila Magi is a major degradation target. Magi overexpression rescues the cellular abnormalities caused by E6+UBE3A coexpression and this activity of Magi is PDZ domain-dependent. Drosophila p53 was not targeted by E6+UBE3A, and E6+UBE3A activity alone is not sufficient to induce tumorigenesis, which only occurs when E6+UBE3A are expressed in conjunction with activated/oncogenic forms of Ras or Notch. Finally, through a genetic screen we have identified the insulin receptor signaling pathway as being required for E6+UBE3A induced hyperplasia. Our results suggest a highly conserved mechanism of HPV E6 mediated cellular transformation, and establish a powerful genetic model to identify and understand the cellular mechanisms that underlie HPV E6-induced malignancy. PMID:27537218

Transforming growth factor-β1 promotes breast cancer metastasis by downregulating miR-196a-3p expression.

PubMed

Chen, Yan; Huang, Shai; Wu, Bo; Fang, Jiankai; Zhu, Minsheng; Sun, Li; Zhang, Lifeng; Zhang, Yongsheng; Sun, Maomin; Guo, Lingling; Wang, Shouli

2017-07-25

Transforming growth factor-β1 is considered a key contributor to the progression of breast cancer. MicroRNAs are important factors in the development and progression of many malignancies. In the present study, upon studies of breast cancer cell lines and tissues, we showed that microRNA -196a-3p is decreased by transforming growth factor-β1 in breast cancer cells and associated with breast cancer progression. We identified neuropilin-2 as a target gene of microRNA -196a-3p and showed that it is regulated by transforming growth factor-β1. Moreover, transforming growth factor-β1-mediated inhibition of microRNA -196a-3p and activation of neuropilin-2were required for transforming growth factor-β1-induced migration and invasion of breast cancer cells. In addition, neuropilin-2 expression was suppressed in breast tumors, particularly in triple-negative breast cancers. Collectively, our findings strongly indicate that microRNA -196a-3p is a predictive biomarker of breast cancer metastasis and patient survival and a potential therapeutic target in metastatic breast cancer.

Localization and treatment of transformed tissues using the photodynamic sensitizer 2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide-a.

PubMed

Furukawa, K; Yamamoto, H; Crean, D H; Kato, H; Mang, T S

1996-01-01

Photofrin is the photosensitizer currently used in most clinical trials examining the efficacy of photodynamic therapy (PDT) for the treatment and/or palliation of neoplasia. Although this drug has been shown to be efficacious in many of these trials, it possesses less than ideal qualities for use in a systemically administered photosensitizer. A new photosensitizer, 2-[l-hexyloxyethyl]-2-devinyl pyropheophorbide-a (HPPH), was developed for PDT. HPPH possesses more rapid clearance from skin and greater cytotoxicity per drug dose than Photofrin. The aims of this study were to: (1) examine the uptake and retention of HPPH in tissues undergoing malignant transformation using laser-induced fluorescence, and (2) evaluate the efficacy of HPPH and 665 nm light in treating carcinogen-induced tumors of the hamster buccal cheek pouch. The model of tissue transformation was the carcinogen (9,10-dimethyl-1, 2-benzanthracene)-induced premalignant and malignant lesions of the hamster buccal cheek pouch. Following induction of the specific transformation stages, hamsters were injected intraperitoneally with 0.5 mg/kg HPPH. Subsequently, the buccal mucosa was examined for fluorescence at various times up to 72 hours after photosensitizer injection. Uptake studies of HPPH showed highest fluorescence levels in tissues 48 hours after HPPH injection. Fluorescence levels of tissues increased significantly as follows. Normal < dysplasia < papillomas < squamous cell carcinomas. Carcinogen-induced tumors in 14 hamsters were treated with surface illuminations of red light (665 nm) via fiber optics coupled to an argon-ion pumped dye laser 48 hours after intraperitoneal injection with either 0.5 or 1.0 mg/kg HPPH. Complete necrosis of tumor tissues 7 days following PDT was observed in 57% (4/7) with 0.5 mg/kg and 86% (6/7) with 1.0 mg/kg HPPH.

Impact of Nrf2 on tumour growth and drug sensitivity in oncogenic K-ras-transformed cells in vitro and in vivo.

PubMed

Shao, Jiajia; Glorieux, Christophe; Liao, Jianwei; Chen, Ping; Lu, Wenhua; Liang, Zhenhao; Wen, Shijun; Hu, Yumin; Huang, Peng

2018-06-01

K-ras is one of the most common oncogenes in human cancers, and its aberrant activation may lead to malignant transformation associated with oxidative stress and activation of the transcription factor Nrf2 that regulates multiple detoxification enzymes. The purpose of this research was to use gene editing technology to evaluate the role of Nrf2 in affecting tumour growth and drug sensitivity of K-ras G12V -transformed cells. We showed that induction of K-ras G12V caused a significant activation of Nrf2 associated with increased expression of its target genes NAD(P)H:quinone oxidoreductase 1 (NQO1) and haem oxygenase-1 (HO-1). Interestingly, knock-out of Nrf2 by CRISPR/Cas9 in K-ras G12V -expressing cells only impacted the expression of NQO1 but not HO-1. We also found that Nrf2 knock-out caused high reactive oxygen species (ROS) stress, suppression of cell proliferation, increased apoptosis in vitro, and a decrease of tumour growth in vivo. Furthermore, abrogation of Nrf2 significantly increased the sensitivity of K-ras G12V cells to multiple anticancer agents including phenethyl isothiocyanate (PEITC), doxorubicin, etoposide, and cisplatin. These results show that genetic abrogation of Nrf2 impairs the malignant phenotype of K-Ras G12V -transformed cells in vitro and in vivo, and demonstrates the critical role of Nrf2 in promoting cell survival and drug resistance in cells harbouring oncogenic K-ras. As such, inhibition of Nrf2 would be an attractive strategy to increase the therapeutic effect and overcome drug resistance in cancer with oncogenic K-ras activation.

Identifying causal networks linking cancer processes and anti-tumor immunity using Bayesian network inference and metagene constructs.

