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Sample records for aggressive tumor progression

  1. Rat Prostate Tumor Cells Progress in the Bone Microenvironment to a Highly Aggressive Phenotype1

    PubMed Central

    Bergström, Sofia Halin; Rudolfsson, Stina H; Bergh, Anders

    2016-01-01

    Prostate cancer generally metastasizes to bone, and most patients have tumor cells in their bone marrow already at diagnosis. Tumor cells at the metastatic site may therefore progress in parallel with those in the primary tumor. Androgen deprivation therapy is often the first-line treatment for clinically detectable prostate cancer bone metastases. Although the treatment is effective, most metastases progress to a castration-resistant and lethal state. To examine metastatic progression in the bone microenvironment, we implanted androgen-sensitive, androgen receptor–positive, and relatively slow-growing Dunning G (G) rat prostate tumor cells into the tibial bone marrow of fully immune-competent Copenhagen rats. We show that tumor establishment in the bone marrow was reduced compared with the prostate, and whereas androgen deprivation did not affect tumor establishment or growth in the bone, this was markedly reduced in the prostate. Moreover, we found that, with time, G tumor cells in the bone microenvironment progress to a more aggressive phenotype with increased growth rate, reduced androgen sensitivity, and increased metastatic capacity. Tumor cells in the bone marrow encounter lower androgen levels and a higher degree of hypoxia than at the primary site, which may cause high selective pressures and eventually contribute to the development of a new and highly aggressive tumor cell phenotype. It is therefore important to specifically study progression in bone metastases. This tumor model could be used to increase our understanding of how tumor cells adapt in the bone microenvironment and may subsequently improve therapy strategies for prostate metastases in bone. PMID:26992916

  2. DNMT3B7 Expression Promotes Tumor Progression to a More Aggressive Phenotype in Breast Cancer Cells

    PubMed Central

    Brambert, Patrick R.; Kelpsch, Daniel J.; Hameed, Rabia; Desai, Charmi V.; Calafiore, Gianfranco; Godley, Lucy A.; Raimondi, Stacey L.

    2015-01-01

    Epigenetic changes, such as DNA methylation, have been shown to promote breast cancer progression. However, the mechanism by which cancer cells acquire and maintain abnormal DNA methylation is not well understood. We have previously identified an aberrant splice form of a DNA methyltransferase, DNMT3B7, expressed in virtually all cancer cell lines but at very low levels in normal cells. Furthermore, aggressive MDA-MB-231 breast cancer cells have been shown to express increased levels of DNMT3B7 compared to poorly invasive MCF-7 cells, indicating that DNMT3B7 may have a role in promoting a more invasive phenotype. Using data gathered from The Cancer Genome Atlas, we show that DNMT3B7 expression is increased in breast cancer patient tissues compared to normal tissue. To determine the mechanism by which DNMT3B7 was functioning in breast cancer cells, two poorly invasive breast cancer cell lines, MCF-7 and T-47D, were stably transfected with a DNMT3B7 expression construct. Expression of DNMT3B7 led to hypermethylation and down-regulation of E-cadherin, altered localization of β-catenin, as well as increased adhesion turnover, cell proliferation, and anchorage-independent growth. The novel results presented in this study suggest a role for DNMT3B7 in the progression of breast cancer to a more aggressive state and the potential for future development of novel therapeutics. PMID:25607950

  3. Overexpression of the growth-hormone-releasing hormone gene in acromegaly-associated pituitary tumors. An event associated with neoplastic progression and aggressive behavior.

    PubMed Central

    Thapar, K.; Kovacs, K.; Stefaneanu, L.; Scheithauer, B.; Killinger, D. W.; Lioyd, R. V.; Smyth, H. S.; Barr, A.; Thorner, M. O.; Gaylinn, B.; Laws, E. R.

    1997-01-01

    The clinical behavior of growth hormone (GH)-producing pituitary tumors is known to vary greatly; however, the events underlying this variability remain poorly understood. Herein we demonstrate that tumor overexpression of the GH-releasing hormone (GHRH) gene is one prognostically informative event associated with the clinical aggressiveness of somatotroph pituitary tumors. Accumulation of GHRH mRNA transcripts was demonstrated in 91 of a consecutive series of 100 somatotroph tumors by in situ hybridization; these findings were corroborated by Northern analysis and reverse transcriptase polymerase chain reaction, and protein translation was confirmed by Western blotting. By comparison, transcript accumulation was absent or negligibly low in 30 normal pituitary glands. GHRH transcripts were found to preferentially accumulate among clinically aggressive tumors. Specifically, GHRH mRNA signal intensity was 1) linearly correlated with Ki-67 tumor growth fractions (r = 0.71; P < 0.001), 2) linearly correlated with preoperative serum GH levels (r = 0.56; p = 0.01), 3) higher among invasive tumors (P < 0.001), and 4) highest in those tumors in which post-operative remission was not achieved (P < 0.001). Using multivariate logistic regression, a model of postoperative remission likelihood was derived wherein remission was defined by the single criterion of suppressibility of GH levels to less than 2 ng/ml during an oral glucose tolerance test. In this outcome model, GHRH mRNA signal intensity proved to be the most important explanatory variable overall, eclipsing any and all conventional clinicopathological predictors as the single most significant predictor of postoperative remission; increases in GHRH mRNA signal were associated with marked declines in remission likelihood. The generalizability of this outcome model was further validated by the model's significant performance in predicting postoperative remission in a random sample of 30 somatotroph tumors treated at

  4. Calpains: markers of tumor aggressiveness?

    PubMed

    Roumes, Hélène; Leloup, Ludovic; Dargelos, Elise; Brustis, Jean-Jacques; Daury, Laetitia; Cottin, Patrick

    2010-05-15

    Rhabdomyosarcoma (RMS) are soft-tissue sarcoma commonly encountered in childhood. RMS cells can acquire invasive behavior and form metastases. The metastatic dissemination implicates many proteases among which are mu-calpain and m-calpain. Study of calpain expression and activity underline the deregulation of calpain activity in RMS. Analysis of kinetic characteristics of RMS cells, compared to human myoblasts LHCN-M2 cells, shows an important migration velocity in RMS cells. One of the major results of this study is the positive linear correlation between calpain activity and migration velocity presenting calpains as a marker of tumor aggressiveness. The RMS cytoskeleton is disorganized. Specifying the role of mu- and m-calpain using antisense oligonucleotides led to show that both calpains up-regulate alpha- and beta-actin in ARMS cells. Moreover, the invasive behavior of these cells is higher than that of LHCN-M2 cells. However, it is similar to that of non-treated LHCN-M2 cells, when calpains are inhibited. In summary, calpains may be involved in the anarchic adhesion, migration and invasion of RMS. The direct relationship between calpain activity and migration velocities or invasive behavior indicates that calpains could be considered as markers of tumor aggressiveness and as potential targets for limiting development of RMS tumor as well as their metastatic behavior. PMID:20193680

  5. CD44 enhances tumor aggressiveness by promoting tumor cell plasticity.

    PubMed

    Paulis, Yvette W J; Huijbers, Elisabeth J M; van der Schaft, Daisy W J; Soetekouw, Patricia M M B; Pauwels, Patrick; Tjan-Heijnen, Vivianne C G; Griffioen, Arjan W

    2015-08-14

    Aggressive tumor cells can obtain the ability to transdifferentiate into cells with endothelial features and thus form vasculogenic networks. This phenomenon, called vasculogenic mimicry (VM), is associated with increased tumor malignancy and poor clinical outcome. To identify novel key molecules implicated in the process of vasculogenic mimicry, microarray analysis was performed to compare gene expression profiles of aggressive (VM+) and non-aggressive (VM-) cells derived from Ewing sarcoma and breast carcinoma. We identified the CD44/c-Met signaling cascade as heavily relevant for vasculogenic mimicry. CD44 was at the center of this cascade, and highly overexpressed in aggressive tumors. Both CD44 standard isoform and its splice variant CD44v6 were linked to increased aggressiveness in VM. Since VM is most abundant in Ewing sarcoma tumors functional analyses were performed in EW7 cells. Overexpression of CD44 allowed enhanced adhesion to its extracellular matrix ligand hyaluronic acid. CD44 expression also facilitated the formation of vasculogenic structures in vitro, as CD44 knockdown experiments repressed migration and vascular network formation. From these results and the observation that CD44 expression is associated with vasculogenic structures and blood lakes in human Ewing sarcoma tissues, we conclude that CD44 increases aggressiveness in tumors through the process of vasculogenic mimicry. PMID:26189059

  6. Deregulation of miR-183 and KIAA0101 in Aggressive and Malignant Pituitary Tumors

    PubMed Central

    Roche, Magali; Wierinckx, Anne; Croze, Séverine; Rey, Catherine; Legras-Lachuer, Catherine; Morel, Anne-Pierre; Fusco, Alfredo; Raverot, Gérald; Trouillas, Jacqueline; Lachuer, Joel

    2015-01-01

    Changes in microRNAs (miRNAs) expression in many types of cancer suggest that they may be involved in crucial steps during tumor progression. Indeed, miRNAs deregulation has been described in pituitary tumorigenesis, but few studies have described their role in pituitary tumor progression toward aggressiveness and malignancy. To assess the role of miRNAs within the hierarchical cascade of events in prolactin (PRL) tumors during progression, we used an integrative genomic approach to associate clinical–pathological features, global miRNA expression, and transcriptomic profiles of the same human tumors. We describe the specific down-regulation of one principal miRNA, miR-183, in the 8 aggressive (A, grade 2b) compared to the 18 non-aggressive (NA, grades 1a, 2a) PRL tumors. We demonstrate that it acts as an anti-proliferative gene by directly targeting KIAA0101, which is involved in cell cycle activation and inhibition of p53–p21-mediated cell cycle arrest. Moreover, we show that miR-183 and KIAA0101 expression significantly correlate with the main markers of pituitary tumors aggressiveness, Ki-67 and p53. These results confirm the activation of proliferation in aggressive and malignant PRL tumors compared to non-aggressive ones. Importantly, these data also demonstrate the ability of such an integrative genomic strategy, applied in the same human tumors, to identify the molecular mechanisms responsible for tumoral progression even from a small cohort of patients. PMID:26322309

  7. MMSET is overexpressed in cancers: Link with tumor aggressiveness

    SciTech Connect

    Kassambara, Alboukadel; Klein, Bernard Moreaux, Jerome

    2009-02-20

    MMSET is expressed ubiquitously in early development and its deletion is associated with the malformation syndrome called Wolf-Hirschhorn syndrome. It is involved in the t(4; 14) (p16; q32) chromosomal translocation, which is the second most common translocation in multiple myeloma (MM) and is associated with the worst prognosis. MMSET expression has been shown to promote cellular adhesion, clonogenic growth and tumorigenicity in multiple myeloma. MMSET expression has been recently shown to increase with ascending tumor proliferation activity in glioblastoma multiforme. These data demonstrate that MMSET could be implicated in tumor emergence and/or progression. Therefore, we compared the expression of MMSET in 40 human tumor types - brain, epithelial, lymphoid - to that of their normal tissue counterparts using publicly available gene expression data, including the Oncomine Cancer Microarray database. We found significant overexpression of MMSET in 15 cancers compared to their normal counterparts. Furthermore MMSET is associated with tumor aggressiveness or prognosis in many types of these aforementioned cancers. Taken together, these data suggest that MMSET potentially acts as a pathogenic agent in many cancers. The identification of the targets of MMSET and their role in cell growth and survival will be key to understand how MMSET is associated with tumor development.

  8. Adaptive (TINT) Changes in the Tumor Bearing Organ Are Related to Prostate Tumor Size and Aggressiveness

    PubMed Central

    Adamo, Hanibal Hani; Strömvall, Kerstin; Nilsson, Maria; Halin Bergström, Sofia; Bergh, Anders

    2015-01-01

    In order to grow, tumors need to induce supportive alterations in the tumor-bearing organ, by us named tumor instructed normal tissue (TINT) changes. We now examined if the nature and magnitude of these responses were related to tumor size and aggressiveness. Three different Dunning rat prostate tumor cells were implanted into the prostate of immune-competent rats; 1) fast growing and metastatic MatLyLu tumor cells 2) fast growing and poorly metastatic AT-1 tumor cells, and 3) slow growing and non-metastatic G tumor cells. All tumor types induced increases in macrophage, mast cell and vascular densities and in vascular cell-proliferation in the tumor-bearing prostate lobe compared to controls. These increases occurred in parallel with tumor growth. The most pronounced and rapid responses were seen in the prostate tissue surrounding MatLyLu tumors. They were, also when small, particularly effective in attracting macrophages and stimulating growth of not only micro-vessels but also small arteries and veins compared to the less aggressive AT-1 and G tumors. The nature and magnitude of tumor-induced changes in the tumor-bearing organ are related to tumor size but also to tumor aggressiveness. These findings, supported by previous observation in patient samples, suggest that one additional way to evaluate prostate tumor aggressiveness could be to monitor its effect on adjacent tissues. PMID:26536349

  9. Biomarkers to Distinguish Aggressive Cancers from Non-aggressive or Non-progressing Cancer — EDRN Public Portal

    Cancer.gov

    Distinguishing aggressive cancers from non-aggressive or non-progressing cancers is an issue of both clinical and public health importance particularly for those cancers with an available screening test. With respect to breast cancer, mammographic screening has been shown in randomized trials to reduce breast cancer mortality, but given the limitations of its sensitivity and specificity some breast cancers are missed by screening. These so called interval detected breast cancers diagnosed between regular screenings are known to have a more aggressive clinical profile. In addition, of those cancers detected by mammography some are indolent while others are more likely to recur despite treatment. The pilot study proposed herein is highly responsive to the EDRN supplement titled “Biomarkers to Distinguish Aggressive Cancers from Nonaggressive or Non-progressing Cancers” in that it addresses both of the research objectives related to these issues outlined in the notice for this supplement: Aim 1: To identify biomarkers in tumor tissue related to risk of interval detected vs. mammography screen detected breast cancer focusing on early stage invasive disease. We will compare gene expression profiles using the whole genome-cDNA-mediated Annealing, Selection, extension and Ligation (DASL) assay of 50 screen detected cancers to those of 50 interval detected cancers. Through this approach we will advance our understanding of the molecular characteristics of interval vs. screen detected breast cancers and discover novel biomarkers that distinguish between them. Aim 2: To identify biomarkers in tumor tissue related to risk of cancer recurrence among patients with screen detected early stage invasive breast cancer. Using the DASL assay we will compare gene expression profiles from screen detected early stage breast cancer that either recurred within five years or never recurred within five years. These two groups of patients will be matched on multiple factors including

  10. Basosquamous carcinoma: is it an aggressive tumor?

    PubMed

    Kececi, Yavuz; Argon, Asuman; Kebat, Tulug; Sir, Emin; Gungor, Melike; Vardar, Enver

    2015-04-01

    Basosquamous carcinoma is a rare cutaneous tumour that is considered an aggressive type of basal cell carcinoma with an increased risk of recurrence and metastases. This impression has been perpetuated in the literature, despite limited scientific data and conflicting results of some authors. This present study was aimed to evaluate the clinical-pathological features of this tumour and follow-up of a series of basosquamous carcinoma. Basosquamous carcinoma patients who underwent surgical excision between January 2000 and February 2012 were analyzed retrospectively. Their medical files were reviewed and the corresponding routinely stained sections (with hematoxylin-eosin) were re-evaluated by two pathologists. Thirty-five patients with basosquamous carcinoma were operated on in this period. Most tumurs were located in the head and neck area (94%), and the mean age of the patients was 69.8 years. Margin involvements were seen in 11 patients (31.4%) and all of them underwent re-excision. There was only one local recurrence. There was neither regional lymph node nor distant metastasis in this series. The recurrence rate of basosquamous carcinoma is found as 4%, lower than that of most other similar studies. Further pathologic studies are needed to better classify basosquamous carcinoma and to increase consistency between the results of studies. Surgical excision and regular follow-up are considered as the treatment of choice. PMID:25139415

  11. Expression Profiling of Primary and Metastatic Ovarian Tumors Reveals Differences Indicative of Aggressive Disease

    PubMed Central

    Brodsky, Alexander S.; Fischer, Andrew; Miller, Daniel H.; Vang, Souriya; MacLaughlan, Shannon; Wu, Hsin-Ta; Yu, Jovian; Steinhoff, Margaret; Collins, Colin; Smith, Peter J. S.; Raphael, Benjamin J.; Brard, Laurent

    2014-01-01

    The behavior and genetics of serous epithelial ovarian cancer (EOC) metastasis, the form of the disease lethal to patients, is poorly understood. The unique properties of metastases are critical to understand to improve treatments of the disease that remains in patients after debulking surgery. We sought to identify the genetic and phenotypic landscape of metastatic progression of EOC to understand how metastases compare to primary tumors. DNA copy number and mRNA expression differences between matched primary human tumors and omental metastases, collected at the same time during debulking surgery before chemotherapy, were measured using microarrays. qPCR and immunohistochemistry validated findings. Pathway analysis of mRNA expression revealed metastatic cancer cells are more proliferative and less apoptotic than primary tumors, perhaps explaining the aggressive nature of these lesions. Most cases had copy number aberrations (CNAs) that differed between primary and metastatic tumors, but we did not detect CNAs that are recurrent across cases. A six gene expression signature distinguishes primary from metastatic tumors and predicts overall survival in independent datasets. The genetic differences between primary and metastatic tumors, yet common expression changes, suggest that the major clone in metastases is not the same as in primary tumors, but the cancer cells adapt to the omentum similarly. Together, these data highlight how ovarian tumors develop into a distinct, more aggressive metastatic state that should be considered for therapy development. PMID:24732363

  12. Hematopoietic Age at Onset of Triple-Negative Breast Cancer Dictates Disease Aggressiveness and Progression.

    PubMed

    Marsh, Timothy; Wong, Irene; Sceneay, Jaclyn; Barakat, Amey; Qin, Yuanbo; Sjödin, Andreas; Alspach, Elise; Nilsson, Björn; Stewart, Sheila A; McAllister, Sandra S

    2016-05-15

    Triple-negative breast cancer (TNBC) is considered an early onset subtype of breast cancer that carries with it a poorer prognosis in young rather than older women for reasons that remain poorly understood. Hematopoiesis in the bone marrow becomes altered with age and may therefore affect the composition of tumor-infiltrating hematopoietic cells and subsequent tumor progression. In this study, we investigated how age- and tumor-dependent changes to bone marrow-derived hematopoietic cells impact TNBC progression. Using multiple mouse models of TNBC tumorigenesis and metastasis, we found that a specific population of bone marrow cells (BMC) upregulated CSF-1R and secreted the growth factor granulin to support stromal activation and robust tumor growth in young mice. However, the same cell population in old mice expressed low levels of CSF1R and granulin and failed to promote tumor outgrowth, suggesting that age influences the tumorigenic capacity of BMCs in response to tumor-associated signals. Importantly, BMCs from young mice were sufficient to activate a tumor-supportive microenvironment and induce tumor progression in old mice. These results indicate that hematopoietic age is an important determinant of TNBC aggressiveness and provide rationale for investigating age-stratified therapies designed to prevent the protumorigenic effects of activated BMCs. Cancer Res; 76(10); 2932-43. ©2016 AACR. PMID:27197230

  13. Oncogenic Properties of Apoptotic Tumor Cells in Aggressive B Cell Lymphoma

    PubMed Central

    Ford, Catriona A.; Petrova, Sofia; Pound, John D.; Voss, Jorine J.L.P.; Melville, Lynsey; Paterson, Margaret; Farnworth, Sarah L.; Gallimore, Awen M.; Cuff, Simone; Wheadon, Helen; Dobbin, Edwina; Ogden, Carol Anne; Dumitriu, Ingrid E.; Dunbar, Donald R.; Murray, Paul G.; Ruckerl, Dominik; Allen, Judith E.; Hume, David A.; van Rooijen, Nico; Goodlad, John R.; Freeman, Tom C.; Gregory, Christopher D.

    2015-01-01

    Summary Background Cells undergoing apoptosis are known to modulate their tissue microenvironments. By acting on phagocytes, notably macrophages, apoptotic cells inhibit immunological and inflammatory responses and promote trophic signaling pathways. Paradoxically, because of their potential to cause death of tumor cells and thereby militate against malignant disease progression, both apoptosis and tumor-associated macrophages (TAMs) are often associated with poor prognosis in cancer. We hypothesized that, in progression of malignant disease, constitutive loss of a fraction of the tumor cell population through apoptosis could yield tumor-promoting effects. Results Here, we demonstrate that apoptotic tumor cells promote coordinated tumor growth, angiogenesis, and accumulation of TAMs in aggressive B cell lymphomas. Through unbiased “in situ transcriptomics” analysis—gene expression profiling of laser-captured TAMs to establish their activation signature in situ—we show that these cells are activated to signal via multiple tumor-promoting reparatory, trophic, angiogenic, tissue remodeling, and anti-inflammatory pathways. Our results also suggest that apoptotic lymphoma cells help drive this signature. Furthermore, we demonstrate that, upon induction of apoptosis, lymphoma cells not only activate expression of the tumor-promoting matrix metalloproteinases MMP2 and MMP12 in macrophages but also express and process these MMPs directly. Finally, using a model of malignant melanoma, we show that the oncogenic potential of apoptotic tumor cells extends beyond lymphoma. Conclusions In addition to its profound tumor-suppressive role, apoptosis can potentiate cancer progression. These results have important implications for understanding the fundamental biology of cell death, its roles in malignant disease, and the broader consequences of apoptosis-inducing anti-cancer therapy. PMID:25702581

  14. Metabolic coupling in urothelial bladder cancer compartments and its correlation to tumor aggressiveness.

    PubMed

    Afonso, Julieta; Santos, Lúcio L; Morais, António; Amaro, Teresina; Longatto-Filho, Adhemar; Baltazar, Fátima

    2016-02-01

    Monocarboxylate transporters (MCTs) are vital for intracellular pH homeostasis by extruding lactate from highly glycolytic cells. These molecules are key players of the metabolic reprogramming of cancer cells, and evidence indicates a potential contribution in urothelial bladder cancer (UBC) aggressiveness and chemoresistance. However, the specific role of MCTs in the metabolic compartmentalization within bladder tumors, namely their preponderance on the tumor stroma, remains to be elucidated. Thus, we evaluated the immunoexpression of MCTs in the different compartments of UBC tissue samples (n = 111), assessing the correlations among them and with the clinical and prognostic parameters. A significant decrease in positivity for MCT1 and MCT4 occurred from normoxic toward hypoxic regions. Significant associations were found between the expression of MCT4 in hypoxic tumor cells and in the tumor stroma. MCT1 staining in normoxic tumor areas, and MCT4 staining in hypoxic regions, in the tumor stroma and in the blood vessels were significantly associated with UBC aggressiveness. MCT4 concomitant positivity in hypoxic tumor cells and in the tumor stroma, as well as positivity in each of these regions concomitant with MCT1 positivity in normoxic tumor cells, was significantly associated with an unfavourable clinicopathological profile, and predicted lower overall survival rates among patients receiving platinum-based chemotherapy. Our results point to the existence of a multi-compartment metabolic model in UBC, providing evidence of a metabolic coupling between catabolic stromal and cancer cells' compartments, and the anabolic cancer cells. It is urgent to further explore the involvement of this metabolic coupling in UBC progression and chemoresistance. PMID:26636903

  15. Defective apical extrusion signaling contributes to aggressive tumor hallmarks.

    PubMed

    Gu, Yapeng; Shea, Jill; Slattum, Gloria; Firpo, Matthew A; Alexander, Margaret; Mulvihill, Sean J; Golubovskaya, Vita M; Rosenblatt, Jody

    2015-01-01

    When epithelia become too crowded, some cells are extruded that later die. To extrude, a cell produces the lipid, Sphingosine 1-Phosphate (S1P), which activates S1P₂ receptors in neighboring cells that seamlessly squeeze the cell out of the epithelium. Here, we find that extrusion defects can contribute to carcinogenesis and tumor progression. Tumors or epithelia lacking S1P₂ cannot extrude cells apically and instead form apoptotic-resistant masses, possess poor barrier function, and shift extrusion basally beneath the epithelium, providing a potential mechanism for cell invasion. Exogenous S1P₂ expression is sufficient to rescue apical extrusion, cell death, and reduce orthotopic pancreatic tumors and their metastases. Focal Adhesion Kinase (FAK) inhibitor can bypass extrusion defects and could, therefore, target pancreatic, lung, and colon tumors that lack S1P₂ without affecting wild-type tissue. PMID:25621765

  16. Mutational Landscape of Aggressive Prostate Tumors in African American Men.

    PubMed

    Lindquist, Karla J; Paris, Pamela L; Hoffmann, Thomas J; Cardin, Niall J; Kazma, Rémi; Mefford, Joel A; Simko, Jeffrey P; Ngo, Vy; Chen, Yalei; Levin, Albert M; Chitale, Dhananjay; Helfand, Brian T; Catalona, William J; Rybicki, Benjamin A; Witte, John S

    2016-04-01

    Prostate cancer is the most frequently diagnosed and second most fatal nonskin cancer among men in the United States. African American men are two times more likely to develop and die of prostate cancer compared with men of other ancestries. Previous whole genome or exome tumor-sequencing studies of prostate cancer have primarily focused on men of European ancestry. In this study, we sequenced and characterized somatic mutations in aggressive (Gleason ≥7, stage ≥T2b) prostate tumors from 24 African American patients. We describe the locations and prevalence of small somatic mutations (up to 50 bases in length), copy number aberrations, and structural rearrangements in the tumor genomes compared with patient-matched normal genomes. We observed several mutation patterns consistent with previous studies, such as large copy number aberrations in chromosome 8 and complex rearrangement chains. However, TMPRSS2-ERG gene fusions and PTEN losses occurred in only 21% and 8% of the African American patients, respectively, far less common than in patients of European ancestry. We also identified mutations that appeared specific to or more common in African American patients, including a novel CDC27-OAT gene fusion occurring in 17% of patients. The genomic aberrations reported in this study warrant further investigation of their biologic significant role in the incidence and clinical outcomes of prostate cancer in African Americans. Cancer Res; 76(7); 1860-8. ©2016 AACR. PMID:26921337

  17. Macrophage Diversity Enhances Tumor Progression and Metastasis

    PubMed Central

    Qian, Binzhi; Pollard, Jeffrey W.

    2016-01-01

    There is persuasive clinical and experimental evidence that macrophages promote cancer initiation and malignant progression. During tumor initiation they create an inflammatory environment that is mutagenic and which promotes growth. As tumors progress to malignancy, macrophages stimulate angiogenesis, enhance tumor cell migration, invasion, and suppress anti-tumor immunity. At metastatic sites macrophages prepare the target tissue for arrival of tumor cells and then a different subpopulation of macrophages promotes tumor cell extravasation, survival, and subsequent growth. Specialized subpopulations of macrophages may represent important new therapeutic targets. PMID:20371344

  18. Testosterone regulates thyroid cancer progression by modifying tumor suppressor genes and tumor immunity

    PubMed Central

    Zhang, Lisa J.; Xiong, Yin; Nilubol, Naris; He, Mei; Bommareddi, Swaroop; Zhu, Xuguang; Jia, Li; Xiao, Zhen; Park, Jeong-Won; Xu, Xia; Patel, Dhaval; Willingham, Mark C.; Cheng, Sheue-yann; Kebebew, Electron

    2015-01-01

    Cancer gender disparity has been observed for a variety of human malignancies. Thyroid cancer is one such cancer with a higher incidence in women, but more aggressive disease in men. There is scant evidence on the role of sex hormones on cancer initiation/progression. Using a transgenic mouse model of follicular thyroid cancer (FTC), we found castration led to lower rates of cancer in females and less advanced cancer in males. Mechanistically, less advanced cancer in castrated males was due to increased expression of tumor suppressor (Glipr1, Sfrp1) and immune-regulatory genes and higher tumor infiltration with M1 macrophages and CD8 cells. Functional study showed that GLIPR1 reduced cell growth and increased chemokine secretion (Ccl5) that activates immune cells. Our data demonstrate that testosterone regulates thyroid cancer progression by reducing tumor suppressor gene expression and tumor immunity. PMID:25576159

  19. Targeting CSCs in Tumor Microenvironment: The Potential Role of ROS-Associated miRNAs in Tumor Aggressiveness

    PubMed Central

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

    2015-01-01

    Reactive oxygen species (ROS) have been widely considered as critical cellular signaling molecules involving in various biological processes such as cell growth, differentiation, proliferation, apoptosis, and angiogenesis. The homeostasis of ROS is critical to maintain normal biological processes. Increased production of ROS, namely oxidative stress, due to either endogenous or exogenous sources causes irreversible damage of bio-molecules such as DNA, proteins, lipids, and sugars, leading to genomic instability, genetic mutation, and altered gene expression, eventually contributing to tumorigenesis. A great amount of experimental studies in vitro and in vivo have produced solid evidence supporting that oxidative stress is strongly associated with increased tumor cell growth, treatment resistance, and metastasis, and all of which contribute to tumor aggressiveness. More recently, the data have indicated that altered production of ROS is also associated with cancer stem cells (CSCs), epithelial-to-mesenchymal transition (EMT), and hypoxia, the most common features or phenomena in tumorigenesis and tumor progression. However, the exact mechanism by which ROS is involved in the regulation of CSC and EMT characteristics as well as hypoxia- and, especially, HIF-mediated pathways is not well known. Emerging evidence suggests the role of miRNAs in tumorigenesis and progression of human tumors. Recently, the data have indicated that altered productions of ROS are associated with deregulated expression of miRNAs, suggesting their potential roles in the regulation of ROS production. Therefore, targeting ROS mediated through the deregulation of miRNAs by novel approaches or by naturally occurring anti-oxidant agents such as genistein could provide a new therapeutic approach for the prevention and/or treatment of human malignancies. In this article, we will discuss the potential role of miRNAs in the regulation of ROS production during tumorigenesis. Finally, we will discuss

  20. Vascular patterns provide therapeutic targets in aggressive neuroblastic tumors

    PubMed Central

    Tadeo, Irene; Bueno, Gloria; Berbegall, Ana P.; Fernández-Carrobles, M. Milagro; Castel, Victoria; García-Rojo, Marcial; Navarro, Samuel; Noguera, Rosa

    2016-01-01

    Angiogenesis is essential for tumor growth and metastasis, nevertheless, in NB, results between different studies on angiogenesis have yielded contradictory results. An image analysis tool was developed to characterize the density, size and shape of total blood vessels and vascular segments in 458 primary neuroblastic tumors contained in tissue microarrays. The results were correlated with clinical and biological features of known prognostic value and with risk of progression to establish histological vascular patterns associated with different degrees of malignancy. Total blood vessels were larger, more abundant and more irregularly-shaped in tumors of patients with associated poor prognostic factors than in the favorable cohort. Tumor capillaries were less abundant and sinusoids more abundant in the patient cohort with unfavorable prognostic factors. Additionally, size of post-capillaries & metarterioles as well as higher sinusoid density can be included as predictive factors for survival. These patterns may therefore help to provide more accurate pre-treatment risk stratification, and could provide candidate targets for novel therapies. PMID:26918726

  1. Histologically Benign, Clinically Aggressive: Progressive Non-Optic Pathway Pilocytic Astrocytomas in Adults with NF1

    PubMed Central

    Strowd, Roy E.; Rodriguez, Fausto J.; McLendon, Roger E.; Vredenburgh, James J.; Chance, Aaron B.; Jallo, George; Olivi, Alessandro; Ahn, Edward S.; Blakeley, Jaishri O.

    2016-01-01

    Although optic pathway gliomas are the most common brain tumors associated with neurofibromatosis type 1 (NF1), extra-optic gliomas occur and may behave more aggressively with outcomes that differ by age. A retrospective case-control study was designed to describe the clinical course of adult NF1 patients with progressive extra-optic pilocytic astrocytomas (PAs) and compare to a pediatric cohort. Data for patients treated at the Johns Hopkins Comprehensive Neurofibromatosis Center from 2003 to 2013 were reviewed to identify cases (adults, age >18) and controls (pediatric, age <18) with clinically or radiographically progressive extra-optic PAs. Demographic, clinical, histologic, and radiographic data were collected. Three adult NF1 cases and four pediatric NF1 controls were identified. Mean age was 32.3 ± 9.5 years, 66% male (cases); 12.8±4.2 years, 100% male (controls). Symptomatic progression occurred in two-of-three adults (67%) while the majority of pediatric patients presented with isolated radiographic progression (n=3, 75%). Onset tended to be more rapid in adults (4±1 vs. 14±8.3 months, P=0.10). Subtotal resection was the treatment for all pediatric patients. Radiotherapy (n=2), chemotherapy (n=2), and targeted, biologic agents (n=2) were administered in adults. Although all pediatric patients are living, outcomes were universally poor in adults with progression to death in all (median survival 17.1 months, range 6.6–30.3). In conclusion, despite grade I histology, all three adult NF1 patients with progressive extra-optic PAs suffered an aggressive clinical course which was not seen in pediatric patients. Clinicians should be aware of this clinico-histologic discrepancy when counseling and managing adult NF1 patients with progressive extra-optic PAs. PMID:26992069

  2. Histologically benign, clinically aggressive: Progressive non-optic pathway pilocytic astrocytomas in adults with NF1.

    PubMed

    Strowd, Roy E; Rodriguez, Fausto J; McLendon, Roger E; Vredenburgh, James J; Chance, Aaron B; Jallo, George; Olivi, Alessandro; Ahn, Edward S; Blakeley, Jaishri O

    2016-06-01

    Although optic pathway gliomas are the most common brain tumors associated with neurofibromatosis type 1 (NF1), extra-optic gliomas occur and may behave more aggressively with outcomes that differ by age. A retrospective case-control study was designed to describe the clinical course of adult NF1 patients with progressive extra-optic pilocytic astrocytomas (PAs) and compare to a pediatric cohort. Data for patients treated at the Johns Hopkins Comprehensive Neurofibromatosis Center from 2003 to 2013 were reviewed to identify cases (adults, age >18) and controls (pediatric, age <18) with clinically or radiographically progressive extra-optic PAs. Demographic, clinical, histologic, and radiographic data were collected. Three adult NF1 cases and four pediatric NF1 controls were identified. Mean age was 32.3 ± 9.5 years, 66% male (cases); 12.8 ± 4.2 years, 100% male (controls). Symptomatic progression occurred in two-of-three adults (67%) while the majority of pediatric patients presented with isolated radiographic progression (n = 3, 75%). Onset tended to be more rapid in adults (4 ± 1 vs. 14 ± 8.3 months, P = 0.10). Subtotal resection was the treatment for all pediatric patients. Radiotherapy (n = 2), chemotherapy (n = 2), and targeted, biologic agents (n = 2) were administered in adults. Although all pediatric patients are living, outcomes were universally poor in adults with progression to death in all (median survival 17.1 months, range 6.6-30.3). In conclusion, despite grade I histology, all three adult NF1 patients with progressive extra-optic PAs suffered an aggressive clinical course which was not seen in pediatric patients. Clinicians should be aware of this clinico-histologic discrepancy when counseling and managing adult NF1 patients with progressive extra-optic PAs. © 2016 Wiley Periodicals, Inc. PMID:26992069

  3. [Multiple involvements of LRP-1 receptor in tumor progression].

    PubMed

    Langlois, B; Emonard, H; Martiny, L; Dedieu, S

    2009-01-01

    Extensive proteolytic remodeling processes constitute a critical step during tumor progression. The endocytic receptor low-density lipoprotein receptor-related protein-1 (LRP-1), by its function in the clearance of multiple extracellular proteases involved in metastatic spreading, has long been considered as a putative tumor suppressor. Moreover, the receptor is likely to control the peritumoral microenvironment by internalization of growth factors and matricial proteins and could therefore participate to the control of signaling events involved in survival and proliferation of cancer cells. Nevertheless, recent data lead to reconsider the initially attributed antitumor properties of LRP-1. A more complex model seems to emerge in which LRP-1 could constitute a sensor of pericellular environment and regulate the membrane proteome dynamics. By its control of focal adhesions composition and turn-over, regulation of the cytoskeleton organization and integrin endocytic recycling, LRP-1 appears as a crucial actor of the epithelial-mesenchymal transition, thereby reinforcing the aggressive phenotype of malignant cells. LRP-1 partitioning into rafts and association with tissue-type and tumor grade specific intracellular scaffold proteins appear crucial to determine its function in tumor progression. Those emerging aspects present numerous promising perspectives in oncology and allow envisaging the development of innovative strategies of control of tumor progression through the targeting of LRP-1. PMID:19233571

  4. Translational progress on tumor biomarkers

    PubMed Central

    Guo, Hongwei; Zhou, Xiaolin; Lu, Yi; Xie, Liye; Chen, Qian; Keller, Evan T; Liu, Qian; Zhou, Qinghua; Zhang, Jian

    2015-01-01

    There is an urgent need to apply basic research achievements to the clinic. In particular, mechanistic studies should be developed by bench researchers, depending upon clinical demands, in order to improve the survival and quality of life of cancer patients. To date, translational medicine has been addressed in cancer biology, particularly in the identification and characterization of novel tumor biomarkers. This review focuses on the recent achievements and clinical application prospects in tumor biomarkers based on translational medicine. PMID:26557902

  5. Three-Dimensional Breast Cancer Models Mimic Hallmarks of Size-Induced Tumor Progression.

    PubMed

    Singh, Manjulata; Mukundan, Shilpaa; Jaramillo, Maria; Oesterreich, Steffi; Sant, Shilpa

    2016-07-01

    Tumor size is strongly correlated with breast cancer metastasis and patient survival. Increased tumor size contributes to hypoxic and metabolic gradients in the solid tumor and to an aggressive tumor phenotype. Thus, it is important to develop three-dimensional (3D) breast tumor models that recapitulate size-induced microenvironmental changes and, consequently, natural tumor progression in real time without the use of artificial culture conditions or gene manipulations. Here, we developed size-controlled multicellular aggregates ("microtumors") of subtype-specific breast cancer cells by using non-adhesive polyethylene glycol dimethacrylate hydrogel microwells of defined sizes (150-600 μm). These 3D microtumor models faithfully represent size-induced microenvironmental changes, such as hypoxic gradients, cellular heterogeneity, and spatial distribution of necrotic/proliferating cells. These microtumors acquire hallmarks of tumor progression in the same cell lines within 6 days. Of note, large microtumors of hormone receptor-positive cells exhibited an aggressive phenotype characterized by collective cell migration and upregulation of mesenchymal markers at mRNA and protein level, which was not observed in small microtumors. Interestingly, triple-negative breast cancer (TNBC) cell lines did not show size-dependent upregulation of mesenchymal markers. In conclusion, size-controlled microtumor models successfully recapitulated clinically observed positive association between tumor size and aggressive phenotype in hormone receptor-positive breast cancer while maintaining clinically proven poor correlation of tumor size with aggressive phenotype in TNBC. Such clinically relevant 3D models generated under controlled experimental conditions can serve as precise preclinical models to study mechanisms involved in breast tumor progression as well as antitumor drug effects as a function of tumor progression. Cancer Res; 76(13); 3732-43. ©2016 AACR. PMID:27216179

  6. Chemokines in tumor development and progression

    SciTech Connect

    Mukaida, Naofumi; Baba, Tomohisa

    2012-01-15

    Chemokines were originally identified as mediators of the inflammatory process and regulators of leukocyte trafficking. Subsequent studies revealed their essential roles in leukocyte physiology and pathology. Moreover, chemokines have profound effects on other types of cells associated with the inflammatory response, such as endothelial cells and fibroblasts. Thus, chemokines are crucial for cancer-related inflammation, which can promote tumor development and progression. Increasing evidence points to the vital effects of several chemokines on the proliferative and invasive properties of tumor cells. The wide range of activities of chemokines in tumorigenesis highlights their roles in tumor development and progression.

  7. The WIP1 Oncogene Promotes Progression and Invasion of Aggressive Medulloblastoma Variants

    PubMed Central

    Buss, Meghan C.; Remke, Marc; Lee, Juhyun; Gandhi, Khanjan; Schniederjan, Matthew J.; Kool, Marcel; Northcott, Paul A.; Pfister, Stefan M.; Taylor, Michael D.; Castellino, Robert C.

    2014-01-01

    Recent studies suggest that medulloblastoma, the most common malignant brain tumor of childhood, is comprised of four disease variants. The WIP1 oncogene is overexpressed in Group 3 and 4 tumors, which contain medulloblastomas with the most aggressive clinical behavior. Our data demonstrate increased WIP1 expression in metastatic medulloblastomas, and inferior progression-free and overall survival of patients with WIP1 high-expressing medulloblastoma. Microarray analysis identified up-regulation of genes involved in tumor metastasis, including the G protein-coupled receptor CXCR4, in medulloblastoma cells with high WIP1 expression. Stimulation with the CXCR4 ligand SDF1ααactivated PI-3 kinase signaling, and promoted growth and invasion of WIP1 high-expressing medulloblastoma cells in a p53-dependent manner. When xenografted into the cerebellum of immunodeficient mice, medulloblastoma cells with stable or endogenous high WIP1 expression exhibited strong expression of CXCR4 and activated AKT in primary and invasive tumor cells. WIP1 or CXCR4 knock-down inhibited medulloblastoma growth and invasion. WIP1 knock-down also improved the survival of mice xenografted with WIP1 high-expressing medulloblastoma cells. WIP1 knock-down inhibited cell surface localization of CXCR4 by suppressing expression of the G protein receptor kinase 5, GRK5. Restoration of wild-type GRK5 promoted Ser339 phosphorylation of CXCR4 and inhibited the growth of WIP1-stable medulloblastoma cells. Conversely, GRK5 knock-down inhibited Ser339 phosphorylation of CXCR4, increased cell surface localization of CXCR4, and promoted the growth of medulloblastoma cells with low WIP1 expression. These results demonstrate cross-talk among WIP1, CXCR4, and GRK5, which may be important for the aggressive phenotype of a subclass of medulloblastomas in children. PMID:24632620

  8. Primary vertebral tumors: a review of epidemiologic, histological and imaging findings, part II: locally aggressive and malignant tumors.

    PubMed

    Ropper, Alexander E; Cahill, Kevin S; Hanna, John W; McCarthy, Edward F; Gokaslan, Ziya L; Chi, John H

    2012-01-01

    This second part of a comprehensive review of primary vertebral tumors focuses on locally aggressive and malignant tumors. As discussed in the earlier part of the review, both benign and malignant types of these tumors affect the adult and the pediatric population, and an understanding of their subtleties may increase their effective resection. In this review, we discuss the epidemiologic, histological, and imaging features of the most common locally aggressive primary vertebral tumors (chordoma and giant-cell tumor) and malignant tumors (chondrosarcoma, Ewing sarcoma, multiple myeloma or plasmacytoma, and osteosarcoma). The figures used for illustration are from operative patients of the senior authors (Z.L.G. and J.H.C.). Taken together, parts 1 and 2 of this article provide a thorough and illustrative review of primary vertebral tumors. PMID:21768918

  9. Computer-Aided Image Analysis and Fractal Synthesis in the Quantitative Evaluation of Tumor Aggressiveness in Prostate Carcinomas

    PubMed Central

    Waliszewski, Przemyslaw

    2016-01-01

    The subjective evaluation of tumor aggressiveness is a cornerstone of the contemporary tumor pathology. A large intra- and interobserver variability is a known limiting factor of this approach. This fundamental weakness influences the statistical deterministic models of progression risk assessment. It is unlikely that the recent modification of tumor grading according to Gleason criteria for prostate carcinoma will cause a qualitative change and improve significantly the accuracy. The Gleason system does not allow the identification of low aggressive carcinomas by some precise criteria. The ontological dichotomy implies the application of an objective, quantitative approach for the evaluation of tumor aggressiveness as an alternative. That novel approach must be developed and validated in a manner that is independent of the results of any subjective evaluation. For example, computer-aided image analysis can provide information about geometry of the spatial distribution of cancer cell nuclei. A series of the interrelated complexity measures characterizes unequivocally the complex tumor images. Using those measures, carcinomas can be classified into the classes of equivalence and compared with each other. Furthermore, those measures define the quantitative criteria for the identification of low- and high-aggressive prostate carcinomas, the information that the subjective approach is not able to provide. The co-application of those complexity measures in cluster analysis leads to the conclusion that either the subjective or objective classification of tumor aggressiveness for prostate carcinomas should comprise maximal three grades (or classes). Finally, this set of the global fractal dimensions enables a look into dynamics of the underlying cellular system of interacting cells and the reconstruction of the temporal-spatial attractor based on the Taken’s embedding theorem. Both computer-aided image analysis and the subsequent fractal synthesis could be performed

  10. Computer-Aided Image Analysis and Fractal Synthesis in the Quantitative Evaluation of Tumor Aggressiveness in Prostate Carcinomas.

    PubMed

    Waliszewski, Przemyslaw

    2016-01-01

    The subjective evaluation of tumor aggressiveness is a cornerstone of the contemporary tumor pathology. A large intra- and interobserver variability is a known limiting factor of this approach. This fundamental weakness influences the statistical deterministic models of progression risk assessment. It is unlikely that the recent modification of tumor grading according to Gleason criteria for prostate carcinoma will cause a qualitative change and improve significantly the accuracy. The Gleason system does not allow the identification of low aggressive carcinomas by some precise criteria. The ontological dichotomy implies the application of an objective, quantitative approach for the evaluation of tumor aggressiveness as an alternative. That novel approach must be developed and validated in a manner that is independent of the results of any subjective evaluation. For example, computer-aided image analysis can provide information about geometry of the spatial distribution of cancer cell nuclei. A series of the interrelated complexity measures characterizes unequivocally the complex tumor images. Using those measures, carcinomas can be classified into the classes of equivalence and compared with each other. Furthermore, those measures define the quantitative criteria for the identification of low- and high-aggressive prostate carcinomas, the information that the subjective approach is not able to provide. The co-application of those complexity measures in cluster analysis leads to the conclusion that either the subjective or objective classification of tumor aggressiveness for prostate carcinomas should comprise maximal three grades (or classes). Finally, this set of the global fractal dimensions enables a look into dynamics of the underlying cellular system of interacting cells and the reconstruction of the temporal-spatial attractor based on the Taken's embedding theorem. Both computer-aided image analysis and the subsequent fractal synthesis could be performed

  11. Are biomechanical changes necessary for tumor progression?

    NASA Astrophysics Data System (ADS)

    Kas, Josef A.; Fritsch, Anatol; Kiessling, Tobias; Nnetu, David K.; Pawlizak, Steve; Wetzel, Franziska; Zink, Mareike

    2011-03-01

    With an increasing knowledge in tumor biology an overwhelming complexity becomes obvious which roots in the diversity of tumors and their heterogeneous molecular composition. Nevertheless in all solid tumors malignant neoplasia, i.e. uncontrolled growth, invasion of adjacent tissues, and metastasis, occurs. Physics sheds some new light on cancer by approaching this problem from a functional, materials perspective. Recent results indicate that all three pathomechanisms require changes in the active and passive cellular biomechanics. Malignant transformation causes cell softening for small deformations which correlates with an increased rate of proliferation and faster cell migration. The tumor cell's ability to strain harden permits tumor growth against a rigid tissue environment. A highly mechanosensitive, enhanced cell contractility is a prerequisite that tumor cells can cross its tumor boundaries and that this cells can migrate through the extracellular matrix. Insights into the biomechanical changes during tumor progression may lead to selective treatments by altering cell mechanics. Such drugs would not cure by killing cancer cells, but slow down tumor progression with only mild side effects and thus may be an option for older and frail patients.

  12. Fragmented sleep accelerates tumor growth and progression through recruitment of tumor-associated macrophages and TLR4 signaling

    PubMed Central

    Hakim, Fahed; Wang, Yang; Zhang, Shelley XL; Zheng, Jiamao; Yolcu, Esma S.; Carreras, Alba; Khlayfa, Abdelnaby; Shirwan, Haval; Almendros, Isaac; Gozal, David

    2014-01-01

    Fragmented sleep (SF) is a highly prevalent condition and a hallmark of sleep apnea, a condition that has been associated with increased cancer incidence and mortality. In this study, we examined the hypothesis that SF promotes tumor growth and progression through pro-inflammatory TLR4 signaling. In the design, we compared mice that were exposed to SF one week before engraftment of syngeneic TC1 or LL3 tumor cells and tumor analysis three weeks later. We also compared host contributions through the use of mice genetically deficient in TLR4 or its effector molecules MYD88 or TRIF. We found that SF enhanced tumor size and weight compared to control mice. Increased invasiveness was apparent in SF tumors, which penetrated the tumor capsule into surrounding tissues including adjacent muscle. Tumor-associated macrophages (TAM) were more numerous in SF tumors where they were distributed in a relatively closer proximity to the tumor capsule, compared to control mice. Although tumors were generally smaller in both MYD88−/− and TRIF−/− hosts, the more aggressive features produced by SF persisted. In contrast, these more aggressive features produced by SF were abolished completely in TLR4−/− mice. Our findings offer mechanistic insights into how sleep perturbations can accelerate tumor growth and invasiveness through TAM recruitment and TLR4 signaling pathways. PMID:24448240

  13. Chemokines in tumor progression and metastasis.

    PubMed

    Sarvaiya, Purvaba J; Guo, Donna; Ulasov, Ilya; Gabikian, Patrik; Lesniak, Maciej S

    2013-12-01

    Chemokines play a vital role in tumor progression and metastasis. Chemokines are involved in the growth of many cancers including breast cancer, ovarian cancer, pancreatic cancer, melanoma, lung cancer, gastric cancer, acute lymphoblastic leukemia, colon cancer, non-small lung cancer, non-hodgkin's lymphoma, etc. The expression of chemokines and their receptors is altered in many malignancies and leads to aberrant chemokine receptor signaling. This review focuses on the role of chemokines in key processes that facilitate tumor progression including proliferation, senescence, angiogenesis, epithelial mesenchymal transition, immune evasion and metastasis. PMID:24259307

  14. Chemokines in tumor progression and metastasis

    PubMed Central

    Sarvaiya, Purvaba J.; Guo, Donna; Ulasov, Ilya; Gabikian, Patrik; Lesniak, Maciej S.

    2013-01-01

    Chemokines play a vital role in tumor progression and metastasis. Chemokines are involved in the growth of many cancers including breast cancer, ovarian cancer, pancreatic cancer, melanoma, lung cancer, gastric cancer, acute lymphoblastic leukemia, colon cancer, non-small lung cancer and non-hodgkin's lymphoma among many others. The expression of chemokines and their receptors is altered in many malignancies and leads to aberrant chemokine receptor signaling. This review focuses on the role of chemokines in key processes that facilitate tumor progression including proliferation, senescence, angiogenesis, epithelial mesenchymal transition, immune evasion and metastasis. PMID:24259307

  15. Progressive Muscle Relaxation and Aggression among Elementary Students with Emotional or Behavioral Disorders.

    ERIC Educational Resources Information Center

    Lopata, Christopher

    2003-01-01

    A study evaluated the effectiveness of progressive muscle relaxation (PMR) as a proactive single-component aggression-reduction intervention for 24 students (ages 6- 9) classified as having emotional disabilities in a day school/treatment program. Students also had histories of aggressive behavior. Results supported PMR as a proactive short-term…

  16. P08: Somatostatin analogs plus prednisone in aggressive histotype and advanced stage of thymic epithelial tumors

    PubMed Central

    Ottaviano, Margaret; Damiano, Vincenzo; Nappi, Lucia; Rescigno, Pasquale; Marino, Mirella; Del Vecchio, Silvana; Tucci, Irene; von Arx, Claudia; Palumbo, Giuliano; Palmieri, Giovannella

    2015-01-01

    Background Thymic epithelial tumors (TETs) are rare neoplasms characterized by histological variability and different expression at the molecular level. Several biological agents have been evaluated in TETs in small phase II trials. Efficacy of octreotide/lanreotide with or without prednisone in TETs OctreoScan positive has been widely demonstrated in thymoma, but no clearly in thymic carcinoma. Methods Twelve patients (five men, seven women; median age 47 years; range, 27–70 years) with advanced stage disease according to the Masaoka-Koga staging system (seven with IVa stage; five with IVb stage), and aggressive histotype according to WHO classification, revised by central review (two B2/B3; five B3; one B3/thymic carcinoma; four thymic carcinoma) were enrolled in this monocentric referral study. All the patients showed a progressive disease according to RECIST 1.1 criteria to previous conventional chemotherapeutic regimens platinum or not platinum-based. All the patients performed OctreoScan. The schedule includes administration of long-acting analog octreotide (30 mg/every 28 days intramuscularly) plus prednisone 0.2 mg/kg/day until progression of disease was documented. Overall response rate and toxicity were evaluated. Results The median time to progression was 6 months (range, 3–24 months), the overall response rate was 74.9%, particularly three patients (25%) obtained stable disease; four patients (33.3%) partial response; two patients (16.6%) complete response; three patients (25%) progression disease. One patient with Good Syndrome interrupted treatment after 6 months for infection disease. One patient has been lost to follow-up after 24 months of treatment. One patient died after progression disease for PRCA. Treatment was generally well tolerated with acceptable toxicity: no symptomatic cholelithiasis (one patient), grade 1 diarrhea (two patients) hyperglycemia (one patient). One patient with thymic carcinoma and IVB stage had PS improvement from 2

  17. MIB-1 labeling indices in benign, aggressive, and malignant meningiomas: a study of 90 tumors.

    PubMed

    Abramovich, C M; Prayson, R A

    1998-12-01

    Predicting tumor behavior in meningiomas based on histology alone has been problematic. This study retrospectively compares histology and MIB-1 (cell proliferation marker) labeling indices (LI) in benign, aggressive, and malignant meningiomas. Six histological features, including mitoses, necrosis, loss of pattern, hypervascularity/hemosiderin deposition, prominent nucleoli, and nuclear pleomorphism, were compared in 90 meningiomas (Fisher's exact test). Tumors with two or more of the above features were designated as aggressive meningiomas. Malignant meningiomas were characterized by brain invasion or metastasis. The MIB-1 LIs (% positive tumor cell nuclei) were compared between the three groups (Kruskal-Wallis test, Wilcoxon two-sample test). Of the benign meningiomas (n=37; mean age, 54 years), 41% had one of the six histological features, with nuclear pleomorphism (n=10) being the most frequent. The aggressive tumors (n=29; mean age, 61 years) were characterized by nuclear pleomorphism (n=28), mitoses (n=20), necrosis (n=16), loss of pattern (n=16), prominent nucleoli (n=6), and hypervascularity/hemosiderin deposition (n=5). Malignant tumors (n=24; mean age, 59 years) were characterized by nuclear pleomorphism (n=22), mitoses (n=21), loss of pattern (n=21), necrosis (n=21), nucleoli (n=17), and hypervascularity/hemosiderin deposition (n=3). Significant differences were found between the aggressive and malignant groups with regard to loss of pattern, necrosis, and nucleoli (P=.0043, .011, and .00029, respectively). Mean MIB-1 LIs for the benign, aggressive, and malignant groups were 1.0% (range, 0 to 5.5%),5.5% (range, 0.1 to 32.5%), and 12.0% (range, 0.3 to 32.5%), respectively. Differences in the mean MIB-1 LI between groups were statistically significant, with P values of <.0001 (benign v aggressive) and .0012 (aggressive v malignant). Mean MIB-1 LIs for recurrent versus nonrecurrent tumors were 7.1% (range, 0 to 32.5%) versus 3.8% (range, 0 to 20.9%) (P=.32

  18. Mitochondrial oncobioenergetic index: A potential biomarker to predict progression from indolent to aggressive prostate cancer

    PubMed Central

    Vayalil, Praveen K.; Landar, Aimee

    2015-01-01

    Mitochondrial function is influenced by alterations in oncogenes and tumor suppressor genes and changes in the microenvironment occurring during tumorigenesis. Therefore, we hypothesized that mitochondrial function will be stably and dynamically altered at each stage of the prostate tumor development. We tested this hypothesis in RWPE-1 cells and its tumorigenic clones with progressive malignant characteristics (RWPE-1 < WPE-NA22 < WPE-NB14 < WPE-NB11 < WPE-NB26) using high-throughput respirometry. Our studies demonstrate that mitochondrial content do not change with increasing malignancy. In premalignant cells (WPE-NA22 and WPE-NB14), OXPHOS is elevated in presence of glucose or glutamine alone or in combination compared to RWPE-1 cells and decreases with increasing malignancy. Glutamine maintained higher OXPHOS than glucose and suggests that it may be an important substrate for the growth and proliferation of prostate epithelial cells. Glycolysis significantly increases with malignancy and follow a classical Warburg phenomenon. Fatty acid oxidation (FAO) is significantly lower in tumorigenic clones and invasive WPE-NB26 does not utilize FAO at all. In this paper, we introduce for the first time the mitochondrial oncobioenergetic index (MOBI), a mathematical representation of oncobioenergetic profile of a cancer cell, which increases significantly upon transformation into localized premalignant form and rapidly falls below the normal as they become aggressive in prostate tumorigenesis. We have validated this in five prostate cancer cell lines and MOBI appears to be not related to androgen dependence or mitochondrial content, but rather dependent on the stage of the cancer. Altogether, we propose that MOBI could be a potential biomarker to distinguish aggressive cancer from that of indolent disease. PMID:26515588

  19. Microenvironmental regulation of tumor progression and metastasis

    PubMed Central

    Quail, DF; Joyce, JA

    2014-01-01

    Cancers develop in complex tissue environments, which they depend upon for sustained growth, invasion and metastasis. Unlike tumor cells, stromal cell types within the tumor microenvironment (TME) are genetically stable, and thus represent an attractive therapeutic target with reduced risk of resistance and tumor recurrence. However, specifically disrupting the pro-tumorigenic TME is a challenging undertaking, as the TME has diverse capacities to induce both beneficial and adverse consequences for tumorigenesis. Furthermore, many studies have shown that the microenvironment is capable of normalizing tumor cells, suggesting that reeducation of stromal cells, rather than targeted ablation per se, may be an effective strategy for treating cancer. Here, we will discuss the paradoxical roles of the TME during specific stages of cancer progression and metastasis, and recent therapeutic attempts to re-educate stromal cells within the TME to have anti-tumorigenic effects. PMID:24202395

  20. Are biomechanical changes necessary for tumor progression?

    NASA Astrophysics Data System (ADS)

    Kas, Josef A.

    2014-03-01

    Already the Roman Celsus recognized rigid tissue as characteristic for solid tumors. Conversely, changes towards a weaker cytoskeleton have been described as a feature of cancer cells since the early days of tumor biology. It remains unclear if a carcinoma's rigid signature stems from more inflexible cells or is caused by the stroma. Despite that the importance of cell biomechanics for tumor progression becomes more and more evident the chicken-and-egg problem to what extent cancer cells already change their mechanical properties within the solid tumor in order to transgress its boundary or mechanical changes are induced by the microenvironment when the cell has left the tumor has been discussed highly controversial. Comprehensive clinical biomechanical measurements only exist from tumor tissue without the possibility to identify individual cells or from individual cancer cells from pleural effusions. Since the biomechanical properties of cells in carcinomas remain unknown measurements on individual cells that directly stem out of primary tumor samples are required, which we have conducted. We found in cervix and mammary carcinomas a distinctive increase of softer cells as well as contractile cells. A soft and contractile cell is like a strong elastic rope. The cell can generate a strong tensile tension to pull its self along and is soft against compression to avoid jamming.

  1. Fructose as a carbon source induces an aggressive phenotype in MDA-MB-468 breast tumor cells

    PubMed Central

    MONZAVI-KARBASSI, BEHJATOLAH; HINE, R. JEAN; STANLEY, JOSEPH S.; RAMANI, VISHNU PRAKASH; CARCEL-TRULLOLS, JAIME; WHITEHEAD, TRACY L.; KELLY, THOMAS; SIEGEL, ERIC R.; ARTAUD, CECILE; SHAAF, SAEID; SAHA, RINKU; JOUSHEGHANY, FARIBA; HENRY-TILLMAN, RONDA; KIEBER-EMMONS, THOMAS

    2012-01-01

    Aberrant glycosylation is a universal feature of cancer cells, and certain glycan structures are well-known markers for tumor progression. Availability and composition of sugars in the microenvironment may affect cell glycosylation. Recent studies of human breast tumor cell lines indicate their ability to take up and utilize fructose. Here we tested the hypothesis that adding fructose to culture as a carbon source induces phenotypic changes in cultured human breast tumor cells that are associated with metastatic disease. MDA-MB-468 cells were adapted to culture media in which fructose was substituted for glucose. Changes in cell surface glycan structures, expression of genes related to glycan assembly, cytoskeleton F-actin, migration, adhesion and invasion were determined. Cells cultured in fructose expressed distinct cell-surface glycans. The addition of fructose affected sialylation and fucosylation patterns. Fructose feeding also increased binding of leukoagglutinating Phaseolus vulgaris isolectin, suggesting a possible rise in expression of branching β-1, 6 GlcNAc structures. Rhodamine-phalloidin staining revealed an altered F-actin cytoskeletal system. Fructose accelerated cellular migration and increased invasion. These data suggest that changing the carbon source of the less aggressive MDA-MB-468 cell line induced characteristics associated with more aggressive phenotypes. These data could be of fundamental importance due to the markedly increased consumption of sweeteners containing free fructose in recent years, as they suggest that the presence of fructose in nutritional micro-environment of tumor cells may negatively affect the outcome for some breast cancer patients. PMID:20664930

  2. Fructose as a carbon source induces an aggressive phenotype in MDA-MB-468 breast tumor cells.

    PubMed

    Monzavi-Karbassi, Behjatolah; Hine, R Jean; Stanley, Joseph S; Ramani, Vishnu Prakash; Carcel-Trullols, Jaime; Whitehead, Tracy L; Kelly, Thomas; Siegel, Eric R; Artaud, Cecile; Shaaf, Saeid; Saha, Rinku; Jousheghany, Fariba; Henry-Tillman, Ronda; Kieber-Emmons, Thomas

    2010-09-01

    Aberrant glycosylation is a universal feature of cancer cells, and certain glycan structures are well-known markers for tumor progression. Availability and composition of sugars in the microenvironment may affect cell glycosylation. Recent studies of human breast tumor cell lines indicate their ability to take up and utilize fructose. Here we tested the hypothesis that adding fructose to culture as a carbon source induces phenotypic changes in cultured human breast tumor cells that are associated with metastatic disease. MDA-MB-468 cells were adapted to culture media in which fructose was substituted for glucose. Changes in cell surface glycan structures, expression of genes related to glycan assembly, cytoskeleton F-actin, migration, adhesion and invasion were determined. Cells cultured in fructose expressed distinct cell-surface glycans. The addition of fructose affected sialylation and fucosylation patterns. Fructose feeding also increased binding of leukoagglutinating Phaseolus vulgaris isolectin, suggesting a possible rise in expression of branching beta-1, 6 GlcNAc structures. Rhodamine-phalloidin staining revealed an altered F-actin cytoskeletal system. Fructose accelerated cellular migration and increased invasion. These data suggest that changing the carbon source of the less aggressive MDA-MB-468 cell line induced characteristics associated with more aggressive phenotypes. These data could be of fundamental importance due to the markedly increased consumption of sweeteners containing free fructose in recent years, as they suggest that the presence of fructose in nutritional microenvironment of tumor cells may negatively affect the outcome for some breast cancer patients. PMID:20664930

  3. Uterine adenolipoleiomyoma: a tumor with potential of aggressive behavior.

    PubMed

    Shaco-Levy, Ruthy; Piura, Benjamin

    2008-04-01

    An unusual uterine adenolipoleiomyoma forming intramural and subserosal masses and recurring within 16 months in the form of huge coalescent uterine masses is described. Histology showed the mass to be composed of benign-appearing smooth muscle, mature adipose tissue, and bland endocervical-type glands. The recurrent adenolipoleiomyoma contained, in addition, benign-appearing endometrial-type glands and stroma and showed small foci of atypically proliferating endocervical-type epithelium. This is the fourth report of adenolipoleiomyoma within the uterus, the second with an intramural location, and the first with an aggressive behavior in the form of massive local recurrence. PMID:18317215

  4. Kidney cancer progression linked to shifts in tumor metabolism

    Cancer.gov

    Investigators in The Cancer Genome Atlas Research Network have uncovered a connection between how tumor cells use energy from metabolic processes and the aggressiveness of the most common form of kidney cancer, clear cell renal cell carcinoma.

  5. Aggressive and impulsive behavior in Alzheimer’s disease and progression of dementia

    PubMed Central

    Bidzan, Leszek; Bidzan, Mariola; Pąchalska, Maria

    2012-01-01

    Summary Background The symptoms of Alzheimer’s disease (AD) are numerous, including worsening of mood, psychotic symptoms, aggressive and impulsive behaviours, and many others. It is generally assumed that there exists a relationship between the severity of dementia and aggressive symptoms. The aim of this study was to assess the relationship between aggressive and impulsive behaviours and cognitive function disorders in AD patients. Material/Methods Forty-eight AD patients living in a nursing home were included in the research group on the basis of NINCDS/ADRDA criteria. The subjects underwent two years of naturalistic observation. The intensity of agitation and aggressive behaviours was assessed on the basis of the Cohen-Mansfield Agitation Inventory (CMAI). The Alzheimer’s Disease Assessment Scale Cog (ADAS-cog) was used to assess cognitive function. Pharmacotherapy administered during the observation period was also taken into account. Results Thirty-one patients completed the two year long observation. Individuals with more severe cognitive deficiencies demonstrated a greater intensity of aggressive and impulsive behaviours, as assessed using the CMAI scale. Aggression escalated together with the development of dementia disorders. The intensity of dementia disorders was most significantly connected with physical agitation and verbal aggression. The use of neuroleptics and mood stabilisers decreased the progression of aggressive and impulsive behaviours. Conclusions There is a relationship between cognitive functioning disorders and the intensification of aggressive and impulsive behaviours. More severe forms of dementia are connected with greater intensification of aggressive and impulsive behaviours as the disease progresses. Periodical administration of pharmacotherapy may reduce the development of aggressive behaviours. PMID:22367129

  6. Exome and deep sequencing of clinically aggressive neuroblastoma reveal somatic mutations that affect key pathways involved in cancer progression.

    PubMed

    Lasorsa, Vito Alessandro; Formicola, Daniela; Pignataro, Piero; Cimmino, Flora; Calabrese, Francesco Maria; Mora, Jaume; Esposito, Maria Rosaria; Pantile, Marcella; Zanon, Carlo; De Mariano, Marilena; Longo, Luca; Hogarty, Michael D; de Torres, Carmen; Tonini, Gian Paolo; Iolascon, Achille; Capasso, Mario

    2016-04-19

    The spectrum of somatic mutation of the most aggressive forms of neuroblastoma is not completely determined. We sought to identify potential cancer drivers in clinically aggressive neuroblastoma.Whole exome sequencing was conducted on 17 germline and tumor DNA samples from high-risk patients with adverse events within 36 months from diagnosis (HR-Event3) to identify somatic mutations and deep targeted sequencing of 134 genes selected from the initial screening in additional 48 germline and tumor pairs (62.5% HR-Event3 and high-risk patients), 17 HR-Event3 tumors and 17 human-derived neuroblastoma cell lines.We revealed 22 significantly mutated genes, many of which implicated in cancer progression. Fifteen genes (68.2%) were highly expressed in neuroblastoma supporting their involvement in the disease. CHD9, a cancer driver gene, was the most significantly altered (4.0% of cases) after ALK.Other genes (PTK2, NAV3, NAV1, FZD1 and ATRX), expressed in neuroblastoma and involved in cell invasion and migration were mutated at frequency ranged from 4% to 2%.Focal adhesion and regulation of actin cytoskeleton pathways, were frequently disrupted (14.1% of cases) thus suggesting potential novel therapeutic strategies to prevent disease progression.Notably BARD1, CHEK2 and AXIN2 were enriched in rare, potentially pathogenic, germline variants.In summary, whole exome and deep targeted sequencing identified novel cancer genes of clinically aggressive neuroblastoma. Our analyses show pathway-level implications of infrequently mutated genes in leading neuroblastoma progression. PMID:27009842

  7. Exome and deep sequencing of clinically aggressive neuroblastoma reveal somatic mutations that affect key pathways involved in cancer progression

    PubMed Central

    Lasorsa, Vito Alessandro; Formicola, Daniela; Pignataro, Piero; Cimmino, Flora; Calabrese, Francesco Maria; Mora, Jaume; Esposito, Maria Rosaria; Pantile, Marcella; Zanon, Carlo; De Mariano, Marilena; Longo, Luca; Hogarty, Michael D.; de Torres, Carmen; Tonini, Gian Paolo; Iolascon, Achille; Capasso, Mario

    2016-01-01

    The spectrum of somatic mutation of the most aggressive forms of neuroblastoma is not completely determined. We sought to identify potential cancer drivers in clinically aggressive neuroblastoma. Whole exome sequencing was conducted on 17 germline and tumor DNA samples from high-risk patients with adverse events within 36 months from diagnosis (HR-Event3) to identify somatic mutations and deep targeted sequencing of 134 genes selected from the initial screening in additional 48 germline and tumor pairs (62.5% HR-Event3 and high-risk patients), 17 HR-Event3 tumors and 17 human-derived neuroblastoma cell lines. We revealed 22 significantly mutated genes, many of which implicated in cancer progression. Fifteen genes (68.2%) were highly expressed in neuroblastoma supporting their involvement in the disease. CHD9, a cancer driver gene, was the most significantly altered (4.0% of cases) after ALK. Other genes (PTK2, NAV3, NAV1, FZD1 and ATRX), expressed in neuroblastoma and involved in cell invasion and migration were mutated at frequency ranged from 4% to 2%. Focal adhesion and regulation of actin cytoskeleton pathways, were frequently disrupted (14.1% of cases) thus suggesting potential novel therapeutic strategies to prevent disease progression. Notably BARD1, CHEK2 and AXIN2 were enriched in rare, potentially pathogenic, germline variants. In summary, whole exome and deep targeted sequencing identified novel cancer genes of clinically aggressive neuroblastoma. Our analyses show pathway-level implications of infrequently mutated genes in leading neuroblastoma progression. PMID:27009842

  8. Mitochondrial Redox Signaling and Tumor Progression

    PubMed Central

    Chen, Yuxin; Zhang, Haiqing; Zhou, Huanjiao Jenny; Ji, Weidong; Min, Wang

    2016-01-01

    Cancer cell can reprogram their energy production by switching mitochondrial oxidative phosphorylation to glycolysis. However, mitochondria play multiple roles in cancer cells, including redox regulation, reactive oxygen species (ROS) generation, and apoptotic signaling. Moreover, these mitochondrial roles are integrated via multiple interconnected metabolic and redox sensitive pathways. Interestingly, mitochondrial redox proteins biphasically regulate tumor progression depending on cellular ROS levels. Low level of ROS functions as signaling messengers promoting cancer cell proliferation and cancer invasion. However, anti-cancer drug-initiated stress signaling could induce excessive ROS, which is detrimental to cancer cells. Mitochondrial redox proteins could scavenger basal ROS and function as “tumor suppressors” or prevent excessive ROS to act as “tumor promoter”. Paradoxically, excessive ROS often also induce DNA mutations and/or promotes tumor metastasis at various stages of cancer progression. Targeting redox-sensitive pathways and transcriptional factors in the appropriate context offers great promise for cancer prevention and therapy. However, the therapeutics should be cancer-type and stage-dependent. PMID:27023612

  9. Identification of Genes Associated with Local Aggressiveness and Metastatic Behavior in Soft Tissue Tumors12

    PubMed Central

    Cunha, Isabela Werneck; Carvalho, Katia Candido; Martins, Waleska Keller; Marques, Sarah Martins; Muto, Nair Hideko; Falzoni, Roberto; Rocha, Rafael Malagoli; Aguiar, Samuel; Simoes, Ana C. Q.; Fahham, Lucas; Neves, Eduardo Jordão; Soares, Fernando Augusto; Reis, Luiz Fernando Lima

    2010-01-01

    Soft tissue tumors represent a group of neoplasia with different histologic and biological presentations varying from benign, locally confined to very aggressive and metastatic tumors. The molecular mechanisms responsible for such differences are still unknown. The understanding of these molecular alterations mechanism will be critical to discriminate patients who need systemic treatment from those that can be treated only locally and could also guide the development of new drugs' against this tumors. Using 102 tumor samples representing a large spectrum of these tumors, we performed expression profiling and defined differentially expression genes that are likely to be involved in tumors that are locally aggressive and in tumors with metastatic potential. We described a set of 12 genes (SNRPD3, MEGF9, SPTAN-1, AFAP1L2, ENDOD1, SERPIN5, ZWINTAS, TOP2A, UBE2C, ABCF1, MCM2, and ARL6IP5) showing opposite expression when these two conditions were compared. These genes are mainly related to cell-cell and cell-extracellular matrix interactions and cell proliferation and might represent helpful tools for a more precise classification and diagnosis as well as potential drug targets. PMID:20165692

  10. Aggressive Calcifying Epithelial Odontogenic Tumor of the Maxillary Sinus with Extraosseous Oral Mucosal Involvement: A Case Report

    PubMed Central

    Rani, Vidya; Masthan, Mahaboob Kadar; Aravindha, Babu; Leena, Sankari

    2016-01-01

    Calcifying epithelial odontogenic tumors are benign odontogenic neoplasms whose occurrence in the maxillary sinus is rare. Maxillary tumors tend to be locally aggressive and may rapidly involve the surrounding vital structures. We report a case of a large calcifying epithelial odontogenic tumor of the maxilla, involving the maxillary sinus in a 48-year-old woman. The tumor was largely intraosseous. In the canine and first premolar regions, the loss of bone could be palpated but the oral mucosa appeared normal. Histologically, the tumor tissue could be seen in the connective tissue below the oral epithelium. The most significant finding was the presence of an intraosseous tumor with an extraosseous involvement in a single tumor, indicating aggressive behavior and warranting aggressive treatment. In this article, we discuss the rare presentation of the tumor and its radiological appearance and histological features. We also highlight the importance of a detailed histopathological examination of the excised specimen. PMID:26989286

  11. Aggressive Calcifying Epithelial Odontogenic Tumor of the Maxillary Sinus with Extraosseous Oral Mucosal Involvement: A Case Report.

    PubMed

    Rani, Vidya; Masthan, Mahaboob Kadar; Aravindha, Babu; Leena, Sankari

    2016-03-01

    Calcifying epithelial odontogenic tumors are benign odontogenic neoplasms whose occurrence in the maxillary sinus is rare. Maxillary tumors tend to be locally aggressive and may rapidly involve the surrounding vital structures. We report a case of a large calcifying epithelial odontogenic tumor of the maxilla, involving the maxillary sinus in a 48-year-old woman. The tumor was largely intraosseous. In the canine and first premolar regions, the loss of bone could be palpated but the oral mucosa appeared normal. Histologically, the tumor tissue could be seen in the connective tissue below the oral epithelium. The most significant finding was the presence of an intraosseous tumor with an extraosseous involvement in a single tumor, indicating aggressive behavior and warranting aggressive treatment. In this article, we discuss the rare presentation of the tumor and its radiological appearance and histological features. We also highlight the importance of a detailed histopathological examination of the excised specimen. PMID:26989286

  12. IL17 Promotes Mammary Tumor Progression by Changing the Behavior of Tumor Cells and Eliciting Tumorigenic Neutrophils Recruitment.

    PubMed

    Benevides, Luciana; da Fonseca, Denise Morais; Donate, Paula Barbim; Tiezzi, Daniel Guimarães; De Carvalho, Daniel D; de Andrade, Jurandyr M; Martins, Gislaine A; Silva, João S

    2015-09-15

    The aggressiveness of invasive ductal carcinoma (IDC) of the breast is associated with increased IL17 levels. Studying the role of IL17 in invasive breast tumor pathogenesis, we found that metastatic primary tumor-infiltrating T lymphocytes produced elevated levels of IL17, whereas IL17 neutralization inhibited tumor growth and prevented the migration of neutrophils and tumor cells to secondary disease sites. Tumorigenic neutrophils promote disease progression, producing CXCL1, MMP9, VEGF, and TNFα, and their depletion suppressed tumor growth. IL17A also induced IL6 and CCL20 production in metastatic tumor cells, favoring the recruitment and differentiation of Th17. In addition, IL17A changed the gene-expression profile and the behavior of nonmetastatic tumor cells, causing tumor growth in vivo, confirming the protumor role of IL17. Furthermore, high IL17 expression was associated with lower disease-free survival and worse prognosis in IDC patients. Thus, IL17 blockade represents an attractive approach for the control of invasive breast tumors. PMID:26208902

  13. Marsupialization of unicystic ameloblastoma: a conservative approach for aggressive odontogenic tumors.

    PubMed

    Dolanmaz, Dogan; Etoz, Osman A; Pampu, Alper; Kalayci, Abdullah; Gunhan, Omer

    2011-01-01

    Unicystic ameloblastoma (UA) is known as a distinct entity which has a less aggressive behavior when compared with conventional ameloblastoma. In this report, we have presented two cases of UAs, (of which one case showed a more aggressive behavior with mural invasion into the adjacent tissues and granular cell differentiation), both of which were successfully managed with enucleation following marsupialization. We aim to highlight how this method can be used for the successful management of such cases, rather than following more aggressive approaches. In both the cases, marsupialization was done for the UA lesions initially and follow-ups were maintained. When the tumor size had regressed on radiographic follow up, an enucleation procedure with ostectomy of the margins was carried out. Special importance was also given to the endodontic treatment of the teeth involved in the area of the lesion. The patients were free of the condition and did not show any signs of recurrence on radiographic follow-ups even after 30 months of the final procedure. Granular variant of UA is quite rare and had been considered to be more aggressive. Marsupialization of UA is an alternative treatment option of resection even for more aggressive variants, as long as the histological behavior of the lesion was carefully evaluated and strict radiographic follow-up is maintained. PMID:22406718

  14. Desmoplastic Fibroma of the Pediatric Cranium: An Aggressive Skull Tumor with Local Recurrence

    PubMed Central

    KOISO, Takao; MUROI, Ai; YAMAMOTO, Tetsuya; SAKAMOTO, Noriaki; MATSUMURA, Akira

    2016-01-01

    Cranial desmoplastic fibroma (DF) is extremely rare and only 20 cases, including only 7 pediatric cases, have been reported previously. We describe the first case of a child with cranial DF that increased in size over a short-term and recurred after resection. The aim of this case report was to discuss the clinical, radiological, and histological characteristics and optimal treatment for this rare and aggressive skull tumor. PMID:26804188

  15. A PAUF-neutralizing antibody targets both carcinoma and endothelial cells to impede pancreatic tumor progression and metastasis

    SciTech Connect

    Kim, Su Jin; Chang, Suhwan; Lee, Yangsoon; Kim, Na Young; Hwang, Yeonsil; Min, Hye Jin; Yoo, Kyung-Sook; Park, Eun Hye; Kim, Seokho; Chung, Young-Hwa; Park, Young Woo; Koh, Sang Seok

    2014-11-07

    Highlights: • PMAb83, a human monoclonal antibody against PAUF, impaired tumor progression in vivo. • PMAb83 attenuated aggressiveness of tumor cells and suppressed angiogenesis. • PMAb83 in combination with gemcitabine conferred improved survival of mouse model. - Abstract: Pancreatic adenocarcinoma up-regulated factor (PAUF) is expressed in pancreatic ductal adenocarcinoma (PDAC) and plays an important role in tumor progression and metastasis. Here we evaluate the anti-tumor efficacy of a human monoclonal antibody against PAUF, PMAb83, to provide a therapeutic intervention to treat the disease. PMAb83 reduced tumor growth and distant metastasis in orthotopically xenografted mice of human PDAC cells. PMAb83 treatment retarded proliferation along with weakened aggressiveness traits of the carcinoma cells. AKT/β-catenin signaling played a role in the carcinoma cell proliferation and the treated xenograft tumors exhibited reduced levels of β-catenin and cyclin D1. Moreover PMAb83 abrogated the PAUF-induced angiogenic responses of endothelial cells, reducing the density of CD31{sup +} vessels in the treated tumors. In combination with gemcitabine, PMAb83 conferred enhanced survival of xenografted mice by about twofold compared to gemcitabine alone. Taken together, our findings show that PMAb83 treatment decreases the aggressiveness of carcinoma cells and suppresses tumor vascularization, which culminates in mitigated tumor growth and metastasis with improved survival in PDAC mouse models.

  16. Biallelic BRCA2 Mutations Shape the Somatic Mutational Landscape of Aggressive Prostate Tumors.

    PubMed

    Decker, Brennan; Karyadi, Danielle M; Davis, Brian W; Karlins, Eric; Tillmans, Lori S; Stanford, Janet L; Thibodeau, Stephen N; Ostrander, Elaine A

    2016-05-01

    To identify clinically important molecular subtypes of prostate cancer (PCa), we characterized the somatic landscape of aggressive tumors via deep, whole-genome sequencing. In our discovery set of ten tumor/normal subject pairs with Gleason scores of 8-10 at diagnosis, coordinated analysis of germline and somatic variants, including single-nucleotide variants, indels, and structural variants, revealed biallelic BRCA2 disruptions in a subset of samples. Compared to the other samples, the PCa BRCA2-deficient tumors exhibited a complex and highly specific mutation signature, featuring a 2.88-fold increased somatic mutation rate, depletion of context-specific C>T substitutions, and an enrichment for deletions, especially those longer than 10 bp. We next performed a BRCA2 deficiency-targeted reanalysis of 150 metastatic PCa tumors, and each of the 18 BRCA2-mutated samples recapitulated the BRCA2 deficiency-associated mutation signature, underscoring the potent influence of these lesions on somatic mutagenesis and tumor evolution. Among all 21 individuals with BRCA2-deficient tumors, only about half carried deleterious germline alleles. Importantly, the somatic mutation signature in tumors with one germline and one somatic risk allele was indistinguishable from those with purely somatic mutations. Our observations clearly demonstrate that BRCA2-disrupted tumors represent a unique and clinically relevant molecular subtype of aggressive PCa, highlighting both the promise and utility of this mutation signature as a prognostic and treatment-selection biomarker. Further, any test designed to leverage BRCA2 status as a biomarker for PCa must consider both germline and somatic mutations and all types of deleterious mutations. PMID:27087322

  17. Extracellular Vesicles in Brain Tumor Progression.

    PubMed

    D'Asti, Esterina; Chennakrishnaiah, Shilpa; Lee, Tae Hoon; Rak, Janusz

    2016-04-01

    also impact the emission rates, types, cargo, and biogenesis of EVs, as reflected by preliminary analyses pointing to differences in profiles of EV-regulating genes (vesiculome) between molecular subtypes of glioblastoma, and in other brain tumors. Molecular regulators of vesiculation can also act as oncogenes. These intimate connections suggest the context-specific roles of different EV subsets in the progression of specific brain tumors. Advanced efforts are underway to capture these events through the use of EVs circulating in biofluids as biomarker reservoirs and to guide diagnostic and therapeutic decisions. PMID:26993504

  18. High CD49f expression is associated with osteosarcoma tumor progression: a study using patient-derived primary cell cultures

    PubMed Central

    Penfornis, Patrice; Cai, David Z; Harris, Michael R; Walker, Ryan; Licini, David; Fernandes, Joseph D A; Orr, Griffin; Koganti, Tejaswi; Hicks, Chindo; Induru, Spandana; Meyer, Mark S; Khokha, Rama; Barr, Jennifer; Pochampally, Radhika R

    2014-01-01

    Overall prognosis for osteosarcoma (OS) is poor despite aggressive treatment options. Limited access to primary tumors, technical challenges in processing OS tissues, and the lack of well-characterized primary cell cultures has hindered our ability to fully understand the properties of OS tumor initiation and progression. In this study, we have isolated and characterized cell cultures derived from four central high-grade human OS samples. Furthermore, we used the cell cultures to study the role of CD49f in OS progression. Recent studies have implicated CD49f in stemness and multipotency of both cancer stem cells and mesenchymal stem cells. Therefore, we investigated the role of CD49f in osteosarcomagenesis. First, single cell suspensions of tumor biopsies were subcultured and characterized for cell surface marker expression. Next, we characterized the growth and differentiation properties, sensitivity to chemotherapy drugs, and anchorage-independent growth. Xenograft assays showed that cell populations expressing CD49fhi/CD90lo cell phenotype produced an aggressive tumor. Multiple lines of evidence demonstrated that inhibiting CD49f decreased the tumor-forming ability. Furthermore, the CD49fhi/CD90lo cell population is generating more aggressive OS tumor growth and indicating this cell surface marker could be a potential candidate for the isolation of an aggressive cell type in OSs. PMID:24802970

  19. High CD49f expression is associated with osteosarcoma tumor progression: a study using patient-derived primary cell cultures.

