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Query: UMLS:C1519670 (tumor angiogenesis)
 6,052 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tumor angiogenesis is a very important process for growth and proliferation of most solid tumors. It insures the delivery of feeding molecules as well as the elimination of degradation products and allows tumoral cells to escape from the primary tumor site and the further establishment of metastases. Tumor neovascularisation is the result of a cascade of events primarily related to the properties of endothelial cells of capillaries. The main steps are: a) degradation of capillary basal lamina and destruction of the surrounding tissues, b) endothelial cell proliferation and c) endothelial cell migration towards the tumor site. A number of substances either synthetic or of natural origin are known to stimulate one of the above mentioned steps and/or to induce the production of factors which, in turn, stimulate one or several steps of the cascade. Such molecules can also be synthesized by tumoral cells; indeed they have often been evidenced in the fluids surrounding the tumor site. Many factors remain to be identified and their mechanism of action wait to be elucidated. However, it is already clear that several molecules are involved in the various steps of tumor angiogenesis. They display a coordinated sequential action and their synthesis is induced and controlled by the tumor itself. Amongst others, the following molecules play a role in tumor angiogenesis: degradative enzymes, E-prostaglandins, specific oligopeptides, fibronectin and heparin. Furthermore, several metal cations are also involved in tumor angiogenesis.
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PMID:[Tumor angiogenesis]. 242 24

In search of biomarkers that predict of human prostate cancer progression, we hypothesized that these markers must be expressed in prostatic epithelial cells during multi-step prostate carcinogenesis. Since both genetic and epigenetic factors have been implicated in human prostate cancer development, two osseous-metastatic experimental models were developed in our laboratory, one based on gene transfection and the other on stromal-epithelial interaction studies. In the genetic model, PC-3 cells transfected with point-mutated c-erbB-2/neu oncogene subsequently acquired the potential to metastasize from the prostate to soft tissues and the skeleton. In the epigenetic model, sublines derived from the parental androgen-dependent LNCaP cell line metastasized from the primary tumor to the lymph node and bone. Cells with known lineage relationships were cloned from both the primary and the metastatic tumors and were characterized extensively using cellular, biochemical, immunohistochemical, and molecular techniques. Relevant stage-specific biomarkers associated with prostate cancer progression in these two models were defined and used to evaluate human prostate tissues obtained from the clinic. In this communication, we focused our discussion on the potential importance of c-erbB-2/neu oncogene, vimentin, hepatocyte growth factor/scatter factor and its receptor, c-met oncogene, tumor angiogenesis and neuroendocrine factors as biomarkers for human prostate cancer progression.
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PMID:Biomarkers associated with prostate cancer progression. 752 53

To clarify the correlation between tumor angiogenesis and tumor growth in head and neck carcinomas, we investigated the number of microvessels, using immunohistochemical factor VIII. No correlations among this number, differences in the primary lesion, histological differentiation and T classification were detected. The incidence of neck lymph node metastases increased as microvessel numbers increased in tumor sites. The number of microvessels increased as N and Stage classification progressed. The number of microvessels in CR cases after induction chemotherapy were increased. The numbers of microvessels in patients without recurrence were apparently greater than those in patients with recurrence. The results of this study suggest that the number of microvessels in a primary tumor correlates with the metastatic ability of the tumor.
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PMID:[Angiogenesis in head and neck tumor]. 768 79