PubMed

Kaiser, Jacob L; Bland, Cassidy L; Klinke, David J

2016-03-01

Cancer arises from a deregulation of both intracellular and intercellular networks that maintain system homeostasis. Identifying the architecture of these networks and how they are changed in cancer is a pre-requisite for designing drugs to restore homeostasis. Since intercellular networks only appear in intact systems, it is difficult to identify how these networks become altered in human cancer using many of the common experimental models. To overcome this, we used the diversity in normal and malignant human tissue samples from the Cancer Genome Atlas (TCGA) database of human breast cancer to identify the topology associated with intercellular networks in vivo. To improve the underlying biological signals, we constructed Bayesian networks using metagene constructs, which represented groups of genes that are concomitantly associated with different immune and cancer states. We also used bootstrap resampling to establish the significance associated with the inferred networks. In short, we found opposing relationships between cell proliferation and epithelial-to-mesenchymal transformation (EMT) with regards to macrophage polarization. These results were consistent across multiple carcinomas in that proliferation was associated with a type 1 cell-mediated anti-tumor immune response and EMT was associated with a pro-tumor anti-inflammatory response. To address the identifiability of these networks from other datasets, we could identify the relationship between EMT and macrophage polarization with fewer samples when the Bayesian network was generated from malignant samples alone. However, the relationship between proliferation and macrophage polarization was identified with fewer samples when the samples were taken from a combination of the normal and malignant samples. © 2016 American Institute of Chemical Engineers Biotechnol. Prog., 32:470-479, 2016. © 2016 American Institute of Chemical Engineers.

Genetic and pharmacological suppression of oncogenic mutations in RAS genes of yeast and humans

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

Schafer, W.R.; Sterne, R.; Thorner, J.

1989-07-28

The activity of an oncoprotein and the secretion of a pheromone can be affected by an unusual protein modification. Specifically, posttranslational modification of yeast-a-factor and Ras protein requires an intermediate of the cholesterol biosynthetic pathway. This modification is apparently essential for biological activity. Studies of yeast mutants blocked in sterol biosynthesis demonstrated that the membrane association and biological activation of the yeast Ras2 protein require mevalonate, a precursor of sterols and other isoprenes such as farnesyl pyrophosphate. Furthermore, drugs that inhibit mevalonate biosynthesis blocked the in vivo action of oncogenic derivatives of human Ras protein in the Xenopus oocyte assay.more » The same drugs and mutations also prevented the posttranslational processing and secretion of yeast a-factor, a peptide that is farnesylated. Thus, the mevalonate requirement for Ras activation may indicate that attachment of a mevalonate-derived (isoprenoid) moiety to Ras proteins is necessary for membrane association and biological function. These observations establish a connection between the cholesterol biosynthetic pathway and transformation by the ras oncogene and offer a novel pharmacological approach to investigating, and possibly controlling, ras-mediated malignant transformations. 50 refs., 3 figs., 3 tabs.« less

Assessment of Microcirculatory Hemoglobin Levels in Normal and Diabetic Subjects using Diffuse Reflectance Spectroscopy in the Visible Region — a Pilot Study

NASA Astrophysics Data System (ADS)

Sujatha, N.; Anand, B. S. Suresh; Nivetha, K. Bala; Narayanamurthy, V. B.; Seshadri, V.; Poddar, R.

2015-07-01

Light-based diagnostic techniques provide a minimally invasive way for selective biomarker estimation when tissues transform from a normal to a malignant state. Spectroscopic techniques based on diffuse reflectance characterize the changes in tissue hemoglobin/oxygenation levels during the tissue transformation process. Recent clinical investigations have shown that changes in tissue oxygenation and microcirculation are observed in diabetic subjects in the initial and progressive stages. In this pilot study, we discuss the potential of diffuse reflectance spectroscopy (DRS) in the visible (Vis) range to differentiate the skin microcirculatory hemoglobin levels between normal and advanced diabetic subjects with and without neuropathy. Average concentration of hemoglobin as well as hemoglobin oxygen saturation within the probed tissue volume is estimated for a total of four different sites in the foot sole. The results indicate a statistically significant decrease in average total hemoglobin and increase in hemoglobin oxygen saturation levels for diabetic foot compared with a normal foot. The present study demonstrates the ability of reflectance spectroscopy in the Vis range to determine and differentiate the changes in tissue hemoglobin and hemoglobin oxygen saturation levels in normal and diabetic subjects.

The Association between Endometriomas and Ovarian Cancer: Preventive Effect of Inhibiting Ovulation and Menstruation during Reproductive Life

PubMed Central

Grandi, Giovanni; Toss, Angela; Cortesi, Laura; Botticelli, Laura; Volpe, Annibale; Cagnacci, Angelo

2015-01-01

Although endometriosis frequently involves multiple sites in the pelvis, malignancies associated with this disease are mostly confined to the ovaries, evolving from an endometrioma. Endometriomas present a 2-3-fold increased risk of transformation in clear-cell, endometrioid, and possibly low-grade serous ovarian cancers, but not in mucinous ovarian cancers. These last cancers are, in some aspects, different from the other epithelial ovarian cancers, as they do not appear to be decreased by the inhibition of ovulation and menstruation. The step by step process of transformation from typical endometrioma, through atypical endometrioma, finally to ovarian cancer seems mainly related to oxidative stress, inflammation, hyperestrogenism, and specific molecular alterations. Particularly, activation of oncogenic KRAS and PI3K pathways and inactivation of tumor suppressor genes PTEN and ARID1A are suggested as major pathogenic mechanisms for endometriosis associated clear-cell and endometrioid ovarian cancer. Both the risk for endometriomas and their associated ovarian cancers seems to be highly and similarly decreased by the inhibition of ovulation and retrograde menstruation, suggesting a common pathogenetic mechanism and common possible preventive strategies during reproductive life. PMID:26413541

The Association between Endometriomas and Ovarian Cancer: Preventive Effect of Inhibiting Ovulation and Menstruation during Reproductive Life.

PubMed

Grandi, Giovanni; Toss, Angela; Cortesi, Laura; Botticelli, Laura; Volpe, Annibale; Cagnacci, Angelo

2015-01-01

Although endometriosis frequently involves multiple sites in the pelvis, malignancies associated with this disease are mostly confined to the ovaries, evolving from an endometrioma. Endometriomas present a 2-3-fold increased risk of transformation in clear-cell, endometrioid, and possibly low-grade serous ovarian cancers, but not in mucinous ovarian cancers. These last cancers are, in some aspects, different from the other epithelial ovarian cancers, as they do not appear to be decreased by the inhibition of ovulation and menstruation. The step by step process of transformation from typical endometrioma, through atypical endometrioma, finally to ovarian cancer seems mainly related to oxidative stress, inflammation, hyperestrogenism, and specific molecular alterations. Particularly, activation of oncogenic KRAS and PI3K pathways and inactivation of tumor suppressor genes PTEN and ARID1A are suggested as major pathogenic mechanisms for endometriosis associated clear-cell and endometrioid ovarian cancer. Both the risk for endometriomas and their associated ovarian cancers seems to be highly and similarly decreased by the inhibition of ovulation and retrograde menstruation, suggesting a common pathogenetic mechanism and common possible preventive strategies during reproductive life.