    PubMed

    Penfornis, Patrice; Cai, David Z; Harris, Michael R; Walker, Ryan; Licini, David; Fernandes, Joseph D A; Orr, Griffin; Koganti, Tejaswi; Hicks, Chindo; Induru, Spandana; Meyer, Mark S; Khokha, Rama; Barr, Jennifer; Pochampally, Radhika R

    2014-08-01

    Overall prognosis for osteosarcoma (OS) is poor despite aggressive treatment options. Limited access to primary tumors, technical challenges in processing OS tissues, and the lack of well-characterized primary cell cultures has hindered our ability to fully understand the properties of OS tumor initiation and progression. In this study, we have isolated and characterized cell cultures derived from four central high-grade human OS samples. Furthermore, we used the cell cultures to study the role of CD49f in OS progression. Recent studies have implicated CD49f in stemness and multipotency of both cancer stem cells and mesenchymal stem cells. Therefore, we investigated the role of CD49f in osteosarcomagenesis. First, single cell suspensions of tumor biopsies were subcultured and characterized for cell surface marker expression. Next, we characterized the growth and differentiation properties, sensitivity to chemotherapy drugs, and anchorage-independent growth. Xenograft assays showed that cell populations expressing CD49f(hi) /CD90(lo) cell phenotype produced an aggressive tumor. Multiple lines of evidence demonstrated that inhibiting CD49f decreased the tumor-forming ability. Furthermore, the CD49f(hi) /CD90(lo) cell population is generating more aggressive OS tumor growth and indicating this cell surface marker could be a potential candidate for the isolation of an aggressive cell type in OSs. PMID:24802970

  20. LGR5 is associated with tumor aggressiveness in papillary thyroid cancer

    PubMed Central

    Michelotti, Gregory; Jiang, Xiaoyin; Sosa, Julie Ann; Diehl, Anna Mae; Henderson, Brittany Bohinc

    2015-01-01

    PURPOSE Leucine-rich repeat-containing G-protein-coupled receptor 5 (LGR5) is a cancer stem cell marker and a down-stream target in Wnt/β-catenin signaling. In human papillary thyroid cancer (PTC), over activation of Wnt/β-catenin has been associated with tumor aggressiveness. PATIENTS AND METHODS Using established human cell lines (TPC-1, KTC-1, Nthy-ori-3–1), we report LGR5 and R-spondin (RSPO1–3) overexpression in PTC and manipulate LGR5 and Wnt/β-catenin signaling via both pharmacologic and genetic interventions. We test the association of LGR5 tumor expression with markers of PTC aggressiveness using a Discovery Cohort (n = 26 patients) and a Validation Cohort (n = 157 patients). Lastly, we explore the association between LGR5 and the BRAFV600E mutation (n = 33 patients). RESULTS Our results reveal that LGR5 and its ligand, RSPO, are overexpressed in human PTC, whereby Wnt/β-catenin signaling regulates LGR5 expression and promotes cellular migration. In two separate cohorts of patients, LGR5 and RSPO2 were associated with markers of tumor aggressiveness including: lymph node metastases, vascular invasion, increased tumor size, aggressive histology, advanced AJCC TNM stage, microscopic extra thyroidal extension, capsular invasion, and macroscopic invasion. As a biomarker, LGR5 positivity predicts lymph node metastasis with 95.5% sensitivity (95% CI 88.8%-98.7%) and 61% specificity (95% CI: 48.4%–72.4%) and has a negative predictive value (NPV) of 91.3% (95% CI 79.2%–97.5%) for lymph node metastatic disease. In human PTC, LGR5 is also strongly associated with the BRAFV600E mutation (p = 0.005). CONCLUSION We conclude that overexpression of LGR5 is associated with markers of tumor aggressiveness in human PTC. LGR5 may serve as a future potential biomarker for patient risk stratification and loco regional metastases in PTC. PMID:26416247

  1. Central nervous system recurrence of desmoplastic small round cell tumor following aggressive multimodal therapy: A case report

    PubMed Central

    UMEDA, KATSUTSUGU; SAIDA, SATOSHI; YAMAGUCHI, HIDEKI; OKAMOTO, SHINYA; OKAMOTO, TAKESHI; KATO, ITARU; HIRAMATSU, HIDEFUMI; IMAI, TSUYOSHI; KODAIRA, TAKESHI; HEIKE, TOSHIO; ADACHI, SOUICHI; WATANABE, KEN-ICHIRO

    2016-01-01

    Patients with desmoplastic small round cell tumors (DSRCTs) have an extremely poor outcome despite the use of aggressive therapy. The current study presents the case of 16-year-old male with metastatic DSRCT, in which multimodal therapy, including intensive chemotherapies using frequent autologous stem cell support, gross resection of primary and metastatic lesions, and whole abdominopelvic intensity-modulated radiation therapy, was administered. Subsequent to these treatments, there was no evidence of active disease. However, cerebellar and pineal body lesions, and bone metastasis to the left humerus were detected 1 year and 2 months after the initial diagnosis. Combination chemotherapy with irinotecan and temozolomide was initially effective against the central nervous system (CNS) metastatic lesions; however, the patient succumbed due to progressive CNS disease after seven courses of combination chemotherapy. Additional studies are required to accumulate information regarding CNS recurrence of DSRCT. PMID:26870296

  2. Tumor-associated macrophages: effectors of angiogenesis and tumor progression.

    PubMed

    Coffelt, Seth B; Hughes, Russell; Lewis, Claire E

    2009-08-01

    Tumor-associated macrophages (TAMs) are a prominent inflammatory cell population in many tumor types residing in both perivascular and avascular, hypoxic regions of these tissues. Analysis of TAMs in human tumor biopsies has shown that they express a variety of tumor-promoting factors and evidence from transgenic murine tumor models has provided unequivocal evidence for the importance of these cells in driving angiogenesis, lymphangiogenesis, immunosuppression, and metastasis. This review will summarize the mechanisms by which monocytes are recruited into tumors, their myriad, tumor-promoting functions within tumors, and the influence of the tumor microenvironment in driving these activities. We also discuss recent attempts to both target/destroy TAMs and exploit them as delivery vehicles for anti-cancer gene therapy. PMID:19269310

  3. Solid pseudopapillary tumor of the pancreas: emphasis on differential diagnosis from aggressive tumors of the pancreas.

    PubMed

    Aydiner, Fatma; Erinanç, Hilal; Savaş, Berna; Erden, Esra; Karayalçin, Kaan

    2006-09-01

    Solid pseudopapillary tumor is an unusual primary tumor of the pancreas with a low potential for malignancy and unknown cell origin, seen mostly in young women. Although it is discussed among pancreatic epithelial tumors, many cases do not express cytokeratin but show neuroendocrine differentiation. Three cases (2 female, 1 male, aged 24, 45 and 50 years, respectively) of solid pseudopapillary tumor localized in the pancreas are presented. All cases displayed a well-circumscribed tumor, with an average diameter of 6 cm and a red-brown colored, hemorrhagic, cystic cut surface. Microscopically they were encapsulated with large areas composed of thin papillary formations and solid areas focally. Tumor cells were dyscohesive with small, round- to-oval, central nuclei, and vacuolated, clear or eosinophilic cytoplasm without mitotic activity. NSE, vimentin, synaptophysin, ER, PR, Ki-67, S-100, Pan CK, a1-antitrypsin, a2-antichymotrypsin, and antibodies were used in the immunohistochemical study. Vimentin, synaptophysin, NSE, PR, and a1-antitrypsin showed expression in all cases, while Pan-CK was expressed in two cases. Ki-67 expression was below 1% in all cases. Morphologic features of solid pseudopapillary tumor may be confused with pancreatic endocrine neoplasm and ductal adenocarcinoma. All cases showed features of histiocytic and neuroendocrine differentiation. Epithelial differentiation was identified in two cases. We conclude that immunohistochemistry is incapable of giving additional information for the diagnosis of solid pseudopapillary tumor due to different lines of differentiation of tumor cells. We believe that macroscopic and microscopic features (using hematoxylin and eosin stain) are more important for the diagnosis and differential diagnosis of this tumor. PMID:16941259

  4. The dual roles of NRF2 in tumor prevention and progression: possible implications in cancer treatment

    PubMed Central

    Moon, Eui Jung; Giaccia, Amato

    2015-01-01

    The Cap’N’Collar (CNC) family serves as cellular sensors of oxidative and electrophilic stresses and shares structural similarities including basic leucine zipper (bZIP) and CNC domains,. They form heterodimers with small MAF proteins to regulate antioxidant and phase II enzymes through antioxidant response element (ARE)-mediated transactivation. Among the CNC family members, NRF2 is required for systemic protection against redox-mediated injury and carcinogenesis. On the other hand, NRF2 is activated by oncogenic pathways, metabolism, and hypoxia. Constitutive NRF2 activation is observed in a variety of human cancers and it is highly correlated with tumor progression and aggressiveness. In this review, we will discuss how NRF2 plays dual roles in cancer prevention and progression depending on the cellular context and environment. Therefore, a better understanding of NRF2 will be necessary to exploit this complex network of balancing antioxidant pathways to inhibit tumor progression. PMID:25458917

  5. Estimation of salivary tumor necrosis factor-alpha in chronic and aggressive periodontitis patients

    PubMed Central

    Varghese, Sheeja S.; Thomas, Hima; Jayakumar, N. D.; Sankari, M.; Lakshmanan, Reema

    2015-01-01

    Introduction: Periodontitis is a chronic bacterial infection characterized by persistent inflammation, connective tissue breakdown and alveolar bone destruction mediated by pro-inflammatory mediators. Tumor necrosis factor-alpha (TNF-α) is an important pro-inflammatory mediator that produced causes destruction of periodontal tissues. Objective: The aim of the study is to estimate the salivary TNF-α in chronic and aggressive periodontitis and control participants and further correlate the levels with clinical parameter such as gingival index (GI), plaque index (PI), probing pocket depth (PPD) and clinical attachment loss. Materials and Methods: The study population consisted of 75 subjects age ranging from 25 to 55 years attending the outpatient section of Department of Periodontics, Saveetha Dental College and Hospital. The study groups included Groups 1, 2, and 3 with participants with healthy periodontium (n = 25), generalized chronic periodontitis (n = 25) and generalized aggressive periodontitis (n = 25), respectively. Salivary samples from the participants were used to assess the TNF-α levels using enzyme-linked immunosorbent assay. Results: GI and PI were found to be significantly higher in chronic and aggressive periodontitis compared to the controls. The mean TNF-α value in chronic periodontitis patients (12.92 ± 17.21 pg/ml) was significantly higher than in control subjects (2.15 ± 3.60 pg/ml). Whereas, in aggressive periodontitis patients the mean TNF-α (7.23 ± 7.67) were not significantly different from chronic periodontitis or healthy subjects. Among periodontitis participants, aggressive periodontitis subjects exhibited a significant positive correlation between the salivary TNF-α and PPD. Conclusion: Salivary TNF-α levels are significantly higher in chronic periodontitis than in healthy subjects, but there was no significant correlation with the clinical parameters. PMID:26604566

  6. APRIL promotes breast tumor growth and metastasis and is associated with aggressive basal breast cancer.

    PubMed

    García-Castro, Araceli; Zonca, Manuela; Florindo-Pinheiro, Douglas; Carvalho-Pinto, Carla E; Cordero, Alex; Gutiérrez del Fernando, Burgo; García-Grande, Aránzazu; Mañes, Santos; Hahne, Michael; González-Suárez, Eva; Planelles, Lourdes

    2015-05-01

    APRIL (a proliferation-inducing ligand) is a cytokine of the tumor necrosis factor family associated mainly with hematologic malignancies. APRIL is also overexpressed in breast carcinoma tissue lesions, although neither its role in breast tumorigenesis nor the underlying molecular mechanism is known. Here, we show that several breast cancer cell lines express APRIL and both its receptors, B cell maturation antigen (BCMA) and transmembrane activator and CAML-interactor (TACI), independently of luminal or basal tumor cell phenotype, and that the mitogen-activated protein kinases p38, ERK1/2, and JNK1/2 are activated in response to APRIL. The inflammatory stimulus poly I:C, a toll-like receptor (TLR) 3 ligand, enhanced APRIL secretion. Silencing experiments decreased cell proliferation, demonstrating that APRIL is a critical autocrine factor for breast tumor growth. Studies of 4T1 orthotopic breast tumors in APRIL transgenic mice showed that an APRIL-enriched environment increased tumor growth and promoted lung metastasis associated with enhanced tumor cell proliferation; BCMA and TACI expression suggests that both participate in these processes. We detected APRIL, BCMA and TACI in human luminal, triple-negative breast carcinomas and HER2 breast carcinomas, with increased levels in more aggressive basal tumors. APRIL was observed near Ki67(+) nuclei and was distributed heterogeneously in the cancer cells, in the leukocyte infiltrate, and in the myoepithelial layer adjacent to the tumor area; these results imply that APRIL provides proliferation signals to tumor cells through paracrine and autocrine signaling. Our study identifies participation of APRIL signaling in breast cancer promotion; we propose impairment of this pathway as a potential therapeutic strategy. PMID:25750171

  7. Neutrophil-Derived Proteases in the Microenvironment of Pancreatic Cancer -Active Players in Tumor Progression

    PubMed Central

    Felix, Klaus; Gaida, Matthias M.

    2016-01-01

    A hallmark of pancreatic ductal adenocarcinoma (PDAC) is the fibro-inflammatory microenvironment, consisting of activated pancreatic stellate cells, extracellular matrix proteins, and a variety of inflammatory cells, such as T cells, macrophages, or neutrophils. Tumor-infiltrating immune cells, which are found in nearly all cancers, including PDAC, often fail to eliminate the tumor, but conversely can promote its progression by altering the tumor microenvironment. Pancreatic cancer cells are able to attract polymorphonuclear neutrophils (PMN) via tumor secreted chemokines and in human PDAC, PMN infiltrates can be observed in the vicinity of tumor cells and in the desmoplastic tumor stroma, which correlate with undifferentiated tumor growth and poor prognosis. The behavior of tumor-infiltrating neutrophils in the tumor micromilieu is not yet understood at a mechanistic level. It has been shown that PMN have the potential to kill tumor cells, either directly or by antibody-dependent cell-mediated cytotoxicity, but on the other side various adverse effects of PMN, such as promotion of aggressive tumor growth with epithelial-to-mesenchymal transition and increased metastatic potential, have been described. Recent therapeutic approaches for PDAC focus not only the tumor cell itself, but also elements of the tumor microenvironment. Therefore, the role of PMN and their derived products (e.g. cytokines, proteases) as a new vein for a therapeutic target should be critically evaluated in this context. This review summarizes the current understanding of the interplay between proteases of tumor-infiltrating neutrophils and pancreatic tumor cells and elements of the desmoplastic stroma. PMID:26929737

  8. In1-ghrelin, a splice variant of ghrelin gene, is associated with the evolution and aggressiveness of human neuroendocrine tumors: Evidence from clinical, cellular and molecular parameters.

    PubMed

    Luque, Raul M; Sampedro-Nuñez, Miguel; Gahete, Manuel D; Ramos-Levi, Ana; Ibáñez-Costa, Alejandro; Rivero-Cortés, Esther; Serrano-Somavilla, Ana; Adrados, Magdalena; Culler, Michael D; Castaño, Justo P; Marazuela, Mónica

    2015-08-14

    Ghrelin system comprises a complex family of peptides, receptors (GHSRs), and modifying enzymes [e.g. ghrelin-O-acyl-transferase (GOAT)] that control multiple pathophysiological processes. Aberrant alternative splicing is an emerging cancer hallmark that generates altered proteins with tumorigenic capacity. Indeed, In1-ghrelin and truncated-GHSR1b splicing variants can promote development/progression of certain endocrine-related cancers. Here, we determined the expression levels of key ghrelin system components in neuroendocrine tumor (NETs) and explored their potential functional role. Twenty-six patients with NETs were prospectively/retrospectively studied [72 samples from primary and metastatic tissues (30 normal/42 tumors)] and clinical data were obtained. The role of In1-ghrelin in aggressiveness was studied in vitro using NET cell lines (BON-1/QGP-1). In1-ghrelin, GOAT and GHSR1a/1b expression levels were elevated in tumoral compared to normal/adjacent tissues. Moreover, In1-ghrelin, GOAT, and GHSR1b expression levels were positively correlated within tumoral, but not within normal/adjacent samples, and were higher in patients with progressive vs. with stable/cured disease. Finally, In1-ghrelin increased aggressiveness (e.g. proliferation/migration) of NET cells. Altogether, our data strongly suggests a potential implication of ghrelin system in the pathogenesis and/or clinical outcome of NETs, and warrant further studies on their possible value for the future development of molecular biomarkers with diagnostic/prognostic/therapeutic value. PMID:26124083

  9. In1-ghrelin, a splice variant of ghrelin gene, is associated with the evolution and aggressiveness of human neuroendocrine tumors: Evidence from clinical, cellular and molecular parameters

    PubMed Central

    Gahete, Manuel D.; Ramos-Levi, Ana; Ibáñez-Costa, Alejandro; Rivero-Cortés, Esther; Serrano-Somavilla, Ana; Adrados, Magdalena; Culler, Michael D.; Castaño, Justo P.; Marazuela, Mónica

    2015-01-01

    Ghrelin system comprises a complex family of peptides, receptors (GHSRs), and modifying enzymes [e.g. ghrelin-O-acyl-transferase (GOAT)] that control multiple pathophysiological processes. Aberrant alternative splicing is an emerging cancer hallmark that generates altered proteins with tumorigenic capacity. Indeed, In1-ghrelin and truncated-GHSR1b splicing variants can promote development/progression of certain endocrine-related cancers. Here, we determined the expression levels of key ghrelin system components in neuroendocrine tumor (NETs) and explored their potential functional role. Twenty-six patients with NETs were prospectively/retrospectively studied [72 samples from primary and metastatic tissues (30 normal/42 tumors)] and clinical data were obtained. The role of In1-ghrelin in aggressiveness was studied in vitro using NET cell lines (BON-1/QGP-1). In1-ghrelin, GOAT and GHSR1a/1b expression levels were elevated in tumoral compared to normal/adjacent tissues. Moreover, In1-ghrelin, GOAT, and GHSR1b expression levels were positively correlated within tumoral, but not within normal/adjacent samples, and were higher in patients with progressive vs. with stable/cured disease. Finally, In1-ghrelin increased aggressiveness (e.g. proliferation/migration) of NET cells. Altogether, our data strongly suggests a potential implication of ghrelin system in the pathogenesis and/or clinical outcome of NETs, and warrant further studies on their possible value for the future development of molecular biomarkers with diagnostic/prognostic/therapeutic value. PMID:26124083

  10. Expression of EGFR Under Tumor Hypoxia: Identification of a Subpopulation of Tumor Cells Responsible for Aggressiveness and Treatment Resistance

    SciTech Connect

    Hoogsteen, Ilse J.; Marres, Henri A.M.; Hoogen, Franciscus J.A. van den

    2012-11-01

    Purpose: Overexpression of epidermal growth factor receptor (EGFR) and tumor hypoxia have been shown to correlate with worse outcome in several types of cancer including head-and-neck squamous cell carcinoma. Little is known about the combination and possible interactions between the two phenomena. Methods and Materials: In this study, 45 cases of histologically confirmed squamous cell carcinomas of the head and neck were analyzed. All patients received intravenous infusions of the exogenous hypoxia marker pimonidazole prior to biopsy. Presence of EGFR, pimonidazole binding, and colocalization between EGFR and tumor hypoxia were examined using immunohistochemistry. Results: Of all biopsies examined, respectively, 91% and 60% demonstrated EGFR- and pimonidazole-positive areas. A weak but significant association was found between the hypoxic fractions of pimonidazole (HFpimo) and EGFR fractions (F-EGFR) and between F-EGFR and relative vascular area. Various degrees of colocalization between hypoxia and EGFR were found, increasing with distance from the vasculature. A high fraction of EGFR was correlated with better disease-free and metastasis-free survival, whereas a high degree of colocalization correlated with poor outcome. Conclusions: Colocalization of hypoxia and EGFR was demonstrated in head-and-neck squamous cell carcinomas, predominantly at longer distances from vessels. A large amount of colocalization was associated with poor outcome, which points to a survival advantage of hypoxic cells that are also able to express EGFR. This subpopulation of tumor cells might be indicative of tumor aggressiveness and be partly responsible for treatment resistance.

  11. Expression of Notch 1 receptor associated with tumor aggressiveness in papillary thyroid carcinoma

    PubMed Central

    Fu, Hongliang; Ma, Chao; Guan, Wenbin; Cheng, Weiwei; Feng, Fang; Wang, Hui

    2016-01-01

    Aim The aim of this study was to assess if the expression of Notch 1 receptor is associated with tumor aggressiveness in papillary thyroid carcinomas (PTCs). Patients and methods By searching the electronic medical record system of Xin Hua Hospital, all cases of PTC patients who underwent thyroidectomy in the hospital between 2013 and 2014 were retrieved. Then, the cases of patients who had a history of any other malignancy or whose thyroid tumor specimen was not available for assay were rejected. Finally, 68 cases of PTC patients were obtained. Formalin-fixed paraffin-embedded tissue blocks of these patients were studied by immunohistochemistry to learn the expression of Notch 1 receptor. Meanwhile, the clinical data of these patients including sex, age, size of the tumor, presence of node metastasis or distant metastasis, and presence of capsule invasion and tumor multicentricity were collected. Pearson’s chi-square test or Fisher’s exact test was used for measuring statistical differences in categorical variables. All the statistical tests were two-sided. A P-value <0.05 was considered to be statistically significant. Results A total of 19 male and 49 female PTC patients with a mean age of 44.8±13.6 years (range 18–78 years) were studied. Notch 1 receptor expression was found in 15/68 (22%) samples of PTC. The expression of Notch 1 receptor was significantly associated with tumor size (P=0.021), distant metastasis (P=0.008), capsule invasion (P=0.001), tumor multicentricity (P=0.018), and age (P=0.033). However, the expression of Notch 1 receptor was not significantly correlated with node metastasis (P=0.096) and sex (P=0.901). Conclusion The expression of Notch 1 receptor is associated with tumor aggressiveness in PTC, and may be used as a molecular marker of tumor invasiveness in PTC. PTC patients who show positive expression of Notch 1 receptor may benefit from radioiodine remnant ablation. PMID:27042120

  12. Prediction of brain tumor progression using a machine learning technique

    NASA Astrophysics Data System (ADS)

    Shen, Yuzhong; Banerjee, Debrup; Li, Jiang; Chandler, Adam; Shen, Yufei; McKenzie, Frederic D.; Wang, Jihong

    2010-03-01

    A machine learning technique is presented for assessing brain tumor progression by exploring six patients' complete MRI records scanned during their visits in the past two years. There are ten MRI series, including diffusion tensor image (DTI), for each visit. After registering all series to the corresponding DTI scan at the first visit, annotated normal and tumor regions were overlaid. Intensity value of each pixel inside the annotated regions were then extracted across all of the ten MRI series to compose a 10 dimensional vector. Each feature vector falls into one of three categories:normal, tumor, and normal but progressed to tumor at a later time. In this preliminary study, we focused on the trend of brain tumor progression during three consecutive visits, i.e., visit A, B, and C. A machine learning algorithm was trained using the data containing information from visit A to visit B, and the trained model was used to predict tumor progression from visit A to visit C. Preliminary results showed that prediction for brain tumor progression is feasible. An average of 80.9% pixel-wise accuracy was achieved for tumor progression prediction at visit C.

  13. Immunological Consequences of Epithelial-Mesenchymal Transition in Tumor Progression.

    PubMed

    Chockley, Peter J; Keshamouni, Venkateshwar G

    2016-08-01

    Microenvironments that tumor cells encounter are different during the stages of cancer progression-primary tumor, metastasis, and at the metastatic site. This suggests potential differences in immune surveillance of primary tumor and metastasis. Epithelial-mesenchymal transition (EMT) is a key reversible process in which cancer cells transition into highly motile and invasive cells for dissemination. Only a tiny proportion successfully metastasize, supporting the notion of metastasis-specific immune surveillance. EMT involves extensive molecular reprogramming of cells conferring many clinically relevant features to cancer cells and affects tumor cell interactions within the tumor microenvironment. We review the impact of tumor immune infiltrates on tumor cell EMT and the consequences of EMT in shaping the immune microenvironment of tumors. The usefulness of EMT as a model to investigate metastasis-specific immune surveillance mechanisms are also explored. Finally, we discuss potential implications of EMT for tumor immunogenicity, as well as current immunotherapies and future strategies. PMID:27431984

  14. Aggressive Locoregional Treatment Improves the Outcome of Liver Metastases from Grade 3 Gastroenteropancreatic Neuroendocrine Tumors.

    PubMed

    Du, Shunda; Ni, Jianjiao; Weng, Linqian; Ma, Fei; Li, Shaohua; Wang, Wenze; Sang, Xinting; Lu, Xin; Zhong, Shouxian; Mao, Yilei

    2015-08-01

    Grade 3 (G3) gastroenteropancreatic (GEP) neuroendocrine tumors (NETs) are rare, and there is no report specifically dealing with patients of liver metastases from G3 GEP NETs.From January 2004 to January 2014, 36 conservative patients with G3 GEP NET liver metastases were retrospectively identified from 3 hepatobiliary centers in China. The clinical features and treatment outcomes were analyzed.Aggressive locoregional treatments (LT, including cytoreductive surgery, radiofrequency ablation, and liver-directed intra-arterial intervention) and systemic therapy (ST) were introduced separately or combined, with 26 (72%) patients receiving resection of primary tumor and/or hepatic metastases, 12 patients receiving non-surgical locoregional interventions (NSLRIs), and 22 patients receiving certain kind of STs. Median overall survival (OS) was 20.0 months (95% confidence interval [CI]: 8.9-31.1 months) and survival rates were 62.6%, 30.1%, and 19.8%, at 1, 3, and 5 years, respectively. The median OS was 9.0 months (95%CI: 3.3-14.7 months) for patients receiving only STs (n = 6), 19 months (95%CI: 1.3-36.8 months) for patients receiving LT followed by STs (n = 16), and 101 months (95%CI: 0.0-210.2 months) for patients receiving only LT (n = 12). Moreover, compared with those receiving only ST or best supportive care, patients given certain types of LTs had higher rates of symptom alleviation (3/8 versus 20/23). On univariate analysis, positive prognostic factors of survival were pancreatic primary tumor (P = 0.013), normal total bilirubin level (P = 0.035), receiving surgery (P = 0.034), receiving NSLRI (P = 0.014), and sum of diameters of remnant tumor < 5 cm (P = 0.008). On multivariate analyses, pancreatic primary tumor (P = 0.015), normal total bilirubin level (P = 0.002), and sum of diameters of remnant tumor < 5 cm (P = 0.001) remained to be independent prognostic factors.For patients with G3 GEP NET liver

  15. Prolactinoma ErbB receptor expression and targeted therapy for aggressive tumors.

    PubMed

    Cooper, Odelia; Mamelak, Adam; Bannykh, Serguei; Carmichael, John; Bonert, Vivien; Lim, Stephen; Cook-Wiens, Galen; Ben-Shlomo, Anat

    2014-06-01

    As ErbB signaling is a determinant of prolactin synthesis, role of ErbB receptors was tested for prolactinoma outcomes and therapy. The objective of this study was to characterize ErbB receptor expression in prolactinomas and then perform a pilot study treating resistant prolactinomas with a targeted tyrosine kinase inhibitor (TKI). Retrospective analysis of prolactinomas and pilot study for dopamine agonist resistant prolactinomas in tertiary referral center. We performed immunofluorescent staining of a tissue array of 29 resected prolactinoma tissues for EGFR, ErbB2, ErbB3, and ErbB4 correlated with clinical features. Two patients with aggressive resistant prolactinomas enrolled and completed trial. They received lapatinib 1,250 mg daily for 6 months with tumor and hormone assessments. Main outcome measures were positive tumor staining of respective ErbB receptors, therapeutic reduction of prolactin levels and tumor shrinkage. Treated PRL levels and tumor volumes were suppressed in both subjects treated with TKI. EGFR expression was positive in 82 % of adenomas, ErbB2 in 92 %, ErbB3 in 25 %, and ErbB4 in 71 %, with ErbB2 score > EGFR > ErbB4 > ErbB3. Higher ErbB3 expression was associated with optic chiasm compression (p = 0.03), suprasellar extension (p = 0.04), and carotid artery encasement (p = 0.01). Higher DA response rates were observed in tumors with higher ErbB3 expression. Prolactinoma expression of specific ErbB receptors is associated with tumor invasion, symptoms, and response to dopamine agonists. Targeting ErbB receptors may be effective therapy in patients with resistant prolactinomas. PMID:24287797

  16. Macrophages in Tumor Microenvironments and the Progression of Tumors

    PubMed Central

    Hao, Ning-Bo; Lü, Mu-Han; Fan, Ya-Han; Cao, Ya-Ling; Zhang, Zhi-Ren; Yang, Shi-Ming

    2012-01-01

    Macrophages are widely distributed innate immune cells that play indispensable roles in the innate and adaptive immune response to pathogens and in-tissue homeostasis. Macrophages can be activated by a variety of stimuli and polarized to functionally different phenotypes. Two distinct subsets of macrophages have been proposed, including classically activated (M1) and alternatively activated (M2) macrophages. M1 macrophages express a series of proinflammatory cytokines, chemokines, and effector molecules, such as IL-12, IL-23, TNF-α, iNOS and MHCI/II. In contrast, M2 macrophages express a wide array of anti-inflammatory molecules, such as IL-10, TGF-β, and arginase1. In most tumors, the infiltrated macrophages are considered to be of the M2 phenotype, which provides an immunosuppressive microenvironment for tumor growth. Furthermore, tumor-associated macrophages secrete many cytokines, chemokines, and proteases, which promote tumor angiogenesis, growth, metastasis, and immunosuppression. Recently, it was also found that tumor-associated macrophages interact with cancer stem cells. This interaction leads to tumorigenesis, metastasis, and drug resistance. So mediating macrophage to resist tumors is considered to be potential therapy. PMID:22778768

  17. Rare Tumors in Children: Progress Through Collaboration

    PubMed Central

    Furman, Wayne L.; Schultz, Kris A.; Ferrari, Andrea; Helman, Lee; Krailo, Mark D.

    2015-01-01

    Rare pediatric tumors account for approximately 10% of all childhood cancers, which in themselves are a rare entity. The diverse histologies and clinical behaviors of rare pediatric tumors pose challenges to the investigation of their biologic and clinical features. National and international cooperative groups such as the Rare Tumor Committee of the Children's Oncology Group, Rare Tumors in Pediatric Age Project, and European Cooperative Study Group for Pediatric Rare Tumors have developed several initiatives to advance knowledge about rare pediatric cancers. However, these programs have been only partially effective, necessitating the development of alternative mechanisms to study these challenging diseases. In this article, we review the current national and international collaborative strategies to study rare pediatric cancers and alternative methods under exploration to enhance those efforts, such as independent registries and disease-specific, National Cancer Institute–sponsored clinics. PMID:26304909

  18. Drastic initial response and subsequent response to two ALK inhibitors in a patient with a highly aggressive ALK-rearranged inflammatory myofibroblastic tumor arising in the pleural cavity.

    PubMed

    Ono, Akira; Murakami, Haruyasu; Serizawa, Masakuni; Wakuda, Kazushige; Kenmotsu, Hirotsugu; Naito, Tateaki; Taira, Tetsuhiko; Koh, Yasuhiro; Ohde, Yasuhisa; Nakajima, Takashi; Endo, Masahiro; Takahashi, Toshiaki

    2016-09-01

    A 57-year-old male current smoker was diagnosed with an aggressive variant of ALK-rearranged inflammatory myofibroblastic tumor (IMT) arising in the pleural cavity. First line treatment with ASP3026 was initiated at a dose of 125mg once daily. A follow-up CT scan revealed drastic regression of the pleural lesion. After disease progression with ASP3026 treatment, LDK378 (ceritinib) was initiated at a dose of 750mg once daily. A follow-up CT scan revealed a second drastic regression of the pleural lesion. Furthermore, it is noteworthy that this case represents the use of serum hyaluronan levels to assist in monitoring of treatment efficacy in an IMT. Herein, we present the first case of a patient with a highly aggressive ALK-rearranged IMT arising in the pleural cavity, who showed both initial and subsequent drastic response to two ALK inhibitors while being monitored for serum hyaluronan. PMID:27565932

  19. Cancer Progression and Tumor Growth Kinetics

    NASA Astrophysics Data System (ADS)

    Blagoev, Krastan; Kalpathy-Cramer, Jayashree; Wilkerson, Julia; Sprinkhuizen, Sara; Song, Yi-Qiao; Bates, Susan; Rosen, Bruce; Fojo, Tito

    2013-03-01

    We present and analyze tumor growth data from prostate and brain cancer. Scaling the data from different patients shows that early stage prostate tumors show non-exponential growth while advanced prostate and brain tumors enter a stage of exponential growth. The scaling analysis points to the existence of cancer stem cells and/or massive apoptosis in early stage prostate cancer and that late stage cancer growth is not dominated by cancer stem cells. Statistical models of these two growth modes are discussed. Work supported by the National Science Foundation and the National Institutes of Health

  20. Desmoid tumor of lung with pleural involvement - the case of unique location of aggressive fibromatosis.

    PubMed

    Tokarek, Tomasz; Szpor, Joanna; Pankowski, Juliusz; Okoń, Krzysztof

    2015-01-01

    Desmoid tumors (DTs) are rare mesenchymal neoplasms with unpredictable natural history. There is a high risk of recurrence despite adequate surgical resection, however DTs do not have the capacity to metastasize. The estimated incidence in general population is 2-4 cases/million/year. They may occur at any age but most commonly in the third and fourth decades. Both sexes may be affected, but there is a slight female predominance. DTs can occur at any body site. The exact etiology remains unclear, but trauma, hormonal disturbances, pregnancy, genetic and hereditary factors are postulated to be in association with its' development. Potential to attain large size, infiltration and destruction of adjacent vital structures and tendency to recur are main management problems and important causes of morbidity and mortality. Wide excision is standard first-line treatment of primary or recurrent symptomatic desmoids. We present case of 33-years-old Caucasian female patient admitted to hospital with 2 months history of squeezing pain in right upper quadrant which appeared after meals. The patient was in general good condition. There were no abnormalities on basic laboratory tests on admission. CT of chest revealed hydrothorax to the level of the apex of the right lung and tumor sized 7 × 13 × 13 cm located in the lower lobe of right lung. Histopathological diagnosis of desmoid tumor of right lung was formulated. We report, to our knowledge for the first time in Poland, case of aggressive fibromatosis of lung with invasion of pleura. PMID:26774632

  1. ACR Appropriateness Criteria Follow-Up of Malignant or Aggressive Musculoskeletal Tumors.

    PubMed

    Roberts, Catherine C; Kransdorf, Mark J; Beaman, Francesca D; Adler, Ronald S; Amini, Behrang; Appel, Marc; Bernard, Stephanie A; Fries, Ian Blair; Germano, Isabelle M; Greenspan, Bennett S; Holly, Langston T; Kubicky, Charlotte D; Shek-Man Lo, Simon; Mosher, Timothy J; Sloan, Andrew E; Tuite, Michael J; Walker, Eric A; Ward, Robert J; Wessell, Daniel E; Weissman, Barbara N

    2016-04-01

    Appropriate imaging modalities for the follow-up of malignant or aggressive musculoskeletal tumors include radiography, MRI, CT, (18)F-2-fluoro-2-deoxy-D-glucose PET/CT, (99m)Tc bone scan, and ultrasound. Clinical scenarios reviewed include evaluation for metastatic disease to the lung in low- and high-risk patients, for osseous metastatic disease in asymptomatic and symptomatic patients, for local recurrence of osseous tumors with and without significant hardware present, and for local recurrence of soft tissue tumors. The timing for follow-up of pulmonary metastasis surveillance is also reviewed. The ACR Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every three years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances in which evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment. PMID:26922595

  2. Sortilin is associated with breast cancer aggressiveness and contributes to tumor cell adhesion and invasion

    PubMed Central

    Roselli, Séverine; Pundavela, Jay; Demont, Yohann; Faulkner, Sam; Keene, Sheridan; Attia, John; Jiang, Chen Chen; Zhang, Xu Dong; Walker, Marjorie M.; Hondermarck, Hubert

    2015-01-01

    The neuronal membrane protein sortilin has been reported in a few cancer cell lines, but its expression and impact in human tumors is unclear. In this study, sortilin was analyzed by immunohistochemistry in a series of 318 clinically annotated breast cancers and 53 normal breast tissues. Sortilin was detected in epithelial cells, with increased levels in cancers, as compared to normal tissues (p = 0.0088). It was found in 79% of invasive ductal carcinomas and 54% of invasive lobular carcinomas (p < 0.0001). There was an association between sortilin expression and lymph node involvement (p = 0.0093), suggesting a relationship with metastatic potential. In cell culture, sortilin levels were higher in cancer cell lines compared to non-tumorigenic breast epithelial cells and siRNA knockdown of sortilin inhibited cancer cell adhesion, while proliferation and apoptosis were not affected. Breast cancer cell migration and invasion were also inhibited by sortilin knockdown, with a decrease in focal adhesion kinase and SRC phosphorylation. In conclusion, sortilin participates in breast tumor aggressiveness and may constitute a new therapeutic target against tumor cell invasion. PMID:25871389

  3. Regulation of prostate cancer progression by the tumor microenvironment.

    PubMed

    Shiao, Stephen L; Chu, Gina Chia-Yi; Chung, Leland W K

    2016-09-28

    Prostate cancer remains the most frequently diagnosed cancer in men in North America, and despite recent advances in treatment patients with metastatic disease continue to have poor five-year survival rates. Recent studies in prostate cancer have revealed the critical role of the tumor microenvironment in the initiation and progression to advanced disease. Experimental data have uncovered a reciprocal relationship between the cells in the microenvironment and malignant tumor cells in which early changes in normal tissue microenvironment can promote tumorigenesis and in turn tumor cells can promote further pro-tumor changes in the microenvironment. In the tumor microenvironment, the presence of persistent immune infiltrates contributes to the recruitment and reprogramming of other non-immune stromal cells including cancer-associated fibroblasts and a unique recently identified population of metastasis-initiating cells (MICs). These MICs, which can also be found as part of the circulating tumor cell (CTC) population in PC patients, promote cancer cell transformation, enhance metastatic potential and confer therapeutic resistance. MICs act can on other cells within the tumor microenvironment in part by secreting exosomes that reprogram adjacent stromal cells to create a more favorable tumor microenvironment to support continued cancer growth and progression. We review here the current data on the intricate relationship between inflammation, reactive stroma, tumor cells and disease progression in prostate cancer. PMID:26828013

  4. [Metastasis and progression mechanisms of soft tissue tumors].

    PubMed

    Steinestel, K; Wardelmann, E

    2015-11-01

    Invasion and metastatic dissemination of tumor cells defines prognosis not only in patients with epithelial, but also mesenchymal neoplasms. Early and clinically inapparent micrometastases occur in many patients, and the risk for metastasis correlates with the tumor subtype and histologic tumor grade. In recent years and analogous to the situation in epithelial tumors, mechanisms of tumor cell dissemination in soft tissue tumors have been increasingly understood, and it has been shown that reorganization of the actin cytoskeleton plays a key role in these processes. This review summarizes current knowledge on the mechanisms of progression and metastasis of soft tissue tumors and points out possible targets for novel anti-invasive and anti-metastatic therapies. PMID:26324521

  5. GLI1 Transcription Factor Affects Tumor Aggressiveness in Patients With Papillary Thyroid Cancers

    PubMed Central

    Lee, Jandee; Jeong, Seonhyang; Lee, Cho Rok; Ku, Cheol Ryong; Kang, Sang-Wook; Jeong, Jong Ju; Nam, Kee-Hyun; Shin, Dong Yeob; Chung, Woong Youn; Lee, Eun Jig; Jo, Young Suk

    2015-01-01

    Abstract A significant proportion of patients with papillary thyroid cancer (PTC) present with extrathyroidal extension (ETE) and lymph node metastasis (LNM). However, the molecular mechanism of tumor invasiveness in PTC remains to be elucidated. The aim of this study is to understand the role of Hedgehog (Hh) signaling in tumor aggressiveness in patients with PTC. Subjects were patients who underwent thyroidectomy from 2012 to 2013 in a single institution. Frozen or paraffin-embedded tumor tissues with contralateral-matched normal thyroid tissues were collected. Hh signaling activity was analyzed by quantitative RT-PCR (qRT-PCR) and immunohistochemical (IHC) staining. Datasets from Gene Expression Omnibus (GEO) (National Center for Biotechnology Information) were subjected to Gene Set Enrichment Analysis (GSEA). BRAFT1799A and telomerase reverse transcriptase promoter mutation C228T were analyzed by direct sequencing. Among 137 patients with PTC, glioma-associated oncogene homolog 1 (GLI1) group III (patients in whom the ratio of GLI1 messenger ribonucleic acid (mRNA) level in tumor tissue to GLI1 mRNA level in matched normal tissue was in the upper third of the subject population) had elevated risk for ETE (odds ratio [OR] 4.381, 95% confidence interval [CI] 1.414–13.569, P = 0.01) and LNM (OR 5.627, 95% CI 1.674–18.913, P = 0.005). Glioma-associated oncogene homolog 2 (GLI2) group III also had elevated risk for ETE (OR 4.152, 95% CI 1.292–13.342, P = 0.017) and LNM (OR 3.924, 95% CI 1.097–14.042, P = 0.036). GSEA suggested that higher GLI1 expression is associated with expression of the KEGG gene set related to axon guidance (P = 0.031, false discovery rate < 0.05), as verified by qRT-PCR and IHC staining in our subjects. GLI1 and GLI2 expressions were clearly related to aggressive clinicopathological features and aberrant activation of GLI1 involved in the axon guidance pathway. These results may contribute to development of new

  6. GLI1 Transcription Factor Affects Tumor Aggressiveness in Patients With Papillary Thyroid Cancers.

    PubMed

    Lee, Jandee; Jeong, Seonhyang; Lee, Cho Rok; Ku, Cheol Ryong; Kang, Sang-Wook; Jeong, Jong Ju; Nam, Kee-Hyun; Shin, Dong Yeob; Chung, Woong Youn; Lee, Eun Jig; Jo, Young Suk

    2015-06-01

    A significant proportion of patients with papillary thyroid cancer (PTC) present with extrathyroidal extension (ETE) and lymph node metastasis (LNM). However, the molecular mechanism of tumor invasiveness in PTC remains to be elucidated. The aim of this study is to understand the role of Hedgehog (Hh) signaling in tumor aggressiveness in patients with PTC. Subjects were patients who underwent thyroidectomy from 2012 to 2013 in a single institution. Frozen or paraffin-embedded tumor tissues with contralateral-matched normal thyroid tissues were collected. Hh signaling activity was analyzed by quantitative RT-PCR (qRT-PCR) and immunohistochemical (IHC) staining. Datasets from Gene Expression Omnibus (GEO) (National Center for Biotechnology Information) were subjected to Gene Set Enrichment Analysis (GSEA). BRAFT1799A and telomerase reverse transcriptase promoter mutation C228T were analyzed by direct sequencing. Among 137 patients with PTC, glioma-associated oncogene homolog 1 (GLI1) group III (patients in whom the ratio of GLI1 messenger ribonucleic acid (mRNA) level in tumor tissue to GLI1 mRNA level in matched normal tissue was in the upper third of the subject population) had elevated risk for ETE (odds ratio [OR] 4.381, 95% confidence interval [CI] 1.414-13.569, P = 0.01) and LNM (OR 5.627, 95% CI 1.674-18.913, P = 0.005). Glioma-associated oncogene homolog 2 (GLI2) group III also had elevated risk for ETE (OR 4.152, 95% CI 1.292-13.342, P = 0.017) and LNM (OR 3.924, 95% CI 1.097-14.042, P = 0.036). GSEA suggested that higher GLI1 expression is associated with expression of the KEGG gene set related to axon guidance (P = 0.031, false discovery rate < 0.05), as verified by qRT-PCR and IHC staining in our subjects.GLI1 and GLI2 expressions were clearly related to aggressive clinicopathological features and aberrant activation of GLI1 involved in the axon guidance pathway. These results may contribute to development of new prognostic markers

  7. LOXL2 in epithelial cell plasticity and tumor progression.

    PubMed

    Cano, Amparo; Santamaría, Patricia G; Moreno-Bueno, Gema

    2012-09-01

    Several members of the lysyl oxidase family have recently emerged as important regulators of tumor progression. Among them, LOXL2 has been shown to be involved in tumor progression and metastasis of several tumor types, including breast carcinomas. Secreted LOXL2 participates in the remodeling of the extracellular matrix of the tumor microenvironment, in a similar fashion to prototypical lysyl oxidase. In addition, new intracellular functions of LOXL2 have been described, such as its involvement in the regulation of the epithelial-to-mesenchymal transition, epithelial cell polarity and differentiation mediated by transcriptional repression mechanisms. Importantly, intracellular (perinuclear) expression of LOXL2 is associated with poor prognosis and distant metastasis of specific tumor types, such as larynx squamous cell carcinoma and basal breast carcinomas. These recent findings open new avenues for the therapeutic utility of LOXL2. PMID:23030485

  8. AT9283, a novel aurora kinase inhibitor, suppresses tumor growth in aggressive B-cell lymphomas.

    PubMed

    Qi, Wenqing; Liu, Xiaobing; Cooke, Laurence S; Persky, Daniel O; Miller, Thomas P; Squires, Matthew; Mahadevan, Daruka

    2012-06-15

    Aurora kinases are oncogenic serine/threonine kinases that play key roles in regulating the mitotic phase of the eukaryotic cell cycle. Auroras are overexpressed in numerous tumors including B-cell non-Hodgkin's lymphomas and are validated oncology targets. AT9283, a pan-aurora inhibitor inhibited growth and survival of multiple solid tumors in vitro and in vivo. In this study, we demonstrated that AT9283 had potent activity against Aurora B in a variety of aggressive B-(non-Hodgkin lymphoma) B-NHL cell lines. Cells treated with AT9283 exhibited endoreduplication confirming the mechanism of action of an Aurora B inhibitor. Also, treatment of B-NHL cell lines with AT9283 induced apoptosis in a dose and time dependent manner and inhibited cell proliferation with an IC(50) < 1 μM. It is well known that inhibition of auroras (A or B) synergistically enhances the effects of microtubule targeting agents such as taxanes and vinca alkaloids to induce antiproliferation and apoptosis. We evaluated whether AT9283 in combination with docetaxel is more efficient in inducing apoptosis than AT9283 or docetaxel alone. At very low doses (5 nM) apoptosis was doubled in the combination (23%) compared to AT9283 or docetaxel alone (10%). A mouse xenograft model of mantle cell lymphoma demonstrated that AT9283 at 15 mg/kg and docetaxel (10 mg/kg) alone had modest anti-tumor activity. However, AT9283 at 20 mg/kg and AT9283 (15 or 20 mg/kg) plus docetaxel (10 mg/kg) demonstrated a statistically significant tumor growth inhibition and enhanced survival. Together, our results suggest that AT9283 plus docetaxel may represent a novel therapeutic strategy in B-cell NHL and warrant early phase clinical trial evaluation. PMID:21796626

  9. Proprotein Convertases in Tumor Progression and Malignancy

    PubMed Central

    Khatib, Abdel-Majid; Siegfried, Géraldine; Chrétien, Michel; Metrakos, Peter; Seidah, Nabil G.

    2002-01-01

    The mammalian subtilisin/kexin-like proprotein convertase (PC) family has been implicated in the activation of a wide spectrum of proteins. These proteins are usually synthesized as inactive precursors before their conversion to fully mature bioactive forms. A large majority of these active proteins such as matrix metalloproteases, growth factors, and adhesion molecules are crucial in the processes of cellular transformation, acquisition of the tumorigenic phenotype, and metastases formation. Inhibition of PCs significantly affects the malignant phenotype of various tumor cells. In addition to direct tumor cell proliferation and migration blockade, PC inhibitors can also be used to target tumor angiogenesis. In this Review article we discuss a number of recent findings on the clinical relevance of PCs in cancer patients, their implication in the regulation of multiple cellular functions that impact on the invasive/metastatic potential of cancer cells. Thus, PC inhibitors may constitute new promising agents for the treatment of multiple tumors and/or in adjuvant therapy to prevent recurrence. PMID:12057895

  10. Obesity increases tumor aggressiveness in a genetically engineered mouse model of serous ovarian cancer☆

    PubMed Central

    Makowski, Liza; Zhou, Chunxiao; Zhong, Yan; Kuan, Pei Fen; Fan, Cheng; Sampey, Brante P.; Difurio, Megan; Bae-Jump, Victoria L.

    2014-01-01

    Objectives Obesity is associated with increased risk and worse outcomes for ovarian cancer. Thus, we examined the effects of obesity on ovarian cancer progression in a genetically engineered mouse model of serous ovarian cancer. Methods We utilized a unique serous ovarian cancer mouse model that specifically deletes the tumor suppressor genes, Brca1 and p53, and inactivates the retinoblastoma (Rb) proteins in adult ovarian surface epithelial cells, via injection of an adenoviral vector expressing Cre (AdCre) into the ovarian bursa cavity of adult female mice (KpB mouse model). KpB mice were subjected to a 60% calories-derived from fat in a high fat diet (HFD) versus 10% calories from fat in a low fat diet (LFD) to mimic diet-induced obesity. Tumors were isolated at 6 months after AdCre injection and evaluated histologically. Untargeted metabolomic and gene expression profiling was performed to assess differences in the ovarian tumors from obese versus non-obese KpB mice. Results At sacrifice, mice on the HFD (obese) were twice the weight of mice on the LFD (non-obese) (51 g versus 31 g, p = 0.0003). Ovarian tumors were significantly larger in the obese versus non-obese mice (3.7 cm2 versus 1.2 cm2, p = 0.0065). Gene expression and metabolomic profiling indicated statistically significant differences between the ovarian tumors from the obese versus non-obese mice, including metabolically relevant pathways. PMID:24680597

  11. Decreased expression of SLC 39A14 is associated with tumor aggressiveness and biochemical recurrence of human prostate cancer

    PubMed Central

    Xu, Xiao-Ming; Wang, Cheng-Gong; Zhu, Yu-Di; Chen, Wei-Hua; Shao, Si-Liang; Jiang, Fu-Neng; Liao, Qian-De

    2016-01-01

    Objective Solute carrier family 39, member 14 (SLC39A14), has been identified as a potential biomarker for various cancers. However, its roles in prostate cancer (PCa) are still unclear. The aim of this study was to investigate the clinical significance of SLC39A14 in patients with PCa and its functions in malignant phenotypes of PCa cells. Patients and methods Subcellular localization and expression pattern of SLC39A14 protein were examined by immunohistochemistry. Then, the associations of SLC39A14 expression with various clinicopathological features and clinical outcome of patients with PCa were statistically evaluated. Subsequently, the effects of SLC39A14 overexpression and knockdown on PCa cell proliferation and motility were, respectively, examined by Cell Counting Kit-8, transwell, and wound-healing assays. Results The immunoreactive scores of SLC39A14 protein in human PCa tissues were significantly lower than those in normal prostate tissues. Based on the Taylor dataset, SLC39A14 downregulation occurred more frequently in patients with PCa with a higher Gleason score (P<0.001), advanced clinical stage (P=0.008), presence of metastasis (P=0.009), and prostate-specific antigen failure (P=0.006). More interestingly, the survival analysis identified SLC39A14 as an independent factor for predicting the biochemical recurrence-free survival of patients with PCa (P=0.017). Functionally, the enforced expression of SLC39A14 could suppress cell proliferation, invasion, and migration of PCa cell lines in vitro, which could be reversed by the knockdown of SLC39A14. Conclusion Decreased expression of SLC39A14 may lead to malignant phenotypes of PCa cells and aggressive tumor progression in patients with PCa. Importantly, SLC39A14 may function as a tumor suppressor and a biomarker for screening patients with biochemical recurrence following radical prostatectomy. PMID:27471394

  12. An unusually large aggressive adenomatoid odontogenic tumor of maxilla involving the third molar: A clinical case report

    PubMed Central

    Dhupar, Vikas; Akkara, Francis; Khandelwal, Pulkit

    2016-01-01

    Adenomatoid odontogenic tumor (AOT) is a rare tumor comprising only 3% of all odontogenic tumors. It is a benign, encapsulated, noninvasive, nonaggressive, slowly growing odontogenic lesion associated with an impacted tooth. These lesions may go unnoticed for years. The usual treatment is enucleation and curettage, and the lesion does not recur. Here, we present a rare case of an unusually large aggressive AOT of maxilla associated with impacted third molar. The authors also discuss clinical, radiographic, histopathologic, and therapeutic features of the case. Subtotal maxillectomy with simultaneous reconstruction of the surgical defect with temporalis myofascial flap was planned and carried out. PMID:27095910

  13. Evolutionary Game Theory Analysis of Tumor Progression

    NASA Astrophysics Data System (ADS)

    Wu, Amy; Liao, David; Sturm, James; Austin, Robert

    2014-03-01

    Evolutionary game theory applied to two interacting cell populations can yield quantitative prediction of the future densities of the two cell populations based on the initial interaction terms. We will discuss how in a complex ecology that evolutionary game theory successfully predicts the future densities of strains of stromal and cancer cells (multiple myeloma), and discuss the possible clinical use of such analysis for predicting cancer progression. Supported by the National Science Foundation and the National Cancer Institute.

  14. Progress in photodynamic therapy on tumors

    NASA Astrophysics Data System (ADS)

    Tian, Y. Y.; Wang, L. L.; Wang, W.

    2008-10-01

    Photodynamic therapy (PDT) is a promising treatment on neoplastic pathologic tissues, which involves the administration of a photosensitizing agent followed by the exposure of the tissue to visible nonthermal light. Light energy is captured and transferred to other molecules resulting in the formation of short-lived energetic species, which interact with biological systems and then produce tissue damage. Photosensitizer can be taken up selectively by tumor cells because of the upregulation of low-density lipoprotein receptor-mediated endocytosis and the acidic tumor environments. In recent years, the application of PDT in the treatment of malignant lesions has increased dramatically. The first health agency approval for PDT was granted for Photofrin in Canada in 1993, and, now, it is licensed in many countries for the treatment of cancers. Although Photofrin is the most commonly used photosensitizer, it has significant side effects. Therefore, major effort has been invested in the development of new sensitizers and, to this end, many photosensitizers have been described and some are now in clinical trials.

  15. KSHV-Mediated Angiogenesis in Tumor Progression

    PubMed Central

    Purushothaman, Pravinkumar; Uppal, Timsy; Sarkar, Roni; Verma, Subhash C.

    2016-01-01

    Human herpesvirus 8 (HHV-8), also known as Kaposi’s sarcoma-associated herpesvirus (KSHV), is a malignant human oncovirus belonging to the gamma herpesvirus family. HHV-8 is closely linked to the pathogenesis of Kaposi’s sarcoma (KS) and two other B-cell lymphoproliferative diseases: primary effusion lymphoma (PEL) and a plasmablastic variant of multicentric Castleman’s disease (MCD). KS is an invasive tumor of endothelial cells most commonly found in untreated HIV-AIDS or immuno-compromised individuals. KS tumors are highly vascularized and have abnormal, excessive neo-angiogenesis, inflammation, and proliferation of infected endothelial cells. KSHV directly induces angiogenesis in an autocrine and paracrine fashion through a complex interplay of various viral and cellular pro-angiogenic and inflammatory factors. KS is believed to originate due to a combination of KSHV’s efficient strategies for evading host immune systems and several pro-angiogenic and pro-inflammatory stimuli. In addition, KSHV infection of endothelial cells produces a wide array of viral oncoproteins with transforming capabilities that regulate multiple host-signaling pathways involved in the activation of angiogenesis. It is likely that the cellular-signaling pathways of angiogenesis and lymph-angiogenesis modulate the rate of tumorigenesis induction by KSHV. This review summarizes the current knowledge on regulating KSHV-mediated angiogenesis by integrating the findings reported thus far on the roles of host and viral genes in oncogenesis, recent developments in cell-culture/animal-model systems, and various anti-angiogenic therapies for treating KSHV-related lymphoproliferative disorders. PMID:27447661

  16. Tumor-Derived Exosomes and Their Role in Cancer Progression.

    PubMed

    Whiteside, Theresa L

    2016-01-01

    Tumor cells actively produce, release, and utilize exosomes to promote tumor growth. Mechanisms through which tumor-derived exosomes subserve the tumor are under intense investigation. These exosomes are information carriers, conveying molecular and genetic messages from tumor cells to normal or other abnormal cells residing at close or distant sites. Tumor-derived exosomes are found in all body fluids. Upon contact with target cells, they alter phenotypic and functional attributes of recipients, reprogramming them into active contributors to angiogenesis, thrombosis, metastasis, and immunosuppression. Exosomes produced by tumors carry cargos that in part mimic contents of parent cells and are of potential interest as noninvasive biomarkers of cancer. Their role in inhibiting the host antitumor responses and in mediating drug resistance is important for cancer therapy. Tumor-derived exosomes may interfere with cancer immunotherapy, but they also could serve as adjuvants and antigenic components of antitumor vaccines. Their biological roles in cancer development or progression as well as cancer therapy suggest that tumor-derived exosomes are critical components of oncogenic transformation. PMID:27117662

  17. Tumor apparent diffusion coefficient as an imaging biomarker to predict tumor aggressiveness in patients with estrogen-receptor-positive breast cancer.

    PubMed

    Shin, Hee Jung; Kim, So Hee; Lee, Hee Jin; Gong, Gyungyub; Baek, Seunghee; Chae, Eun Young; Choi, Woo Jung; Cha, Joo Hee; Kim, Hak Hee

    2016-08-01

    The purpose of this retrospective study was to evaluate whether tumor apparent diffusion coefficient (ADC) was correlated with pathologic biomarkers such as tumor cellularity, Ki67, tumor-infiltrating lymphocytes (TILs), and peritumoral lymphocytic infiltrate (PLI) in patients with estrogen receptor (ER)-positive breast cancer. The study was approved by the institutional review board and informed consent was waived. From July 2014 to December 2014, we reviewed 140 ER-positive tumors in 138 consecutive patients (range, 28-77 years; mean, 52 years) who underwent preoperative breast MRI and definitive surgery. All patients underwent diffusion-weighted imaging with a 3T scanner. Two radiologists drew the region of interest of the entire tumor and obtained the mean and pixel-based histogram of ADC. On pathology, two pathologists reviewed tumor cellularity, Ki67, TILs, and PLI. Multiple linear regression analysis was used to determine pathologic variables independently associated with ADC. Tumors with high tumor cellularity and high Ki67 had significantly lower ADCs than those with low tumor cellularity and low Ki67 (P < 0.05 for all). Tumors without PLI had significantly higher standard deviation than those with PLI (0.23 ± 0.08 versus 0.18 ± 0.05; P < 0.001). Median ADC was negatively correlated with tumor cellularity (r = -0.441), and Ki67 (r = -0.382). The standard deviation of ADC was also negatively correlated with the degree of PLI (r = -0.319). On multivariate linear regression analysis, tumor cellularity and Ki67 were independently associated with tumor ADC. Tumor ADC would be an MRI biomarker for the prediction of tumor aggressiveness indicators such as Ki67, tumor cellularity, and PLI in ER-positive breast cancer. Copyright © 2016 John Wiley & Sons, Ltd. PMID:27332719

  18. Pazopanib Hydrochloride in Treating Patients With Progressive Carcinoid Tumors

    ClinicalTrials.gov

    2016-09-14

    Atypical Carcinoid Tumor; Foregut Carcinoid Tumor; Hindgut Carcinoid Tumor; Lung Carcinoid Tumor; Metastatic Carcinoid Tumor; Metastatic Digestive System Neuroendocrine Tumor G1; Midgut Carcinoid Tumor; Recurrent Digestive System Neuroendocrine Tumor G1; Regional Digestive System Neuroendocrine Tumor G1

  19. Downregulation of cytokeratin 18 is associated with paclitaxel‑resistance and tumor aggressiveness in prostate cancer.

    PubMed

    Yin, Bo; Zhang, Mo; Zeng, Yu; Li, Youqiang; Zhang, Chao; Song, Yongsheng

    2016-04-01

    Paclitaxel frequently serves as the first-line chemotherapeutic agent for castration-resistant prostate cancer (PCa) patients. However, acquired paclitaxel-resistance almost always occurs after initial responses, and the mechanisms by which this occurs remain largely unknown. The goal of the present study was to identify differentially expressed protein(s) associated with paclitaxel-resistance and further explore the potential mechanisms involved in drug resistance. By comparing the nuclear matrix protein (NMP) patterns of DU145-TxR cells, the previously established stable paclitaxel-resistant PCa cells, with that of the parental DU145 cells using two-dimensional electrophoresis, we found that cytokeratin 18 (CK18) is downregulated in DU145-TxR cells. The downregulation of CK18 in DU145-TxR cells at mRNA, NMP and total cellular protein levels was validated by real-time RT-PCR, immunoblotting and immunofluorescence, indicating that the downregulation of CK18 was a global effect in DU145-TxR cells due to paclitaxel-resistance. Furthermore, in vivo assay of xenograft transplantation confirmed the higher tumorigenicity of DU145-TxR cells, suggesting that these paclitaxel-resistant PCa cells possessed potent cancer stem cell (CSC)-like properties and eventually developed paclitaxel-resistance. Moreover, we determined by immunohistochemistry that CK18 expression in PCa tissues was inversely correlated with tumor grade in a statistically significant fashion, indicating a potential association of the downregulation of CK18 with tumor aggressiveness. Therefore, further study to define the potential role of CK18 may lead to novel therapy strategies as well as clinically useful biomarker for PCa patients. PMID:26892177

  20. Gastric-type Endocervical Adenocarcinoma: An Aggressive Tumor With Unusual Metastatic Patterns and Poor Prognosis.

    PubMed

    Karamurzin, Yevgeniy S; Kiyokawa, Takako; Parkash, Vinita; Jotwani, Anjali R; Patel, Prusha; Pike, Malcolm C; Soslow, Robert A; Park, Kay J

    2015-11-01

    Gastric-type adenocarcinoma of the uterine cervix (GAS) is a rare variant of mucinous endocervical adenocarcinoma not etiologically associated with human papillomavirus (HPV) infection, with minimal deviation adenocarcinoma (MDA) at the well-differentiated end of the morphologic spectrum. These tumors are reported to have worse prognosis than usual HPV associated endocervical adenocarcinoma (UEA). A retrospective review of GAS was performed from the pathology databases of 3 institutions spanning 20 years. Stage, metastatic patterns, and overall survival were documented. Forty GAS cases were identified, with clinical follow-up data available for 38. The tumors were subclassified as MDA (n=13) and non-MDA GAS (n=27). Two patients were syndromic (1 Li-Fraumeni, 1 Peutz-Jeghers). At presentation, 59% were advanced stage (FIGO II to IV), 50% had lymph node metastases, 35% had ovarian involvement, 20% had abdominal disease, 39% had at least 1 site of metastasis at the time of initial surgery, and 12% of patients experienced distant recurrence. The metastatic sites included lymph nodes, adnexa, omentum, bowel, peritoneum, diaphragm, abdominal wall, bladder, vagina, appendix, and brain. Follow-up ranged from 1.4 to 136.0 months (mean, 33.9 mo); 20/38 (52.6%) had no evidence of disease, 3/38 (7.9%) were alive with disease, and 15/38 (39.5%) died of disease. Disease-specific survival at 5 years was 42% for GAS versus 91% for UEA. There were no survival differences between MDA and non-MDA GAS. GAS represents a distinct, biologically aggressive type of endocervical adenocarcinoma. The majority of patients present at advanced stage and pelvic, abdominal, and distant metastases are not uncommon. PMID:26457350

  1. Bidirectional effect of CD200 on breast cancer development and metastasis, with ultimate outcome determined by tumor aggressiveness and a cancer-induced inflammatory response.

    PubMed

    Erin, N; Podnos, A; Tanriover, G; Duymuş, Ö; Cote, E; Khatri, I; Gorczynski, R M

    2015-07-01

    CD200 acts through its receptor (CD200R) to inhibit excessive inflammation. The role of CD200-CD200R1 interaction in tumor immunity is poorly understood. In this study, we examined the role of CD200-CD200R1 interaction in the progression and metastasis of highly aggressive 4THM murine-breast carcinoma using CD200 transgenic (CD200(tg)) and CD200R1 knock-out (CD200R1(-)(/-)) BALB/c mice. 4THM cells induce extensive visceral metastasis and neutrophil infiltration in affected tissues. CD200 overexpression in the host was associated with decreased primary tumor growth and metastasis, whereas lack of CD200R1 expression by host cells was associated with enhanced visceral metastasis. Absence of CD200R1 expression led to decreased tumor-infiltrating-cytotoxic T cells and increased the release of inflammatory cytokines, such as tumor necrosis factor-α (TNF-α) and interleukin (IL)-6. In contrast, CD200 overexpression led to increased tumor-induced interferon-γ and IL-10 response and decreased TNF-α and IL-6 release. Neutrophil infiltration of tissues was markedly decreased in CD200(tg) animals and increased in CD200R1(-/-) mice. These findings are contradictory to what has been reported in the EMT6 mouse breast-cancer model. Other distinguishing features of tumor elicited by EMT6 and 4THM cell injections were also examined. Visceral tissues from mice bearing EMT6 tumors showed a lack of neutrophil infiltration and decreased IL-6 release in CD200R1(-/-) mice. EMT6 and 4THM cells also differed in vimentin expression and in vitro migration rate, which was markedly lower in EMT6 tumors. These results support the hypothesis that CD200 expression can alter immune responses, and can inhibit metastatic growth of tumor cells that induce systemic and local inflammatory response. Increasing CD200 activity/signaling might be an important therapeutic strategy for treatment of aggressive breast carcinomas. PMID:25263452

  2. Targeting YAP-dependent MDSC infiltration impairs tumor progression

    PubMed Central

    Wang, Guocan; Lu, Xin; Dey, Prasenjit; Deng, Pingna; Wu, Chia Chin; Jiang, Shan; Fang, Zhuangna; Zhao, Kun; Konaparthi, Ramakrishna; Hua, Sujun; Zhang, Jianhua; Li-Ning-Tapia, Elsa M.; Kapoor, Avnish; Wu, Chang-Jiun; Patel, Neelay Bhaskar; Guo, Zhenglin; Ramamoorthy, Vandhana; Tieu, Trang N.; Heffernan, Tim; Zhao, Di; Shang, Xiaoying; Khadka, Sunada; Hou, Pingping; Hu, Baoli; Jin, Eun-Jung; Yao, Wantong; Pan, Xiaolu; Ding, Zhihu; Shi, Yanxia; Li, Liren; Chang, Qing; Troncoso, Patricia; Logothetis, Christopher J.; McArthur, Mark J.; Chin, Lynda; Wang, Y. Alan; DePinho, Ronald A.

    2015-01-01

    The signaling mechanisms between prostate cancer cells and infiltrating immune cells may illuminate novel therapeutic approaches. Here, utilizing a prostate adenocarcinoma model driven by loss of Pten and Smad4, we identify polymorphonuclear myeloid-derived suppressor cells (MDSCs) as the major infiltrating immune cell type and depletion of MDSCs blocks progression. Employing a novel dual reporter prostate cancer model, epithelial and stromal transcriptomic profiling identified Cxcl5 as a cancer-secreted chemokine to attract Cxcr2-expressing MDSCs and, correspondingly, pharmacological inhibition of Cxcr2 impeded tumor progression. Integrated analyses identified hyperactivated Hippo-YAP signaling in driving Cxcl5 upregulation in cancer cells through YAP-TEAD complex and promoting MDSCs recruitment. Clinico-pathological studies reveal upregulation and activation of YAP1 in a subset of human prostate tumors, and the YAP1 signature is enriched in primary prostate tumor samples with stronger expression of MDSC relevant genes. Together, YAP-driven MDSC recruitment via heterotypic Cxcl5-Cxcr2 signaling reveals effective therapeutic strategy for advanced prostate cancer. Significance We demonstrate a critical role of MDSCs in prostate tumor progression and discover a cancer cell non-autonomous function of Hippo-YAP pathway in regulation of Cxcl5, a ligand for Cxcr2 expressing MDSCs. Pharmacologic elimination of MDSCs or blocking the heterotypic CxCl5-Cxcr2 signaling circuit elicits robust anti-tumor responses and prolongs survival. PMID:26701088

  3. Second harmonic generation reveals matrix alterations during breast tumor progression

    NASA Astrophysics Data System (ADS)

    Burke, Kathleen; Tang, Ping; Brown, Edward

    2013-03-01

    Alteration of the extracellular matrix in tumor stroma influences efficiency of cell locomotion away from the primary tumor into surrounding tissues and vasculature, thereby affecting metastatic potential. We study matrix changes in breast cancer through the use of second harmonic generation (SHG) of collagen in order to improve the current understanding of breast tumor stromal development. Specifically, we utilize a quantitative analysis of the ratio of forward to backward propagating SHG signal (F/B ratio) to monitor collagen throughout ductal and lobular carcinoma development. After detection of a significant decrease in the F/B ratio of invasive but not in situ ductal carcinoma compared with healthy tissue, the collagen F/B ratio is investigated to determine the evolution of fibrillar collagen changes throughout tumor progression. Results are compared with the progression of lobular carcinoma, whose F/B signature also underwent significant evolution during progression, albeit in a different manner, which offers insight into varying methods of tissue penetration and collagen manipulation between the carcinomas. This research provides insights into trends of stromal reorganization throughout breast tumor development.

  4. CDC42 inhibition suppresses progression of incipient intestinal tumors

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Mutations in the APC or Beta-catenin genes are well-established initiators of colorectal cancer, yet modifiers that facilitate the survival and progression of nascent tumor cells are not well defined. Using genetic and pharmacologic approaches in mouse colorectal cancer and human colorectal cancer x...

  5. Genotype tunes pancreatic ductal adenocarcinoma tissue tension to induce matricellular fibrosis and tumor progression.

    PubMed

    Laklai, Hanane; Miroshnikova, Yekaterina A; Pickup, Michael W; Collisson, Eric A; Kim, Grace E; Barrett, Alex S; Hill, Ryan C; Lakins, Johnathon N; Schlaepfer, David D; Mouw, Janna K; LeBleu, Valerie S; Roy, Nilotpal; Novitskiy, Sergey V; Johansen, Julia S; Poli, Valeria; Kalluri, Raghu; Iacobuzio-Donahue, Christine A; Wood, Laura D; Hebrok, Matthias; Hansen, Kirk; Moses, Harold L; Weaver, Valerie M

    2016-05-01

    Fibrosis compromises pancreatic ductal carcinoma (PDAC) treatment and contributes to patient mortality, yet antistromal therapies are controversial. We found that human PDACs with impaired epithelial transforming growth factor-β (TGF-β) signaling have high epithelial STAT3 activity and develop stiff, matricellular-enriched fibrosis associated with high epithelial tension and shorter patient survival. In several KRAS-driven mouse models, both the loss of TGF-β signaling and elevated β1-integrin mechanosignaling engaged a positive feedback loop whereby STAT3 signaling promotes tumor progression by increasing matricellular fibrosis and tissue tension. In contrast, epithelial STAT3 ablation attenuated tumor progression by reducing the stromal stiffening and epithelial contractility induced by loss of TGF-β signaling. In PDAC patient biopsies, higher matricellular protein and activated STAT3 were associated with SMAD4 mutation and shorter survival. The findings implicate epithelial tension and matricellular fibrosis in the aggressiveness of SMAD4 mutant pancreatic tumors and highlight STAT3 and mechanics as key drivers of this phenotype. PMID:27089513

  6. NPAS3 Demonstrates Features of a Tumor Suppressive Role in Driving the Progression of Astrocytomas

    PubMed Central

    Moreira, Frederico; Kiehl, Tim-Rasmus; So, Kelvin; Ajeawung, Norbert F.; Honculada, Carmelita; Gould, Peter; Pieper, Russell O.; Kamnasaran, Deepak

    2011-01-01

    Malignant astrocytomas, the most common primary brain tumors, are predominantly fatal. Improved treatments will require a better understanding of the biological features of high-grade astrocytomas. To better understand the role of neuronal PAS 3 (NPAS3) in diseases in human beings, it was investigated as a candidate for astrocytomagenesis based on the presence of aberrant protein expression in greater than 70% of a human astrocytoma panel (n = 433) and most notably in surgically resected malignant lesions. In subsequent functional studies, it was concluded that NPAS3 exhibits features of a tumor-suppressor, which drives the progression of astrocytomas by modulating the cell cycle, proliferation, apoptosis, and cell migration/invasion and has a further influence on the viability of endothelial cells. Of clinical importance, absence of NPAS3 expression in glioblastomas was a significantly negative prognostic marker of survival. In addition, malignant astrocytomas lacking NPAS3 expression demonstrated loss of function mutations, which were associated with loss of heterozygosity. While overexpressed NPAS3 in malignant glioma cell lines significantly suppressed transformation, the converse decreased expression considerably induced more aggressive growth. In addition, knockdown NPAS3 expression in a human astrocyte cell line in concert with the human papillomavirus E6 and E7 oncogenes induced growth of malignant astrocytomas. In conclusion, NPAS3 drives the progression of human malignant astrocytomas as a tumor suppressor and is a negative prognostication marker for survival. PMID:21703424

  7. Sub-100nm gold nanomatryoshkas improve photo-thermal therapy efficacy in large and highly aggressive triple negative breast tumors.

    PubMed

    Ayala-Orozco, Ciceron; Urban, Cordula; Bishnoi, Sandra; Urban, Alexander; Charron, Heather; Mitchell, Tamika; Shea, Martin; Nanda, Sarmistha; Schiff, Rachel; Halas, Naomi; Joshi, Amit

    2014-10-10

    There is an unmet need for efficient near-infrared photothermal transducers for the treatment of highly aggressive cancers and large tumors where the penetration of light can be substantially reduced, and the intra-tumoral nanoparticle transport is restricted due to the presence of hypoxic or necrotic regions. We report the performance advantages obtained by sub 100nm gold nanomatryushkas, comprising concentric gold-silica-gold layers compared to conventional ~150nm silica core gold nanoshells for photothermal therapy of triple negative breast cancer. We demonstrate that a 33% reduction in silica-core-gold-shell nanoparticle size, while retaining near-infrared plasmon resonance, and keeping the nanoparticle surface charge constant, results in a four to five fold tumor accumulation of nanoparticles following equal dose of injected gold for both sizes. The survival time of mice bearing large (>1000mm(3)) and highly aggressive triple negative breast tumors is doubled for the nanomatryushka treatment group under identical photo-thermal therapy conditions. The higher absorption cross-section of a nanomatryoshka results in a higher efficiency of photonic to thermal energy conversion and coupled with 4-5× accumulation within large tumors results in superior therapy efficacy. PMID:25051221

  8. Sub-100 nm Gold Nanomatryoshkas Improve Photo-thermal Therapy Efficacy in Large and Highly Aggressive Triple Negative Breast Tumors

    PubMed Central

    Bishnoi, Sandra; Urban, Alexander; Charron, Heather; Mitchell, Tamika; Shea, Martin; Nanda, Sarmistha; Schiff, Rachel; Halas, Naomi; Joshi, Amit

    2014-01-01

    There is an unmet need for efficient near-infrared photothermal transducers for the treatment of highly aggressive cancers and large tumors where the penetration of light can be substantially reduced, and the intra-tumoral nanoparticle transport is restricted due to the presence of hypoxic or nectrotic regions. We report the performance advantages obtained by sub 100 nm gold nanomatryushkas, comprising of concentric gold-silica-gold layers compared to conventional ~150 nm silica core gold nanoshells for photothermal therapy of triple negative breast cancer. We demonstrate that a 33% reduction in silica-core-gold-shell nanoparticle size, while retaining near-infrared plasmon resonance, and keeping the nanoparticle surface charge constant, results in a four to five fold tumor accumulation of nanoparticles following equal dose of injected gold for both sizes. The survival time of mice bearing large (>1000 mm3) and highly aggressive triple negative breast tumors is doubled for the nanomatryushka treatment group under identical photo-thermal therapy conditions. The higher absorption cross-section of a nanomatryoshka results in a higher efficiency of photonic to thermal energy conversion and coupled with 4-5X accumulation within large tumors results in superior therapy efficacy. PMID:25051221

  9. 5′-AMP-activated Protein Kinase (AMPK) Supports the Growth of Aggressive Experimental Human Breast Cancer Tumors*

    PubMed Central

    Laderoute, Keith R.; Calaoagan, Joy M.; Chao, Wan-ru; Dinh, Dominc; Denko, Nicholas; Duellman, Sarah; Kalra, Jessica; Liu, Xiaohe; Papandreou, Ioanna; Sambucetti, Lidia; Boros, Laszlo G.

    2014-01-01

    Rapid tumor growth can establish metabolically stressed microenvironments that activate 5′-AMP-activated protein kinase (AMPK), a ubiquitous regulator of ATP homeostasis. Previously, we investigated the importance of AMPK for the growth of experimental tumors prepared from HRAS-transformed mouse embryo fibroblasts and for primary brain tumor development in a rat model of neurocarcinogenesis. Here, we used triple-negative human breast cancer cells in which AMPK activity had been knocked down to investigate the contribution of AMPK to experimental tumor growth and core glucose metabolism. We found that AMPK supports the growth of fast-growing orthotopic tumors prepared from MDA-MB-231 and DU4475 breast cancer cells but had no effect on the proliferation or survival of these cells in culture. We used in vitro and in vivo metabolic profiling with [13C]glucose tracers to investigate the contribution of AMPK to core glucose metabolism in MDA-MB-231 cells, which have a Warburg metabolic phenotype; these experiments indicated that AMPK supports tumor glucose metabolism in part through positive regulation of glycolysis and the nonoxidative pentose phosphate cycle. We also found that AMPK activity in the MDA-MB-231 tumors could systemically perturb glucose homeostasis in sensitive normal tissues (liver and pancreas). Overall, our findings suggest that the contribution of AMPK to the growth of aggressive experimental tumors has a critical microenvironmental component that involves specific regulation of core glucose metabolism. PMID:24993821

  10. TGF-β switches from tumor suppressor to prometastatic factor in a model of breast cancer progression

    PubMed Central

    Tang, Binwu; Vu, Mary; Booker, Timberly; Santner, Steven J.; Miller, Fred R.; Anver, Miriam R.; Wakefield, Lalage M.

    2003-01-01

    The TGF-β signaling network plays a complex role in carcinogenesis because it has the potential to act as either a tumor suppressor or a pro-oncogenic pathway. Currently, it is not known whether TGF-β can switch from tumor suppressor to pro-oncogenic factor during the course of carcinogenic progression in a single cell lineage with a defined initiating oncogenic event or whether the specific nature of the response is determined by cell type and molecular etiology. To address this question, we have introduced a dominant negative type II TGF-β receptor into a series of genetically related human breast–derived cell lines representing different stages in the progression process. We show that decreased TGF-β responsiveness alone cannot initiate tumorigenesis but that it can cooperate with an initiating oncogenic lesion to make a premalignant breast cell tumorigenic and a low-grade tumorigenic cell line histologically and proliferatively more aggressive. In a high-grade tumorigenic cell line, however, reduced TGF-β responsiveness has no effect on primary tumorigenesis but significantly decreases metastasis. Our results demonstrate a causal role for loss of TGF-β responsiveness in promoting breast cancer progression up to the stage of advanced, histologically aggressive, but nonmetastatic disease and suggest that at that point TGF-β switches from tumor suppressor to prometastatic factor. PMID:14523048

  11. IL-1β promotes malignant transformation and tumor aggressiveness in oral cancer.

    PubMed

    Lee, Chia-Huei; Chang, Jeffrey Shu-Ming; Syu, Shih-Han; Wong, Thian-Sze; Chan, Jimmy Yu-Wai; Tang, Ya-Chu; Yang, Zhi-Ping; Yang, Wen-Chan; Chen, Chiung-Tong; Lu, Shao-Chun; Tang, Pei-Hua; Yang, Tzu-Ching; Chu, Pei-Yi; Hsiao, Jenn-Ren; Liu, Ko-Jiunn

    2015-04-01

    Chronic inflammation, coupled with alcohol, betel quid, and cigarette consumption, is associated with oral squamous cell carcinoma (OSCC). Interleukin-1 beta (IL-1β) is a critical mediator of chronic inflammation and implicated in many cancers. In this study, we showed that increased pro-IL-1β expression was associated with the severity of oral malignant transformation in a mouse OSCC model induced by 4-Nitroquinolin-1-oxide (4-NQO) and arecoline, two carcinogens related to tobacco and betel quid, respectively. Using microarray and quantitative PCR assay, we showed that pro-IL-1β was upregulated in human OSCC tumors associated with tobacco and betel quid consumption. In a human OSCC cell line TW2.6, we demonstrated nicotine-derived nitrosamine ketone (NNK) and arecoline stimulated IL-1β secretion in an inflammasome-dependent manner. IL-1β treatment significantly increased the proliferation and dysregulated the Akt signaling pathways of dysplastic oral keratinocytes (DOKs). Using cytokine antibodies and inflammation cytometric bead arrays, we found that DOK and OSCC cells secreted high levels of IL-6, IL-8, and growth-regulated oncogene-α following IL-1β stimulation. The conditioned medium of IL-1β-treated OSCC cells exerted significant proangiogenic effects. Crucially, IL-1β increased the invasiveness of OSCC cells through the epithelial-mesenchymal transition (EMT), characterized by downregulation of E-cadherin, upregulation of Snail, Slug, and Vimentin, and alterations in morphology. These findings provide novel insights into the mechanism underlying OSCC tumorigenesis. Our study suggested that IL-1β can be induced by tobacco and betel quid-related carcinogens, and participates in the early and late stages of oral carcinogenesis by increasing the proliferation of dysplasia oral cells, stimulating oncogenic cytokines, and promoting aggressiveness of OSCC. PMID:25204733

  12. Warburg effect's manifestation in aggressive pheochromocytomas and paragangliomas: insights from a mouse cell model applied to human tumor tissue.

