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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Low oxygen tension influences tumor progression by enhancing angiogenesis; and histone deacetylases (HDAC) are implicated in alteration of chromatin assembly and tumorigenesis. Here we show induction of HDAC under hypoxia and elucidate a role for HDAC in the regulation of hypoxia-induced angiogenesis. Overexpressed wild-type HDAC1 downregulated expression of p53 and von Hippel-Lindau tumor suppressor genes and stimulated angiogenesis of human endothelial cells. A specific HDAC inhibitor, trichostatin A (TSA), upregulated p53 and von Hippel-Lindau expression and downregulated hypoxia-inducible factor-1alpha and vascular endothelial growth factor. TSA also blocked angiogenesis in vitro and in vivo. TSA specifically inhibited hypoxia-induced angiogenesis in the Lewis lung carcinoma model. These results indicate that hypoxia enhances HDAC function and that HDAC is closely involved in angiogenesis through suppression of hypoxia-responsive tumor suppressor genes.
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PMID:Histone deacetylases induce angiogenesis by negative regulation of tumor suppressor genes. 1128 70

To elucidate the sequence of molecular events intricate with angiogenesis and the initiation and progression prostate cancer, the temporal and spatial expression patterns of platelet endothelial cell adhesion molecule-1 (PECAM1/CD31), hypoxia-induced factor-1alpha (HIF-1alpha), vascular endothelial growth factor (VEGF), and the cognate receptors VEGFR1 and VEGFR2 were characterized. Immunohistochemical and in situ analyses of prostate tissue specimens derived from the spontaneous autochthonous transgenic adenocarcinoma of the mouse prostate (TRAMP) model identified a distinct early angiogenic switch consistent with the expression of PECAM-1, HIF-1alpha, and VEGFR1 and the recruitment of new vasculature to lesions representative of high-grade prostatic epithelial neoplasia (PIN). During progression of prostate cancer, the intraductal microvessel density (IMVD) was also observed to increase as a function of tumor grade. Immunoblot and in situ analyses further demonstrated a distinct late angiogenic switch consistent with decreased expression of VEGFR1, increased expression of VEGFR2, and the transition from a differentiated adenocarcinoma to a more poorly differentiated state. Analysis of clinical prostate cancer specimens validated the predictions of the TRAMP model. This resolution of prostate cancer-associated angiogenesis into distinct early and late molecular events establishes the basis for a "progression-switch" model to explain how the targets of antiangiogenic therapy might change as a function of tumor progression.
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PMID:Angiogenesis and prostate cancer: identification of a molecular progression switch. 1128 56

Ets-1 proto-oncogene is a transcription factor involved in several cellular functions, including the activation of several proteases participating in tumor invasion and metastasis. The objective of this study was to analyze the possible correlation between Ets-1 mRNA expression and survival in advanced-stage ovarian carcinomas, studying two patient groups with extremely different disease outcome. Sections from 66 primary ovarian carcinomas and metastatic lesions from 41 patients diagnosed with advanced-stage ovarian carcinoma (International Federation of Gynecologists and Obstetricians stages III and IV) were evaluated for expression of Ets-1 using mRNA in situ hybridization. Patients were divided into long-term (n = 17) and short-term (n = 24) survivors. The mean values for disease-free survival and overall survival were 116 and 133 months for long-term survivors, as compared to 3 and 21 months for short-term survivors, respectively. Expression of Ets-1 mRNA was detected in carcinoma cells and stromal cells in 28 of 66 (42%) and 22 of 66 (33%) lesions, respectively. Ets-1 expression showed an association with mRNA expression of vascular endothelial growth factor (P = 0.001 for carcinoma cells; P = 0.004 for stromal cells), basic fibroblast growth factor (P = 0.049 for carcinoma cells), and membrane type-1 matrix metalloproteinase (P = 0.045), which were previously studied in this patient cohort. Ets-1 mRNA was detected more often in both carcinoma and stromal cells in tumors of short-term survivors (P = 0.038 for carcinoma cells). In univariate survival analysis for all cases, Ets-1 expression in both tumor (P = 0.018) and stroma (P = 0.026) correlated with poor survival. These findings were reproduced in an analysis of primary tumors alone (P = 0.039 for tumor cells; P < 0.001 for stromal cells). Ets-1 mRNA expression in stromal cells retained its predictive power in a multivariate survival analysis in which all molecules studied previously in this patient cohort were included (P = 0.007). To our knowledge, this is the first evidence associating Ets-1 mRNA expression and poor survival in human epithelial malignancy. Ets-1 is thus a novel prognostic marker in advanced-stage ovarian carcinoma. The association between Ets-1 mRNA expression and the expression of membrane type-1 matrix metalloproteinase and angiogenic genes, first documented here in a study of patient material, points to the central role of this transcription factor in tumor progression in ovarian carcinoma.
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PMID:Ets-1 messenger RNA expression is a novel marker of poor survival in ovarian carcinoma. 1129 32