Mitogen-Inducible Gene-6 Mediates Feedback Inhibition from Mutated BRAF towards the Epidermal Growth Factor Receptor and Thereby Limits Malignant Transformation

PubMed Central

Milewska, Malgorzata; Romano, David; Herrero, Ana; Guerriero, Maria Luisa; Birtwistle, Marc; Quehenberger, Franz; Hatzl, Stefan; Kholodenko, Boris N.; Segatto, Oreste; Kolch, Walter; Zebisch, Armin

2015-01-01

BRAF functions in the RAS-extracellular signal-regulated kinase (ERK) signaling cascade. Activation of this pathway is necessary to mediate the transforming potential of oncogenic BRAF, however, it may also cause a negative feedback that inhibits the epidermal growth factor receptor (EGFR). Mitogen-inducible gene-6 (MIG-6) is a potent inhibitor of the EGFR and has been demonstrated to function as a tumor suppressor. As MIG-6 can be induced via RAS-ERK signaling, we investigated its potential involvement in this negative regulatory loop. Focus formation assays were performed and demonstrated that MIG-6 significantly reduces malignant transformation induced by oncogenic BRAF. Although this genetic interaction was mirrored by a physical interaction between MIG-6 and BRAF, we did not observe a direct regulation of BRAF kinase activity by MIG-6. Interestingly, a selective chemical EGFR inhibitor suppressed transformation to a similar degree as MIG-6, whereas combining these approaches had no synergistic effect. By analyzing a range of BRAF mutated and wildtype cell line models, we could show that BRAF V600E causes a strong upregulation of MIG-6, which was mediated at the transcriptional level via the RAS-ERK pathway and resulted in downregulation of EGFR activation. This feedback loop is operational in tumors, as shown by the analysis of almost 400 patients with papillary thyroid cancer (PTC). Presence of BRAF V600E correlated with increased MIG-6 expression on the one hand, and with inactivation of the EGFR and of PI3K/AKT signaling on the other hand. Importantly, we also observed a more aggressive disease phenotype when BRAF V600E coexisted with low MIG-6 expression. Finally, analysis of methylation data was performed and revealed that higher methylation of MIG-6 correlated to its decreased expression. Taken together, we demonstrate that MIG-6 efficiently reduces cellular transformation driven by oncogenic BRAF by orchestrating a negative feedback circuit directed towards the EGFR. PMID:26065894

Interleukin-8 (IL-8) over-production and autocrine cell activation are key factors in monomethylarsonous acid [MMA(III)]-induced malignant transformation of urothelial cells.

PubMed

Escudero-Lourdes, C; Wu, T; Camarillo, J M; Gandolfi, A J

2012-01-01

The association between chronic human exposure to arsenicals and bladder cancer development is well recognized; however, the underlying molecular mechanisms have not been fully determined. We propose that inflammatory responses can play a pathogenic role in arsenic-related bladder carcinogenesis. In previous studies, it was demonstrated that chronic exposure to 50 nM monomethylarsenous acid [MMA(III)] leads to malignant transformation of an immortalized model of urothelial cells (UROtsa), with only 3 mo of exposure necessary to trigger the transformation-related changes. In the three-month window of exposure, the cells over-expressed pro-inflammatory cytokines (IL-1β, IL-6 and IL-8), consistent with the sustained activation of NFKβ and AP1/c-jun, ERK2, and STAT3. IL-8 was over-expressed within hours after exposure to MMA(III), and sustained over-expression was observed during chronic exposure. In this study, we profiled IL-8 expression in UROtsa cells exposed to 50 nM MMA(III) for 1 to 5 mo. IL-8 expression was increased mainly in cells after 3 mo MMA(III) exposure, and its production was also found increased in tumors derived from these cells after heterotransplantation in SCID mice. UROtsa cells do express both receptors, CXCR1 and CXCR2, suggesting that autocrine cell activation could be important in cell transformation. Supporting this observation and consistent with IL-8 over-expression, CXCR1 internalization was significantly increased after three months of exposure to MMA(III). The expression of MMP-9, cyclin D1, bcl-2, and VGEF was significantly increased in cells exposed to MMA(III) for 3 mo, but these mitogen-activated kinases were significantly decreased after IL-8 gene silencing, together with a decrease in cell proliferation rate and in anchorage-independent colony formation. These results suggest a relevant role of IL-8 in MMA(III)-induced UROtsa cell transformation. Copyright © 2011 Elsevier Inc. All rights reserved.

Insight into the tumor suppressor function of CBP through the viral oncoprotein tax.

PubMed

Van Orden, K; Nyborg, J K

2000-01-01

CREB binding protein (CBP) is a cellular coactivator protein that regulates essentially all known pathways of gene expression. The transcriptional coactivator properties of CBP are utilized by at least 25 different transcription factors representing nearly all known classes of DNA binding proteins. Once bound to their target genes, these transcription factors are believed to tether CBP to the promoter, leading to activated transcription. CBP functions to stimulate transcription through direct recruitment of the general transcription machinery as well as acetylation of both histone and transcription factor substrates. Recent observations indicate that a critical dosage of CBP is required for normal development and tumor suppression, and that perturbations in CBP concentrations may disrupt cellular homeostasis. Furthermore, there is accumulating evidence that CBP deregulation plays a direct role in hematopoietic malignancies. However, the molecular events linking CBP deregulation and malignant transformation are unclear. Further insight into the function of CBP, and its role as a tumor suppressor, can be gained through recent studies of the human T-cell leukemia virus, type I (HTLV-I) Tax oncoprotein. Tax is known to utilize CBP to stimulate transcription from the viral promoter. However, recent data suggest that as a consequence of the Tax-CBP interaction, many cellular transcription factor pathways may be deregulated. Tax disruption of CBP function may play a key role in transformation of the HTLV-I-infected cell. Thus, Tax derailment of CBP may lend important information about the tumor suppressor properties of CBP and serve as a model for the role of CBP in hematopoietic malignancies.

Comparative analysis of cell proliferation ratio in plaque and erosive oral lichen planus: An immunohistochemical study.