    PubMed

    Fliedner, Stephanie M J; Kaludercic, Nina; Jiang, Xiao-Sheng; Hansikova, Hana; Hajkova, Zuzana; Sladkova, Jana; Limpuangthip, Andrea; Backlund, Peter S; Wesley, Robert; Martiniova, Lucia; Jochmanova, Ivana; Lendvai, Nikoletta K; Breza, Jan; Yergey, Alfred L; Paolocci, Nazareno; Tischler, Arthur S; Zeman, Jiri; Porter, Forbes D; Lehnert, Hendrik; Pacak, Karel

    2012-01-01

    A glycolytic profile unifies a group of pheochromocytomas and paragangliomas (PHEOs/PGLs) with distinct underlying gene defects, including von Hippel-Lindau (VHL) and succinate dehydrogenase B (SDHB) mutations. Nevertheless, their tumor aggressiveness is distinct: PHEOs/PGLs metastasize rarely in VHL-, but frequently in SDHB-patients. To date, the molecular mechanisms causing the more aggressive phenotype in SDHB-PHEOs/PGLs remain largely unknown. Recently, however, an excellent model to study aggressive PHEOs (mouse tumor tissue (MTT) cells) has been developed from mouse PHEO cells (MPC). We employed this model for a proteomics based approach to identify changes characteristic for tumor aggressiveness, which we then explored in a homogeneous set of human SDHB- and VHL-PHEOs/PGLs. The increase of glucose transporter 1 in VHL, and of hexokinase 2 in VHL and SDHB, confirmed their glycolytic profile. In agreement with the cell model and in support of decoupling of glycolysis, the Krebs cycle and oxidative phosphorylation (OXPHOS), SDHB tumors showed increased lactate dehydrogenase levels. In SDHB-PGLs OXPHOS complex activity was increased at complex III and, as expected, decreased at complex II. Moreover, protein and mRNA expression of all tested OXPHOS-related genes were higher in SDHB- than in VHL-derived tumors. Although there was no direct evidence for increased reactive oxygen species production, elevated superoxide dismutase 2 expression may reflect elevated oxidative stress in SDHB-derived PHEOs/PGLs. For the first time, we show that despite dysfunction in complex II and evidence for a glycolytic phenotype, the Warburg effect does not seem to fully apply to SDHB-PHEOs/PGLs with respect to decreased OXPHOS. In addition, we present evidence for increased LDHA and SOD2 expression in SDHB-PHEOs/PGLs, proteins that have been proposed as promising therapeutic targets in other cancers. This study provides new insight into pathogenic mechanisms in aggressive human

  13. Cytoskeletal protein flightless I inhibits apoptosis, enhances tumor cell invasion and promotes cutaneous squamous cell carcinoma progression

    PubMed Central

    Kopecki, Zlatko; Yang, Gink N.; Jackson, Jessica E.; Melville, Elizabeth L.; Cal1ey, Matthew P.; Murrell, Dedee F.; Darby, Ian A.; O'Toole, Edel A.; Samuel, Michael S.; Cowin, Allison J.

    2015-01-01

    Flightless I (Flii) is an actin remodeling protein that affects cellular processes including adhesion, proliferation and migration. In order to determine the role of Flii during carcinogenesis, squamous cell carcinomas (SCCs) were induced in Flii heterozygous (Flii+/−), wild-type and Flii overexpressing (FliiTg/Tg) mice by intradermal injection of 3-methylcholanthrene (MCA). Flii levels were further assessed in biopsies from human SCCs and the human SCC cell line (MET-1) was used to determine the effect of Flii on cellular invasion. Flii was highly expressed in human SCC biopsies particularly by the invading cells at the tumor edge. FliiTg/Tg mice developed large, aggressive SCCs in response to MCA. In contrast Flii+/− mice had significantly smaller tumors that were less invasive. Intradermal injection of Flii neutralizing antibodies during SCC initiation and progression significantly reduced the size of the tumors and, in vitro, decreased cellular sphere formation and invasion. Analysis of the tumors from the Flii overexpressing mice showed reduced caspase I and annexin V expression suggesting Flii may negatively regulate apoptosis within these tumors. These studies therefore suggest that Flii enhances SCC tumor progression by decreasing apoptosis and enhancing tumor cell invasion. Targeting Flii may be a potential strategy for reducing the severity of SCCs. PMID:26497552

  14. High levels of EGFR expression in tumor stroma are associated with aggressive clinical features in epithelial ovarian cancer

    PubMed Central

    Wang, Ke; Li, Dan; Sun, Lu

    2016-01-01

    Purpose The aim of this study was to investigate the clinical significance and biological function of epidermal growth factor receptor (EGFR) expressed in tumor stroma of epithelial ovarian cancer. Methods Immunohistological staining of EGFR was evaluated in 242 patients with epithelial ovarian cancer. The correlations of EGFR expression in tumor stroma with clinicopathological features and with the expression level of Ki-67 were analyzed by SPSS software. Kaplan–Meier analysis and the Cox proportional hazard model were used to analyze the effect of EGFR expression in tumor stroma on the prognosis of patients with epithelial ovarian cancer. Meanwhile, the activities of proliferation and migration of tumor cells were detected when EGFR overexpressed in stroma cells. Results EGFR expression in tumor stroma correlated significantly with clinical stage (χ2=7.002, P=0.008) and distant metastases (χ2=16.59, P<0.001). Furthermore, there was a significantly positive correlation between the level of EGFR expressed in tumor stroma and the level of Ki-67 expressed in tumor cells (χ2=6.120, P=0.013). Patients with high EGFR expression level in tumor stroma showed poor survival (P=0.002). Multivariate analysis showed that high expression of EGFR in tumor stroma was an independent predictor for epithelial ovarian cancer patients (hazard ratio =1.703; 95% confidence interval 1.125–2.578, P=0.012). Furthermore, stroma cells overexpressing EGFR could promote the proliferation and migration of adjacent tumor cells. Conclusion High expression of EGFR in tumor stroma correlates with aggressive clinical features in epithelial ovarian cancer, and is an independent prognostic factor. PMID:26855586

  15. Impact of the physical microenvironment on tumor progression and metastasis.

    PubMed

    Spill, Fabian; Reynolds, Daniel S; Kamm, Roger D; Zaman, Muhammad H

    2016-08-01

    The tumor microenvironment is increasingly understood to contribute to cancer development and progression by affecting the complex interplay of genetic and epigenetic changes within the cells themselves. Moreover, recent research has highlighted that, besides biochemical cues from the microenvironment, physical cues can also greatly alter cellular behavior such as proliferation, cancer stem cell properties, and metastatic potential. Whereas initial assays have focused on basic ECM physical properties, such as stiffness, novel in vitro systems are becoming increasingly sophisticated in differentiating between distinct physical cues-ECM pore size, fiber alignment, and molecular composition-and elucidating the different roles these properties play in driving tumor progression and metastasis. Combined with advances in our understanding of the mechanisms responsible for how cells sense these properties, a new appreciation for the role of mechanics in cancer is emerging. PMID:26938687

  16. Outgrowth of drug-resistant carcinomas expressing markers of tumor aggression after long term TβRI/II kinase inhibition with LY2109761

    PubMed Central

    Connolly, Erin C.; Saunier, Elise F.; Quigley, David; Luu, Minh Thu; Sapio, Angela De; Hann, Byron; Yingling, Jonathan M.; Akhurst, Rosemary J.

    2011-01-01

    Transforming Growth Factor β (TGF-β) is produced excessively by many solid tumors and can drive malignant progression through multiple effects on the tumor cell and microenvironment. TGF-β signaling pathway inhibitors have shown efficacy in pre-clinical models of metastatic cancer. Here we investigated the effect of systemic LY2109761, a type I /II receptor (TβRI/TβRII) kinase inhibitor, in both a tumor allograft model and in the mouse skin model of de novo chemically-induced carcinogenesis in vivo. Systemic LY2109761 administration disrupted tumor vascular architecture and reduced myofibroblast differentiation of E4 skin carcinoma cells in a tumor allograft. In the 7,12 dimethyl-benzanthracene plus phorbol-myristate-acetate -induced skin chemical carcinogenesis model, acute dosing of established naïve primary carcinomas with LY2109761 (100mg/Kg) every eight hours for ten days (100mg/kg) diminished P-Smad2 levels and marginally decreased the expression of inflammatory and invasive markers. Sustained exposure to LY2109761 (100mg/kg/day) throughout the tumor outgrowth phase had no effect on carcinoma latency or incidence. However, molecular analysis of resultant carcinomas by microarray gene expression, Western blot and immunohistochemistry suggests that long term LY2109761 exposure leads to the outgrowth of carcinomas with elevated P-Smad2 levels that do not respond to drug. This is the first description of acquired resistance to a small molecule inhibitor of the TGF-βRI/II kinase. Resultant carcinomas were more aggressive and inflammatory in nature, with delocalized E-Cadherin and elevated expression of Il23a, laminin V and MMPs. Therefore, TGF-β inhibitors might be clinically useful for applications requiring acute administration, but chronic patient exposure to such drugs should be undertaken with caution. PMID:21282335

  17. The combinatorial activation of the PI3K and Ras/MAPK pathways is sufficient for aggressive tumor formation, while individual pathway activation supports cell persistence

    PubMed Central

    Thompson, Keyata N.; Whipple, Rebecca A.; Yoon, Jennifer R.; Lipsky, Michael; Charpentier, Monica S.; Boggs, Amanda E.; Chakrabarti, Kristi R.; Bhandary, Lekhana; Hessler, Lindsay K.; Martin, Stuart S.; Vitolo, Michele I.

    2015-01-01

    A high proportion of human tumors maintain activation of both the PI3K and Ras/MAPK pathways. In basal-like breast cancer (BBC), PTEN expression is decreased/lost in over 50% of cases, leading to aberrant activation of the PI3K pathway. Additionally, BBC cell lines and tumor models have been shown to exhibit an oncogenic Ras-like gene transcriptional signature, indicating activation of the Ras/MAPK pathway. To directly test how the PI3K and Ras/MAPK pathways contribute to tumorigenesis, we deleted PTEN and activated KRas within non-tumorigenic MCF-10A breast cells. Neither individual mutation was sufficient to promote tumorigenesis, but the combination promoted robust tumor growth in mice. However, in vivo bioluminescence reveals that each mutation has the ability to promote a persistent phenotype. Inherent in the concept of tumor cell dormancy, a stage in which residual disease is present but remains asymptomatic, viable cells with each individual mutation can persist in vivo during a period of latency. The persistent cells were excised from the mice and showed increased levels of the cell cycle arrest proteins p21 and p27 compared to the aggressively growing PTEN−/−KRAS(G12V) cells. Additionally, when these persistent cells were placed into growth-promoting conditions, they were able to re-enter the cell cycle and proliferate. These results highlight the potential for either PTEN loss or KRAS activation to promote cell survival in vivo, and the unique ability of the combined mutations to yield rapid tumor growth. This could have important implications in determining recurrence risk and disease progression in tumor subtypes where these mutations are common. PMID:26497685

  18. Epidermal growth factor receptor as a novel molecular target for aggressive papillary tumors in the middle ear and temporal bone

    PubMed Central

    Kawabata, Shigeru; Christine Hollander, M; Munasinghe, Jeeva P.; Brinster, Lauren R.; Mercado-Matos, José R.; Li, Jie; Regales, Lucia; Pao, William; Jänne, Pasi A.; Wong, Kwok-Kin; Butman, John A.; Lonser, Russell R.; Hansen, Marlan R.; Gurgel, Richard K.; Vortmeyer, Alexander O.; Dennis, Phillip A.

    2015-01-01

    Adenomatous tumors in the middle ear and temporal bone are rare but highly morbid because they are difficult to detect prior to the development of audiovestibular dysfunction. Complete resection is often disfiguring and difficult because of location and the late stage at diagnosis, so identification of molecular targets and effective therapies is needed. Here, we describe a new mouse model of aggressive papillary ear tumor that was serendipitously discovered during the generation of a mouse model for mutant EGFR-driven lung cancer. Although these mice did not develop lung tumors, 43% developed head tilt and circling behavior. Magnetic resonance imaging (MRI) scans showed bilateral ear tumors located in the tympanic cavity. These tumors expressed mutant EGFR as well as active downstream targets such as Akt, mTOR and ERK1/2. EGFR-directed therapies were highly effective in eradicating the tumors and correcting the vestibular defects, suggesting these tumors are addicted to EGFR. EGFR activation was also observed in human ear neoplasms, which provides clinical relevance for this mouse model and rationale to test EGFR-targeted therapies in these rare neoplasms. PMID:26027747

  19. [Research progress on anti-tumor effect of Huaier].

    PubMed

    Yang, Ai-lin; Hu, Zhong-dong; Tu, Peng-fei

    2015-12-01

    Huaier (Trametes robiniophila) has been widely used as an adjuvant drug for cancer treatment in China. The anti-cancer effect of Huaier extract has been confirmed in liver cancer, lung cancer, breast cancer, ovarian cancer, gastric cancer, and so on. The main mechanisms by which Huaier exerts an anti-neoplastic effect include inhibition of the growth and proliferation of cancer cells, induction of apoptosis of cancer cells, suppression of angiogenesis, inhibition of the invasion and migration of cancer cells, regulation of oncogenes and tumor suppressor genes expression, improving immunity, and reversal of drug resistance in cancer cells. In order to provide references for further study and clinical application on anti-tumor effect of Huaier, the latest research progress on anti-tumor effect of Huaier in recent years is summarized in this paper. PMID:27245026

  20. [Research progress of tumor infiltrating lymphocytes in breast cancer].

    PubMed

    Huang, Jiahui; Chen, Xiaosong; Shen, Kunwei

    2015-09-01

    Breast cancer is a heterogeneous disease. The formation and progression of tumor and the sensitivity to treatment differs from patient to patient. In addition to the widely used molecular subtype, novel markers are needed to better personalize the treatment of breast cancer. Tumor infiltrating lymphocyte (TIL) have been consistently documented in breast cancer lesions especially in triple negative and human epidermal growth factor receptor-2 positive breast cancer. Several clinical trials have revealed that TIL are associated with prognosis and can predict therapeutic efficacy of special therapy. TIL could be divided to different subtypes including CD8 + TIL, CD4 + TIL, cytotoxic T lymphocyte-associated antigen-4 + TIL, programmed death-1 + TIL. They play different roles in the process of anti-tumor immunity and can predict different prognosis. Screening out special TIL subtype which is well associated with prognosis and therapeutic efficacy and developing targeting immunotherapy can help to improve outcomes of breast cancer patients. PMID:26654152

  1. Overcoming Hypoxia-Mediated Tumor Progression: Combinatorial Approaches Targeting pH Regulation, Angiogenesis and Immune Dysfunction

    PubMed Central

    McDonald, Paul C.; Chafe, Shawn C.; Dedhar, Shoukat

    2016-01-01

    Hypoxia is an important contributor to the heterogeneity of the microenvironment of solid tumors and is a significant environmental stressor that drives adaptations which are essential for the survival and metastatic capabilities of tumor cells. Critical adaptive mechanisms include altered metabolism, pH regulation, epithelial-mesenchymal transition, angiogenesis, migration/invasion, diminished response to immune cells and resistance to chemotherapy and radiation therapy. In particular, pH regulation by hypoxic tumor cells, through the modulation of cell surface molecules such as extracellular carbonic anhydrases (CAIX and CAXII) and monocarboxylate transporters (MCT-1 and MCT-4) functions to increase cancer cell survival and enhance cell invasion while also contributing to immune evasion. Indeed, CAIX is a vital regulator of hypoxia mediated tumor progression, and targeted inhibition of its function results in reduced tumor growth, metastasis, and cancer stem cell function. However, the integrated contributions of the repertoire of hypoxia-induced effectors of pH regulation for tumor survival and invasion remain to be fully explored and exploited as therapeutic avenues. For example, the clinical use of anti-angiogenic agents has identified a conundrum whereby this treatment increases hypoxia and cancer stem cell components of tumors, and accelerates metastasis. Furthermore, hypoxia results in the infiltration of myeloid-derived suppressor cells (MDSCs), regulatory T cells (Treg) and Tumor Associated Macrophages (TAMs), and also stimulates the expression of PD-L1 on tumor cells, which collectively suppress T-cell mediated tumor cell killing. Therefore, combinatorial targeting of angiogenesis, the immune system and pH regulation in the context of hypoxia may lead to more effective strategies for curbing tumor progression and therapeutic resistance, thereby increasing therapeutic efficacy and leading to more effective strategies for the treatment of patients with

  2. Tumor angiogenesis and progression are enhanced by Sema4D produced by tumor-associated macrophages

    PubMed Central

    Sierra, Jose Rafael; Corso, Simona; Caione, Luisa; Cepero, Virna; Conrotto, Paolo; Cignetti, Alessandro; Piacibello, Wanda; Kumanogoh, Atsushi; Kikutani, Hitoshi; Comoglio, Paolo Maria; Tamagnone, Luca; Giordano, Silvia

    2008-01-01

    Increased evidence suggests that cancer-associated inflammation supports tumor growth and progression. We have previously shown that semaphorin 4D (Sema4D), a ligand produced by different cell types, is a proangiogenic molecule that acts by binding to its receptor, plexin B1, expressed on endothelial cells (Conrotto, P., D. Valdembri, S. Corso, G. Serini, L. Tamagnone, P.M. Comoglio, F. Bussolino, and S. Giordano. 2005. Blood. 105:4321–4329). The present work highlights the role of Sema4D produced by the tumor microenvironment on neoplastic angiogenesis. We show that in an environment lacking Sema4D, the ability of cancer cells to generate tumor masses and metastases is severely impaired. This condition can be explained by a defective vascularization inside the tumor. We demonstrate that tumor-associated macrophages (TAMs) are the main cells producing Sema4D within the tumor stroma and that their ability to produce Sema4D is critical for tumor angiogenesis and vessel maturation. This study helps to explain the protumoral role of inflammatory cells of the tumor stroma and leads to the identification of an angiogenic molecule that might be a novel therapeutic target. PMID:18559453

  3. Th17 Cells in Protection from Tumor or Promotion of Tumor Progression

    PubMed Central

    Young, M. Rita I.

    2016-01-01

    The roles of inflammation and inflammatory cells such as Th17 cells in the development and progression of cancer have been extensively studied. However, the results have been varied, with conflicting conclusions. Most studies have focused on changes in inflammatory phenotypes once cancers have developed and disease is progressing. Far fewer studies have looked at the immune phenotypic changes that occur during progression of premalignant lesions to cancer. The impact of inflammation and, in particular, Th17 cells on tumor biology is summarized in this review, with a focus on the differences in the outcomes of studies. Possible explanations for the contradictory conclusions are also suggested. PMID:27453801

  4. Research progress of oncogene and tumor suppressor gene in bladder cancer.

    PubMed

    Zhang, X; Han, C; He, J

    2015-12-01

    Bladder cancer is amongst the most common malignant tumor of the urinary tract system and has the worst outcomes. The factors related to the occurrence and progression of this urological cancer has received considerable research attention. The discovery of marker genes enhances the sensitivity and specificity of early diagnosis and treatment of bladder cancer. Furthermore, these genes can be used as targets for antitumor drugs. Biomarkers that prospectively evaluate disease aggressiveness, progression risk, probability of recurrence and overall prognosis could improve patient care. Integration of molecular markers with conventional pathologic staging of bladder cancers may refine clinical decision making for the selection of adjuvant and salvage therapy. In the past decade, numerous bladder cancer biomarkers have been identified, including various tumor suppressor genes, oncogenes, growth factors, growth factor receptors, hormone receptors, proliferation and apoptosis markers, cell adhesion molecules, stromal factors, and oncoproteins. Several studies on the biological characters and mechanism of the related proteins have provided a theoretical basis for the diagnosis and treatment of bladder cancer. In this review article, we summarized the status of the current studies in this field. PMID:25634585

  5. FBI-1 Is Overexpressed in Gestational Trophoblastic Disease and Promotes Tumor Growth and Cell Aggressiveness of Choriocarcinoma via PI3K/Akt Signaling.

    PubMed

    Mak, Victor C Y; Wong, Oscar G W; Siu, Michelle K Y; Wong, Esther S Y; Ng, Wai-Yan; Wong, Richard W C; Chan, Ka-Kui; Ngan, Hextan Y S; Cheung, Annie N Y

    2015-07-01

    Human placental trophoblasts can be considered pseudomalignant, with tightly controlled proliferation, apoptosis, and invasiveness. Gestational trophoblastic disease (GTD) represents a family of heterogeneous trophoblastic lesions with aberrant apoptotic and proliferative activities and dysregulation of cell signaling pathways. We characterize the oncogenic effects of factor that binds to the inducer of short transcripts of HIV-1 [FBI-1, alias POZ and Krüppel erythroid myeloid ontogenic factor (POKEMON)/ZBTB7A] in GTD and its role in promoting cell aggressiveness in vitro and tumor growth in vivo. IHC studies showed increased nuclear expression of FBI-1, including hydatidiform moles, choriocarcinoma (CCA), and placental site trophoblastic tumor, in GTD. In JAR and JEG-3 CCA cells, ectopic FBI-1 expression opposed apoptosis through repression of proapoptotic genes (eg, BAK1, FAS, and CASP8). FBI-1 overexpression also promoted Akt activation, as indicated by Akt-pS473 phosphorylation. FBI-1 overexpression promoted mobility and invasiveness of JEG-3 and JAR, but not in the presence of the phosphoinositide 3-kinase inhibitor LY294002. These findings suggest that FBI-1 could promote cell migration and invasion via phosphoinositide 3-kinase/Akt signaling. In vivo, nude mice injected with CCA cells with stable FBI-1 knockdown demonstrated reduced tumor growth compared with that in control groups. These findings suggest that FBI-1 is clinically associated with the progression of, and may be a therapeutic target in, GTD, owing to its diverse oncogenic effects on dysregulated trophoblasts. PMID:26093985

  6. Cancer-associated mesenchymal stem cells aggravate tumor progression

    PubMed Central

    Kudo-Saito, Chie

    2015-01-01

    Mesenchymal stem cells (MSCs) have both stemness and multi-modulatory activities on other cells, and the immunosuppressive and tumor-promotive mechanisms have been intensively investigated in cancer. The role of MSCs appears to be revealed in tumor aggravation, and targeting MSCs seems to be a promising strategy for treating cancer patients. However, it is still impractical in clinical therapy, since the precise MSCs are poorly understood in the in vivo setting. In previous studies, MSCs were obtained from different sources, and were prepared by ex vivo expansion for a long term. The inconsistent experimental conditions made the in vivo MSCs obscure. To define the MSCs in the host is a priority issue for targeting MSCs in cancer therapy. We recently identified a unique subpopulation of MSCs increasing in mice and human with cancer metastasis. These MSCs are specifically expanded by metastatic tumor cells, and promote tumor progression and dissemination accompanied by immune suppression and dysfunction in the host, more powerfully than normal MSCs growing without interference of cancer. In this review, we summarize current knowledge of the role of MSCs in tumor aggravation, along with our new findings of the bizarre MSCs. PMID:25883937

  7. Sorafenib Tosylate in Treating Patients With Progressive Metastatic Neuroendocrine Tumors

    ClinicalTrials.gov

    2014-11-14

    Gastrinoma; Glucagonoma; Insulinoma; Metastatic Gastrointestinal Carcinoid Tumor; Neuroendocrine Tumor; Pancreatic Polypeptide Tumor; Recurrent Gastrointestinal Carcinoid Tumor; Recurrent Islet Cell Carcinoma; Somatostatinoma; WDHA Syndrome

  8. Cytoplasmic localization of Nrf2 promotes colorectal cancer with more aggressive tumors via upregulation of PSMD4.

    PubMed

    Lin, Po-Lin; Chang, Jinghua Tsai; Wu, De-Wei; Huang, Chi-Chou; Lee, Huei

    2016-06-01

    Differences in subcellular localization of Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) have been associated with poor outcomes in human cancers. However, the prognostic value of subcellular localization of Nrf2 in colorectal cancer and the underlying mechanism in tumor invasion remain unknown. We enrolled tumors from colorectal patients to evaluate Nrf2, NQO1, and HO-1 expression by immunohistochemistry. NQO1 and HO-1 positive tumors showed nearly complete expression of Nrf2 in the nucleus and/or showed partial expression in the nucleus/cytoplasm (nNrf2); however, tumors negative for NQO1 and HO-1 showed almost complete expression of Nrf2 in the cytoplasm and/or partial expression in the nucleus/cytoplasm (cNrf2). Kaplan-Meier and Cox regression analysis indicated poorer overall survival in patients with cNrf2 tumors than with nNrf2 tumors. Cell models provided evidence that cNrf2, rather than nNrf2, was responsible for cell invasion and soft agar growth triggered by activation of the NF-κB/AKT/β-catenin cascade. Mechanistically, cNrf2 persistently increased PSMD4 expression by the HIF1α/β-catenin axis, whereas PSMD4 reciprocally enhanced Nrf2 nuclear export by increasing CRM1 expression through p53 degradation. The mechanistic action of the cell model was further confirmed with a nude mouse animal model in which xenograft tumors induced by cNrf2 were nearly completely suppressed by the proteasomal inhibitor carfilzomib or the β-catenin inhibitor XAV939. We therefore suggest that PSMD4 or β-catenin might be potential targets for suppressing tumor aggressiveness, and consequently, improving outcomes in patients whose tumors express cNrf2. PMID:27033953

  9. High expression of Sox10 correlates with tumor aggressiveness and poor prognosis in human nasopharyngeal carcinoma

    PubMed Central

    Zhao, Yu; Liu, Zhi-gang; Tang, Jiao; Zou, Ren-fang; Chen, Xiao-yan; Jiang, Guan-min; Qiu, Yan-fang; Wang, Hui

    2016-01-01

    Purpose The aim of the study was to detect the expression of Sox10 in human nasopharyngeal carcinoma (NPC) and investigate the relationship between its expression and the clinicopathological characteristics of NPC patients. Patients and methods Tumor specimens (n=105) were retrospectively collected from patients with NPC diagnosed between 2004 and 2005 who presented at Hunan Cancer Hospital. Immunohistochemistry analyses were performed to characterize the expression of Sox10 in NPC. Kaplan–Meier survival and Cox regression analyses were employed to evaluate the prognosis of 105 NPC patients. Results The results showed that Sox10 was markedly overexpressed in human NPC tissues. Analysis of clinicopathological parameters showed that high Sox10 expression was significantly correlated with the clinical stage (P=0.032), T classification (P=0.034), and lymph node metastasis (P=0.03). Cox regression analyses further showed that Sox10 expression was an independent prognostic factor for overall survival (P=0.005). This is the first time Sox10 has shown its importance in predicting NPC progressiveness and survival outcomes. Conclusion Sox10 serves as a potential biomarker for NPC patients. It may hopefully become a novel therapeutic target for NPC patients. PMID:27051302

  10. A think tank of TINK/TANKs: tumor-infiltrating/tumor-associated natural killer cells in tumor progression and angiogenesis.

    PubMed

    Bruno, Antonino; Ferlazzo, Guido; Albini, Adriana; Noonan, Douglas M

    2014-08-01

    Tumor-infiltrating leukocytes are often induced by the cancer microenvironment to display a protumor, proangiogenic phenotype. This "polarization" has been described for several myeloid cells, in particular macrophages. Natural killer (NK) cells represent another population of innate immune cells able to infiltrate tumors. The role of NK in tumor progression and angiogenesis has not yet been fully investigated. Several studies have shown that tumor-infiltrating NK (here referred to as "TINKs") and tumor-associated NK (altered peripheral NK cells, which here we call "TANKs") are compromised in their ability to lysew tumor cells. Recent data have suggested that they are potentially protumorigenic and can also acquire a proangiogenic phenotype. Here we review the properties of TINKs and TANKs and compare their activities to that of NK cells endowed with a physiological proangiogenic phenotype, in particular decidual NK cells. We speculate on the potential origins of TINKs and TANKs and on the immune signals involved in their differentiation and polarization. The TINK and TANK phenotype has broad implications in the immune response to tumors, ranging from a deficient control of cancer and cancer stem cells to an altered crosstalk with other relevant players of the immune response, such as dendritic cells, to induction of cancer angiogenesis. With this recently acquired knowledge that has not yet been put into perspective, we point out new potential avenues for therapeutic intervention involving NK cells as a target or an ally in oncology. PMID:25178695

  11. A Think Tank of TINK/TANKs: Tumor-Infiltrating/Tumor-Associated Natural Killer Cells in Tumor Progression and Angiogenesis

    PubMed Central

    Bruno, Antonino; Ferlazzo, Guido; Albini, Adriana; Noonan, Douglas M.

    2014-01-01

    Tumor-infiltrating leukocytes are often induced by the cancer microenvironment to display a protumor, proangiogenic phenotype. This “polarization” has been described for several myeloid cells, in particular macrophages. Natural killer (NK) cells represent another population of innate immune cells able to infiltrate tumors. The role of NK in tumor progression and angiogenesis has not yet been fully investigated. Several studies have shown that tumor-infiltrating NK (here referred to as “TINKs”) and tumor-associated NK (altered peripheral NK cells, which here we call “TANKs”) are compromised in their ability to lysew tumor cells. Recent data have suggested that they are potentially protumorigenic and can also acquire a proangiogenic phenotype. Here we review the properties of TINKs and TANKs and compare their activities to that of NK cells endowed with a physiological proangiogenic phenotype, in particular decidual NK cells. We speculate on the potential origins of TINKs and TANKs and on the immune signals involved in their differentiation and polarization. The TINK and TANK phenotype has broad implications in the immune response to tumors, ranging from a deficient control of cancer and cancer stem cells to an altered crosstalk with other relevant players of the immune response, such as dendritic cells, to induction of cancer angiogenesis. With this recently acquired knowledge that has not yet been put into perspective, we point out new potential avenues for therapeutic intervention involving NK cells as a target or an ally in oncology. PMID:25178695

  12. CDC42 inhibition suppresses progression of incipient intestinal tumors

    PubMed Central

    Sakamori, Ryotaro; Yu, Shiyan; Zhang, Xiao; Hoffman, Andrew; Sun, Jiaxin; Das, Soumyashree; Vedula, Pavan; Li, Guangxun; Fu, Jiang; Walker, Francesca; Yang, Chung S.; Yi, Zheng; Hsu, Wei; Yu, Da-Hai; Shen, Lanlan; Rodriguez, Alexis J.; Taketo, Makoto M.; Bonder, Edward M.; Verzi, Michael P.; Gao, Nan

    2014-01-01

    Mutations in the APC or β-catenin genes are well established initiators of colorectal cancer (CRC), yet modifiers that facilitate the survival and progression of nascent tumor cells are not well defined. Using genetic and pharmacological approaches in mouse CRC and human CRC xenograft models, we show that incipient intestinal tumor cells activate CDC42, an APC-interacting small GTPase, as a crucial step in malignant progression. In the mouse, Cdc42 ablation attenuated the tumorigenicity of mutant intestinal cells carrying single APC or β-catenin mutations. Similarly, human CRC with relatively higher levels of CDC42 activity were particularly sensitive to CDC42 blockade. Mechanistic studies suggested that Cdc42 may be activated at different levels, including at the level of transcriptional activation of the stem-cell-enriched Rho family exchange factor Arhgef4. Our results suggest that early-stage mutant intestinal epithelial cells must recruit the pleiotropic functions of Cdc42 for malignant progression, suggesting its relevance as a biomarker and therapeutic target for selective CRC intervention. PMID:25113996

  13. SIAH1 inactivation correlates with tumor progression in hepatocellular carcinomas.

    PubMed

    Matsuo, Koichi; Satoh, Seiji; Okabe, Hiroshi; Nomura, Akinari; Maeda, Toshiki; Yamaoka, Yoshio; Ikai, Iwao

    2003-03-01

    Accumulation of loss of heterozygosity (LOH) on chromosome 16 is frequently observed in human hepatocellular carcinomas (HCCs). To identify tumor-suppressor genes (TSGs) involved in hepatocarcinogenesis, we performed deletion mapping of chromosome 16 in 59 HCCs. Three commonly deleted regions, located in 16q12.1, 16q22.1, and 16q24.2, were observed. Because there has been no study on LOH at locus 16q12.1 in HCCs, we focused on this region. By searching the Human Genome Database at the National Center for Biotechnology Information web site, we identified 14 known genes in 16q12.1 as TSG candidates. Among these, the expression of SIAH1 was markedly downregulated in HCCs, and inactivation of SIAH1 expression was associated with LOH at 16q12.1. A mutation analysis of SIAH1 revealed no somatic mutations, but one single nucleotide polymorphism was found among the 35 HCCs investigated. Subsequently, we evaluated the relation between SIAH1 expression, confirmed by semiquantitative RT-PCR, and clinicopathological parameters in HCCs. SIAH1 was significantly downregulated in advanced HCCs, including poorly differentiated tumors, larger tumors, and tumors in advanced stages. These findings suggest that inactivation of SIAH1 plays an important role in HCC progression. PMID:12557228

  14. [Inactivation of failsafe programs by Twist oncoproteins and tumor progression].

    PubMed

    Puisieux, A

    2008-01-01

    Multicellular organisms have developed innate defense mechanisms to prevent the expansion of abnormal cells with significant proliferative potential. The two major safeguard mechanisms are premature senescence, which is characterized by definitive cell cycle arrest, and apoptosis, the most common form of programmed cell death. In normal and premalignant cells, the control of these processes is coupled to the regulation of cell proliferation, mainly through the p16 (Ink4A) -Rb and ARF-p53 intracellular signaling pathways. Hence, in benign tumors, aberrant mitogenic activity is counterbalanced by the induction of these oncosuppressive pathways, leading to either apoptosis or senescence which both limit tumor outgrowth. Progression towards malignant and potentially metastatic tumors requires the inhibition of these failsafe programs. Based on our work on Twist oncoproteins, we propose a presentation of recent data on cellular mechanisms by which cancer cells override the surveillance machinery and escape senescence and apoptosis, and we will describe the biological impact of this process on tumor metastasis. PMID:19061727

  15. Expression of DNA damage response genes indicate progressive breast tumors.

    PubMed

    Gochhait, Sailesh; Dar, Surabhi; Pal, Ranjana; Gupta, Pawan; Bamezai, Rameshwar N K

    2009-01-18

    To assess how the abnormal expression of DNA damage response (DDR) genes correlate with oncogenesis, we analyzed mRNA levels of ATM-CHK2-P53 axis in 65 sporadic breast tumors by real-time PCR followed by evaluation of P53 protein and its activation status in representative samples. Univariate analysis showed a significantly higher transcript level for ATM (P=0.002), MDM2 (P=0.015) and p21 (P=0.013) in stage 1 tumors when compared against those of later stages. Although p53 transcript levels showed the characteristic increase in stage 1, a fourfold increase of p53 in N3 tumors than other nodal stages (P=0.0007) significantly increased its expression in stage 3B. The accumulated p53 at stage 3B, confirmed also at the protein level (P=0.012), was rendered nonfunctional by reduced P53 activation (p-P53Ser15; P=0.00007) or increased rate of mutation, substantiated further by the corresponding failure of upregulation of downstream genes, MDM2 and p21. We conclude that the alteration of DDR expression facilitates tumor progression and its possible therapeutic implications need to be studied in future. PMID:18805634

  16. Hypoxia in Microscopic Tumors

    PubMed Central

    Li, Xiao-Feng; O’Donoghue, Joseph A

    2008-01-01

    Tumor hypoxia has been commonly observed in a broad spectrum of primary solid malignancies. Hypoxia is associated with tumor progression, increased aggressiveness, enhanced metastatic potential and poor prognosis. Hypoxic tumor cells are resistant to radiotherapy and some forms of chemotherapy. Using an animal model, we recently showed that microscopic tumors less than 1 mm diameter were severely hypoxic. In this review, models and techniques for the study of hypoxia in microscopic tumors are discussed. PMID:18384940

  17. Plasticity underlies tumor progression: role of Nodal signaling.

    PubMed

    Bodenstine, Thomas M; Chandler, Grace S; Seftor, Richard E B; Seftor, Elisabeth A; Hendrix, Mary J C

    2016-03-01

    The transforming growth factor beta (TGFβ) superfamily member Nodal is an established regulator of early embryonic development, with primary roles in endoderm induction, left-right asymmetry, and primitive streak formation. Nodal signals through TGFβ family receptors at the plasma membrane and induces signaling cascades leading to diverse transcriptional regulation. While conceptually simple, the regulation of Nodal and its molecular effects are profoundly complex and context dependent. Pioneering work by developmental biologists has characterized the signaling pathways, regulatory components, and provided detailed insight into the mechanisms by which Nodal mediates changes at the cellular and organismal levels. Nodal is also an important factor in maintaining pluripotency of embryonic stem cells through regulation of core transcriptional programs. Collectively, this work has led to an appreciation for Nodal as a powerful morphogen capable of orchestrating multiple cellular phenotypes. Although Nodal is not active in most adult tissues, its reexpression and signaling have been linked to multiple types of human cancer, and Nodal has emerged as a driver of tumor growth and cellular plasticity. In vitro and in vivo experimental evidence has demonstrated that inhibition of Nodal signaling reduces cancer cell aggressive characteristics, while clinical data have established associations with Nodal expression and patient outcomes. As a result, there is great interest in the potential targeting of Nodal activity in a therapeutic setting for cancer patients that may provide new avenues for suppressing tumor growth and metastasis. In this review, we evaluate our current understanding of the complexities of Nodal function in cancer and highlight recent experimental evidence that sheds light on the therapeutic potential of its inhibition. PMID:26951550

  18. Manganese superoxide dismutase (SOD2/MnSOD)/catalase and SOD2/GPx1 ratios as biomarkers for tumor progression and metastasis in prostate, colon, and lung cancer.

    PubMed

    Miar, Ana; Hevia, David; Muñoz-Cimadevilla, Henar; Astudillo, Aurora; Velasco, Julio; Sainz, Rosa M; Mayo, Juan C

    2015-08-01

    The role of manganese-dependent superoxide dismutase (SOD2/MnSOD) during tumor progression has been studied for several decades with controversial results. While SOD2 downregulation was initially associated with tumor initiation and was proposed as a tumor suppressor gene, recent studies have reported that SOD2 might favor tumor progression and dissemination. To our knowledge this is the first time that changes in SOD2 expression in three different types of tumors, i.e., prostate, lung, and colon cancer, are studied by analyzing both SOD2 mRNA and protein levels in a total of 246 patients' samples. In prostate samples, SOD2 protein levels were also increased, especially in middle stage tumors. In the case of colon and lung tumors both mRNA and protein SOD2 levels were increased in malignant tissues compared to those in nontumor samples. More importantly, all metastases analyzed showed increased levels of SOD2 when compared to those of normal primary tissue and healthy adjacent tissue. Together, these results suggest that a common redox imbalance in these three types of tumor occurs at intermediate stages which then might favor migration and invasion, leading to a more aggressive cancer type. Consequently, the ratios SOD2/catalase and SOD2/Gpx1 could be considered as potential markers during progression from tumor growth to metastasis. PMID:25866291

  19. Gefitinib in Treating Patients With Progressive Metastatic Neuroendocrine Tumors

    ClinicalTrials.gov

    2013-06-03

    Gastrinoma; Glucagonoma; Insulinoma; Metastatic Gastrointestinal Carcinoid Tumor; Pancreatic Polypeptide Tumor; Recurrent Gastrointestinal Carcinoid Tumor; Recurrent Islet Cell Carcinoma; Somatostatinoma; WDHA Syndrome

  20. Tumor-derived exosomes in cancer progression and treatment failure

    PubMed Central

    Shen, Bo; Feng, Jifeng

    2015-01-01

    Exosomes have diameter within the range of 30-100nm and spherical to cup-shaped nanoparticles with specific surface molecular characteristics, such as CD9 and CD63. These vesicles are present in nearly all human body fluids, including blood plasma/serum, saliva, breast milk, cerebrospinal fluid, urine, semen, and particularly enriched in tumor microenvironment. Exosomes contain multiple proteins, DNA, mRNA, miRNA, long non-coding RNA, and even genetic materials of viruses/prions. These materials are biochemically and functionally distinct and can be transferred to a recipient cell where they regulate protein expression and signaling pathways. Recently, exosomes are demonstrated to have a close relationship with tumor development and metastasis. Exosomes influence therapeutic effect in cancer patients. In this review, we describe the biogenesis, composition, and function of exosomes. The mechanism on how tumor-derived exosomes contribute to cancer progression and clinical treatment failure is also described, with special focus on their potential applications in cancer therapy. PMID:26452221

  1. Tumor-derived exosomes in cancer progression and treatment failure.

    PubMed

    Yu, Shaorong; Cao, Haixia; Shen, Bo; Feng, Jifeng

    2015-11-10

    Exosomes have diameter within the range of 30-100 nm and spherical to cup-shaped nanoparticles with specific surface molecular characteristics, such as CD9 and CD63. These vesicles are present in nearly all human body fluids, including blood plasma/serum, saliva, breast milk, cerebrospinal fluid, urine, semen, and particularly enriched in tumor microenvironment. Exosomes contain multiple proteins, DNA, mRNA, miRNA, long non-coding RNA, and even genetic materials of viruses/prions. These materials are biochemically and functionally distinct and can be transferred to a recipient cell where they regulate protein expression and signaling pathways. Recently, exosomes are demonstrated to have a close relationship with tumor development and metastasis. Exosomes influence therapeutic effect in cancer patients. In this review, we describe the biogenesis, composition, and function of exosomes. The mechanism on how tumor-derived exosomes contribute to cancer progression and clinical treatment failure is also described, with special focus on their potential applications in cancer therapy. PMID:26452221

  2. The biological kinship of hypoxia with CSC and EMT and their relationship with deregulated expression of miRNAs and tumor aggressiveness

    PubMed Central

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

    2013-01-01

    Hypoxia is one of the fundamental biological phenomena that are intricately associated with the development and aggressiveness of a variety of solid tumors. Hypoxia-inducible factors (HIF) function as a master transcription factor, which regulates hypoxia responsive genes and has been recognized to play critical roles in tumor invasion, metastasis, and chemo-radiation resistance, and contributes to increased cell proliferation, survival, angiogenesis and metastasis. Therefore, tumor hypoxia with deregulated expression of HIF and its biological consequence lead to poor prognosis of patients diagnosed with solid tumors, resulting in higher mortality, suggesting that understanding of the molecular relationship of hypoxia with other cellular features of tumor aggressiveness would be invaluable for developing newer targeted therapy for solid tumors. It has been well recognized that cancer stem cells (CSCs) and epithelial-to-mesenchymal transition (EMT) phenotypic cells are associated with therapeutic resistance and contribute to aggressive tumor growth, invasion, metastasis and believed to be the cause of tumor recurrence. Interestingly, hypoxia and HIF signaling pathway are known to play an important role in the regulation and sustenance of CSCs and EMT phenotype. However, the molecular relationship between HIF signaling pathway with the biology of CSCs and EMT remains unclear although NF-κB, PI3K/Akt/mTOR, Notch, Wnt/β-catenin, and Hedgehog signaling pathways have been recognized as important regulators of CSCs and EMT. In this article, we will discuss the state of our knowledge on the role of HIF-hypoxia signaling pathway and its kinship with CSCs and EMT within the tumor microenvironment. We will also discuss the potential role of hypoxia-induced microRNAs (miRNAs) in tumor development and aggressiveness, and finally discuss the potential effects of nutraceuticals on the biology of CSCs and EMT in the context of tumor hypoxia. PMID:22579961

  3. Dermatofibrosarcoma protuberans, a rare but locally aggressive tumor on finger: clinical and aeromedical considerations

    PubMed Central

    Chiang, Kwo-Tsao; Lee, Shih-Yu; Chu, Hsin

    2015-01-01

    Abstract Dermatofibrosarcoma protuberans (DFSP) is a rare, slow growing, locally infiltrative tumor of intermediate malignancy. It is mostly found on the trunk and head, rarely on hands. The course of evaluation and treatment of a young pilot with DFSP on left middle finger is reported. The clinical issues and aeromedical considerations of this rare tumor is discussed.

  4. Tumor size-independence of telomere length indicates an aggressive feature of HCC.

    PubMed

    Nakajima, Tomoki; Katagishi, Tatsuo; Moriguchi, Michihisa; Sekoguchi, Satoru; Nishikawa, Taichirou; Takashima, Hidetaka; Watanabe, Tadashi; Kimura, Hiroyuki; Minami, Masahito; Itoh, Yoshito; Kagawa, Keizo; Okanoue, Takeshi

    2004-12-24

    Using quantitative fluorescence in situ hybridization (Q-FISH), the average telomere length of hepatoma cells was assessed by the average telomeric signal intensity of cancer cells relative to that of stromal cells. We demonstrated first the applicability of Q-FISH for tissue sections by comparing Q-FISH and Southern blotting results. Tumors less than 50mm in diameter and with a relative telomeric intensity of less than 0.6 were categorized as group A and the remainder as group B. In group A, the telomere length correlated negatively with tumor size, whereas in group B there was no correlation. Compared with the group A tumors, the group B tumors were of significantly more advanced stage, showed higher telomerase and proliferative activities, and exhibited less differentiated histology. Therefore, we considered that a lack of correlation between telomere length and tumor size, namely, size-independence of telomere length, is associated with unfavorable clinicopathological features of hepatocellular carcinomas. PMID:15555545

  5. The Bladder Tumor Suppressor Protein TERE1 (UBIAD1)Modulates Cell Cholesterol: Implications for Tumor Progression

    PubMed Central

    McGarvey, Terry; Wang, Huiyi; Lal, Priti; Puthiyaveettil, Raghunath; Tomaszewski, John; Sepulveda, Jorge; Labelle, Ed; Weiss, Jayne S.; Nickerson, Michael L.; Kruth, Howard S.; Brandt, Wolfgang; Wessjohann, Ludger A.; Malkowicz, S. Bruce

    2011-01-01

    Convergent evidence implicates the TERE1 protein in human bladder tumor progression and lipid metabolism. Previously, reduced TERE1 expression was found in invasive urologic cancers and inhibited cell growth upon re-expression. A role in lipid metabolism was suggested by TERE1 binding to APOE, a cholesterol carrier, and to TBL2, a candidate protein in triglyceride disorders. Natural TERE1 mutations associate with Schnyder's corneal dystrophy, characterized by lipid accumulation. TERE1 catalyzes menaquinone synthesis, known to affect cholesterol homeostasis. To explore this relationship, we altered TERE1 and TBL2 dosage via ectopic expression and interfering RNA and measured cholesterol by Amplex red. Protein interactions of wild-type and mutant TERE1 with GST-APOE were evaluated by binding assays and molecular modeling. We conducted a bladder tumor microarray TERE1 expression analysis and assayed tumorigenicity of J82 cells ectopically expressing TERE1. TERE1 expression was reduced in a third of invasive specimens. Ectopic TERE1 expression in J82 bladder cancer cells dramatically inhibited nude mouse tumorigenesis. TERE1 and TBL2 proteins inversely modulated cellular cholesterol in HEK293 and bladder cancer cells from 20% to 50%. TERE1 point mutations affected APOE interactions, and resulted in cholesterol levels that differed from wild type. Elevated tumor cell cholesterol is known to affect apoptosis and growth signaling; thus, loss of TERE1 in invasive bladder cancer may represent a defect in menaquinone-mediated cholesterol homeostasis that contributes to progression. PMID:21740188

  6. Analysis of lung tumor initiation and progression in transgenic mice for Cre-inducible overexpression of Cul4A gene

    DOE PAGESBeta

    Wang, Yang; Xu, Zhidong; Mao, Jian -Hua; Hung, Ming -Szu; Hsieh, David; Au, Alfred; Jablons, David M.; You, Liang

    2015-06-08

    Background: Lung cancer is the leading cause of morbidity and death worldwide. Although the available lung cancer animal models have been informative and further propel our understanding of human lung cancer, they still do not fully recapitulate the complexities of human lung cancer. The pathogenesis of lung cancer remains highly elusive because of its aggressive biologic nature and considerable heterogeneity, compared to other cancers. The association of Cul4A amplification with aggressive tumor growth and poor prognosis has been suggested. Our previous study suggested that Cul4A is oncogenic in vitro, but its oncogenic role in vivo has not been studied. Methods:more » Viral delivery approaches have been used extensively to model cancer in mouse models. In our experiments, we used Cre-recombinase induced overexpression of the Cul4A gene in transgenic mice to study the role of Cul4A on lung tumor initiation and progression and have developed a new model of lung tumor development in mice harboring a conditionally expressed allele of Cul4A. Results: Here we show that the use of a recombinant adenovirus expressing Cre-recombinase (“AdenoCre”) to induce Cul4A overexpression in the lungs of mice allows controls of the timing and multiplicity of tumor initiation. Following our mouse models, we are able to study the potential role of Cul4A in the development and progression in pulmonary adenocarcinoma as well. Conclusion: Our findings indicate that Cul4A is oncogenic in vivo, and this mouse model is a tool in understanding the mechanisms of Cul4A in human cancers and for testing experimental therapies targeting Cul4A.« less

  7. Analysis of lung tumor initiation and progression in transgenic mice for Cre-inducible overexpression of Cul4A gene

    SciTech Connect

    Wang, Yang; Xu, Zhidong; Mao, Jian -Hua; Hung, Ming -Szu; Hsieh, David; Au, Alfred; Jablons, David M.; You, Liang

    2015-06-08

    Background: Lung cancer is the leading cause of morbidity and death worldwide. Although the available lung cancer animal models have been informative and further propel our understanding of human lung cancer, they still do not fully recapitulate the complexities of human lung cancer. The pathogenesis of lung cancer remains highly elusive because of its aggressive biologic nature and considerable heterogeneity, compared to other cancers. The association of Cul4A amplification with aggressive tumor growth and poor prognosis has been suggested. Our previous study suggested that Cul4A is oncogenic in vitro, but its oncogenic role in vivo has not been studied. Methods: Viral delivery approaches have been used extensively to model cancer in mouse models. In our experiments, we used Cre-recombinase induced overexpression of the Cul4A gene in transgenic mice to study the role of Cul4A on lung tumor initiation and progression and have developed a new model of lung tumor development in mice harboring a conditionally expressed allele of Cul4A. Results: Here we show that the use of a recombinant adenovirus expressing Cre-recombinase (“AdenoCre”) to induce Cul4A overexpression in the lungs of mice allows controls of the timing and multiplicity of tumor initiation. Following our mouse models, we are able to study the potential role of Cul4A in the development and progression in pulmonary adenocarcinoma as well. Conclusion: Our findings indicate that Cul4A is oncogenic in vivo, and this mouse model is a tool in understanding the mechanisms of Cul4A in human cancers and for testing experimental therapies targeting Cul4A.

  8. miR-221/222 control luminal breast cancer tumor progression by regulating different targets

    PubMed Central

    Dentelli, Patrizia; Traversa, Matteo; Rosso, Arturo; Togliatto, Gabriele; Olgasi, Cristina; Marchiò, Caterina; Provero, Paolo; Lembo, Antonio; Bon, Giulia; Annaratone, Laura; Sapino, Anna; Falcioni, Rita; Brizzi, Maria Felice

    2014-01-01

    α6β4 integrin is an adhesion molecule for laminin receptors involved in tumor progression. We present a link between β4 integrin expression and miR-221/222 in the most prevalent human mammary tumor: luminal invasive carcinomas (Lum-ICs). Using human primary tumors that display different β4 integrin expression and grade, we show that miR-221/222 expression inversely correlates with tumor proliferating index, Ki67. Interestingly, most high-grade tumors express β4 integrin and low miR-221/222 levels. We ectopically transfected miR-221/222 into a human-derived mammary tumor cell line that recapitulates the luminal subtype to investigate whether miR-221/222 regulates β4 expression. We demonstrate that miR-221/222 overexpression results in β4 expression downregulation, breast cancer cell proliferation, and invasion inhibition. The role of miR-221/222 in driving β4 integrin expression is also confirmed via mutating the miR-221/222 seed sequence for β4 integrin 3′UTR. Furthermore, we show that these 2 miRNAs are also key breast cancer cell proliferation and invasion regulators, via the post-transcriptional regulation of signal transducer and activator of transcription 5A (STAT5A) and of a disintegrin and metalloprotease-17 (ADAM-17). We further confirm these data by silencing ADAM-17, using a dominant-negative or an activated STAT5A form. miR-221/222-driven β4 integrin, STAT5A, and ADAM-17 did not occur in MCF-10A cells, denoted “normal” breast epithelial cells, indicating that the mechanism is cancer cell-specific.   These results provide the first evidence of a post-transcriptional mechanism that regulates β4 integrin, STAT5A, and ADAM-17 expression, thus controlling breast cancer cell proliferation and invasion. Pre-miR-221/222 use in the aggressive luminal subtype may be a powerful therapeutic anti-cancer strategy. PMID:24736554

  9. LCN2 Promoter Methylation Status as Novel Predictive Marker for Microvessel Density and Aggressive Tumor Phenotype in Breast Cancer Patients.

    PubMed

    Meka, Phanni bhushann; Jarjapu, Sarika; Nanchari, Santhoshi Rani; Vishwakarma, Sandeep Kumar; Edathara, Prajitha Mohandas; Gorre, Manjula; Cingeetham, Anuradha; Vuree, Sugunakar; Annamaneni, Sandhya; Dunna, Nageswara Rao; Mukta, Srinivasulu; B, Triveni; Satti, Vishnupriya

    2015-01-01

    LCN2 (Lipocalin 2) is a 25 KD secreted acute phase protein, reported to be a novel regulator of angiogenesis in breast cancer. Up regulation of LCN2 had been observed in multiple cancers including breast cancer, pancreatic cancer and ovarian cancer. However, the role of LCN2 promoter methylation in the formation of microvessels is poorly understood. The aim of this study was to analyze the association of LCN 2 promoter methylation with microvessel formation and tumor cell proliferation in breast cancer patients. The LCN2 promoter methylation status was studied in 64 breast cancer tumors by methylation specific PCR (MSP). Evaluation of microvessel density (MVD) and Ki67 cell proliferation index was achieved by immunohistochemical staining using CD34 and MIB-1 antibodies, respectively. LCN2 promoter unmethylation status was observed in 43 (67.2%) of breast cancer patients whereas LCN2 methylation status was seen in 21 (32.8%). Further, LCN2 promoter unmethylation status was associated with aggressive tumor phenotype and elevated mean MVD in breast cancer patients. PMID:26163623

  10. In vivo gene manipulation reveals the impact of stress-responsive MAPK pathways on tumor progression

    PubMed Central

    Kamiyama, Miki; Naguro, Isao; Ichijo, Hidenori

    2015-01-01

    It has been widely accepted that tumor cells and normal stromal cells in the host environment coordinately modulate tumor progression. Mitogen-activated protein kinase pathways are the representative stress-responsive cascades that exert proper cellular responses to divergent environmental stimuli. Genetically engineered mouse models and chemically induced tumorigenesis models have revealed that components of the MAPK pathway not only regulate the behavior of tumor cells themselves but also that of surrounding normal stromal cells in the host environment during cancer pathogenesis. The individual functions of MAPK pathway components in tumor initiation and progression vary depending on the stimuli and the stromal cell types involved in tumor progression, in addition to the molecular isoforms of the components and the origins of the tumor. Recent studies have indicated that MAPK pathway components synergize with environmental factors (e.g. tobacco smoke and diet) to affect tumor initiation and progression. Moreover, some components play distinct roles in the course of tumor progression, such as before and after the establishment of tumors. Hence, a comprehensive understanding of the multifaceted functions of MAPK pathway components in tumor initiation and progression is essential for the improvement of cancer therapy. In this review, we focus on the reports that utilized knockout, conditional knockout, and transgenic mice of MAPK pathway components to investigate the effects of MAPK pathway components on tumor initiation and progression in the host environment. PMID:25880821

  11. Intramedullary tumors in children

    PubMed Central

    Chatterjee, Sandip; Chatterjee, Uttara

    2011-01-01

    Intramedullary tumors of the spinal cord account for 35-40% of intraspinal tumors in children. The biological behavior of these tumors is of slow progression, and hence aggressive surgery has been advocated. Surgical adjuncts include use of intraoperative neurophysiological monitoring, preoperative ultrasound, microsurgical techniques and ultrasonic suction devices. Osteoplastic laminoplasty approaches avoid post-laminectomy deformities in younger children. Postoperative radiotherapy and more recently chemotherapy regimes have been proposed for incompletely resected tumors. PMID:22069435

  12. Postictal Magnetic Resonance Imaging Changes Masquerading as Brain Tumor Progression: A Case Series

    PubMed Central

    Dunn-Pirio, Anastasie M.; Billakota, Santoshi; Peters, Katherine B.

    2016-01-01

    Seizures are common among patients with brain tumors. Transient, postictal magnetic resonance imaging abnormalities are a long recognized phenomenon. However, these radiographic changes are not as well studied in the brain tumor population. Moreover, reversible neuroimaging abnormalities following seizure activity may be misinterpreted for tumor progression and could consequently result in unnecessary tumor-directed treatment. Here, we describe two cases of patients with brain tumors who developed peri-ictal pseudoprogression and review the relevant literature. PMID:27462237

  13. DEC1 and DEC2 Crosstalk between Circadian Rhythm and Tumor Progression

    PubMed Central

    Sato, Fuyuki; Bhawal, Ujjal K.; Yoshimura, Tomohiro; Muragaki, Yasuteru

    2016-01-01

    Clock genes, major regulators of circadian rhythm, are involved in tumor progression. We have shown that clock genes basic helix-loop-helix (BHLH) transcription factors, differentiated embryonic chondrocyte gene 1 (DEC1/BHLHE40/Sharp2/Stra13) and DEC2 (BHLHE41/Sharp1) play important roles in circadian rhythm, cell proliferation, apoptosis, hypoxia response, various stresses, and epithelial-to-mesenchymal transition (EMT) of tumor cells. Various stresses, such as exposure to transforming growth factor-beta (TGF-β), hypoxia, cytokines, serum-free, and anti-tumor drugs affect DEC1 and DEC2 expression. An increased or decreased expression of DEC1 and DEC2 regulated tumor progression. However, DEC1 and DEC2 have opposite effects in tumor progression, where the reason behind remains unclear. We found that DEC2 has circadian expression in implanted mouse sarcoma cells, suggesting that DEC2 regulates tumor progression under circadian rhythm. In addition to that, we showed that DEC1 and DEC2 regulate target genes via positive or negative feedback system in tumor progression. We propose that DEC1 and DEC2 act as an accelerator or a brake in tumor progression. In this review, we summarize current progress of knowledge in the function of DEC1 and DEC2 genes in tumor progression. PMID:26819638

  14. Glycoproteomic Analysis of Prostate Cancer Tissues by SWATH Mass Spectrometry Discovers N-acylethanolamine Acid Amidase and Protein Tyrosine Kinase 7 as Signatures for Tumor Aggressiveness*

    PubMed Central

    Liu, Yansheng; Chen, Jing; Sethi, Atul; Li, Qing K.; Chen, Lijun; Collins, Ben; Gillet, Ludovic C. J.; Wollscheid, Bernd; Zhang, Hui; Aebersold, Ruedi

    2014-01-01

    The identification of biomarkers indicating the level of aggressiveness of prostate cancer (PCa) will address the urgent clinical need to minimize the general overtreatment of patients with non-aggressive PCa, who account for the majority of PCa cases. Here, we isolated formerly N-linked glycopeptides from normal prostate (n = 10) and from non-aggressive (n = 24), aggressive (n = 16), and metastatic (n = 25) PCa tumor tissues and analyzed the samples using SWATH mass spectrometry, an emerging data-independent acquisition method that generates a single file containing fragment ion spectra of all ionized species of a sample. The resulting datasets were searched using a targeted data analysis strategy in which an a priori spectral reference library representing known N-glycosites of the human proteome was used to identify groups of signals in the SWATH mass spectrometry data. On average we identified 1430 N-glycosites from each sample. Out of those, 220 glycoproteins showed significant quantitative changes associated with diverse biological processes involved in PCa aggressiveness and metastasis and indicated functional relationships. Two glycoproteins, N-acylethanolamine acid amidase and protein tyrosine kinase 7, that were significantly associated with aggressive PCa in the initial sample cohort were further validated in an independent set of patient tissues using tissue microarray analysis. The results suggest that N-acylethanolamine acid amidase and protein tyrosine kinase 7 may be used as potential tissue biomarkers to avoid overtreatment of non-aggressive PCa. PMID:24741114

  15. Tumor-propagating cells and Yap/Taz activity contribute to lung tumor progression and metastasis

    PubMed Central

    Lau, Allison N; Curtis, Stephen J; Fillmore, Christine M; Rowbotham, Samuel P; Mohseni, Morvarid; Wagner, Darcy E; Beede, Alexander M; Montoro, Daniel T; Sinkevicius, Kerstin W; Walton, Zandra E; Barrios, Juliana; Weiss, Daniel J; Camargo, Fernando D; Wong, Kwok-Kin; Kim, Carla F

    2014-01-01

    Metastasis is the leading cause of morbidity for lung cancer patients. Here we demonstrate that murine tumor propagating cells (TPCs) with the markers Sca1 and CD24 are enriched for metastatic potential in orthotopic transplantation assays. CD24 knockdown decreased the metastatic potential of lung cancer cell lines resembling TPCs. In lung cancer patient data sets, metastatic spread and patient survival could be stratified with a murine lung TPC gene signature. The TPC signature was enriched for genes in the Hippo signaling pathway. Knockdown of the Hippo mediators Yap1 or Taz decreased in vitro cellular migration and transplantation of metastatic disease. Furthermore, constitutively active Yap was sufficient to drive lung tumor progression in vivo. These results demonstrate functional roles for two different pathways, CD24-dependent and Yap/Taz-dependent pathways, in lung tumor propagation and metastasis. This study demonstrates the utility of TPCs for identifying molecules contributing to metastatic lung cancer, potentially enabling the therapeutic targeting of this devastating disease. PMID:24497554

  16. T cells from the tumor microenvironment of patients with progressive myeloma can generate strong, tumor-specific cytolytic responses to autologous, tumor-loaded dendritic cells

    NASA Astrophysics Data System (ADS)

    Dhodapkar, Madhav V.; Krasovsky, Joseph; Olson, Kara

    2002-10-01

    Most untreated cancer patients develop progressive tumors. We tested the capacity of T lymphocytes from patients with clinically progressive, multiple myeloma to develop killer function against fresh autologous tumor. In this malignancy, it is feasible to reproducibly evaluate freshly isolated tumor cells and T cells from the marrow tumor environment. When we did this with seven consecutive patients, with all clinical stages of disease, we did not detect reactivity to autologous cancer cells. However, both cytolytic and IFN--producing responses to autologous myeloma were generated in six of seven patients after stimulation ex vivo with dendritic cells that had processed autologous tumor cells. The antitumor effectors recognized fresh autologous tumor but not nontumor cells in the bone marrow, myeloma cell lines, dendritic cells loaded with tumor-derived Ig, or allogeneic tumor. Importantly, these CD8+ effectors developed with similar efficiency by using T cells from both the blood and the bone marrow tumor environment. Therefore, even in the setting of clinical tumor progression, the tumor bed of myeloma patients contains T cells that can be activated readily by dendritic cells to kill primary autologous tumor.

  17. NGF-induced TrkA/CD44 association is involved in tumor aggressiveness and resistance to lestaurtinib

    PubMed Central

    Corbet, Cyril; Génot, Elisabeth; Adriaenssens, Eric; Chassat, Thierry; Bertucci, François; Daubon, Thomas; Magné, Nicolas

    2015-01-01

    There is accumulating evidence that TrkA and its ligand Nerve Growth Factor (NGF) are involved in cancer development. Staurosporine derivatives such as K252a and lestaurtinib have been developed to block TrkA kinase signaling, but no clinical trial has fully demonstrated their therapeutic efficacy. Therapeutic failures are likely due to the existence of intrinsic signaling pathways in cancer cells that impede or bypass the effects of TrkA tyrosine kinase inhibitors. To verify this hypothesis, we combined different approaches including mass spectrometry proteomics, co-immunoprecipitation and proximity ligation assays. We found that NGF treatment induced CD44 binding to TrkA at the plasma membrane and subsequent activation of the p115RhoGEF/RhoA/ROCK1 pathway to stimulate breast cancer cell invasion. The NGF-induced CD44 signaling was independent of TrkA kinase activity. Moreover, both TrkA tyrosine kinase inhibition with lestaurtinib and CD44 silencing with siRNA inhibited cell growth in vitro as well as tumor development in mouse xenograft model; combined treatment significantly enhanced the antineoplastic effects of either treatment alone. Altogether, our results demonstrate that NGF-induced tyrosine kinase independent TrkA signaling through CD44 was sufficient to maintain tumor aggressiveness. Our findings provide an alternative mechanism of cancer resistance to lestaurtinib and indicate that dual inhibition of CD44 and TrkA tyrosine kinase activity may represent a novel therapeutic strategy. PMID:25840418

  18. (1) H NMR spectroscopy of glioblastoma stem-like cells identifies alpha-aminoadipate as a marker of tumor aggressiveness.

    PubMed

    Rosi, Antonella; Ricci-Vitiani, Lucia; Biffoni, Mauro; Grande, Sveva; Luciani, Anna Maria; Palma, Alessandra; Runci, Daniele; Cappellari, Marianna; De Maria, Ruggero; Guidoni, Laura; Pallini, Roberto; Viti, Vincenza

    2015-03-01

    Patients suffering from glioblastoma multiforme (GBM) face a poor prognosis with median survival of about 14 months. High recurrence rate and failure of conventional treatments are attributed to the presence of GBM cells with stem-like properties (GSCs). Metabolite profiles of 42 GSC lines established from the tumor tissue of adult GBM patients were screened with (1) H NMR spectroscopy and compared with human neural progenitor cells from human adult olfactory bulb (OB-NPCs) and from the developing human brain (HNPCs). A first subset (n=12) of GSCs exhibited a dramatic accumulation of the metabolite α-aminoadipate (αAAD), product of the oxidation of α-aminoadipic semialdehyde catalyzed by the ALDH7A1 aldehyde dehydrogenase (ALDH) family in lysine catabolism. αAAD was low/not detectable in a second GSC subset (n=13) with the same neural metabolic profile as well as in a third GSC subset (n=17) characterized by intense lipid signals. Likewise, αAAD was not detected in the spectra of OB-NPCs or HNPCs. Inhibition of mitochondrial ATP synthase by oligomycin treatment revealed that the lysine degradative pathway leading to αAAD formation proceeds through saccharopine, as usually observed in developing brain. Survival curves indicated that high αAAD levels in GSCs significantly correlated with poor patient survival, similarly to prostate and non-small-cell-lung cancers, where activity of ALDH7A1 correlates with tumor aggressiveness. PMID:25581615

  19. β-Catenin Signaling Increases during Melanoma Progression and Promotes Tumor Cell Survival and Chemoresistance

    PubMed Central

    Sinnberg, Tobias; Menzel, Moritz; Ewerth, Daniel; Sauer, Birgit; Schwarz, Michael; Schaller, Martin; Garbe, Claus; Schittek, Birgit

    2011-01-01

    Beta-catenin plays an important role in embryogenesis and carcinogenesis by controlling either cadherin-mediated cell adhesion or transcriptional activation of target gene expression. In many types of cancers nuclear translocation of beta-catenin has been observed. Our data indicate that during melanoma progression an increased dependency on the transcriptional function of beta-catenin takes place. Blockade of beta-catenin in metastatic melanoma cell lines efficiently induces apoptosis, inhibits proliferation, migration and invasion in monolayer and 3-dimensional skin reconstructs and decreases chemoresistance. In addition, subcutaneous melanoma growth in SCID mice was almost completely inhibited by an inducible beta-catenin knockdown. In contrast, the survival of benign melanocytes and primary melanoma cell lines was less affected by beta-catenin depletion. However, enhanced expression of beta-catenin in primary melanoma cell lines increased invasive capacity in vitro and tumor growth in the SCID mouse model. These data suggest that beta-catenin is an essential survival factor for metastatic melanoma cells, whereas it is dispensable for the survival of benign melanocytes and primary, non-invasive melanoma cells. Furthermore, beta-catenin increases tumorigenicity of primary melanoma cell lines. The differential requirements for beta-catenin signaling in aggressive melanoma versus benign melanocytic cells make beta-catenin a possible new target in melanoma therapy. PMID:21858114

  20. MicroRNA-202 inhibits tumor progression by targeting LAMA1 in esophageal squamous cell carcinoma.

    PubMed

    Meng, Xiangrui; Chen, Xiaoqi; Lu, Peng; Ma, Wang; Yue, Dongli; Song, Lijie; Fan, Qingxia

    2016-05-13

    Esophageal squamous cell carcinoma (ESCC) is one of the most aggressive malignancies in the gastrointestinal tract. Emerging studies have indicated that microRNAs (miRNAs) are strongly implicated in the development and progression of ESCC. Here, we focused on the function and the underlying molecular mechanism of miR-202 in ESCC. The results showed that miR-202 was significantly down-regulated in ESCC tissues and cell lines. Overexpression of miR-202 in ECa-109 and KYSE-510 cells markedly suppressed cell proliferation and cell migration, and induced cell apoptosis. Furthermore, laminin α1 (LAMA1) expression was frequently positive in ESCC tissues and inversely correlated with miR-202 expression. Then we demonstrated that miR-202 targeted 3'-untranslated region (UTR) of LAMA1 and inhibited its protein expression. Additionally, LAMA1 overexpression rescued the proliferation inhibition and cell apoptosis elevation induced by miR-202. MiR-202 also inhibited the protein expression of p-FAK and p-Akt, which were all reversed by LAMA1 overexpression. Taken together, these findings suggest that miR-202 may function as a novel tumor suppressor in ESCC by repressing cell proliferation and migration, and its biological effects may attribute the inhibition of LAMA1-mediated FAK-PI3K-Akt signaling. PMID:27045085

  1. TLR5 signaling, commensal microbiota and systemic tumor promoting inflammation: the three parcae of malignant progression

    PubMed Central

    Rutkowski, Melanie R; Conejo-Garcia, Jose R

    2015-01-01

    We have reported that TLR5-mediated recognition of commensal microbiota modulates systemic tumor-promoting inflammation and malignant progression of tumors at distal locations. Approximately 7–10% of the general population harbors a deleterious single nucleotide polymorphism in TLR5, implicating a novel role for genetic variation during the initiation and progression of cancer. PMID:26405577

  2. YKL-40/CHI3L1 drives inflammation on the road of tumor progression.

    PubMed

    Libreros, Stephania; Iragavarapu-Charyulu, Vijaya

    2015-12-01

    Inflammation plays a vital role at different stages of tumor progression. The development of tumors is affected by inflammatory mediators produced by the tumor and the host. YKL-40/chitinase-3-like-1 protein is often up-regulated in inflammation-associated diseases. With the use of chronic inflammatory disease systems, we describe the role of YKL-40/chitinase-3-like-1 protein in enhancing the inflammatory response and its implications in tumorigenesis. We also discuss how pre-existing inflammation enhances tumor growth and metastasis. In this mini-review, we highlight the effect of YKL-40/chitinase-3-like-1 protein-associated inflammation in promoting tumor progression. PMID:26310833

  3. NK Cells, Tumor Cell Transition, and Tumor Progression in Solid Malignancies: New Hints for NK-Based Immunotherapy?

    PubMed Central

    Huergo-Zapico, Leticia; Parodi, Monica; Pedrazzi, Marco; Mingari, Maria Cristina; Sparatore, Bianca; Gonzalez, Segundo; Olive, Daniel; Bottino, Cristina

    2016-01-01

    Several evidences suggest that NK cells can patrol the body and eliminate tumors in their initial phases but may hardly control established solid tumors. Multiple factors, including the transition of tumor cells towards a proinvasive/prometastatic phenotype, the immunosuppressive effect of the tumor microenvironment, and the tumor structure complexity, may account for limited NK cell efficacy. Several putative mechanisms of NK cell suppression have been defined in these last years; conversely, the cross talk between NK cells and tumor cells undergoing different transitional phases remains poorly explored. Nevertheless, recent in vitro studies and immunohistochemical analyses on tumor biopsies suggest that NK cells could not only kill tumor cells but also influence their evolution. Indeed, NK cells may induce tumor cells to change the expression of HLA-I, PD-L1, or NKG2D-L and modulate their susceptibility to the immune response. Moreover, NK cells may be preferentially located in the borders of tumor masses, where, indeed, tumor cells can undergo Epithelial-to-Mesenchymal Transition (EMT) acquiring prometastatic phenotype. Finally, the recently highlighted role of HMGB1 both in EMT and in amplifying the recruitment of NK cells provides further hints on a possible effect of NK cells on tumor progression and fosters new studies on this issue. PMID:27294158

  4. Nano-Scaled Particles of Titanium Dioxide Convert Benign Mouse Fibrosarcoma Cells into Aggressive Tumor Cells

    PubMed Central

    Onuma, Kunishige; Sato, Yu; Ogawara, Satomi; Shirasawa, Nobuyuki; Kobayashi, Masanobu; Yoshitake, Jun; Yoshimura, Tetsuhiko; Iigo, Masaaki; Fujii, Junichi; Okada, Futoshi

    2009-01-01

    Nanoparticles are prevalent in both commercial and medicinal products; however, the contribution of nanomaterials to carcinogenesis remains unclear. We therefore examined the effects of nano-sized titanium dioxide (TiO2) on poorly tumorigenic and nonmetastatic QR-32 fibrosarcoma cells. We found that mice that were cotransplanted subcutaneously with QR-32 cells and nano-sized TiO2, either uncoated (TiO2−1, hydrophilic) or coated with stearic acid (TiO2−2, hydrophobic), did not form tumors. However, QR-32 cells became tumorigenic after injection into sites previously implanted with TiO2−1, but not TiO2−2, and these developing tumors acquired metastatic phenotypes. No differences were observed either histologically or in inflammatory cytokine mRNA expression between TiO2−1 and TiO2−2 treatments. However, TiO2−2, but not TiO2−1, generated high levels of reactive oxygen species (ROS) in cell-free conditions. Although both TiO2−1 and TiO2−2 resulted in intracellular ROS formation, TiO2−2 elicited a stronger response, resulting in cytotoxicity to the QR-32 cells. Moreover, TiO2−2, but not TiO2−1, led to the development of nuclear interstices and multinucleate cells. Cells that survived the TiO2 toxicity acquired a tumorigenic phenotype. TiO2-induced ROS formation and its related cell injury were inhibited by the addition of antioxidant N-acetyl-l-cysteine. These results indicate that nano-sized TiO2 has the potential to convert benign tumor cells into malignant ones through the generation of ROS in the target cells. PMID:19815711

  5. Antiphospholipid antibodies promote tissue factor-dependent angiogenic switch and tumor progression.

    PubMed

    Wu, Yuan-Yuan; V Nguyen, Andrew; Wu, Xiao-Xuan; Loh, Mingyu; Vu, Michelle; Zou, Yiyu; Liu, Qiang; Guo, Peng; Wang, Yanhua; Montgomery, Leslie L; Orlofsky, Amos; Rand, Jacob H; Lin, Elaine Y

    2014-12-01

    Progression to an angiogenic state is a critical event in tumor development, yet few patient characteristics have been identified that can be mechanistically linked to this transition. Antiphospholipid autoantibodies (aPLs) are prevalent in many human cancers and can elicit proangiogenic expression in several cell types, but their role in tumor biology is unknown. Herein, we observed that the elevation of circulating aPLs among breast cancer patients is specifically associated with invasive-stage tumors. By using multiple in vivo models of breast cancer, we demonstrated that aPL-positive IgG from patients with autoimmune disease rapidly accelerates tumor angiogenesis and consequent tumor progression, particularly in slow-growing avascular tumors. The action of aPLs was local to the tumor site and elicited leukocytic infiltration and tumor invasion. Tumor cells treated with aPL-positive IgG expressed multiple proangiogenic genes, including vascular endothelial growth factor, tissue factor (TF), and colony-stimulating factor 1. Knockdown and neutralization studies demonstrated that the effects of aPLs on tumor angiogenesis and growth were dependent on tumor cell-derived TF. Tumor-derived TF was essential for the development of pericyte coverage of tumor microvessels and aPL-induced tumor cell expression of chemokine ligand 2, a mediator of pericyte recruitment. These findings identify antiphospholipid autoantibodies as a potential patient-specific host factor promoting the transition of indolent tumors to an angiogenic malignant state through a TF-mediated pathogenic mechanism. PMID:25451155

  6. Role of Collagen Matrix in Tumor Angiogenesis and Glioblastoma Multiforme Progression

    PubMed Central

    Mammoto, Tadanori; Jiang, Amanda; Jiang, Elisabeth; Panigrahy, Dipak; Kieran, Mark W.; Mammoto, Akiko

    2014-01-01

    Glioblastoma is a highly vascularized brain tumor, and antiangiogenic therapy improves its progression-free survival. However, current antiangiogenic therapy induces serious adverse effects including neuronal cytotoxicity and tumor invasiveness and resistance to therapy. Although it has been suggested that the physical microenvironment has a key role in tumor angiogenesis and progression, the mechanism by which physical properties of extracellular matrix control tumor angiogenesis and glioblastoma progression is not completely understood. Herein we show that physical compaction (the process in which cells gather and pack together and cause associated changes in cell shape and size) of human glioblastoma cell lines U87MG, U251, and LN229 induces expression of collagen types IV and VI and the collagen crosslinking enzyme lysyl oxidase and up-regulates in vitro expression of the angiogenic factor vascular endothelial growth factor. The lysyl oxidase inhibitor β-aminopropionitrile disrupts collagen structure in the tumor and inhibits tumor angiogenesis and glioblastoma multiforme growth in a mouse orthotopic brain tumor model. Similarly, d-penicillamine, which inhibits lysyl oxidase enzymatic activity by depleting intracerebral copper, also exhibits antiangiogenic effects on brain tumor growth in mice. These findings suggest that tumor microenvironment controlled by collagen structure is important in tumor angiogenesis and brain tumor progression. PMID:23928381

  7. RUNX2 and the PI3K/AKT axis reciprocal activation as a driving force for tumor progression.

    PubMed

    Cohen-Solal, Karine A; Boregowda, Rajeev K; Lasfar, Ahmed

    2015-01-01

    From the first reported role of the transcription factor RUNX2 in osteoblast and chondrocyte differentiation and migration to its involvement in promigratory/proinvasive behavior of breast, prostate, and thyroid cancer cells, osteosarcoma, or melanoma cells, RUNX2 currently emerges as a key player in metastasis. In this review, we address the interaction of RUNX2 with the PI3K/AKT signaling pathway, one of the critical axes controlling cancer growth and metastasis. AKT, either by directly phosphorylating/activating RUNX2 or phosphorylating/inactivating regulators of RUNX2 stability or activity, contributes to RUNX2 transcriptional activity. Reciprocally, the activation of the PI3K/AKT pathway by RUNX2 regulation of its different components has been described in non-transformed and transformed cells. This mutual activation in the context of cancer cells exhibiting constitutive AKT activation and high levels of RUNX2 might constitute a major driving force in tumor progression and aggressiveness. PMID:26204939

  8. Fibroblast activation protein α in tumor microenvironment: Recent progression and implications (Review)

    PubMed Central

    ZI, FUMING; HE, JINGSONG; HE, DONGHUA; LI, YI; YANG, LI; CAI, ZHEN

    2015-01-01

    Accumulated evidence has demonstrated that the microenvironment of a given tumor is important in determining its drug resistance, tumorigenesis, progression and metastasis. These microenvironments, like tumor cells, are vital targets for cancer therapy. The cross-talk between tumor cells and cancer-associated fibroblasts (CAFs, alternatively termed activated fibroblasts) is crucial in regulating the drug resistance, tumorigenesis, neoplastic progression, angiogenesis, invasion and metastasis of a tumor. Fibroblast activation protein α (FAPα) is a transmembrane serine protease and is highly expressed on CAFs present in >90% of human epithelial neoplasms. FAPα activity, alongside that of gelatinase and type I collagenase, has become increasingly important in cancer therapy due to its effectiveness in modulating tumor behavior. In this review, recent progression in the knowledge of the role of FAPα in tumor microenvironments is discussed. PMID:25593080

  9. MICROBIAL DRIVEN TLR5-DEPENDENT SIGNALING GOVERNS DISTAL MALIGNANT PROGRESSION THROUGH TUMOR-PROMOTING INFLAMMATION

    PubMed Central

    Rutkowski, Melanie R.; Stephen, Tom L.; Svoronos, Nikolaos; Allegrezza, Michael J.; Tesone, Amelia J.; Perales-Puchalt, Alfredo; Brencicova, Eva; Escovar-Fadul, Ximena; Nguyen, Jenny M.; Cadungog, Mark G.; Zhang, Rugang; Salatino, Mariana; Tchou, Julia; Rabinovich, Gabriel A.; Conejo-Garcia, Jose R.

    2014-01-01

    The dominant TLR5R392X polymorphism abrogates flagellin responses in >7% of humans. We report that TLR5-dependent commensal bacteria drive malignant progression at extra-mucosal locations by increasing systemic IL-6, which drives mobilization of myeloid derived suppressor cells (MDSCs). Mechanistically, expanded granulocytic MDSCs cause γδ lymphocytes in TLR5-responsive tumors to secrete galectin-1, dampening anti-tumor immunity and accelerating malignant progression. In contrast, IL-17 is consistently up-regulated in TLR5-unresponsive tumor-bearing mice, but only accelerates malignant progression in IL-6-unresponsive tumors. Importantly, depletion of commensal bacteria abrogates TLR5-dependent differences in tumor growth. Contrasting differences in inflammatory cytokines and malignant evolution are recapitulated in TLR5-responsive/unresponsive ovarian and breast cancer patients. Therefore, inflammation, anti-tumor immunity and the clinical outcome of cancer patients are influenced by a common TLR5 polymorphism. PMID:25533336

  10. Inhibition of focal adhesion kinase (FAK) activity prevents anchorage-independent ovarian carcinoma cell growth and tumor progression

    PubMed Central

    Ward, Kristy K.; Tancioni, Isabelle; Lawson, Christine; Miller, Nichol L.G.; Jean, Christine; Chen, Xiao Lei; Uryu, Sean; Kim, Josephine; Tarin, David; Stupack, Dwayne G.; Plaxe, Steven C.; Schlaepfer, David D.