Tumor progression requires normally quiescent endothelial cells to form new vascular networks. This angiogenesis is dependent upon several soluble factors, prominent among which is vascular endothelial growth factor (VEGF). Other tumor-associated molecules, such as gangliosides, sialic acid-containing glycosphingolipids expressed by tumor cells and shed into the tumor microenvironment, may also modulate tumor angiogenesis. Here we assessed the influence of a highly purified ganglioside, G(D1a), on responses of normal human umbilical vein endothelial cells (HUVEC) to VEGF. Preincubation of HUVEC with G(D1a) enhanced VEGF-induced cell proliferation; 10 microM G(D1a) caused a twofold increase in DNA synthesis. The migration of HUVEC across a VEGF gradient was also enhanced by 50%, even with only a brief (1 h) preexposure of the cells to the same concentration of G(D1a). These findings suggest that gangliosides shed by tumor cells can promote tumor angiogenesis by enhancing the VEGF response of endothelial cells in the tumor microenvironment.
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PMID:Ganglioside GD1a enhances VEGF-induced endothelial cell proliferation and migration. 1135 56

Vascular endothelial growth factor is a major inducer of angiogenesis and a vascular permeability inducing factor. Its expression is upregulated in many types of tumors and it is thought to be a major inducer of tumor angiogenesis. This article focuses on the role of vascular endothelial growth factor in tumor progression and on current efforts aimed at the inhibition of tumor progression through the inhibition of vascular endothelial growth factor activity.
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PMID:The contribution of proangiogenic factors to the progression of malignant disease: role of vascular endothelial growth factor and its receptors. 1138 91

Tumor-stroma interactions are of primary importance in determining the pathogenesis of metastasis. Here, we describe the application of sensitive competitive polymerase chain reaction (PCR) techniques for detection and quantitation of human breast cancer cells (MDA-MB-231) in an in vivo mouse model of experimental metastasis. Human-specific oligonucleotide primers in competitive PCR reactions were used to quantify the amount of MDA-MB-231 cells per tissue per organ. Using this species-specific (semi)quantitative PCR approach, gene expression patterns of (human) tumor cells or (mouse) stromal cells in metastatic lesions in the skeleton or soft tissues were investigated and compared. In all metastatic lesions, MDA-MB-231 cells express angiogenic factors (vascular endothelial growth factors [VEGFs]; VEGF-A, -B, and -C) and bone-acting cytokines (parathyroid hormone-related protein [PTHrP] and macrophage colony-stimulating factor [M-CSF]). In these metastases, PECAM-1-positive blood vessels and stromal cells of mouse origin are detected. The latter express angiogenic factors and markers of sprouting vessels (VEGF receptors flt-1/flk - 1/flk-4 and CD31/PECAM-1). Strikingly, steady-state messenger RNA (mRNA) levels of VEGF-A and -B and the major bone resorption stimulators PTHrP and M-CSF by tumor cells were elevated significantly in bone versus soft tissues (p < or = 0.05, p < or = 0.0001, p < or = 0.001, and p < or = 0.05, respectively), indicating tissue-specific expression of these tumor progression factors. In conclusion, MDA-MB-231 breast cancer cells express a variety of factors in vivo that have been implicated in metastatic bone disease and that correlate with poor survival of patients with breast cancer. We hypothesize that the observed up-regulated expression of angiogenic and bone-resorbing factors by the breast cancer cells in the skeleton underlie the clinically observed osteotropism of breast cancer cells and pathogenesis of osteolytic bone metastases. The application of the species-specific competitive PCR-based assay in vivo can provide new information concerning the involvement of gene families in tumor progression and metastatic disease and greatly facilitates the study of tumor-stroma interactions in cancer invasion and metastasis.
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PMID:Monitoring metastatic behavior of human tumor cells in mice with species-specific polymerase chain reaction: elevated expression of angiogenesis and bone resorption stimulators by breast cancer in bone metastases. 1139 85

Neuropilin-2 (np-2) is a receptor for semaphorin-3F (sema-3F) and semaphorin-3C (sema-3C). These semaphorins repel tips of growing axons that express np-2. In addition, np-2 functions as a receptor for heparin binding forms of the angiogenic factor vascular endothelial growth factor (VEGF) such as VEGF145 and VEGF165. We report that np-2 is strongly expressed in neuroendocrine cells located all along the human digestive tract. Confocal fluorescent microscopy revealed that np-2 is concentrated in vesicle-like structures located near the nucleus at the basolateral side of these cells. In the colon, the np-2-expressing subpopulation of neuroendocrine cell is almost identical with the serotonin-producing subpopulation of neuroendocrine cells. Gastrointestinal carcinoid tumors are digestive tract tumors that develop from neuroendocrine cells. Interestingly, most of the carcinoid tumors derived from the colon and the appendix did not contain np-2-producing cells. However, some carcinoid tumors derived from the small intestine and stomach did express low levels of np-2 in isolated foci of cells. By contrast, strong serotonin and chromogranin-A expression was observed in all of the carcinoid tumors that were examined. These results suggest that loss of np-2 expression may accompany tumor progression in carcinoid tumors.
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PMID:Neuroendocrine cells along the digestive tract express neuropilin-2. 1139 92