PubMed

Redder, C Pramod; Pandit, Siddharth; Desai, Dinkar; Kandagal, V Suresh; Ingaleshwar, Pramod S; Shetty, Sharan J; Vibhute, Nupura

2014-05-01

Proliferating cell nuclear antigen (PCNA) is a nuclear protein synthesized in the late G1 and S-phase of the cell cycle. Detection of this protein represents a useful marker of the proliferation status of lesions. This study has been carried out to evaluate the cell proliferation rate in oral lichen planus (OLP) and comparison between plaque and erosive lichen planus, which indicates the potential for malignant transformation. This study was comprised of 64 cases of histologically proven lichen planus, out of which 32 cases of plaque and erosive each was taken. Two sections were taken from each, one for H and E staining to verify histological diagnosis according to Eisenberg criteria, other sections were stained according to super sensitive polymer horse radish peroxidise method for identifying immunohistochemical expression of PCNA. Data were statistically analyzed by Tukey high-range statistical domain test. Statistically significant P value was considered <0.05. In two types of lichen planus, erosive type (66.86%) showed higher expression of PCNA followed by plaque (17.07%). Overall, P value was <0.001, which was statistically significant. It indicates that proliferation activity is more in erosive lichen planus followed by plaque type, which ultimately results in increased rate of malignant transformation. PCNA is a good nuclear protein marker to evaluate the proliferation status of OLP. Out of the two types of lichen planus, erosive type possesses more proliferative ratio and chances of malignant change is more in this type. It emphasizes the importance of long-term follow-up with erosive type when compared with plaque type.

Improving the signal analysis for in vivo photoacoustic flow cytometry

NASA Astrophysics Data System (ADS)

Niu, Zhenyu; Yang, Ping; Wei, Dan; Tang, Shuo; Wei, Xunbin

2015-03-01

At early stage of cancer, a small number of circulating tumor cells (CTCs) appear in the blood circulation. Thus, early detection of malignant circulating tumor cells has great significance for timely treatment to reduce the cancer death rate. We have developed an in vivo photoacoustic flow cytometry (PAFC) to monitor the metastatic process of CTCs and record the signals from target cells. Information of target cells which is helpful to the early therapy would be obtained through analyzing and processing the signals. The raw signal detected from target cells often contains some noise caused by electronic devices, such as background noise and thermal noise. We choose the Wavelet denoising method to effectively distinguish the target signal from background noise. Processing in time domain and frequency domain would be combined to analyze the signal after denoising. This algorithm contains time domain filter and frequency transformation. The frequency spectrum image of the signal contains distinctive features that can be used to analyze the property of target cells or particles. The PAFC technique can detect signals from circulating tumor cells or other particles. The processing methods have a great potential for analyzing signals accurately and rapidly.

Evolutionary Ecology of Organs: A Missing Link in Cancer Development?

PubMed

Thomas, Frédéric; Nesse, Randolph M; Gatenby, Robert; Gidoin, Cindy; Renaud, François; Roche, Benjamin; Ujvari, Beata

2016-08-01

There is striking variation in the incidence of cancer in human organs. Malignant tumors are common in the colon and breast but rare in the heart and small bowel. The uterus frequently develops benign fibroid tumors but uterine cancers are relatively rare. The organ-specific difference in cancer prevalence has been explained primarily by the relative roles of intrinsic and extrinsic risk factors. In this opinion article, we propose also considering organs as distinct but connected ecosystems whose different vulnerabilities to malignant transformation may be partially explained by how essential each organ is for survival through the age of reproduction. We present and discuss some of the basic concepts and assumptions of this perspective on evolutionary medicine. Copyright © 2016 Elsevier Inc. All rights reserved.

Overlapping DNA Methylation Dynamics in Mouse Intestinal Cell Differentiation and Early Stages of Malignant Progression

PubMed Central

Forn, Marta; Díez-Villanueva, Anna; Merlos-Suárez, Anna; Muñoz, Mar; Lois, Sergi; Carriò, Elvira; Jordà, Mireia; Bigas, Anna; Batlle, Eduard; Peinado, Miguel A.

2015-01-01

Mouse models of intestinal crypt cell differentiation and tumorigenesis have been used to characterize the molecular mechanisms underlying both processes. DNA methylation is a key epigenetic mark and plays an important role in cell identity and differentiation programs and cancer. To get insights into the dynamics of cell differentiation and malignant transformation we have compared the DNA methylation profiles along the mouse small intestine crypt and early stages of tumorigenesis. Genome-scale analysis of DNA methylation together with microarray gene expression have been applied to compare intestinal crypt stem cells (EphB2high), differentiated cells (EphB2negative), ApcMin/+ adenomas and the corresponding non-tumor adjacent tissue, together with small and large intestine samples and the colon cancer cell line CT26. Compared with late stages, small intestine crypt differentiation and early stages of tumorigenesis display few and relatively small changes in DNA methylation. Hypermethylated loci are largely shared by the two processes and affect the proximities of promoter and enhancer regions, with enrichment in genes associated with the intestinal stem cell signature and the PRC2 complex. The hypermethylation is progressive, with minute levels in differentiated cells, as compared with intestinal stem cells, and reaching full methylation in advanced stages. Hypomethylation shows different signatures in differentiation and cancer and is already present in the non-tumor tissue adjacent to the adenomas in ApcMin/+ mice, but at lower levels than advanced cancers. This study provides a reference framework to decipher the mechanisms driving mouse intestinal tumorigenesis and also the human counterpart. PMID:25933092

Functions of TET Proteins in Hematopoietic Transformation.

PubMed

Han, Jae-A; An, Jungeun; Ko, Myunggon

2015-11-01

DNA methylation is a well-characterized epigenetic modification that plays central roles in mammalian development, genomic imprinting, X-chromosome inactivation and silencing of retrotransposon elements. Aberrant DNA methylation pattern is a characteristic feature of cancers and associated with abnormal expression of oncogenes, tumor suppressor genes or repair genes. Ten-eleven-translocation (TET) proteins are recently characterized dioxygenases that catalyze progressive oxidation of 5-methylcytosine to produce 5-hydroxymethylcytosine and further oxidized derivatives. These oxidized methylcytosines not only potentiate DNA demethylation but also behave as independent epigenetic modifications per se. The expression or activity of TET proteins and DNA hydroxymethylation are highly dysregulated in a wide range of cancers including hematologic and non-hematologic malignancies, and accumulating evidence points TET proteins as a novel tumor suppressor in cancers. Here we review DNA demethylation-dependent and -independent functions of TET proteins. We also describe diverse TET loss-of-function mutations that are recurrently found in myeloid and lymphoid malignancies and their potential roles in hematopoietic transformation. We discuss consequences of the deficiency of individual Tet genes and potential compensation between different Tet members in mice. Possible mechanisms underlying facilitated oncogenic transformation of TET-deficient hematopoietic cells are also described. Lastly, we address non-mutational mechanisms that lead to suppression or inactivation of TET proteins in cancers. Strategies to restore normal 5mC oxidation status in cancers by targeting TET proteins may provide new avenues to expedite the development of promising anti-cancer agents.