    2013-01-01

    Recurrence and spread of ovarian cancer is the 5th leading cause of death for women in the United States. Focal adhesion kinase (FAK) is a cytoplasmic protein-tyrosine kinase located on chromosome 8q24.3 (gene is Ptk2), a site commonly amplified in serous ovarian cancer. Elevated FAK mRNA levels in serous ovarian carcinoma are associated with decreased (logrank P = 0.0007, hazard ratio 1.43) patient overall survival, but how FAK functions in tumor progression remains undefined. We have isolated aggressive ovarian carcinoma cells termed ID8-IP after intraperitoneal (IP) growth of murine ID8 cells in C57Bl6 mice. Upon orthotopic implantation within the periovarian bursa space, ID8-IP cells exhibit greater tumor growth, local and distant metastasis, and elevated numbers of ascites-associated cells compared to parental ID8 cells. ID8-IP cells exhibit enhanced growth under non-adherent conditions with elevated FAK and c-Src tyrosine kinase activation compared to parental ID8 cells. In vitro, the small molecule FAK inhibitor (Pfizer, PF562,271, PF-271) at 0.1 uM selectively prevented anchorage-independent ID8-IP cell growth with the inhibition of FAK tyrosine (Y)397 but not c-Src Y416 phosphorylation. Oral PF-271 administration (30 mg/kg, twice daily) blocked FAK but not c-Src tyrosine phosphorylation in ID8-IP tumors. This was associated with decreased tumor size, prevention of peritoneal metastasis, reduced tumor-associated endothelial cell number, and increased tumor cell-associated apoptosis. FAK knockdown and re-expression assays showed that FAK activity selectively promoted anchorage-independent ID8-IP cell survival. These results support the continued evaluation of FAK inhibitors as a promising clinical treatment for ovarian cancer. PMID:23275034

  11. Upregulation of long noncoding RNA LOC100507661 promotes tumor aggressiveness in thyroid cancer.

    PubMed

    Kim, Daham; Lee, Woo Kyung; Jeong, Seonhyang; Seol, Mi-Youn; Kim, Hyunji; Kim, Kyung-Sup; Lee, Eun Jig; Lee, Jandee; Jo, Young Suk

    2016-08-15

    Recent advances in next-generation sequencing have revealed a variety of long noncoding RNAs (lncRNAs). However, studies of lncRNAs are at a very early stage, our knowledge of the biological functions and clinical implications remains limited. To investigate the roles of lncRNAs in thyroid cancers, we verified 56 lncRNAs identified as potential cancer-promoting genes in a previous study that analyzed 2394 tumor SNP arrays from 12 types of cancer. Based on verified sequence information in NCBI and Ensembl, we ultimately selected three candidate lncRNAs for detailed analysis. One of the candidates, LOC100507661, was strongly upregulated in thyroid cancer tissues relative to paired contralateral normal tissue. LOC100507661 was easily detectable in papillary and anaplastic thyroid cancer cell lines such as TPC1, BCPAP, C643, and 8505C, but not in the follicular thyroid cancer cell line FTC133. Stable overexpression of LOC100507661 promoted cell proliferation, migration, and invasion of thyroid cancer cells. Lymph node metastasis and BRAF V600E mutations were more frequent in papillary thyroid cancers with high LOC100507661 expression. Our data demonstrate that LOC100507661 expression is elevated in human thyroid cancer and may play a critical role in thyroid carcinogenesis. PMID:27151833

  12. Epithelial derived CTGF promotes breast tumor progression via inducing EMT and collagen I fibers deposition

    PubMed Central

    Zhao, Zhen; Sheng, Jianting; Wang, Jiang; Liu, Jiyong; Cui, Kemi; Chang, Jenny; Zhao, Hong; Wong, Stephen

    2015-01-01

    Interactions among tumor cells, stromal cells, and extracellular matrix compositions are mediated through cytokines during tumor progression. Our analysis of 132 known cytokines and growth factors in published clinical breast cohorts and our 84 patient-derived xenograft models revealed that the elevated connective tissue growth factor (CTGF) in tumor epithelial cells significantly correlated with poor clinical prognosis and outcomes. CTGF was able to induce tumor cell epithelial-mesenchymal transition (EMT), and promote stroma deposition of collagen I fibers to stimulate tumor growth and metastasis. This process was mediated through CTGF-tumor necrosis factor receptor I (TNFR1)-IκB autocrine signaling. Drug treatments targeting CTGF, TNFR1, and IκB signaling each prohibited the EMT and tumor progression. PMID:26318291

  13. A novel thermal treatment modality for controlling breast tumor growth and progression.

    PubMed

    Xie, Yifan; Liu, Ping; Xu, Lisa X

    2012-01-01

    The new concept of keeping primary tumor under control in situ to suppress distant foci sheds light on the novel treatment of metastatic tumor. Hyperthermia is considered as one of the means for controlling tumor growth. In this study, a novel thermal modality was built to introduce hyperthermia effect on tumor to suppress its growth and progression using 4T1 murine mammary carcinoma, a common animal model of metastatic breast cancer. A mildly raised temperature (i.e.39°C) was imposed on the skin surface of the implanted tumor using a thermal heating pad. Periodic heating (12 hours per day) was carried out for 3 days, 7 days, 14 days, and 21 days, respectively. The tumor growth rate was found significantly decreased in comparison to the control without hyperthermia. Biological evidences associated with tumor angiogenesis and metastasis were examined using histological analyses. Accordingly, the effect of mild hyperthermia on immune cell infiltration into tumors was also investigated. It was demonstrated that a delayed tumor growth and malignancy progression was achieved by mediating tumor cell apoptosis, vascular injury, degrading metastasis potential and as well as inhibiting the immunosuppressive cell myeloid derived suppressor cells (MDSCs) recruitment. Further mechanistic studies will be performed to explore the quantitative relationship between tumor progression and thermal dose in the near future. PMID:23367225

  14. Protein Kinase A Effects of an Expressed PRKAR1A Mutation Associated with Aggressive Tumors

    PubMed Central

    Meoli, Elise; Bossis, Ioannis; Cazabat, Laure; Mavrakis, Manos; Horvath, Anelia; Stergiopoulos, Sotiris; Shiferaw, Miriam L.; Fumey, Glawdys; Perlemoine, Karine; Muchow, Michael; Robinson-White, Audrey; Weinberg, Frank; Nesterova, Maria; Patronas, Yianna; Groussin, Lionel; Bertherat, Jérôme; Stratakis, Constantine A.

    2011-01-01

    Most PRKAR1A tumorigenic mutations lead to nonsense mRNA that is decayed; tumor formation has been associated with an increase in type II protein kinase A (PKA) subunits. The IVS6+1G>T PRKAR1A mutation leads to a protein lacking exon 6 sequences [R1αΔ184-236 (R1αΔ6)]. We compared in vitro R1αΔ6 with wild-type (wt) R1α. We assessed PKA activity and subunit expression, phosphorylation of target molecules, and properties of wt-R1α and mutant (mt) R1α; we observed by confocal microscopy R1α tagged with green fluorescent protein and its interactions with Cerulean-tagged catalytic subunit (Cα). Introduction of the R1αΔ6 led to aberrant cellular morphology and higher PKA activity but no increase in type II PKA subunits. There was diffuse, cytoplasmic localization of R1α protein in wt-R1α– and R1αΔ6-transfected cells but the former also exhibited discrete aggregates of R1α that bound Cα; these were absent in R1αΔ6-transfected cells and did not bind Cα at baseline or in response to cyclic AMP. Other changes induced by R1αΔ6 included decreased nuclear Cα. We conclude that R1αΔ6 leads to increased PKA activity through the mt-R1α decreased binding to Cα and does not involve changes in other PKA subunits, suggesting that a switch to type II PKA activity is not necessary for increased kinase activity or tumorigenesis. PMID:18451138

  15. The retinoblastoma tumor suppressor controls androgen signaling and human prostate cancer progression.

    PubMed

    Sharma, Ankur; Yeow, Wen-Shuz; Ertel, Adam; Coleman, Ilsa; Clegg, Nigel; Thangavel, Chellappagounder; Morrissey, Colm; Zhang, Xiaotun; Comstock, Clay E S; Witkiewicz, Agnieszka K; Gomella, Leonard; Knudsen, Erik S; Nelson, Peter S; Knudsen, Karen E

    2010-12-01

    Retinoblastoma (RB; encoded by RB1) is a tumor suppressor that is frequently disrupted in tumorigenesis and acts in multiple cell types to suppress cell cycle progression. The role of RB in tumor progression, however, is poorly defined. Here, we have identified a critical role for RB in protecting against tumor progression through regulation of targets distinct from cell cycle control. In analyses of human prostate cancer samples, RB loss was infrequently observed in primary disease and was predominantly associated with transition to the incurable, castration-resistant state. Further analyses revealed that loss of the RB1 locus may be a major mechanism of RB disruption and that loss of RB function was associated with poor clinical outcome. Modeling of RB dysfunction in vitro and in vivo revealed that RB controlled nuclear receptor networks critical for tumor progression and that it did so via E2F transcription factor 1-mediated regulation of androgen receptor (AR) expression and output. Through this pathway, RB depletion induced unchecked AR activity that underpinned therapeutic bypass and tumor progression. In agreement with these findings, disruption of the RB/E2F/nuclear receptor axis was frequently observed in the transition to therapy resistance in human disease. Together, these data reveal what we believe to be a new paradigm for RB function in controlling prostate tumor progression and lethal tumor phenotypes. PMID:21099110

  16. [Aggressive angiomyxoma of the vulva. Case report and literature review].

    PubMed

    Nava Flores, Elda Lizeth; Alvarez Blanco, Mario A; Figueroa Vadillo, Jazmín; Cruz Ortiz, Humberto

    2009-10-01

    Aggressive angiomyxoma is a rare vulvovaginal, perineal or pelvic mesenchymal neoplasm with a marked tendency to local recurrence but does not metastasize. A case of an aggressive angiomyxoma of vulva in a 39-years-old women with an illness of one year prior to examination, with a slow and progressive growth of the left vulvar region, without other symptoms. During physical examination, a piriform tumor of 15x10 cm was found, located on the left labia majora, soft tissue dependent. Wide resection of the tumor were performed. Hystopathology reported an aggressive angiomyxoma of the vulva, with tumor in resection margins. The patient was treated with a 65Gy postsurgical radiotherapy and gosereline 3.6 mg monthly, during 6 cycles. Aggressive angiomyxoma is a rare neoplasm 150 cases has been reported. The treatment is surgical resection. Radiotherapy and hormonal adyuvant is not fully stablished. PMID:19902678

  17. The Role of Nitric Oxide Synthase Uncoupling in Tumor Progression

    PubMed Central

    Rabender, Christopher S.; Alam, Asim; Sundaresan, Gobalakrishnan; Cardnell, Robert J.; Yakovlev, Vasily A.; Mukhopadhyay, Nitai D.; Graves, Paul; Zweit, Jamal; Mikkelsen, Ross B.

    2015-01-01

    Here evidence suggests that nitric oxide synthases (NOS) of tumor cells, in contrast to normal tissues, synthesize predominantly superoxide and peroxynitrite. Based on HPLC analysis, the underlying mechanism for this uncoupling is a reduced tetrahydrobiopterin: dihydrobiopterin ratio (BH4:BH2) found in breast, colorectal, epidermoid and head and neck tumors compared to normal tissues. Increasing BH4:BH2 and reconstitution of coupled NOS activity in breast cancer cells with the BH4 salvage pathway precursor, sepiapterin, causes significant shifts in downstream signaling including increased cGMP-dependent protein kinase (PKG) activity, decreased β-catenin expression and TCF4 promoter activity, and reduced NF-κB promoter activity. Sepiapterin inhibited breast tumor cell growth in vitro and in vivo as measured by clonogenic assay, Ki67 staining and 18F-deoxyglucose positron emission tomography (FDG-PET). In summary, using diverse tumor types, it is demonstrated that the BH4:BH2 ratio is lower in tumor tissues and as a consequence nitric oxide synthase activity generates more peroxynitrite and superoxide anion than nitric oxide resulting in important tumor growth promoting and anti-apoptotic signaling properties. Implications The synthetic BH4, Kuvan®, is used to elevate BH4:BH2 in some phenylketonuria patients and to treat diseases associated with endothelial dysfunction suggesting a novel, testable approach for correcting an abnormality of tumor metabolism to control tumor growth. PMID:25724429

  18. Fibroblast-Mediated Collagen Remodeling Within the Tumor Microenvironment Facilitates Progression of Thyroid Cancers Driven by BrafV600E and Pten Loss.

    PubMed

    Jolly, Lee Ann; Novitskiy, Sergey; Owens, Phillip; Massoll, Nicole; Cheng, Nikki; Fang, Wei; Moses, Harold L; Franco, Aime T

    2016-04-01

    Contributions of the tumor microenvironment (TME) to progression in thyroid cancer are largely unexplored and may illuminate a basis for understanding rarer aggressive cases of this disease. In this study, we investigated the relationship between the TME and thyroid cancer progression in a mouse model where thyroid-specific expression of oncogenic BRAF and loss of Pten (Braf(V600E)/Pten(-/-)/TPO-Cre) leads to papillary thyroid cancers (PTC) that rapidly progress to poorly differentiated thyroid cancer (PDTC). We found that fibroblasts were recruited to the TME of Braf(V600E)/Pten(-/-)/TPO-Cre thyroid tumors. Conditioned media from cell lines established from these tumors, but not tumors driven by mutant H-ras, induced fibroblast migration and proliferation in vitro Notably, the extracellular matrix of Braf(V600E)/Pten(-/-)/TPO-Cre tumors was enriched with stromal-derived fibrillar collagen, compared with wild-type or Hras-driven tumors. Further, type I collagen enhanced the motility of Braf(V600E)/Pten(-/-)/TPO-Cre tumor cells in vitro In clinical specimens, we found COL1A1 and LOX to be upregulated in PTC and expressed at highest levels in PDTC and anaplastic thyroid cancer. Additionally, increased expression levels of COL1A1 and LOX were associated with decreased survival in thyroid cancer patients. Overall, our results identified fibroblast recruitment and remodeling of the extracellular matrix as pivotal features of the TME in promoting thyroid cancer progression, illuminating candidate therapeutic targets and biomarkers in advanced forms of this malignancy. Cancer Res; 76(7); 1804-13. ©2016 AACR. PMID:26818109

  19. Melanoma susceptibility as a complex trait: genetic variation controls all stages of tumor progression.

    PubMed

    Ferguson, B; Ram, R; Handoko, H Y; Mukhopadhyay, P; Muller, H K; Soyer, H P; Morahan, G; Walker, G J

    2015-05-28

    Susceptibility to most common cancers is likely to involve interaction between multiple low risk genetic variants. Although there has been great progress in identifying such variants, their effect on phenotype and the mechanisms by which they contribute to disease remain largely unknown. We have developed a mouse melanoma model harboring two mutant oncogenes implicated in human melanoma, CDK4(R24C) and NRAS(Q61K). In these mice, tumors arise from benign precursor lesions that are a recognized strong risk factor for this neoplasm in humans. To define molecular events involved in the pathway to melanoma, we have for the first time applied the Collaborative Cross (CC) to cancer research. The CC is a powerful resource designed to expedite discovery of genes for complex traits. We characterized melanoma genesis in more than 50 CC strains and observed tremendous variation in all traits, including nevus and melanoma age of onset and multiplicity, anatomical site predilection, time for conversion of nevi to melanoma and metastases. Intriguingly, neonatal ultraviolet radiation exposure exacerbated nevus and melanoma formation in most, but not all CC strain backgrounds, suggesting that genetic variation within the CC will help explain individual sensitivity to sun exposure, the major environmental skin carcinogen. As genetic variation brings about dramatic phenotypic diversity in a single mouse model, melanoma-related endophenotype comparisons provide us with information about mechanisms of carcinogenesis, such as whether melanoma incidence is dependent upon the density of pre-existing nevus cells. Mouse models have been used to examine the functional role of gene mutations in tumorigenesis. This work represents their next phase of development to study how biological variation greatly influences lesion onset and aggressiveness even in the setting of known somatic driver mutations. PMID:25088201

  20. The New Deal: A Potential Role for Secreted Vesicles in Innate Immunity and Tumor Progression

    PubMed Central

    Benito-Martin, Alberto; Di Giannatale, Angela; Ceder, Sophia; Peinado, Héctor

    2015-01-01

    Tumors must evade the immune system to survive and metastasize, although the mechanisms that lead to tumor immunoediting and their evasion of immune surveillance are far from clear. The first line of defense against metastatic invasion is the innate immune system that provides immediate defense through humoral immunity and cell-mediated components, mast cells, neutrophils, macrophages, and other myeloid-derived cells that protect the organism against foreign invaders. Therefore, tumors must employ different strategies to evade such immune responses or to modulate their environment, and they must do so prior metastasizing. Exosomes and other secreted vesicles can be used for cell–cell communication during tumor progression by promoting the horizontal transfer of information. In this review, we will analyze the role of such extracellular vesicles during tumor progression, summarizing the role of secreted vesicles in the crosstalk between the tumor and the innate immune system. PMID:25759690

  1. Accessing key steps of human tumor progression in vivo by using an avian embryo model

    NASA Astrophysics Data System (ADS)

    Hagedorn, Martin; Javerzat, Sophie; Gilges, Delphine; Meyre, Aurélie; de Lafarge, Benjamin; Eichmann, Anne; Bikfalvi, Andreas

    2005-02-01

    Experimental in vivo tumor models are essential for comprehending the dynamic process of human cancer progression, identifying therapeutic targets, and evaluating antitumor drugs. However, current rodent models are limited by high costs, long experimental duration, variability, restricted accessibility to the tumor, and major ethical concerns. To avoid these shortcomings, we investigated whether tumor growth on the chick chorio-allantoic membrane after human glioblastoma cell grafting would replicate characteristics of the human disease. Avascular tumors consistently formed within 2 days, then progressed through vascular endothelial growth factor receptor 2-dependent angiogenesis, associated with hemorrhage, necrosis, and peritumoral edema. Blocking of vascular endothelial growth factor receptor 2 and platelet-derived growth factor receptor signaling pathways by using small-molecule receptor tyrosine kinase inhibitors abrogated tumor development. Gene regulation during the angiogenic switch was analyzed by oligonucleotide microarrays. Defined sample selection for gene profiling permitted identification of regulated genes whose functions are associated mainly with tumor vascularization and growth. Furthermore, expression of known tumor progression genes identified in the screen (IL-6 and cysteine-rich angiogenic inducer 61) as well as potential regulators (lumican and F-box-only 6) follow similar patterns in patient glioma. The model reliably simulates key features of human glioma growth in a few days and thus could considerably increase the speed and efficacy of research on human tumor progression and preclinical drug screening. angiogenesis | animal model alternatives | glioblastoma

  2. Molecular Biomarkers of Cancer Stem/Progenitor Cells Associated with Progression, Metastases, and Treatment Resistance of Aggressive Cancers

    PubMed Central

    Mimeault, Murielle; Batra, Surinder K.

    2014-01-01

    The validation of novel diagnostic, prognostic, and predictive biomarkers and therapeutic targets in tumor cells is of critical importance for optimizing the choice and efficacy of personalized therapies. Importantly, recent advances have led to the identification of gene-expression signatures in cancer cells, including cancer stem/progenitor cells, in the primary tumors, exosomes, circulating tumor cells (CTC), and disseminated cancer cells at distant metastatic sites. The gene-expression signatures may help to improve the accuracy of diagnosis and predict the therapeutic responses and overall survival of patients with cancer. Potential biomarkers in cancer cells include stem cell–like markers [CD133, aldehyde dehydrogenase (ALDH), CD44, and CD24], growth factors, and their cognate receptors [epidermal growth factor receptor (EGFR), EGFRvIII, and HER2], molecules associated with epithelial–mesenchymal transition (EMT; vimentin, N-cadherin, snail, twist, and Zeb1), regulators of altered metabolism (phosphatidylinositol-3′ kinase/Akt/mTOR), and drug resistance (multidrug transporters and macrophage inhibitory cytokine-1). Moreover, different pluripotency-associated transcription factors (Oct3/4, Nanog, Sox2, and Myc) and microRNAs that are involved in the epigenetic reprogramming and acquisition of stem cell–like properties by cancer cells during cancer progression may also be exploited as molecular biomarkers to predict the risk of metastases, systemic treatment resistance, and disease relapse of patients with cancer. PMID:24273063

  3. Progress on the diagnosis and evaluation of brain tumors

    PubMed Central

    Gao, Huile

    2013-01-01

    Abstract Brain tumors are one of the most challenging disorders encountered, and early and accurate diagnosis is essential for the management and treatment of these tumors. In this article, diagnostic modalities including single-photon emission computed tomography, positron emission tomography, magnetic resonance imaging, and optical imaging are reviewed. We mainly focus on the newly emerging, specific imaging probes, and their potential use in animal models and clinical settings. PMID:24334439

  4. Detection of N-Glycolyl GM3 Ganglioside in Neuroectodermal Tumors by Immunohistochemistry: An Attractive Vaccine Target for Aggressive Pediatric Cancer

    PubMed Central

    Scursoni, Alejandra M.; Galluzzo, Laura; Camarero, Sandra; Lopez, Jessica; Lubieniecki, Fabiana; Sampor, Claudia; Segatori, Valeria I.; Gabri, Mariano R.; Alonso, Daniel F.; Chantada, Guillermo; de Dávila, María Teresa G.

    2011-01-01

    The N-glycolylated ganglioside NeuGc-GM3 has been described in solid tumors such as breast carcinoma, nonsmall cell lung cancer, and melanoma, but is usually not detected in normal human cells. Our aim was to evaluate the presence of NeuGc-GM3 in pediatric neuroectodermal tumors by immunohistochemistry. Twenty-seven archival cases of neuroblastoma and Ewing sarcoma family of tumors (ESFT) were analyzed. Formalin-fixed, paraffin-embedded tumor samples were cut into 5 μm sections. The monoclonal antibody 14F7, a mouse IgG1 that specifically recognizes NeuGc-GM3, and a peroxidase-labeled polymer conjugated to secondary antibodies were used. Presence of NeuGc-GM3 was evident in 23 of 27 cases (85%), with an average of about 70% of positive tumors cells. Immunoreactivity was moderate to intense in most tumors, showing a diffuse cytoplasmic and membranous staining, although cases of ESFT demonstrated a fine granular cytoplasmic pattern. No significant differences were observed between neuroblastoma with and without NMYC oncogene amplification, suggesting that expression of NeuGc-GM3 is preserved in more aggressive cancers. Until now, the expression of N-glycolylated gangliosides in pediatric neuroectodermal tumors has not been investigated. The present study evidenced the expression of NeuGc-GM3 in a high proportion of neuroectodermal tumors, suggesting its potential utility as a specific target of immunotherapy. PMID:21941577

  5. (Study of plant cells and tumors): Progress report

    SciTech Connect

    Not Available

    1989-01-01

    Studies of the cell and molecular biology of animal cell tumors has long been recognized as a fertile and productive area for obtaining new and fundamental insights into mechanisms regulating the growth and differentiation of animal cells. As a novel approach to studying similar phenomena in plant cells, we have isolated a number of tumors in the small cruciferous plant Arabidopsis thaliana and have begun to characterize these at the cellular and molecular levels. Studies at the cellular level should lead to new insights into the relationships between hormones, cell growth and cell differentiation, while studies at the molecular level may reveal and allow us to isolate genes involved either in the hormone response, or in other important aspects of the cells' growth regulatory network. Tumors were induced on the plant by irradiation of seed or seedlings with Co-60 gamma rays. When placed in culture, these tumors were able to grow on hormone-free medium, in contrast to normal plant tissues which requires both an auxin and a cytokinin for growth. In the first phase of this project, we have concentrated on characterizing the growth, general phenotype, and hormonal sensitivity of the tumors. These studies will lead into a molecular analysis of the changes expressed in each tumor which may be responsible for the altered phenotype. 7 refs., 1 tab.

  6. AIP1 expression in tumor niche suppresses tumor progression and metastasis

    PubMed Central

    Ji, Weidong; Li, Yonghao; He, Yun; Yin, Mingzhu; Zhou, Huanjiao Jenny; Boggon, Titus J.; Zhang, Haifeng; Min, Wang

    2015-01-01

    Studies from tumor cells suggest that tumor suppressor AIP1 inhibits epithelial-mesenchymal transition (EMT). However, the role of AIP1 in the tumor microenvironment has not been examined. We show that a global or vascular endothelial cell (EC)-specific deletion of the AIP1 gene in mice augments tumor growth and metastasis in melanoma and breast cancer models. AIP1-deficient vascular environment not only enhances tumor neovascularization and increases pre-metastatic niche formation, but also secrets tumor EMT-promoting factors. These effects from AIP1 loss are associated with increased VEGFR2 signaling in the vascular EC and could be abrogated by systemic administration of VEGFR2 kinase inhibitors. Mechanistically, AIP1 blocks VEGFR2-dependent signaling by directly binding to the phosphotyrosine residues within the activation loop of VEGFR2. Our data reveal that AIP1, by inhibiting VEGFR2-dependent signaling in tumor niche, suppresses tumor EMT switch, tumor angiogenesis and tumor pre-metastatic niche formation to limit tumor growth and metastasis. PMID:26139244

  7. Long-term ex vivo and in vivo monitoring of tumor progression by using dual luciferases.

    PubMed

    Morita, Naoki; Haga, Sanae; Ohmiya, Yoshihiro; Ozaki, Michitaka

    2016-03-15

    We propose a new concept of tumor progression monitoring using dual luciferases in living animals to reduce stress for small animals and the cost of luciferin. The secreted Cypridina luciferase (CLuc) was used as an ex vivo indicator to continuously monitor tumor progression. On the other hand, the non-secreted firefly luciferase was used as an in vivo indicator to analyze the spatial distribution of the tumor at suitable time points indicated by CLuc. Thus, the new monitoring systems that use dual luciferases are available, allowing long-term bioluminescence imaging under minimal stress for the experimental animals. PMID:26717897

  8. Intravital imaging reveals new ancillary mechanisms co-opted by cancer cells to drive tumor progression

    PubMed Central

    Lucas, Morghan C.; Timpson, Paul

    2016-01-01

    Intravital imaging is providing new insights into the dynamics of tumor progression in native tissues and has started to reveal the layers of complexity found in cancer. Recent advances in intravital imaging have allowed us to look deeper into cancer behavior and to dissect the interactions between tumor cells and the ancillary host niche that promote cancer development. In this review, we provide an insight into the latest advances in cancer biology achieved by intravital imaging, focusing on recently discovered mechanisms by which tumor cells manipulate normal tissue to facilitate disease progression. PMID:27239290

  9. Intravital imaging reveals new ancillary mechanisms co-opted by cancer cells to drive tumor progression.

    PubMed

    Vennin, Claire; Herrmann, David; Lucas, Morghan C; Timpson, Paul

    2016-01-01

    Intravital imaging is providing new insights into the dynamics of tumor progression in native tissues and has started to reveal the layers of complexity found in cancer. Recent advances in intravital imaging have allowed us to look deeper into cancer behavior and to dissect the interactions between tumor cells and the ancillary host niche that promote cancer development. In this review, we provide an insight into the latest advances in cancer biology achieved by intravital imaging, focusing on recently discovered mechanisms by which tumor cells manipulate normal tissue to facilitate disease progression. PMID:27239290

  10. Regulatory T Cells in the Tumor Microenvironment and Cancer Progression: Role and Therapeutic Targeting.

    PubMed

    Chaudhary, Belal; Elkord, Eyad

    2016-01-01

    Recent years have seen significant efforts in understanding and modulating the immune response in cancer. In this context, immunosuppressive cells, including regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), have come under intense investigation for their proposed roles in suppressing tumor-specific immune responses and establishing an immunosuppressive tumor microenvironment, thus enabling tumor immune evasion. Additionally, recent evidence indicates that Tregs comprise diverse and heterogeneous subsets; phenotypically and functionally distinct subsets of tumor-infiltrating Tregs could contribute differently to cancer prognosis and clinical outcomes. Understanding Treg biology in the setting of cancer, and specifically the tumor microenvironment, is important for designing effective cancer therapies. In this review, we critically examine the role of Tregs in the tumor microenvironment and in cancer progression focusing on human studies. We also discuss the impact of current therapeutic modalities on Treg biology and the therapeutic opportunities for targeting Tregs to enhance anti-tumor immune responses and clinical benefits. PMID:27509527

  11. Signaling Mechanism(S) of Reactive Oxygen Species in Epithelial-Mesenchymal Transition Reminiscent of Cancer Stem Cells in Tumor Progression

    PubMed Central

    Wang, Zhiwei; Li, Yiwei; Sarkar, Fazlul H.

    2013-01-01

    Reactive oxygen species (ROS) are known to serve as a second messenger in the intracellular signal transduction pathway for a variety of cellular processes, including inflammation, cell cycle progression, apoptosis, aging and cancer. Recently, ROS have been found to be associated with tumor metastasis involving the processes of tumor cell migration, invasion and angiogenesis. Emerging evidence also suggests that Epithelial-Mesenchymal Transition (EMT), a process that is reminiscent of cancer stem cells, is an important step towards tumor invasion and metastasis, and intimately involved in de novo and acquired drug resistance. In the light of recent advances, we are summarizing the role of ROS in EMT by cataloging how its deregulation is involved in EMT and tumor aggressiveness. Further attempts have been made to summarize the role of several chemopreventive agents that could be useful for targeted inactivation of ROS, suggesting that many natural agents could be useful for the reversal of EMT, which would become a novel approach for the prevention of tumor progression and/or the treatment of human malignancies especially by killing EMT-type cells that share similar characteristics with cancer stem cells. PMID:19951255

  12. Nanomedicinal strategies to treat multidrug-resistant tumors: current progress

    PubMed Central

    Dong, Xiaowei; Mumper, Russell J

    2010-01-01

    Multidrug resistance (MDR) is a major impediment to the success of cancer chemotherapy. P-glycoprotein is an important and the best-known membrane transporter involved in MDR. Several strategies have been used to address MDR, especially P-glycoprotein-mediated drug resistance in tumors. However, clinical success has been limited, largely due to issues regarding lack of efficacy and/or safety. Nanoparticles have shown the ability to target tumors based on their unique physical and biological properties. To date, nanoparticles have been investigated primarily to address P-glycoprotein and the observed improved anticancer efficacy suggests that nanomedicinal strategies provide a new opportunity to overcome MDR. This article focuses on nanotechnology-based formulations and current nanomedicine approaches to address MDR in tumors and discusses the proposed mechanisms of action. PMID:20528455

  13. DCA promotes progression of neuroblastoma tumors in nude mice

    PubMed Central

    Feuerecker, Benedikt; Seidl, Christof; Pirsig, Sabine; Bruchelt, Gernot; Senekowitsch-Schmidtke, Reingard

    2015-01-01

    Even in the presence of oxygen most cancer cells convert glucose to lactate via pyruvate instead of performing oxidative phosphorylation (aerobic glycolysis-Warburg effect). Thus, it has been considered to shift pyruvate - the metabolite of aerobic glycolysis - to acetylCoA by activation of pyruvate dehydrogenase (PDH). AcetylCoA will then be metabolized by oxidative phosphorylation. Therefore, the purpose of this study was to shift tumor cells from aerobic glycolysis to oxidative phosphorylation using dichloroacetate (DCA), an inhibitor of PDH-kinase. The effects of DCA were assayed in vitro in Neuro-2a (murine neuroblastoma), Kelly and SK-N-SH (human neuroblastoma) as well as SkBr3 (human breast carcinoma) cell lines. The effects of DCA on tumor development were investigated in vivo using NMRI nu/nu mice bearing subcutaneous Neuro-2a xenografts. For that purpose animals were treated continuously with DCA in the drinking water. Tumor volumes were monitored using caliper measurements and via [18F]-FDG-positron emission tomography. DCA treatment increased viability/proliferation in Neuro-2a and SkBr3 cells, but did not cause significant alterations of PDH activity. However, no significant effects of DCA could be observed in Kelly and SK-N-SH cells. Accordingly, in mice bearing Neuro-2a xenografts, DCA significantly increased tumor proliferation compared to mock-treated mice. Thus, we could demonstrate that DCA - an indicated inhibitor of tumor growth - efficiently promotes tumor growth in Neuro-2a cells in vitro and in vivo. PMID:25973318

  14. Microbially driven TLR5-dependent signaling governs distal malignant progression through tumor-promoting inflammation.

    PubMed

    Rutkowski, Melanie R; Stephen, Tom L; Svoronos, Nikolaos; Allegrezza, Michael J; Tesone, Amelia J; Perales-Puchalt, Alfredo; Brencicova, Eva; Escovar-Fadul, Ximena; Nguyen, Jenny M; Cadungog, Mark G; Zhang, Rugang; Salatino, Mariana; Tchou, Julia; Rabinovich, Gabriel A; Conejo-Garcia, Jose R

    2015-01-12

    The dominant TLR5(R392X) polymorphism abrogates flagellin responses in >7% of humans. We report that TLR5-dependent commensal bacteria drive malignant progression at extramucosal locations by increasing systemic IL-6, which drives mobilization of myeloid-derived suppressor cells (MDSCs). Mechanistically, expanded granulocytic MDSCs cause γδ lymphocytes in TLR5-responsive tumors to secrete galectin-1, dampening antitumor immunity and accelerating malignant progression. In contrast, IL-17 is consistently upregulated in TLR5-unresponsive tumor-bearing mice but only accelerates malignant progression in IL-6-unresponsive tumors. Importantly, depletion of commensal bacteria abrogates TLR5-dependent differences in tumor growth. Contrasting differences in inflammatory cytokines and malignant evolution are recapitulated in TLR5-responsive/unresponsive ovarian and breast cancer patients. Therefore, inflammation, antitumor immunity, and the clinical outcome of cancer patients are influenced by a common TLR5 polymorphism. PMID:25533336

  15. MMP3-Mediated tumor progression is controlled transcriptionally by a novel IRF8-MMP3 interaction

    PubMed Central

    Banik, Debarati; Netherby, Colleen S.; Bogner, Paul N.; Abrams, Scott I.

    2015-01-01

    Interferon regulatory factor-8 (IRF8), originally identified as a leukemic tumor suppressor, can also exert anti-neoplastic activities in solid tumors. We previously showed that IRF8-loss enhanced tumor growth, which was accompanied by reduced tumor-cell susceptibility to apoptosis. However, the impact of IRF8 expression on tumor growth could not be explained solely by its effects on regulating apoptotic response. Exploratory gene expression profiling further revealed an inverse relationship between IRF8 and MMP3 expression, implying additional intrinsic mechanisms by which IRF8 modulated neoplastic behavior. Although MMP3 expression was originally linked to tumor initiation, the role of MMP3 beyond this stage has remained unclear. Therefore, we hypothesized that MMP3 governed later stages of disease, including progression to metastasis, and did so through a novel IRF8-MMP3 axis. Altogether, we showed an inverse mechanistic relationship between IRF8 and MMP3 expression in tumor progression. Importantly, the growth advantage due to IRF8-loss was significantly compromised after silencing MMP3 expression. Moreover, MMP3-loss reduced spontaneous lung metastasis in an orthotopic mouse model of mammary carcinoma. MMP3 acted, in part, in a cell-intrinsic manner and served as a direct transcriptional target of IRF8. Thus, we identified a novel role of an IRF8-MMP3 axis in tumor progression, which unveils new therapeutic opportunities. PMID:26008967

  16. Growth hormone therapy and risk of recurrence/progression in intracranial tumors: a meta-analysis.

    PubMed

    Shen, Liang; Sun, Chun Ming; Li, Xue Tao; Liu, Chuan Jin; Zhou, You Xin

    2015-10-01

    Growth hormone deficiency is common in intracranial tumors, which is usually treated with surgery and radiotherapy. A number of previous studies have investigated the relationship between the growth hormone replacement therapy (GHRT) and risk of tumor recurrence/progression; however, the evidence remains controversial. We conducted a meta-analysis of published studies to estimate the potential relation between GHRT and intracranial tumors recurrence/progression. Three comprehensive databases, PUBMED, EMBASE, and Cochrane Library, were researched with no limitations, covering all published studies till the end of July, 2014. Reference lists from identified studies were also screened for additional database. The summary relative risks (RR) and 95% confidence intervals (CI) were calculated by fixed-effects models for estimation. Fifteen eligible studies, involving more than 2232 cases and 3606 controls, were included in our meta-analysis. The results indicated that intracranial tumors recurrence/progression was not associated with GHRT (RR 0.48, 95% CI 0.39-0.56), and for children, the pooled RR was 0.44 and 95% CI was 0.34-0.54. In subgroup analysis, risks of recurrence/progression were decreased for craniopharyngioma, medulloblastoma, astrocytoma, glioma, but not for pituitary adenomas, and non-functioning pituitary adenoma (NFPA), ependymoma. Results from our analysis indicate that GHRT decreases the risk of recurrence/progression in children with intracranial tumors, craniopharyngioma, medulloblastoma, astrocytoma, or glioma. However, GHRT for pituitary adenomas, NFPA, and ependymoma was not associated with the recurrence/progression of the tumors. GH replacement seems safe from the aspect of risk of tumor progression. PMID:26048536

  17. Epigenetic clustering of gastric carcinomas based on DNA methylation profiles at the precancerous stage: its correlation with tumor aggressiveness and patient outcome

    PubMed Central

    Yamanoi, Kazuhiro; Arai, Eri; Tian, Ying; Takahashi, Yoriko; Miyata, Sayaka; Sasaki, Hiroki; Chiwaki, Fumiko; Ichikawa, Hitoshi; Sakamoto, Hiromi; Kushima, Ryoji; Katai, Hitoshi; Yoshida, Teruhiko; Sakamoto, Michiie; Kanai, Yae

    2015-01-01

    The aim of this study was to clarify the significance of DNA methylation alterations during gastric carcinogenesis. Single-CpG resolution genome-wide DNA methylation analysis using the Infinium assay was performed on 109 samples of non-cancerous gastric mucosa (N) and 105 samples of tumorous tissue (T). DNA methylation alterations in T samples relative to N samples were evident for 3861 probes. Since N can be at the precancerous stage according to the field cancerization concept, unsupervised hierarchical clustering based on DNA methylation levels was performed on N samples (βN) using the 3861 probes. This divided the 109 patients into three clusters: A (n = 20), B1 (n = 20), and B2 (n = 69). Gastric carcinomas belonging to Cluster B1 showed tumor aggressiveness more frequently than those belonging to Clusters A and B2. The recurrence-free and overall survival rates of patients in Cluster B1 were lower than those of patients in Clusters A and B2. Sixty hallmark genes for which βN characterized the epigenetic clustering were identified. We then focused on DNA methylation levels in T samples (βT) of the 60 hallmark genes. In 48 of them, including the ADAM23, OLFM4, AMER2, GPSM1, CCL28, DTX1 and COL23A1 genes, βT was again significantly correlated with tumor aggressiveness, and the recurrence-free and/or overall survival rates. Multivariate analyses revealed that βT was a significant prognostic factor, being independent of clinicopathological parameters. These data indicate that DNA methylation profiles at the precancerous stage may be inherited by gastric carcinomas themselves, thus determining tumor aggressiveness and patient outcome. PMID:25740824

  18. Sunitinib impedes brain tumor progression and reduces tumor-induced neurodegeneration in the microenvironment

    PubMed Central

    Hatipoglu, Gökçe; Hock, Stefan W; Weiss, Ruth; Fan, Zheng; Sehm, Tina; Ghoochani, Ali; Buchfelder, Michael; Savaskan, Nicolai E; Eyüpoglu, Ilker Y

    2015-01-01

    Malignant gliomas can be counted to the most devastating tumors in humans. Novel therapies do not achieve significant prolonged survival rates. The cancer cells have an impact on the surrounding vital tissue and form tumor zones, which make up the tumor microenvironment. We investigated the effects of sunitinib, a small molecule multitargeted receptor tyrosine kinase inhibitor, on constituents of the tumor microenvironment such as gliomas, astrocytes, endothelial cells, and neurons. Sunitinib has a known anti-angiogenic effect. We found that sunitinib normalizes the aberrant tumor-derived vasculature and reduces tumor vessel pathologies (i.e. auto-loops). Sunitinib has only minor effects on the normal, physiological, non-proliferating vasculature. We found that neurons and astrocytes are protected by sunitinib against glutamate-induced cell death, whereas sunitinib acts as a toxin towards proliferating endothelial cells and tumor vessels. Moreover, sunitinib is effective in inducing glioma cell death. We determined the underlying pathways by which sunitinib operates as a toxin on gliomas and found vascular endothelial growth factor receptor 2 (VEGFR2, KDR/Flk1) as the main target to execute gliomatoxicity. The apoptosis-inducing effect of sunitinib can be mimicked by inhibition of VEGFR2. Knockdown of VEGFR2 can, in part, foster the resistance of glioma cells to receptor tyrosine kinase inhibitors. Furthermore, sunitinib alleviates tumor-induced neurodegeneration. Hence, we tested whether temozolomide treatment could be potentiated by sunitinib application. Here we show that sunitinib can amplify the effects of temozolomide in glioma cells. Thus, our data indicate that combined treatment with temozolomide does not abrogate the effects of sunitinib. In conclusion, we found that sunitinib acts as a gliomatoxic agent and at the same time carries out neuroprotective effects, reducing tumor-induced neurodegeneration. Thus, this report uncovered sunitinib's actions on

  19. Multiwalled Carbon Nanotubes Inhibit Tumor Progression in a Mouse Model.

    PubMed

    García-Hevia, Lorena; Villegas, Juan C; Fernández, Fidel; Casafont, Íñigo; González, Jesús; Valiente, Rafael; Fanarraga, Mónica L

    2016-05-01

    Understanding the molecular mechanisms underlying the biosynthetic interactions between particular nanomaterials with specific cells or proteins opens new alternatives in nanomedicine and nanotoxicology. Multiwalled carbon nanotubes (MWCNTs) have long been explored as drug delivery systems and nanomedicines against cancer. There are high expectations for their use in therapy and diagnosis. These filaments can translocate inside cultured cells and intermingle with the protein nanofilaments of the cytoskeleton, interfering with the biomechanics of cell division mimicking the effect of traditional microtubule-binding anti-cancer drugs such as paclitaxel. Here, it is shown how MWCNTs can trigger significant anti-tumoral effects in vivo, in solid malignant melanomas produced by allograft transplantation. Interestingly, the MWCNT anti-tumoral effects are maintained even in solid melanomas generated from paclitaxel-resistant cells. These findings provide great expectation in the development of groundbreaking adjuvant synthetic microtubule-stabilizing chemotherapies to overcome drug resistance in cancer. PMID:26866927

  20. Alteration of liver glycopatterns during cirrhosis and tumor progression induced by HBV.

    PubMed

    Qin, Yannan; Zhong, Yaogang; Ma, Tianran; Wu, Fei; Wu, Haoxiang; Yu, Hanjie; Huang, Chen; Li, Zheng

    2016-04-01

    The incidence of hepatocellular carcinoma (HCC) is closely correlated with hepatitis B virus (HBV)-induced liver cirrhosis. Structural changes in the glycans of serum and tissue proteins are reliable indicators of liver damage. However, little is known about the alteration of liver glycopatterns during cirrhosis and tumor progression induced by HBV infection. This study compared the differential expression of liver glycopatterns in 7 sets of normal pericarcinomatous tissues (PCTs), cirrhotic, and tumor tissues from patients with liver cirrhosis and HCC induced by HBV using lectin microarrays. Fluorescence-based lectin histochemistry and lectin blotting were further utilized to validate and assess the expression and distribution of certain glycans in 9 sets of corresponding liver tissue sections. Eight lectins (e.g., Jacalin and AAL) revealed significant difference in cirrhotic tissues versus PCTs. Eleven lectins (e.g., EEL and SJA) showed significant alteration during cirrhotic and tumor progression. The expression of Galα1-3(Fucα1-2)Gal (EEL) and fucosyltransferase 1 was mainly increasing in the cytoplasm of hepatocytes during PCTs-cirrhotic-tumor tissues progression, while the expression of T antigen (ACA and PNA) was decreased sharply in cytoplasm of tumor hepatocytes. Understanding the precision alteration of liver glycopatterns related to the development of hepatitis, cirrhosis, and tumor induced by HBV infection may help elucidate the molecular mechanisms underlying the progression of chronic liver diseases and develop new antineoplastic therapeutic strategies. PMID:26833199

  1. Composite implants coated with biodegradable polymers prevent stimulating tumor progression

    NASA Astrophysics Data System (ADS)

    Litviakov, N. V.; Tverdokhlebov, S. I.; Perelmuter, V. M.; Kulbakin, D. E.; Bolbasov, E. N.; Tsyganov, M. M.; Zheravin, A. A.; Svetlichnyi, V. A.; Cherdyntseva, N. V.

    2016-08-01

    In this experiment we studied oncologic safety of model implants created using the solution blow spinning method with the use of the PURASORB PL-38 polylactic acid polymer and organic mineral filler which was obtained via laser ablation of a solid target made of dibasic calcium phosphate dihydrate. For this purpose the implant was introduced into the area of Wistar rats' iliums, and on day 17 after the surgery the Walker sarcoma was transplanted into the area of the implant. We evaluated the implant's influence on the primary tumor growth, hematogenous and lymphogenous metastasis of the Walker sarcoma. In comparison with sham operated animals the implant group demonstrated significant inhibition of hematogenous metastasis on day 34 after the surgery. The metastasis inhibition index (MII) equaled 94% and the metastases growth inhibition index (MGII) equaled 83%. The metastasis frequency of the Walker sarcoma in para aortic lymph nodes in the implant group was not statistically different from the control frequency; there was also no influence of the implant on the primary tumor growth noted. In case of the Walker sarcoma transplantation into the calf and the palmar pad of the ipsilateral limb to the one with the implant in the ilium, we could not note any attraction of tumor cells to the implant area, i.e. stimulation of the Walker sarcoma relapse by the implant. Thus, the research concluded that the studied implant meets the requirements of oncologic safety.

  2. Expression of FAP, ADAM12, WISP1, and SOX11 is heterogeneous in aggressive fibromatosis and spatially relates to the histologic features of tumor activity

    PubMed Central

    Misemer, Benjamin S; Skubitz, Amy P N; Carlos Manivel, J; Schmechel, Stephen C; Cheng, Edward Y; Henriksen, Jonathan C; Koopmeiners, Joseph S; Corless, Christopher L; Skubitz, Keith M

    2014-01-01

    Aggressive fibromatosis (AF) represents a group of tumors with a variable and unpredictable clinical course, characterized by a monoclonal proliferation of myofibroblastic cells. The optimal treatment for AF remains unclear. Identification and validation of genes whose expression patterns are associated with AF may elucidate biological mechanisms in AF, and aid treatment selection. This study was designed to examine the protein expression by immunohistochemistry (IHC) of four genes, ADAM12, FAP, SOX11, and WISP1, that were found in an earlier study to be uniquely overexpressed in AF compared with normal tissues. Digital image analysis was performed to evaluate inter- and intratumor heterogeneity, and correlate protein expression with histologic features, including a histopathologic assessment of tumor activity, defined by nuclear chromatin density ratio (CDR). AF tumors exhibited marked inter- and intratumor histologic heterogeneity. Pathologic assessment of tumor activity and digital assessment of average nuclear size and CDR were all significantly correlated. IHC revealed protein expression of all four genes. IHC staining for ADAM12, FAP, and WISP1 correlated with CDR and was higher, whereas SOX11 staining was lower in tumors with earlier recurrence following excision. All four proteins were expressed, and the regional variation in tumor activity within and among AF cases was demonstrated. A spatial correlation between protein expression and nuclear morphology was observed. IHC also correlated with the probability of recurrence following excision. These proteins may be involved in AF pathogenesis and the corresponding pathways could serve as potential targets of therapy. PMID:24402778

  3. Expression of FAP, ADAM12, WISP1, and SOX11 is heterogeneous in aggressive fibromatosis and spatially relates to the histologic features of tumor activity.

    PubMed

    Misemer, Benjamin S; Skubitz, Amy P N; Carlos Manivel, J; Schmechel, Stephen C; Cheng, Edward Y; Henriksen, Jonathan C; Koopmeiners, Joseph S; Corless, Christopher L; Skubitz, Keith M

    2014-02-01

    Aggressive fibromatosis (AF) represents a group of tumors with a variable and unpredictable clinical course, characterized by a monoclonal proliferation of myofibroblastic cells. The optimal treatment for AF remains unclear. Identification and validation of genes whose expression patterns are associated with AF may elucidate biological mechanisms in AF, and aid treatment selection. This study was designed to examine the protein expression by immunohistochemistry (IHC) of four genes, ADAM12, FAP, SOX11, and WISP1, that were found in an earlier study to be uniquely overexpressed in AF compared with normal tissues. Digital image analysis was performed to evaluate inter- and intratumor heterogeneity, and correlate protein expression with histologic features, including a histopathologic assessment of tumor activity, defined by nuclear chromatin density ratio (CDR). AF tumors exhibited marked inter- and intratumor histologic heterogeneity. Pathologic assessment of tumor activity and digital assessment of average nuclear size and CDR were all significantly correlated. IHC revealed protein expression of all four genes. IHC staining for ADAM12, FAP, and WISP1 correlated with CDR and was higher, whereas SOX11 staining was lower in tumors with earlier recurrence following excision. All four proteins were expressed, and the regional variation in tumor activity within and among AF cases was demonstrated. A spatial correlation between protein expression and nuclear morphology was observed. IHC also correlated with the probability of recurrence following excision. These proteins may be involved in AF pathogenesis and the corresponding pathways could serve as potential targets of therapy. PMID:24402778

  4. Norepinephrine promotes tumor microenvironment reactivity through β3-adrenoreceptors during melanoma progression

    PubMed Central

    Calvani, Maura; Pelon, Floriane; Comito, Giuseppina; Taddei, Maria Letizia; Moretti, Silvia; Innocenti, Stefania; Nassini, Romina; Gerlini, Gianni; Borgognoni, Lorenzo; Bambi, Franco; Giannoni, Elisa; Filippi, Luca; Chiarugi, Paola

    2015-01-01

    Stress has an emerging role in cancer and targeting stress-related β-adrenergic receptors (AR) has been proposed as a potential therapeutic approach in melanoma. Here we report that β3-AR expression correlates with melanoma aggressiveness. In addition, we highlight that β3-AR expression is not only restricted to cancer cells, but it is also expressed in vivo in stromal, inflammatory and vascular cells of the melanoma microenvironment. Particularly, we demonstrated that β3-AR can (i) instruct melanoma cells to respond to environmental stimuli, (ii) enhance melanoma cells response to stromal fibroblasts and macrophages, (iii) increase melanoma cell motility and (iv) induce stem-like traits. Noteworthy, β3-AR activation in melanoma accessory cells drives stromal reactivity by inducing pro-inflammatory cytokines secretion and de novo angiogenesis, sustaining tumor growth and melanoma aggressiveness. β3-ARs also play a mandatory role in the recruitment to tumor sites of circulating stromal cells precursors, in the differentiation of these cells towards different lineages, further favoring tumor inflammation, angiogenesis and ultimately melanoma malignancy. Our findings validate selective β3-AR antagonists as potential promising anti-metastatic agents. These could be used to complement current therapeutic approaches for melanoma patients (e.g. propranolol) by targeting non-neoplastic stromal cells, hence reducing therapy resistance of melanoma. PMID:25474135

  5. An epitope-specific novel anti-EMMPRIN polyclonal antibody inhibits tumor progression

    PubMed Central

    Walter, Miriam; Simanovich, Elina; Brod, Vera; Lahat, Nitza; Bitterman, Haim; Rahat, Michal A.

    2016-01-01

    ABSTRACT Extracellular matrix metalloproteinase inducer (EMMPRIN/CD147) mediates tumor cell–macrophage interactions, and has been shown to induce both matrix metalloproteinases (MMPs) and vascular endothelial growth factor (VEGF). However, the epitope responsible for MMP induction is controversial, and the epitope responsible for VEGF induction is yet unknown. We generated a novel anti-EMMPRIN antibody directed against a specific epitope that successfully inhibited the production of both MMP-9 and VEGF in tumor cell–macrophage in vitro co-culture systems, exhibiting a U-shaped dose response. Furthermore, this antibody efficiently inhibited in vivo tumor progression in both the RENCA renal cell carcinoma and CT26 colon carcinoma subcutaneous tumor models, and reduced tumor size and number of metastatic foci in the 4T1 orthotopic model. This was achieved by inhibiting angiogenesis as assessed by immunohistochemical staining for the endothelial marker CD31, by inhibiting tumor cell proliferation as assessed by the staining for Ki-67, and by enhancing tumor cell apoptosis as assessed in the TUNEL assay. Moreover, administration of the antibody recruited more macrophages into the tumor, and skewed the tumor microenvironment for macrophages from TGFβ-dominated anti-inflammatory microenvironment, to a less immunosuppressive one. The antibody improved the ability of stimulated macrophages to perform antibody-dependent cell cytotoxicity (ADCC) and kill tumor cells. Thus, our new antibody maps the epitope capable of inducing both MMPs and VEGF, and places EMMPRIN as a good target for cancer therapy. PMID:27057452

  6. [Progression of tumors: etiologic, morphologic and molecular-biological aspects].

    PubMed

    Turosov, V S

    1992-01-01

    Two aspects can be distinguished in multistage carcinogenesis: etiological one (every stage is induced by a specific for this stage agent) and morphobiological aspect (every stage is characterized by specific morphological, genetic and other properties). The schema of the multistage carcinogenesis is presented in which morphological stages (diffuse and focal hyperplasia, benign tumours, dysplasia, carcinoma in situ, various phases of malignant tumour progression) are placed against genetic alterations. L. Foulds concept of tumour progression is discussed with special emphasis on precancerous stages, possibilities of cancer development de novo, and independent progression of different tumour characters. The following types of carcinogenesis are listed on the basis of interrelationship between etiological and genetic factors: 1) carcinogenesis induced by genotoxic agents; a) one agent is acting at high dose and for a long time thus ensuring the activation of protooncogenes and all stages of tumour progression (initiation, promotion, various phases of malignant tumour); b) those acting during a very short time, however sufficient for developing the genetic program working automatically without further exposure to known carcinogens (irradiation in case of the atomic bomb explosion or effect of short-living alkylating agents): in this case there is no stage of promotion; 2) carcinogenesis by non-genotoxic carcinogens (their mode of action is still unclear, the only human example is carcinogenesis by hormones); 3) development of tumours in frane of the two (or three) stage carcinogenesis when every stage is provoked by its own etiological factor, no human examples are known as yet; 4) development of tumours due to the genetic mechanism making the organism highly susceptible to the minimal doses of carcinogens as is the case with skin cancer by ultraviolet light in patients with xeroderma pigmentosum, the genetic damage in itself has nothing to do with tumour formation; 5

  7. Whole Exome Sequencing of Rapid Autopsy Tumors and Xenograft Models Reveals Possible Driver Mutations Underlying Tumor Progression

    PubMed Central

    Xie, Tao; Musteanu, Monica; Lopez-Casas, Pedro P.; Shields, David J.; Olson, Peter; Rejto, Paul A.; Hidalgo, Manuel

    2015-01-01

    Pancreatic Ductal Adenocarcinoma (PDAC) is a highly lethal malignancy due to its propensity to invade and rapidly metastasize and remains very difficult to manage clinically. One major hindrance towards a better understanding of PDAC is the lack of molecular data sets and models representative of end stage disease. Moreover, it remains unclear how molecularly similar patient-derived xenograft (PDX) models are to the primary tumor from which they were derived. To identify potential molecular drivers in metastatic pancreatic cancer progression, we obtained matched primary tumor, metastases and normal (peripheral blood) samples under a rapid autopsy program and performed whole exome sequencing (WES) on tumor as well as normal samples. PDX models were also generated, sequenced and compared to tumors. Across the matched data sets generated for three patients, there were on average approximately 160 single-nucleotide mutations in each sample. The majority of mutations in each patient were shared among the primary and metastatic samples and, importantly, were largely retained in the xenograft models. Based on the mutation prevalence in the primary and metastatic sites, we proposed possible clonal evolution patterns marked by functional mutations affecting cancer genes such as KRAS, TP53 and SMAD4 that may play an important role in tumor initiation, progression and metastasis. These results add to our understanding of pancreatic tumor biology, and demonstrate that PDX models derived from advanced or end-stage likely closely approximate the genetics of the disease in the clinic and thus represent a biologically and clinically relevant pre-clinical platform that may enable the development of effective targeted therapies for PDAC. PMID:26555578

  8. Advanced multimodal nanoparticles delay tumor progression with clinical radiation therapy.

    PubMed

    Detappe, Alexandre; Kunjachan, Sijumon; Sancey, Lucie; Motto-Ros, Vincent; Biancur, Douglas; Drane, Pascal; Guieze, Romain; Makrigiorgos, G Mike; Tillement, Olivier; Langer, Robert; Berbeco, Ross

    2016-09-28

    Radiation therapy is a major treatment regimen for more than 50% of cancer patients. The collateral damage induced on healthy tissues during radiation and the minimal therapeutic effect on the organ-of-interest (target) is a major clinical concern. Ultra-small, renal clearable, silica based gadolinium chelated nanoparticles (SiGdNP) provide simultaneous MR contrast and radiation dose enhancement. The high atomic number of gadolinium provides a large photoelectric cross-section for increased photon interaction, even for high-energy clinical radiation beams. Imaging and therapy functionality of SiGdNP were tested in cynomolgus monkeys and pancreatic tumor-bearing mice models, respectively. A significant improvement in tumor cell damage (double strand DNA breaks), growth suppression, and overall survival under clinical radiation therapy conditions were observed in a human pancreatic xenograft model. For the first time, safe systemic administration and systematic renal clearance was demonstrated in both tested species. These findings strongly support the translational potential of SiGdNP for MR-guided radiation therapy in cancer treatment. PMID:27423325

  9. Activation of mesenchymal stem cells by macrophages promotes tumor progression through immune suppressive effects

    PubMed Central

    Jia, Xiao-hua; Feng, Guo-wei; Wang, Zhong-liang; Du, Yang; Shen, Chen; Hui, Hui; Peng, Dong; Li, Zong-jin; Kong, De-ling; Tian, Jie

    2016-01-01

    Cancer development and progression is linked to tumor-associated macrophages (TAMs). Distinct TAMs subsets perform either protective or pathogenic effects in cancer. A protective role in carcinogenesis has been described for M1 macrophages, which activate antitumor mechanisms. By comparison, TAMs isolated from solid and metastatic tumors have a suppressive M2-like phenotype, which could support multiple aspects of tumor progression. Currently, it has not been clearly understood how macrophages in tumor-associated stroma could be hijacked to support tumor growth. Mesenchymal stem cells (MSCs) actively interact with components of the innate immune system and display both anti-inflammatory and pro-inflammatory effects. Here, we tested whether MSCs could favor the tumor to escape from immunologic surveillance in the presence of M1 macrophages. We found that MSCs educated by M1 condition medium (cMSCs) possessed a greatly enhanced ability in promoting tumor growth in vivo. Examination of cytokines/chemokines showed that the cMSCs acquired a regulatory profile, which expressed high levels of iNOS and MCP1. Consistent with an elevated MCP1 expression in cMSCs, the tumor-promoting effect of the cMSCs depended on MCP1 mediated macrophage recruitment to tumor sites. Furthermore, IL-6 secreted by the cMSCs could polarize infiltrated TAMs into M2-like macrophages. Therefore, when macrophages changed into M1 pro-inflammation type in tumor microenvironment, the MSCs would act as poor sensors and switchers to accelerate tumor growth. PMID:26988913

  10. Fibroblasts—a key host cell type in tumor initiation, progression, and metastasis

    PubMed Central

    Strell, Carina; Rundqvist, Helene

    2012-01-01

    Tumor initiation, growth, invasion, and metastasis occur as a consequence of a complex interplay between the host environment and cancer cells. Fibroblasts are now recognized as a key host cell type involved in host–cancer signaling. This review discusses some recent studies that highlight the roles of fibroblasts in tumor initiation, early progression, invasion, and metastasis. Some clinical studies describing the prognostic significance of fibroblast-derived markers and signatures are also discussed. PMID:22509805

  11. Apolipoprotein E gene polymorphism influences aggressive behavior in prostate cancer cells by deregulating cholesterol homeostasis

    PubMed Central

    IFERE, GODWIN O.; DESMOND, RENEE; DEMARK-WAHNEFRIED, WENDY; NAGY, TIM R.

    High circulating cholesterol and its deregulated homeostasis may facilitate prostate cancer progression. Genetic polymorphism in Apolipoprotein (Apo) E, a key cholesterol regulatory protein may effect changes in systemic cholesterol levels. In this investigation, we determined whether variants of the Apo E gene can trigger defective intracellular cholesterol efflux, which could promote aggressive prostate cancer. ApoE genotypes of weakly (non-aggressive), moderate and highly tumorigenic (aggressive) prostate cancer cell lines were characterized, and we explored whether the ApoE variants were associated with tumor aggressiveness generated by intra cellular cholesterol imbalance, using the expression of caveolin-1 (cav-1), a pro-malignancy surrogate of cholesterol overload. Restriction isotyping of ApoE isoforms revealed that the non-aggressive cell lines carried ApoE ε3/ε3 or ε3/ε4 alleles, while the aggressive cell lines carried the Apoε2/ε4 alleles. Our data suggest a contrast between the non-aggressive and the aggressive prostate cancer cell lines in the pattern of cholesterol efflux and cav-1 expression. Our exploratory results suggest a relationship between prostate aggressiveness, ApoE isoforms and cholesterol imbalance. Further investigation of this relationship may elucidate the molecular basis for considering cholesterol as a risk factor of aggressive prostate tumors, and underscore the potential of the dysfunctional ApoE2/E4 isoform as a biomarker of aggressive disease. PMID:23934233

  12. Progress in Treatment Development for Neuropsychiatric Symptoms in Alzheimer’s Disease: Focus on Agitation and Aggression. A Report from the EU/US/CTAD Task Force

    PubMed Central

    Soto, M.; Abushakra, S.; Cummings, J.; Siffert, J.; Robert, P.; Vellas, B.; Lyketsos, C.G.

    2015-01-01

    BACKGROUND The management of neuropsychiatric symptoms (NPS) such as agitation and aggression is a major priority in caring for people with Alzheimer’s disease (AD). Agitation and aggression (A/A) are among the most disruptive symptoms, and given their impact, they are increasingly an important target for development of effective treatments. Considerable progress has been made in the last years with a growing number of randomized controlled trials (RCTs) of drugs for NPS. The limited benefits reported in some RCTs may be accounted for by the absence of a biological link of the tested molecule to NPS and also by key methodological issues. In recent RCTs of A/A, a great heterogeneity design was found. Designing trials for dementia populations with NPS presents many challenges, including identification of appropriate participants for such trials, engagement and compliance of patients and caregivers in the trials and the choice of optimal outcome measures to demonstrate treatment effectiveness. The EU/US -CTAD Task Force, an international collaboration of investigators from academia, industry, non-profit foundations, and regulatory agencies met in Philadelphia on November 19, 2014 to address some of these challenges. Despite potential heterogeneity in clinical manifestations and neurobiology, agitation and aggression seems to be accepted as an entity for drug development. The field appears to be reaching a consensus in using both agitation and aggression (or other NPS)-specific quantitative measures plus a global rating of change for agitation outcomes based on clinician judgment as the main outcomes. PMID:26413494

  13. STAT3 in Epithelial Cells Regulates Inflammation and Tumor Progression to Malignant State in Colon1

    PubMed Central

    Nguyen, Andrew V; Wu, Yuan-Yuan; Liu, Qiang; Wang, Donghai; Nguyen, Stephanie; Loh, Ricky; Pang, Joey; Friedman, Kenneth; Orlofsky, Amos; Augenlicht, Leonard; Pollard, Jeffrey W; Lin, Elaine Y

    2013-01-01

    Chronic inflammation is an important risk factor for the development of colorectal cancer; however, the mechanism of tumorigenesis especially tumor progression to malignancy in the inflamed colon is still unclear. Our study shows that epithelial signal transducer and activator of transcription 3 (STAT3), persistently activated in inflamed colon, is not required for inflammation-induced epithelial overproliferation and the development of early-stage tumors; however, it is essential for tumor progression to advanced malignancy. We found that one of the mechanisms that epithelial STAT3 regulates in tumor progression might be to modify leukocytic infiltration in the large intestine. Activation of epithelial STAT3 promotes the infiltration of the CD8+ lymphocyte population but inhibits the recruitment of regulatory T (Treg) lymphocytes. The loss of Stat3 in epithelial cells promoted the expression of cytokines/chemokines including CCL19, CCL28, and RANTES, which are known to be able to recruit Treg lymphocytes. Linked to these changes was the pathway mediated by sphingosine 1-phosphate receptor 1 and sphingosine 1-phosphate kinases, which is activated in colonic epithelial cells in inflamed colon with functional STAT3 but not in epithelial cells deleted of STAT3. Our data suggest that epithelial STAT3 plays a critical role in inflammation-induced tumor progression through regulation of leukocytic recruitment especially the infiltration of Treg cells in the large intestine. PMID:24027425

  14. Hypoxia Up-Regulates Galectin-3 in Mammary Tumor Progression and Metastasis

    PubMed Central

    Barros, Rita; Gomes, Catarina; de Matos, Augusto J.; Reis, Celso A.; Rutteman, Gerard R.; Gärtner, Fátima

    2015-01-01

    The tumor microenvironment encompasses several stressful conditions for cancer cells such as hypoxia, oxidative stress and pH alterations. Galectin-3, a well-studied member of the beta-galactoside-binding animal family of lectins has been implicated in multiple steps of metastasis as cell-cell and cell-ECM adhesion, promotion of angiogenesis, cell proliferation and resistance to apoptosis. However, both its aberrantly up- and down-regulated expression was observed in several types of cancer. Thus, the mechanisms that regulate galectin-3 expression in neoplastic settings are not clear. In order to demonstrate the putative role of hypoxia in regulating galectin-3 expression in canine mammary tumors (CMT), in vitro and in vivo studies were performed. In malignant CMT cells, hypoxia was observed to induce expression of galectin-3, a phenomenon that was almost completely prevented by catalase treatment of CMT-U27 cells. Increased galectin-3 expression was confirmed at the mRNA level. Under hypoxic conditions the expression of galectin-3 shifts from a predominant nuclear location to cytoplasmic and membrane expressions. In in vivo studies, galectin-3 was overexpressed in hypoxic areas of primary tumors and well-established metastases. Tumor hypoxia thus up-regulates the expression of galectin-3, which may in turn increase tumor aggressiveness. PMID:26222311

  15. Hypoxia Up-Regulates Galectin-3 in Mammary Tumor Progression and Metastasis.

    PubMed

    de Oliveira, Joana T; Ribeiro, Cláudia; Barros, Rita; Gomes, Catarina; de Matos, Augusto J; Reis, Celso A; Rutteman, Gerard R; Gärtner, Fátima

    2015-01-01

    The tumor microenvironment encompasses several stressful conditions for cancer cells such as hypoxia, oxidative stress and pH alterations. Galectin-3, a well-studied member of the beta-galactoside-binding animal family of lectins has been implicated in multiple steps of metastasis as cell-cell and cell-ECM adhesion, promotion of angiogenesis, cell proliferation and resistance to apoptosis. However, both its aberrantly up- and down-regulated expression was observed in several types of cancer. Thus, the mechanisms that regulate galectin-3 expression in neoplastic settings are not clear. In order to demonstrate the putative role of hypoxia in regulating galectin-3 expression in canine mammary tumors (CMT), in vitro and in vivo studies were performed. In malignant CMT cells, hypoxia was observed to induce expression of galectin-3, a phenomenon that was almost completely prevented by catalase treatment of CMT-U27 cells. Increased galectin-3 expression was confirmed at the mRNA level. Under hypoxic conditions the expression of galectin-3 shifts from a predominant nuclear location to cytoplasmic and membrane expressions. In in vivo studies, galectin-3 was overexpressed in hypoxic areas of primary tumors and well-established metastases. Tumor hypoxia thus up-regulates the expression of galectin-3, which may in turn increase tumor aggressiveness. PMID:26222311

  16. Radiologic response to radiation therapy concurrent with temozolomide for progressive simple dysembryoplastic neuroepithelial tumor.

    PubMed

    Morr, Simon; Qiu, Jingxin; Prasad, Dheerendra; Mechtler, Laszlo L; Fenstermaker, Robert A

    2016-07-01

    Dysembryoplastic neuroepithelial tumors (DNETs) are low-grade neuroglial tumors that are traditionally considered to be benign hamartoma-like mass lesions. Malignant transformation and disease progression have been reported in complex DNETs. We report a case of a simple DNET with disease progression following subtotal resection. A 34-year-old woman underwent craniotomy with subtotal resection of a large nonenhancing right temporal lobe and insular mass. Histopathological analysis revealed a simple DNET. Magnetic resonance imaging obtained 6 months after surgery demonstrated disease progression with no enhancement or change in signal characteristics. Following concurrent therapy with temozolomide and external beam radiation therapy, a significant radiologic response was observed. Progressive DNET with malignant transformation exhibits predominantly glial transformation and occurs predominantly in complex DNETs. The histological classification of DNETs into simple, complex, and nonspecific are reviewed. Contrast-enhancing regions are more frequently seen in complex tumors, with nonenhancing regions having fewer complex histologic features. Close clinical and radiographic follow-up is important in all cases of DNET. Following tumor progression, radiation therapy with concurrent and adjuvant temozolomide chemotherapy may be an effective treatment. PMID:27181792

  17. Starved and Asphyxiated: How Can CD8+ T Cells within a Tumor Microenvironment Prevent Tumor Progression

    PubMed Central

    Zhang, Ying; Ertl, Hildegund C. J.

    2016-01-01

    Although cancer immunotherapy has achieved significant breakthroughs in recent years, its overall efficacy remains limited in the majority of patients. One major barrier is exhaustion of tumor antigen-specific CD8+ tumor-infiltrating lymphocytes (TILs), which conventionally has been attributed to persistent stimulation with antigen within the tumor microenvironment (TME). A series of recent studies have highlighted that the TME poses significant metabolic challenges to TILs, which may contribute to their functional exhaustion. Hypoxia increases the expression of coinhibitors on activated CD8+ T cells, which in general reduces the T cells’ effector functions. It also impairs the cells’ ability to gain energy through oxidative phosphorylation. Glucose limitation increases the expression of programed cell death protein-1 and reduces functions of activated CD8+ T cells. A combination of hypoxia and hypoglycemia, as is common in solid tumors, places CD8+ TILs at dual metabolic jeopardy by affecting both major pathways of energy production. Recently, a number of studies addressed the effects of metabolic stress on modulating CD8+ T cell metabolism, differentiation, and functions. Here, we discuss recent findings on how different types of metabolic stress within the TME shape the tumor-killing capacity of CD8+ T cells. We propose that manipulating the metabolism of TILs to more efficiently utilize nutrients, especially during intermittent periods of hypoxia could maximize their performance, prolong their survival and improve the efficacy of active cancer immunotherapy. PMID:26904023

  18. Potential role of tumor microenvironment in the progression of oral cancer.

    PubMed

    Patil, Shankargouda; Rao, Roopa; Raj, Thirumal

    2015-03-01

    The stromal cells adjacent to the tumor including the fibroblasts, infammatory cells, lymphatic and vascular endothelial cells constitute the 'tumor microenvironment' (TM).(1) Recent in vivo and invitro studies have emphasized the role of stromal components on the growth, differentiation and invasiveness of the tumor cells. In addition, vascular, lymphatic or perineural invasion have proven to have independent prognostic value.(2) Despite the compelling evidence correlating the TM with the initiation and progression of cancer, our knowledge on the role of the genes mediating the various cellular interactions in the tumour stroma is limited.(2,3). PMID:26057928

  19. Loss of photoreceptorness and gain of genomic alterations in retinoblastoma reveal tumor progression

    PubMed Central

    Kooi, Irsan E.; Mol, Berber M.; Moll, Annette C.; van der Valk, Paul; de Jong, Marcus C.; de Graaf, Pim; van Mil, Saskia E.; Schouten-van Meeteren, Antoinette Y.N.; Meijers-Heijboer, Hanne; Kaspers, Gertjan L.; te Riele, Hein; Cloos, Jacqueline; Dorsman, Josephine C.

    2015-01-01

    Background Retinoblastoma is a pediatric eye cancer associated with RB1 loss or MYCN amplification (RB1+/+MYCNA). There are controversies concerning the existence of molecular subtypes within RB1−/− retinoblastoma. To test whether these molecular subtypes exist, we performed molecular profiling. Methods Genome-wide mRNA expression profiling was performed on 76 primary human retinoblastomas. Expression profiling was complemented by genome-wide DNA profiling and clinical, histopathological, and ex vivo drug sensitivity data. Findings RNA and DNA profiling identified major variability between retinoblastomas. While gene expression differences between RB1+/+MYCNA and RB1−/− tumors seemed more dichotomous, differences within the RB1−/− tumors were gradual. Tumors with high expression of a photoreceptor gene signature were highly differentiated, smaller in volume and diagnosed at younger age compared with tumors with low photoreceptor signature expression. Tumors with lower photoreceptor expression showed increased expression of genes involved in M-phase and mRNA and ribosome synthesis and increased frequencies of somatic copy number alterations. Interpretation Molecular, clinical and histopathological differences between RB1−/− tumors are best explained by tumor progression, reflected by a gradual loss of differentiation and photoreceptor expression signature. Since copy number alterations were more frequent in tumors with less photoreceptorness, genomic alterations might be drivers of tumor progression. Research in context Retinoblastoma is an ocular childhood cancer commonly caused by mutations in the RB1 gene. In order to determine optimal treatment, tumor subtyping is considered critically important. However, except for very rare retinoblastomas without an RB1 mutation, there are controversies as to whether subtypes of retinoblastoma do exist. Our study shows that retinoblastomas are highly diverse but rather than reflecting distinct tumor types with

  20. Selective participation of c-Jun with Fra-2/c-Fos promotes aggressive tumor phenotypes and poor prognosis in tongue cancer

    PubMed Central

    Gupta, Shilpi; Kumar, Prabhat; Kaur, Harsimrut; Sharma, Nishi; Saluja, Daman; Bharti, Alok C.; Das, Bhudev C.

    2015-01-01

    Tongue squamous cell carcinoma (TSCC) is most aggressive head and neck cancer often associated with HR-HPV infection. The role of AP-1 which is an essential regulator of HPV oncogene expression and tumorigenesis is not reported in tongue cancer. One hundred tongue tissue biopsies comprising precancer, cancer and adjacent controls including two tongue cancer cell lines were employed to study the role of HPV infection and AP-1 family proteins. An exclusive prevalence (28%) of HR-HPV type 16 was observed mainly in well differentiated tongue carcinomas (78.5%). A higher expression and DNA binding activity of AP-1 was observed in tongue tumors and cancer cell lines with c-Fos and Fra-2 as the major binding partners forming the functional AP-1 complex but c-Jun participated only in HPV negative and poorly differentiated carcinoma. Knocking down of Fra-2 responsible for aggressive tongue tumorigenesis led to significant reduction in c-Fos, c-Jun, MMP-9 and HPVE6/E7 expression but Fra-1 and p53 were upregulated. The binding and expression of c-Fos/Fra-2 increased as a function of severity of tongue lesions, yet selective participation of c-Jun appears to promote poor differentiation and aggressive tumorigenesis only in HPV negative cases while HPV infection leads to well differentiation and better prognosis preferably in nonsmokers. PMID:26581505

  1. TGF-β and immune cells: an important regulatory axis in the tumor microenvironment and progression

    PubMed Central

    Yang, Li; Pang, Yanli; Moses, Harold L.

    2010-01-01

    Transforming growth factor β (TGF-β) plays an important role in tumor initiation and progression, functioning as both a suppressor and a promoter. The mechanisms underlying this dual role of TGF-β remain unclear. TGF-β exerts systemic immune suppression and inhibits host immunosurveillance. Neutralizing TGF-β enhances CD8+ T-cell- and NK-cell-mediated anti-tumor immune responses. It also increases neutrophil-attracting chemokines resulting in recruitment and activation of neutrophils with an antitumor phenotype. In addition to its systemic effects, TGF-β regulates infiltration of inflammatory/immune cells and cancer-associated fibroblasts in the tumor microenvironment causing direct changes in tumor cells. Understanding TGF-β regulation at the interface of tumor and host immunity should provide insights into developing effective TGF-β antagonists and biomarkers for patient selection and efficacy of TGF-β antagonist treatment. PMID:20538542

  2. SKAP2 Promotes Podosome Formation to Facilitate Tumor-Associated Macrophage Infiltration and Metastatic Progression.

    PubMed

    Tanaka, Masamitsu; Shimamura, Shintaro; Kuriyama, Sei; Maeda, Daichi; Goto, Akiteru; Aiba, Namiko

    2016-01-15

    Tumor-associated macrophages (TAM) play complex and pivotal roles during cancer progression. A subset of metastasis-associated macrophages accumulates within metastatic sites to promote the invasion and growth of tumor cells. Src kinase-associated phosphoprotein 2 (SKAP2), a substrate of Src family kinases, is highly expressed in macrophages from various tumors, but its contribution to the tumor-promoting behavior of TAMs is unknown. Here, we report that SKAP2 regulates podosome formation in macrophages to promote tumor invasion and metastasis. SKAP2 physically interacted with Wiskott-Aldrich syndrome protein (WASP) and localized to podosomes, which were rarely observed in SKAP2-null macrophages. The invasion of peritoneal macrophages derived from SKAP2-null mice was significantly reduced compared with wild-type macrophages, but could be rescued by the restoration of functional SKAP2 containing an intact tyrosine phosphorylation site and the ability to interact with WASP. Furthermore, SKAP2-null mice inoculated with lung cancer cells exhibited markedly decreased lung metastases characterized by reduced macrophage infiltration compared with wild-type mice. Moreover, intravenously injected SKAP2-null macrophages failed to efficiently infiltrate established tumors and promote their growth. Taken together, these findings reveal a novel mechanism by which macrophages assemble the appropriate motile machinery to infiltrate tumors and promote disease progression, and implicate SKAP2 as an attractive candidate for therapeutically targeting TAMs. PMID:26577701

  3. Monitoring breast tumor progression by photoacoustic measurements: a xenograft mice model study

    NASA Astrophysics Data System (ADS)

    Priya, Mallika; Satish Rao, Bola Sadashiva; Chandra, Subhash; Datta, Anirbit; Nayak, Subramanya G.; Mahato, Krishna Kishore

    2015-10-01

    The current study reports the photoacoustic spectroscopy-based assessment of breast tumor progression in a nude mice xenograft model. The tumor was induced through subcutaneous injection of MCF-7 cells in female nude mice and was monitored for 20 days until the tumor volume reached 1000 mm3. The tumor tissues were extracted at three different time points (days 10, 15, and 20) after tumor inoculation and subjected to photoacoustic spectral recordings in time domain ex vivo at 281 nm pulsed laser excitations. The spectra were converted into the frequency domain using the fast Fourier transformed tools of MATLAB® algorithms and further utilized to extract seven statistical features (mean, median, area under the curve, variance and standard deviation, skewness and kurtosis) from each time point sample to assess the tumor growth with wavelet principal component analysis based logistic regression analysis performed on the data. The prediction accuracies of the analysis for day 10 versus day 15, day 15 versus day 20, and day 10 versus day 20 were found to be 92.31, 87.5, and 95.2%, respectively. Also, receiver operator characteristics area under the curve analysis for day 10 versus day 15, day 15 versus day 20, and day 10 versus day 20 were found to be 0.95, 0.85, and 0.93, respectively. The ability of photoacoustic measurements in the objective assessment of tumor progression has been clearly demonstrated, indicating its clinical potential.

  4. Monitoring breast tumor progression by photoacoustic measurements: a xenograft mice model study.

    PubMed

    Priya, Mallika; Satish Rao, Bola Sadashiva; Chandra, Subhash; Datta, Anirbit; Nayak, Subramanya G; Mahato, Krishna Kishore

    2015-10-01

    The current study reports the photoacoustic spectroscopy-based assessment of breast tumor progression in a nude mice xenograft model. The tumor was induced through subcutaneous injection of MCF-7 cells in female nude mice and was monitored for 20 days until the tumor volume reached 1000  mm3. The tumor tissues were extracted at three different time points (days 10, 15, and 20) after tumor inoculation and subjected to photoacoustic spectral recordings in time domain ex vivo at 281 nm pulsed laser excitations. The spectra were converted into the frequency domain using the fast Fourier transformed tools of MATLAB® algorithms and further utilized to extract seven statistical features (mean, median, area under the curve, variance and standard deviation, skewness and kurtosis) from each time point sample to assess the tumor growth with wavelet principal component analysis based logistic regression analysis performed on the data. The prediction accuracies of the analysis for day 10 versus day 15, day 15 versus day 20, and day 10 versus day 20 were found to be 92.31, 87.5, and 95.2%, respectively. Also, receiver operator characteristics area under the curve analysis for day 10 versus day 15, day 15 versus day 20, and day 10 versus day 20 were found to be 0.95, 0.85, and 0.93, respectively. The ability of photoacoustic measurements in the objective assessment of tumor progression has been clearly demonstrated, indicating its clinical potential. PMID:26442962

  5. Role of the tumor microenvironment in regulating apoptosis and cancer progression.

    PubMed

    Yaacoub, Katherine; Pedeux, Remy; Tarte, Karin; Guillaudeux, Thierry

    2016-08-10

    Apoptosis is a gene-directed program that is engaged to efficiently eliminate dysfunctional cells. Evasion of apoptosis may be an important gate to tumor initiation and therapy resistance. Like any other developmental program, apoptosis can be disrupted by several genetic aberrations driving malignant cells into an uncontrolled progression and survival. For its sustained growth, cancer develops in a complex environment, which provides survival signals and rescues malignant cells from apoptosis. Recent studies have clearly shown a wide interaction between tumor cells and their microenvironment, confirming the influence of the surrounding cells on tumor expansion and invasion. These non-malignant cells not only intensify tumor cells growth but also upgrade the process of metastasis. The strong crosstalk between malignant cells and a reactive microenvironment is mediated by soluble chemokines and cytokines, which act on tumor cells through surface receptors. Disturbing the microenvironment signaling might be an encouraging approach for patient's treatment. Therefore, the ultimate knowledge of "tumor-microenvironment" interactions facilitates the identification of novel therapeutic procedures that mobilize cancer cells from their supportive cells. This review focuses on cancer progression mediated by the dysfunction of apoptosis and by the fundamental relationship between tumor and reactive cells. New insights and valuable targets for cancer prevention and therapy are also presented. PMID:27224890

  6. A PDE approach for quantifying and visualizing tumor progression and regression

    NASA Astrophysics Data System (ADS)

    Sintay, Benjamin J.; Bourland, J. Daniel

    2009-02-01

    Quantification of changes in tumor shape and size allows physicians the ability to determine the effectiveness of various treatment options, adapt treatment, predict outcome, and map potential problem sites. Conventional methods are often based on metrics such as volume, diameter, or maximum cross sectional area. This work seeks to improve the visualization and analysis of tumor changes by simultaneously analyzing changes in the entire tumor volume. This method utilizes an elliptic partial differential equation (PDE) to provide a roadmap of boundary displacement that does not suffer from the discontinuities associated with other measures such as Euclidean distance. Streamline pathways defined by Laplace's equation (a commonly used PDE) are used to track tumor progression and regression at the tumor boundary. Laplace's equation is particularly useful because it provides a smooth, continuous solution that can be evaluated with sub-pixel precision on variable grid sizes. Several metrics are demonstrated including maximum, average, and total regression and progression. This method provides many advantages over conventional means of quantifying change in tumor shape because it is observer independent, stable for highly unusual geometries, and provides an analysis of the entire three-dimensional tumor volume.