BACKGROUND: Known influence of the immune system on metastases of renal cell cancer (RCC) has led to the development of several therapeutic approaches for further stimulation of the host immune system by cytokines and the retransfusion of tumor-infiltrating lymphocytes (TIL). Based on observations in human prostate adenocarcinomas and transitional cell carcinomas, we have investigated the presence of TIL in different stages of RCC in correlation to vascular endothelial growth factor (VEGF) expression as a parameter for tumor progression and adverse survival in RCC patients. METHODS: Samples from surgically obtained RCC (n = 28) and benign renal parenchyma (n =10) were snap-frozen and processed by double-immunofluorescence staining with CD4/CD8 and VEGF antibodies. RESULTS: In 20 of 28 RCCs a coexpression of TIL-specific markers CD4 and/or CD8 and VEGF was demonstrated. Control tissues were VEGF-negative and showed only negligible infiltration by CD4- or CD8-positive lymphocytes. CONCLUSION: The results indicate that at least 71% of TIL produce VEGF and may promote tumor progression rather than represent an abortive antitumor response of the host immune system. Copyright 2000 S. Karger GmbH, Freiburg
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PMID:Tumor-Infiltrating Lymphocytes Express Vascular Endothelial Growth Factor in Renal Cell Carcinomas. 1144 Dec 41

Growth and metastasis of solid tumors depend on the formation of new blood vessels which originate from the existing vascular system. These blood vessels grow into the tumor and thus provide the necessary nutrients and growth factors for tumor progression. At the same time, the newly formed blood vessels allow tumor cells to disseminate and form metastases in distant organs. Normally, vascular homeostasis is regulated by a balance of angiogenic and antiangiogenic mechanisms. Tumor-induced angiogenesis is mainly sustained by the production and secretion of angiogenic factors originating from tumor and stroma cells. The most prominent angiogenic factor is the vascular endothelial growth factor (VEGF). Recently, additional angiogenic factors and their respective receptors have been identified and related to tumor angiogenesis. Among these, the angiopoietins and their receptor TIE-2 have been investigated to some detail. Angiopoietin-1 which binds to and activates TIE-2 is obviously responsible for the stabilization of vessels under homeostatic conditions. Angiopoietin-2 binds to the same receptor as angiopoietin-1 but is antagonistic with respect to angiopoietin-1. It destabilizes blood vessels and, under appropriate conditions, induces complete regression. In the similar situation angiopoietin-2 induces the destabilization of blood vessels, and the angiogenic factor VEGF produced by the tumor induces the massive formation of new vessels. When human melanoma cells A375 are stably transfected to produce the soluble variant of the angiopoietin receptor TIE-2 (sTIE-2), they show a substantial inhibition of tumor growth on nude mice. Similar effects have been seen with the soluble variant of the VEGF receptor FLT-1 (sFLT-1). In both cases, the vessel density of the tumors is significantly reduced. These experiments show that the inhibition of the angiopoietin/TIE-2 system, similar to the inhibition of the VEGF/VEGF receptor system, has an antitumoral effect, most probably due to the inhibition of tumor angiogenesis. Thus, inhibition of both signalling systems seem to be a valid strategy for the development of novel antiangiogenic therapies. Recently, the inhibition of the VEGF receptor tyrosine kinase by the compound PTK787/ZK222584 has been shown to substantially inhibit tumor growth and metastases formation. This compound has now entered clinical trials at the Tumor Biology Center in Freiburg i.Br. A preliminary evaluation of phase I study shows a very promising clinical outcome.
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PMID:[Tumor angiogenesis: new approaches to cancer therapy]. 1144 5

Tumour progression is regulated by the balance of proliferation and apoptosis in the tumour cell population. To date, the role of vascular endothelial growth factor (VEGF) in tumour growth has been attributed to the induction of angiogenesis. VEGF has been shown to be a survival factor for endothelial cells, preventing apoptosis by inducing Bcl-2 expression. In both murine (4T1) and human (MDA-MB-231) metastatic mammary carcinoma cell lines, we found that VEGF upregulated Bcl-2 expression and anti-VEGF antibodies reduced Bcl-2 expression. These alterations in Bcl-2 expression were reflected by the levels of tumour cell apoptosis. VEGF resulted in reduced tumour cell apoptosis, whereas its inhibition with anti-VEGF neutralizing antibodies induced apoptosis directly in tumour cells. Therefore, in addition to its role in angiogenesis and vessel permeability, VEGF acts as a survival factor for tumour cells, inducing Bcl-2 expression and inhibiting tumour cell apoptosis.
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PMID:Vascular endothelial growth factor (VEGF) upregulates BCL-2 and inhibits apoptosis in human and murine mammary adenocarcinoma cells. 1146 Oct 89


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