Oral proliferative verrucous leucoplakia: are there particular features for such an ambiguous entity? A systematic review.

PubMed

Pentenero, M; Meleti, M; Vescovi, P; Gandolfo, S

2014-05-01

Proliferative verrucous leucoplakia (PVL) is a distinct, particularly aggressive form of oral leucoplakia. Given the low prevalence of PVL, data are sparse and are mostly from case reports, case series and only a few case-control studies, meaning that the literature is able to provide only weak evidence. The present systematic literature review aims to collate the available evidence on the following issues: patient demographics, aetiology, lesion location(s), malignant potential, location and histopathological features of transformed lesions, disease-specific survival rates and treatment response. Electronic databases were searched for studies in the English language reporting original data from at least 10 patients with PVL on the target issues of the present review. The retrieved data were merged and a descriptive analysis performed. The 20 studies selected indicated that PVL does not seem to be correlated with the major risk factors for oral carcinoma (tobacco, alcohol and/or areca nut/betel leaf chewing). The disorder affects mainly adult/elderly women and has a very high malignant transformation rate, particular site distribution and particular location and histopathological features of transformed lesions. The present results may be limited by some articles being unintentionally excluded as they were not found during the electronic search, a lack of worldwide accepted diagnostic criteria for PVL, and overlapping data from multiple studies performed in a limited number of centres. Despite these potential drawbacks, the present results demonstrate that PVL does have particular features. © 2014 British Association of Dermatologists.

MicroRNA Gene Regulatory Networks in Peripheral Nerve Sheath Tumors

DTIC Science & Technology

2012-09-01

chondrosarcoma are identified based on the unique histology, cell of origin, clinical features and site distribution. The following are the major... Chondrosarcoma Chondrosarcoma is a cancer composed of cells derived from transformed cells that produce cartilage. Peripheral chondrosarcoma is a malignant...biosynthesis. This is in line with gene expression analyses previously performed in osteochondroma and chondrosarcoma samples showing modulation of

Malignant transformation of a unicameral bone cyst in a cat.

PubMed

Berger, Björn; Brühschwein, Andreas; Eddicks, Lina; Meyer-Lindenberg, Andrea

2016-04-01

A unicameral bone cyst in the proximal humerus of a 3-year-old Norwegian forest cat was diagnosed by dynamic contrast-enhanced magnetic resonance imaging, surgical exploration, and histopathology. Surgical curettage and incorporation of bone cement led to full recovery. An osteosarcoma developed at the surgical site 17 months later. Thoracic radiographs showed pulmonary lesions consistent with metastasis.

Malignant transformation of a unicameral bone cyst in a cat

PubMed Central

Berger, Björn; Brühschwein, Andreas; Eddicks, Lina; Meyer-Lindenberg, Andrea

2016-01-01

A unicameral bone cyst in the proximal humerus of a 3-year-old Norwegian forest cat was diagnosed by dynamic contrast-enhanced magnetic resonance imaging, surgical exploration, and histopathology. Surgical curettage and incorporation of bone cement led to full recovery. An osteosarcoma developed at the surgical site 17 months later. Thoracic radiographs showed pulmonary lesions consistent with metastasis. PMID:27041754

Colorectal cancer: genetic abnormalities, tumor progression, tumor heterogeneity, clonal evolution and tumor-initiating cells.

PubMed

Testa, Ugo; Pelosi, Elvira; Castelli, Germana

2018-04-13

Colon cancer is the third most common cancer worldwide. Most colorectal cancer occurrences are sporadic, not related to genetic predisposition or family history; however, 20-30% of patients with colorectal cancer have a family history of colorectal cancer and 5% of these tumors arise in the setting of a Mendelian inheritance syndrome. In many patients, the development of a colorectal cancer is preceded by a benign neoplastic lesion: either an adenomatous polyp or a serrated polyp. Studies carried out in the last years have characterized the main molecular alterations occurring in colorectal cancers, showing that the tumor of each patient displays from two to eight driver mutations. The ensemble of molecular studies, including gene expression studies, has led to two proposed classifications of colorectal cancers, with the identification of four/five non-overlapping groups. The homeostasis of the rapidly renewing intestinal epithelium is ensured by few stem cells present at the level of the base of intestinal crypts. Various experimental evidence suggests that colorectal cancers may derive from the malignant transformation of intestinal stem cells or of intestinal cells that acquire stem cell properties following malignant transformation. Colon cancer stem cells seem to be involved in tumor chemoresistance, radioresistance and relapse.

Vibrational mapping of sinonasal lesions by Fourier transform infrared imaging spectroscopy

NASA Astrophysics Data System (ADS)

Giorgini, Elisabetta; Sabbatini, Simona; Conti, Carla; Rubini, Corrado; Rocchetti, Romina; Re, Massimo; Vaccari, Lisa; Mitri, Elisa; Librando, Vito

2015-12-01

Fourier transform infrared imaging (FTIRI) is a powerful tool for analyzing biochemical changes in tumoral tissues. The head and neck region is characterized by a great variety of lesions, with different degrees of malignancy, which are often difficult to diagnose. Schneiderian papillomas are sinonasal benign neoplasms arising from the Schneiderian mucosa; they can evolve into malignant tumoral lesions (squamous cell carcinoma). In addition, they can sometimes be confused with the more common inflammatory polyps. Therefore, an early and definitive diagnosis of this pathology is mandatory. Progressing in our research on the study of oral cavity lesions, 15 sections consisting of inflammatory sinonasal polyps, benign Schneiderian papillomas, and sinonasal undifferentiated carcinomas were analyzed using FTIRI. To allow a rigorous description of these pathologies and to gain objective diagnosis, the epithelial layer and the adjacent connective tissue of each section were separately investigated by following a multivariate analysis approach. According to the nature of the lesion, interesting modifications were detected in the average spectra of the different tissue components, above all in the lipid and protein patterns. Specific band-area ratios acting as spectral markers of the different pathologies were also highlighted.

Non-standard radiotherapy fractionations delay the time to malignant transformation of low-grade gliomas.

PubMed

Henares-Molina, Araceli; Benzekry, Sebastien; Lara, Pedro C; García-Rojo, Marcial; Pérez-García, Víctor M; Martínez-González, Alicia

2017-01-01

Grade II gliomas are slowly growing primary brain tumors that affect mostly young patients. Cytotoxic therapies (radiotherapy and/or chemotherapy) are used initially only for patients having a bad prognosis. These therapies are planned following the "maximum dose in minimum time" principle, i. e. the same schedule used for high-grade brain tumors in spite of their very different behavior. These tumors transform after a variable time into high-grade gliomas, which significantly decreases the patient's life expectancy. In this paper we study mathematical models describing the growth of grade II gliomas in response to radiotherapy. We find that protracted metronomic fractionations, i.e. therapeutical schedules enlarging the time interval between low-dose radiotherapy fractions, may lead to a better tumor control without an increase in toxicity. Other non-standard fractionations such as protracted or hypoprotracted schemes may also be beneficial. The potential survival improvement depends on the tumor's proliferation rate and can be even of the order of years. A conservative metronomic scheme, still being a suboptimal treatment, delays the time to malignant progression by at least one year when compared to the standard scheme.