  7. K+ channels and cell cycle progression in tumor cells

    PubMed Central

    Ouadid-Ahidouch, Halima; Ahidouch, Ahmed

    2013-01-01

    K+ ions play a major role in many cellular processes. The deregulation of K+ signaling is associated with a variety of diseases such as hypertension, atherosclerosis, or diabetes. K+ ions are important for setting the membrane potential, the driving force for Ca2+ influx, and regulate volume of growing cells. Moreover, it is increasingly recognized that K+ channels control cell proliferation through a novel signaling mechanisms triggered and modulated independently of ion fluxes. In cancer, aberrant expression, regulation and/or sublocalization of K+ channels can alter the downstream signals that converge on the cell cycle machinery. Various K+ channels are involved in cell cycle progression and are needed only at particular stages of the cell cycle. Consistent with this idea, the expression of Eag1 and HERG channels fluctuate along the cell cycle. Despite of acquired knowledge, our understanding of K+ channels functioning in cancer cells requires further studies. These include identifying the molecular mechanisms controlling the cell cycle machinery. By understanding how K+ channels regulate cell cycle progression in cancer cells, we will gain insights into how cancer cells subvert the need for K+ signal and its downstream targets to proliferate. PMID:23970866

  8. Bisected, complex N-glycans and galectins in mouse mammary tumor progression and human breast cancer

    PubMed Central

    Miwa, Hazuki E; Koba, Wade R; Fine, Eugene J; Giricz, Orsi; Kenny, Paraic A; Stanley, Pamela

    2013-01-01

    Bisected, complex N-glycans on glycoproteins are generated by the glycosyltransferase MGAT3 and cause reduced cell surface binding of galectins. Previously, we showed that MGAT3 reduces growth factor signaling and retards mammary tumor progression driven by the Polyoma middle T antigen (PyMT) expressed in mammary epithelium under the mouse mammary tumor virus (MMTV) promoter. However, the penetrance of the tumor phenotype became variable in mixed FVB/N and C57BL/6 female mice and we therefore investigated a congenic C57BL/6 Mgat3−/−/MMTV-PyMT model. In the absence of MGAT3, C57BL/6 Mgat3−/−/MMTV-PyMT females exhibited accelerated tumor appearance and increased tumor burden, glucose uptake in tumors and lung metastasis. Nevertheless, activation of extracellular signal-regulated kinase (ERK)1/2 or protein kinase B (AKT) was reduced in ∼20-week C57BL/6 MMTV-PyMT tumors lacking MGAT3. Activation of focal adhesion kinase (FAK), protein tyrosine kinase Src, and p38 mitogen-activated protein kinase were similar to that of controls. All the eight mouse galectin genes were expressed in mammary tumors and tumor epithelial cells (TECs), but galectin-2 and -12 were not detected by western analysis in tumors, and galectin-7 was not detected in 60% of the TEC lines. From microarray data reported for human breast cancers, at least 10 galectin and 7 N-glycan N-acetylglucosaminyl (GlcNAc)-transferase (MGAT) genes are expressed in tumor tissue, and expression often varies significantly between different breast cancer subtypes. Thus, in summary, while MGAT3 and bisected complex N-glycans retard mouse mammary tumor progression, genetic background may modify this effect; identification of key galectins that promote mammary tumor progression in mice is not straightforward because all the eight galectin genes are expressed; and high levels of MGAT3, galectin-4, -8, -10, -13 and -14 transcripts correlate with better relapse-free survival in human breast cancer. PMID:24037315

  9. Carbidopa abrogates L-dopa decarboxylase coactivation of the androgen receptor and delays prostate tumor progression.

    PubMed

    Wafa, Latif A; Cheng, Helen; Plaa, Nathan; Ghaidi, Fariba; Fukumoto, Takahiro; Fazli, Ladan; Gleave, Martin E; Cox, Michael E; Rennie, Paul S

    2012-06-15

    The androgen receptor (AR) plays a central role in prostate cancer progression to the castration-resistant (CR) lethal state. L-Dopa decarboxylase (DDC) is an AR coactivator that increases in expression with disease progression and is coexpressed with the receptor in prostate adenocarcinoma cells, where it may enhance AR activity. Here, we hypothesize that the DDC enzymatic inhibitor, carbidopa, can suppress DDC-coactivation of AR and retard prostate tumor growth. Treating LNCaP prostate cancer cells with carbidopa in transcriptional assays suppressed the enhanced AR transactivation seen with DDC overexpression and decreased prostate-specific antigen (PSA) mRNA levels. Carbidopa dose-dependently inhibited cell growth and decreased survival in LNCaP cell proliferation and apoptosis assays. The inhibitory effect of carbidopa on DDC-coactivation of AR and cell growth/survival was also observed in PC3 prostate cancer cells (stably expressing AR). In vivo studies demonstrated that serum PSA velocity and tumor growth rates elevated ∼2-fold in LNCaP xenografts, inducibly overexpressing DDC, were reverted to control levels with carbidopa administration. In castrated mice, treating LNCaP tumors, expressing endogenous DDC, with carbidopa delayed progression to the CR state from 6 to 10 weeks, while serum PSA and tumor growth decreased 4.3-fold and 5.4-fold, respectively. Our study is a first time demonstration that carbidopa can abrogate DDC-coactivation of AR in prostate cancer cells and tumors, decrease serum PSA, reduce tumor growth and delay CR progression. Since carbidopa is clinically approved, it may be readily used as a novel therapeutic strategy to suppress aberrant AR activity and delay prostate cancer progression. PMID:21780103

  10. Potential markers of tongue tumor progression selected by cDNA microarray.

    PubMed

    Carinci, F; Lo Muzio, L; Piattelli, A; Rubini, C; Chiesa, F; Ionna, F; Palmieri, A; Maiorano, E; Pastore, A; Laino, G; Dolci, M; Pezzetti, F

    2005-01-01

    Squamous cell carcinoma (SCC), the most frequent malignant tumor of the oral cavity, generally exhibits a poor prognosis and metastases are the main cause of death. This tumor often arises from pre-malignant lesions. To date, it is difficult to predict if and which pre-malignant lesions may progress into oral SCC using traditional methods. For these reasons, several studies are trying to identify markers useful in the progression of pre-malignant lesions and tumors. To define the genetic expression profile of tongue tumor progression we compared 9 dysplasias (DS), 8 tumors without metastasis (TWM), 11 metastasizing SCCs (MT) of the tongue, and a baseline of 11 normal tissues by using cDNA microarray containing 19.2 K clones. We initially applied hierarchical agglomerative clustering based on information from all 6026 clones. Results were obtained by performing a two steps analysis: a Significance Analysis of Microarray (SAM) and a Gene Ontology search. One hundred and five clones have statistically significant different expression levels (FDR < 0.01) between DS and TWM, whereas 570 genes have statistically significant difference expression levels between TWM and MT (FDR < 0.01) as detected by SAM. By filtering with FatiGo only 33 genes were differentially expressed in TWN, respect to DS, whereas 155 genes were differentially expressed in MT respect to TWM. We detected some genes which encode for oncogenes, transcription factors and cell cycle regulators as potential markers of DS progression. Examples are BAG4, PAX3 and CCNI, respectively. Among potential markers of metastases are some genes related to cell mobility (TSPAN-2 and SNTA1), intercellular adhesion (integrin alpha 7) or extracellular matrix components (ADAMTS2 and cathepsin O). Additionally, under-expressed genes encoded apoptosis-related proteins (PDCD4 and CASP4). In conclusion, we identified several genes differentially expressed in tumor progression which can potentially help in better classifying

  11. Morphine Promotes Tumor Angiogenesis and Increases Breast Cancer Progression

    PubMed Central

    Bimonte, Sabrina; Barbieri, Antonio; Palma, Giuseppe; Luciano, Antonio; Cuomo, Arturo; Arra, Claudio; Izzo, Francesco

    2015-01-01

    Morphine is considered a highly potent analgesic agent used to relieve suffering of patients with cancer. Several in vitro and in vivo studies showed that morphine also modulates angiogenesis and regulates tumour cell growth. Unfortunately, the results obtained by these studies are still contradictory. In order to better dissect the role of morphine in cancer cell growth and angiogenesis we performed in vitro studies on ER-negative human breast carcinoma cells, MDA.MB231 and in vivo studies on heterotopic mouse model of human triple negative breast cancer, TNBC. We demonstrated that morphine in vitro enhanced the proliferation and inhibited the apoptosis of MDA.MB231 cells. In vivo studies performed on xenograft mouse model of TNBC revealed that tumours of mice treated with morphine were larger than those observed in other groups. Moreover, morphine was able to enhance the neoangiogenesis. Our data showed that morphine at clinical relevant doses promotes angiogenesis and increases breast cancer progression. PMID:26064880

  12. Vitamin D, intermediary metabolism and prostate cancer tumor progression

    PubMed Central

    Wang, Wei-Lin W.; Tenniswood, Martin

    2014-01-01

    Epidemiological data have demonstrated an inverse association between serum vitamin D3 levels, cancer incidence and related mortality. However, the effects of vitamin D on prostate cancer biology and its utility for prevention of prostate cancer progression are not as well-defined. The data are often conflicting: some reports suggest that vitamin D3 induces apoptosis in androgen dependent prostate cancer cell lines, while others suggest that vitamin D3 only induces cell cycle arrest. Recent molecular studies have identified an extensive synergistic crosstalk between the vitamin D- and androgen-mediated mRNA and miRNA expression, adding an additional layer of post-transcriptional regulation to the known VDR- and AR-regulated gene activation. The Warburg effect, the inefficient metabolic pathway that converts glucose to lactate for rapid energy generation, is a phenomenon common to many different types of cancer. This process supports cell proliferation and promotes cancer progression via alteration of glucose, glutamine and lipid metabolism. Prostate cancer is a notable exception to this general process since the metabolic switch that occurs early during malignancy is the reverse of the Warburg effect. This “anti-Warburg effect” is due to the unique biology of normal prostate cells that harbor a truncated TCA cycle that is required to produce and secret citrate. In prostate cancer cells, the TCA cycle activity is restored and citrate oxidation is used to produce energy for cancer cell proliferation. 1,25(OH)2D3 and androgen together modulates the TCA cycle via transcriptional regulation of zinc transporters, suggesting that 1,25(OH)2D3 and androgen maintain normal prostate metabolism by blocking citrate oxidation. These data demonstrate the importance of androgens in the anti-proliferative effect of vitamin D in prostate cancer and highlight the importance of understanding the crosstalk between these two signaling pathways. PMID:24860512

  13. Vitamin D, intermediary metabolism and prostate cancer tumor progression.

    PubMed

    Wang, Wei-Lin W; Tenniswood, Martin

    2014-01-01

    Epidemiological data have demonstrated an inverse association between serum vitamin D3 levels, cancer incidence and related mortality. However, the effects of vitamin D on prostate cancer biology and its utility for prevention of prostate cancer progression are not as well-defined. The data are often conflicting: some reports suggest that vitamin D3 induces apoptosis in androgen dependent prostate cancer cell lines, while others suggest that vitamin D3 only induces cell cycle arrest. Recent molecular studies have identified an extensive synergistic crosstalk between the vitamin D- and androgen-mediated mRNA and miRNA expression, adding an additional layer of post-transcriptional regulation to the known VDR- and AR-regulated gene activation. The Warburg effect, the inefficient metabolic pathway that converts glucose to lactate for rapid energy generation, is a phenomenon common to many different types of cancer. This process supports cell proliferation and promotes cancer progression via alteration of glucose, glutamine and lipid metabolism. Prostate cancer is a notable exception to this general process since the metabolic switch that occurs early during malignancy is the reverse of the Warburg effect. This "anti-Warburg effect" is due to the unique biology of normal prostate cells that harbor a truncated TCA cycle that is required to produce and secret citrate. In prostate cancer cells, the TCA cycle activity is restored and citrate oxidation is used to produce energy for cancer cell proliferation. 1,25(OH)2D3 and androgen together modulates the TCA cycle via transcriptional regulation of zinc transporters, suggesting that 1,25(OH)2D3 and androgen maintain normal prostate metabolism by blocking citrate oxidation. These data demonstrate the importance of androgens in the anti-proliferative effect of vitamin D in prostate cancer and highlight the importance of understanding the crosstalk between these two signaling pathways. PMID:24860512

  14. IL12 and IL27 sequential gene therapy via intramuscular electroporation delivery for eliminating distal aggressive tumors1

    PubMed Central

    Zhu, Shiguo; Lee, Dean Anthony; Li, Shulin

    2010-01-01

    Eradication of residual malignancies and metastatic tumors via a systemic approach is the key for successfully treating cancer and increasing the cancer patient survival. Systemic administration of IL12 protein in an acute large dose is effective but toxic. Systemic administration of IL12 gene by persistently expressing a low level of IL12 protein may reduce the systemic toxicity, but only eradicates IL12 sensitive tumors. Here, we discovered that sequential administration of IL12 and IL27 encoding DNA, referred to as sequential IL12-IL27 gene therapy, not only eradicated IL12 sensitive tumors from 100% of mice but also eradicated the highly malignant 4T1 tumors from 33% of treated mice in multiple independent experiments. This IL12-IL27 sequential gene therapy is not only superior to IL12-IL12 sequential gene therapy for eliminating tumors, but also for inducing CTL activity, increasing T cell infiltration into tumors, and yielding a large number of tumor-specific IFNγ positive CD8 T cells. Notably, depletion of either T- or NK-cells during the IL27 treatment phase reverses tumor eradication, suggesting an NK-cell requirement for this sequential gene therapy-mediated tumor eradication. Both reversal of the administration sequence and co-administration of IL12 and IL27 impaired the tumor eradication in 4T1 tumor bearing mice. This IL12-IL27 sequential gene therapy, via sequential administration of IL12 and IL27 encoding plasmid DNA into tumor-bearing mice through intramuscular electroporation, provides a simple but effective approach for eliminating inaccessible residual tumors. PMID:20139275

  15. The tumoral A genotype of the MGMT rs34180180 single-nucleotide polymorphism in aggressive gliomas is associated with shorter patients' survival.

    PubMed

    Fogli, Anne; Chautard, Emmanuel; Vaurs-Barrière, Catherine; Pereira, Bruno; Müller-Barthélémy, Mélanie; Court, Franck; Biau, Julian; Pinto, Afonso Almeida; Kémény, Jean-Louis; Khalil, Toufic; Karayan-Tapon, Lucie; Verrelle, Pierre; Costa, Bruno Marques; Arnaud, Philippe

    2016-02-01

    Malignant gliomas are the most common primary brain tumors. Grade III and IV gliomas harboring wild-type IDH1/2 are the most aggressive. In addition to surgery and radiotherapy, concomitant and adjuvant chemotherapy with temozolomide (TMZ) significantly improves overall survival (OS). The methylation status of the O(6)-methylguanine-DNA methyltransferase (MGMT) promoter is predictive of TMZ response and a prognostic marker of cancer outcome. However, the promoter regions the methylation of which correlates best with survival in aggressive glioma and whether the promoter methylation status predictive value could be refined or improved by other MGMT-associated molecular markers are not precisely known. In a cohort of 87 malignant gliomas treated with radiotherapy and TMZ-based chemotherapy, we retrospectively determined the MGMT promoter methylation status, genotyped single nucleotide polymorphisms (SNPs) in the promoter region and quantified MGMT mRNA expression level. Each of these variables was correlated with each other and with the patients' OS. We found that methylation of the CpG sites within MGMT exon 1 best correlated with OS and MGMT expression levels, and confirmed MGMT methylation as a stronger independent prognostic factor compared to MGMT transcription levels. Our main finding is that the presence of only the A allele at the rs34180180 SNP in the tumor was significantly associated with shorter OS, independently of the MGMT methylation status. In conclusion, in the clinic, rs34180180 SNP genotyping could improve the prognostic value of the MGMT promoter methylation assay in patients with aggressive glioma treated with TMZ. PMID:26717998

  16. Tumor-associated macrophages are involved in tumor progression in papillary renal cell carcinoma.

    PubMed

    Behnes, Carl Ludwig; Bremmer, Felix; Hemmerlein, Bernhard; Strauss, Arne; Ströbel, Philipp; Radzun, Heinz-Joachim

    2014-02-01

    Tumor-associated macrophages (TAMs) play a key role in cancer development. Especially, the immunosuppressive M2 phenotype is associated with increased tumor growth, invasiveness and metastasis. The differentiation of macrophages to the alternative phenotype M2 is mediated, inter alia, by macrophage colony-stimulating factor (M-CSF). Papillary renal cell carcinoma (RCC) represents a rare tumor type which, based upon histological criteria, can be subdivided into two subtypes (I and II), of which type II is associated with poor prognosis. In both subtypes, typically, a dense infiltrate of macrophages is found. In the present study, the expression of CD68, CD163, M-CSF, Ki-67, and CD31 was examined in 30 type I and 30 type II papillary RCCs (n = 60). Both types of papillary RCCs contained an equally dense infiltrate of CD68-positive macrophages. Nearly all macrophages in papillary RCC type II expressed CD163, a characteristic for M2 macrophages. In type I papillary RCC, less than 30 % of macrophages expressed CD163. Furthermore, tumor cells in type II papillary RCC expressed significantly more M-CSF and showed increased (Ki-67 expression defined) proliferative activity in comparison with type I papillary RCC. In addition, the (CD31 defined) capillary density was higher in type II than in type I papillary RCC. A dense infiltrate of M2 phenotype TAM and high M-CSF expression in tumor cells are key features of type II papillary RCC. These findings might explain why the prognosis of papillary RCC type II is worse than that of type I. PMID:24327306

  17. Stimulatory versus suppressive effects of GM-CSF on tumor progression in multiple cancer types

    PubMed Central

    Hong, In-Sun

    2016-01-01

    Granulocyte-macrophage colony-stimulating factor (GM-CSF, also called CSF-2) is best known for its critical role in immune modulation and hematopoiesis. A large body of experimental evidence indicates that GM-CSF, which is frequently upregulated in multiple types of human cancers, effectively marks cancer cells with a ‘danger flag' for the immune system. In this context, most studies have focused on its function as an immunomodulator, namely its ability to stimulate dendritic cell (DC) maturation and monocyte/macrophage activity. However, recent studies have suggested that GM-CSF also promotes immune-independent tumor progression by supporting tumor microenvironments and stimulating tumor growth and metastasis. Although some studies have suggested that GM-CSF has inhibitory effects on tumor growth and metastasis, an even greater number of studies show that GM-CSF exerts stimulatory effects on tumor progression. In this review, we summarize a number of findings to provide the currently available information regarding the anticancer immune response of GM-CSG. We then discuss the potential roles of GM-CSF in the progression of multiple types of cancer to provide insights into some of the complexities of its clinical applications. PMID:27364892

  18. Stimulatory versus suppressive effects of GM-CSF on tumor progression in multiple cancer types.

    PubMed

    Hong, In-Sun

    2016-01-01

    Granulocyte-macrophage colony-stimulating factor (GM-CSF, also called CSF-2) is best known for its critical role in immune modulation and hematopoiesis. A large body of experimental evidence indicates that GM-CSF, which is frequently upregulated in multiple types of human cancers, effectively marks cancer cells with a 'danger flag' for the immune system. In this context, most studies have focused on its function as an immunomodulator, namely its ability to stimulate dendritic cell (DC) maturation and monocyte/macrophage activity. However, recent studies have suggested that GM-CSF also promotes immune-independent tumor progression by supporting tumor microenvironments and stimulating tumor growth and metastasis. Although some studies have suggested that GM-CSF has inhibitory effects on tumor growth and metastasis, an even greater number of studies show that GM-CSF exerts stimulatory effects on tumor progression. In this review, we summarize a number of findings to provide the currently available information regarding the anticancer immune response of GM-CSG. We then discuss the potential roles of GM-CSF in the progression of multiple types of cancer to provide insights into some of the complexities of its clinical applications. PMID:27364892

  19. Low expression of ARHI is associated with shorter progression-free survival in pancreatic endocrine tumors.

    PubMed

    Dalai, Irene; Missiaglia, Edoardo; Barbi, Stefano; Butturini, Giovanni; Doglioni, Claudio; Falconi, Massimo; Scarpa, Aldo

    2007-03-01

    Little is known about the molecular anomalies involved in the development and progression of malignancy of pancreatic endocrine tumors (PETs). A recently identified member of the Ras family, Ras homologue member I (ARHI), has been shown to be involved in breast, ovary, and thyroid carcinogenesis. Unlike other members, it acts as a tumor suppressor gene that inhibits cell growth. Here we analyzed the mRNA expression of ARHI in 52 primary PETs and 16 normal pancreata using quantitative reverse transcription-polymerase chain reaction. ARHI expression showed a statistically significant difference between either normal pancreas or well-differentiated endocrine tumors (WDET) and poorly differentiated endocrine carcinomas (PDECs) (P < .001 and P < .001, respectively). Moreover, ARHI expression among WDEC samples was more heterogeneous than in WDET, with several tumors showing level of expression analogous to that observed in PDECs. A significant correlation between lower ARHI expression and shorter survival (P = .020) was identified, and a low ARHI expression was associated to a shorter time to progression (P < .001), even considering the proliferation index Ki67 in the multivariate analysis. ARHI is involved in PET progression. Its mRNA expression seemed to be a prognostic factor for disease outcome and, in association with the proliferative index Ki67, a predictor for a rapid tumor relapse. PMID:17401457

  20. Deletion of tumor progression locus 2 attenuates alcohol induced hepatic inflammation

    Technology Transfer Automated Retrieval System (TEKTRAN)

    BACKGROUND: The pathogenesis of alcoholic liver disease (ALD) involves the interaction of several inflammatory signaling pathways. Tumor progression locus 2 (TPL2), also known as Cancer Osaka Thyroid (COT) and MAP3K8, is a serine threonine kinase that functions as a critical regulator of inflammator...

  1. CD47 blockade inhibits tumor progression human osteosarcoma in xenograft models

    PubMed Central

    Zhang, Shui-Jun; Zhao, Chen; Qiu, Bin-Song; Gu, Hai-Feng; Hong, Jian-Fei; Cao, Li; Chen, Yu; Xia, Bing; Bi, Qin; Wang, Ya-Ping

    2015-01-01

    Osteosarcoma is the most common bone tumors in children and adolescents. Despite intensive chemotherapy, patients with advanced disease still have a poor prognosis, illustrating the need for alternative therapies. In this study, we explored the use of antibodies that block CD47 with a tumor growth suppressive effect on osteosarcoma. We first found that up-regulation of CD47 mRNA levels in the tumorous tissues from eight patients with osteosarcoma when compared with that in adjacent non-tumorous tissues. Further western-blot (WB) and immunohistochemistry (IHC) demonstrated that CD47 protein level was highly expressed in osteosarcoma compared to normal osteoblastic cells and adjacent non-tumorous tissues. Osteosarcoma cancer stem cell markers staining shown that the majority of CD44+ cells expressed CD47 albeit with different percentages (ranging from 80% to 99%). Furthermore, high CD47 mRNA expression levels were associated with a decreased probability of progression-free and overall survival. In addition, blockade of CD47 by specific Abs suppresses the invasive ability of osteosarcoma tumor cells and further inhibits spontaneous pulmonary metastasis of KRIB osteosarcoma cells in vivo. Finally, CD47 blockade increases macrophage phagocytosis of osteosarcoma tumor cells. In conclusion, our findings demonstrate that CD47 is a critical regulator in the metastasis of osteosarcoma and suggest that targeted inhibition of this antigen by anti-CD47 may be a novel immunotherapeutic approach in the management of this tumor. PMID:26093091

  2. Metabolic Competition in the Tumor Microenvironment Is a Driver of Cancer Progression.

    PubMed

    Chang, Chih-Hao; Qiu, Jing; O'Sullivan, David; Buck, Michael D; Noguchi, Takuro; Curtis, Jonathan D; Chen, Qiongyu; Gindin, Mariel; Gubin, Matthew M; van der Windt, Gerritje J W; Tonc, Elena; Schreiber, Robert D; Pearce, Edward J; Pearce, Erika L

    2015-09-10

    Failure of T cells to protect against cancer is thought to result from lack of antigen recognition, chronic activation, and/or suppression by other cells. Using a mouse sarcoma model, we show that glucose consumption by tumors metabolically restricts T cells, leading to their dampened mTOR activity, glycolytic capacity, and IFN-γ production, thereby allowing tumor progression. We show that enhancing glycolysis in an antigenic "regressor" tumor is sufficient to override the protective ability of T cells to control tumor growth. We also show that checkpoint blockade antibodies against CTLA-4, PD-1, and PD-L1, which are used clinically, restore glucose in tumor microenvironment, permitting T cell glycolysis and IFN-γ production. Furthermore, we found that blocking PD-L1 directly on tumors dampens glycolysis by inhibiting mTOR activity and decreasing expression of glycolysis enzymes, reflecting a role for PD-L1 in tumor glucose utilization. Our results establish that tumor-imposed metabolic restrictions can mediate T cell hyporesponsiveness during cancer. PMID:26321679

  3. Killing Is Not Enough: How Apoptosis Hijacks Tumor-Associated Macrophages to Promote Cancer Progression.

    PubMed

    Weigert, Andreas; Mora, Javier; Sekar, Divya; Syed, Shahzad; Brüne, Bernhard

    2016-01-01

    Macrophages are a group of heterogeneous cells of the innate immune system that are crucial to the initiation, progression, and resolution of inflammation. Moreover, they control tissue homeostasis in healthy tissue and command a broad sensory arsenal to detect disturbances in tissue integrity. Macrophages possess a remarkable functional plasticity to respond to irregularities and to initiate programs that allow overcoming them in order to return back to normal. Thus, macrophages kill malignant or transformed cells, rearrange extracellular matrix, take up and recycle cellular as well as molecular debris, initiate cellular growth cascades, and favor directed migration of cells. As an example, apoptotic death of bystander cells is sensed by macrophages, initiating functional responses that support all hallmarks of cancer. In this chapter, we describe how tumor cell apoptosis hijacks tumor-associated macrophages to promote tumor growth. We propose that tumor therapy should not only kill malignant cells but also target the interaction of the host with apoptotic cancer cells, as this might be efficient to limit the protumor action of apoptotic cells and boost the antitumor potential of macrophages. Leaving the apoptotic cell/macrophage interaction untouched might also limit the benefit of conventional tumor cell apoptosis-focused therapy since surviving tumor cells might receive overwhelming support by the wound healing response that apoptotic tumor cells will trigger in local macrophages, thereby enhancing tumor recurrence. PMID:27558823

  4. Male patients presenting with rapidly progressive puberty associated with malignant tumors

    PubMed Central

    Kim, Soo Jung; Ko, A Ra; Jung, Mo Kyung; Kim, Ki Eun; Chae, Hyun Wook; Kim, Duk Hee; Kim, Ho-Seong

    2016-01-01

    In males, precocious puberty (PP) is defined as the development of secondary sexual characteristics before age 9 years. PP is usually idiopathic; though, organic abnormalities including tumors are more frequently found in male patients with PP. However, advanced puberty in male also can be an important clinical manifestation in tumors. We report 2 cases of rapidly progressive puberty in males, each associated with a germ-cell tumor. First, an 11-year-old boy presented with mild fever and weight loss for 1 month. Physical examination revealed a pubertal stage of G3P3 with 10-mL testes. Investigations revealed advanced bone age (16 years) with elevated basal luteinizing hormone and testosterone levels. An anterior mediastinal tumor was identified by chest radiography and computed tomography, and elevated α-fetoprotein (AFP) and β-human chorionic gonadotropin (β-hCG) levels were noted. Histopathologic analysis confirmed a yolk-sac tumor. Second, a 12-year-old boy presented with diplopia, polydipsia, and polyuria for 4 months. Physical examination revealed a pubertal stage of G3P3 with 8-mL testes. Bone age was advanced (16 years) and laboratory tests indicated panhypopituitarism with elevated testosterone level. A mixed germ-cell tumor was diagnosed with elevated AFP and β-hCG levels. Of course, these patients also have other symptoms of suspecting tumors, however, rapidly progressive puberty can be the more earlier screening sign of tumors. Therefore, in male patients with accelerated or advanced puberty, malignancy should be considered, with evaluation of tumor markers. In addition, advanced puberty in male should be recognized more widely as a unique sign of neoplasm. PMID:27104181

  5. Real-time Imaging of Tumor Progression in a Fluorescent Orthotopic Mouse Model of Thyroid Cancer

    PubMed Central

    TRAN CAO, HOP S.; KAUSHAL, SHARMEELA; SNYDER, CYNTHIA S.; ONGKEKO, WEG M.; HOFFMAN, ROBERT M.; BOUVET, MICHAEL

    2015-01-01

    There is a need for a clinically relevant mouse model of thyroid cancer that enables real-time, non-invasive monitoring of tumor growth, progression, and drug response over time. Human thyroid cancer cell lines NPA (papillary) and KAK-1 (anaplastic) were stably transfected to express either red or green fluorescent protein. Cancer cells were injected into the thyroid glands of 8-week-old athymic mice. The animals were imaged with whole-body fluorescence imaging weekly and sacrificed when premorbid. At necropsy, the primary tumor was resected en bloc with the respiratory system for processing and analysis. Histology was performed on fixed tissue specimens for review of morphologic findings. Both anaplastic and papillary thyroid cancer cell lines led to robust development of orthotopic fluorescent tumors in nude mice. Injection of 5×105 cancer cells was sufficient for tumor development. Tumors were visualized for both cell lines via non-invasive imaging as early as 3 weeks post-implantation and were monitored over time. Time to premorbid condition varied between mice and was associated with a primary tumor growth pattern (early local compression of the esophagus vs. late metastatic disease) rather than tumor size. At necropsy, tumor fluorescence demonstrated metastases in the lungs, lymph nodes and vessels that were not visible under white light. Thus an orthotopic mouse model of thyroid cancer has been developed that replicates the major clinical features of thyroid cancer and enables real-time, non-invasive monitoring of tumor progression. This model should permit preclinical evaluation of novel thyroid cancer therapeutics. PMID:21115887

  6. VEGF-A acts via neuropilin-1 to enhance epidermal cancer stem cell survival and formation of aggressive and highly vascularized tumors.

    PubMed

    Grun, D; Adhikary, G; Eckert, R L

    2016-08-18

    We identify a limited subpopulation of epidermal cancer stem cells (ECS cells), in squamous cell carcinoma, that form rapidly growing, invasive and highly vascularized tumors, as compared with non-stem cancer cells. These ECS cells grow as non-attached spheroids, and display enhanced migration and invasion. We show that ECS cell-produced vascular endothelial growth factor (VEGF)-A is required for the maintenance of this phenotype, as knockdown of VEGF-A gene expression or treatment with VEGF-A-inactivating antibody reduces these responses. In addition, treatment with bevacizumab reduces tumor vascularity and growth. Surprisingly, the classical mechanism of VEGF-A action via interaction with VEGF receptors does not mediate these events, as these cells lack VEGFR1 and VEGFR2. Instead, VEGF-A acts via the neuropilin-1 (NRP-1) co-receptor. Knockdown of NRP-1 inhibits ECS cell spheroid formation, invasion and migration, and attenuates tumor formation. These studies suggest that VEGF-A acts via interaction with NRP-1 to trigger intracellular events leading to ECS cell survival and formation of aggressive, invasive and highly vascularized tumors. PMID:26804163

  7. 4th international conference on tumor progression and therapeutic resistance: meeting report

    PubMed Central

    Prabhu, Varun V; El-Deiry, Wafik S

    2015-01-01

    The fourth international conference on tumor progression and therapeutic resistance organized in association with GTCbio was held in Boston, MA from March 9 to 11, 2014. The meeting attracted a diverse group of experts in the field of cancer biology, therapeutics and medical oncology from academia and industry. The meeting addressed the current challenges in the treatment of cancer including tumor heterogeneity, therapy resistance and metastasis along with the need for improved biomarkers of tumor progression and clinical trial design. Keynote speakers included Clifton Leaf, Editor at Fortune Magazine, Dr. Mina Bissell from the Lawrence Berkeley National Laboratory and Dr. Levi Garraway from the Dana Farber Cancer Institute. The meeting featured cutting edge tools, preclinical models and the latest basic, translational and clinical research findings in the field. PMID:25782066

  8. Matrix Hyaluronan Promotes Specific MicroRNA Upregulation Leading to Drug Resistance and Tumor Progression

    PubMed Central

    Bourguignon, Lilly Y. W.

    2016-01-01

    Solid tumor invasion, metastasis and therapeutic drug resistance are the common causes for serious morbidity and cancer recurrence in patients. A number of research studies have searched for malignancy-related biomarkers and drug targets that are closely linked to tumor cell properties. One of the candidates is matrix hyaluronan (HA), which is known as one of the major extracellular matrix (ECM) components. HA serves as a physiological ligand for surface CD44 molecule and also functions as a bio-regulator. The binding of HA to CD44 has been shown to stimulate concomitant activation of a number of oncogenic pathways and abnormal cellular processes in cancer cells and cancer stem cells (CSCs). MicroRNAs (miRNAs) belong to a class of small RNAs containing ~20–25 nucleotides and are known to promote aberrant cellular functions in cancer cells. In this article, I have focused on the role of HA interaction with CD44 and several important signaling molecules in the regulation of unique miRNAs (e.g., miR-21, miR-302 and miR-10b) and their downstream targets leading to multiple tumor cell-specific functions (e.g., tumor cell growth, drug resistance and metastasis) and cancer progression. This new knowledge could provide the groundwork necessary for establishing new tumor markers and developing important, novel drugs targeted against HA/CD44-associated tumor progression, which can be utilized in the therapeutic treatment of metastatic cancer patients. PMID:27070574

  9. Molecular genetics of bladder cancer: Emerging mechanisms of tumor initiation and progression.

    PubMed

    McConkey, David J; Lee, Sangkyou; Choi, Woonyoung; Tran, Mai; Majewski, Tadeusz; Lee, Sooyong; Siefker-Radtke, Arlene; Dinney, Colin; Czerniak, Bogdan

    2010-01-01

    Urothelial cancer has served as one of the most important sources of information about the mutational events that underlie the development of human solid malignancies. Although "field effects" that affect the entire bladder mucosa appear to initiate disease, tumors develop along 2 distinct biological "tracks" that present vastly different challenges for clinical management. Recent whole genome methodologies have facilitated even more rapid progress in the identification of the molecular mechanisms involved in bladder cancer initiation and progression. Specifically, whole organ mapping combined with high resolution, high throughput SNP analyses have identified a novel class of candidate tumor suppressors ("forerunner genes") that localize near more familiar tumor suppressors but are disrupted at an earlier stage of cancer development. Furthermore, whole genome comparative genomic hybridization (CGH) and mRNA expression profiling have demonstrated that the 2 major subtypes of urothelial cancer (papillary/superficial and non-papillary/muscle-invasive) are truly distinct molecular entities, and in recent work our group has discovered that muscle-invasive tumors express molecular markers characteristic of a developmental process known as "epithelial-to-mesenchymal transition" (EMT). Emerging evidence indicates that urothelial cancers contain subpopulations of tumor-initiating cells ("cancer stem cells") but the phenotypes of these cells in different tumors are heterogeneous, raising questions about whether or not the 2 major subtypes of cancer share a common precursor. This review will provide an overview of these new insights and discuss priorities for future investigation. PMID:20610280

  10. AZU-1: A Candidate Breast Tumor Suppressor and Biomarker for Tumor Progression

    SciTech Connect

    Chen, Huei-Mei; Schmeichel, Karen L; Mian, I. Saira; Lelie`vre, Sophie; Petersen, Ole W; Bissell, Mina J

    2000-02-04

    To identify genes misregulated in the final stages of breast carcinogenesis, we performed differential display to compare the gene expression patterns of the human tumorigenic mammary epithelial cells, HMT-3522-T4-2, with those of their immediate premalignant progenitors, HMT-3522-S2. We identified a novel gene, called anti-zuai-1 (AZU-1), that was abundantly expressed in non- and premalignant cells and tissues but was appreciably reduced in breast tumor cell types and in primary tumors. The AZU-1 gene encodes an acidic 571-amino-acid protein containing at least two structurally distinct domains with potential protein-binding functions: an N-terminal serine and proline-rich domain with a predicted immunoglobulin-like fold and a C-terminal coiled-coil domain. In HMT-3522 cells, the bulk of AZU-1 protein resided in a detergent-extractable cytoplasmic pool and was present at much lower levels in tumorigenic T4-2 cells than in their nonmalignant counterparts. Reversion of the tumorigenic phenotype of T4-2 cells, by means described previously, was accompanied by the up-regulation of AZU-1. In addition, reexpression of AZU-1 in T4-2 cells, using viral vectors, was sufficient to reduce their malignant phenotype substantially, both in culture and in vivo. These results indicate that AZU-1 is a candidate breast tumor suppressor that may exert its effects by promoting correct tissue morphogenesis.

  11. Presence of sst5TMD4, a truncated splice variant of the somatostatin receptor subtype 5, is associated to features of increased aggressiveness in pancreatic neuroendocrine tumors

    PubMed Central

    Gahete, Manuel D.; Serrano-Somavilla, Ana; Villa-Osaba, Alicia; Adrados, Magdalena; Ibáñez-Costa, Alejandro; Martín-Pérez, Elena; Culler, Michael D.

    2016-01-01

    Purpose Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are rare and heterogeneous tumors, and their biological behavior is not well known. We studied the presence and potential functional roles of somatostatin receptors (sst1-5), focusing particularly on the truncated variants (sst5TMD4, sst5TMD5) and on their relationships with the angiogenic system (Ang/Tie-2 and VEGF) in human GEP-NETs. Experimental Design We evaluated 42 tumor tissue samples (26 primary/16 metastatic) from 26 patients with GEP-NETs, and 30 non-tumoral tissues (26 from adjacent non-tumor regions and 4 from normal controls) from a single center. Expression of sst1-5, sst5TMD4, sst5TMD5, Ang1-2, Tie-2 and VEGF was analyzed using real-time qPCR, immunofluorescence and immunohistochemistry. Expression levels were associated with tumor characteristics and clinical outcomes. Functional role of sst5TMD4 was analyzed in GEP-NET cell lines. Results sst1 exhibited the highest expression in GEP-NET, whilst sst2 was the most frequently observed sst-subtype (90.2%). Expression levels of sst1, sst2, sst3, sst5TMD4, and sst5TMD5 were significantly higher in tumor tissues compared to their adjacent non-tumoral tissue. Lymph-node metastases expressed higher levels of sst5TMD4 than in its corresponding primary tumor tissue. sst5TMD4 was also significantly higher in intestinal tumor tissues from patients with residual disease of intestinal origin compared to those with non-residual disease. Functional assays demonstrated that the presence of sst5TMD4 was associated to enhanced malignant features in GEP-NET cells. Angiogenic markers correlated positively with sst5TMD4, which was confirmed by immunohistochemical/fluorescence studies. Conclusions sst5TMD4 is overexpressed in GEP-NETs and is associated to enhanced aggressiveness, suggesting its potential value as biomarker and target in GEP-NETs. PMID:26673010

  12. [An analysis of 117 cases of patients who died from tumor recurrence or from the progression of ovarian malignancies].

    PubMed

    Kano, T; Sakakibara, K; Kamiya, N; Mizuno, K; Miyazaki, T; Ohta, M; Tomoda, Y

    1987-10-01

    Out of 403 patients with ovarian with malignancies during 1978 to, 1985, 117 (29.0%) died from the progression of a non-curative cancer (56 cases, 47.9%) or from a cancer recurrence (61 cases, 52.1%). The mean survival rate 117 cases was 13.4 months, of which 103 (88.0%) cases concerned patients who died within 2 years and 114 (97.4%) who died within 3 years. A histological analysis revealed that patients with a serous or an endometrial cancer had a longer survival rate than others. Among 61 recurrent cases, 59 (96.7%) fell into recurrence within 2 years. Regarding the relationship between a recurrent of cancer and its prognosis, patients with a recurrence of an ascitic or a metastatic disease had a poorer prognosis than patients with a pelvic or an abdominal mass. An aggressive operation, such as a resection of a recurrent tumor, even if small in volume, led to a better prognostic result than no therapy. PMID:3694804

  13. Intra-adrenal murine TH-MYCN neuroblastoma tumors grow more aggressive and exhibit a distinct tumor microenvironment relative to their subcutaneous equivalents.

    PubMed

    Kroesen, Michiel; Brok, Ingrid C; Reijnen, Daphne; van Hout-Kuijer, Maaike A; Zeelenberg, Ingrid S; Den Brok, Martijn H; Hoogerbrugge, Peter M; Adema, Gosse J

    2015-05-01

    In around half of the patients with neuroblastoma (NBL), the primary tumor is located in one of the adrenal glands. We have previously reported on a transplantable TH-MYCN model of subcutaneous (SC) growing NBL in C57Bl/6 mice for immunological studies. In this report, we describe an orthotopic TH-MYCN transplantable model where the tumor cells were injected intra-adrenally (IA) by microsurgery. Strikingly, 9464D cells grew out much faster in IA tumors compared to the subcutis. Tumors were infiltrated by equal numbers of lymphocytes and myeloid cells. Within the myeloid cell population, however, tumor-infiltrating macrophages were more abundant in IA tumors compared to SC tumors and expressed lower levels of MHC class II, indicative of a more immunosuppressive phenotype. Using 9464D cells stably expressing firefly luciferase, enhanced IA tumor growth could be confirmed using bioluminescence. Collectively, these data show that the orthotopic IA localization of TH-MYCN cells impacts the NBL tumor microenvironment, resulting in a more stringent NBL model to study novel immunotherapeutic approaches for NBL. PMID:25687736

  14. The DACH/EYA/SIX gene network and its role in tumor initiation and progression.

    PubMed

    Liu, Yu; Han, Na; Zhou, Si; Zhou, Rong; Yuan, Xun; Xu, Hanxiao; Zhang, Cuntai; Yin, Tiejun; Wu, Kongming

    2016-03-01

    The functional abnormality of developmental genes is a common phenomenon in cancer initiation and progression. The retinal determination gene network (RDGN) is a key signal in Drosophila eye specification, and this conservative pathway is also required for the development of multiple organs in mammalian species. Recent studies demonstrated that aberrant expressions of RDGN components in vertebrates, mainly Dach, Six, and Eya, represent a novel tumor signal. RDGN regulates proliferation, apoptosis, tumor growth and metastasis through interactions with multiple signaling pathways in a co-ordinated fashion; Dach acts as a tumor suppressor, whereas Six and Eya function as oncogenes. Clinical analyses demonstrated that the expression levels of RDGN correlate with tumor stage, metastasis and survival, suggesting that combinational detection of this pathway might be used as a promising biomarker for the stratification of therapy and for the prediction of the prognosis of cancer patients. PMID:26096807

  15. Canonical Wnt/β-catenin signaling drives human schwann cell transformation, progression, and tumor maintenance.

    PubMed

    Watson, Adrienne L; Rahrmann, Eric P; Moriarity, Branden S; Choi, Kwangmin; Conboy, Caitlin B; Greeley, Andrew D; Halfond, Amanda L; Anderson, Leah K; Wahl, Brian R; Keng, Vincent W; Rizzardi, Anthony E; Forster, Colleen L; Collins, Margaret H; Sarver, Aaron L; Wallace, Margaret R; Schmechel, Stephen C; Ratner, Nancy; Largaespada, David A

    2013-06-01

    Genetic changes required for the formation and progression of human Schwann cell tumors remain elusive. Using a Sleeping Beauty forward genetic screen, we identified several genes involved in canonical Wnt signaling as potential drivers of benign neurofibromas and malignant peripheral nerve sheath tumors (MPNSTs). In human neurofibromas and MPNSTs, activation of Wnt signaling increased with tumor grade and was associated with downregulation of β-catenin destruction complex members or overexpression of a ligand that potentiates Wnt signaling, R-spondin 2 (RSPO2). Induction of Wnt signaling was sufficient to induce transformed properties in immortalized human Schwann cells, and downregulation of this pathway was sufficient to reduce the tumorigenic phenotype of human MPNST cell lines. Small-molecule inhibition of Wnt signaling effectively reduced the viability of MPNST cell lines and synergistically induced apoptosis when combined with an mTOR inhibitor, RAD-001, suggesting that Wnt inhibition represents a novel target for therapeutic intervention in Schwann cell tumors. PMID:23535903

  16. Combining Microbubbles and Ultrasound for Drug Delivery to Brain Tumors: Current Progress and Overview

    PubMed Central

    Liu, Hao-Li; Fan, Ching-Hsiang; Ting, Chien-Yu; Yeh, Chih-Kuang

    2014-01-01

    Malignant glioma is one of the most challenging central nervous system (CNS) diseases, which is typically associated with high rates of recurrence and mortality. Current surgical debulking combined with radiation or chemotherapy has failed to control tumor progression or improve glioma patient survival. Microbubbles (MBs) originally serve as contrast agents in diagnostic ultrasound but have recently attracted considerable attention for therapeutic application in enhancing blood-tissue permeability for drug delivery. MB-facilitated focused ultrasound (FUS) has already been confirmed to enhance CNS-blood permeability by temporally opening the blood-brain barrier (BBB), thus has potential to enhance delivery of various kinds of therapeutic agents into brain tumors. Here we review the current preclinical studies which demonstrate the reports by using FUS with MB-facilitated drug delivery technology in brain tumor treatment. In addition, we review newly developed multifunctional theranostic MBs for FUS-induced BBB opening for brain tumor therapy. PMID:24578726

  17. Vitamin D Receptor Protein Expression in Tumor Tissue and Prostate Cancer Progression

    PubMed Central

    Hendrickson, Whitney K.; Flavin, Richard; Kasperzyk, Julie L.; Fiorentino, Michelangelo; Fang, Fang; Lis, Rosina; Fiore, Christopher; Penney, Kathryn L.; Ma, Jing; Kantoff, Philip W.; Stampfer, Meir J.; Loda, Massimo; Mucci, Lorelei A.; Giovannucci, Edward

    2011-01-01

    Purpose Data suggest that circulating 25-hydroxyvitamin D [25(OH)D] interacts with the vitamin D receptor (VDR) to decrease proliferation and increase apoptosis for some malignancies, although evidence for prostate cancer is less clear. How VDR expression in tumor tissue may influence prostate cancer progression has not been evaluated in large studies. Patients and Methods We examined protein expression of VDR in tumor tissue among 841 patients with prostate cancer in relation to risk of lethal prostate cancer within two prospective cohorts, the Physicians' Health Study and Health Professionals Follow-Up Study. We also examined the association of VDR expression with prediagnostic circulating 25(OH)D and 1,25-dihydroxyvitamin D levels and with two VDR single nucleotide polymorphisms, FokI and BsmI. Results Men whose tumors had high VDR expression had significantly lower prostate-specific antigen (PSA) at diagnosis (P for trend < .001), lower Gleason score (P for trend < .001), and less advanced tumor stage (P for trend < .001) and were more likely to have tumors harboring the TMPRSS2:ERG fusion (P for trend = .009). Compared with the lowest quartile, men whose tumors had the highest VDR expression had significantly reduced risk of lethal prostate cancer (hazard ratio [HR], 0.17; 95% CI, 0.07 to 0.41). This association was only slightly attenuated after adjustment for Gleason score and PSA at diagnosis (HR, 0.33; 95% CI, 0.13 to 0.83) or, additionally, for tumor stage (HR, 0.37; 95% CI, 0.14 to 0.94). Neither prediagnostic plasma vitamin D levels nor VDR polymorphisms were associated with VDR expression. Conclusion High VDR expression in prostate tumors is associated with a reduced risk of lethal cancer, suggesting a role of the vitamin D pathway in prostate cancer progression. PMID:21537045

  18. Endothelial progenitor cells promote tumor growth and progression by enhancing new vessel formation

    PubMed Central

    Zhao, Xin; Liu, Huan-Qiu; Li, Ji; Liu, Xiao-Liang

    2016-01-01

    Tumor growth and progression require new blood vessel formation to deliver nutrients and oxygen for further cell proliferation and to create a neovascular network exit for tumor cell metastasis. Endothelial progenitor cells (EPCs) are a bone marrow (BM)-derived stem cell population that circulates in the peripheral circulation and homes to the tumor bed to participate in new blood vessel formation. In addition to structural support to nascent vessels, these cells can also regulate the angiogenic process by paracrine secretion of a number of proangiogenic growth factors and cytokines, thus playing a crucial role in tumor neovascularization and development. Inhibition of EPC-mediated new vessel formation may be a promising therapeutic strategy in tumor treatment. EPC-mediated neovascularization is a complex process that includes multiple steps and requires a series of cytokines and modulators, thus understanding the underlying mechanisms may provide anti-neovasculogenesis targets that may be blocked for the prevention of tumor development. The present review stresses the process and contribution of EPCs to the formation of new blood vessels in solid tumors, in an attempt to gain an improved understanding of the underlying cellular and molecular mechanisms involved, and to provide a potential effective therapeutic target for cancer treatment. PMID:27446353

  19. Overexpression of Cell Cycle Progression Inhibitor Geminin is Associated with Tumor Stem-Like Phenotype of Triple-Negative Breast Cancer

    PubMed Central

    Di Bonito, Maurizio; Collina, Francesca; Scognamiglio, Giosuè; Cerrone, Margherita; La Mantia, Elvira; Barbato, Antonio; Liguori, Giuseppina; Botti, Gerardo

    2012-01-01

    Purpose Triple-negative breast cancer, has a significant clinical relevance being associated with a shorter median time to relapse and death and does not respond to endocrine therapy or other available targeted agents. For this reason, identifying the molecular pathways associated with increased aggressiveness, for example the presence of stem cell populations within the tumor and alteration of genes associated with cell cycle regulation represents an important objective in the clinical research into this neoplasm. Methods To investigate the role of cell cycle progression inhibitor Geminin in triple-negative breast cancers and its potential correlation with stem-like phenotype of this neoplasm, we used tissue microarray technology to build a specific triple-negative breast cancer tissue micro-array. Geminin and cancer stem cell marker CD133 expression was further investigated at the mRNA level for selected breast tumor samples through realtime polymerase chain reaction quantification. Results Our results showed that CD133 expression was significantly associated to high Geminin expression (p=0.017), a strong association between Ki-67 and tumor grade (p=0.020) and an inverse association between Geminin expression and lymphonode metastases (p=0.058), and a trend of statistically significance between Geminin marker expression and survival of triple-negative breast cancer patients (p=0.076). Conclusion The strong association between the expression of CD133 and Geminin could be useful in molecular stratification of breast tumors and in particular of triple-negative breast cancers. PMID:22807933

  20. HSET overexpression fuels tumor progression via centrosome clustering-independent mechanisms in breast cancer patients.

    PubMed

    Pannu, Vaishali; Rida, Padmashree C G; Ogden, Angela; Turaga, Ravi Chakra; Donthamsetty, Shashikiran; Bowen, Nathan J; Rudd, Katie; Gupta, Meenakshi V; Reid, Michelle D; Cantuaria, Guilherme; Walczak, Claire E; Aneja, Ritu

    2015-03-20

    Human breast tumors harbor supernumerary centrosomes in almost 80% of tumor cells. Although amplified centrosomes compromise cell viability via multipolar spindles resulting in death-inducing aneuploidy, cancer cells tend to cluster extra centrosomes during mitosis. As a result cancer cells display bipolar spindle phenotypes to maintain a tolerable level of aneuploidy, an edge to their survival. HSET/KifC1, a kinesin-like minus-end directed microtubule motor has recently found fame as a crucial centrosome clustering molecule. Here we show that HSET promotes tumor progression via mechanisms independent of centrosome clustering. We found that HSET is overexpressed in breast carcinomas wherein nuclear HSET accumulation correlated with histological grade and predicted poor progression-free and overall survival. In addition, deregulated HSET protein expression was associated with gene amplification and/or translocation. Our data provide compelling evidence that HSET overexpression is pro-proliferative, promotes clonogenic-survival and enhances cell-cycle kinetics through G2 and M-phases. Importantly, HSET co-immunoprecipitates with survivin, and its overexpression protects survivin from proteasome-mediated degradation, resulting in its increased steady-state levels. We provide the first evidence of centrosome clustering-independent activities of HSET that fuel tumor progression and firmly establish that HSET can serve both as a potential prognostic biomarker and as a valuable cancer-selective therapeutic target. PMID:25788277

  1. HSET overexpression fuels tumor progression via centrosome clustering-independent mechanisms in breast cancer patients

    PubMed Central

    Pannu, Vaishali; Rida, Padmashree C.G.; Ogden, Angela; Turaga, Ravi Chakra; Donthamsetty, Shashikiran; Bowen, Nathan J.; Rudd, Katie; Gupta, Meenakshi V.; Reid, Michelle D.; Cantuaria, Guilherme; Walczak, Claire E.; Aneja, Ritu

    2015-01-01

    Human breast tumors harbor supernumerary centrosomes in almost 80% of tumor cells. Although amplified centrosomes compromise cell viability via multipolar spindles resulting in death-inducing aneuploidy, cancer cells tend to cluster extra centrosomes during mitosis. As a result cancer cells display bipolar spindle phenotypes to maintain a tolerable level of aneuploidy, an edge to their survival. HSET/KifC1, a kinesin-like minus-end directed microtubule motor has recently found fame as a crucial centrosome clustering molecule. Here we show that HSET promotes tumor progression via mechanisms independent of centrosome clustering. We found that HSET is overexpressed in breast carcinomas wherein nuclear HSET accumulation correlated with histological grade and predicted poor progression-free and overall survival. In addition, deregulated HSET protein expression was associated with gene amplification and/or translocation. Our data provide compelling evidence that HSET overexpression is pro-proliferative, promotes clonogenic-survival and enhances cell-cycle kinetics through G2 and M-phases. Importantly, HSET co-immunoprecipitates with survivin, and its overexpression protects survivin from proteasome-mediated degradation, resulting in its increased steady-state levels. We provide the first evidence of centrosome clustering-independent activities of HSET that fuel tumor progression and firmly establish that HSET can serve both as a potential prognostic biomarker and as a valuable cancer-selective therapeutic target. PMID:25788277

  2. Tumor-promoting functions of transforming growth factor-β in progression of cancer

    PubMed Central

    2012-01-01

    Transforming growth factor-β (TGF-β) elicits both tumor-suppressive and tumor-promoting functions during cancer progression. Here, we describe the tumor-promoting functions of TGF-β and how these functions play a role in cancer progression. Normal epithelial cells undergo epithelial-mesenchymal transition (EMT) through the action of TGF-β, while treatment with TGF-β and fibroblast growth factor (FGF)-2 results in transdifferentiation into activated fibroblastic cells that are highly migratory, thereby facilitating cancer invasion and metastasis. TGF-β also induces EMT in tumor cells, which can be regulated by oncogenic and anti-oncogenic signals. In addition to EMT promotion, invasion and metastasis of cancer are facilitated by TGF-β through other mechanisms, such as regulation of cell survival, angiogenesis, and vascular integrity, and interaction with the tumor microenvironment. TGF-β also plays a critical role in regulating the cancer-initiating properties of certain types of cells, including glioma-initiating cells. These findings thus may be useful for establishing treatment strategies for advanced cancer by inhibiting TGF-β signaling. PMID:22111550

  3. Pathological functions of the small GTPase Arf6 in cancer progression: Tumor angiogenesis and metastasis

    PubMed Central

    Hongu, Tsunaki; Yamauchi, Yohei; Funakoshi, Yuji; Katagiri, Naohiro; Ohbayashi, Norihiko; Kanaho, Yasunori

    2016-01-01

    ABSTRACT Although several lines of evidence have shown that the small GTPase ADP-ribosylation factor 6 (Arf6) plays pivotal roles in cancer progression of several types of cancers, little is known about the functions of Arf6 in tumor microenvironment. We demonstrated that Arf6 in vascular endothelial cells (VECs) plays a crucial role in tumor angiogenesis and growth using endothelial cell-specific Arf6 conditional knockout mice into which B16 melanoma and Lewis lung carcinoma cells were implanted. It was also found that Arf6 in VECs positively regulates hepatocyte growth factor (HGF)-induced β1 integrin recycling, which is a critical event for tumor angiogenesis by promoting cell migration. Importantly, pharmacological inhibition of HGF-induced Arf6 activation significantly suppresses tumor angiogenesis and growth in mice, suggesting that Arf6 signaling would be a potential target for anti-angiogenic therapy. In this manuscript, we summarize the multiple roles of Arf6 in cancer progression, particularly in cancer cell invasion/metastasis and our recent findings on tumor angiogenesis, and discuss a possible approach to develop innovative anti-cancer drugs. PMID:26909552

  4. Metabolic Tumor Burden Predicts for Disease Progression and Death in Lung Cancer

    SciTech Connect

    Lee, Percy; Weerasuriya, Dilani K.; Lavori, Philip W.; Quon, Andrew; Hara, Wendy; Maxim, Peter G.; Le, Quynh-Thu; Wakelee, Heather A.; Donington, Jessica S.; Graves, Edward E.; Loo, Billy W.

    2007-10-01

    Purpose: In lung cancer, stage is an important prognostic factor for disease progression and survival. However, stage may be simply a surrogate for underlying tumor burden. Our purpose was to assess the prognostic value of tumor burden measured by {sup 18}F-fluorodeoxyglucose-positron emission tomography (FDG-PET) imaging. Patients and Methods: We identified 19 patients with lung cancer who had staging PET-CT scans before any therapy, and adequate follow-up (complete to time of progression for 18, and death for 15 of 19). Metabolically active tumor regions were segmented on pretreatment PET scans semi-automatically using custom software. We determined the relationship between times to progression (TTP) and death (OS) and two PET parameters: total metabolic tumor volume (MTV), and standardized uptake value (SUV). Results: The estimated median TTP and OS for the cohort were 9.3 months and 14.8 months. On multivariate Cox proportional hazards regression analysis, an increase in MTV of 25 ml (difference between the 75th and 25th percentiles) was associated with increased hazard of progression and of death (5.4-fold and 7.6-fold), statistically significant (p = 0.0014 and p = 0.001) after controlling for stage, treatment intent (definitive or palliative), age, Karnofsky performance status, and weight loss. We did not find a significant relationship between SUV and TTP or OS. Conclusions: In this study, high tumor burden assessed by PET MTV is an independent poor prognostic feature in lung cancer, promising for stratifying patients in randomized trials and ultimately for selecting risk-adapted therapies. These results will need to be validated in larger cohorts with longer follow-up, and evaluated prospectively.

  5. Prediction of brain tumor progression using multiple histogram matched MRI scans

    NASA Astrophysics Data System (ADS)

    Banerjee, Debrup; Tran, Loc; Li, Jiang; Shen, Yuzhong; McKenzie, Frederic; Wang, Jihong

    2011-03-01

    In a recent study [1], we investigated the feasibility of predicting brain tumor progression based on multiple MRI series and we tested our methods on seven patients' MRI images scanned at three consecutive visits A, B and C. Experimental results showed that it is feasible to predict tumor progression from visit A to visit C using a model trained by the information from visit A to visit B. However, the trained model failed when we tried to predict tumor progression from visit B to visit C, though it is clinically more important. Upon a closer look at the MRI scans revealed that histograms of MRI scans such as T1, T2, FLAIR etc taken at different times have slight shifts or different shapes. This is because those MRI scans are qualitative instead of quantitative so MRI scans taken at different times or by different scanners might have slightly different scales or have different homogeneities in the scanning region. In this paper, we proposed a method to overcome this difficulty. The overall goal of this study is to assess brain tumor progression by exploring seven patients' complete MRI records scanned during their visits in the past two years. There are ten MRI series in each visit, including FLAIR, T1-weighted, post-contrast T1-weighted, T2-weighted and five DTI derived MRI volumes: ADC, FA, Max, Min and Middle Eigen Values. After registering all series to the corresponding DTI scan at the first visit, we applied a histogram matching algorithm to non-DTI MRI scans to match their histograms to those of the corresponding MRI scans at the first visit. DTI derived series are quantitative and do not require the histogram matching procedure. A machine learning algorithm was then trained using the data containing information from visit A to visit B, and the trained model was used to predict tumor progression from visit B to visit C. An average of 72% pixel-wise accuracy was achieved for tumor progression prediction from visit B to visit C.

  6. Upregulation of the EP1 receptor for prostaglandin E2 promotes skin tumor progression.

    PubMed

    Surh, Inok; Rundhaug, Joyce; Pavone, Amy; Mikulec, Carol; Abel, Erika; Fischer, Susan M

    2011-06-01

    Prostaglandin E(2) (PGE(2) ) has been shown to promote the development of murine skin tumors. EP1 is 1 of the 4 PGE(2) G-protein-coupled membrane receptors expressed by murine keratinocytes. EP1 mRNA levels were increased ∼2-fold after topical treatment with 12-O-tetradecanoylphorbol-13-acetate (TPA) or exposure to ultraviolet (UV) light, as well as increased ∼3- to 12-fold in tumors induced by 7,12-dimethyl-benz[a]anthracene (DMBA) initiation/TPA promotion or by UV exposure. To determine the effect of EP1 levels on tumor development, we generated BK5.EP1 transgenic mice that overexpress EP1 in the basal layer of the epidermis. Skins of these mice were histologically indistinguishable from wild type (WT) mice and had similar levels of proliferation after TPA treatment. Using a DMBA/TPA carcinogenesis protocol, BK5.EP1 mice had a reduced tumor multiplicity compared to WT mice, likely due to the observed down-regulation of protein kinase C (PKC). However, the BK5.EP1 mice had an ∼8-fold higher papilloma to carcinoma conversion rate. When DMBA/anthralin was used, BK5.EP1 mice produced more tumors than WT mice, as well as a ninefold increase in carcinomas, indicating that the tumor response is dependent on the type of tumor promoter agent used. Additionally, although almost undetectable in WT mice, cyclooxygenase-2 (COX-2) was expressed in the untreated epidermis of BK5.EP1 mice. While TPA highly induced COX-2 in WT mice, COX-2 expression in the BK5.EP1 mice did not change after TPA treatment; PGE(2) levels were likewise affected. These data indicate that EP1 is more important in tumor progression than in tumor promotion and that it indirectly regulates COX-2 expression. PMID:21268127

  7. PROX1 is involved in progression of rectal neuroendocrine tumors, NETs.

    PubMed

    Jernman, Juha; Kallio, Pauliina; Hagström, Jaana; Välimäki, Matti J; Haapasalo, Hannu; Alitalo, Kari; Arola, Johanna; Haglund, Caj

    2015-09-01

    PROX1 is a homeobox transcription factor involved in the development of the lens, liver and heart and found upregulated in colorectal cancers. We studied PROX1 expression by immunohistochemistry in rectal neuroendocrine tumors (NETs). Approximately 10 to 15 % of gastroenteropancreatic NETs occur in the rectum, and some may metastasize. Yet little is known about the molecular pathogenesis of rectal NETs or their metastasis propensity. The objectives were to find out whether PROX1 plays a role in progression of rectal NETs and whether it has value as prognostic marker. In grading of rectal NETs, we applied the WHO 2010 classification. We carried out immunohistochemical staining of PROX1 on 72 primary tumors and six metastases and evaluated nuclear positivity in each tumor. Correlation between PROX1 expression, metastasis and patient survival was then assessed. Annexin A1, a downstream target of PROX1, was immunohistochemically assessed in 18 tumors. PROX1 protein was detected in about half of the tumors, with stronger expression in metastasized cases. PROX1 expression correlated with tumor metastasis and patient prognosis. Annexin A1 was negative in most of the high-grade tumors correlating strongly with grade and metastatic potential. Our results indicate that immunohistochemical detection of PROX1 correlates with a more malignant phenotype in rectal NETs. High PROX1 expression was associated with increased metastatic potential and poor patient survival but not as strongly as grade by the WHO 2010 classification. PROX1 may be involved in progression of rectal NETs as a part of the Wnt pathway. PMID:26063416

  8. MMP1, MMP9, and COX2 Expressions in Promonocytes Are Induced by Breast Cancer Cells and Correlate with Collagen Degradation, Transformation-Like Morphological Changes in MCF-10A Acini, and Tumor Aggressiveness

    PubMed Central

    Chimal-Ramírez, G. K.; Espinoza-Sánchez, N. A.; Utrera-Barillas, D.; Benítez-Bribiesca, L.; Velázquez, J. R.; Arriaga-Pizano, L. A.; Monroy-García, A.; Reyes-Maldonado, E.; Domínguez-López, M. L.; Piña-Sánchez, Patricia; Fuentes-Pananá, E. M.

    2013-01-01

    Tumor-associated immune cells often lack immune effector activities, and instead they present protumoral functions. To understand how tumors promote this immunological switch, invasive and noninvasive breast cancer cell (BRC) lines were cocultured with a promonocytic cell line in a Matrigel-based 3D system. We hypothesized that if communication exists between tumor and immune cells, coculturing would result in augmented expression of genes associated with tumor malignancy. Upregulation of proteases MMP1 and MMP9 and inflammatory COX2 genes was found likely in response to soluble factors. Interestingly, changes were more apparent in promonocytes and correlated with the aggressiveness of the BRC line. Increased gene expression was confirmed by collagen degradation assays and immunocytochemistry of prostaglandin 2, a product of COX2 activity. Untransformed MCF-10A cells were then used as a sensor of soluble factors with transformation-like capabilities, finding that acini formed in the presence of supernatants of the highly aggressive BRC/promonocyte cocultures often exhibited total loss of the normal architecture. These data support that tumor cells can modify immune cell gene expression and tumor aggressiveness may importantly reside in this capacity. Modeling interactions in the tumor stroma will allow the identification of genes useful as cancer prognostic markers and therapy targets. PMID:23762835

  9. The role of splicing factors in deregulation of alternative splicing during oncogenesis and tumor progression

    PubMed Central

    Shilo, Asaf; Siegfried, Zahava; Karni, Rotem

    2015-01-01

    In past decades, cancer research has focused on genetic alterations that are detected in malignant tissues and contribute to the initiation and progression of cancer. These changes include mutations, copy number variations, and translocations. However, it is becoming increasingly clear that epigenetic changes, including alternative splicing, play a major role in cancer development and progression. There are relatively few studies on the contribution of alternative splicing and the splicing factors that regulate this process to cancer development and progression. Recently, multiple studies have revealed altered splicing patterns in cancers and several splicing factors were found to contribute to tumor development. Studies using high-throughput genomic analysis have identified mutations in components of the core splicing machinery and in splicing factors in several cancers. In this review, we will highlight new findings on the role of alternative splicing and its regulators in cancer initiation and progression, in addition to novel approaches to correct oncogenic splicing. PMID:27308389

  10. Resistin and interleukin-6 exhibit racially-disparate expression in breast cancer patients, display molecular association and promote growth and aggressiveness of tumor cells through STAT3 activation.

    PubMed

    Deshmukh, Sachin K; Srivastava, Sanjeev K; Bhardwaj, Arun; Singh, Ajay P; Tyagi, Nikhil; Marimuthu, Saravanakumar; Dyess, Donna L; Dal Zotto, Valeria; Carter, James E; Singh, Seema

    2015-05-10

    African-American (AA) women with breast cancer (BC) are diagnosed with more aggressive disease, have higher risk of recurrence and poorer prognosis as compared to Caucasian American (CA) women. Therefore, it is imperative to define the factors associated with such disparities to reduce the unequal burden of cancer. Emerging data suggest that inherent differences exist in the tumor microenvironment of AA and CA BC patients, however, its molecular bases and functional impact have remained poorly understood. Here, we conducted cytokine profiling in serum samples from AA and CA BC patients and identified resistin and IL-6 to be the most differentially-expressed cytokines with relative greater expression in AA patients. Resistin and IL-6 exhibited positive correlation in serum levels and treatment of BC cells with resistin led to enhanced production of IL-6. Moreover, resistin also enhanced the expression and phosphorylation of STAT3, and treatment of BC cells with IL-6-neutralizing antibody prior to resistin stimulation abolished STAT3 phosphorylation. In addition, resistin promoted growth and aggressiveness of BC cells, and these effects were mediated through STAT3 activation. Together, these findings suggest a crucial role of resistin, IL-6 and STAT3 in BC racial disparity. PMID:25868978

  11. Resistin and interleukin-6 exhibit racially-disparate expression in breast cancer patients, display molecular association and promote growth and aggressiveness of tumor cells through STAT3 activation

    PubMed Central

    Bhardwaj, Arun; Singh, Ajay P.; Tyagi, Nikhil; Marimuthu, Saravanakumar; Dyess, Donna L.; Zotto, Valeria Dal; Carter, James E.; Singh, Seema

    2015-01-01

    African-American (AA) women with breast cancer (BC) are diagnosed with more aggressive disease, have higher risk of recurrence and poorer prognosis as compared to Caucasian American (CA) women. Therefore, it is imperative to define the factors associated with such disparities to reduce the unequal burden of cancer. Emerging data suggest that inherent differences exist in the tumor microenvironment of AA and CA BC patients, however, its molecular bases and functional impact have remained poorly understood. Here, we conducted cytokine profiling in serum samples from AA and CA BC patients and identified resistin and IL-6 to be the most differentially-expressed cytokines with relative greater expression in AA patients. Resistin and IL-6 exhibited positive correlation in serum levels and treatment of BC cells with resistin led to enhanced production of IL-6. Moreover, resistin also enhanced the expression and phosphorylation of STAT3, and treatment of BC cells with IL-6-neutralizing antibody prior to resistin stimulation abolished STAT3 phosphorylation. In addition, resistin promoted growth and aggressiveness of BC cells, and these effects were mediated through STAT3 activation. Together, these findings suggest a crucial role of resistin, IL-6 and STAT3 in BC racial disparity. PMID:25868978

  12. Cysteine cathepsins: their role in tumor progression and recent trends in the development of imaging probes

    NASA Astrophysics Data System (ADS)

    Löser, Reik; Pietzsch, Jens

    2015-06-01

    Papain-like cysteine proteases bear an enormous potential as drug discovery targets for both infectious and systemic human diseases. The considerable progress in this field over the last two decades has also raised interest in the visualization of these enzymes in their native context, especially with regard to tumor imaging. After a short introduction to structure and general functions of human cysteine cathepsins, we highlight their importance for drug discovery and development and provide a critical update on the current state of knowledge towards their involvement in tumor progression, with a special emphasis on their role in therapy response. In accordance with a radiopharmaceutical point of view, the main focus of this review article will be the discussion of recently developed fluorescence and radiotracer-based imaging agents together with related molecular probes.

  13. Cysteine cathepsins: their role in tumor progression and recent trends in the development of imaging probes

    PubMed Central

    Löser, Reik; Pietzsch, Jens

    2015-01-01

    Papain-like cysteine proteases bear an enormous potential as drug discovery targets for both infectious and systemic human diseases. The considerable progress in this field over the last two decades has also raised interest in the visualization of these enzymes in their native context, especially with regard to tumor imaging. After a short introduction to structure and general functions of human cysteine cathepsins, we highlight their importance for drug discovery and development and provide a critical update on the current state of knowledge toward their involvement in tumor progression, with a special emphasis on their role in therapy response. In accordance with a radiopharmaceutical point of view, the main focus of this review article will be the discussion of recently developed fluorescence and radiotracer-based imaging agents together with related molecular probes. PMID:26157794

  14. [Current Research of the Roles of IL-35 in Tumor Progression].

    PubMed

    Huang, Chongbiao; Tian, Ye; Cui, Yan; Xu, Jie; Xin, Liang; Yang, Xueling; Qi, Daliang

    2016-04-20

    Interleukin(IL)-35 is a new member of the interleukin-12 superfamily. Since its first report in 2007, IL-35 rapidly became a research highlight in the field of immunology. Like other IL-12 superfamily members, IL-35 was a heterodimer which was composed of an α chain P35 and a β chain Epstein-Barr virus induced gene 3 (EBI3). Recent research work revealed two distinct roles of IL-35. Firstly, IL-35 is highly expressed in some kinds of inflammatory diseases and autoimmune diseases and plays import roles in the pathogenesis. Secondly, IL-35 is positively expressed in some cancers and plays some roles in the process of tumor progression. Here we demonstrate the structure and the signalling of IL-35. We reviewed the the roles of IL-35 in promoting tumor progression. PMID:27118652

  15. Extract of Vernonia condensata, Inhibits Tumor Progression and Improves Survival of Tumor-allograft Bearing Mouse.

    PubMed

    Thomas, Elizabeth; Gopalakrishnan, Vidya; Somasagara, Ranganatha R; Choudhary, Bibha; Raghavan, Sathees C

    2016-01-01

    Medicinal plants are considered as one of the ideal sources for cancer therapy due to their bioactive contents and low toxicity to humans. Vernonia genus is one of the common medicinal plants, which has wide spread usage in food and medicine. However, there are limited studies to explore its anticancer properties. In the current study, we have used Vernonia condensata, to explore its anticancer activity using various approaches. Here, we show that extract prepared from Vernonia condensata (VCE) exhibits cytotoxic properties against various cancer cells in a dose- and time-dependent manner. Interestingly, when treated with VCE, there was no significant cytotoxicity in peripheral blood mononuclear cells (PBMCs). Flow cytometry analysis revealed that although VCE induced cell death, arrest was not observed. VCE treatment led to disruption of mitochondrial membrane potential in a concentration dependent manner resulting in activation of apoptosis culminating in cell death. Immunoblotting studies revealed that VCE activated intrinsic pathway of apoptosis. More importantly, VCE treatment resulted in tumor regression leading to significant enhancement in life span in treated mice, without showing any detectable side effects. Therefore, for the first time our study reveals the potential of extract from Vernonia condensata to be used as an anticancer agent. PMID:27009490

  16. Extract of Vernonia condensata, Inhibits Tumor Progression and Improves Survival of Tumor-allograft Bearing Mouse

    PubMed Central

    Thomas, Elizabeth; Gopalakrishnan, Vidya; Somasagara, Ranganatha R.; Choudhary, Bibha; Raghavan, Sathees C.

    2016-01-01

    Medicinal plants are considered as one of the ideal sources for cancer therapy due to their bioactive contents and low toxicity to humans. Vernonia genus is one of the common medicinal plants, which has wide spread usage in food and medicine. However, there are limited studies to explore its anticancer properties. In the current study, we have used Vernonia condensata, to explore its anticancer activity using various approaches. Here, we show that extract prepared from Vernonia condensata (VCE) exhibits cytotoxic properties against various cancer cells in a dose- and time-dependent manner. Interestingly, when treated with VCE, there was no significant cytotoxicity in peripheral blood mononuclear cells (PBMCs). Flow cytometry analysis revealed that although VCE induced cell death, arrest was not observed. VCE treatment led to disruption of mitochondrial membrane potential in a concentration dependent manner resulting in activation of apoptosis culminating in cell death. Immunoblotting studies revealed that VCE activated intrinsic pathway of apoptosis. More importantly, VCE treatment resulted in tumor regression leading to significant enhancement in life span in treated mice, without showing any detectable side effects. Therefore, for the first time our study reveals the potential of extract from Vernonia condensata to be used as an anticancer agent. PMID:27009490

  17. Architectural Transcription Factor HMGI(Y) Promotes Tumor Progression and Mesenchymal Transition of Human Epithelial Cells

    PubMed Central

    Reeves, Raymond; Edberg, Dale D.; Li, Ying

    2001-01-01

    Numerous studies have demonstrated that overexpression or aberrant expression of the HMGI(Y) family of architectural transcription factors is frequently associated with both neoplastic transformation of cells and metastatic tumor progression. Little is known, however, about the molecular roles played by the HMGI(Y) proteins in these events. Here we report that human breast epithelial cells harboring tetracycline-regulated HMGI(Y) transgenes acquire the ability to form both primary and metastatic tumors in nude mice only when the transgenes are actively expressed. Unexpectedly, the HMG-Y, rather than the HMG-I, isoform of these proteins is the most effective elicitor of both neoplastic transformation and metastatic progression in vivo. Furthermore, expression of either antisense or dominant-negative HMGI(Y) constructs inhibits both the rate of proliferation of tumor cells and their ability to grow anchorage independently in soft agar. Array analysis of transcription profiles demonstrates that the HMG-I and HMG-Y isoform proteins each modulate the expression of distinctive constellations of genes known to be involved in signal transduction, cell proliferation, tumor initiation, invasion, migration, induction of angiogenesis, and colonization. Immunohistochemical analyses of tumors formed in nude mice indicate that many have undergone an epithelial-mesenchymal transition in vivo. Together, these findings demonstrate that overexpression of the HMGI(Y) proteins, more specifically, the HMG-Y isoform protein, is causally associated with both neoplastic transformation and metastatic progression and suggest that induction of integrins and their signaling pathways may play significant molecular roles in these biological events. PMID:11134344

  18. Architectural transcription factor HMGI(Y) promotes tumor progression and mesenchymal transition of human epithelial cells.

    PubMed

    Reeves, R; Edberg, D D; Li, Y

    2001-01-01

    Numerous studies have demonstrated that overexpression or aberrant expression of the HMGI(Y) family of architectural transcription factors is frequently associated with both neoplastic transformation of cells and metastatic tumor progression. Little is known, however, about the molecular roles played by the HMGI(Y) proteins in these events. Here we report that human breast epithelial cells harboring tetracycline-regulated HMGI(Y) transgenes acquire the ability to form both primary and metastatic tumors in nude mice only when the transgenes are actively expressed. Unexpectedly, the HMG-Y, rather than the HMG-I, isoform of these proteins is the most effective elicitor of both neoplastic transformation and metastatic progression in vivo. Furthermore, expression of either antisense or dominant-negative HMGI(Y) constructs inhibits both the rate of proliferation of tumor cells and their ability to grow anchorage independently in soft agar. Array analysis of transcription profiles demonstrates that the HMG-I and HMG-Y isoform proteins each modulate the expression of distinctive constellations of genes known to be involved in signal transduction, cell proliferation, tumor initiation, invasion, migration, induction of angiogenesis, and colonization. Immunohistochemical analyses of tumors formed in nude mice indicate that many have undergone an epithelial-mesenchymal transition in vivo. Together, these findings demonstrate that overexpression of the HMGI(Y) proteins, more specifically, the HMG-Y isoform protein, is causally associated with both neoplastic transformation and metastatic progression and suggest that induction of integrins and their signaling pathways may play significant molecular roles in these biological events. PMID:11134344

  19. Case History Report: Immediate Rehabilitation with a Prefabricated Fibula Flap Following Removal of a Locally Aggressive Maxillary Tumor.

    PubMed

    Nkenke, Emeka; Agaimy, Abbas; Vairaktaris, Elefterios; Lell, Michael; von Wilmowsky, Cornelius; Eitner, Stephan

    2016-01-01

    The present clinical case history report describes an interdisciplinary treatment protocol that combines maxillary tumor resection with immediate reconstruction to achieve functional rehabilitation. A fibula flap that received four dental implants and a split-thickness graft epithelial layer was prefabricated for a 31-year-old man. The flap was designed so that it could be adapted to fit in different extents of tumor resection. Resection and immediate reconstruction were successfully performed 6 weeks after flap prefabrication, with the final bar-retained dental prosthesis delivered 4 weeks later. PMID:26757329

  20. Sapodilla plum (Achras sapota) induces apoptosis in cancer cell lines and inhibits tumor progression in mice.

    PubMed

    Srivastava, Mrinal; Hegde, Mahesh; Chiruvella, Kishore K; Koroth, Jinsha; Bhattacharya, Souvari; Choudhary, Bibha; Raghavan, Sathees C

    2014-01-01

    Intake of fruits rich in antioxidants in daily diet is suggested to be cancer preventive. Sapota is a tropical fruit grown and consumed extensively in several countries including India and Mexico. Here we show that methanolic extracts of Sapota fruit (MESF) induces cytotoxicity in a dose-dependent manner in cancer cell lines. Cell cycle analysis suggested activation of apoptosis, without arresting cell cycle progression. Annexin V-propidium iodide double-staining demonstrated that Sapota fruit extracts potentiate apoptosis rather than necrosis in cancer cells. Loss of mitochondrial membrane potential, upregulation of proapoptotic proteins, activation of MCL-1, PARP-1, and Caspase 9 suggest that MESF treatment leads to activation of mitochondrial pathway of apoptosis. More importantly, we show that MESF treatment leads to significant inhibition of tumor growth and a 3-fold increase in the life span of tumor bearing animals compared to untreated tumor mice. PMID:25142835

  1. A stochastic model featuring acid-induced gaps during tumor progression

    NASA Astrophysics Data System (ADS)

    Athni Hiremath, Sandesh; Surulescu, Christina

    2016-03-01

    In this paper we propose a phenomenological model for the formation of an interstitial gap between the tumor and the stroma. The gap is mainly filled with acid produced by the progressing edge of the tumor front. Our setting extends existing models for acid-induced tumor invasion models to incorporate several features of local invasion like formation of gaps, spikes, buds, islands, and cavities. These behaviors are obtained mainly due to the random dynamics at the intracellular level, the go-or-grow-or-recede dynamics on the population scale, together with the nonlinear coupling between the microscopic (intracellular) and macroscopic (population) levels. The wellposedness of the model is proved using the semigroup technique and 1D and 2D numerical simulations are performed to illustrate model predictions and draw conclusions based on the observed behavior.

  2. Sapodilla Plum (Achras sapota) Induces Apoptosis in Cancer Cell Lines and Inhibits Tumor Progression in Mice

    PubMed Central

    Srivastava, Mrinal; Hegde, Mahesh; Chiruvella, Kishore K.; Koroth, Jinsha; Bhattacharya, Souvari; Choudhary, Bibha; Raghavan, Sathees C.