Effects of wildfire on sea otter (Enhydra lutris) gene transcript profiles

USGS Publications Warehouse

Bowen, Lizabeth; Miles, A. Keith; Kolden, Crystal A.; Saarinen, Justin A.; Bodkin, James L.; Murray, Michael J.; Tinker, M. Tim

2015-01-01

Wildfires have been shown to impact terrestrial species over a range of temporal scales. Little is known, however, about the more subtle toxicological effects of wildfires, particularly in downstream marine or downwind locations from the wildfire perimeter. These down-current effects may be just as substantial as those effects within the perimeter. We used gene transcription technology, a sensitive indicator of immunological perturbation, to study the effects of the 2008 Basin Complex Fire on the California coast on a sentinel marine species, the sea otter (Enhydra lutris). We captured sea otters in 2008 (3 mo after the Basin Complex Fire was controlled) and 2009 (15 mo after the Basin Complex Fire was controlled) in the adjacent nearshore environment near Big Sur, California. Gene responses were distinctly different between Big Sur temporal groups, signifying detoxification of PAHs, possible associated response to potential malignant transformation, and suppression of immune function as the primary responses of sea otters to fire in 2008 compared to those captured in 2009. In general, gene transcription patterns in the 2008 sea otters were indicative of molecular reactions to organic exposure, malignant transformation, and decreased ability to respond to pathogens that seemed to consistent with short-term hydrocarbon exposure.

Free radicals in chemical carcinogenesis.

PubMed

Clemens, M R

1991-12-15

During the past decade, remarkable progress has been made in our understanding of cancer-causing agents, mechanisms of cancer formation and the behavior of cancer cells. Cancer is characterized primarily by an increase in the number of abnormal cells derived from a given normal tissue, invasion of adjacent tissues by these abnormal cells, and lymphatic or blood-borne spread of malignant cells to regional lymph nodes and to distant sites (metastasis). It has been estimated that about 75-80% of all human cancers are environmentally induced, 30-40% of them by diet. Only a small minority, possibly no more than 2% of all cases, result purely from inherent genetic changes. Several lines of evidence confirm that the fundamental molecular event or events that cause a cell to become malignant occur at the level of the DNA and a variety of studies indicate that the critical molecular event in chemical carcinogenesis is the interaction of the chemical agent with DNA. The demonstration that DNA isolated from tumor cells can transfect normal cells and render them neoplastic provides direct proof that an alteration of the DNA is responsible for cancer. The transforming genes, or oncogenes, have been identified by restriction endonuclease mapping. One of the characteristics of tumor cells generated by transformation with viruses, chemicals, or radiation is their reduced requirement for serum growth factors. A critical significance of electrophilic metabolites of carcinogenes in chemical carcinogenesis has been demonstrated. A number of "proximate" and "ultimate" metabolites, especially those of aromatic amines, were described. The "ultimate" forms of carcinogens actually interact with cellular constituents to cause neoplastic transformation and are the final metabolic products in most pathways. Recent evidence indicates that free radical derivatives of chemical carcinogens may be produced both metabolically and nonenzymatically during their metabolism. Free radicals carry no charge but do possess a single unpaired electron, making the radical extremely reactive. That such forms may be important in the introduction of neoplastic transformation by chemicals from two lines of evidence. (1) Various molecules that inhibit the formation of free radicals, many of which are termed antioxidants, can inhibit the carcinogenic action of a variety of chemical carcinogens. (2) There are relatively specific metabolic reactions of certain chemical carcinogens, particularly of polycyclic hydrocarbons, for which it has been shown to proceed through free radical intermediates. In conclusion, free radical processes with direct effects on DNA can be proposed for a variety of human and animal carcinogens.(ABSTRACT TRUNCATED AT 400 WORDS)

Cystic fibrous dysplasia in the long bone.

PubMed

Bahk, Won-Jong; Kang, Yong-Koo; Rhee, Seung-Koo; Chung, Yang-Guk; Lee, An-Hee; Bahk, Yong-Whee

2007-10-01

Prominent osteolysis associated with "ground glass" density of fibrous dysplasia may indicate cystic change or sarcomatous transformation. This complication has been reported only sporadically in the long bones. This article presents clinical, radiographic, and pathologic findings, and outcome of simple curettage and bone graft observed in a series of 8 patients with prominent cystic fibrous dysplasia of the long bone. Magnetic resonance imaging features provide a basis for separation of benign cystic change from malignant transformation. However, biopsy is necessary to distinguish nonspecific cystic degeneration from secondary aneurysmal bone cyst. Simple curettage with allo-chip-bone graft is an effective treatment for cystic fibrous dysplasia.

Retroviral expression screening of oncogenes in natural killer cell leukemia.

PubMed

Choi, Young Lim; Moriuchi, Ryozo; Osawa, Mitsujiro; Iwama, Atsushi; Makishima, Hideki; Wada, Tomoaki; Kisanuki, Hiroyuki; Kaneda, Ruri; Ota, Jun; Koinuma, Koji; Ishikawa, Madoka; Takada, Shuji; Yamashita, Yoshihiro; Oshimi, Kazuo; Mano, Hiroyuki

2005-08-01

Aggressive natural killer cell leukemia (ANKL) is an intractable malignancy that is characterized by the outgrowth of NK cells. To identify transforming genes in ANKL, we constructed a retroviral cDNA expression library from an ANKL cell line KHYG-1. Infection of 3T3 cells with recombinant retroviruses yielded 33 transformed foci. Nucleotide sequencing of the DNA inserts recovered from these foci revealed that 31 of them encoded KRAS2 with a glycine-to-alanine mutation at codon 12. Mutation-specific PCR analysis indicated that the KRAS mutation was present only in KHYG-1 cells, not in another ANKL cell line or in clinical specimens (n=8).

Liposarcoma of the chest wall. Transformation of dedifferentiated liposarcoma from a recurrent lipoma.

PubMed

Bicakcioglu, Pinar; Sak, Serpil D; Tastepe, Abdullah I

2012-08-01

Liposarcoma is the second most common soft tissue sarcoma after malignant fibrous histiocytoma in adults. It is frequently found in the extremities and retroperitoneum; rarely it can be seen in the chest wall. We report a rare case of giant liposarcoma originating from the chest wall representing a transformation of a relapsing lipoma in the same region. We performed chest wall resection, reconstruction with latissimus dorsi muscle transposition via posterolateral thoracotomy. The patient received 4 series of adjuvant chemotherapy after the postoperative diagnosis of dedifferentiated liposarcoma. The patient had no postoperative complication and has remained disease-free for 30 months.

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.

Regulation of the oncodevelopmental expression of type 1 chain ABH and Lewis(b) blood group antigens in human colon by alpha-2-L-fucosylation.

PubMed Central

Orntoft, T F; Greenwell, P; Clausen, H; Watkins, W M

1991-01-01

Blood group antigen expression in the distal human colon is related to the development of the organ and is modified by malignant transformation. To elucidate the biochemical basis for these changes, we have (a) analysed the activity of glycosyltransferases coded for by the H, Se, Le, X, and A genes, in tissue biopsy specimens from normal and malignant proximal and distal human colon; (b) characterised the glycosphingolipids expressed in the various regions of normal and malignant colon by immunostaining of high performance thin layer chromatography plates; and (c) located the antigens on tissue sections from the same subjects by immunohistochemistry. In both secretors and non-secretors we found a significantly higher activity of alpha-2-L-fucosyltransferases in carcinomatous rectal tissue than in tissue from normal subjects, whereas the other transferase activities studied showed no significant differences. The acceptor substrate specificity suggested that both the Se and the H gene dependent alpha-2-L-fucosyltransferases are increased in carcinomas. In non-malignant tissue the only enzyme which showed appreciably higher activity in caecum than in rectum was alpha-2-L-fucosyltransferase. Immunochemistry and immunohistochemistry showed alpha-2-L-fucosylated structures in normal caecum from secretors and in tumour tissue from both secretors and non-secretors. We conclude that the alpha-2-L-fucosyltransferases control the expression of ABH, and Lewis(b) structures in normal and malignant colon. Images Figure 4 PMID:1826491

Examining the Relationship between Pre-Malignant Breast Lesions, Carcinogenesis and Tumor Evolution in the Mammary Epithelium Using an Agent-Based Model.

PubMed

Chapa, Joaquin; An, Gary; Kulkarni, Swati A

2016-01-01

Breast cancer, the product of numerous rare mutational events that occur over an extended time period, presents numerous challenges to investigators interested in studying the transformation from normal breast epithelium to malignancy using traditional laboratory methods, particularly with respect to characterizing transitional and pre-malignant states. Dynamic computational modeling can provide insight into these pathophysiological dynamics, and as such we use a previously validated agent-based computational model of the mammary epithelium (the DEABM) to investigate the probabilistic mechanisms by which normal populations of ductal cells could transform into states replicating features of both pre-malignant breast lesions and a diverse set of breast cancer subtypes. The DEABM consists of simulated cellular populations governed by algorithms based on accepted and previously published cellular mechanisms. Cells respond to hormones, undergo mitosis, apoptosis and cellular differentiation. Heritable mutations to 12 genes prominently implicated in breast cancer are acquired via a probabilistic mechanism. 3000 simulations of the 40-year period of menstrual cycling were run in wild-type (WT) and BRCA1-mutated groups. Simulations were analyzed by development of hyperplastic states, incidence of malignancy, hormone receptor and HER-2 status, frequency of mutation to particular genes, and whether mutations were early events in carcinogenesis. Cancer incidence in WT (2.6%) and BRCA1-mutated (45.9%) populations closely matched published epidemiologic rates. Hormone receptor expression profiles in both WT and BRCA groups also closely matched epidemiologic data. Hyperplastic populations carried more mutations than normal populations and mutations were similar to early mutations found in ER+ tumors (telomerase, E-cadherin, TGFB, RUNX3, p < .01). ER- tumors carried significantly more mutations and carried more early mutations in BRCA1, c-MYC and genes associated with epithelial-mesenchymal transition. The DEABM generates diverse tumors that express tumor markers consistent with epidemiologic data. The DEABM also generates non-invasive, hyperplastic populations, analogous to atypia or ductal carcinoma in situ (DCIS), via mutations to genes known to be present in hyperplastic lesions and as early mutations in breast cancers. The results demonstrate that agent-based models are well-suited to studying tumor evolution through stages of carcinogenesis and have the potential to be used to develop prevention and treatment strategies.

Dynamic Contrast Magnetic Resonance Imaging (DCE-MRI) and Diffusion Weighted MR Imaging (DWI) for Differentiation between Benign and Malignant Salivary Gland Tumors

PubMed Central

Assili, S.; Fathi Kazerooni, A.; Aghaghazvini, L.; Saligheh Rad, H.R.; Pirayesh Islamian, J.

2015-01-01

Background Salivary gland tumors form nearly 3% of head and neck tumors. Due to their large histological variety and vicinity to facial nerves, pre-operative diagnosis and differentiation of benign and malignant parotid tumors are a major challenge for radiologists. Objective The majority of these tumors are benign; however, sometimes they tend to transform into a malignant form. Functional MRI techniques, namely dynamic contrast enhanced (DCE-) MRI and diffusion-weighted MRI (DWI) can indicate the characteristics of tumor tissue. Methods DCE-MRI analysis is based on the parameters of time intensity curve (TIC) before and after contrast agent injection. This method has the potential to identify the angiogenesis of tumors. DWI analysis is performed according to diffusion of water molecules in a tissue for determination of the cellularity of tumors. Conclusion According to the literature, these methods cannot be used individually to differentiate benign from malignant salivary gland tumors. An effective approach could be to combine the aforementioned methods to increase the accuracy of discrimination between different tumor types. The main objective of this study is to explore the application of DCE-MRI and DWI for assessment of salivary gland tumor types. PMID:26688794

High wavenumber Raman spectroscopy in the characterization of urinary metabolites of normal subjects, oral premalignant and malignant patients

NASA Astrophysics Data System (ADS)

Brindha, Elumalai; Rajasekaran, Ramu; Aruna, Prakasarao; Koteeswaran, Dornadula; Ganesan, Singaravelu

2017-01-01

Urine has emerged as one of the diagnostically potential bio fluids, as it has many metabolites. As the concentration and the physiochemical properties of the urinary metabolites may vary under pathological transformation, Raman spectroscopic characterization of urine has been exploited as a significant tool in identifying several diseased conditions, including cancers. In the present study, an attempt was made to study the high wavenumber (HWVN) Raman spectroscopic characterization of urine samples of normal subjects, oral premalignant and malignant patients. It is concluded that the urinary metabolites flavoproteins, tryptophan and phenylalanine are responsible for the observed spectral variations between the normal and abnormal groups. Principal component analysis-based linear discriminant analysis was carried out to verify the diagnostic potentiality of the present technique. The discriminant analysis performed across normal and oral premalignant subjects classifies 95.6% of the original and 94.9% of the cross-validated grouped cases correctly. In the second analysis performed across normal and oral malignant groups, the accuracy of the original and cross-validated grouped cases was 96.4% and 92.1% respectively. Similarly, the third analysis performed across three groups, normal, oral premalignant and malignant groups, classifies 93.3% and 91.2% of the original and cross-validated grouped cases correctly.