    2014-01-01

    Intake of fruits rich in antioxidants in daily diet is suggested to be cancer preventive. Sapota is a tropical fruit grown and consumed extensively in several countries including India and Mexico. Here we show that methanolic extracts of Sapota fruit (MESF) induces cytotoxicity in a dose-dependent manner in cancer cell lines. Cell cycle analysis suggested activation of apoptosis, without arresting cell cycle progression. Annexin V-propidium iodide double-staining demonstrated that Sapota fruit extracts potentiate apoptosis rather than necrosis in cancer cells. Loss of mitochondrial membrane potential, upregulation of proapoptotic proteins, activation of MCL-1, PARP-1, and Caspase 9 suggest that MESF treatment leads to activation of mitochondrial pathway of apoptosis. More importantly, we show that MESF treatment leads to significant inhibition of tumor growth and a 3-fold increase in the life span of tumor bearing animals compared to untreated tumor mice. PMID:25142835

  3. A synthetic modular approach for modeling the role of the 3D microenvironment in tumor progression.

    PubMed

    Singh, S P; Schwartz, M P; Tokuda, E Y; Luo, Y; Rogers, R E; Fujita, M; Ahn, N G; Anseth, K S

    2015-01-01

    Here, we demonstrate the flexibility of peptide-functionalized poly(ethylene glycol) (PEG) hydrogels for modeling tumor progression. The PEG hydrogels were formed using thiol-ene chemistry to incorporate a matrix metalloproteinase-degradable peptide crosslinker (KKCGGPQG↓IWGQGCKK) permissive to proteolytic remodeling and the adhesive CRGDS peptide ligand. Tumor cell function was investigated by culturing WM239A melanoma cells on PEG hydrogel surfaces or encapsulating cells within the hydrogels, and either as monocultures or indirect (non-contact) cocultures with primary human dermal fibroblasts (hDFs). WM239A cluster size and proliferation rate depended on the shear elastic modulus for cells cultured on PEG hydrogels, while growth was inhibited by coculture with hDFs regardless of hydrogel stiffness. Cluster size was also suppressed by hDFs for WM239A cells encapsulated in PEG hydrogels, which is consistent with cells seeded on top of hydrogels. Notably, encapsulated WM239A clusters and single cells adopted invasive phenotypes in the hDF coculture model, which included single cell and collective migration modes that resembled invasion from human melanoma patient-derived xenograft tumors encapsulated in equivalent PEG hydrogels. Our combined results demonstrate that peptide-functionalized PEG hydrogels provide a useful platform for investigating aspects of tumor progression in 2D and 3D microenvironments, including single cell migration, cluster growth and invasion. PMID:26638791

  4. A synthetic modular approach for modeling the role of the 3D microenvironment in tumor progression

    PubMed Central

    Singh, S. P.; Schwartz, M. P.; Tokuda, E. Y.; Luo, Y.; Rogers, R. E.; Fujita, M.; Ahn, N. G.; Anseth, K. S.

    2015-01-01

    Here, we demonstrate the flexibility of peptide-functionalized poly(ethylene glycol) (PEG) hydrogels for modeling tumor progression. The PEG hydrogels were formed using thiol-ene chemistry to incorporate a matrix metalloproteinase-degradable peptide crosslinker (KKCGGPQG↓IWGQGCKK) permissive to proteolytic remodeling and the adhesive CRGDS peptide ligand. Tumor cell function was investigated by culturing WM239A melanoma cells on PEG hydrogel surfaces or encapsulating cells within the hydrogels, and either as monocultures or indirect (non-contact) cocultures with primary human dermal fibroblasts (hDFs). WM239A cluster size and proliferation rate depended on the shear elastic modulus for cells cultured on PEG hydrogels, while growth was inhibited by coculture with hDFs regardless of hydrogel stiffness. Cluster size was also suppressed by hDFs for WM239A cells encapsulated in PEG hydrogels, which is consistent with cells seeded on top of hydrogels. Notably, encapsulated WM239A clusters and single cells adopted invasive phenotypes in the hDF coculture model, which included single cell and collective migration modes that resembled invasion from human melanoma patient-derived xenograft tumors encapsulated in equivalent PEG hydrogels. Our combined results demonstrate that peptide-functionalized PEG hydrogels provide a useful platform for investigating aspects of tumor progression in 2D and 3D microenvironments, including single cell migration, cluster growth and invasion. PMID:26638791

  5. Evaluation of the effects of hyaluronic acid-carboxymethyl cellulose barrier on ovarian tumor progression

    PubMed Central

    2014-01-01

    Background Hyaluronic acid is a prognostic factor in ovarian cancers. It is also a component of Hyaluronic Acid-Carboxymethyl Cellulose (HA-CMC) barrier, an anti-adhesion membrane widely used during abdominal surgeries in particular for ovarian carcinosis. 70% of patients who undergo ovarian surgery will relapse due to the persistence of cancer cells. This study’s objective was to determine the oncological risk from use of this material, in the presence of residual disease, despite the benefit gained by it decreasing post-surgical adhesions in order to provide an unambiguous assessment of its appropriateness for use in ovarian surgical management. Methods We assessed the effects of HA-CMC barrier on the in vitro proliferation of human ovarian tumor cell lines (OVCAR-3, IGROV-1 and SKOV-3). We next evaluated, in vivo in nude mice, the capacity of this biomaterial to regulate the tumor progression of subcutaneous and intraperitoneal models of ovarian tumor xenografts. Results We showed that HA-CMC barrier does not increase in vitro proliferation of ovarian cancer cell lines compared to control. In vivo, HA-CMC barrier presence with subcutaneous xenografts induced neither an increase in tumor volume nor cell proliferation (Ki67 and mitotic index). With the exception of an increased murine carcinosis score in peritoneum, the presence of HA-CMC barrier with intraperitoneal xenografts modified neither macro nor microscopic tumor growth. Finally, protein analysis of survival (Akt), proliferation (ERK) and adhesion (FAK) pathways highlighted no activation on the xenografts imputable to HA-CMC barrier. Conclusions For the most part, our results support the lack of tumor progression activation due to HA-CMC barrier. We conclude that the benefits gained from using HA-CMC barrier membrane during ovarian cancer surgeries seem to outweigh the potential oncological risks. PMID:24739440

  6. Salmonella-Based Therapy Targeting Indoleamine 2,3-Dioxygenase Coupled with Enzymatic Depletion of Tumor Hyaluronan Induces Complete Regression of Aggressive Pancreatic Tumors.

    PubMed

    Manuel, Edwin R; Chen, Jeremy; D'Apuzzo, Massimo; Lampa, Melanie G; Kaltcheva, Teodora I; Thompson, Curtis B; Ludwig, Thomas; Chung, Vincent; Diamond, Don J

    2015-09-01

    Bacterial-based therapies are emerging as effective cancer treatments and hold promise for refractory neoplasms, such as pancreatic ductal adenocarcinoma (PDAC), which has not shown significant improvement in therapy for more than 25 years. Using a novel combination of shIDO-ST, a Salmonella-based therapy targeting the immunosuppressive molecule indoleamine 2,3-dioxygenase (IDO), with an enzyme, PEGPH20, which depletes extracellular matrix hyaluronan, we observed extended survival with frequent total regression of autochthonous and orthotopic PDAC tumors. This observation was associated with migration and accumulation of activated polymorphonuclear neutrophils (PMN) from spleens into tumors, which was not seen using a scrambled control (shScr-ST). Purified splenic PMNs from PEGPH20/shIDO-ST-treated mice exhibited significant IDO knockdown and were able to kill tumor targets ex vivo through mechanisms involving FasL and serine proteases. In addition, CD8(+) T cells were observed to contribute to late control of pancreatic tumors. Collectively, our data demonstrate that entry of shIDO-ST and PMNs into otherwise impermeable desmoplastic tumors is facilitated by PEGPH20-mediated HA removal, further highlighting an important component of effective treatment for PDAC. PMID:26134178

  7. Aggressiveness Niche: Can It Be the Foster Ground for Cancer Metastasis Precursors?

    PubMed

    ElShamy, Wael M; Sinha, Abhilasha; Said, Neveen

    2016-01-01

    The relationship between tumor initiation and tumor progression can follow a linear projection in which all tumor cells are equally endowed with the ability to progress into metastasis. Alternatively, not all tumor cells are equal genetically and/or epigenetically, and only few cells are induced to become metastatic tumor cells. The location of these cells within the tumor can also impact the fate of these cells. The most inner core of a tumor where an elevated pressure of adverse conditions forms, such as necrosis-induced inflammation and hypoxia-induced immunosuppressive environment, seems to be the most fertile ground to generate such tumor cells with metastatic potential. Here we will call this necrotic/hypoxic core the "aggressiveness niche" and will present data to support its involvement in generating these metastatic precursors. Within this niche, interaction of hypoxia-surviving cells with the inflammatory microenvironment influenced by newly recruited mesenchymal stromal cells (MSCs), tumor-associated macrophages (TAMs), and other types of cells and the establishment of bidirectional interactions between them elevate the aggressiveness of these tumor cells. Additionally, immune evasion properties induced in these cells most likely contribute in the formation and maintenance of such aggressiveness niche. PMID:27493669

  8. Aggressiveness Niche: Can It Be the Foster Ground for Cancer Metastasis Precursors?

    PubMed Central

    2016-01-01

    The relationship between tumor initiation and tumor progression can follow a linear projection in which all tumor cells are equally endowed with the ability to progress into metastasis. Alternatively, not all tumor cells are equal genetically and/or epigenetically, and only few cells are induced to become metastatic tumor cells. The location of these cells within the tumor can also impact the fate of these cells. The most inner core of a tumor where an elevated pressure of adverse conditions forms, such as necrosis-induced inflammation and hypoxia-induced immunosuppressive environment, seems to be the most fertile ground to generate such tumor cells with metastatic potential. Here we will call this necrotic/hypoxic core the “aggressiveness niche” and will present data to support its involvement in generating these metastatic precursors. Within this niche, interaction of hypoxia-surviving cells with the inflammatory microenvironment influenced by newly recruited mesenchymal stromal cells (MSCs), tumor-associated macrophages (TAMs), and other types of cells and the establishment of bidirectional interactions between them elevate the aggressiveness of these tumor cells. Additionally, immune evasion properties induced in these cells most likely contribute in the formation and maintenance of such aggressiveness niche. PMID:27493669

  9. Primary extragastrointestinal stromal tumor arising in the vaginal wall: Significant clinicopathological characteristics of a rare aggressive soft tissue neoplasm.

    PubMed

    Liu, Qiu-Yu; Kan, Yun-Zhen; Zhang, Meng-Yang; Sun, Ting-Yi; Kong, Ling-Fei

    2016-04-16

    Gastrointestinal (GI) stromal tumor is the most common mesenchymal neoplasm of the GI tract but also occurs with a lower frequency in extragastrointestinal regions and is called extragastrointestinal stromal tumor (EGIST). We report an unusual case of EGIST presenting as a vaginal mass. A 41-year-old woman presented with a gradually enlarging vaginal mass for the last 2 years. Physical examination revealed an elliptical, non-tender mass about 7.5 cm × 7 cm in size in the posterior vaginal wall and was resected completely. Under histological examination, the tumor showed a spindle cell type with coagulation necrosis, hemorrhage and high mitotic count. Immunohistochemical analysis revealed tumor cells were positive for DOG1, CD117, CD34 and p53 protein. Ki-67 labeling was 8%. Genetic analysis showed a deletion of exon 11 of the c-kit gene at codons 557-558. EGISTs should be kept in mind in the differential diagnosis in patients presenting with solid mass of the vaginal wall. PMID:27099863

  10. Glucose utilization by intracranial meningiomas as an index of tumor aggressivity and probability of recurrence: a PET study

    SciTech Connect

    Di Chiro, G.; Hatazawa, J.; Katz, D.A.; Rizzoli, H.V.; De Michele, D.J.

    1987-08-01

    Seventeen patients with intracranial meningiomas were studied with positron emission tomography and fluorine-18-2-fluorodeoxyglucose (PET-FDG) to assess the glucose utilization of these tumors. Four meningiomas followed for 3-5 years after PET-FDG and surgery showed no evidence of recurrence. These tumors had significantly lower glucose utilization rates (1.9 mg/dl/min +/- 1.0) than 11 recurrent or regrowing meningiomas (4.5 mg/dl/min +/- 1.96). The glucose metabolic rates of meningiomas correlated with tumor growth, as estimated from changes in tumor size on repeated computed tomographic scans. Histopathologically, a syncytial (atypical) meningioma had the highest glucose utilization rate, followed by a papillary meningioma and an angioblastic meningioma. Individual transitional and syncytial (typical) meningiomas showed marked differences in glucose metabolism despite similar microscopic appearance. Glucose utilization rate appears to be at least as reliable as histologic classification and other proposed criteria for predicting the behavior and recurrence of intracranial meningiomas.

  11. Primary extragastrointestinal stromal tumor arising in the vaginal wall: Significant clinicopathological characteristics of a rare aggressive soft tissue neoplasm

    PubMed Central

    Liu, Qiu-Yu; Kan, Yun-Zhen; Zhang, Meng-Yang; Sun, Ting-Yi; Kong, Ling-Fei

    2016-01-01

    Gastrointestinal (GI) stromal tumor is the most common mesenchymal neoplasm of the GI tract but also occurs with a lower frequency in extragastrointestinal regions and is called extragastrointestinal stromal tumor (EGIST). We report an unusual case of EGIST presenting as a vaginal mass. A 41-year-old woman presented with a gradually enlarging vaginal mass for the last 2 years. Physical examination revealed an elliptical, non-tender mass about 7.5 cm × 7 cm in size in the posterior vaginal wall and was resected completely. Under histological examination, the tumor showed a spindle cell type with coagulation necrosis, hemorrhage and high mitotic count. Immunohistochemical analysis revealed tumor cells were positive for DOG1, CD117, CD34 and p53 protein. Ki-67 labeling was 8%. Genetic analysis showed a deletion of exon 11 of the c-kit gene at codons 557-558. EGISTs should be kept in mind in the differential diagnosis in patients presenting with solid mass of the vaginal wall. PMID:27099863

  12. Down-Regulation of CD9 Expression and its Correlation to Tumor Progression in B Lymphomas

    PubMed Central

    Yoon, Sun-Ok; Zhang, Xin; Freedman, Arnold S.; Zahrieh, David; Lossos, Izidore S.; Li, Li; Choi, Yong Sung

    2010-01-01

    Histological transformation, a pivotal event in the natural history of cancers including lymphomas, is typically associated with more aggressive clinical behavior. L3055, a B lymphoma cell line of germinal center (GC) origin, is dependent on follicular dendritic cells (FDCs) for survival and proliferation, similar to GC-B cells. However, L3055 cells become less FDC-dependent after prolonged culture, which is analogous to transformation in vivo. Comparison of two L3055 subclones (i.e., the FDC-dependent indolent clone 12 and the FDC-independent aggressive clone 33) by DNA microarray revealed that CD9 was the most differentially expressed gene (P = 0.05). L3055-12 expresses high levels of CD9 while L3055-33 does not. Reduced levels or loss of CD9 expression is also observed in other CD9-positive B lymphoma cell lines. The resultant CD9-negative cells grow faster than CD9-positive cells due to their greater resistance to apoptosis. Furthermore, CD9-negative cells are less dependent on FDCs for their survival and growth compared with CD9-positive cells. CD9 down-regulation in B lymphomas appears to be controlled epigenetically, mainly through histone modifications. These findings imply that CD9 is inversely correlated with B lymphoma progression, and CD9 inactivation may play an important role in B lymphoma transformation. PMID:20566742

  13. Correlating tumor metabolic progression index measured by serial FDG PET-CT, apparent diffusion coefficient measured by magnetic resonance imaging (MRI) and blood genomics to patient’s outcome in advanced colorectal cancer: the CORIOLAN study

    PubMed Central

    2014-01-01

    Background Metastatic colorectal cancer (mCRC) may present various behaviours that define different courses of tumor evolution. There is presently no available tool designed to assess tumor aggressiveness, despite the fact that this is considered to have a major impact on patient outcome. Methods/Design CORIOLAN is a single-arm prospective interventional non-therapeutic study aiming mainly to assess the natural tumor metabolic progression index (TMPI) measured by serial FDG PET-CT without any intercurrent antitumor therapy as a prognostic factor for overall survival (OS) in patients with mCRC. Secondary objectives of the study aim to test the TMPI as a prognostic marker for progression-free survival (PFS), to assess the prognostic value of baseline tumor FDG uptake on PFS and OS, to compare TMPI to classical clinico-biological assessment of prognosis, and to test the prognostic value on OS and PFS of MRI-based apparent diffusion coefficient (ADC) and variation of vADC using voxel-based diffusion maps. Additionally, this study intends to identify genomic and epigenetic factors that correlate with progression of tumors and the OS of patients with mCRC. Consequently, this analysis will provide information about the signaling pathways that determine the natural and therapy-free course of the disease. Finally, it would be of great interest to investigate whether in a population of patients with mCRC, for which at present no known effective therapy is available, tumor aggressiveness is related to elevated levels of circulating tumor cells (CTCs) and to patient outcome. Discussion Tumor aggressiveness is one of the major determinants of patient outcome in advanced disease. Despite its importance, supported by findings reported in the literature of extreme outcomes for patients with mCRC treated with chemotherapy, no objective tool allows clinicians to base treatment decisions on this factor. The CORIOLAN study will characterize TMPI using FDG-PET-based metabolic imaging

  14. Loss of Snail2 favors skin tumor progression by promoting the recruitment of myeloid progenitors

    PubMed Central

    Villarejo, Ana; Molina-Ortiz, Patricia; Montenegro, Yenny; Moreno-Bueno, Gema; Morales, Saleta; Santos, Vanesa; Gridley, Tom; Pérez-Moreno, Mirna A.; Peinado, Héctor; Portillo, Francisco; Calés, Carmela; Cano, Amparo

    2015-01-01

    Snail2 is a zinc finger transcription factor involved in driving epithelial to mesenchymal transitions. Snail2 null mice are viable, but display defects in melanogenesis, gametogenesis and hematopoiesis, and are markedly radiosensitive. Here, using mouse genetics, we have studied the contributions of Snail2 to epidermal homeostasis and skin carcinogenesis. Snail2 −/− mice presented a defective epidermal terminal differentiation and, unexpectedly, an increase in number, size and malignancy of tumor lesions when subjected to the two-stage mouse skin chemical carcinogenesis protocol, compared with controls. Additionally, tumor lesions from Snail2 −/− mice presented a high inflammatory component with an elevated percentage of myeloid precursors in tumor lesions that was further increased in the presence of the anti-inflammatory agent dexamethasone. In vitro studies in Snail2 null keratinocytes showed that loss of Snail2 leads to a decrease in proliferation indicating a non-cell autonomous role for Snail2 in the skin carcinogenic response observed in vivo. Bone marrow (BM) cross-reconstitution assays between Snail2 wild-type and null mice showed that Snail2 absence in the hematopoietic system fully reproduces the tumor behavior of the Snail2 null mice and triggers the accumulation of myeloid precursors in the BM, blood and tumor lesions. These results indicate a new role for Snail2 in preventing myeloid precursors recruitment impairing skin chemical carcinogenesis progression. PMID:25784375

  15. Microfluidic culture models to study the hydrodynamics of tumor progression and therapeutic response.

    PubMed

    Buchanan, Cara; Rylander, Marissa Nichole

    2013-08-01

    The integration of tissue engineering strategies with microfluidic technologies has enabled the design of in vitro microfluidic culture models that better adapt to morphological changes in tissue structure and function over time. These biomimetic microfluidic scaffolds accurately mimic native 3D microenvironments, as well as permit precise and simultaneous control of chemical gradients, hydrodynamic stresses, and cellular niches within the system. The recent application of microfluidic in vitro culture models to cancer research offers enormous potential to aid in the development of improved therapeutic strategies by supporting the investigation of tumor angiogenesis and metastasis under physiologically relevant flow conditions. The intrinsic material properties and fluid mechanics of microfluidic culture models enable high-throughput anti-cancer drug screening, permit well-defined and controllable input parameters to monitor tumor cell response to various hydrodynamic conditions or treatment modalities, as well as provide a platform for elucidating fundamental mechanisms of tumor physiology. This review highlights recent developments and future applications of microfluidic culture models to study tumor progression and therapeutic targeting under conditions of hydrodynamic stress relevant to the complex tumor microenvironment. PMID:23616255

  16. Loss of Snail2 favors skin tumor progression by promoting the recruitment of myeloid progenitors.

    PubMed

    Villarejo, Ana; Molina-Ortiz, Patricia; Montenegro, Yenny; Moreno-Bueno, Gema; Morales, Saleta; Santos, Vanesa; Gridley, Tom; Pérez-Moreno, Mirna A; Peinado, Héctor; Portillo, Francisco; Calés, Carmela; Cano, Amparo

    2015-05-01

    Snail2 is a zinc finger transcription factor involved in driving epithelial to mesenchymal transitions. Snail2 null mice are viable, but display defects in melanogenesis, gametogenesis and hematopoiesis, and are markedly radiosensitive. Here, using mouse genetics, we have studied the contributions of Snail2 to epidermal homeostasis and skin carcinogenesis. Snail2 (-/-) mice presented a defective epidermal terminal differentiation and, unexpectedly, an increase in number, size and malignancy of tumor lesions when subjected to the two-stage mouse skin chemical carcinogenesis protocol, compared with controls. Additionally, tumor lesions from Snail2 (-/-) mice presented a high inflammatory component with an elevated percentage of myeloid precursors in tumor lesions that was further increased in the presence of the anti-inflammatory agent dexamethasone. In vitro studies in Snail2 null keratinocytes showed that loss of Snail2 leads to a decrease in proliferation indicating a non-cell autonomous role for Snail2 in the skin carcinogenic response observed in vivo. Bone marrow (BM) cross-reconstitution assays between Snail2 wild-type and null mice showed that Snail2 absence in the hematopoietic system fully reproduces the tumor behavior of the Snail2 null mice and triggers the accumulation of myeloid precursors in the BM, blood and tumor lesions. These results indicate a new role for Snail2 in preventing myeloid precursors recruitment impairing skin chemical carcinogenesis progression. PMID:25784375

  17. High frequency of tumor cells with nuclear Egr-1 protein expression in human bladder cancer is associated with disease progression

    PubMed Central

    2009-01-01

    Background Egr-1 (early growth response-1 transcription factor) has been proposed to be involved in invasion and metastasis processes of human bladder cancer, but Egr-1 protein expression levels in human bladder cancer have not been investigated. In the present study we investigated the expression levels of Egr-1 protein in early stages of human bladder cancer and correlated it to later progression. Methods Expression of Egr-1 protein in human bladder cancer was examined by immunohistochemistry, on a tissue microarray constructed from tumors from 289 patients with non-muscle invasive urothelial bladder cancer. Results The frequency of tumor cells with nuclear Egr-1 immunolabelling correlated to bladder cancer stage, grade and to later progression to muscle-invasive bladder cancer (T2-4). Stage T1 tumors exhibited significantly higher frequencies of tumor cells with nuclear Egr-1 immunolabelling than Ta tumors (P = 0.001). Furthermore, Kaplan-Meier survival analysis showed that a high frequency of tumor cells with nuclear Egr-1 immunolabelling was significantly associated with a higher risk of progression to stage T2-4 (log-rank test, P = 0.035). Tumor cells with nuclear Egr-1 immunolabelling were found to localize at the tumor front in some of the tumor biopsies. Conclusion The results from this study support a potential involvement of Egr-1 in the progression from non-muscle invasive bladder cancers to muscle invasive bladder cancer. PMID:19878561

  18. Targeting lactate dehydrogenase-A inhibits tumorigenesis and tumor progression in mouse models of lung cancer and impacts tumor initiating cells

    PubMed Central

    Xie, Han; Hanai, Jun-ichi; Ren, Jian-Guo; Kats, Lev; Burgess, Kerri; Bhargava, Parul; Signoretti, Sabina; Billiard, Julia; Duffy, Kevin J.; Grant, Aaron; Wang, Xiaoen; Lorkiewicz, Pawel K.; Schatzman, Sabrina; Bousamra, Michael; Lane, Andrew N.; Higashi, Richard M.; Fan, Teresa W.M.; Pandolfi, Pier Paolo; Sukhatme, Vikas P.; Seth, Pankaj

    2014-01-01

    Summary The lactate dehydrogenase-A (LDH-A) enzyme catalyzes the inter-conversion of pyruvate and lactate, is upregulated in human cancers and is associated with aggressive tumor outcomes. Here we use a novel inducible murine model and demonstrate that inactivation of LDH-A in mouse models of NSCLC driven by oncogenic K-RAS or EGFR leads to decreased tumorigenesis and disease regression in established tumors. We also show that abrogation of LDH-A results in reprogramming of pyruvate metabolism, with decreased lactic fermentation in vitro, in vivo, and ex vivo. This was accompanied by re-activation of mitochondrial function in vitro but not in vivo or ex vivo. Finally, using a specific small molecule LDH-A inhibitor, we demonstrated that LDH-A is essential for cancer initiating cell survival and proliferation. Thus, LDH-A can be a viable therapeutic target for NSCLC including cancer stem cell-dependent drug resistant tumors. PMID:24726384

  19. The ubiquitin E3 ligase ITCH enhances breast tumor progression by inhibiting the Hippo tumor suppressor pathway

    PubMed Central

    Salah, Zaidoun; Itzhaki, Ella; Aqeilan, Rami I

    2014-01-01

    The Hippo kinase pathway is emerging as a conserved signaling pathway that is essential for organ growth and tumorigenesis. Recently, we reported that the ubiquitin E3 ligase ITCH negatively regulates LATS1, thereby increasing YAP activity, which leads to increased cell proliferation and decreased apoptosis. Here, we investigated the role of ITCH in breast tumorigenesis. In particular, we show that ITCH enhances epithelial-to-mesenchymal transition (EMT) through boosting YAP oncogenic function. By contrast, a point mutation in the catalytic domain or WW1 domain of ITCH abolished its EMT-mediated effects. Furthermore, while overexpression of ITCH expression in breast cells is associated with increased incidence of mammary tumor formation and progression, its knockdown inhibited breast cancer cell tumorigenicity and metastasis. Importantly, YAP knockdown was able to attenuate ITCH pro-tumorigenic functions. Lastly, we found that ITCH expression is significantly upregulated in invasive and metastatic breast cancer cases and is associated with worse survival. Together, our results reveal that ITCH pro-tumorigenic functions in breast cancer are mediated, at least in part, through inactivation of the Hippo tumor suppressor pathway. PMID:25350971

  20. ELK1 is up-regulated by androgen in bladder cancer cells and promotes tumor progression

    PubMed Central

    Aljarah, Ali Kadhim; Ide, Hiroki; Li, Yi; Kashiwagi, Eiji; Netto, George J.; Zheng, Yichun; Miyamoto, Hiroshi

    2015-01-01

    Little is known about biological significance of ELK1, a transcriptional factor that activates downstream targets including c-fos proto-oncogene, in bladder cancer. Recent preclinical evidence also suggests the involvement of androgen receptor (AR) signaling in bladder cancer progression. In this study, we aim to investigate the functions of ELK1 in bladder cancer growth and their regulation by AR signals. Immunohistochemistry in bladder tumor specimens showed that the levels of phospho-ELK1 (p-ELK1) expression were significantly elevated in urothelial neoplasms, compared with non-neoplastic urothelium tissues, and were also correlated with AR positivity. Patients with p-ELK1-positive non-muscle-invasive and muscle-invasive tumors had significantly higher risks for tumor recurrence and progression, respectively. In AR-positive bladder cancer cell lines, dihydrotestosterone treatment increased ELK1 expression (mRNA, protein) and its nuclear translocation, ELK1 transcriptional activity, and c-fos expression, which was restored by an anti-androgen hydroxyflutamide. ELK1 silencing via short hairpin RNA (shRNA) resulted in decreases in cell viability/colony formation, and cell migration/invasion as well as an increase in apoptosis. Importantly, ELK1 appears to require activated AR to regulate bladder cancer cell proliferation, but not cell migration. Androgen also failed to significantly induce AR transactivation in ELK1-knockdown cells. In accordance with our in vitro findings, ELK1-shRNA expression considerably retarded tumor formation as well as its growth in xenograft-bearing male mice. Our results suggest that ELK1 plays an important role in bladder tumorigenesis and cancer progression, which is further induced by AR activation. Accordingly, ELK1 inhibition, together with AR inactivation, has the potential of being a therapeutic approach for bladder cancer. PMID:26342199

  1. Locoregional Tumor Progression After Radiation Therapy Influences Overall Survival in Pediatric Patients With Neuroblastoma

    SciTech Connect

    Pai Panandiker, Atmaram S.; McGregor, Lisa; Krasin, Matthew J.; Wu Shengjie; Xiong Xiaoping; Merchant, Thomas E.

    2010-03-15

    Purpose: There is renewed attention to primary site irradiation and local control for patients with high-risk neuroblastoma (NB). We conducted a retrospective review to identify factors that might predict for locoregional tumor control and its impact on overall survival. Methods and Materials: Between July 2000 through August 2006, a total of 44 pediatric patients with NB received radiation therapy (RT) with curative intent using computed tomography (CT)-based treatment planning. The median age was 3.4 years and the median cumulative dose was 23.4 Gy. Overall survival and locoregional tumor control were measured from the start of RT to the date of death or event as determined by CT/magnetic resonance imaging/meta-iodobenzylguanidine. The influence of age at irradiation, gender, race, cumulative radiation dose, International Neuroblastoma Staging System stage, treatment protocol and resection status was determined with respect to locoregional tumor control. Results: With a median follow-up of 34 months +- 21 months, locoregional tumor progression was observed in 11 (25%) and was evenly divided between primary site and adjacent nodal/visceral site failure. The influence of locoregional control reached borderline statistical significance (p = 0.06). Age (p = 0.5), dose (p = 0.6), resection status (p = 0.7), and International Neuroblastoma Staging System stage (p = 0.08) did not influence overall survival. Conclusions: Overall survival in high-risk neuroblastoma is influenced by locoregional tumor control. Despite CT-based planning, progression in adjacent nodal/visceral sites appears to be common; this requires further investigation regarding target volume definitions, dose, and the effects of systemic therapy.

  2. Enhanced neutrophil activity is associated with shorter time to tumor progression in glioblastoma patients

    PubMed Central

    Rahbar, Afsar; Cederarv, Madeleine; Wolmer-Solberg, Nina; Tammik, Charlotte; Stragliotto, Giuseppe; Peredo, Inti; Fornara, Olesja; Xu, Xinling; Dzabic, Mensur; Taher, Chato; Skarman, Petra; Söderberg-Nauclér, Cecilia

    2016-01-01

    ABSTRACT Glioblastoma multiforme (GBM) is a highly malignant tumor with a poor outcome that is often positive for human cytomegalovirus (HCMV). GBM patients often have excessive numbers of neutrophils and macrophages near and within the tumor. Here, we characterized the cytokine patterns in the blood of GBM patients with and without Valganciclovir treatment. Furthermore, we determined whether neutrophil activation is related to HCMV status and patient outcome. Blood samples for analyses of cytokines and growth factors were collected from 42 GBM patients at the time of diagnosis (n = 42) and at weeks 12 and 24 after surgery. Blood neutrophils of 28 GBM patients were examined for CD11b expression. The levels of pro- and anti-inflammatory cytokines and chemokines—including interleukin (IL)-1β, IL-2, IL-6, IL-8, IL-10, IL-12p70, IL-17A, transforming growth factor (TGF)-β1, interferon-γ, interferon-α, tumor necrosis factor α, and monocyte chemoattractant protein (MCP)-1were analyzed with a bead-based flow cytometry assay. During the first six months after surgery, neutrophil activity was increased in 12 patients and was unchanged or decreased in 16. Patients with increased neutrophil activity had enhanced IL-12p70, high grade HCMV and a shorter time to tumor progression (TTP) than patients without or decreased neutrophil activity (median TTP; 5.4 vs. 12 months, 95% confidence interval; 1.6–10 vs. 0.1–0.6, hazard ratio = 3 vs. 0.4, p = 0.004). The levels of IL-12p70 were significantly decreased in Valganciclovir treated patients (n = 22, T 12W vs. T 24W, p = 0.03). In conclusion, our findings suggest that neutrophil activation is an early sign of tumor progression in GBM patients. PMID:27057448

  3. Lack of gp130 expression in hepatocytes attenuates tumor progression in the DEN model

    PubMed Central

    Hatting, M; Spannbauer, M; Peng, J; Al Masaoudi, M; Sellge, G; Nevzorova, Y A; Gassler, N; Liedtke, C; Cubero, F J; Trautwein, C

    2015-01-01

    Chronic liver inflammation is a crucial event in the development and growth of hepatocellular carcinoma (HCC). Compelling evidence has shown that interleukin-6 (IL-6)/gp130-dependent signaling has a fundamental role in liver carcinogenesis. Thus, in the present study we aimed to investigate the role of gp130 in hepatocytes for the initiation and progression of HCC. Hepatocyte-specific gp130 knockout mice (gp130Δhepa) and control animals (gp130f/f) were treated with diethylnitrosamine (DEN). The role of gp130 for acute injury (0–144 h post treatment), tumor initiation (24 weeks) and progression (40 weeks) was analyzed. After acute DEN-induced liver injury we observed a reduction in the inflammatory response in gp130Δhepa animals as reflected by decreased levels of IL-6 and oncostatin M. The loss of gp130 slightly attenuated the initiation of HCC 24 weeks after DEN treatment. In contrast, 40 weeks after DEN treatment, male and female gp130Δhepa mice showed smaller tumors and reduced tumor burden, indicating a role for hepatocyte-specific gp130 expression during HCC progression. Oxidative stress and DNA damage were substantially and similarly increased by DEN in both gp130f/f and gp130Δhepa animals. However, gp130Δhepa livers revealed aberrant STAT5 activation and decreased levels of transforming growth factor-β (TGFβ), pSMAD2/3 and SMAD2, whereas phosphorylation of STAT3 at Tyr705 and Ser727 was absent. Our results indicate that gp130 deletion in hepatocytes reduces progression, but not HCC initiation in the DEN model. Gp130 deletion resulted in STAT3 inhibition but increased STAT5 activation and diminished TGF-dependent signaling. Hence, blocking gp130 in hepatocytes might be an interesting therapeutic target to inhibit the growth of HCC. PMID:25741592

  4. Tissue Regeneration in the Chronically Inflamed Tumor Environment: Implications for Cell Fusion Driven Tumor Progression and Therapy Resistant Tumor Hybrid Cells.

    PubMed

    Dittmar, Thomas; Zänker, Kurt S

    2015-01-01

    The biological phenomenon of cell fusion in a cancer context is still a matter of controversial debates. Even though a plethora of in vitro and in vivo data have been published in the past decades the ultimate proof that tumor hybrid cells could originate in (human) cancers and could contribute to the progression of the disease is still missing, suggesting that the cell fusion hypothesis is rather fiction than fact. However, is the lack of this ultimate proof a valid argument against this hypothesis, particularly if one has to consider that appropriate markers do not (yet) exist, thus making it virtually impossible to identify a human tumor cell clearly as a tumor hybrid cell. In the present review, we will summarize the evidence supporting the cell fusion in cancer concept. Moreover, we will refine the cell fusion hypothesis by providing evidence that cell fusion is a potent inducer of aneuploidy, genomic instability and, most likely, even chromothripsis, suggesting that cell fusion, like mutations and aneuploidy, might be an inducer of a mutator phenotype. Finally, we will show that "accidental" tissue repair processes during cancer therapy could lead to the origin of therapy resistant cancer hybrid stem cells. PMID:26703575

  5. Tissue Regeneration in the Chronically Inflamed Tumor Environment: Implications for Cell Fusion Driven Tumor Progression and Therapy Resistant Tumor Hybrid Cells

    PubMed Central

    Dittmar, Thomas; Zänker, Kurt S.

    2015-01-01

    The biological phenomenon of cell fusion in a cancer context is still a matter of controversial debates. Even though a plethora of in vitro and in vivo data have been published in the past decades the ultimate proof that tumor hybrid cells could originate in (human) cancers and could contribute to the progression of the disease is still missing, suggesting that the cell fusion hypothesis is rather fiction than fact. However, is the lack of this ultimate proof a valid argument against this hypothesis, particularly if one has to consider that appropriate markers do not (yet) exist, thus making it virtually impossible to identify a human tumor cell clearly as a tumor hybrid cell. In the present review, we will summarize the evidence supporting the cell fusion in cancer concept. Moreover, we will refine the cell fusion hypothesis by providing evidence that cell fusion is a potent inducer of aneuploidy, genomic instability and, most likely, even chromothripsis, suggesting that cell fusion, like mutations and aneuploidy, might be an inducer of a mutator phenotype. Finally, we will show that “accidental” tissue repair processes during cancer therapy could lead to the origin of therapy resistant cancer hybrid stem cells. PMID:26703575

  6. mTORC1/2 targeted by n-3 polyunsaturated fatty acids in the prevention of mammary tumorigenesis and tumor progression.

    PubMed

    Chen, Z; Zhang, Y; Jia, C; Wang, Y; Lai, P; Zhou, X; Wang, Y; Song, Q; Lin, Jun; Ren, Z; Gao, Q; Zhao, Z; Zheng, H; Wan, Z; Gao, T; Zhao, A; Dai, Y; Bai, X

    2014-09-11

    Although epidemiological and preclinical studies have shown the preventative effects of n-3 polyunsaturated fatty acids (PUFAs) on breast cancer, inconsistencies still remain in the data and the underlying mechanisms remain unclear. In this study, we identified mammalian target of rapamycin (mTOR) signaling, which plays an essential role in cell proliferation and breast tumorigenesis, as a target of n-3 PUFAs. In breast cancer cell lines, n-3 PUFAs rapidly and efficiently suppress both mTOR complex 1 (mTORC1) and mTORC2 and their downstream signaling, and subsequently inhibit cell proliferation and angiogenesis while promoting apoptosis. Further study indicates that stabilization of the mTOR-raptor complex by n-3 PUFAs may contribute to their inhibitory effect on mTORC1. Importantly, four complementary and well-controlled animal models were utilized to identify the role and molecular target of n-3 PUFAs in the prevention of breast carcinogenesis and progression, namely: (1) chemically induced mammary tumor rats with a high dietary intake of n-3 PUFAs; (2) nude mice implanted with mammary tumor cell lines stably expressing fat-1, a desaturase that catalyzes the conversion of n-6 to n-3 PUFAs and produces n-3 PUFAs endogenously; (3) fat-1 transgenic severe combined immune deficiency mice implanted with breast tumor cells; and (4) the fat-1 transgenic mouse mammary tumor virus-polyoma virus middle T oncogene double-hybrid mice, a model of aggressive breast cancer. In summary, dietary and endogenous n-3 PUFAs abrogate the activity of mTORC1/2 pathways in vitro and in vivo and prevent breast carcinogenesis, tumor growth and metastasis. Taken together, our findings convincingly clarify the causal relationship between n-3 PUFAs and breast cancer prevention and establish mTORC1/2 as a target of n-3 PUFAs. PMID:24096482

  7. Protease Activated Receptors 1 and 2 Correlate Differently with Breast Cancer Aggressiveness Depending on Tumor ER Status

    PubMed Central

    Lidfeldt, Jon; Bendahl, Pär-Ola; Forsare, Carina; Malmström, Per; Fernö, Mårten; Belting, Mattias

    2015-01-01

    Experimental models implicate protease activated receptors (PARs) as important sensors of the proteolytic tumor microenvironment during breast cancer development. However, the role of the major PARs, PAR-1 and PAR-2, in human breast tumors remains to be elucidated. Here, we have investigated how PAR-1 and PAR-2 protein expression correlate with established clinicopathological variables and patient outcome in a well-characterized cohort of 221 breast cancer patients. Univariable and multivariable hazard ratios (HR) were estimated by the Cox proportional hazards model, distant disease-free survival (DDFS) and overall survival by the Kaplan–Meier method, and survival in different strata was determined by the log-rank test. Associations between PARs and clinicopathological variables were analyzed using Pearson’s χ2-test. We find that PAR-2 associates with DDFS (HR = 3.1, P = 0.003), whereas no such association was found with PAR-1 (HR = 1.2, P = 0.6). Interestingly, the effect of PAR-2 was confined to the ER-positive sub-group (HR = 5.5, P = 0.003 vs. HR = 1.2 in ER-negative; P = 0.045 for differential effect), and PAR-2 was an independent prognostic factor specifically in ER-positive tumors (HR = 3.9, P = 0.045). On the contrary, PAR-1 correlated with worse prognosis specifically in the ER-negative group (HR = 2.6, P = 0.069 vs. HR = 0.5, P = 0.19 in ER-positive; P = 0.026 for differential effect). This study provides novel insight into the respective roles of PAR-1 and PAR-2 in human breast cancer and suggests a hitherto unknown association between PARs and ER signaling that warrants further investigation. PMID:26244666

  8. Epithelial-Mesenchymal Transition in Cancer: Parallels Between Normal Development and Tumor Progression

    PubMed Central

    Micalizzi, Douglas S.; Farabaugh, Susan M.

    2010-01-01

    From the earliest stages of embryonic development, cells of epithelial and mesenchymal origin contribute to the structure and function of developing organs. However, these phenotypes are not always permanent, and instead, under the appropriate conditions, epithelial and mesenchymal cells convert between these two phenotypes. These processes, termed Epithelial-Mesenchymal Transition (EMT), or the reverse Mesenchymal-Epithelial Transition (MET), are required for complex body patterning and morphogenesis. In addition, epithelial plasticity and the acquisition of invasive properties without the full commitment to a mesenchymal phenotype are critical in development, particularly during branching morphogenesis in the mammary gland. Recent work in cancer has identified an analogous plasticity of cellular phenotypes whereby epithelial cancer cells acquire mesenchymal features that permit escape from the primary tumor. Because local invasion is thought to be a necessary first step in metastatic dissemination, EMT and epithelial plasticity are hypothesized to contribute to tumor progression. Similarities between developmental and oncogenic EMT have led to the identification of common contributing pathways, suggesting that the reactivation of developmental pathways in breast and other cancers contributes to tumor progression. For example, developmental EMT regulators including Snail/Slug, Twist, Six1, and Cripto, along with developmental signaling pathways including TGF-β and Wnt/β-catenin, are misexpressed in breast cancer and correlate with poor clinical outcomes. This review focuses on the parallels between epithelial plasticity/EMT in the mammary gland and other organs during development, and on a selection of developmental EMT regulators that are misexpressed specifically during breast cancer. PMID:20490631

  9. Role and molecular mechanism of heterogeneous nuclear ribonucleoprotein K in tumor development and progression

    PubMed Central

    LU, JING; GAO, FENG-HOU

    2016-01-01

    Heterogeneous nuclear ribonucleoprotein K (hnRNP K) is a member of the hnRNP family, which exists in the nucleus and the cytoplasm simultaneously. It is a multifunctional protein that can participate in a variety of regulatory progressions of gene expression and signal transduction, such as chromatin remodeling, transcription, RNA alternative splicing and translation. hnRNP K not only directly binds to the kinases, but also recruits the associated factors regarding transcription, splicing and translation to control gene expression, and therefore, it serves as a docking platform for integrating transduction pathways to nucleic acid-directed processes. Numerous studies also show that abnormal expression of hnRNP K is closely associated with the tumor formation. This protein is overexpressed in numerous types of cancer and its aberrant cytoplasmic localization is also associated with a worse prognosis for patients. These results consistently indicate that hnRNP K has a key role in cancer progression. To understand the hnRNP K pathophysiological process in tumor disease, the previous research results regarding the association between hnRNP K and tumors were reviewed. PMID:27284403

  10. Deficiency for the cysteine protease cathepsin L promotes tumor progression in mouse epidermis

    PubMed Central

    Dennemärker, J; Lohmüller, T; Mayerle, J; Tacke, M; Lerch, MM; Coussens, LM; Peters, C; Reinheckel, T

    2011-01-01

    To define a functional role for the endosomal/lysosomal cysteine protease cathepsin L (Ctsl) during squamous carcinogenesis, we generated mice harboring a constitutive Ctsl deficiency in addition to epithelial expression of the human papillomavirus type 16 oncogenes (human cytokeratin 14 (K14)–HPV16).We found enhanced tumor progression and metastasis in the absence of Ctsl. As tumor progression in K14–HPV16 mice is dependent on inflammation and angiogenesis, we examined immune cell infiltration and vascularization without finding any effect of the Ctsl genotype. In contrast, keratinocyte-specific transgenic expression of cathepsin V, the human orthologue of mouse Ctsl, in otherwise Ctsl-deficient K14–HPV16 mice restored the phenotype observed in the control HPV16 skin. To better understand this phenotype at the molecular level, we measured several oncogenic signal transduction pathways in primary keratinocytes on stimulation with keratinocyte-conditioned cell culture medium. We found increased activation of protein kinase B/Akt and mitogen-activated protein kinase pathways in protease-deficient cells, especially if treated with media conditioned by Ctsl-deficient keratinocytes. Similarly, the level of active GTP-Ras was increased in Ctsl-deficient epidermis. We conclude that Ctsl is critical for the termination of growth factor signaling in the endosomal/lysosomal compartment of keratinocytes and, therefore, functions as an anti-tumor protease. PMID:20023699

  11. The Bisecting GlcNAc on N-Glycans Inhibits Growth Factor Signaling and Retards Mammary Tumor Progression

    PubMed Central

    Song, Yinghui; Aglipay, Jason A.; Bernstein, Joshua D.; Goswami, Sumanta; Stanley, Pamela

    2010-01-01

    The branching of complex N-glycans attached to growth factor receptors promotes tumor progression by prolonging growth factor signaling. The addition of the bisecting GlcNAc to complex N-glycans by Mgat3 has varying effects on cell adhesion, cell migration and hepatoma formation. Here we show that Chinese hamster ovary (CHO) cells expressing Mgat3 and the Polyoma Middle T (PyMT) antigen have reduced cell proliferation and growth factor signaling dependent on a galectin lattice. The Mgat3 gene is not expressed in virgin mammary gland but is upregulated during lactation and is expressed in MMTV/PyMT tumors. Mice lacking Mgat3 that cannot transfer the bisecting GlcNAc to N-glycans acquire PyMT-induced mammary tumors more rapidly, have an increased tumor burden, increased migration of tumor cells, and increased early metastasis to lung. Tumors and tumor-derived cells lacking Mgat3 exhibit enhanced signaling through the Ras pathway, and reduced amounts of functionally-glycosylated α-dystroglycan. Constitutive overexpression of an MMTV/Mgat3 transgene inhibits early mammary tumor development and tumor cell migration. Thus the addition of the bisecting GlcNAc to complex N-glycans of mammary tumor cell glycoprotein receptors is a cell-autonomous mechanism serving to retard tumor progression by reducing growth factor signaling. PMID:20395209

  12. Tumor progression locus 2 (TPL2) is a novel target for regulating obesity associated liver inflammation and steatosis

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Tumor progression locus 2 (TPL2) is a MAP 3-kinase that is required for toll receptor and tumor necrosis factor-alpha (TNF-alpha) stimulation of the ERK/MAP kinase cascade. TPL-2 knockout (KO) mice exhibit a dramatic reduction in LPS induced TNF-alpha production due to defective ERK-1/2 activation....

  13. Simultaneous inference of cancer pathways and tumor progression from cross-sectional mutation data.

    PubMed

    Raphael, Benjamin J; Vandin, Fabio

    2015-06-01

    Recent cancer sequencing studies provide a wealth of somatic mutation data from a large number of patients. One of the most intriguing and challenging questions arising from this data is to determine whether the temporal order of somatic mutations in a cancer follows any common progression. Since we usually obtain only one sample from a patient, such inferences are commonly made from cross-sectional data from different patients. This analysis is complicated by the extensive variation in the somatic mutations across different patients, variation that is reduced by examining combinations of mutations in various pathways. Thus far, methods to reconstruct tumor progression at the pathway level have restricted attention to known, a priori defined pathways. In this work we show how to simultaneously infer pathways and the temporal order of their mutations from cross-sectional data, leveraging on the exclusivity property of driver mutations within a pathway. We define the pathway linear progression model, and derive a combinatorial formulation for the problem of finding the optimal model from mutation data. We show that with enough samples the optimal solution to this problem uniquely identifies the correct model with high probability even when errors are present in the mutation data. We then formulate the problem as an integer linear program (ILP), which allows the analysis of datasets from recent studies with large numbers of samples. We use our algorithm to analyze somatic mutation data from three cancer studies, including two studies from The Cancer Genome Atlas (TCGA) on large number of samples on colorectal cancer and glioblastoma. The models reconstructed with our method capture most of the current knowledge of the progression of somatic mutations in these cancer types, while also providing new insights on the tumor progression at the pathway level. PMID:25785493

  14. Anti-Tumor Effects of Second Generation β-Hydroxylase Inhibitors on Cholangiocarcinoma Development and Progression

    PubMed Central

    Chung, Waihong; de la Monte, Suzanne; Thomas, John-Michael; Olsen, Mark; Carlson, Rolf; Yu, Tunan; Dong, Xiaoqun; Wands, Jack

    2016-01-01

    Cholangiocarcinoma (CCA) has a poor prognosis due to widespread intrahepatic spread. Aspartate β-hydroxylase (ASPH) is a transmembrane protein and catalyzes the hydroxylation of aspartyl and asparaginyl residues in calcium binding epidermal growth factor (cbEGF)-like domains of various proteins, including Notch receptors and ligands. ASPH is highly overexpressed (>95%) in human CCA tumors. We explored the molecular mechanisms by which ASPH mediated the CCA malignant phenotype and evaluated the potential of ASPH as a therapeutic target for CCA. The importance of expression and enzymatic activity of ASPH for CCA growth and progression was examined using shRNA “knockdown” and a mutant construct that reduced its catalytic activity. Second generation small molecule inhibitors (SMIs) of β-hydroxylase activity were developed and used to target ASPH in vitro and in vivo. Subcutaneous and intrahepatic xenograft rodent models were employed to determine anti-tumor effects on CCA growth and development. It was found that the enzymatic activity of ASPH was critical for mediating CCA progression, as well as inhibiting apoptosis. Mechanistically, ASPH overexpression promoted Notch activation and modulated CCA progression through a Notch1-dependent cyclin D1 pathway. Targeting ASPH with shRNAs or a SMI significantly suppressed CCA growth in vivo. PMID:26954680

  15. Beyond a tumor suppressor: Soluble E-cadherin promotes the progression of cancer.

    PubMed

    Hu, Qi-Ping; Kuang, Jing-Ya; Yang, Qing-Kai; Bian, Xiu-Wu; Yu, Shi-Cang

    2016-06-15

    E-cadherin (E-cad) plays important roles in tumorigenesis as well as in tumor progression, invasion and metastasis. This protein exists in two forms: a membrane-tethered form and a soluble form. Full-length E-cad is membrane tethered. As a type I transmembrane glycoprotein, E-cad mainly mediates adherens junctions between cells and is involved in maintaining the normal structure of epithelial tissues. Soluble E-cad (sE-cad) is the extracellular fragment of the protein that is cleaved from the membrane after proteolysis of full-length E-cad. The production of sE-cad undermines adherens junctions, causing a reduction in cell aggregation capacity; furthermore, sE-cad can diffuse into the extracellular environment and the blood. As a paracrine/autocrine signaling molecule, sE-cad activates or inhibits multiple signaling pathways and participates in the progression of various types of cancer, such as breast cancer, ovarian cancer, and lung cancer, by promoting invasion and metastasis. This article briefly reviews the role of sE-cad in tumorigenesis and tumor progression and its significance in clinical therapeutics. PMID:26704932

  16. Antiangiogenic Therapy Elicits Malignant Progression of Tumors to Increased Local Invasion and Distant Metastasis

    PubMed Central

    Pàez-Ribes, Marta; Allen, Elizabeth; Hudock, James; Takeda, Takaaki; Okuyama, Hiroaki; Viñals, Francesc; Inoue, Masahiro; Bergers, Gabriele; Hanahan, Douglas; Casanovas, Oriol

    2009-01-01

    SUMMARY Multiple angiogenesis inhibitors have been therapeutically validated in preclinical cancer models, and several in clinical trials. Here we report that angiogenesis inhibitors targeting the VEGF pathway demonstrate antitumor effects in mouse models of pancreatic neuroendocrine carcinoma and glioblastoma but concomitantly elicit tumor adaptation and progression to stages of greater malignancy, with heightened invasiveness and in some cases increased lymphatic and distant metastasis. Increased invasiveness is also seen by genetic ablation of the Vegf-A gene in both models, substantiating the results of the pharmacological inhibitors. The realization that potent angiogenesis inhibition can alter the natural history of tumors by increasing invasion and metastasis warrants clinical investigation, as the prospect has important implications for the development of enduring antiangiogenic therapies. PMID:19249680

  17. Steering tumor progression through the transcriptional response to growth factors and stroma.

    PubMed

    Feldman, Morris E; Yarden, Yosef

    2014-08-01

    Tumor progression can be understood as a collaborative effort of mutations and growth factors, which propels cell proliferation and matrix invasion, and also enables evasion of drug-induced apoptosis. Concentrating on EGFR, we discuss downstream signaling and the initiation of transcriptional events in response to growth factors. Specifically, we portray a wave-like program, which initiates by rapid disappearance of two-dozen microRNAs, followed by an abrupt rise of immediate early genes (IEGs), relatively short transcripts encoding transcriptional regulators. Concurrent with the fall of IEGs, some 30-60 min after stimulation, a larger group, the delayed early genes, is up-regulated and its own fall overlaps the rise of the final wave of late response genes. This late wave persists and determines long-term phenotype acquisition, such as invasiveness. Key regulatory steps in the orderly response to growth factors provide a trove of potential oncogenes and tumor suppressors. PMID:24873881

  18. Breast cancer-associated fibroblasts: their roles in tumor initiation, progression and clinical applications.

    PubMed

    Qiao, Aixiu; Gu, Feng; Guo, Xiaojing; Zhang, Xinmin; Fu, Li

    2016-03-01

    Breast cancer is the most common malignant tumor in women, and the incidence of this disease has increased in recent years because of changes in diet, living environment, gestational age, and other unknown factors. Previous studies focused on cancer cells, but an increasing number of recent studies have analyzed the contribution of cancer microenvironment to the initiation and progression of breast cancer. Cancer-associated fibroblasts (CAFs), the most abundant cells in tumor stroma, secrete various active biomolecules, including extracellular matrix components, growth factors, cytokines, proteases, and hormones. CAFs not only facilitate the initiation, growth, angiogenesis, invasion, and metastasis of cancer but also serve as biomarkers in the clinical diagnosis, therapy, and prognosis of breast cancer. In this article, we reviewed the literature and summarized the research findings on CAFs in breast cancer. PMID:26791754

  19. Hypothalamic tumor

    MedlinePlus

    ... occur at any age. They are often more aggressive in adults than in children. In adults, tumors ... The treatment depends on how aggressive the tumor is, and whether it is a glioma or another type of cancer. Treatment may involve combinations of surgery, radiation , ...

  20. Altered mRNA expression of the Rb and p16 tumor suppressor genes and of CDK4 in transitional cell carcinomas of the urinary bladder associated with tumor progression.

    PubMed

    Quentin, Thomas; Henke, Christian; Korabiowska, Monika; Schlott, Thilo; Zimmerman, Britt; Kunze, Ekkehard

    2004-01-01

    and adhesives displayed altered partly elevated, partly reduced levels of Rb, p16 and CDK4 mRNA compared to non-exposed subjects. Although the underlying molecular-genetic pathways are not yet fully understood, the current results suggest functional reduction of the tumor suppressor genes Rb and p16 to be associated with progression of bladder cancer to a more malignant and aggressive behaviour. PMID:15161057

  1. Ablation of Neuropilin 1 from glioma-associated microglia and macrophages slows tumor progression.

    PubMed

    Miyauchi, Jeremy T; Chen, Danling; Choi, Matthew; Nissen, Jillian C; Shroyer, Kenneth R; Djordevic, Snezana; Zachary, Ian C; Selwood, David; Tsirka, Stella E

    2016-03-01

    Gliomas are the most commonly diagnosed primary tumors of the central nervous system (CNS). Median times of survival are dismal regardless of the treatment approach, underlying the need to develop more effective therapies. Modulation of the immune system is a promising strategy as innate and adaptive immunity play important roles in cancer progression. Glioma associated microglia and macrophages (GAMs) can comprise over 30% of the cells in glioma biopsies. Gliomas secrete cytokines that suppress the anti-tumorigenic properties of GAMs, causing them to secrete factors that support the tumor's spread and growth. Neuropilin 1 (Nrp1) is a transmembrane receptor that in mice both amplifies pro-angiogenic signaling in the tumor microenvironment and affects behavior of innate immune cells. Using a Cre-lox system, we generated mice that lack expression of Nrp1 in GAMs. We demonstrate, using an in vivo orthotopic glioma model, that tumors in mice with Nrp1-deficient GAMs exhibit less vascularity, grow at a slower pace, and are populated by increased numbers of anti-tumorigenic GAMs. Moreover, glioma survival times in mice with Nrp1-deficient GAMs were significantly longer. Treating wild-type mice with a small molecule inhibitor of Nrp1's b1 domain, EG00229, which we show here is selective for Nrp1 over Nrp2, yielded an identical outcome. Nrp1-deficient or EG00229-treated wild-type microglia exhibited a shift towards anti-tumorigenicity as evident by altered inflammatory marker profiles in vivo and decreased SMAD2/3 activation when conditioned in the presence of glioma-derived factors. These results provide support for the proposal that pharmacological inhibition of Nrp1 constitutes a potential strategy for suppressing glioma progression. PMID:26755653

  2. Ablation of Neuropilin 1 from glioma-associated microglia and macrophages slows tumor progression

    PubMed Central

    Miyauchi, Jeremy T.; Chen, Danling; Choi, Matthew; Nissen, Jillian C.; Shroyer, Kenneth R.; Djordevic, Snezana; Zachary, Ian C.; Selwood, David; Tsirka, Stella E.

    2016-01-01

    Gliomas are the most commonly diagnosed primary tumors of the central nervous system (CNS). Median times of survival are dismal regardless of the treatment approach, underlying the need to develop more effective therapies. Modulation of the immune system is a promising strategy as innate and adaptive immunity play important roles in cancer progression. Glioma associated microglia and macrophages (GAMs) can comprise over 30% of the cells in glioma biopsies. Gliomas secrete cytokines that suppress the anti-tumorigenic properties of GAMs, causing them to secrete factors that support the tumor's spread and growth. Neuropilin 1 (Nrp1) is a transmembrane receptor that in mice both amplifies pro-angiogenic signaling in the tumor microenvironment and affects behavior of innate immune cells. Using a Cre-lox system, we generated mice that lack expression of Nrp1 in GAMs. We demonstrate, using an in vivo orthotopic glioma model, that tumors in mice with Nrp1-deficient GAMs exhibit less vascularity, grow at a slower pace, and are populated by increased numbers of anti-tumorigenic GAMs. Moreover, glioma survival times in mice with Nrp1-deficient GAMs were significantly longer. Treating wild-type mice with a small molecule inhibitor of Nrp1's b1 domain, EG00229, which we show here is selective for Nrp1 over Nrp2, yielded an identical outcome. Nrp1-deficient or EG00229-treated wild-type microglia exhibited a shift towards anti-tumorigenicity as evident by altered inflammatory marker profiles in vivo and decreased SMAD2/3 activation when conditioned in the presence of glioma-derived factors. These results provide support for the proposal that pharmacological inhibition of Nrp1 constitutes a potential strategy for suppressing glioma progression. PMID:26755653

  3. MUC16 (CA125): tumor biomarker to cancer therapy, a work in progress

    PubMed Central

    2014-01-01

    Over three decades have passed since the first report on the expression of CA125 by ovarian tumors. Since that time our understanding of ovarian cancer biology has changed significantly to the point that these tumors are now classified based on molecular phenotype and not purely on histological attributes. However, CA125 continues to be, with the recent exception of HE4, the only clinically reliable diagnostic marker for ovarian cancer. Many large-scale clinical trials have been conducted or are underway to determine potential use of serum CA125 levels as a screening modality or to distinguish between benign and malignant pelvic masses. CA125 is a peptide epitope of a 3–5 million Da mucin, MUC16. Here we provide an in-depth review of the literature to highlight the importance of CA125 as a prognostic and diagnostic marker for ovarian cancer. We focus on the increasing body of literature describing the biological role of MUC16 in the progression and metastasis of ovarian tumors. Finally, we consider previous and on-going efforts to develop therapeutic approaches to eradicate ovarian tumors by targeting MUC16. Even though CA125 is a crucial marker for ovarian cancer, the exact structural definition of this antigen continues to be elusive. The importance of MUC16/CA125 in the diagnosis, progression and therapy of ovarian cancer warrants the need for in-depth research on the biochemistry and biology of this mucin. A renewed focus on MUC16 is likely to culminate in novel and more efficient strategies for the detection and treatment of ovarian cancer. PMID:24886523

  4. Galectin-1 Upregulates CXCR4 to Promote Tumor Progression and Poor Outcome in Kidney Cancer

    PubMed Central

    Huang, Chang-Shuo; Tang, Shye-Jye; Chung, Ling-Yen; Yu, Cheng-Ping; Ho, Jar-Yi; Cha, Tai-Lung; Hsieh, Chii-Cheng; Wang, Hsiao-Hsien

    2014-01-01

    Galectin-1, a β-galactoside–binding lectin, is involved in many physiologic and pathologic processes, including cell adhesion, differentiation, angiogenesis, and tumor progression. However, the role of galectin-1 in kidney cancer remains elusive. This study evaluated the role of galectin-1 in the progression and clinical prognosis of renal cell carcinoma. We found significant overexpression of galectin-1 in both kidney cancer cell lines and metastatic tissue specimens from patients with renal cell carcinoma. Knockdown of galectin-1 gene expression in renal cancer cell lines reduced cell invasion, clonogenic ability, and epithelial-mesenchymal transition in vitro; reduced tumor outgrowth in vivo; and inhibited the angiogenesis-inducing activity of these cells in vitro and in vivo. Galectin-1 knockdown decreased CXCR4 expression levels in kidney cancer cells, and restoration of CXCR4 expression in galectin-1–silenced cells rescued cell motility and clonogenic ability. Additional studies suggested that galectin-1 induced CXCR4 expression through activation of nuclear factor-κB (NF-κB). Analysis of patient specimens confirmed the clinical significance and positive correlation between galectin-1 and CXCR4 expression levels and revealed concomitant overexpression of galectin-1 and CXCR4 associated adversely with overall and disease-free survival. Our findings suggest that galectin-1 promotes tumor progression through upregulation of CXCR4 via NF-κB. The coordinated upregulation of galectin-1 and CXCR4 may be a novel prognostic factor for survival in patients with renal cell carcinoma and the galectin-1-CXCR4 axis may serve as a therapeutic target in this disease. PMID:24511119

  5. High levels of class III β-tubulin expression are associated with aggressive tumor features in breast cancer

    PubMed Central

    LEBOK, PATRICK; ÖZTÜRK, MELIKE; HEILENKÖTTER, UWE; JAENICKE, FRITZ; MÜLLER, VOLKMAR; PALUCHOWSKI, PETER; GEIST, STEFAN; WILKE, CHRISTIAN; BURANDT, EICKE; LEBEAU, ANNETTE; WILCZAK, WALDEMAR; KRECH, TILL; SIMON, RONALD; SAUTER, GUIDO; QUAAS, ALEXANDER

    2016-01-01

    Overexpression of class III β-tubulin (TUBB3), a factor that confers dynamic properties to microtubules, is a candidate biomarker for resistance to microtubule-targeting chemotherapeutics in breast and other types of solid cancer. Discrepant results from previous studies, with respect to the association of TUBB3 expression levels with breast cancer phenotype and patient prognosis, prompted the present study to investigate TUBB3 expression in a large cohort of breast cancer cases, with available clinical follow-up data. A preexisting breast cancer prognosis tissue microarray, containing a single 0.6 mm tissue core from each of 2,197 individual patients with breast cancer, was analyzed for TUBB3 expression by immunohistochemistry. The results of the present study revealed that TUBB3 expression was less frequent in lobular breast cancer cases (34%), compared with that of cancer cases of alternative histologies, including breast cancer of no special type (60%; P<0.0001). High TUBB3 positivity was associated with high tumor grade (P<0.0001), negativity for estrogen (P<0.0001) and progesterone receptors (P<0.004), as well as the presence of human epidermal growth factor 2 amplification (P<0.0001) and a triple-negative phenotype (P<0.0001). TUBB3 overexpression was additionally associated with reduced patient survival if all breast cancer cases of any histology were jointly analyzed (P=0.0088); however this link was not evident in the subset of breast cancer cases of no special type, or in a multivariate analysis including the established prognostic factors of tumor stage, grade and nodal stage. In conclusion, the present study demonstrated that TUBB3 overexpression was associated with adverse features of breast cancer, and that TUBB3 may possess a distinct role in lobular breast cancer cases, compared with alternative histological subtypes. The results of the present study do not support a clinically relevant role for TUBB3 as a prognostic marker in breast cancer. PMID

  6. Role of Serum Cholesterol and Statin Use in the Risk of Prostate Cancer Detection and Tumor Aggressiveness

    PubMed Central

    Morote, Juan; Celma, Anna; Planas, Jacques; Placer, José; de Torres, Inés; Olivan, Mireia; Carles, Juan; Reventós, Jaume; Doll, Andreas

    2014-01-01

    The aim of this study was to analyze the relationship between statin use along with serum cholesterol levels and prostate cancer (PCa) detection and aggressiveness. Statin users of three years or more and serum cholesterol levels (SC) were assessed in 2408 men scheduled for prostate biopsy. SC was classified as normal (NSC: <200 mg/dL) or high (HSC: >200 mg/dL). High-grade PCa (HGPCa) was considered if the Gleason score was greater than 7. Statin users comprised 30.9% of those studied. The PCa detection rate was 31.2% of men on statins and 37% of non-statin users (p < 0.006). The PCa detection rate was 26.3% in men with NSC and 40.6% in those with HSC (p < 0.001). In the subset of NSC men, the PCa rate was 26.5% for statin users and 26.2% for non-users (p = 0.939), while in men with HSC, the PCa rate was 36.4% for statin users and 42.0% for non-statin users (p = 0.063). The HGPCa rate was 41.8% for statin users and 32.5% for non-users (p = 0.012). NSC men had a 53.8% rate of HGPCa, while the rate was only 27.6% in HSC men (p < 0.001). NSC men on statins had an HGPCa rate of 70.2%, while non-statin users had a rate of 41.2% (p < 0.001). The HGPCa rate for HSC men on statins was 18.8%, while the rate was 30.0% (p = 0.011) for non-users. Logistic regression analysis suggested that serum cholesterol levels could serve as an independent predictor of PCa risk, OR 1.87 (95% CI 1.56–2.24) and HGPCa risk, OR 0.31 (95% CI 0.23–0.44), while statin usage could not. Statin treatment may prevent PCa detection through serum cholesterol-mediated mechanisms. A disturbing increase in the HGPCa rate was observed in statin users who normalized their serum cholesterol. PMID:25101846

  7. Human Breast Cancer Invasion and Aggression Correlates with ECM Stiffening and Immune Cell Infiltration

    PubMed Central

    Acerbi, I; Cassereau, L; Dean, I; Shi, Q; Au, A; Park, C; Chen, YY; Liphardt, J; Hwang, ES; Weaver, VM

    2015-01-01

    Tumors are stiff and data suggest that the extracellular matrix stiffening that correlates with experimental mammary malignancy drives tumor invasion and metastasis. Nevertheless, the relationship between tissue and extracellular matrix stiffness and human breast cancer progression and aggression remains unclear. We undertook a biophysical and biochemical assessment of stromal-epithelial interactions in noninvasive, invasive and normal adjacent human breast tissue and in breast cancers of increasingly aggressive subtype. Our analysis revealed that human breast cancer transformation is accompanied by an incremental increase in collagen deposition and a progressive linearization and thickening of interstitial collagen. The linearization of collagen was visualized as an overall increase in tissue birefringence and was most striking at the invasive front of the tumor where the stiffness of the stroma and cellular mechanosignaling were the highest. Amongst breast cancer subtypes we found that the stroma at the invasive region of the more aggressive Basal-like and Her2 tumor subtypes was the most heterogeneous and the stiffest when compared to the less aggressive Luminal A and B subtypes. Intriguingly, we quantified the greatest number of infiltrating macrophages and the highest level of TGF beta signaling within the cells at the invasive front. We also established that stroma stiffness and the level of cellular TGF beta signaling positively correlated with each other and with the number of infiltrating tumor-activated, macrophages, which was highest in the more aggressive tumor subtypes. These findings indicate that human breast cancer progression and aggression, collagen linearization and stromal stiffening are linked and implicate tissue inflammation and TGF beta. PMID:25959051

  8. Human breast cancer invasion and aggression correlates with ECM stiffening and immune cell infiltration.

    PubMed

    Acerbi, I; Cassereau, L; Dean, I; Shi, Q; Au, A; Park, C; Chen, Y Y; Liphardt, J; Hwang, E S; Weaver, V M

    2015-10-01

    Tumors are stiff and data suggest that the extracellular matrix stiffening that correlates with experimental mammary malignancy drives tumor invasion and metastasis. Nevertheless, the relationship between tissue and extracellular matrix stiffness and human breast cancer progression and aggression remains unclear. We undertook a biophysical and biochemical assessment of stromal-epithelial interactions in noninvasive, invasive and normal adjacent human breast tissue and in breast cancers of increasingly aggressive subtype. Our analysis revealed that human breast cancer transformation is accompanied by an incremental increase in collagen deposition and a progressive linearization and thickening of interstitial collagen. The linearization of collagen was visualized as an overall increase in tissue birefringence and was most striking at the invasive front of the tumor where the stiffness of the stroma and cellular mechanosignaling were the highest. Amongst breast cancer subtypes we found that the stroma at the invasive region of the more aggressive Basal-like and Her2 tumor subtypes was the most heterogeneous and the stiffest when compared to the less aggressive luminal A and B subtypes. Intriguingly, we quantified the greatest number of infiltrating macrophages and the highest level of TGF beta signaling within the cells at the invasive front. We also established that stroma stiffness and the level of cellular TGF beta signaling positively correlated with each other and with the number of infiltrating tumor-activated macrophages, which was highest in the more aggressive tumor subtypes. These findings indicate that human breast cancer progression and aggression, collagen linearization and stromal stiffening are linked and implicate tissue inflammation and TGF beta. PMID:25959051

  9. Modulation of tumor induction and progression of oncogenic K-ras-positive tumors in the presence of TGF- b1 haploinsufficiency.

    PubMed

    Pandey, Jyotsna; Umphress, Sarah M; Kang, Yang; Angdisen, Jerry; Naumova, Alena; Mercer, Kim L; Jacks, Tyler; Jakowlew, Sonia B

    2007-12-01

    Oncogenic K-ras is one of the most common genetic alterations in human lung adenocarcinomas. In addition, inactivation of clusters of tumor suppressor genes is required to bring about classical characteristics of cancer including angiogenesis as a prelude to invasion and metastasis. Transforming growth factor-beta (TGF-beta) 1 is a tumor suppressor gene that is implicated in lung cancer progression. Although in vitro studies have shown that TGF-beta1 and Ras pathways cooperate during tumorigenesis, the biology of interaction of TGF-beta1 and Ras has not been studied in in vivo tumorigenesis. We hypothesized that inactivation of TGF-beta1 in addition to oncogeneic activation of K-ras would lead to early initiation and faster progression to lung adenocarcinoma and invasion and metastasis. Heterozygous (HT) TGF-beta1 mice were mated with latent activatable (LA) mutated K-ras mice to generate TGF-beta1(+/+), K-ras LA (wild-type (WT)/LA) and TGF-beta1(+/-), K-ras LA (HT/LA) mice. Both HT/LA and WT/LA mice developed spontaneous lung tumors, but HT/LA mice progressed to adenocarcinomas significantly earlier compared with WT/LA mice. In addition, WT/LA adenocarcinomas had significantly higher angiogenic activity compared with HT/LA adenocarcinomas. Thus, while oncogenic K-ras mutation and insensitivity to the growth regulatory effects of TGF-beta1 is essential for initiation and progression of mouse lung tumors to adenocarcinoma, a full gene dosage of TGF-beta1 is required for tumor-induced angiogenesis and invasive potential. This study identifies a number of genes not previously associated with lung cancer that are involved in tumor induction and progression. In addition, we provide evidence that progression to invasive angiogenic lesions requires TGF-beta1 responsiveness in addition to Ras mutation. PMID:17690114

  10. Research in radiobiology: Final report of work in progress in immunobiology of experimental host-tumor relationships

    SciTech Connect

    Not Available

    1993-03-15

    Our work on the immunobiology of tumors induced in normal mice by non-ionizing radiation and chemical carcinogens has previously demonstrated a correlation between MHC molecule expression and the immunogenicity of tumors in a transplanted syngeneic host. Such that immunogenic or regressive tumors were found to demonstrate higher constitutive or inducible levels of MHC expression, while most virulent, aggressive tumors exhibited a low level of MHC Class I expression. We attributed much of the control of MHC molecule expression by antigen-bearing tumors and normal cells to the immunological status of the host since the host must provide the appropriate stimulus to enhance MHC antigen expression by the invading tumor. Our results with UVR-induced tumors suggested that a significant role is played by the T-cell lymphokine, [gamma]-interferon ([gamma]IFN), in the modulation of MHC molecule expression in vivo. Virulent tumors, induced by boneseeking radionuclides, may be refractory to [gamma]IFN stimulation of MHC molecule expression. It is also possible that certain tumors might be fully responsive to the Class I modulatory influences by [gamma]IFN, but exhibit a reduced capacity to stimulate the synthesis of this lymphokine by host T cells. We present experiments designed to : Describe the virulence, latency period, and transplantation characteristics of [sup 238]PU, [sup 24l]Am, and [sup 228]Th tumors arising as osteogenic sarcomas and hepatic carcinomas, to determine the relationship between inducible expression of MHC Class I molecules by [gamma]IFN and in vivo immunogenicity of these radioisotype-induced tumors, and to elucidate any molecular mechanisms responsible for a lack of responsiveness to a [gamma]IFN failure by the host to induce host [gamma]IFN production.

  11. Research in radiobiology: Final report of work in progress in immunobiology of experimental host-tumor relationships

    SciTech Connect

    Not Available

    1993-03-15

    Our work on the immunobiology of tumors induced in normal mice by non-ionizing radiation and chemical carcinogens has previously demonstrated a correlation between MHC molecule expression and the immunogenicity of tumors in a transplanted syngeneic host. Such that immunogenic or regressive tumors were found to demonstrate higher constitutive or inducible levels of MHC expression, while most virulent, aggressive tumors exhibited a low level of MHC Class I expression. We attributed much of the control of MHC molecule expression by antigen-bearing tumors and normal cells to the immunological status of the host since the host must provide the appropriate stimulus to enhance MHC antigen expression by the invading tumor. Our results with UVR-induced tumors suggested that a significant role is played by the T-cell lymphokine, {gamma}-interferon ({gamma}IFN), in the modulation of MHC molecule expression in vivo. Virulent tumors, induced by boneseeking radionuclides, may be refractory to {gamma}IFN stimulation of MHC molecule expression. It is also possible that certain tumors might be fully responsive to the Class I modulatory influences by {gamma}IFN, but exhibit a reduced capacity to stimulate the synthesis of this lymphokine by host T cells. We present experiments designed to : Describe the virulence, latency period, and transplantation characteristics of {sup 238}PU, {sup 24l}Am, and {sup 228}Th tumors arising as osteogenic sarcomas and hepatic carcinomas, to determine the relationship between inducible expression of MHC Class I molecules by {gamma}IFN and in vivo immunogenicity of these radioisotype-induced tumors, and to elucidate any molecular mechanisms responsible for a lack of responsiveness to a {gamma}IFN failure by the host to induce host {gamma}IFN production.

  12. Targeting Aggressive Cancer Stem Cells in Glioblastoma

    PubMed Central

    Seymour, Tracy; Nowak, Anna; Kakulas, Foteini

    2015-01-01

    Glioblastoma (GBM) is the most common and fatal type of primary brain tumor. Gliosarcoma (GSM) is a rarer and more aggressive variant of GBM that has recently been considered a potentially different disease. Current clinical treatment for both GBM and GSM includes maximal surgical resection followed by post-operative radiotherapy and concomitant and adjuvant chemotherapy. Despite recent advances in treating other solid tumors, treatment for GBM and GSM still remains palliative, with a very poor prognosis and a median survival rate of 12–15 months. Treatment failure is a result of a number of causes, including resistance to radiotherapy and chemotherapy. Recent research has applied the cancer stem cells theory of carcinogenesis to these tumors, suggesting the existence of a small subpopulation of glioma stem-like cells (GSCs) within these tumors. GSCs are thought to contribute to tumor progression, treatment resistance, and tumor recapitulation post-treatment and have become the focus of novel therapy strategies. Their isolation and investigation suggest that GSCs share critical signaling pathways with normal embryonic and somatic stem cells, but with distinct alterations. Research must focus on identifying these variations as they may present novel therapeutic targets. Targeting pluripotency transcription factors, SOX2, OCT4, and Nanog homeobox, demonstrates promising therapeutic potential that if applied in isolation or together with current treatments may improve overall survival, reduce tumor relapse, and achieve a cure for these patients. PMID:26258069

  13. Overview: Progression-Free Survival as an Endpoint in Clinical Trials with Solid Tumors

    PubMed Central

    Korn, Ronald L.; Crowley, John J.

    2013-01-01

    Progression-free survival (PFS) is increasingly used as an important and even a primary endpoint in randomized cancer clinical trials in the evaluation of patients with solid tumors, because of both practical and clinical considerations. Although in its simplest form PFS is the time from randomization to a pre-defined endpoint, there are many factors that can influence the exact moment of when disease progression is recorded. In this overview, we review the circumstances that can devalue the use of PFS as a primary endpoint, and attempt to provide a pathway for a future desired state when PFS will become not just a secondary alternative to overall survival but rather an endpoint of choice. PMID:23669420

  14. Mammary Gland ECM Remodeling, Stiffness, and Mechanosignaling in Normal Development and Tumor Progression

    PubMed Central

    Schedin, Pepper; Keely, Patricia J.

    2011-01-01

    Cells of the mammary gland are in intimate contact with other cells and with the extracellular matrix (ECM), both of which provide not only a biochemical context, but a mechanical context as well. Cell-mediated contraction allows cells to sense the stiffness of their microenvironment, and respond with appropriate mechanosignaling events that regulate gene expression and differentiation. ECM composition and organization are tightly regulated throughout development of the mammary gland, resulting in corresponding regulation of the mechanical environment and proper tissue architecture. Mechanical regulation is also at play during breast carcinoma progression, as changes in ECM deposition, composition, and organization accompany breast carcinoma. These changes result in stiffer matrices that activate mechanosignaling pathways and thereby induce cell proliferation, facilitate local tumor cell invasion, and promote progression. Thus, understanding the role of forces in the mammary gland is crucial to understanding both normal developmental and pathological processes. PMID:20980442

  15. Therapeutic inhibition of Jak activity inhibits progression of gastrointestinal tumors in mice.

    PubMed

    Stuart, Emma; Buchert, Michael; Putoczki, Tracy; Thiem, Stefan; Farid, Ryan; Elzer, Joachim; Huszar, Dennis; Waring, Paul M; Phesse, Toby J; Ernst, Matthias

    2014-02-01

    Aberrant activation of the latent transcription factor STAT3 and its downstream targets is a common feature of epithelial-derived human cancers, including those of the gastrointestinal tract. Mouse models of gastrointestinal malignancy implicate Stat3 as a key mediator of inflammatory-driven tumorigenesis, in which its cytokine/gp130/Janus kinase (Jak)-dependent activation provides a functional link through which the microenvironment sustains tumor promotion. Although therapeutic targeting of STAT3 is highly desirable, such molecules are not available for immediate clinical assessment. Here, we investigated whether the small-molecule Jak1/2 inhibitor AZD1480 confers therapeutic benefits in two mouse models of inflammation-associated gastrointestinal cancer, which are strictly dependent of excessive Stat3 activation. We confirm genetically that Cre-mediated, tumor cell-specific reduction of Stat3 expression arrests the growth of intestinal-type gastric tumors in gp130(F/F) mice. We find that systemic administration of AZD1480 readily replicates this effect, which is associated with reduced Stat3 activation and correlates with diminished tumor cell proliferation and increased apoptosis. Likewise, AZD1480 therapy also conferred a cytostatic effect on established tumors in a colitis-associated colon cancer model in wild-type mice. As predicted from our genetic observations in gp130(F/F) mice, the therapeutic effect of AZD1480 remains fully reversible upon cessation of compound administration. Collectively, our results provide the first evidence that pharmacologic targeting of excessively activated wild-type Jak kinases affords therapeutic suppression of inflammation-associated gastrointestinal cancers progression in vivo. PMID:24398427

  16. Wound healing-like immune program facilitates postpartum mammary gland involution and tumor progression

    PubMed Central

    Martinson, Holly A.; Jindal, Sonali; Durand-Rougely, Clarissa; Borges, Virginia F.; Schedin, Pepper

    2014-01-01

    Women diagnosed with breast cancer within 5 years postpartum have poor survival rates. The process of postpartum mammary gland involution, whereby the lactating gland remodels to its pre-pregnant state, promotes breast cancer progression in xenograft models. Macrophage influx occurs during mammary gland involution, implicating immune modulation in the promotion of postpartum breast cancer. Herein, we characterize the postpartum murine mammary gland and find an orchestrated influx of immune cells similar to that which occurs during wound healing. Further, the normal involuting gland may be in an immunosuppressed state as discerned by the transient presence of Foxp3+ regulatory T cells and IL-10+ macrophages with T cell suppressive function. To determine the influence of the postpartum immune microenvironment on mammary tumor promotion, we developed an immune-competent model. In this model, mammary tumors in the involution group are six-fold larger than nulliparous group tumors, have decreased CD4+ and CD8+ T cell infiltrates and contain a greater number of macrophages with the ability to inhibit T cell activation. Targeting involution with a neutralizing antibody against the immunosuppressive cytokine IL-10 reduces tumor growth in involution group mice but not in nulliparous mice, implicating the involution microenvironment as the primary target of αIL-10 treatment. Relevance to women is implicated, as we find post-lactational human breast tissue has transient high IL-10+ and Foxp3+ immune cell infiltrate. These data show an immune modulated microenvironment within the normal involuting mammary gland suggestive of immunosuppression, that when targeted reduces tumor promotion, revealing possible immune-based strategies for postpartum breast cancer. PMID:25187059

  17. SOX2 boosts major tumor progression genes in prostate cancer and is a functional biomarker of lymph node metastasis

    PubMed Central

    Russo, Marco Vincenzo; Esposito, Silvia; Tupone, Maria Grazia; Manzoli, Lamberto; Airoldi, Irma; Pompa, Paolo; Cindolo, Luca; Schips, Luigi; Sorrentino, Carlo; Di Carlo, Emma

    2016-01-01

    Critical issues in prostate cancer (PC) are a. identification of molecular drivers of the highly aggressive neuroendocrine differentiation (NED) in adenocarcinoma, and b. early assessment of disease progression. The SRY (sex determining region Y)-box 2 gene, SOX2, is an essential embryonic stem cell gene involved in prostate tumorigenesis. Here we assessed its implications in NED and progression of PC and its diagnostic and prognostic value. Laser microdissection, qRT-PCR, quantitative Methylation-Specific PCR and immunohistochemistry were used to analyze SOX2 gene expression and regulation in 206 PC samples. Results were examined according to the patient's clinical pathological profile and follow-ups. Functional studies were performed using PC cells transfected to overexpress or silence SOX2. SOX2 was consistently downregulated in PC, except in cell clusters lying within lymph node (LN)-positive PC. Multivariate analysis revealed that SOX2 mRNA expression in the primary tumor was significantly associated with LN metastasis. When SOX2 mRNA levels were ≥1.00, relative to (XpressRef) Universal Total RNA, adjusted Odds Ratio was 24.4 (95% CI: 7.54–79.0), sensitivity 0.81 (95% CI: 0.61–0.93) and specificity 0.87 (95% CI: 0.81–0.91). Patients experiencing biochemical recurrence had high median levels of SOX2 mRNA. In both PC and LN metastasis, SOX2 and NED marker, Chromogranin-A, were primarily co-expressed. In PC cells, NED genes were upregulated by SOX2 overexpression and downregulated by its silencing, which also abolished SNAI2/Slug dependent NED. Moreover, SOX2 upregulated neural CAMs, neurotrophins/neurotrophin receptors, pluripotency and epithelial-mesenchymal transition transcription factors, growth, angiogenic and lymphangiogenic factors, and promoted PC cell invasiveness and motility. This study discloses novel SOX2 target genes driving NED and spread of PC and proposes SOX2 as a functional biomarker of LN metastasization for PC. PMID:26540632

  18. Loss of gastrokine-2 drives premalignant gastric inflammation and tumor progression.

    PubMed

    Menheniott, Trevelyan R; O'Connor, Louise; Chionh, Yok Teng; Däbritz, Jan; Scurr, Michelle; Rollo, Benjamin N; Ng, Garrett Z; Jacobs, Shelley; Catubig, Angelique; Kurklu, Bayzar; Mercer, Stephen; Minamoto, Toshinari; Ong, David E; Ferrero, Richard L; Fox, James G; Wang, Timothy C; Sutton, Philip; Judd, Louise M; Giraud, Andrew S

    2016-04-01

    Chronic mucosal inflammation is associated with a greater risk of gastric cancer (GC) and, therefore, requires tight control by suppressive counter mechanisms. Gastrokine-2 (GKN2) belongs to a family of secreted proteins expressed within normal gastric mucosal cells. GKN2 expression is frequently lost during GC progression, suggesting an inhibitory role; however, a causal link remains unsubstantiated. Here, we developed Gkn2 knockout and transgenic overexpressing mice to investigate the functional impact of GKN2 loss in GC pathogenesis. In mouse models of GC, decreased GKN2 expression correlated with gastric pathology that paralleled human GC progression. At baseline, Gkn2 knockout mice exhibited defective gastric epithelial differentiation but not malignant progression. Conversely, Gkn2 knockout in the IL-11/STAT3-dependent gp130F/F GC model caused tumorigenesis of the proximal stomach. Additionally, gastric immunopathology was accelerated in Helicobacter pylori-infected Gkn2 knockout mice and was associated with augmented T helper cell type 1 (Th1) but not Th17 immunity. Heightened Th1 responses in Gkn2 knockout mice were linked to deregulated mucosal innate immunity and impaired myeloid-derived suppressor cell activation. Finally, transgenic overexpression of human gastrokines (GKNs) attenuated gastric tumor growth in gp130F/F mice. Together, these results reveal an antiinflammatory role for GKN2, provide in vivo evidence that links GKN2 loss to GC pathogenesis, and suggest GKN restoration as a strategy to restrain GC progression. PMID:26974160

  19. Loss of gastrokine-2 drives premalignant gastric inflammation and tumor progression

    PubMed Central

    Menheniott, Trevelyan R.; O’Connor, Louise; Chionh, Yok Teng; Scurr, Michelle; Rollo, Benjamin N.; Ng, Garrett Z.; Jacobs, Shelley; Catubig, Angelique; Kurklu, Bayzar; Mercer, Stephen; Minamoto, Toshinari; Ong, David E.; Ferrero, Richard L.; Fox, James G.; Wang, Timothy C.; Judd, Louise M.; Giraud, Andrew S.