Role of different hematologic variables in defining the risk of malignant transformation in monoclonal gammopathy.

PubMed

Baldini, L; Guffanti, A; Cesana, B M; Colombi, M; Chiorboli, O; Damilano, I; Maiolo, A T

1996-02-01

The presenting clinico-hematologic features of 386 patients with nonmyelomatous monoclonal gammopathy (MG) were correlated with the frequency of malignant transformation to evaluate the most important variables conditioning its evolution into multiple myeloma (MM) or Waldenström macroglobulinemia (WM). Most of the patients (335) had monoclonal gammopathy of undetermined significance (MGUS: 39 IgA, 242 IgG, 54 IgM): the remaining 51 patients (12 IgA, 39 IgG) fulfilled all of the MGUS diagnostic criteria (according to Durie) except that bone marrow plasma cell (BMPC) content was 10% to 30%, and so they were defined as having monoclonal gammopathy of borderline significance (MGBS). There were no significant differences between the MGUS and MGBS groups in terms of age, sex, or median follow-up. After a median follow-up of 70 and 53 months, respectively, 23 of 335 MGUS and 19 of 51 MGBS patients had undergone a malignant evolution. Univariate analysis of the IgA and IgG patients showed that the cumulative probability of the disease evolving into MM correlated with diagnostic definition (MGBS v MGUS), BMPC content (> or = 10% v < 5% and < or = 5% v > 5%) and reduced serum polyclonal Ig. In the IgG cases, there was also a significant correlation with detectable Bence Jones proteinuria, serum monoclonal component (MC) levels and age at diagnosis (> 70 v < = or 55 years). In the IgG cases as a whole, the same variables remained in the Cox model where the BMPC percentage was considered after natural logarithmic transformation and the monoclonal component as g/dL value. The relative risks of developing MM are the following: 2.4 for each 1 g/dL increase of IgG, serum MC, 3.5 for detectable light chain proteinuria, 4.4 for the increase of 1 unit in log. BMPC percentage, 6.1 for age > 70, 3.6 and 13.1 for a reduction in one or two polyclonal Ig. In conclusion, our study allows the identification of a particular subset of MGUS patients (MC < = or 1.5 g/dL, BMPC < 5%, no reduction in polyclonal Ig and no detectable light chain proteinuria) at very low-risk of evolution, who can be considered as having benign monoclonal gammopathies. We also describe a previously undefined group of MG patients (with monoclonal gammopathy of borderline significance) who are at high-risk of malignant evolution. These findings could have a considerable impact on the cost/benefit ratio of monitoring programs in these patients.

Predictors of malignancy in patients with pheochromocytomas/paragangliomas: Asian Indian experience

PubMed Central

Sarathi, Vijaya; Kasaliwal, Rajeev; Pandit, Reshma; Goroshi, Manjunath; Malhotra, Gaurav; Dalvi, Abhay; Bakshi, Ganesh; Bhansali, Anil; Rajput, Rajesh; Shivane, Vyankatesh; Lila, Anurag; Bandgar, Tushar; Shah, Nalini S

2016-01-01

Background and aims Malignant transformation of pheochromocytomas/paragangliomas (PCC/PGL) is a rare occurrence, and predictive factors for the same are not well understood. This study aims to identify the predictors of malignancy in patients with PCC/PGL. Materials and methods We performed a retrospective analysis of 142 patients with either PCC or PGL registered at our institute between 2000 and 2015. Records were evaluated for clinical parameters like age, gender, familial/syndromic presentation, symptomatic presentation, biochemistry, size, number and location of tumours and presence of metastases and mode of its diagnosis. Results Twenty patients were found to have metastases; 13 had metastases at diagnosis and seven during follow-up. Metastases were detected by radiology (CT-neck to pelvis) in 11/20 patients (5/13 synchronous and 6/7 metachronous), 131I-metaiodobenzylguanidine in five (2/12 synchronous and 3/6 metachronous) patients and 18F-flurodeoxyglucose PET/CT in 15 (12/12 synchronous and 3/3 metachronous) patients. Malignant tumours were significantly larger than benign tumours (8.3 ± 4.1 cm, range: 3–22 cm vs 5.7 ± 2.3 cm, range: 2–14 cm, P = 0.0001) and less frequently metanephrine secreting. On linear regression analysis, tumour size and lack of metanephrine secretion were the independent predictors of malignancy. Conclusions Patients with primary tumour size >5.7 cm and lack of metanephrine secretory status should be evaluated for possible malignancy not only at diagnosis but also in the postoperative period. As compared to CT and 131I-MIBG scan, 18F-flurodeoxyglucose PET/CT analyses are better (sensitivity: 100%) for the diagnosis of metastases in our study. PMID:27852633

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.

Phosphorylation-dependent interaction between antigenic peptides and MHC class I: a molecular basis for presentation of transformed self

PubMed Central

Mohammed, Fiyaz; Cobbold, Mark; Zarling, Angela L.; Salim, Mahboob; Barrett-Wilt, Gregory A.; Shabanowitz, Jeffrey; Hunt, Donald F.; Engelhard, Victor H.; Willcox, Benjamin E.

2008-01-01

Protein phosphorylation generates a source of phosphopeptides that are presented by major histocompatibility complex (MHC) class I molecules and recognized by T cells. As deregulated phosphorylation is a hallmark of malignant transformation, the differential display of phosphorylated peptides on cancer cells provides an immunological signature of “transformed self”. Here, we demonstrate that phosphorylation can radically increase peptide binding affinity for HLA-A2. To understand this, we solved crystal structures of four phosphopeptide–HLA-A2 complexes. These revealed a novel peptide binding motif centered on a solvent-exposed phosphate anchor. Our findings indicate that deregulated phosphorylation can create neoantigens by promoting MHC binding, or by affecting the antigenic identity of presented epitopes. These results highlight the potential of phosphopeptides as novel targets for cancer immunotherapy. PMID:18836451