    2016-01-01

    Chronic mucosal inflammation is associated with a greater risk of gastric cancer (GC) and, therefore, requires tight control by suppressive counter mechanisms. Gastrokine-2 (GKN2) belongs to a family of secreted proteins expressed within normal gastric mucosal cells. GKN2 expression is frequently lost during GC progression, suggesting an inhibitory role; however, a causal link remains unsubstantiated. Here, we developed Gkn2 knockout and transgenic overexpressing mice to investigate the functional impact of GKN2 loss in GC pathogenesis. In mouse models of GC, decreased GKN2 expression correlated with gastric pathology that paralleled human GC progression. At baseline, Gkn2 knockout mice exhibited defective gastric epithelial differentiation but not malignant progression. Conversely, Gkn2 knockout in the IL-11/STAT3-dependent gp130F/F GC model caused tumorigenesis of the proximal stomach. Additionally, gastric immunopathology was accelerated in Helicobacter pylori–infected Gkn2 knockout mice and was associated with augmented T helper cell type 1 (Th1) but not Th17 immunity. Heightened Th1 responses in Gkn2 knockout mice were linked to deregulated mucosal innate immunity and impaired myeloid-derived suppressor cell activation. Finally, transgenic overexpression of human gastrokines (GKNs) attenuated gastric tumor growth in gp130F/F mice. Together, these results reveal an antiinflammatory role for GKN2, provide in vivo evidence that links GKN2 loss to GC pathogenesis, and suggest GKN restoration as a strategy to restrain GC progression. PMID:26974160

  20. Dopamine D2 receptor agonists inhibit lung cancer progression by reducing angiogenesis and tumor infiltrating myeloid derived suppressor cells.

    PubMed

    Hoeppner, Luke H; Wang, Ying; Sharma, Anil; Javeed, Naureen; Van Keulen, Virginia P; Wang, Enfeng; Yang, Ping; Roden, Anja C; Peikert, Tobias; Molina, Julian R; Mukhopadhyay, Debabrata

    2015-01-01

    We sought to determine whether Dopamine D2 Receptor (D2R) agonists inhibit lung tumor progression and identify subpopulations of lung cancer patients that benefit most from D2R agonist therapy. We demonstrate D2R agonists abrogate lung tumor progression in syngeneic (LLC1) and human xenograft (A549) orthotopic murine models through inhibition of tumor angiogenesis and reduction of tumor infiltrating myeloid derived suppressor cells. Pathological examination of human lung cancer tissue revealed a positive correlation between endothelial D2R expression and tumor stage. Lung cancer patients with a smoking history exhibited greater levels of D2R in lung endothelium. Our results suggest D2R agonists may represent a promising individualized therapy for lung cancer patients with high levels of endothelial D2R expression and a smoking history. PMID:25226814

  1. Dopamine D2 Receptor Agonists Inhibit Lung Cancer Progression by Reducing Angiogenesis and Tumor Infiltrating Myeloid Derived Suppressor Cells

    PubMed Central

    Hoeppner, Luke H.; Wang, Ying; Sharma, Anil; Javeed, Naureen; Van Keulen, Virginia P.; Wang, Enfeng; Yang, Ping; Roden, Anja C.; Peikert, Tobias; Molina, Julian R.; Mukhopadhyay, Debabrata

    2014-01-01

    We sought to determine whether Dopamine D2 Receptor (D2R) agonists inhibit lung tumor progression and identify subpopulations of lung cancer patients that benefit most from D2R agonist therapy. We demonstrate D2R agonists abrogate lung tumor progression in syngeneic (LLC1) and human xenograft (A549) orthotopic murine models through inhibition of tumor angiogenesis and reduction of tumor infiltrating myeloid derived suppressor cells. Pathological examination of human lung cancer tissue revealed a positive correlation between endothelial D2R expression and tumor stage. Lung cancer patients with a smoking history exhibited greater levels of D2R in lung endothelium. Our results suggest D2R agonists may represent a promising individualized therapy for lung cancer patients with high levels of endothelial D2R expression and a smoking history. PMID:25226814

  2. Surgical treatment of aggressive vertebral hemangiomas.

    PubMed

    Vasudeva, Viren S; Chi, John H; Groff, Michael W

    2016-08-01

    OBJECTIVE Vertebral hemangiomas are common tumors that are benign and generally asymptomatic. Occasionally these lesions can exhibit aggressive features such as bony expansion and erosion into the epidural space resulting in neurological symptoms. Surgery is often recommended in these cases, especially if symptoms are severe or rapidly progressive. Some surgeons perform decompression alone, others perform gross-total resection, while others perform en bloc resection. Radiation, embolization, vertebroplasty, and ethanol injection have also been used in combination with surgery. Despite the variety of available treatment options, the optimal management strategy is unclear because aggressive vertebral hemangiomas are uncommon lesions, making it difficult to perform large trials. For this reason, the authors chose instead to report their institutional experience along with a comprehensive review of the literature. METHODS A departmental database was searched for patients with a pathological diagnosis of "hemangioma" between 2008 and 2015. Medical records were reviewed to identify patients with aggressive vertebral hemangiomas, and these cases were reviewed in detail. RESULTS Five patients were identified who underwent surgery for treatment of aggressive vertebral hemangiomas during the specified time period. There were 2 lumbar and 3 thoracic lesions. One patient underwent en bloc spondylectomy, 2 patients had piecemeal gross-total resection, and the remaining 2 had subtotal tumor resection. Intraoperative vertebroplasty was used in 3 cases to augment the anterior column or to obliterate residual tumor. Adjuvant radiation was used in 1 case where there was residual tumor as well. The patient who underwent en bloc spondylectomy experienced several postoperative complications requiring additional medical care and reoperation. At an average follow-up of 31 months (range 3-65 months), no patient had any recurrence of disease and all were clinically asymptomatic, except the

  3. Tumor-derived microvesicles in sera of patients with head and neck cancer and their role in tumor progression

    PubMed Central

    Bergmann, Christoph; Strauss, Laura; Wieckowski, Eva; Czystowska, Malgorzata; Albers, Andreas; Wang, Yun; Zeidler, Reinhard; Lang, Stephan; Whiteside, Theresa L.

    2008-01-01

    Background: Tumor-derived membranous vesicles (MV) isolated from HNSCC patients' sera induce apoptosis of activated CD8+ T cells. We tested if MV molecular profile and activity correlate with disease progression. Methods: CD8+ Jurkat cells were incubated with MAGE 3/6+, FasL+, MHC class I+ MV isolated from sera of 60 HNSCC patients and 25 normal controls (NC) by exclusion chromatography and ultracentrifugation. Z-VAD-FITC binding to Jurkat was measured and correlated with clinical data. Results: MV from patients' but not from NC sera induced Jurkat cell apoptosis. 45% T cells+MV from N1–N3 patients were apoptotic vs. 18% T cells+MV from N0 patients (p<0.008). MV from patients with active disease (AD) expressed higher FasL levels than MV from patients with no evident disease (NED) or NC (p≤0.01). Conclusion: MAGE 3/6+, FasL+ and MHCI+ MV in sera of patients induced T-cell apoptosis which correlated with disease activity and the presence of LN metastases. PMID:19073006

  4. p28 in Treating Younger Patients With Recurrent or Progressive Central Nervous System Tumors

    ClinicalTrials.gov

    2015-10-19

    Teratoid Tumor, Atypical; Choroid Plexus Neoplasms; Anaplastic Astrocytoma; Anaplastic Oligodendroglioma; Brainstem Tumors; Giant Cell Glioblastoma; Glioblastoma; Gliosarcoma; Medulloblastoma; Neuroectodermal Tumor, Primitive

  5. [Initiation, promotion, initiation experiments with radon and cigarette smoke: Lung tumors in rats]. Progress report

    SciTech Connect

    Moolgavkar, S.H.

    1994-10-01

    During the past several years, the authors have made considerable progress in modeling carcinogenesis in general, and in modeling radiation carcinogenesis, in particular. They present an overview of their progress in developing stochastic carcinogenesis models and applying them to experimental and epidemiologic data sets. Traditionally, cancer models have been used for the analysis of incidence (or prevalence) data in epidemiology and time to tumor data in experimental studies. The relevant quantities for the analysis of these data are the hazard function and the probability of tumor. The derivation of these quantities is briefly described here. More recently, the authors began to use these models for the analysis of data on intermediate lesions on the pathway to cancer. Such data are available in experimental carcinogenesis studies, in particular in initiation and promotion studies on the mouse skin and the rat liver. If however, quantitative information on intermediate lesions on the pathway to lung cancer were to be come available at some future date, the methods that they have developed for the analysis of initiation-promotion experiments could easily be applied to the analysis of these lesions. The mathematical derivations here are couched in terms of a particular two-mutation model of carcinogenesis. Extension to models postulating more than two mutations is not always straightforward.

  6. Targeting pancreatitis blocks tumor-initiating stem cells and pancreatic cancer progression.

    PubMed

    Mohammed, Altaf; Janakiram, Naveena B; Madka, Venkateshwar; Brewer, Misty; Ritchie, Rebekah L; Lightfoot, Stan; Kumar, Gaurav; Sadeghi, Michael; Patlolla, Jagan Mohan R; Yamada, Hiroshi Y; Cruz-Monserrate, Zobeida; May, Randal; Houchen, Courtney W; Steele, Vernon E; Rao, Chinthalapally V

    2015-06-20

    Recent development of genetically engineered mouse models (GEMs) for pancreatic cancer (PC) that recapitulates human disease progression has helped to identify new strategies to delay/inhibit PC development. We first found that expression of the pancreatic tumor-initiating/cancer stem cells (CSC) marker DclK1 occurs in early stage PC and in both early and late pancreatic intraepithelial neoplasia (PanIN) and that it increases as disease progresses in GEM and also in human PC. Genome-wide next generation sequencing of pancreatic ductal adenocarcinoma (PDAC) from GEM mice revealed significantly increased DclK1 along with inflammatory genes. Genetic ablation of cyclo-oxygenase-2 (COX-2) decreased DclK1 in GEM. Induction of inflammation/pancreatitis with cerulein in GEM mice increased DclK1, and the novel dual COX/5-lipoxygenase (5-LOX) inhibitor licofelone reduced it. Dietary licofelone significantly inhibited the incidence of PDAC and carcinoma in situ with significant inhibition of pancreatic CSCs. Licofelone suppressed pancreatic tumor COX-2 and 5-LOX activities and modulated miRNAs characteristic of CSC and inflammation in correlation with PDAC inhibition. These results offer a preclinical proof of concept to target the inflammation initiation to inhibit cancer stem cells early for improving the treatment of pancreatic cancers, with immediate clinical implications for repositioning dual COX/5-LOX inhibitors in human trials for high risk patients. PMID:25906749

  7. Regulative Effect of Nampt on Tumor Progression and Cell Viability in Human Colorectal Cancer

    PubMed Central

    Lv, Xiaoqun; Zhang, Lingyun; Zhu, Yanyan; Said, Harun M.; Shi, Jimin; Xu, Guoxiong

    2015-01-01

    Colorectal cancer (CRC) is the third most common cancer disease. Here we examined Nampt expression in patients with CRC and the effect of Nampt on cell viability in CRC cells. Nampt protein was overexpressed in colorectal adenoma as well as colorectal carcinoma. The immunoreactive staining of Nampt was negative in the adjacent normal colorectal tissue, weak in colorectal adenoma, and strong in colorectal carcinoma, which may represent tumor progression. Further evaluation of clinical data showed that Nampt expression was not correlated with the clinicopathological characteristics of CRC. Additionally, our in vitro studies demonstrated that Nampt promotes CRC cell viability, whereas the Nampt inhibitor FK866 suppressed CRC cell viability, which was in concordance with the previous studies in other cancer cells. Treatment with Nampt-siRNA reduced the Nampt protein expression resulting in the inhibition of the cell viability of HCT116 and Caco2. Thus, the involvement of Nampt in cell growth indicates that Nampt may play an important role in colorectal tumorigenesis. As a consequence, our results suggest that Nampt may be considered as a progression marker of colorectal tumor and a potentially therapeutic target for the treatment of CRC. PMID:26284136

  8. MicroRNAs and Growth Factors: An Alliance Propelling Tumor Progression

    PubMed Central

    Kedmi, Merav; Sas-Chen, Aldema; Yarden, Yosef

    2015-01-01

    Tumor progression requires cancer cell proliferation, migration, invasion, and attraction of blood and lymph vessels. These processes are tightly regulated by growth factors and their intracellular signaling pathways, which culminate in transcriptional programs. Hence, oncogenic mutations often capture growth factor signaling, and drugs able to intercept the underlying biochemical routes might retard cancer spread. Along with messenger RNAs, microRNAs play regulatory roles in growth factor signaling and in tumor progression. Because growth factors regulate abundance of certain microRNAs and the latter modulate the abundance of proteins necessary for growth factor signaling, the two classes of molecules form a dense web of interactions, which are dominated by a few recurring modules. We review specific examples of the alliance formed by growth factors and microRNAs and refer primarily to the epidermal growth factor (EGF) pathway. Clinical applications of the crosstalk between microRNAs and growth factors are described, including relevance to cancer therapy and to emergence of resistance to specific drugs. PMID:26287249

  9. Four individually druggable MET hotspots mediate HGF-driven tumor progression

    PubMed Central

    Basilico, Cristina; Hultberg, Anna; Blanchetot, Christophe; de Jonge, Natalie; Festjens, Els; Hanssens, Valérie; Osepa, Sjudry-Ilona; De Boeck, Gitte; Mira, Alessia; Cazzanti, Manuela; Morello, Virginia; Dreier, Torsten; Saunders, Michael; de Haard, Hans; Michieli, Paolo

    2014-01-01

    Activation of MET by HGF plays a key role in tumor progression. Using a recently developed llama platform that generates human-like immunoglobulins, we selected 68 different antibodies that compete with HGF for binding to MET. HGF-competing antibodies recognized 4 distinct hotspots localized in different MET domains. We identified 1 hotspot that coincides with the known HGF β chain binding site on blades 2–3 of the SEMA domain β-propeller. We determined that a second and a third hotspot lie within blade 5 of the SEMA domain and IPT domains 2–3, both of which are thought to bind to HGF α chain. Characterization of the fourth hotspot revealed a region across the PSI-IPT 1 domains not previously associated with HGF binding. Individual or combined targeting of these hotspots effectively interrupted HGF/MET signaling in multiple cell-based biochemical and biological assays. Selected antibodies directed against SEMA blades 2–3 and the PSI-IPT 1 region inhibited brain invasion and prolonged survival in a glioblastoma multiforme model, prevented metastatic disease following neoadjuvant therapy in a triple-negative mammary carcinoma model, and suppressed cancer cell dissemination to the liver in a KRAS-mutant metastatic colorectal cancer model. These results identify multiple regions of MET responsible for HGF-mediated tumor progression, unraveling the complexity of HGF-MET interaction, and provide selective molecular tools for targeting MET activity in cancer. PMID:24865428

  10. Lower expression of Nrdp1 in human glioma contributes tumor progression by reducing apoptosis.

    PubMed

    Shi, Hengliang; Du, Jin; Wang, Lei; Zheng, Bao; Gong, Hui; Wu, Yuxuan; Tang, Yuan; Gao, Yong; Yu, Rutong

    2014-10-01

    Ubiquitin ligase Nrdp1 (neuregulin receptor degradation protein 1) plays important roles in multiple physiological process because it can ubiquitinate various substrates such as ErbB3, BRUCE, MyD88, C/EBPβ, and Parkin, and so forth. In addition to the physiological function, it was also found to be involved in tumor progression. It has been shown that loss of Nrdp1 enhances breast cancer cell growth. Up to now, the role of Nrdp1 in glioma has not been elucidated. Here, we reported that Nrdp1 as well as cleaved caspase 3 was lower expressed in human glioma tissues comparing with the nontumorous. And then we found that the expression of Nrdp1 and cleaved caspase 3 was increased in the treatment of Temozolomide (TMZ), a drug for glioma chemotherapy. Further investigation indicated that transient transfection of Nrdp1 significantly promoted cell apoptosis by aggravating the degradation of BRUCE and activation of caspase 3. In addition, overexpression of Nrdp1 augmented TMZ induced apoptosis by evaluating the degradation of BRUCE and the activation of caspase 3, while silencing of Nrdp1 reduced the sensitivity to the TMZ by inhibiting the degradation of BRUCE and the activation of caspase 3 in human glioma cells. These observations show that Nrdp1 is a pro-apoptotic protein in human glioma and lower expression of Nrdp1 in human glioma may promote tumor progression by reducing apoptosis, suggesting that Nrdp1 may be an important regulator in the development of human glioma. PMID:25355637

  11. Tumor suppressor Lzap regulates cell cycle progression, doming and zebrafish epiboly

    PubMed Central

    Liu, Dan; Wang, Wen-Der; Melville, David B.; Cha, Yong I.; Yin, Zhirong; Issaeva, Natalia; Knapik, Ela W.; Yarbrough, Wendell G.

    2012-01-01

    Initial stages of embryonic development rely on rapid, synchronized cell divisions of the fertilized egg followed by a set of morphogenetic movements collectively called epiboly and gastrulation. Lzap is a putative tumor suppressor whose expression is lost in 30% of head and neck squamous cell carcinomas. Lzap activities include regulation of cell cycle progression and response to therapeutic agents. Here we explore developmental roles of the lzap gene during zebrafish morphogenesis. Lzap is highly conserved among vertebrates and is maternally deposited. Expression is initially ubiquitous during gastrulation, and later becomes more prominent in the pharyngeal arches, digestive tract and brain. Antisense morpholino-mediated depletion of Lzap resulted in delayed cell divisions and apoptosis during blastomere formation, resulting in fewer, larger cells. Cell cycle analysis suggested that Lzap loss in early embryonic cells resulted in a G2/M arrest. Furthermore, the Lzap-deficient embryos failed to initiate epiboly – the earliest morphogenetic movement in animal development – which has been shown to be dependent on cell adhesion and migration of epithelial sheets. Our results strongly implicate Lzap in regulation of cell cycle progression, adhesion and migratory activity of epithelial cell sheets during early development. These functions provide further insight into Lzap activity that may contribute not only to development, but also to tumor formation. PMID:21523853

  12. Fatty acid synthase overexpression in adult testicular germ cell tumors: potential role in the progression of non-seminomatous germ cell tumors.

    PubMed

    Miyai, Kosuke; Iwaya, Keiichi; Asano, Tomohiko; Tamai, Seiichi; Matsubara, Osamu; Tsuda, Hitoshi

    2014-02-01

    Overexpression of fatty acid synthase (FASN), which is a key enzyme responsible for the endogenous synthesis of fatty acids, and its association with multistep progression have been demonstrated in various human malignant tumors. We aimed to clarify the potential role of FASN overexpression in the development and progression of adult testicular germ cell tumors (TGCTs). From the primary sites of a cohort of 113 TGCT cases, we obtained 221 histological components: 53 intratubular germ cell neoplasias, unclassified (IGCNUs), 84 seminomas, 32 embryonal carcinomas, seven choriocarcinomas, 21 yolk sac tumors, and 24 teratomas. Samples were analyzed for overexpression of FASN by immunohistochemistry. Intensities of immunoreactivity and the fraction of positive cells were classified into each four categories (intensity, 0 to 3; fraction, 0-10 % = 1, 11-50 % = 2, 51-80 % = 3, and >80 % = 4). The overall score was determined by multiplication of both scores and overall scores greater than 6 were considered FASN overexpression. On a component basis, FASN overexpression was detected in 8 % of seminomas but not in IGCNUs (0 %) and was detected frequently in non-seminomatous germ cell tumors (NSGCTs) (88 % of embryonal carcinomas, all choriocarcinomas, 81 % of yolk sac tumors, and 54 % of teratomas). There were no cases of a mixed tumor (i.e., a tumor with multiple histological components) that overexpressed FASN in seminoma components but not in co-existing NSGCT components, suggesting sequential progression. Our immunohistochemical data suggest that FASN overexpression occurs as a late event during the progression from IGCNUs/seminomas to NSGCTs. PMID:24337182

  13. Interleukin-1-induced changes in the glioblastoma secretome suggest its role in tumor progression

    PubMed Central

    Weatherly, D. Brent; Angeletti, Ruth H.; Lee, Sunhee C.

    2014-01-01

    The tumor microenvironment including glial cells and their inflammatory products regulates brain tumor development and progression. We have previously established that human glioma cells are exquisitely sensitive to IL-1 stimulation leading us to undertake a comparative analysis of the secretome of unstimulated and cytokine (IL-1)-stimulated glioblastoma cells. We performed label-free quantitative proteomic analysis and detected 190 proteins which included cytokines, chemokines, growth factors, proteases, cell adhesion molecules, extracellular matrix (ECM) and related proteins. Measuring area under the curve (AUC) of peptides for quantitation, the IL-1-induced secretome contained 13 upregulated and 5 downregulated extracellular proteins (p<0.05) compared to controls. Of these, IL-8, CCL2, TNC, Gal-1 and PTX3 were validated as upregulated and SERPINE1, STC2, CTGF and COL4A2 were validated as downregulated factors by immunochemical methods. A major representation of the ECM and related proteins in the glioblastoma secretome and their modulation by IL-1 suggested that IL-1 induces its effect in part by altering TGFβ expression, activity and signaling. These findings enhance our understanding of IL-1-induced modulation of glioma microenvironment, with implications for increased tumor invasion, migration and angiogenesis. They further provide novel targets for the glioblastoma intervention. PMID:24503185

  14. Progress in the surgical treatment of malignant liver tumors in children.

    PubMed

    Otte, Jean-Bernard

    2010-06-01

    During the last decade, important progress has been made in the surgical treatment of malignant liver tumors in children. For hepatoblastoma, there is a general consensus for combining surgical resection with neoadjuvant (and adjuvant) chemotherapy. Long-term disease-free survival of around 85-90% can be achieved for resectable HB involving no more than three sections of the liver (PRETEXT I-III). For unresectable HB without extrahepatic invasion (PRETEXT IV with involvement of all four sections and some cases of PRETEXT III with invasion of, or close contact with major venous structures), similar results can be obtained with total hepatectomy and liver transplantation. For hepatocellular carcinoma, most often without underlying liver disease in children of the western world, results of resection with partial hepatectomy remain dismal, due to a high rate of recurrence. In contrast, remarkable survival rates have been obtained during the last decade with liver transplantation. There is no argument, either biological or based on evidence, that the selection of pediatric candidates for transplantation should be based on the same criteria as in adult patients (the Milan criteria). Optimization of results require to concentrate children with a malignant liver tumors in specialized, multidisciplinary pediatric centers with expertise in chemotherapy and in both major liver resections and transplantation. Enrolling these children in prospective trials should be encouraged, as well as prospective registration of transplanted patients in PLUTO (Pediatric Liver Unresectable Tumor Observatory-http://Pluto.cineca.org) in order to clarify issues unresolved by retrospective studies. PMID:20227190

  15. Postmenopausal obesity promotes tumor angiogenesis and breast cancer progression in mice.

    PubMed

    Gu, Jian-Wei; Young, Emily; Patterson, Sharla G; Makey, Kristina L; Wells, Jeremy; Huang, Min; Tucker, Kevan B; Miele, Lucio

    2011-05-15

    Obese postmenopausal women have a 50% higher risk of breast cancer than non-obese women. There is not an animal model that mimics postmenopausal obesity related to breast cancer progression. Using age-relevant C57BL/6 mice, this study determined whether postmenopausal obesity increases VEGF expression, tumor angiogenesis, and breast tumor growth. Ovariectomy (OVX) was performed in 12 sixty week-old female mice, then followed by a low-fat (5%, LF, n=6) or a high-fat (60%, HF, n=6) diet for 12 weeks. In the eighth week of the dietary program, 10(6) E0771 (mouse breast cancer) cells were injected in the left fourth mammary gland. Tumor size was monitored for 4 weeks. Body weights were monitored weekly. At the end of the experiment, blood samples, visceral fat and tumors were collected for measuring VEGF expression using ELISA and intratumoral microvessel density (IMD) using CD31 immunochemistry. Body weight was significantly increased in OVX/HF mice, compared to OVX/LF group (55.3±1.7 vs. 41.5±1.5 g; p < 0.01). There was a two-fold increase in the ratio of visceral fat/BW in OVX/HF mice, compared to those in OVX/LF group (0.062±0.005 vs. 0.032±0.003; p < 0.01). Postmenopausal obesity significantly increased breast tumor weight over the control (4.62±0.63 vs. 1.98±0.27 g; p < 0.01) and IMD (173±3.7 vs. 139±4.3 IM#/mm^2; p < 0.01). Tumor VEGF levels were higher in OVX/HF mice, compared to OVX/LF group (73.3±3.8 vs. 49.5±4.3 pg/mg protein; p < 0.01). Plasma VEGF levels (69±7.1 vs. 48±3.5 pg/ml) and visceral fat VEGF levels (424.4±39.5 vs. 208.5±22.4 pg/mg protein) were significantly increased in OVX/HF mice, compared to OVX/LF group, respectively (n=6; p < 0.01). Interestingly, adipose tissue primary culture showed that subcutaneous fat released more VEGF, compared to visceral fat (6.77±1.14 vs. 0.94±0.16 pg/mg tissue; n=6; p < 0.01). These findings support the hypothesis that postmenopausal obesity promotes tumor angiogenesis and breast cancer

  16. Postmenopausal obesity promotes tumor angiogenesis and breast cancer progression in mice

    PubMed Central

    Young, Emily; Patterson, Sharla G; Makey, Kristina L; Wells, Jeremy; Huang, Min; Tucker, Kevan B; Miele, Lucio

    2011-01-01

    Obese postmenopausal women have a 50% higher risk of breast cancer than non-obese women. There is not an animal model that mimics postmenopausal obesity related to breast cancer progression. Using age-relevant C57BL/6 mice, this study determined whether postmenopausal obesity increases VEGF expression, tumor angiogenesis and breast tumor growth. Ovariectomy (OVX) was performed in 12 sixty week-old female mice, then followed by a low-fat (5%, LF, n = 6) or a high-fat (60%, HF, n = 6) diet for 12 weeks. In the eighth week of the dietary program, 106 E0771 (mouse breast cancer) cells were injected in the left fourth mammary gland. Tumor size was monitored for 4 weeks. Body weights were monitored weekly. At the end of the experiment, blood samples, visceral fat and tumors were collected for measuring VEGF expression using ELISA and intratumoral microvessel density (IMD) using CD31 immunochemistry. Body weight was significantly increased in OVX/HF mice, compared to OVX/LF group (55.3 ± 1.7 vs. 41.5 ± 1.5 g; p < 0.01). There was a two-fold increase in the ratio of visceral fat/BW in OVX/HF mice, compared to those in OVX/LF group (0.062 ± 0.005 vs. 0.032 ± 0.003; p < 0.01). Postmenopausal obesity significantly increased breast tumor weight over the control (4.62 ± 0.63 vs. 1.98 ± 0.27 g; p < 0.01) and IMD (173 ± 3.7 vs. 139 ± 4.3 IM#/mm2; p < 0.01). Tumor VEGF levels were higher in OVX/HF mice, compared to OVX/LF group (73.3 ± 3.8 vs. 49.5 ± 4.3 pg/mg protein; p < 0.01). Plasma VEGF levels (69 ± 7.1 vs. 48 ± 3.5 pg/ml) and visceral fat VEGF levels (424.4 ± 39.5 vs. 208.5 ± 22.4 pg/mg protein) were significantly increased in OVX/HF mice, compared to OVX/LF group, respectively (n = 6; p < 0.01). Interestingly, adipose tissue primary culture showed that subcutaneous fat released more VEGF, compared to visceral fat (6.77 ± 1.14 vs. 0.94 ± 0.16 pg/mg tissue; n = 6; p < 0.01). These findings support the hypothesis that postmenopausal obesity promotes tumor

  17. Pazopanib in metastatic multiply treated progressive gastrointestinal stromal tumors: feasible and efficacious

    PubMed Central

    Ramaswamy, Anant; Pande, Nikhil; Shetty, Omshree; Shetty, Nitin; Gupta, Sudeep

    2016-01-01

    Background A median progression free survival (PFS) of 18–20 months and median overall survival (OS) of 51–57 months can be achieved with the use of imatinib, in metastatic or advanced gastrointestinal stromal tumor (GIST). Sunitinib and regorafenib are approved options for patients progressing on imatinib, but with markedly decreased survival. pazopanib is a broad spectrum TKI targeting KIT, PDGFR and VEGFR receptors and has shown promising activity in phase 2 trials in GIST. Methods All patients who received pazopanib for GIST between March 2014 and September 2015 in our institution were reviewed. Patients were assessed for response with CT or PET CT scans. Patients continued pazopanib until progression or unacceptable toxicity. Survival was evaluated by Kaplan Meier product method. Results A total of 11 consecutive patients were included in our study. Median duration of follow up was seven months. The median lines of prior therapy was 2 [1-5]. Partial response (PR) was observed in seven patients and two had stable disease (SD). Two patients died within one month of start of pazopanib. Five of ten patients had progressed during the study with eight patients still alive. The median PFS was 11.9 months and the median OS was not reached. Common adverse events seen were hand-foot-syndrome (HFS) in four patients, anemia in four patients and fatigue in three patients. Grade 3/4 adverse events were uncommon. Three patients required dose modification of pazopanib. Conclusions Pazopanib is a reasonably efficacious well tolerated TKI and can be explored as a treatment option in advanced GIST that has progressed on imatinib. PMID:27563456

  18. Chemopreventive Efficacy of Inositol Hexaphosphate against Prostate Tumor Growth and Progression in TRAMP Mice

    PubMed Central

    Raina, Komal; Rajamanickam, Subapriya; Singh, Rana P.; Agarwal, Rajesh

    2010-01-01

    Purpose Herein, for the first time, we evaluated in vivo chemopreventive efficacy of inositol hexaphosphate (IP6), a major constituent of high fiber containing diets, against prostate tumor growth and progression in transgenic adenocarcinoma of the mouse prostate (TRAMP) model. Experimental Design Beginning 4 weeks of age, male TRAMP mice were fed with 2% (w/v) IP6 in drinking water or only drinking water till 24 weeks of age, and then sacrificed. Prostate tissue was subjected to histopathology, and immunohistochemical analyses for proliferation and apoptosis. Results IP6 feeding did not show any adverse effect on fluid and diet consumption, and body weight. There was a significant reduction (40%, P<0.01) in the weight of lower urogenital tract organs in the IP6-fed mice. IP6 inhibited prostate cancer (PCa) progression at prostatic intraepithelial neoplasia (PIN) stage and strongly reduced the incidence of adenocarcinoma (PIN:adenocarcinoma, 75:25% mice in IP6 group versus 39:61% in control group, P<0.05). The incidences of well differentiated and poorly differentiated adenocarcinomas in IP6-fed group were reduced by 44% and 62%, respectively. Immunohistochemical analysis of prostate tissue showed 26% (P<0.05) decrease in proliferation cell nuclear antigen (PCNA)-positive cells, and 3.5-fold increase in apoptotic cells with no effect on Tag expression by IP6. Conclusions These findings are both novel and highly significant in establishing for the first time that oral IP6 feeding, without any toxicity, suppresses prostate tumor growth and progression at the neoplastic stage thereby reducing the incidence of adenocarcinoma involving anti-proliferative and pro-apoptotic effects, and thus could have potential against human PCa. PMID:18483386

  19. Breast cancer associated a2 isoform vacuolar ATPase immunomodulates neutrophils: potential role in tumor progression.

    PubMed

    Ibrahim, Safaa A; Katara, Gajendra K; Kulshrestha, Arpita; Jaiswal, Mukesh K; Amin, Magdy A; Beaman, Kenneth D

    2015-10-20

    In invasive breast cancer, tumor associated neutrophils (TAN) represent a significant portion of the tumor mass and are associated with increased angiogenesis and metastasis. Identifying the regulatory factors that control TAN behavior will help in developing ideal immunotherapies. Vacuolar ATPases (V-ATPases), multi-subunit proton pumps, are highly expressed in metastatic breast cancer cells. A cleaved peptide from a2 isoform V-ATPase (a2NTD) has immunomodulatory role in tumor microenvironment. Here, we report for the first time the role of V-ATPase in neutrophils modulation. In invasive breast cancer cells, a2NTD was detected and a2V was highly expressed on the surface. Immunohistochemical analysis of invasive breast cancer tissues revealed that increased neutrophil recruitment and blood vessel density correlated with increased a2NTD levels. In order to determine the direct regulatory role of a2NTD on neutrophils, recombinant a2NTD was used for the treatment of neutrophils isolated from the peripheral blood of healthy volunteers. Neutrophils treated with a2NTD (a2Neuɸ) showed increased secretion of IL-1RA, IL-10, CCL-2 and IL-6 that are important mediators in cancer related inflammation. Moreover, a2Neuɸ exhibited an increased production of protumorigenic factors including IL-8, matrix metaloprotinase-9 and vascular endothelial growth factor. Further, functional characterization of a2Neuɸ revealed that a2Neuɸ derived products induce in vitro angiogenesis as well as increase the invasiveness of breast cancer cells. This study establishes the modulatory effect of breast cancer associated a2V on neutrophils, by the action of a2NTD, which has a positive impact on tumor progression, supporting that a2V can be a potential selective target for breast cancer therapy. PMID:26460736

  20. Breast cancer associated a2 isoform vacuolar ATPase immunomodulates neutrophils: potential role in tumor progression

    PubMed Central

    Ibrahim, Safaa A.; Katara, Gajendra K.; Kulshrestha, Arpita; Jaiswal, Mukesh K.; Amin, Magdy A.; Beaman, Kenneth D.

    2015-01-01

    In invasive breast cancer, tumor associated neutrophils (TAN) represent a significant portion of the tumor mass and are associated with increased angiogenesis and metastasis. Identifying the regulatory factors that control TAN behavior will help in developing ideal immunotherapies. Vacuolar ATPases (V-ATPases), multi-subunit proton pumps, are highly expressed in metastatic breast cancer cells. A cleaved peptide from a2 isoform V-ATPase (a2NTD) has immunomodulatory role in tumor microenvironment. Here, we report for the first time the role of V-ATPase in neutrophils modulation. In invasive breast cancer cells, a2NTD was detected and a2V was highly expressed on the surface. Immunohistochemical analysis of invasive breast cancer tissues revealed that increased neutrophil recruitment and blood vessel density correlated with increased a2NTD levels. In order to determine the direct regulatory role of a2NTD on neutrophils, recombinant a2NTD was used for the treatment of neutrophils isolated from the peripheral blood of healthy volunteers. Neutrophils treated with a2NTD (a2Neuɸ) showed increased secretion of IL-1RA, IL-10, CCL-2 and IL-6 that are important mediators in cancer related inflammation. Moreover, a2Neuɸ exhibited an increased production of protumorigenic factors including IL-8, matrix metaloprotinase-9 and vascular endothelial growth factor. Further, functional characterization of a2Neuɸ revealed that a2Neuɸ derived products induce in vitro angiogenesis as well as increase the invasiveness of breast cancer cells. This study establishes the modulatory effect of breast cancer associated a2V on neutrophils, by the action of a2NTD, which has a positive impact on tumor progression, supporting that a2V can be a potential selective target for breast cancer therapy. PMID:26460736

  1. Circulating tumor cells are correlated with disease progression and treatment response in an orthotopic hepatocellular carcinoma model.

    PubMed

    Yan, Jun; Fan, Zhichao; Wu, Xiufeng; Xu, Min; Jiang, Jiahao; Tan, Changjun; Wu, Weizhong; Wei, Xunbin; Zhou, Jian

    2015-11-01

    Hepatocellular carcinoma (HCC) is a highly malignant tumor characterized by rapid progression, poor prognosis, and frequent hematogenous metastasis. A minimally invasive diagnostic biomarker that can predict disease progression and treatment response would be of extraordinary benefit. Therefore, we have investigated whether the number of circulating tumor cells (CTCs) is correlated with disease progression and treatment response in HCC. Here we report that the number of CTCs, monitored by in vivo flow cytometry (IVFC), is strongly correlated with disease progression and treatment response in a highly metastatic orthotopic nude mouse model of green fluorescent protein (GFP)-labeled HCC. Sorafenib treatment reduces the number of CTCs significantly. The decreased number of CTCs is consistent with low lung metastasis. This study has demonstrated a considerable clinical value of CTCs as a biomarker in predicting disease progression and monitoring therapeutic efficacy in patients with HCC. PMID:26355643

  2. High Milk Consumption Does Not Affect Prostate Tumor Progression in Two Mouse Models of Benign and Neoplastic Lesions

    PubMed Central

    Boutillon, Florence; Verkarre, Virginie; Camparo, Philippe; Viltard, Mélanie; Méjean, Arnaud; Oudard, Stéphane; Souberbielle, Jean-Claude; Friedlander, Gérard; Goffin, Vincent

    2015-01-01

    Epidemiological studies that have investigated whether dairy (mainly milk) diets are associated with prostate cancer risk have led to controversial conclusions. In addition, no existing study clearly evaluated the effects of dairy/milk diets on prostate tumor progression, which is clinically highly relevant in view of the millions of men presenting with prostate pathologies worldwide, including benign prostate hyperplasia (BPH) or high-grade prostatic intraepithelial neoplasia (HGPIN). We report here a unique interventional animal study to address this issue. We used two mouse models of fully penetrant genetically-induced prostate tumorigenesis that were investigated at the stages of benign hyperplasia (probasin-Prl mice, Pb-Prl) or pre-cancerous PIN lesions (KIMAP mice). Mice were fed high milk diets (skim or whole) for 15 to 27 weeks of time depending on the kinetics of prostate tumor development in each model. Prostate tumor progression was assessed by tissue histopathology examination, epithelial proliferation, stromal inflammation and fibrosis, tumor invasiveness potency and expression of various tumor markers relevant for each model (c-Fes, Gprc6a, activated Stat5 and p63). Our results show that high milk consumption (either skim or whole) did not promote progression of existing prostate tumors when assessed at early stages of tumorigenesis (hyperplasia and neoplasia). For some parameters, and depending on milk type, milk regimen could even exhibit slight protective effects towards prostate tumor progression by decreasing the expression of tumor-related markers like Ki-67 and Gprc6a. In conclusion, our study suggests that regular milk consumption should not be considered detrimental for patients presenting with early-stage prostate tumors. PMID:25938513

  3. A comparative study of two prediction models for brain tumor progression

    NASA Astrophysics Data System (ADS)

    Zhou, Deqi; Tran, Loc; Wang, Jihong; Li, Jiang

    2015-03-01

    MR diffusion tensor imaging (DTI) technique together with traditional T1 or T2 weighted MRI scans supplies rich information sources for brain cancer diagnoses. These images form large-scale, high-dimensional data sets. Due to the fact that significant correlations exist among these images, we assume low-dimensional geometry data structures (manifolds) are embedded in the high-dimensional space. Those manifolds might be hidden from radiologists because it is challenging for human experts to interpret high-dimensional data. Identification of the manifold is a critical step for successfully analyzing multimodal MR images. We have developed various manifold learning algorithms (Tran et al. 2011; Tran et al. 2013) for medical image analysis. This paper presents a comparative study of an incremental manifold learning scheme (Tran. et al. 2013) versus the deep learning model (Hinton et al. 2006) in the application of brain tumor progression prediction. The incremental manifold learning is a variant of manifold learning algorithm to handle large-scale datasets in which a representative subset of original data is sampled first to construct a manifold skeleton and remaining data points are then inserted into the skeleton by following their local geometry. The incremental manifold learning algorithm aims at mitigating the computational burden associated with traditional manifold learning methods for large-scale datasets. Deep learning is a recently developed multilayer perceptron model that has achieved start-of-the-art performances in many applications. A recent technique named "Dropout" can further boost the deep model by preventing weight coadaptation to avoid over-fitting (Hinton et al. 2012). We applied the two models on multiple MRI scans from four brain tumor patients to predict tumor progression and compared the performances of the two models in terms of average prediction accuracy, sensitivity, specificity and precision. The quantitative performance metrics were

  4. IRF1 and NF-kB Restore MHC Class I-Restricted Tumor Antigen Processing and Presentation to Cytotoxic T Cells in Aggressive Neuroblastoma

    PubMed Central

    Cifaldi, Loredana; Antonucci, Chiara; Citti, Arianna; Boldrini, Renata; Pezzullo, Marco; Castellano, Aurora; Russo, Vincenzo; van der Bruggen, Pierre; Giacomini, Patrizio; Locatelli, Franco; Fruci, Doriana

    2012-01-01

    Neuroblastoma (NB), the most common solid extracranial cancer of childhood, displays a remarkable low expression of Major Histocompatibility Complex class I (MHC-I) and Antigen Processing Machinery (APM) molecules, including Endoplasmic Reticulum (ER) Aminopeptidases, and poorly presents tumor antigens to Cytotoxic T Lymphocytes (CTL). We have previously shown that this is due to low expression of the transcription factor NF-kB p65. Herein, we show that not only NF-kB p65, but also the Interferon Regulatory Factor 1 (IRF1) and certain APM components are low in a subset of NB cell lines with aggressive features. Whereas single transfection with either IRF1, or NF-kB p65 is ineffective, co-transfection results in strong synergy and substantial reversion of the MHC-I/APM-low phenotype in all NB cell lines tested. Accordingly, linked immunohistochemistry expression patterns between nuclear IRF1 and p65 on the one hand, and MHC-I on the other hand, were observed in vivo. Absence and presence of the three molecules neatly segregated between high-grade and low-grade NB, respectively. Finally, APM reconstitution by double IRF1/p65 transfection rendered a NB cell line susceptible to killing by anti MAGE-A3 CTLs, lytic efficiency comparable to those seen upon IFN-γ treatment. This is the first demonstration that a complex immune escape phenotype can be rescued by reconstitution of a limited number of master regulatory genes. These findings provide molecular insight into defective MHC-I expression in NB cells and provide the rational for T cell-based immunotherapy in NB variants refractory to conventional therapy. PMID:23071666

  5. Tumor necrosis factor-α G-308A (rs1800629) polymorphism and aggressive periodontitis susceptibility: a meta-analysis of 16 case-control studies

    PubMed Central

    Wei, Xue-Mei; Chen, Yong-Ji; Wu, Lan; Cui, Li-Jun; Hu, Ding-Wei; Zeng, Xian-Tao

    2016-01-01

    Association between tumor necrosis factor-α (TNF-α) G-308A (rs1800629) polymorphism and susceptibility to aggressive periodontitis (AgP) were inconsistent, hence we performed this meta-analysis to clarify the association between them using Comprehensive Meta-Analysis v2.2 software. 16 case-control studies were searched from the PubMed, Embase and CNKI databases up to February 2, 2015. The meta-analysis showed a significantly increased risk in A vs. G (OR = 1.23, 95%CI = 1.04–1.44), AA vs. GG (OR = 2.07, 95%CI = 1.11–3.87), and AA vs. AG+GG genetic models (OR = 2.09, 95%CI = 1.13–3.86); however, the non-significantly increased risk was shown in AG vs. GG (OR = 1.06, 95%CI = 0.85–1.32) and AA+AG vs. GG genetic models (OR = 1.06, 95%CI = 0.85–1.31). Cumulative analysis showed that the association changed from non-significant to significant with new studies accumulated and the CIs became more and more narrow, sensitivity analysis indicated results were statistically robust. Stratified analyses of confirmed of HWE, Asians, Caucasians, and population-based controls obtained results similar to that of overall analysis. There was no evidence of publication bias. In summary, current evidence demonstrates that TNF-a G-308A polymorphism might be associated with AgP susceptibility, especially in Asians and Caucasians. PMID:26750615

  6. Dysregulation of JAM-A plays an important role in human tumor progression

    PubMed Central

    Zhao, Chen; Lu, Funian; Chen, Hongxia; Zhao, Xianda; Sun, Jun; Chen, Honglei

    2014-01-01

    Junctional adhesion molecule A (JAM-A) is a transmembrane protein that belongs to the immunoglobulin (Ig) superfamily. Evidence determines that JAM-A plays a role in numerous cellular processes, including tight junction assembly, leukocyte migration, platelet activation, angiogenesis and virus binding. Recent research suggests that JAM-A is dysregulated in various cancers and is vital for tumor progression. JAM-A is implicated in carcinogenesis via different signal pathways such as TGF-β1 signaling. Furthermore, JAM-A expression in cancers is usually associated with certain outcome of patients and might be a prognostic indicator. In this review, the correlation between JAM-A expression and human cancers will be described. PMID:25400822

  7. FGF19 Contributes to Tumor Progression in Gastric Cancer by Promoting Migration and Invasion.

    PubMed

    Wang, Shuang; Zhao, Daqi; Tian, Ruihua; Shi, Hailong; Chen, Xiangming; Liu, Wenzhi; Wei, Lin

    2016-01-01

    Gastric cancer is the fourth most common type of cancer and second leading cause of cancer-related death in the world. Since patients are often diagnosed at a late stage, very few effective therapies are left in the arsenal. FGF19, as a hormone, has been reported to promote tumor growth in various types of cancer; however, its function in gastric cancer remains unknown. In the current study, we showed that FGF19 is overexpressed in gastric cancer and is associated with depth of invasion, lymph node metastasis, and TNM stage. In addition, in vitro experiments demonstrated that FGF19 is able to enhance migration and invasion abilities of gastric cancer cells. Given its great potency in gastric cancer progression, FGF19 may be an effective target of treatment for advanced gastric cancer patients. PMID:27053348

  8. Progress with anti-tumor necrosis factor therapeutics for the treatment of inflammatory bowel disease.

    PubMed

    Fernandes, Carlos; Allocca, Mariangela; Danese, Silvio; Fiorino, Gionata

    2015-01-01

    Anti-tumor necrosis factor (TNF) therapy is a valid, effective and increasingly used option in inflammatory bowel disease management. Nevertheless, further knowledge and therapeutic indications regarding these drugs are still evolving. Anti-TNF therapy may be essential to achieve recently proposed end points, namely mucosal healing, prevention of bowel damage and prevention of patient's disability. Anti-TNF drugs are also suggested to be more effective in early disease, particularly in early Crohn's disease. Moreover, its efficacy for prevention of postoperative recurrence in Crohn's disease is still debated. Costs and adverse effects, the relevance of drug monitoring and the possibility of anti-TNF therapy withdrawal in selected patients are still debated issues. This review aimed to describe and discuss the most relevant data about the progress with anti-TNF therapy for the management of inflammatory bowel disease. PMID:25713992

  9. Glucocorticoid Receptor-Targeted Liposomal Codelivery of Lipophilic Drug and Anti-Hsp90 Gene: Strategy to Induce Drug-Sensitivity, EMT-Reversal, and Reduced Malignancy in Aggressive Tumors.

    PubMed

    Mondal, Sujan Kumar; Jinka, Sudhakar; Pal, Krishnendu; Nelli, Swetha; Dutta, Shamit Kumar; Wang, Enfeng; Ahmad, Ajaz; AlKharfy, Khalid M; Mukhopadhyay, Debabrata; Banerjee, Rajkumar

    2016-07-01

    Many cancers including the late stage ones become drug-resistant and undergo epithelial-to-mesenchymal transition (EMT). These lead to enhanced invasion, migration, and metastasis toward manifesting its aggressiveness and malignancy. One of the key hallmarks of cancer is its overdependence on glycolysis as its preferred energy metabolism pathway. The strict avoidance of alternate energy pathway gluconeogenesis by cancer cells points to a yet-to-be hoisted role of glucocorticoid receptor (GR) especially in tumor microenvironment, where cells are known to become drug-sensitive through induction of gluconeogenesis. However, since GR is involved in metabolism, anti-inflammatory reactions, immunity besides inducing gluconeogenesis, a greater role of GR in tumor microenvironment is envisaged. We have shown previously that GR, although ubiquitously expressed in all cells; afford to be an effective cytoplasmic target for killing cancer cells selectively. Herein, we report the therapeutic use of a newly developed GR-targeted liposomal concoction (DXE) coformulating a lipophilic drug (ESC8) and an anti-Hsp90 anticancer gene against aggressive tumor models. This induced drug-sensitivity and apoptosis while reversing EMT in tumor cells toward effective retardation of aggressive growth in pancreas and skin tumor models. Additionally, the ESC8-free lipid formulation upon cotreatment with hydrophilic drugs, gemcitabine and doxorubicin, could effectively sensitize and kill pancreatic cancer and melanoma cells, respectively. The formulation-triggered EMT-reversal was GR-dependent. Overall, we found a new strategy for drug sensitization that led to the advent of new GR-targeted anticancer therapeutics. PMID:27184196

  10. Targeted tumor delivery and controlled release of neuronal drugs with ferritin nanoparticles to regulate pancreatic cancer progression.

    PubMed

    Lei, Yifeng; Hamada, Yoh; Li, Jun; Cong, Liman; Wang, Nuoxin; Li, Ying; Zheng, Wenfu; Jiang, Xingyu

    2016-06-28

    Pancreatic cancer is a lethal malignancy whose progression is highly dependent on the nervous microenvironment. This study develops neural drug-loaded ferritin nanoparticles (Ft NPs) to regulate the nervous microenvironment, in order to control the pancreatic cancer progression. The drug-loaded Ft NPs can target pancreatic tumors via passive targeting of EPR effects of tumors and active targeting via transferrin receptor 1 (TfR1) binding on cancer cells, with a triggered drug release in acidic tumor environment. Two drugs, one activates neural activity (carbachol), the other impairs neural activity (atropine), are encapsulated into the Ft NPs to form two kinds of nano drugs, Nano-Cab NPs and Nano-Ato NPs, respectively. The activation of the nervous microenvironment by Nano-Cab NPs significantly promotes the pancreatic tumor progression, whereas the blockage of neural niche by Nano-Ato NPs remarkably impairs the neurogenesis in tumors and the progression of pancreatic cancer. The Ft-based nanoparticles thus comprise an effective and safe route of delivery of neural drugs for novel anti-cancer therapy. PMID:27046157

  11. Creatine supplementation prevents hyperhomocysteinemia, oxidative stress and cancer-induced cachexia progression in Walker-256 tumor-bearing rats.

    PubMed

    Deminice, Rafael; Cella, Paola Sanches; Padilha, Camila S; Borges, Fernando H; da Silva, Lilian Eslaine Costa Mendes; Campos-Ferraz, Patrícia L; Jordao, Alceu Afonso; Robinson, Jason Lorne; Bertolo, Robert F; Cecchini, Rubens; Guarnier, Flávia Alessandra

    2016-08-01

    The purpose of this study was to investigate (1) the impact of tumor growth on homocysteine (Hcy) metabolism, liver oxidative stress and cancer cachexia and, (2) the potential benefits of creatine supplementation in Walker-256 tumor-bearing rats. Three experiments were conducted. First, rats were killed on days 5 (D5), 10 (D10) and 14 (D14) after tumor implantation. In experiment 2, rats were randomly assigned to three groups designated as control (C), tumor-bearing (T) and tumor-bearing supplemented with creatine (TCr). A life span experiment was conducted as the third experiment. Creatine was supplied in drinking water for 21 days (8 g/L) in all cases. Tumor implantation consisted of a suspension of Walker-256 cells (8.0 × 10(7) cells in 0.5 mL of PBS). The progressive increase (P < 0.05) in tumor mass coincided with a progressively lower body weight and higher hepatic oxidative stress; plasma Hcy concentration was 80 % higher (P < 0.05) by 10 days of tumor implantation. Impaired Hcy metabolism was evidenced by decreased hepatic betaine-homocysteine methyltransferase (Bhmt), glycine N-methyltransferase (Gnmt) and cystathionine beta synthase (CBS) gene expression. In contrast, creatine supplementation promoted a 28 % reduction of tumor weight (P < 0.05). Plasma Hcy (C 6.1 ± 0.6, T 10.3 ± 1.5, TCr 6.3 ± 0.9, µmol/L) and hepatic oxidative stress were lower in the TCr group compared to T. Creatine supplementation was unable to decrease Hcy concentration and to increase SAM/SAH ratio in tumor tissue. These data suggest that creatine effects on hepatic impaired Hcy metabolism promoted by tumor cell inoculation are responsible to decrease plasma Hcy in tumor-bearing rats. In conclusion, Walker-256 tumor growth is associated with progressive hyperhomocysteinemia, body weight loss and liver oxidative stress in rats. Creatine supplementation, however, prevented these tumor-associated perturbations. PMID:26781304

  12. YB-1 regulates stress granule formation and tumor progression by translationally activating G3BP1

    PubMed Central

    Somasekharan, Syam Prakash; El-Naggar, Amal; Leprivier, Gabriel; Cheng, Hongwei; Hajee, Shamil; Grunewald, Thomas G.P.; Zhang, Fan; Ng, Tony; Delattre, Olivier; Evdokimova, Valentina; Wang, Yuzhuo; Gleave, Martin

    2015-01-01

    Under cell stress, global protein synthesis is inhibited to preserve energy. One mechanism is to sequester and silence mRNAs in ribonucleoprotein complexes known as stress granules (SGs), which contain translationally silent mRNAs, preinitiation factors, and RNA-binding proteins. Y-box binding protein 1 (YB-1) localizes to SGs, but its role in SG biology is unknown. We now report that YB-1 directly binds to and translationally activates the 5′ untranslated region (UTR) of G3BP1 mRNAs, thereby controlling the availability of the G3BP1 SG nucleator for SG assembly. YB-1 inactivation in human sarcoma cells dramatically reduces G3BP1 and SG formation in vitro. YB-1 and G3BP1 expression are highly correlated in human sarcomas, and elevated G3BP1 expression correlates with poor survival. Finally, G3BP1 down-regulation in sarcoma xenografts prevents in vivo SG formation and tumor invasion, and completely blocks lung metastasis in mouse models. Together, these findings demonstrate a critical role for YB-1 in SG formation through translational activation of G3BP1, and highlight novel functions for SGs in tumor progression. PMID:25800057

  13. Expression of Neuropilin-2 in salivary adenoid cystic carcinoma: its implication in tumor progression and angiogenesis.

    PubMed

    Cai, Yu; Wang, Rong; Zhao, Yi-Fang; Jia, Jun; Sun, Zhi-Jun; Chen, Xin-Ming

    2010-12-15

    Neuropilin-2(Nrp2), which is a nontyrosine kinase transmembrane glycoprotein, can promote angiogenesis and is a poor prognostic factor in some human cancers. In the present study, to explore the expression and potential function of Nrp2 in salivary adenoid cystic carcinoma (SACC), immunohistochemistry was used to examine the Nrp2 expression in 50 SACCs and 20 normal salivary gland tissues nearby SACCs. The result showed that immunoreactivity for Nrp2 was detected in 47 of 50 SACCs, and its expression level had significant correlations with microvessel density, tumor size, TMN clinical stage, vascular invasion, and metastasis (P<0.05) of SACCs. In addition, inhibition of Nrp2 function by the receptor-ligand interaction-blocking antibody decreased cell migration, invasion, and angiogenic promotion without influences on the cell proliferation of Acc-3 cells. Taken together, the expression of Nrp2 protein is significantly correlated with tumor progression and angiogenesis in SACCs. These results suggest that Nrp2 may be a potential therapeutic target for SACCs. PMID:20851535

  14. Heme oxygenase-1 promotes tumor progression and metastasis of colorectal carcinoma cells by inhibiting antitumor immunity

    PubMed Central

    Seo, Geom Seog; Jiang, Wen-Yi; Chi, Jin Hua; Jin, Hao; Park, Won-Chul; Sohn, Dong Hwan; Park, Pil-Hoon; Lee, Sung Hee

    2015-01-01

    Heme oxygenase-1 (HO-1) is upregulated in colorectal carcinoma (CRC) cells. However, the role of HO-1 in the metastatic potential of CRC remains to be elucidated. In this study, we investigated the potential of HO-1 to control the antitumor immunity of CRC. Intercellular adhesion molecule-1 (ICAM-1) plays an important role in the immune surveillance system. Hemin-induced HO-1 expression suppressed the expression of ICAM-1 in human CRC cells. HO-1 regulated ICAM-1 expression via tristetraprolin, an mRNA-binding protein, at the posttranscriptional level in CRC cells. The upregulated HO-1 expression in CRC cells markedly decreased the adhesion of peripheral blood mononuclear lymphocytes (PBMLs) to CRC cells and PBML-mediated cytotoxicity against CRC cells. Production of CXCL10, an effector T cell-recruiting chemokine, was significantly reduced by the increased HO-1 expression. The expression of the CXCL10 receptor, CXCR3, decreased significantly in PBMLs that adhered to CRC cells. HO-1 expression correlated negatively, although nonsignificantly, with ICAM-1 and CXCL10 expression in xenograft tumors. Taken together, our data suggest that HO-1 expression is functionally linked to the mediation of tumor progression and metastasis of CRC cells by inhibiting antitumor immunity. PMID:26087182

  15. Involvement of 14-3-3 Proteins in Regulating Tumor Progression of Hepatocellular Carcinoma.

    PubMed

    Wu, Yi-Ju; Jan, Yee-Jee; Ko, Bor-Sheng; Liang, Shu-Man; Liou, Jun-Yang

    2015-01-01

    There are seven mammalian isoforms of the 14-3-3 protein, which regulate multiple cellular functions via interactions with phosphorylated partners. Increased expression of 14-3-3 proteins contributes to tumor progression of various malignancies. Several isoforms of 14-3-3 are overexpressed and associate with higher metastatic risks and poorer survival rates of hepatocellular carcinoma (HCC). 14-3-3β and 14-3-3ζ regulate HCC cell proliferation, tumor growth and chemosensitivity via modulating mitogen-activated protein kinase (MAPK), c-Jun N-terminal kinase (JNK) and p38 signal pathways. Moreover, 14-3-3ε suppresses E-cadherin and induces focal adhesion kinase (FAK) expression, thereby enhancing epithelial-mesenchymal transition (EMT) and HCC cell migration. 14-3-3ζ forms complexes with αB-crystallin, which induces EMT and is the cause of sorafenib resistance in HCC. Finally, a recent study has indicated that 14-3-3σ induces heat shock protein 70 (HSP70) expression, which increases HCC cell migration. These results suggest that selective 14-3-3 isoforms contribute to cell proliferation, EMT and cell migration of HCC by regulating distinct targets and signal pathways. Targeting 14-3-3 proteins together with specific downstream effectors therefore has potential to be therapeutic and prognostic factors of HCC. In this article, we will overview 14-3-3's regulation of its downstream factors and contributions to HCC EMT, cell migration and proliferation. PMID:26083935

  16. Decreased expression of SOX17 is associated with tumor progression and poor prognosis in breast cancer.

    PubMed

    Fu, De-Yuan; Tan, Hao-Sheng; Wei, Jin-Li; Zhu, Chang-Ren; Jiang, Ji-Xin; Zhu, Yu-Xiang; Cai, Feng-Lin; Chong, Mei-Hong; Ren, Chuan-Li

    2015-09-01

    The SOX17 (SRY-related HMG-box) transcription factor is involved in a variety of biological processes and is related to the tumorigenesis and progression of multiple tumors. However, the clinical application of SOX17 for breast cancer prognosis is currently limited. The aim of this study was to investigate the clinicopathologic and prognostic significance of SOX17 expression in human breast cancer. qPCR and western blot assays were performed to measure the expression of SOX17 in breast cancer cell lines and 30 matched pairs of breast cancer and corresponding noncancerous tissues. A SOX17 overexpression cell model was used to examine changes in cell growth in vitro. Immunohistochemical analyses were performed to retrospectively examine the prognostic impact of SOX17 expression in 187 additional breast cancer patients. Our results showed that SOX17 expression was decreased at both the messenger RNA (mRNA) and protein levels in the breast cancer cell lines and tissues, and that SOX17 overexpression could strongly suppress cell growth in vitro. Furthermore, the lack of SOX17 protein expression was strongly correlated with higher tumor grade (P = 0.002), lymph node metastasis (P < 0.001), and tumor node metastasis (TNM) stage (P = 0.001) and had poorer disease-free survival (DFS) and overall survival (OS) compared to normal SOX17 expression (P = 0.002 and 0.001, respectively). Univariate and multivariate analyses indicated that lower SOX17 expression was an independent prognostic factor for DFS (P = 0.007; HR = 2.854; 95 % CI 1.326-6.147) and OS (P = 0.005; HR = 5.035; 95 % CI 1.648-15.385) for breast cancer. Our findings indicate that SOX17 expression is a useful prognostic biomarker for breast cancer. PMID:25971583

  17. Pretreatment serum interleukin-1β, interleukin-6, and tumor necrosis factor-α levels predict the progression of colorectal cancer.

    PubMed

    Chang, Pei-Hung; Pan, Yi-Ping; Fan, Chung-Wei; Tseng, Wen-Ko; Huang, Jen-Seng; Wu, Tsung-Han; Chou, Wen-Chi; Wang, Cheng-Hsu; Yeh, Kun-Yun

    2016-03-01

    The correlations of pretreatment serum concentrations of proinflammatory cytokines such as interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNFα) with the clinicopathologic features and progression of colorectal cancer (CRC) were investigated. The pretreatment serum levels of IL-1β, IL-6, and TNFα were measured in 164 CRC patients before treatment. The relationships between changes in proinflammatory cytokine and C-reactive protein (CRP) levels and both clinicopathologic variables and disease progression were examined by univariate and multivariate analysis. Advanced tumor stage was associated with a poorer histologic differentiation, higher CRP level, lower albumin level, and inferior progression-free survival rate (PFSR). Furthermore, high levels of CRP (>5 mg/L) were associated with proinflammatory cytokine intensity, defined according to the number of proinflammatory cytokines with levels above the median level (IL-1β ≥10 pg/mL; IL-6 ≥ 10 pg/mL; and TNFα ≥55 pg/mL). Under different inflammation states, proinflammatory cytokine intensity, in addition to tumor stage, independently predicted PFSR in patients with CRP <5 mg/L, whereas tumor stage was the only independent predictor of PFSR in patients with CRP ≥5 mg/L. Proinflammatory cytokine intensity and the CRP level are clinically relevant for CRC progression. Measurement of IL-1β, IL-6, and TNFα serum levels may help identify early cancer progression among patients with CRP <5 mg/L in routine practice. PMID:26799163

  18. The pro-inflammatory peptide LL-37 promotes ovarian tumor progression through recruitment of multipotent mesenchymal stromal cells.

    PubMed

    Coffelt, Seth B; Marini, Frank C; Watson, Keri; Zwezdaryk, Kevin J; Dembinski, Jennifer L; LaMarca, Heather L; Tomchuck, Suzanne L; Honer zu Bentrup, Kerstin; Danka, Elizabeth S; Henkle, Sarah L; Scandurro, Aline B

    2009-03-10

    Bone marrow-derived mesenchymal stem cells or multipotent mesenchymal stromal cells (MSCs) have been shown to engraft into the stroma of several tumor types, where they contribute to tumor progression and metastasis. However, the chemotactic signals mediating MSC migration to tumors remain poorly understood. Previous studies have shown that LL-37 (leucine, leucine-37), the C-terminal peptide of human cationic antimicrobial protein 18, stimulates the migration of various cell types and is overexpressed in ovarian, breast, and lung cancers. Although there is evidence to support a pro-tumorigenic role for LL-37, the function of the peptide in tumors remains unclear. Here, we demonstrate that neutralization of LL-37 in vivo significantly reduces the engraftment of MSCs into ovarian tumor xenografts, resulting in inhibition of tumor growth as well as disruption of the fibrovascular network. Migration and invasion experiments conducted in vitro indicated that the LL-37-mediated migration of MSCs to tumors likely occurs through formyl peptide receptor like-1. To assess the response of MSCs to the LL-37-rich tumor microenvironment, conditioned medium from LL-37-treated MSCs was assessed and found to contain increased levels of several cytokines and pro-angiogenic factors compared with controls, including IL-1 receptor antagonist, IL-6, IL-10, CCL5, VEGF, and matrix metalloproteinase-2. Similarly, Matrigel mixed with LL-37, MSCs, or the combination of the two resulted in a significant number of vascular channels in nude mice. These data indicate that LL-37 facilitates ovarian tumor progression through recruitment of progenitor cell populations to serve as pro-angiogenic factor-expressing tumor stromal cells. PMID:19234121

  19. The pro-inflammatory peptide LL-37 promotes ovarian tumor progression through recruitment of multipotent mesenchymal stromal cells

    PubMed Central

    Coffelt, Seth B.; Marini, Frank C.; Watson, Keri; Zwezdaryk, Kevin J.; Dembinski, Jennifer L.; LaMarca, Heather L.; Tomchuck, Suzanne L.; zu Bentrup, Kerstin Honer; Danka, Elizabeth S.; Henkle, Sarah L.; Scandurro, Aline B.

    2009-01-01

    Bone marrow-derived mesenchymal stem cells or multipotent mesenchymal stromal cells (MSCs) have been shown to engraft into the stroma of several tumor types, where they contribute to tumor progression and metastasis. However, the chemotactic signals mediating MSC migration to tumors remain poorly understood. Previous studies have shown that LL-37 (leucine, leucine-37), the C-terminal peptide of human cationic antimicrobial protein 18, stimulates the migration of various cell types and is overexpressed in ovarian, breast, and lung cancers. Although there is evidence to support a pro-tumorigenic role for LL-37, the function of the peptide in tumors remains unclear. Here, we demonstrate that neutralization of LL-37 in vivo significantly reduces the engraftment of MSCs into ovarian tumor xenografts, resulting in inhibition of tumor growth as well as disruption of the fibrovascular network. Migration and invasion experiments conducted in vitro indicated that the LL-37-mediated migration of MSCs to tumors likely occurs through formyl peptide receptor like-1. To assess the response of MSCs to the LL-37-rich tumor microenvironment, conditioned medium from LL-37-treated MSCs was assessed and found to contain increased levels of several cytokines and pro-angiogenic factors compared with controls, including IL-1 receptor antagonist, IL-6, IL-10, CCL5, VEGF, and matrix metalloproteinase-2. Similarly, Matrigel mixed with LL-37, MSCs, or the combination of the two resulted in a significant number of vascular channels in nude mice. These data indicate that LL-37 facilitates ovarian tumor progression through recruitment of progenitor cell populations to serve as pro-angiogenic factor-expressing tumor stromal cells. PMID:19234121

  20. Pharmacological or genetic inhibition of LDHA reverses tumor progression of pediatric osteosarcoma.

    PubMed

    Gao, Shan; Tu, Dan-Na; Li, Heng; Jiang, Jian-Xin; Cao, Xin; You, Jin-Bin; Zhou, Xiao-Qin

    2016-07-01

    Reprogrammed energy metabolism is an emerging hallmark of cancer. Lactate dehydrogenase A (LDHA), a key enzyme involved in anaerobic glycolysis, is frequently deregulated in human malignancies. However, limited knowledge is known about its roles in the progression of osteosarcoma (OS). In this study, we found that LDHA is commonly upregulated in four OS cell lines compared with the normal osteoblast cells (hFOB1.19). Treatment with FX11, a specific inhibitor of LDHA, significantly reduced LDHA activity, and inhibited cell proliferation and invasive potential in a dose dependent manner. Genetic silencing of LDHA resulted in a decreased lactate level in the culture medium, reduced cell viability and decreased cell invasion ability. Meanwhile, silencing of LDHA also compromised tumorigenesis in vivo. Furthermore, knockdown of LDHA remarkably reduced extracellular acidification rate (ECAR) as well as glucose consumption. In the presence of 2-DG, a glycolysis inhibitor, LDHA-mediated cell proliferation and invasion were completely blocked, indicating the oncogenic activities of LDHA may dependent on Warburg effect. Finally, pharmacological inhibition of c-Myc or HIF1α significantly attenuated LDHA expression. Taken together, upregulated LDHA facilitates tumor progression of OS and might be a potential target for OS treatment. PMID:27261617

  1. Phase II Study of Intraventricular Methotrexate in Children With Recurrent or Progressive Malignant Brain Tumors

    ClinicalTrials.gov

    2016-06-30

    Recurrent Childhood Medulloblastoma; Recurrent Childhood Ependymoma; Childhood Atypical Teratoid/Rhabdoid Tumor; Embryonal Tumor With Abundant Neuropil and True Rosettes; Metastatic Malignant Neoplasm to the Leptomeninges

  2. Determinants of Local Progression After Computed Tomography-Guided Percutaneous Radiofrequency Ablation for Unresectable Lung Tumors: 9-Year Experience in a Single Institution

    SciTech Connect

    Okuma, Tomohisa Matsuoka, Toshiyuki; Yamamoto, Akira; Oyama, Yoshimasa; Hamamoto, Shinichi; Toyoshima, Masami; Nakamura, Kenji; Miki, Yukio

    2010-08-15

    The purpose of this study was to retrospectively determine the local control rate and contributing factors to local progression after computed tomography (CT)-guided radiofrequency ablation (RFA) for unresectable lung tumor. This study included 138 lung tumors in 72 patients (56 men and 16 women; age 70.0 {+-} 11.6 years (range 31-94); mean tumor size 2.1 {+-} 1.2 cm [range 0.2-9]) who underwent lung RFA between June 2000 and May 2009. Mean follow-up periods for patients and tumors were 14 and 12 months, respectively. The local progression-free rate and survival rate were calculated to determine the contributing factors to local progression. During follow-up, 44 of 138 (32%) lung tumors showed local progression. The 1-, 2-, 3-, and 5-year overall local control rates were 61, 57, 57, and 38%, respectively. The risk factors for local progression were age ({>=}70 years), tumor size ({>=}2 cm), sex (male), and no achievement of roll-off during RFA (P < 0.05). Multivariate analysis identified tumor size {>=}2 cm as the only independent factor for local progression (P = 0.003). For tumors <2 cm, 17 of 68 (25%) showed local progression, and the 1-, 2-, and 3-year overall local control rates were 77, 73, and 73%, respectively. Multivariate analysis identified that age {>=}70 years was an independent determinant of local progression for tumors <2 cm in diameter (P = 0.011). The present study showed that 32% of lung tumors developed local progression after CT-guided RFA. The significant risk factor for local progression after RFA for lung tumors was tumor size {>=}2 cm.

  3. MUC1 enhances tumor progression and contributes toward immunosuppression in a mouse model of spontaneous pancreatic adenocarcinoma.

    PubMed

    Tinder, Teresa L; Subramani, Durai B; Basu, Gargi D; Bradley, Judy M; Schettini, Jorge; Million, Arefayene; Skaar, Todd; Mukherjee, Pinku

    2008-09-01

    MUC1, a membrane tethered mucin glycoprotein, is overexpressed and aberrantly glycosylated in >80% of human ductal pancreatic adenocarcinoma. However, the role of MUC1 in pancreatic cancer has been elusive, partly due to the lack of an appropriate model. We report the characterization of a novel mouse model that expresses human MUC1 as a self molecule (PDA.MUC1 mice). Pancreatic tumors arise in an appropriate MUC1-tolerant background within an immune-competent host. Significant enhancement in the development of pancreatic intraepithelial preneoplastic lesions and progression to adenocarcinoma is observed in PDA.MUC1 mice, possibly due to increased proliferation. Tumors from PDA.MUC1 mice express higher levels of cyclooxygenase-2 and IDO compared with PDA mice lacking MUC1, especially during early stages of tumor development. The increased proinflammatory milieu correlates with an increased percentage of regulatory T cells and myeloid suppressor cells in the pancreatic tumor and tumor draining lymph nodes. Data shows that during pancreatic cancer progression, MUC1-mediated mechanisms enhance the onset and progression of the disease, which in turn regulate the immune responses. Thus, the mouse model is ideally suited for testing novel chemopreventive and therapeutic strategies against pancreatic cancer. PMID:18713982

  4. MUC1 enhances tumor progression and contributes towards immunosuppression in a mouse model of spontaneous pancreatic adenocarcinoma

    PubMed Central

    Tinder, Teresa L.; Subramani, Durai B.; Basu, Gargi D.; Bradley, Judy M.; Schettini, Jorge; Million, Arefayene; Skaar, Todd

    2008-01-01

    MUC1, a membrane tethered mucin glycoprotein, is overexpressed and aberrantly glycosylated in >80% of human ductal pancreatic adenocarcinoma. However, the role of MUC1 in pancreatic cancer has been elusive, partly due to the lack of an appropriate model. We report the characterization of a novel mouse model that expresses human MUC1 as a self molecule (PDA.MUC1 mice). Pancreatic tumors arise in an appropriate MUC1-tolerant background within an immune competent host. Significant enhancement in the development of pancreatic intraepithelial pre-neoplastic lesions (PanINs) and progression to adenocarcinoma is observed in PDA.MUC1 mice, possibly due to increased proliferation. Tumors from PDA.MUC1 mice express higher levels of cyclooxygenase-2 and indoleamine 2,3, dioxygenase compared to PDA mice lacking MUC1, especially during early stages of tumor development. The increased pro-inflammatory milieu correlates with an increased percentage of regulatory T cells and myeloid suppressor cells in the pancreatic tumor and tumor draining lymph nodes. Data shows that during pancreatic cancer progression, MUC1-mediated mechanisms enhance the onset and progression of the disease which in turn regulate the immune responses. Thus, the mouse model is ideally-suited for testing novel chemopreventive and therapeutic strategies against pancreatic cancer. PMID:18713982

  5. Tumor progression locus 2 ablation suppressed hepatocellular carcinoma development by inhibiting hepatic inflammation and steatosis in mice

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Background: Tumor progression locus 2 (TPL2), a serine threonine kinase, functions as a critical regulator of inflammatory pathways and mediates oncogenic events. The potential role of Tpl2 in nonalcoholic fatty liver disease (NAFLD) associated hepatocellular carcinoma (HCC) development remains unkn...

  6. Tumor-induced inflammation in mammary adipose tissue stimulates a vicious cycle of autotaxin expression and breast cancer progression.

    PubMed

    Benesch, Matthew G K; Tang, Xiaoyun; Dewald, Jay; Dong, Wei-Feng; Mackey, John R; Hemmings, Denise G; McMullen, Todd P W; Brindley, David N

    2015-09-01

    Compared to normal tissues, many cancer cells overexpress autotaxin (ATX). This secreted enzyme produces extracellular lysophosphatidate, which signals through 6 GPCRs to drive cancer progression. Our previous work showed that ATX inhibition decreases 4T1 breast tumor growth in BALB/c mice by 60% for about 11 d. However, 4T1 cells do not produce significant ATX. Instead, the ATX is produced by adjacent mammary adipose tissue. We investigated the molecular basis of this interaction in human and mouse breast tumors. Inflammatory mediators secreted by breast cancer cells increased ATX production in adipose tissue. The increased lysophosphatidate signaling further increased inflammatory mediator production in adipose tissue and tumors. Blocking ATX activity in mice bearing 4T1 tumors with 10 mg/kg/d ONO-8430506 (a competitive ATX inhibitor, IC90 = 100 nM; Ono Pharma Co., Ltd., Osaka, Japan) broke this vicious inflammatory cycle by decreasing 20 inflammatory mediators by 1.5-8-fold in cancer-inflamed adipose tissue. There was no significant decrease in inflammatory mediator levels in fat pads that did not bear tumors. ONO-8430506 also decreased plasma TNF-α and G-CSF cytokine levels by >70% and leukocyte infiltration in breast tumors and adjacent adipose tissue by >50%. Hence, blocking tumor-driven inflammation by ATX inhibition is effective in decreasing tumor growth in breast cancers where the cancer cells express negligible ATX. PMID:26071407

  7. microRNA-217 inhibits tumor progression and metastasis by downregulating EZH2 and predicts favorable prognosis in gastric cancer

    PubMed Central

    Lu, Yun-xin; Chen, Le-zong; Zeng, Zhao-lei; He, Ming-ming; Wang, Feng-hua; Li, Yu-hong; Zhang, Hui-zhong; Pelicano, Helene; Zhang, Wei; Xu, Rui-hua

    2015-01-01

    microRNA-217 (miR-217) is frequently dysregulated in cancer. Here, we report that miR-217 levels were lower in tumor tissue compared with the adjacent normal tissue. Low levels of miR-217 were associated with aggressive tumor phenotypes and poor overall survival in gastric cancer patients. The ectopic expression of miR-217 inhibited cell proliferation, migration and invasion in vitro and tumor growth and metastasis in vivo, whereas knockdown of endogenous miR-217 increased cell proliferation and invasion. Further experiments revealed that Polycomb group protein enhancer of zeste homolog 2 (EZH2) was a direct target of miR-217 in gastric cancer cells. Knockdown of EZH2 mimicked the tumor-suppressive effects of miR-217 in gastric cancer cells, whereas the reintroduction of EZH2 abolished its effects. Taken together, these results demonstrated that miR-217 may be used as a prognostic marker, and the newly identified miR-217-EZH2 axis may be a potential target in the development of therapeutic strategies for gastric cancer patients. PMID:25869101

  8. Structure and function of IQ-domain GTPase-activating protein 1 and its association with tumor progression (Review)

    PubMed Central

    WU, YAN; CHEN, YONG-CHANG

    2014-01-01

    IQ-domain GTPase-activating proteins (IQGAPs) are evolutionary conserved multidomain proteins that are found in numerous organisms, from yeast to mammals. To date, three IQGAP proteins have been identified in humans, of which IQGAP1 is the best characterized. As a scaffold protein, IQGAP1 contains multiple protein-interacting domains, which modulate binding to target proteins. Recent mounting studies demonstrated a role for IQGAP1 in tumor progression, supported by the altered expression and subcellular distribution of IQGAP1 in tumors. The contribution of IQGAP1 to tumor progression appears to involve a complex interplay of cell functions by integrating diverse signal transduction pathways and coordinating activities, such as cell adhesion, migration, invasion, proliferation and angiogenesis. PMID:24649059

  9. Researchers Find 8 Immune Genes in Aggressive Brain Cancer

    MedlinePlus

    ... 159031.html Researchers Find 8 Immune Genes in Aggressive Brain Cancer Discovery might eventually lead to better ... tissue samples from 170 people with a less aggressive type of brain tumor. This led to the ...

  10. Extensive Surgery Best for an Aggressive Brain Cancer

    MedlinePlus

    ... 159415.html Extensive Surgery Best for an Aggressive Brain Cancer: Study Although larger procedure carries more risk, ... comes to battling a particularly aggressive form of brain tumor, more extensive surgeries may be best to ...

  11. Extensive Surgery Best for an Aggressive Brain Cancer

    MedlinePlus

    ... fullstory_159415.html Extensive Surgery Best for an Aggressive Brain Cancer: Study Although larger procedure carries more ... News) -- When it comes to battling a particularly aggressive form of brain tumor, more extensive surgeries may ...

  12. The axon guidance molecule semaphorin 3F is a negative regulator of tumor progression and proliferation in ileal neuroendocrine tumors

    PubMed Central

    Vercherat, Cécile; Blanc, Martine; Lepinasse, Florian; Gadot, Nicolas; Couderc, Christophe; Poncet, Gilles; Walter, Thomas; Joly, Marie-Odile; Hervieu, Valérie; Scoazec, Jean-Yves; Roche, Colette

    2015-01-01

    Gastro-intestinal neuroendocrine tumors (GI-NETs) are rare neoplasms, frequently metastatic, raising difficult clinical and therapeutic challenges due to a poor knowledge of their biology. As neuroendocrine cells express both epithelial and neural cell markers, we studied the possible involvement in GI-NETs of axon guidance molecules, which have been shown to decrease tumor cell proliferation and metastatic dissemination in several tumor types. We focused on the role of Semaphorin 3F (SEMA3F) in ileal NETs, one of the most frequent subtypes of GI-NETs. SEMA3F expression was detected in normal neuroendocrine cells but was lost in most of human primary tumors and all their metastases. SEMA3F loss of expression was associated with promoter gene methylation. After increasing endogenous SEMA3F levels through stable transfection, enteroendocrine cell lines STC-1 and GluTag showed a reduced proliferation rate in vitro. In two different xenograft mouse models, SEMA3F-overexpressing cells exhibited a reduced ability to form tumors and a hampered liver dissemination potential in vivo. This resulted, at least in part, from the inhibition of mTOR and MAPK signaling pathways. This study demonstrates an anti-tumoral role of SEMA3F in ileal NETs. We thus suggest that SEMA3F and/or its cellular signaling pathway could represent a target for ileal NET therapy. PMID:26447612

  13. Deletion of tumor progression locus 2 attenuates alcohol-induced hepatic inflammation

    PubMed Central

    Stice, Camilla P.; Hussain, Sajid; Liu, Chun; Ausman, Lynne M.

    2016-01-01

    Background The pathogenesis of alcoholic liver disease (ALD) involves the interaction of several inflammatory signaling pathways. Tumor progression locus 2 (TPL2), also known as Cancer Osaka Thyroid (COT) and MAP3K8, is a serine-threonine kinase that functions as a critical regulator of inflammatory pathways by up-regulating production of inflammatory cytokines. The present study aims to fill the gap in knowledge regarding the involvement of TPL2 in the mechanism of alcohol-induced hepatic inflammation. Methods Male TPL2−/− knockout (TPL2KO) mice and TPL2+/+ wild-type (WT) mice were group pair-fed with Lieber-DeCarli liquid ethanol diet (EtOH diet, 27% energy from EtOH) or control diet (ctrl diet) for 4 weeks. Both histological and molecular biomarkers involved in the induction of hepatic inflammation by alcohol consumption were examined. Results Consumption of the EtOH diet in WT mice lead to a significant induction of TPL2 mRNA expression as compared with WT mice fed ctrl diet. A significant induction in inflammatory foci and steatosis was also observed in WT mice fed EtOH diet. The deletion of TPL2 significantly reduced inflammatory foci in the liver of mice consuming both ctrl and EtOH diets as compared to their respective WT controls. This reduction was associated with suppression of hepatic inflammatory gene expression of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β) and macrophage marker F4/80. In addition, histological analysis of livers revealed that TPL2 deletion resulted in reduced steatosis in both ctrl (significant) and EtOH (non-significant) diet-fed mice as compared to their respective WT controls. Conclusions The demonstration that TPL2 deletion attenuates alcohol-induced hepatic inflammation provides evidence of a novel role for TPL2 in the pathogenesis of ALD. PMID:26904554

  14. Persistent Uroplakin Expression in Advanced Urothelial Carcinomas: Implications in Urothelial Tumor Progression and Clinical Outcome

    PubMed Central

    Huang, Hong-Ying; Shariat, Shahrokh F.; Sun, Tung-Tien; Lepor, Herbert; Shapiro, Ellen; Hsieh, Jer-Tsong; Ashfaq, Raheela; Lotan, Yair; Wu, Xue-Ru

    2007-01-01

    As the terminal differentiation products of human urothelium, uroplakins (UPs) would be expected to diminish during urothelial tumorigenesis. Surprisingly, recent studies found UPs to be retained even by well-advanced urothelial carcinomas, suggesting that the loss of UPs does not strictly parallel urothelial transformation. Little is known, however, about whether the status of UPs is associated with a particular pathological parameter, tumor’s biological behavior or patient outcome. Here we assessed UP expression by immunohistochemistry on tissue arrays from 285 patients with bladder urothelial carcinomas or non-tumor conditions. UPs were expressed in all 9 normal urothelial specimens, 63/74 (85%) patients with non-muscle-invasive urothelial carcinomas on transurethral resection, 104/202 (51.5%) patients who underwent radical cystectomy for advanced urothelial carcinomas, and 33/50 (66%) lymph node metastases. Normally associated with urothelial apical surface, UPs were localized aberrantly in tumors, including micro-luminal, basal-laminal, cytoplasmic or uniform patterns. In non-muscle-invasive diseases, there was no association between UP expression and disease recurrence, progression or mortality. In contrast, in invasive diseases, absent UP expression was significantly associated with advanced pathologic stage, lymph node metastases, disease recurrence and bladder cancer-specific mortality (p=0.042, p=0.035, p=0.023 and p=0.022, respectively) in univariate analyses. Furthermore, UP status was independent of key cell-cycle regulators, including p53, pRb, p27 and cyclin D1, thus excluding a functional link between these two groups of proteins. Our data demonstrate for the first time that persistent UP expression is associated with a favorable clinical outcome and that UPs may be used as adjunct markers for predicting the prognoses of patients with invasive and metastatic bladder carcinomas. Our results also suggest that UP-positive and –negative carcinomas

  15. Loss of CD73-mediated actin polymerization promotes endometrial tumor progression

    PubMed Central

    Bowser, Jessica L.; Blackburn, Michael R.; Shipley, Gregory L.; Molina, Jose G.; Dunner, Kenneth; Broaddus, Russell R.

    2015-01-01

    Ecto-5′-nucleotidase (CD73) is central to the generation of extracellular adenosine. Previous studies have highlighted a detrimental role for extracellular adenosine in cancer, as it dampens T cell–mediated immune responses. Here, we determined that, in contrast to other cancers, CD73 is markedly downregulated in poorly differentiated and advanced-stage endometrial carcinoma compared with levels in normal endometrium and low-grade tumors. In murine models, CD73 deficiency led to a loss of endometrial epithelial barrier function, and pharmacological CD73 inhibition increased in vitro migration and invasion of endometrial carcinoma cells. Given that CD73-generated adenosine is central to regulating tissue protection and physiology in normal tissues, we hypothesized that CD73-generated adenosine in endometrial carcinoma induces an innate reflex to protect epithelial integrity. CD73 associated with cell-cell contacts, filopodia, and membrane zippers, indicative of involvement in cell-cell adhesion and actin polymerization–dependent processes. We determined that CD73-generated adenosine induces cortical actin polymerization via adenosine A1 receptor (A1R) induction of a Rho GTPase CDC42–dependent conformational change of the actin-related proteins 2 and 3 (ARP2/3) actin polymerization complex member N-WASP. Cortical F-actin elevation increased membrane E-cadherin, β-catenin, and Na+K+ ATPase. Together, these findings reveal that CD73-generated adenosine promotes epithelial integrity and suggest why loss of CD73 in endometrial cancer allows for tumor progression. Moreover, our data indicate that the role of CD73 in cancer is more complex than previously described. PMID:26642367

  16. Microbiology of aggressive periodontitis.

    PubMed

    Könönen, Eija; Müller, Hans-Peter

    2014-06-01

    For decades, Aggregatibacter actinomycetemcomitans has been considered the most likely etiologic agent in aggressive periodontitis. Implementation of DNA-based microbiologic methodologies has considerably improved our understanding of the composition of subgingival biofilms, and advanced open-ended molecular techniques even allow for genome mapping of the whole bacterial spectrum in a sample and characterization of both the cultivable and not-yet-cultivable microbiota associated with periodontal health and disease. Currently, A. actinomycetemcomitans is regarded as a minor component of the resident oral microbiota and as an opportunistic pathogen in some individuals. Its specific JP2 clone, however, shows properties of a true exogenous pathogen and has an important role in the development of aggressive periodontitis in certain populations. Still, limited data exist on the impact of other microbes specifically in aggressive periodontitis. Despite a wide heterogeneity of bacteria, especially in subgingival samples collected from patients, bacteria of the red complex in particular, and those of the orange complex, are considered as potential pathogens in generalized aggressive periodontitis. These types of bacterial findings closely resemble those found for chronic periodontitis, representing a mixed polymicrobial infection without a clear association with any specific microorganism. In aggressive periodontitis, the role of novel and not-yet-cultivable bacteria has not yet been elucidated. There are geographic and ethnic differences in the carriage of periodontitis-associated microorganisms, and they need to be taken into account when comparing study reports on periodontal microbiology in different study populations. In the present review, we provide an overview on the colonization of potential periodontal pathogens in childhood and adolescence, and on specific microorganisms that have been suspected for their role in the initiation and progression of aggressive

  17. Wilms Tumor

    MedlinePlus

    ... diagnosis, and the condition, or histology , of the cancer cells when observed under a microscope. "Favorable" histology is associated with a good chance of a cure; tumors with "unfavorable" histology are more aggressive and ...

  18. Real-World Study of Everolimus in Advanced Progressive Neuroendocrine Tumors

    PubMed Central

    Panzuto, Francesco; Rinzivillo, Maria; Fazio, Nicola; de Braud, Filippo; Luppi, Gabriele; Zatelli, Maria Chiara; Lugli, Francesca; Tomassetti, Paola; Riccardi, Ferdinando; Nuzzo, Carmen; Brizzi, Maria Pia; Faggiano, Antongiulio; Zaniboni, Alberto; Nobili, Elisabetta; Pastorelli, Davide; Cascinu, Stefano; Merlano, Marco; Chiara, Silvana; Antonuzzo, Lorenzo; Funaioli, Chiara; Spada, Francesca; Pusceddu, Sara; Fontana, Annalisa; Ambrosio, Maria Rosaria; Cassano, Alessandra; Campana, Davide; Cartenì, Giacomo; Appetecchia, Marialuisa; Berruti, Alfredo; Colao, Annamaria; Falconi, Massimo

    2014-01-01

    Everolimus is a valid therapeutic option for neuroendocrine tumors (NETs); however, data in a real-world setting outside regulatory trials are sparse. The aim of this study was to determine everolimus tolerability and efficacy, in relation to previous treatments, in a compassionate use program. A total of 169 patients with advanced progressive NETs treated with everolimus were enrolled, including 85 with pancreatic NETs (pNETs) and 84 with nonpancreatic NETs (non-pNETs). Previous treatments included somatostatin analogs (92.9%), peptide receptor radionuclide therapy (PRRT; 50.3%), chemotherapy (49.7%), and PRRT and chemotherapy (22.8%). Overall, 85.2% of patients experienced adverse events (AEs), which were severe (grade 3–4) in 46.1%. The most frequent severe AEs were pneumonitis (8.3%), thrombocytopenia (7.7%), anemia (5.3%), and renal failure (3.5%). In patients previously treated with PRRT and chemotherapy, a 12-fold increased risk for severe toxicity was observed, with grade 3–4 AEs reported in 86.8% (vs. 34.3% in other patients). In addition, 63.3% of patients required temporarily everolimus discontinuation due to toxicity. Overall, 27.8% of patients died during a median follow-up of 12 months. Median progression-free survival (PFS) and overall survival (OS) were 12 months and 32 months, respectively. Similar disease control rates, PFS, and OS were reported in pNETs and non-pNETs. In the real-world setting, everolimus is safe and effective for the treatment of NETs of different origins. Higher severe toxicity occurred in patients previously treated with systemic chemotherapy and PRRT. This finding prompts caution when using this drug in pretreated patients and raises the issue of planning for everolimus before PRRT and chemotherapy in the therapeutic algorithm for advanced NETs. PMID:25117065

  19. Regulatory mechanisms underlying sepsis progression in patients with tumor necrosis factor-α genetic variations

    PubMed Central

    LIU, YANGZHOU; HAN, NING; LI, QINCHUAN; LI, ZENGCHUN

    2016-01-01

    The present study aimed to investigate the regulatory mechanisms underlying sepsis progression in patients with tumor necrosis factor (TNF)-α genetic variations. The GSE5760 expression profile data, which was downloaded from the Gene Expression Omnibus database, contained 30 wild-type (WT) and 28 mutation (MUT) samples. Differentially expressed genes (DEGs) between the two types of samples were identified using the Student's t-test, and the corresponding microRNAs (miRNAs) were screened using WebGestalt software. An integrated miRNA-DEG network was constructed using the Cytoscape software, based on the interactions between the DEGs, as identified using the Search Tool for the Retrieval of Interacting Genes/Proteins database, and the correlation between miRNAs and their target genes. Furthermore, Gene Ontology and pathway enrichment analyses were conducted for the DEGs using the Database for Annotation, Visualization and Integrated Discovery and the KEGG Orthology Based Annotation System, respectively. A total of 390 DEGS between the WT and MUT samples, along with 11 -associated miRNAs, were identified. The integrated miRNA-DEG network consisted of 38 DEGs and 11 miRNAs. Within this network, COPS2 was found to be associated with transcriptional functions, while FUS was found to be involved in mRNA metabolic processes. Other DEGs, including FBXW7 and CUL3, were enriched in the ubiquitin-mediated proteolysis pathway. In addition, miR-15 was predicted to target COPS2 and CUL3. The results of the present study suggested that COPS2, FUS, FBXW7 and CUL3 may be associated with sepsis in patients with TNF-α genetic variations. In the progression of sepsis, FBXW7 and CUL3 may participate in the ubiquitin-mediated proteolysis pathway, whereas COPS2 may regulate the phosphorylation and ubiquitination of the FUS protein. Furthermore, COPS2 and CUL3 may be novel targets of miR-15. PMID:27347057

  20. Real-world study of everolimus in advanced progressive neuroendocrine tumors.

    PubMed

    Panzuto, Francesco; Rinzivillo, Maria; Fazio, Nicola; de Braud, Filippo; Luppi, Gabriele; Zatelli, Maria Chiara; Lugli, Francesca; Tomassetti, Paola; Riccardi, Ferdinando; Nuzzo, Carmen; Brizzi, Maria Pia; Faggiano, Antongiulio; Zaniboni, Alberto; Nobili, Elisabetta; Pastorelli, Davide; Cascinu, Stefano; Merlano, Marco; Chiara, Silvana; Antonuzzo, Lorenzo; Funaioli, Chiara; Spada, Francesca; Pusceddu, Sara; Fontana, Annalisa; Ambrosio, Maria Rosaria; Cassano, Alessandra; Campana, Davide; Cartenì, Giacomo; Appetecchia, Marialuisa; Berruti, Alfredo; Colao, Annamaria; Falconi, Massimo; Delle Fave, Gianfranco

    2014-09-01

    Everolimus is a valid therapeutic option for neuroendocrine tumors (NETs); however, data in a real-world setting outside regulatory trials are sparse. The aim of this study was to determine everolimus tolerability and efficacy, in relation to previous treatments, in a compassionate use program. A total of 169 patients with advanced progressive NETs treated with everolimus were enrolled, including 85 with pancreatic NETs (pNETs) and 84 with nonpancreatic NETs (non-pNETs). Previous treatments included somatostatin analogs (92.9%), peptide receptor radionuclide therapy (PRRT; 50.3%), chemotherapy (49.7%), and PRRT and chemotherapy (22.8%). Overall, 85.2% of patients experienced adverse events (AEs), which were severe (grade 3-4) in 46.1%. The most frequent severe AEs were pneumonitis (8.3%), thrombocytopenia (7.7%), anemia (5.3%), and renal failure (3.5%). In patients previously treated with PRRT and chemotherapy, a 12-fold increased risk for severe toxicity was observed, with grade 3-4 AEs reported in 86.8% (vs. 34.3% in other patients). In addition, 63.3% of patients required temporarily everolimus discontinuation due to toxicity. Overall, 27.8% of patients died during a median follow-up of 12 months. Median progression-free survival (PFS) and overall survival (OS) were 12 months and 32 months, respectively. Similar disease control rates, PFS, and OS were reported in pNETs and non-pNETs. In the real-world setting, everolimus is safe and effective for the treatment of NETs of different origins. Higher severe toxicity occurred in patients previously treated with systemic chemotherapy and PRRT. This finding prompts caution when using this drug in pretreated patients and raises the issue of planning for everolimus before PRRT and chemotherapy in the therapeutic algorithm for advanced NETs. PMID:25117065

  1. Cavin-2 in oral cancer: A potential predictor for tumor progression.

    PubMed

    Unozawa, Motoharu; Kasamatsu, Atsushi; Higo, Morihiro; Fukumoto, Chonji; Koyama, Tomoyoshi; Sakazume, Tomomi; Nakashima, Dai; Ogawara, Katsunori; Yokoe, Hidetaka; Shiiba, Masashi; Tanzawa, Hideki; Uzawa, Katsuhiro

    2016-06-01

    Cavin-2 (CVN2) affects formation of large caveolae, which are membrane-rich cholesterol domains associated with several functions in signal transduction. Accumulating evidence suggests that CVN2 is present in many cellular types; however, the molecular mechanisms of CVN2 in cancers and its clinical relevance are unknown. We proposed a mechanism by which CVN2 regulates caveolin-1 expression leading to slow cellular proliferation by inactivation of the extracellular regulated kinase (ERK) pathway. Quantitative reverse transcriptase-polymerase chain reaction and immunoblot analyses were used to assess the CVN2 regulation mechanism in oral squamous cell carcinoma (OSCC). Immunohistochemistry (IHC) was performed to analyze the correlation between CVN2 expression and clinical behavior in 115 patients with OSCC. A CVN2 overexpressed model of OSCC cells (oeCVN2 cells) was used for functional experiments. CVN2 expression was down-regulated significantly (P < 0.05) in OSCCs compared with normal counterparts in vitro and in vivo. In addition to the findings that a serum deprivation culture induced up-regulation of CVN2 and slowed cellular proliferation, oeCVN2 cell growth decreased because of cell-cycle arrest at the G1 phase resulting from up-regulated cyclin-dependent kinase inhibitors (p21(Cip1) and p27(Kip1) ) and down-regulated cyclins (cyclin D1, cyclin E) and cyclin-dependent kinases (CDK2, CDK4, and CDK6). Interestingly, CVN2 overexpression facilitated caveolin-1 recruitment and colocalization with each other. We also found decreased ERK phosphorylation levels, an upstream event in cell-cycle arrest. Clinically, IHC data from primary OSCCs showed high tumoral progression in CVN2-negative patients with OSCC. CVN2 may be a possible key regulator of OSCC progression via the CVN2/caveolin-1/ERK pathway and a potential therapeutic target for developing new treatments for OSCCs. © 2015 Wiley Periodicals, Inc. PMID:26086332

  2. Podocalyxin expression in malignant astrocytic tumors.

    PubMed

    Hayatsu, Norihito; Kaneko, Mika Kato; Mishima, Kazuhiko; Nishikawa, Ryo; Matsutani, Masao; Price, Janet E; Kato, Yukinari

    2008-09-19

    Podocalyxin is an anti-adhesive mucin-like transmembrane sialoglycoprotein that has been implicated in the development of aggressive forms of cancer. Podocalyxin is also known as keratan sulfate (KS) proteoglycan. Recently, we revealed that highly sulfated KS or another mucin-like transmembrane sialoglycoprotein podoplanin/aggrus is upregulated in malignant astrocytic tumors. The aim of this study is to examine the relationship between podocalyxin expression and malignant progression of astrocytic tumors. In this study, 51 astrocytic tumors were investigated for podocalyxin expression using immunohistochemistry, Western blot analysis, and quantitative real-time PCR. Immunohistochemistry detected podocalyxin on the surface of tumor cells in six of 14 anaplastic astrocytomas (42.9%) and in 17 of 31 glioblastomas (54.8%), especially around proliferating endothelial cells. In diffuse astrocytoma, podocalyxin expression was observed only in vascular endothelial cells. Podocalyxin might be associated with the malignant progression of astrocytic tumors, and be a useful prognostic marker for astrocytic tumors. PMID:18639524

  3. Podocalyxin expression in malignant astrocytic tumors

    SciTech Connect

    Hayatsu, Norihito; Kaneko, Mika Kato; Mishima, Kazuhiko; Nishikawa, Ryo; Matsutani, Masao; Price, Janet E.; Kato, Yukinari

    2008-09-19

    Podocalyxin is an anti-adhesive mucin-like transmembrane sialoglycoprotein that has been implicated in the development of aggressive forms of cancer. Podocalyxin is also known as keratan sulfate (KS) proteoglycan. Recently, we revealed that highly sulfated KS or another mucin-like transmembrane sialoglycoprotein podoplanin/aggrus is upregulated in malignant astrocytic tumors. The aim of this study is to examine the relationship between podocalyxin expression and malignant progression of astrocytic tumors. In this study, 51 astrocytic tumors were investigated for podocalyxin expression using immunohistochemistry, Western blot analysis, and quantitative real-time PCR. Immunohistochemistry detected podocalyxin on the surface of tumor cells in six of 14 anaplastic astrocytomas (42.9%) and in 17 of 31 glioblastomas (54.8%), especially around proliferating endothelial cells. In diffuse astrocytoma, podocalyxin expression was observed only in vascular endothelial cells. Podocalyxin might be associated with the malignant progression of astrocytic tumors, and be a useful prognostic marker for astrocytic tumors.

  4. Haploinsufficiency in the prometastasis Kiss1 Receptor Gpr54 delays breast tumor initiation, progression and lung metastasis

    PubMed Central

    Cho, Sung-Gook; Wang, Ying; Rodriguez, Melissa; Tan, Kunrong; Zhang, Wenzheng; Luo, Jian; Li, Dali; Liu, Mingyao

    2016-01-01

    Activation of KISS1 receptor (KISS1R or GPR54) by its ligands (kisspeptins) regulates a diverse function both in normal physiology and pathophysiology. In cancer, KISS1-induced KISS1R signaling is known to inhibit tumor angiogenesis and metastasis. However, roles of KISS1 and KISS1R in earlier stages of tumor progression and metastasis in vivo are still unknown. In this study, we demonstrate a critical role for Kiss1r in early stages of tumor progression using mouse tumor models. PyMT/Kiss1r mice with different Kiss1r genotypes were obtained by crossing MMTV-PyMT transgenic mouse with Kiss1r heterozygous mouse (Kiss1r+/−). Kiss1r heterozygosity attenuated breast tumor initiation, growth, latency, multiplicity and metastasis in MMTV-PyMT/Kiss1r+/− mouse models. To confirm the effects of Kiss1r in tumor progression and limit any effect of endogenous hormones, we isolated primary tumor cells from PyMT/Kiss1r+/+ or PyMT/Kiss1r+/− mice and performed in vitro and in vivo tumorigenesis assays. Kiss1r heterozygosity inhibited PyMT-induced in vitro tumorigeneity and in vivo tumor growth in NOD.SCID/NCr mice. To understand the underlying mechanism, we showed that activation of KISS1R by kisspeptin-10 led to RhoA activation and RhoA-dependent gene expression through Gαq-p63RhoGEF signaling pathway. Furthermore, anchorage-independent growth was tightly linked to the dosage-dependent regulation of RhoA by KISS1R. When MCF10A cells overexpressing H-RasV12 were subjected to in vitro tumorigenesis assays, knockdown of KISS1R or inactivation of RhoA in MCF10A cells reduced Ras-induced anchorage-independent growth, similar to our data obtained from PyMT-Kiss1r+/− mouse models. Altogether, we conclude that Kiss1r haploinsufficiency delays breast tumor initiation, progression and metastasis through its downstream Gαq-p63RhoGEF-RhoA signaling pathway. PMID:21852382

  5. Gr-1+CD11b+ cells are responsible for tumor promoting effect of TGF-β in breast cancer progression

    PubMed Central

    Li, Zhaoyang; Pang, Yanli; Gara, Sudheer Kumar; Achyut, B.R.; Heger, Christopher; Goldsmith, Paul K.; Lonning, Scott; Yang, Li

    2012-01-01

    One great challenge in our understanding of TGF-β cancer biology and the successful application of TGF-β targeted therapy is that TGF-β works as both a tumor suppressor and a tumor promoter. The underlying mechanisms for its functional change remain to be elucidated. Using 4T1 mammary tumor model that shares many characteristics with human breast cancer, particularly its ability to spontaneously metastasize to the lungs, we demonstrate that Gr-1+CD11b+ cells or myeloid derived suppressor cells (MDSCs) are important mediators in TGF-β regulation of mammary tumor progression. Depletion of Gr-1+CD11b+ cells diminished the anti-tumor effect of TGF-β neutralization. Two mechanisms were involved: first, treatment with TGF-β neutralization antibody (1D11) significantly decreased the number of Gr-1+CD11b+ cells in tumor tissues and premetastatic lung. This is mediated through increased Gr-1+CD11b+ cell apoptosis. In addition, 1D11 treatment significantly decreased the expression of Th2 cytokines & Arginase 1. Interestingly, the number and property of Gr-1+CD11b+ cells in peripheral blood/draining lymph nodes correlated with tumor size and metastases in response to 1D11 treatment. Our data suggest that the efficacy of TGF-β neutralization depends on the presence of Gr-1+CD11b+ cells, and these cells could be good biomarkers for TGF-β targeted therapy. PMID:22487809

  6. MicroRNA expression in ileal carcinoid tumors: downregulation of microRNA-133a with tumor progression.

    PubMed

    Ruebel, Katharina; Leontovich, Alexey A; Stilling, Gail A; Zhang, Shuya; Righi, Alberto; Jin, Long; Lloyd, Ricardo V

    2010-03-01

    MicroRNAs (miRNAs) are involved in cell proliferation, differentiation, and apoptosis and can function as tumor suppressor genes or oncogenes. The role of miRNAs in neuroendocrine tumors such as ileal carcinoids is largely unknown. We examined the differential expression of 95 miRNAs by RT-PCR using the QuantiMir System in eight matching primary and metastatic carcinoid tumors from the ileum. All miRNAs chosen for the QuantiMir System array were based on their potential functions related to cancer biology, cell development, and apoptosis. The expression of miRNAs for the samples was normalized to miRNA-197, and the matching primary and metastatic tumors were compared. There was downregulation of miRNA-133a, -145, -146, -222, and -10b in all samples between the primary and matching metastatic tumors and upregulation of miRNA-183, -488, and -19a+b in six of eight metastatic carcinoids compared to the primary tumors. miRNA-133a was further analyzed by TaqMan real-time RT-PCR and northern hybridization using six additional matching primary and metastatic samples, which supported the PCR array findings. There were significant differences in miRNA-133a expression with downregulation in the metastasis compared to the primary in the eight original cases (P<0.009) and in the six additional cases used for validation (P<0.014). Laser capture microdissection and real-time RT-PCR analysis using normal ileum found miRNA-133a expression in normal enterochromaffin cells. In situ hybridization in normal ileum showed that some of the mucosal endocrine cells expressed miRNA-133a. Both primary and metastatic ileal carcinoid tumors expressed miRNA-133a by in situ hybridization. These results provide information about novel marker miRNAs that may be used as biomarkers and/or therapeutic targets in intestinal carcinoid tumors. PMID:20037573

  7. THE ROLE OF TUMOR PROGRESSION LOCUS 2 (TPL-2) PROTEIN KINASE IN GLIAL INFLAMMATORY RESPONSE

    PubMed Central

    Hirschhorn, Joshua; Mohanty, Sangeeta; Bhat, Narayan R.

    2013-01-01

    Tumor progression locus 2 (Tpl2)/Cot kinase is a newer member of MAP3K family that is now known for its essential role in TNFα expression in macrophages, but its proinflammatory signaling, if any, in glia is unknown. When cultures of murine microglia and astrocytes were exposed to lipopolysaccharide, there was a rapid activation (i.e., phosphorylation) of Tpl2 in parallel to the activation of down-stream effector MAPKs i.e., ERK, p38 MAPK and JNK. Pre-incubation of the cultures with a Tpl2 inhibitor selectively suppressed the activation of the primary down-stream target i.e., ERK relative to p38 MAPK and JNK. That Tpl2 activation was functionally involved in glial inflammatory response was indicated by a reduced release of the cytokines i.e., TNFα and the expression of inducible nitric oxide synthase (iNOS) in the presence of the kinase inhibitor. Further, overexpression of a wild-type Tpl2 construct in C-6 glia resulted in an enhanced transcriptional activation of iNOS while transfection with a dominant negative form of Tpl-2 had the opposite effect. The findings assign an important proinflammatory signaling function for Tpl2 pathway in glial cells. PMID:24188160

  8. Imbalance of tumor necrosis factor receptors during progression in bovine leukemia virus infection

    SciTech Connect

    Konnai, Satoru . E-mail: konnai@vetmed.hokudai.ac.jp; Usui, Tatsufumi; Ikeda, Manabu; Kohara, Junko; Hirata, Toh-ichi; Okada, Kosuke; Ohashi, Kazuhiko; Onuma, Misao

    2005-09-01

    Previously, we found an up-regulation of tumor necrosis factor alpha (TNF)-{alpha} and an imbalance of TNF receptors in sheep experimentally infected with bovine leukemia virus (BLV). In order to investigate the different TNF-{alpha}-induced responses, in this study we examined the TNF-{alpha}-induced proliferative response and the expression levels of two distinct TNF receptors on peripheral blood mononuclear cells (PBMC) derived from BLV-uninfected cattle and BLV-infected cattle that were aleukemic (AL) or had persistent lymphocytosis (PL). The proliferative response of PBMC isolated from those cattle with PL in the presence of recombinant bovine TNF-{alpha} (rTNF-{alpha}) was significantly higher than those from AL cattle and uninfected cattle and the cells from PL cattle expressed significantly higher mRNA levels of TNF receptor type II (TNF-RII) than those from AL and BLV-uninfected cattle. No difference was found in TNF-RI mRNA levels. Most cells expressing TNF-RII in PL cattle were CD5{sup +} or sIgM{sup +} cells and these cells showed resistance to TNF-{alpha}-induced apoptosis. Additionally, there were significant positive correlations between the changes in provirus load and TNF-RII mRNA levels, and TNF-{alpha}-induced proliferation and TNF-RII mRNA levels. These data suggest that imbalance in the expression of TNF receptors could at least in part contribute to the progression of lymphocytosis in BLV infection.

  9. Overexpressed HDAC4 is associated with poor survival and promotes tumor progression in esophageal carcinoma

    PubMed Central

    Mai, Shi-Juan; Wang, Meng-He; Zhang, Mei-Yin; Zheng, X.F. Steven; Wang, Hui-Yun

    2016-01-01

    Histone deacetylases (HDACs) mediate histone deacetylation, leading to transcriptional repression, which is involved in many diseases, including age-related tissue degeneration, heart failure and cancer. In this study, we were aimed to investigate the expression, clinical significance and biological function of HDAC4 in esophageal carcinoma (EC). We found that HDAC4 mRNA and protein are overexpressed in esophageal squamous cell carcinoma (ESCC) tissues and cell lines. HDAC4 overexpression is associated with higher tumor grade, advanced clinical stage and poor survival. Mechanistically, HDAC4 promotes proliferation and G1/S cell cycle progression in EC cells by inhibiting cyclin-dependent kinase (CDK) inhibitors p21 and p27 and up-regulating CDK2/4 and CDK-dependent Rb phosphorylation. HDAC4 also enhances ESCC cell migration. Furthermore, HDAC4 positively regulates epithelial-mesenchymal transition (EMT) by increasing the expression of Vimentin and decreasing the expression of E-Cadherin/α-Catenin. Together, our study shows that HDAC4 overexpression is important for the oncogenesis of EC, which may serve as a useful prognostic biomarker and therapeutic target for this malignancy. PMID:27295551

  10. Registered report: Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF.

    PubMed

    Bhargava, Ajay; Anant, Madan; Mack, Hildegard

    2016-01-01

    The Reproducibility Project: Cancer Biology seeks to address growing concerns about reproducibility in scientific research by conducting replications of selected experiments from a number of high-profile papers in the field of cancer biology. The papers, which were published between 2010 and 2012, were selected on the basis of citations and Altmetric scores (Errington et al., 2014). This Registered Report describes the proposed replication plan of key experiments from "Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF" by Heidorn and colleagues, published in Cell in 2010 (Heidorn et al., 2010). The experiments to be replicated are those reported in Figures 1A, 1B, 3A, 3B, and 4D. Heidorn and colleagues report that paradoxical activation of the RAF-RAS-MEK-ERK pathway by BRAF inhibitors when applied to BRAF(WT) cells is a result of BRAF/CRAF heterodimer formation upon inactivation of BRAF kinase activity, and occurs only in the context of active RAS. The Reproducibility Project: Cancer Biology is a collaboration between the Center for Open Science and Science Exchange, and the results of the replications will be published by eLife. PMID:26885666

  11. Ovarian cancer progression is controlled by phenotypic changes in dendritic cells

    PubMed Central

    Scarlett, Uciane K.; Rutkowski, Melanie R.; Rauwerdink, Adam M.; Fields, Jennifer; Escovar-Fadul, Ximena; Baird, Jason; Cubillos-Ruiz, Juan R.; Jacobs, Ana C.; Gonzalez, Jorge L.; Weaver, John; Fiering, Steven

    2012-01-01

    We characterized the initiation and evolution of the immune response against a new inducible p53-dependent model of aggressive ovarian carcinoma that recapitulates the leukocyte infiltrates and cytokine milieu of advanced human tumors. Unlike other models that initiate tumors before the development of a mature immune system, we detect measurable anti-tumor immunity from very early stages, which is driven by infiltrating dendritic cells (DCs) and prevents steady tumor growth for prolonged periods. Coinciding with a phenotypic switch in expanding DC infiltrates, tumors aggressively progress to terminal disease in a comparatively short time. Notably, tumor cells remain immunogenic at advanced stages, but anti-tumor T cells become less responsive, whereas their enduring activity is abrogated by different microenvironmental immunosuppressive DCs. Correspondingly, depleting DCs early in the disease course accelerates tumor expansion, but DC depletion at advanced stages significantly delays aggressive malignant progression. Our results indicate that phenotypically divergent DCs drive both immunosurveillance and accelerated malignant growth. We provide experimental support for the cancer immunoediting hypothesis, but we also show that aggressive cancer progression after a comparatively long latency period is primarily driven by the mobilization of immunosuppressive microenvironmental leukocytes, rather than loss of tumor immunogenicity. PMID:22351930

  12. Deletion of 5-Lipoxygenase in the Tumor Microenvironment Promotes Lung Cancer Progression and Metastasis through Regulating T Cell Recruitment.

    PubMed

    Poczobutt, Joanna M; Nguyen, Teresa T; Hanson, Dwight; Li, Howard; Sippel, Trisha R; Weiser-Evans, Mary C M; Gijon, Miguel; Murphy, Robert C; Nemenoff, Raphael A

    2016-01-15

    Eicosanoids, including PGs, produced by cyclooxygenases (COX), and leukotrienes, produced by 5-lipoxygenase (5-LO) have been implicated in cancer progression. These molecules are produced by both cancer cells and the tumor microenvironment (TME). We previously reported that both COX and 5-LO metabolites increase during progression in an orthotopic immunocompetent model of lung cancer. Although PGs in the TME have been well studied, less is known regarding 5-LO products produced by the TME. We examined the role of 5-LO in the TME using a model in which Lewis lung carcinoma cells are directly implanted into the lungs of syngeneic WT mice or mice globally deficient in 5-LO (5-LO-KO). Unexpectedly, primary tumor volume and liver metastases were increased in 5-LO-KO mice. This was associated with an ablation of leukotriene (LT) production, consistent with production mainly mediated by the microenvironment. Increased tumor progression was partially reproduced in global LTC4 synthase KO or mice transplanted with LTA4 hydrolase-deficient bone marrow. Tumor-bearing lungs of 5-LO-KO had decreased numbers of CD4 and CD8 T cells compared with WT controls, as well as fewer dendritic cells. This was associated with lower levels of CCL20 and CXL9, which have been implicated in dendritic and T cell recruitment. Depletion of CD8 cells increased tumor growth and eliminated the differences between WT and 5-LO mice. These data reveal an antitumorigenic role for 5-LO products in the microenvironment during lung cancer progression through regulation of T cells and suggest that caution should be used in targeting this pathway in lung cancer. PMID:26663781

  13. Deletion of 5-Lipoxygenase in the Tumor Microenvironment Promotes Lung Cancer Progression and Metastasis through Regulating T Cell Recruitment

    PubMed Central

    Poczobutt, Joanna M.; Nguyen, Teresa T.; Hanson, Dwight; Li, Howard; Sippel, Trisha R.; Weiser-Evans, Mary C. M.; Gijon, Miguel; Murphy, Robert C.

    2016-01-01

    Eicosanoids, including PGs, produced by cyclooxygenases (COX), and leukotrienes, produced by 5-lipoxygenase (5-LO) have been implicated in cancer progression. These molecules are produced by both cancer cells and the tumor microenvironment (TME). We previously reported that both COX and 5-LO metabolites increase during progression in an orthotopic immunocompetent model of lung cancer. Although PGs in the TME have been well studied, less is known regarding 5-LO products produced by the TME. We examined the role of 5-LO in the TME using a model in which Lewis lung carcinoma cells are directly implanted into the lungs of syngeneic WT mice or mice globally deficient in 5-LO (5-LO-KO). Unexpectedly, primary tumor volume and liver metastases were increased in 5-LO-KO mice. This was associated with an ablation of leukotriene (LT) production, consistent with production mainly mediated by the microenvironment. Increased tumor progression was partially reproduced in global LTC4 synthase KO or mice transplanted with LTA4 hydrolase-deficient bone marrow. Tumor-bearing lungs of 5-LO-KO had decreased numbers of CD4 and CD8 T cells compared with WT controls, as well as fewer dendritic cells. This was associated with lower levels of CCL20 and CXL9, which have been implicated in dendritic and T cell recruitment. Depletion of CD8 cells increased tumor growth and eliminated the differences between WT and 5-LO mice. These data reveal an antitumorigenic role for 5-LO products in the microenvironment during lung cancer progression through regulation of T cells and suggest that caution should be used in targeting this pathway in lung cancer. PMID:26663781

  14. RD3 loss dictates high-risk aggressive neuroblastoma and poor clinical outcomes

    PubMed Central

    Aravindan, Sheeja; Natarajan, Mohan; Azadi, Seifollah; Herman, Terence S.; Aravindan, Natarajan

    2015-01-01

    Clinical outcomes for high-risk neuroblastoma patients remains poor, with only 40–50% 5-Year overall survival (OS) and <10% long-term survival. The ongoing acquisition of genetic/molecular rearrangements in undifferentiated neural crest cells may endorse neuroblastoma progression. This study recognized the loss of Retinal Degeneration protein 3, RD3 in aggressive neuroblastoma, and identified its influence in better clinical outcomes and defined its novel metastasis suppressor function. The results showed ubiquitous expression of RD3 in healthy tissues, complete-loss and significant TNM-stage association of RD3 in clinical samples. RD3-loss was intrinsically associated with reduced OS, abridged relapse-free survival, aggressive stage etc., in neuroblastoma patient cohorts. RD3 was transcriptionally and translationally regulated in metastatic site-derived aggressive (MSDAC) cells (regardless of CSC status) ex vivo and in tumor manifolds from metastatic sites in reproducible aggressive disease models in vivo. Re-expressing RD3 in MSDACs reverted their metastatic potential both in vitro and in vivo. Conversely muting RD3 in neuroblastoma cells not only heightened invasion/migration but also dictated aggressive disease with metastasis. These results demonstrate the loss of RD3 in high-risk neuroblastoma, its novel, thus-far unrecognized metastasis suppressor function and further imply that RD3-loss may directly relate to tumor aggressiveness and poor clinical outcomes. PMID:26375249

  15. Bioluminescence-Based Tumor Quantification Method for Monitoring Tumor Progression and Treatment Effects in Mouse Lymphoma Models.

    PubMed

    Cosette, Jeremie; Ben Abdelwahed, Rym; Donnou-Triffault, Sabrina; Sautès-Fridman, Catherine; Flaud, Patrice; Fisson, Sylvain

    2016-01-01

    Although bioluminescence imaging (BLI) shows promise for monitoring tumor burden in animal models of cancer, these analyses remain mostly qualitative. Here we describe a method for bioluminescence imaging to obtain a semi-quantitative analysis of tumor burden and treatment response. This method is based on the calculation of a luminoscore, a value that allows comparisons of two animals from the same or different experiments. Current BLI instruments enable the calculation of this luminoscore, which relies mainly on the acquisition conditions (back and front acquisitions) and the drawing of the region of interest (manual markup around the mouse). Using two previously described mouse lymphoma models based on cell engraftment, we show that the luminoscore method can serve as a noninvasive way to verify successful tumor cell inoculation, monitor tumor burden, and evaluate the effects of in situ cancer treatment (CpG-DNA). Finally, we show that this method suits different experimental designs. We suggest that this method be used for early estimates of treatment response in preclinical small-animal studies. PMID:27501019

  16. NOK/STYK1 promotes the genesis and remodeling of blood and lymphatic vessels during tumor progression.

    PubMed

    Liu, Yue; Li, Tianqi; Hu, Dan; Zhang, Shuping

    2016-09-01

    Previous studies have indicated that the overexpression of NOK, also named STYK1, led to tumorigenesis and metastasis. Here, we provide evidence that increased expression of NOK/STYK1 caused marked alterations in the overall and inner structures of tumors and substantially facilitates the genesis and remodeling of the blood and lymphatic vessels during tumor progression. In particular, NOK-expressed HeLa stable cells (HeLa-K) significantly enhanced tumor growth and metastasis in xenografted nude mice. Hematoxylin and eosin (HE) staining demonstrated that the tumor tissues generated by HeLa-K cells were much more ichorous and had more interspaces than those generated by control HeLa cells (HeLa-C). The fluorescent areas stained with cluster of differentiation 31 (CD31), a marker protein for blood vessels, appeared to be in different patterns. The total blood vessels, especially the ring patterns, within the tumors of the HeLa-K group were highly enriched compared with those in the HeLa-C group. NOK-HA was demonstrated to be well colocalized with CD31 in the wall of the tubular structures within tumor tissues. Interestingly, antibody staining of the lymphatic vessel endothelial hyaluronan receptor (LYVE-1) further revealed the increase in ring (oratretic strip-like) lymphatic vessels in either the peritumoral or intratumoral areas in the HeLa-K group compared with the HeLa-C group. Consistently, the analysis of human cancerous tissue also showed that NOK was highly expressed in the walls of tubular structures. Thus, our results reveal a novel tumorigenic function of NOK to mediate the genesis and remodeling of blood and lymphatic vessels during tumor progression. PMID:27444381

  17. B cells promote tumor progression in a mouse model of HPV-mediated cervical cancer.

    PubMed

    Tang, Alexandre; Dadaglio, Gilles; Oberkampf, Marine; Di Carlo, Selene; Peduto, Lucie; Laubreton, Daphné; Desrues, Belinda; Sun, Cheng-Ming; Montagutelli, Xavier; Leclerc, Claude

    2016-09-15

    Enhancing anti-tumor immunity and preventing tumor escape are efficient strategies to increase the efficacy of therapeutic cancer vaccines. However, the treatment of advanced tumors remains difficult, mainly due to the immunosuppressive tumor microenvironment. Regulatory T cells and myeloid-derived suppressor cells have been extensively studied, and their role in suppressing tumor immunity is now well established. In contrast, the role of B lymphocytes in tumor immunity remains unclear because B cells can promote tumor immunity or display regulatory functions to control excessive inflammation, mainly through IL-10 secretion. Here, in a mouse model of HPV-related cancer, we demonstrate that B cells accumulated in the draining lymph node of tumor-bearing mice, due to a prolonged survival, and showed a decreased expression of MHC class II and CD86 molecules and an increased expression of Ly6A/E, PD-L1 and CD39, suggesting potential immunoregulatory properties. However, B cells from tumor-bearing mice did not show an increased ability to secrete IL-10 and a deficiency in IL-10 production did not impair tumor growth. In contrast, in B cell-deficient μMT mice, tumor rejection occurred due to a strong T cell-dependent anti-tumor response. Genetic analysis based on single nucleotide polymorphisms identified genetic variants associated with tumor rejection in μMT mice, which could potentially affect reactive oxygen species production and NK cell activity. Our results demonstrate that B cells play a detrimental role in anti-tumor immunity and suggest that targeting B cells could enhance the anti-tumor response and improve the efficacy of therapeutic cancer vaccines. PMID:27130719

  18. Lenalidomide in Treating Young Patients With Recurrent, Progressive, or Refractory CNS Tumors

    ClinicalTrials.gov

    2013-09-27

    Childhood Atypical Teratoid/Rhabdoid Tumor; Childhood Central Nervous System Germ Cell Tumor; Childhood Choroid Plexus Tumor; Childhood Craniopharyngioma; Childhood Ependymoblastoma; Childhood Grade I Meningioma; Childhood Grade II Meningioma; Childhood Grade III Meningioma; Childhood High-grade Cerebellar Astrocytoma; Childhood High-grade Cerebral Astrocytoma; Childhood Infratentorial Ependymoma; Childhood Low-grade Cerebellar Astrocytoma; Childhood Low-grade Cerebral Astrocytoma; Childhood Medulloepithelioma; Childhood Mixed Glioma; Childhood Oligodendroglioma; Childhood Supratentorial Ependymoma; Recurrent Childhood Brain Tumor; Recurrent Childhood Cerebellar Astrocytoma; Recurrent Childhood Cerebral Astrocytoma; Recurrent Childhood Ependymoma; Recurrent Childhood Medulloblastoma; Recurrent Childhood Pineoblastoma; Recurrent Childhood Subependymal Giant Cell Astrocytoma; Recurrent Childhood Supratentorial Primitive Neuroectodermal Tumor; Recurrent Childhood Visual Pathway and Hypothalamic Glioma

  19. [Progress in study of chemical constituents and anti-tumor activities of Cnidium monnieri].

    PubMed

    Zhou, Ze-wei; Liu, Pei-xun

    2005-09-01

    The main pharmacological constituents of Chinese traditional medicine herb Cnidium monnieri are coumarin compounds and volatile oil. In addition, it contains monoterpene polyols, glucides, as well as recently discovered sesquiterpene components. In recent years, rather active investigations of its anti-tumor were performed at home and abroad. C. monnieri possesses multi-aspect and comprehensive anti-tumor functions, involving directly tumor-inhibitory activity, anti-mutagenicity, reversing multi-drug tolerance of tumor, as well as improving immune functions and so on. In this review, chemical constituents, anti-tumor activities and relevant investigations of Fructus Cnidii were summarized recent decade. PMID:16323535

  20. Breast cancer cells mechanosensing in engineered matrices: Correlation with aggressive phenotype.

    PubMed

    Li, Ji; Wu, Yang; Schimmel, Nicholas; Al-Ameen, Mohammad Ali; Ghosh, Gargi

    2016-08-01

    The pathogenesis of cancer is often driven by the modulation of the tumor microenvironment. Recent reports have highlighted that the progressive stiffening of tumor matrix is crucial for malignant transformation. Though extensive work has been done analyzing the mechanotransductive signals involved in tumor progression, it is still not clear whether the stiffness induced changes in cancer cell behavior is conserved across the invasive/aggressive phenotype of cells. Here, we used synthetic hydrogel based cell culture platform to correlate the aggressive potential of the breast cancer cells to the responses to matrix stiffness. The cellular functions such as proliferation, migration, and angiogenic capability were characterized. We report that the proliferation and motility of the highly aggressive cell line MDA-MB-231 increased with increase in matrix rigidity. We also demonstrated for the first time that the change in matrix stiffness stimulated the angiogenic activity of these cells as manifested from enhanced expression of vascular endothelial growth factor (VEGF). Inhibition of actomyosin contractility attenuated proliferation of MDA-MB-231 cells on stiff matrices while promoted the growth on soft gels. In addition, the release of VEGF was reduced upon inhibition of contractility. The less and non-aggressive breast cancer cells, SKBr3 and MCF-7 respectively displayed less dependency on matrix stiffness. PMID:26874251

  1. Decreased Expression of Fructose-1,6-bisphosphatase Associates with Glucose Metabolism and Tumor Progression in Hepatocellular Carcinoma.

    PubMed

    Hirata, Hidenari; Sugimachi, Keishi; Komatsu, Hisateru; Ueda, Masami; Masuda, Takaaki; Uchi, Ryutaro; Sakimura, Shotaro; Nambara, Sho; Saito, Tomoko; Shinden, Yoshiaki; Iguchi, Tomohiro; Eguchi, Hidetoshi; Ito, Shuhei; Terashima, Kotaro; Sakamoto, Katsumi; Hirakawa, Masakazu; Honda, Hiroshi; Mimori, Koshi

    2016-06-01

    Fructose-1,6-bisphosphatase (FBP1), the rate-limiting enzyme in gluconeogenesis, is reduced in expression in certain cancers where it has been hypothesized to act as a tumor suppressor, including in hepatocellular carcinoma (HCC). Here, we report functional evidence supporting this hypothesis, providing a preclinical rationale to develop FBP1 as a therapeutic target for HCC treatment. Three independent cohorts totaling 594 cases of HCC were analyzed to address clinical significance. Lower FBP1 expression associated with advanced tumor stage, poor overall survival, and higher tumor recurrence rates. In HCC cell lines, where endogenous FBP1 expression is low, engineering its ectopic overexpression inhibited tumor growth and intracellular glucose uptake by reducing aerobic glycolysis. In patient specimens, promoter methylation and copy-number loss of FBP1 were independently associated with decreased FBP1 expression. Similarly, FBP1 downregulation in HCC cell lines was also associated with copy-number loss. HCC specimens exhibiting low expression of FBP1 had a highly malignant phenotype, including large tumor size, poor differentiation, impaired gluconeogenesis, and enhanced aerobic glycolysis. The effects of FBP1 expression on prognosis and glucose metabolism were confirmed by gene set enrichment analysis. Overall, our findings established that FBP1 downregulation in HCC contributed to tumor progression and poor prognosis by altering glucose metabolism, and they rationalize further study of FBP1 as a prognostic biomarker and therapeutic target in HCC patients. Cancer Res; 76(11); 3265-76. ©2016 AACR. PMID:27197151

  2. Recent progress towards development of effective systemic chemotherapy for the treatment of malignant brain tumors

    PubMed Central

    Sarin, Hemant

    2009-01-01

    Systemic chemotherapy has been relatively ineffective in the treatment of malignant brain tumors even though systemic chemotherapy drugs are small molecules that can readily extravasate across the porous blood-brain tumor barrier of malignant brain tumor microvasculature. Small molecule systemic chemotherapy drugs maintain peak blood concentrations for only minutes, and therefore, do not accumulate to therapeutic concentrations within individual brain tumor cells. The physiologic upper limit of pore size in the blood-brain tumor barrier of malignant brain tumor microvasculature is approximately 12 nanometers. Spherical nanoparticles ranging between 7 nm and 10 nm in diameter maintain peak blood concentrations for several hours and are sufficiently smaller than the 12 nm physiologic upper limit of pore size in the blood-brain tumor barrier to accumulate to therapeutic concentrations within individual brain tumor cells. Therefore, nanoparticles bearing chemotherapy that are within the 7 to 10 nm size range can be used to deliver therapeutic concentrations of small molecule chemotherapy drugs across the blood-brain tumor barrier into individual brain tumor cells. The initial therapeutic efficacy of the Gd-G5-doxorubicin dendrimer, an imageable nanoparticle bearing chemotherapy within the 7 to 10 nm size range, has been demonstrated in the orthotopic RG-2 rodent malignant glioma model. Herein I discuss this novel strategy to improve the effectiveness of systemic chemotherapy for the treatment of malignant brain tumors and the therapeutic implications thereof. PMID:19723323

  3. Application of Circulating Tumor DNA as a Non-Invasive Tool for Monitoring the Progression of Colorectal Cancer

    PubMed Central

    Guan, Yanfang; Yang, Ling; Xia, Xuefeng; Cui, Liqiang; Yi, Xin; Lin, Guole

    2016-01-01

    Background Liquid biopsy has been proposed to be a promising noninvasive tool to obtain information on tumor progression. Through a clinical observation of a case series of 6 consecutive patients, we aim to determine the value of circulating tumor DNA (ctDNA) for monitoring the tumor burden during the treatment of colorectal cancer (CRC). Materials and Methods We used capture sequencing of 545 genes to identify somatic alternations in primary tumor tissues of the six CRC patients who underwent radical surgery and in 23 plasma samples collected at serial time points. We compared the mutation patterns and variant allele frequencies (VAFs) between the matched tissue and the plasma samples and evaluated the potential advantage of using ctDNA as a better tumor load indicator to detect disease relapse over carcinoembryonic antigen (CEA), cancer antigen (CA) 19–9 and imaging studies. Results We identified low-frequency mutations with a mean VAF of 0.88% (corresponding to a mean tumor burden of 0.20ng/mL) in the preoperative plasmas of four patients with locally advanced CRC and a subset of mutations shared by their primary tumors. The tumor loads appeared a sudden decrease upon surgery or other adjuvant treatments and then generally maintained at low levels (0.092ng/mL) until disease recurred. ctDNA increased by 13-fold when disease relapsed in one patient while the CEA and CA 19–9 levels remained normal. In this patient, all six somatic mutations identified in the preoperative plasma were detected in the recrudescent plasma again, with five mutations showing allele fraction increase. Conclusions We described a multi-time-point profile of ctDNA of CRC patients during the course of comprehensive treatment and observed a correlation of ctDNA level with the clinically evaluated tumor progression. This demonstrated a new strategy by analyzing the heterogeneous ctDNA to evaluate and monitor the tumor burden in the treatment and follow-up of CRC patients, with potentially

  4. Upregulated microRNA-301a in osteosarcoma promotes tumor progression by targeting CDC14A.

    PubMed

    Ni, Z; Shang, X F; Wang, Y F; Sun, Y J; Fu, D J

    2016-01-01

    MicroRNAs (miRs) are associated with tumor progression in various cancers, such as gastric and hepatic carcinomas, and lung cancer. miR-301a is overexpressed and displays oncogenic activity in cancers. We investigated the biological involvement of miR-301a in osteosarcoma (OS). Quantitative real-time polymerase chain reaction (qRT-PCR) was used to analyze expression levels of miR-301a in 24 OS and matched adjacent non-tumor tissues. A miR-301a mimic was transferred into OS cell lines U-2 OS and MG-63 to upregulate miR-301a. The effects of miR-301a were investigated by examining cell proliferation, migration, and the cell cycle. The miR-301 target was predicted by TargetScan and confirmed by western blotting and qRT-PCR. The expression of miR-301a was significantly higher in OS tissues compared with the matched adjacent non-tumor tissues (0.959 ± 0.39 vs 3.9516 ± 1.18). Upregulated miR-301a significantly increased proliferation at 48 and 72 h compared to the negative control (U-2 OS: 2.11 ± 0.21 vs 2.88 ± 0.24; 2.70 ± 0.26 vs 3.71 ± 0.24; MG-63: 2.19 ± 0.20 vs 3.19 ± 0.22; 3.1 ± 0.25 vs 4.01 ± 0.27) and migration capability (U-2 OS: 100 ± 20.19 vs 150.68 ± 32.83; MG-63: 100 ± 17.20 vs 133.35 ± 26.26), and decreased apoptosis in both U-2 OS (10.87 ± 2.53 vs 4.01 ± 2.23) and MG-63 (15.26 ± 2.15 vs 8.25 ± 3.07). The cell cycle studies revealed that miR-301a caused an increase of the G2 population in U-2 OS (38.6 ± 6.58 vs 47.2 ± 7.27) and MG-63 (44.01 ± 5.28 vs 57.9 ± 4.25). Additional experiments indicated that CDC14A was upregulated by miR-301a (0.63 ± 0.06 vs 0.98 ± 0.06; 1.49 ± 0.25 vs 2.99 ± 0.14). Overexpressed miR-301a may increase CDC14A expression and promote cell proliferation and migration in OS cells. Therefore, miR- 301a may be useful for osteosarcoma diagnosis and therapy. PMID:27323075

  5. Risk assessment of multistate progression of breast tumor with state-dependent genetic and environmental covariates.

    PubMed

    Wu, Yi-Ying; Yen, Ming-Fang; Yu, Cheng-Ping; Chen, Hsiu-Hsi

    2014-02-01

    Few studies have focused on the different roles risk factors play in the multistate temporal natural course of breast cancer. We proposed a three-state Markov regression model to predict the risk from free of breast cancer (FBC) to the preclinical screen-detectable phase (PCDP) and from the PCDP to the clinical phase (CP). We searched the initiators and promoters affecting onset and subsequent progression of breast tumor to build up a three-state temporal natural history model with state-dependent genetic and environmental covariates. This risk assessment model was applied to a 1 million Taiwanese women cohort. The proposed model was verified by external validation with another independent data set. We identified three kinds of initiators, including the BRCA gene, seven single nucleotides polymorphism, and breast density. ER, Ki-67, and HER-2 were found as promoters. Body mass index and age at first pregnancy both played a role. Among women carrying the BRCA gene, the 10-year predicted risk for the transition from FBC to CP was 25.83%, 20.31%, and 13.84% for the high-, intermediate-, and low-risk group, respectively. The corresponding figures were 1.55%, 1.22%, and 0.76% among noncarriers. The mean sojourn time of staying at the PCDP ranged from 0.82 years for the highest risk group to 6.21 years for the lowest group. The lack of statistical significance for external validation (x(4)2=5.30,p=0.26) revealed the adequacy of our proposed model. The three-state model with state-dependent covariates of initiators and promoters was proposed for achieving individually tailored screening and also for personalized clinical surveillance of early breast cancer. PMID:24111840

  6. Translation factors and ribosomal proteins control tumor onset and progression: how?

    PubMed

    Loreni, F; Mancino, M; Biffo, S

    2014-04-24

    Gene expression is shaped by translational control. The modalities and the extent by which translation factors modify gene expression have revealed therapeutic scenarios. For instance, eukaryotic initiation factor (eIF)4E activity is controlled by the signaling cascade of growth factors, and drives tumorigenesis by favoring the translation of specific mRNAs. Highly specific drugs target the activity of eIF4E. Indeed, the antitumor action of mTOR complex 1 (mTORc1) blockers like rapamycin relies on their capability to inhibit eIF4E assembly into functional eIF4F complexes. eIF4E biology, from its inception to recent pharmacological targeting, is proof-of-principle that translational control is druggable. The case for eIF4E is not isolated. The translational machinery is involved in the biology of cancer through many other mechanisms. First, untranslated sequences on mRNAs as well as noncoding RNAs regulate the translational efficiency of mRNAs that are central for tumor progression. Second, other initiation factors like eIF6 show a tumorigenic potential by acting downstream of oncogenic pathways. Third, genetic alterations in components of the translational apparatus underlie an entire class of inherited syndromes known as 'ribosomopathies' that are associated with increased cancer risk. Taken together, data suggest that in spite of their evolutionary conservation and ubiquitous nature, variations in the activity and levels of ribosomal proteins and translation factors generate highly specific effects. Beside, as the structures and biochemical activities of several noncoding RNAs and initiation factors are known, these factors may be amenable to rational pharmacological targeting. The future is to design highly specific drugs targeting the translational apparatus. PMID:23644661

  7. Long non-coding RNA HOTAIR is a marker for hepatocellular carcinoma progression and tumor recurrence

    PubMed Central

    GAO, JIAN-ZHI; LI, JIA; DU, JING-LI; LI, XIAO-LEI

    2016-01-01

    The present study aimed to investigate the expression level of HOX transcript antisense RNA (HOTAIR) in hepatocellular carcinoma (HCC) and its association with various clinicopathological characteristics, and to further explore the molecular mechanisms of HOTAIR function in HCC. Quantitative reverse transcription-polymerase chain reaction (RT-PCR) was used to detect the expression level of HOTAIR in 60 paired fresh HCC samples and adjacent normal liver tissue samples. The association between HOTAIR expression and clinicopathological parameters was analyzed. Lentivirus-mediated HOTAIR-specific small hairpin RNA vectors were transfected into HepG2 cells. Cell proliferation and invasion in vitro were examined by MTT and Transwell assays, respectively. A xenograft model was used to analyze the tumorigenesis of liver cancer cells in vivo. In addition, semi-quantitative RT-PCR was used to detect the expression level of Wnt/β-catenin signaling molecules under the condition of HOTAIR inhibition. The results revealed that the expression level of HOTAIR in HCC tissues was higher than that in adjacent non-cancerous tissues. HOTAIR expression was significantly associated with poor tumor differentiation (P=0.002), metastasis (P=0.002) and early recurrence (P=0.001). In vitro, the inhibition of HOTAIR in liver cancer cells resulted in the suppression of cell proliferation and invasion. HOTAIR depletion significantly inhibited the rate of growth of liver cancer cells in vivo. Furthermore, the expression levels of Wnt and β-catenin were downregulated when HOTAIR expression was suppressed. In conclusion, HOTAIR is important in the progression and recurrence of HCC, partly through the regulation of the Wnt/β-catenin signaling pathway. Targeting HOTAIR may be a novel therapeutic strategy for HCC. PMID:26998078

  8. Soy Protein Isolate Protects Against Ethanol-Mediated Tumor Progression in Diethylnitrosamine-Treated Male Mice.

    PubMed

    Mercer, Kelly E; Pulliam, Casey; Hennings, Leah; Lai, Keith; Cleves, Mario; Jones, Ellen; Drake, Richard R; Ronis, Martin

    2016-06-01

    In this study, diethylnitrosamine-treated male mice were assigned to three groups: (i) a 35% high fat ethanol liquid diet (EtOH) with casein as the protein source, (ii) the same EtOH liquid diet with soy protein isolate as the sole protein source (EtOH/SPI), (iii) and a chow group. EtOH feeding continued for 16 weeks. As expected, EtOH increased the incidence and multiplicity of basophilic lesions and adenomas compared with the chow group, P < 0.05. Soy protein replacement of casein in the EtOH diet significantly reduced adenoma progression when compared with the EtOH and EtOH/SPI group (P < 0.05). Tumor reduction in the EtOH/SPI group corresponded to reduced liver injury associated with decreased hepatic Tnfα and Cd14 antigen (Cd14) expression and decreased nuclear accumulation of NF-κB1 protein compared with the EtOH group (P < 0.05). Detection of sphingolipids using high-resolution matrix-assisted laser desorption/ionization-Fourier transform ion cyclotron resonance (MALDI-FTICR) imaging mass spectrometry revealed increased accumulation of long acyl chain ceramide species, and sphingosine-1-phosphate (S1P) in the EtOH group that were significantly reduced in the EtOH/SPI group. Chronic EtOH feeding also increased mRNA expression of β-catenin transcriptional targets, including cyclin D1 (Ccnd1), matrix metallopeptidase 7 (Mmp7), and glutamine synthetase (Glns), which were reduced in the EtOH/SPI group (P < 0.05). We conclude that soy prevents tumorigenesis by reducing proinflammatory and oxidative environment resulting from EtOH-induced hepatic injury, and by reducing hepatocyte proliferation through inhibition of β-catenin signaling. These mechanisms may involve changes in sphingolipid signaling. Cancer Prev Res; 9(6); 466-75. ©2016 AACR. PMID:27006377

  9. Aspirin delays mesothelioma growth by inhibiting HMGB1-mediated tumor progression

    PubMed Central

    Yang, H; Pellegrini, L; Napolitano, A; Giorgi, C; Jube, S; Preti, A; Jennings, C J; De Marchis, F; Flores, E G; Larson, D; Pagano, I; Tanji, M; Powers, A; Kanodia, S; Gaudino, G; Pastorino, S; Pass, H I; Pinton, P; Bianchi, M E; Carbone, M

    2015-01-01

    High-mobility group box 1 (HMGB1) is an inflammatory molecule that has a critical role in the initiation and progression of malignant mesothelioma (MM). Aspirin (acetylsalicylic acid, ASA) is the most widely used nonsteroidal anti-inflammatory drug that reduces the incidence, metastatic potential and mortality of many inflammation-induced cancers. We hypothesized that ASA may exert anticancer properties in MM by abrogating the carcinogenic effects of HMGB1. Using HMGB1-secreting and -non-secreting human MM cell lines, we determined whether aspirin inhibited the hallmarks of HMGB1-induced MM cell growth in vitro and in vivo. Our data demonstrated that ASA and its metabolite, salicylic acid (SA), inhibit motility, migration, invasion and anchorage-independent colony formation of MM cells via a novel HMGB1-mediated mechanism. ASA/SA, at serum concentrations comparable to those achieved in humans taking therapeutic doses of aspirin, and BoxA, a specific inhibitor of HMGB1, markedly reduced MM growth in xenograft mice and significantly improved survival of treated animals. The effects of ASA and BoxA were cyclooxygenase-2 independent and were not additive, consistent with both acting via inhibition of HMGB1 activity. Our findings provide a rationale for the well documented, yet poorly understood antitumorigenic activity of aspirin, which we show proceeds via HMGB1 inhibition. Moreover, the use of BoxA appears to allow a more efficient HMGB1 targeting while eluding the known gastrointestinal side effects of ASA. Our findings are directly relevant to MM. Given the emerging importance of HMGB1 and its tumor-promoting functions in many cancer types, and of aspirin in cancer prevention and therapy, our investigation is poised to provide broadly applicable information. PMID:26068794

  10. Aspirin delays mesothelioma growth by inhibiting HMGB1-mediated tumor progression.

    PubMed

    Yang, H; Pellegrini, L; Napolitano, A; Giorgi, C; Jube, S; Preti, A; Jennings, C J; De Marchis, F; Flores, E G; Larson, D; Pagano, I; Tanji, M; Powers, A; Kanodia, S; Gaudino, G; Pastorino, S; Pass, H I; Pinton, P; Bianchi, M E; Carbone, M

    2015-01-01

    High-mobility group box 1 (HMGB1) is an inflammatory molecule that has a critical role in the initiation and progression of malignant mesothelioma (MM). Aspirin (acetylsalicylic acid, ASA) is the most widely used nonsteroidal anti-inflammatory drug that reduces the incidence, metastatic potential and mortality of many inflammation-induced cancers. We hypothesized that ASA may exert anticancer properties in MM by abrogating the carcinogenic effects of HMGB1. Using HMGB1-secreting and -non-secreting human MM cell lines, we determined whether aspirin inhibited the hallmarks of HMGB1-induced MM cell growth in vitro and in vivo. Our data demonstrated that ASA and its metabolite, salicylic acid (SA), inhibit motility, migration, invasion and anchorage-independent colony formation of MM cells via a novel HMGB1-mediated mechanism. ASA/SA, at serum concentrations comparable to those achieved in humans taking therapeutic doses of aspirin, and BoxA, a specific inhibitor of HMGB1, markedly reduced MM growth in xenograft mice and significantly improved survival of treated animals. The effects of ASA and BoxA were cyclooxygenase-2 independent and were not additive, consistent with both acting via inhibition of HMGB1 activity. Our findings provide a rationale for the well documented, yet poorly understood antitumorigenic activity of aspirin, which we show proceeds via HMGB1 inhibition. Moreover, the use of BoxA appears to allow a more efficient HMGB1 targeting while eluding the known gastrointestinal side effects of ASA. Our findings are directly relevant to MM. Given the emerging importance of HMGB1 and its tumor-promoting functions in many cancer types, and of aspirin in cancer prevention and therapy, our investigation is poised to provide broadly applicable information. PMID:26068794

  11. Ascorbate as a Co-Factor for Fe- and 2-Oxoglutarate Dependent Dioxygenases: Physiological Activity in Tumor Growth and Progression

    PubMed Central

    Kuiper, Caroline; Vissers, Margreet C. M.

    2014-01-01

    Ascorbate is a specific co-factor for a large family of enzymes known as the Fe- and 2-oxoglutarate-dependent dioxygenases. These enzymes are found throughout biology and catalyze the addition of a hydroxyl group to various substrates. The proline hydroxylase that is involved in collagen maturation is well known, but in recent times many new enzymes and functions have been uncovered, including those involved in epigenetic control and hypoxia-inducible factor (HIF) regulation. These discoveries have provided crucial mechanistic insights into how ascorbate may affect tumor biology. In particular, there is growing evidence that HIF-1-dependent tumor progression may be inhibited by increasing tumor ascorbate levels. However, rigorous clinical intervention studies are lacking. This review will explore the physiological role of ascorbate as an enzyme co-factor and how this mechanism relates to cancer biology and treatment. The use of ascorbate in cancer should be informed by clinical studies based on such mechanistic hypotheses. PMID:25540771

  12. Dynamical Observation on Biological Progression of VX2 Liver Tumors to Identify the Optimal Time for Intervention in Animal Models

    PubMed Central

    Wang, Zhenguang; Yang, Guangjie; Nie, Pei; Fu, Junhua; Wang, Xufu; Liu, Dan

    2013-01-01

    Purpose Based on practice guideline of “management of hepatocellular carcinoma (HCC): update” published by American Association for the Study of Liver Diseases (AASLD) and “Barcelona Clinic Liver Cancer staging system (BCLC),” this study investigated how to enroll the optimal VX2 liver tumor model for HCC researches by dynamically observing the biological progression of the tumor. Materials Thirty-two healthy New Zealand white rabbits were implanted VX2 liver tumor by cell suspension method (n=24) and tissue fragment method (n=8). All the rabbits underwent CT scans on day 7, 14, 21 and 28 after implantation to observe the size of the tumors, the time when metastases and ascites occurred and the survival time. Appropriate intervention times were estimated corresponding to different clinical HCC stages by using tumor diameter-time curve. Results The VX2 liver tumors grew rapidly within 28 days after implantation. And the tumors in the cell suspension group grew faster than those of the tissue fragment group. The appropriate intervention time corresponding to very early stage, early stage and intermediate stage were <11 days, 11–16.9 days and >16.9 days, respectively in the cell suspension group, and <19.9 days, 19.9–25.5 days and >25.5 days, respectively in the tissue fragment group. Conclusion Preclinical animal research needs to improve on different levels to yield best predictions for human patients. Researchers should seek for an individualized proposal to select optimal VX2 liver tumor models for their experiments. This approach may lead to a more accurate determination of therapeutic outcomes. PMID:23977399

  13. An Aggressive Retroperitoneal Fibromatosis

    PubMed Central

    Campara, Zoran; Spasic, Aleksandar; Aleksic, Predrag; Milev, Bosko

    2016-01-01

    Introduction: Aggressive fibromatosis (AF) is a heterogeneous group of mesenchymal tumors that have locally infiltrative growth and a tendency to relapse. The clinical picture is often conditioned by the obstruction of the ureter or small intestine. Diagnosis is based on clinical, radiological and histological parameters. A case report: We report a case of male patient, aged 35 years, with the retroperitoneal fibromatosis. He reported to the physician because of frequent urination with the feeling of pressure and pain. Computed tomography revealed the tumor mass on the front wall of the bladder with diameter of 70mm with signs of infiltration of the musculature of the anterior abdominal wall. Endoscopic transurethral biopsy showed proliferative lesion binders by type of fibromatosis. The tumor was surgically removed in a classical way. The patient feels well and has no recurrence thirty-six months after the operative procedure. Conclusion: The complete tumor resection is the therapeutic choice for the primary tumor as well as for a relapse. PMID:27147794

  14. Rab11-FIP1C Is a Critical Negative Regulator in ErbB2-Mediated Mammary Tumor Progression.

    PubMed

    Boulay, Pierre-Luc; Mitchell, Louise; Turpin, Jason; Huot-Marchand, Julie-Émilie; Lavoie, Cynthia; Sanguin-Gendreau, Virginie; Jones, Laura; Mitra, Shreya; Livingstone, Julie M; Campbell, Shirley; Hallett, Michael; Mills, Gordon B; Park, Morag; Chodosh, Lewis; Strathdee, Douglas; Norman, Jim C; Muller, William J

    2016-05-01

    Rab coupling protein (FIP1C), an effector of the Rab11 GTPases, including Rab25, is amplified and overexpressed in 10% to 25% of primary breast cancers and correlates with poor clinical outcome. Rab25 is also frequently silenced in triple-negative breast cancer, suggesting its ability to function as either an oncogene or a tumor suppressor, depending on the breast cancer subtype. However, the pathobiologic role of FIP family members, such as FIP1C, in a tumor-specific setting remains elusive. In this study, we used ErbB2 mouse models of human breast cancer to investigate FIP1C function in tumorigenesis. Doxycycline-induced expression of FIP1C in the MMTV-ErbB2 mouse model resulted in delayed mammary tumor progression. Conversely, targeted deletion of FIP1C in the mammary epithelium of an ErbB2 model coexpressing Cre recombinase led to accelerated tumor onset. Genetic and biochemical characterization of these FIP1C-proficient and -deficient tumor models revealed that FIP1C regulated E-cadherin (CDH1) trafficking and ZONAB (YBX3) function in Cdk4-mediated cell-cycle progression. Furthermore, we demonstrate that FIP1C promoted lysosomal degradation of ErbB2. Consistent with our findings in the mouse, the expression of FIP1C was inversely correlated with ErbB2 levels in breast cancer patients. Taken together, our findings indicate that FIP1C acts as a tumor suppressor in the context of ErbB2-positive breast cancer and may be therapeutically exploited as an alternative strategy for targeting aberrant ErbB2 expression. Cancer Res; 76(9); 2662-74. ©2016 AACR. PMID:26933086

  15. Margin Size is an Independent Predictor of Local Tumor Progression After Ablation of Colon Cancer Liver Metastases

    SciTech Connect

    Wang Xiaodong; Sofocleous, Constantinos T. Erinjeri, Joseph P.; Petre, Elena N.; Gonen, Mithat; Do, Kinh G.; Brown, Karen T.; Covey, Anne M.; Brody, Lynn A.; Alago, William; Thornton, Raymond H.; Kemeny, Nancy E.; Solomon, Stephen B.

    2013-02-15

    This study was designed to evaluate the relationship between the minimal margin size and local tumor progression (LTP) following CT-guided radiofrequency ablation (RFA) of colorectal cancer liver metastases (CLM). An institutional review board-approved, HIPPA-compliant review identified 73 patients with 94 previously untreated CLM that underwent RFA between March 2003 and May 2010, resulting in an ablation zone completely covering the tumor 4-8 weeks after RFA dynamic CT. Comparing the pre- with the post-RFA CT, the minimal margin size was categorized to 0, 1-5, 6-10, and 11-15 mm. Follow-up included CT every 2-4 months. Kaplan-Meier methodology and Cox regression analysis were used to evaluate the effect of the minimal margin size, tumor location, size, and proximity to a vessel on LTP. Forty-five of 94 (47.9 %) CLM progressed locally. Median LTP-free survival (LPFS) was 16 months. Two-year LPFS rates for ablated CLM with minimal margin of 0, 1-5 mm, 6-10 mm, 11-15 mm were 26, 46, 74, and 80 % (p < 0.011). Minimal margin (p = 0.002) and tumor size (p = 0.028) were independent risk factors for LTP. The risk for LTP decreased by 46 % for each 5-mm increase in minimal margin size, whereas each additional 5-mm increase in tumor size increased the risk of LTP by 22 %. An ablation zone with a minimal margin uniformly larger than 5 mm 4-8 weeks postablation CT is associated with the best local tumor control.

  16. Antibody mediated therapy targeting CD47 inhibits tumor progression of hepatocellular carcinoma.

    PubMed

    Xiao, Zhenyu; Chung, Haniee; Banan, Babak; Manning, Pamela T; Ott, Katherine C; Lin, Shin; Capoccia, Benjamin J; Subramanian, Vijay; Hiebsch, Ronald R; Upadhya, Gundumi A; Mohanakumar, Thalachallour; Frazier, William A; Lin, Yiing; Chapman, William C

    2015-05-01

    Human hepatocellular carcinoma (HCC) has a high rate of tumor recurrence and metastasis, resulting in shortened survival times. The efficacy of current systemic therapies for HCC is limited. In this study, we used xenograft tumor models to investigate the use of antibodies that block CD47 and inhibit HCC tumor growth. Immunostaining of tumor tissue and HCC cell lines demonstrated CD47 over-expression in HCC as compared to normal hepatocytes. Macrophage phagocytosis of HCC cells was increased after treatment with CD47 antibodies (CD47mAbs) that block CD47 binding to SIRPα. Further, CD47 blockade inhibited tumor growth in both heterotopic and orthotopic models of HCC, and promoted the migration of macrophages into the tumor mass. Our results demonstrate that targeting CD47 by specific antibodies has potential immunotherapeutic efficacy in human HCC. PMID:25721088

  17. Antibody mediated therapy targeting CD47 inhibits tumor progression of hepatocellular carcinoma

    PubMed Central

    Xiao, Zhenyu; Chung, Haniee; Banan, Babak; Manning, Pamela T.; Ott, Katherine C.; Lin, Shin; Capoccia, Benjamin J.; Subramanian, Vijay; Hiebsch, Ronald R.; Upadhya, Gundumi A.; Mohanakumar, Thalachallour; Frazier, William A.; Lin, Yiing; Chapman, William C.

    2016-01-01

    Human hepatocellular carcinoma (HCC) has a high rate of tumor recurrence and metastasis, resulting in shortened survival times. The efficacy of current systemic therapies for HCC is limited. In this study, we used xenograft tumor models to investigate the use of antibodies that block CD47 and inhibit HCC tumor growth. Immunostaining of tumor tissue and HCC cell lines demonstrated CD47 over-expression in HCC as compared to normal hepatocytes. Macrophage phagocytosis of HCC cells was increased after treatment with CD47 antibodies (CD47mAbs) that block CD47 binding to SIRPα. Further, CD47 blockade inhibited tumor growth in both heterotopic and orthotopic models of HCC, and promoted the migration of macrophages into the tumor mass. Our results demonstrate that targeting CD47 by specific antibodies has potential immunotherapeutic efficacy in human HCC. PMID:25721088

  18. Tumor

    MedlinePlus

    ... be removed because of their location or harmful effect on the surrounding normal brain tissue. If a tumor is cancer , possible treatments may include: Chemotherapy Radiation Surgery Targeted cancer therapy Biologic therapy Other treatment options

  19. Co-evolution of solid stress and interstitial fluid pressure in tumors during progression: Implications for vascular collapse

    PubMed Central

    Stylianopoulos, Triantafyllos; Martin, John D.; Snuderl, Matija; Mpekris, Fotios; Jain, Saloni R.; Jain, Rakesh K.

    2013-01-01

    The stress harbored by the solid phase of tumors is known as solid stress. Solid stress can be either applied externally by the surrounding normal tissue or induced by the tumor itself due to its growth. Fluid pressure is the isotropic stress exerted by the fluid phase. We recently demonstrated that growth-induced solid stress is on the order of 1.3–13.0 kPa (10–100 mmHg) - high enough to cause compression of fragile blood vessels resulting in poor perfusion and hypoxia. However, the evolution of growth-induced stress with tumor progression and its effect on cancer cell proliferation in vivo is not understood. To this end, we developed a mathematical model for tumor growth that takes into account all three types of stresses: growth-induced stress, externally applied stress and fluid pressure. First, we performed in vivo experiments and found that growth-induced stress is related to tumor volume through a bi-exponential relationship. Then, we incorporated this information into our mathematical model and showed that due to the evolution of growth-induced stress, total solid stress levels are higher in the tumor interior and lower in the periphery. Elevated compressive solid stress in the interior of the tumor is sufficient to cause the collapse of blood vessels and results in a lower growth rate of cancer cells compared to the periphery, independently from that caused by the lack of nutrients due to vessel collapse. Furthermore, solid stress in the periphery of the tumor causes blood vessels in the surrounding normal tissue to deform to elliptical shapes. We present histological sections of human cancers that demonstrate such vessel deformations. Finally, we found that fluid pressure increases with tumor growth due to increased vascular permeability and lymphatic impairment, and is governed by the microvascular pressure. Crucially, fluid pressure does not cause vessel compression of tumor vessels. Major Findings. Growth-induced solid stress is accumulated in

  20. Transcriptional profiling of macrophage and tumor cell interactions in vitro.

    PubMed

    Roudnicky, Filip; Hollmén, Maija

    2016-06-01

    Macrophages are important mediators of tumor progression and their function is broadly influenced by different microenvironmental stimuli. To understand the molecular basis of the tumor-supporting role of macrophages in aggressive breast cancer we co-cultured human peripheral monocytes with two breast cancer cell lines representing distinct aggressive cellular phenotype and transcriptionally profiled the changes occurring in both cells during in vitro activated crosstalk. Here we provide a detailed description of the experimental design, sample identity and analysis of the Illumina RNA-Seq data, which have been deposited into Gene Expression Omnibus (GEO): GSE75130. PMID:27081631

  1. Novel Phenotypic Fluorescent Three-Dimensional Co-Culture Platforms for Recapitulating Tumor in vivo Progression and for Personalized Therapy

    PubMed Central

    Fang, Changge; Man, Yan-Gao; Cuttitta, Frank; Stetler-Stevenson, William; Salomon, David; Mazar, Andrew; Kulesza, Piotr; Rosen, Steve; Avital, Itzhak; Stojadinovic, Alexander; Jewett, Anahid; Jiang, Bin; Mulshine, James

    2013-01-01

    Because three-dimensional (3D) in vitro models are more accurate than 2D cell culture models and faster and cheaper than animal models, they have become a prospective trend in the biomedical and pharmaceutical fields, especially for personalized and targeted therapies. Because appropriate 3D models can be customized to mimic the in vivo microenvironment wherein various cell populations grow within an intricate but well organized extracellular matrix (ECM), they can accurately recapitulate physiological and pathophysiological progressions. The majority of cancers are carcinomas, which originate from epithelial cells, and dynamically interact with non-malignant cells including stromal cells (fibroblasts), vascular cells (endothelial cells and pericytes), immune cells (macrophages and mast cells), and the ECM. Employing a tumor monoclonal colony, tumor xenograft or patient cancer biopsy into an in vivo-like microenvironment, the native signaling pathways, cell-cell and cell-matrix interactions, and cell phenotypes are preserved and our fluorescent phenotypic 3D co-culture platforms can then accurately recapitulate the tumor in vivo scenario including tumor induced angiogenesis, tumor growth, and metastasis. In this paper, we describe a robust and standardized method to co-culture a tumor colony or biopsy with different cell populations, e.g., endothelial cells, immune cells, pericytes, etc. The procedures for recovering cells from the co-culture for molecular analyses, imaging, and analyzing are also described. We selected ECM solubilized extract derived from Engelbreth-Holm-Swam sarcoma cells. Because the 3D co-culture platforms can provide drug chemosensitivity data within 9 days that is equivalent to the results generated from mouse tumor xenograft models in 50 days, the 3D co-culture platforms are more accurate, efficient, and cost-effective and may replace animal models in the near future to predict drug efficacy, personalize therapies, prevent drug resistance

  2. Progress estimating incidence rates of tumors and deformities in St. Louis River white sucker

    EPA Science Inventory

    The St. Louis River Area of Concern (AOC) was listed for the Beneficial Use Impairment (BUI) of Fish Tumors and Other Deformities without the benefit of histological information. Information on the fish tumor incidence rate is important for the future removal of the BUI. Two year...

  3. Nitroxoline impairs tumor progression in vitro and in vivo by regulating cathepsin B activity.

    PubMed

    Mirković, Bojana; Markelc, Boštjan; Butinar, Miha; Mitrović, Ana; Sosič, Izidor; Gobec, Stanislav; Vasiljeva, Olga; Turk, Boris; Čemažar, Maja; Serša, Gregor; Kos, Janko

    2015-08-01

    Cathepsin B is a ubiquitously expressed lysosomal cysteine protease that participates in protein turnover within lysosomes. However, its protein and activity levels have been shown to be increased in cancer. Cathepsin B endopeptidase activity is involved in the degradation of extracellular matrix, a process that promotes tumor invasion, metastasis and angiogenesis. Previously, we reported an established antibiotic nitroxoline as a potent and selective inhibitor of cathepsin B. In the present study, we elucidated its anti-tumor properties in in vitro and in vivo tumor models. Tumor and endothelial cell lines with high levels of active cathepsin B were selected for fun