Tumor progression is frequently associated with changes in responsiveness of tumor cells to paracrine growth factors. A potential major source of such paracrine factors in solid tumors are endothelial cells since this type of cell can constitute a sizeable fraction of the cellular composition of solid tumors. As an initial step to examining the possible effects of endothelial cell-associated growth factors on tumor cell growth, a panel of human melanoma cell lines representative of different stages of tumor progression was employed for studies utilizing endothelial cell-derived growth modulators. Macrovascular or microvascular human endothelial cells from umbilical vein or from skin, respectively, inhibited melanoma cell growth in direct coculture experiments. The potency of this inhibitory effect diminished as a function of melanoma progression. Conditioned media from endothelial cell cultures mimicked the effect of the cell coculture experiments, suggesting the involvement of soluble growth factor(s). Approximately 50-75% of the conditioned media inhibitory effect was abrogated by addition of the neutralizing antibody to interleukin-6 (IL-6). Gel filtration chromatography revealed the presence of additional inhibitors in endothelial cell conditioned medium. Two peaks of activity were detected with apparent molecular weights of approximately 100-150 Kd and 20-30 Kd, the latter containing IL-6 activity. Whereas early-stage radial growth phase (RGP) primary tumor-derived melanoma cells were sensitive to at least three different endothelial products of high or low molecular weight (including IL-6), melanoma cells from more advanced metastatic lesions were resistant to the latter activities, and retained only partial sensitivity to the high molecular weight inhibitor. More advanced vertical growth phase (VGP) primary melanoma cell lines expressed intermediate inhibition-sensitive phenotypes. Thus human melanoma development appears to be associated with progressive loss of sensitivity to the growth inhibitory effects of IL-6 and other factors produced by endothelial cells. This is likely to be a result of a selection process when tumor cells are confronted with adjacent vasculature during the progress of tumor angiogenesis.
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PMID:Progressive loss of sensitivity to endothelium-derived growth inhibitors expressed by human melanoma cells during disease progression. 816 65

At present the most used method to quantify tumor angiogenesis in human solid tumors is the count of intratumoral microvessels in the primary lesion. This method requires the use of specific markers to vascular endothelium and of immunohistochemical procedures to visualize microvessels. Several studies have found that intratumoral microvessel density (IMD) determined in the primary tumor is significantly associated with metastasis and prognosis in some solid neoplasia, particularly in operable breast carcinoma. The subjective evaluation of IMD made by two observers at the microscope is rapid and of low cost, but presents some difficulties, mainly the identification of the most vascularized area ("hot-spot") within each tumor. This method can be improved upon to attain a better reproducibility among different pathologists. For example, the use of a multiparametric computerized image analysis system (CIAS) seems to be a promising tool to improve accuracy, feasibility and reproducibility of microvessel counts, although there are still some open technical problems to completely automate its use. Angiogenic activity is the result of a balance between angiogenic stimuli and angio-inhibition. Therefore the determination of angiogenic peptides and/or natural angiogenesis inhibitors in the tumor tissue, serum, or urine of cancer patients seems to be a promising alternative to microvessel counting. At present it is possible to determine the expression of basic fibroblast growth factor (bFGF), vascular endothelial growth factor, and transforming growth factor beta using immunohistochemical methods. Serum and urine levels of bFGF can be assessed using an immunoenzymatic assay. Methods used to assess the expression and levels of urokinase-type plasminogen activator (uPA) or plasminogen activator inhibitor-1 (PAI-1) have also been developed, and correlate with angiogenic activity and prognosis of patients with breast cancer. Finally, some investigational methods to assess angiogenesis in vivo are presented and discussed. Angiogenesis is a very complex phenomenon. Thus it seems reasonable to hypothesize that its assessment by using concurrently several of the available methods may provide more valid, accurate, and comprehensive information on the angiogenic activity of each single tumor. For a reliable and reproducible assessment of angiogenesis for all of the assays, validation procedures and quality control protocols are mandatory.
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PMID:Novel methods for the determination of the angiogenic activity of human tumors. 853 66

Clinical and experimental evidence suggests that spreading of malignant cells from a localized tumor (metastasis) is directly related to the number of microvessels in the primary tumor. This tumor angiogenesis is thought to be mediated by tumor-cell-derived growth factors. However, most tumor cells express a multitude of candidate angiogenesis factors and it is difficult to decipher which of these are rate-limiting factors in vivo. Herein we use ribozyme targeting of pleiotrophin (PTN) in metastatic human melanoma cells to assess the significance of this secreted growth factor for angiogenesis and metastasis. As a model we used human melanoma cells (1205LU) that express high levels of PTN and metastasize from subcutaneous tumors to the lungs of experimental animals. In these melanoma cells, we reduced PTN mRNA and growth factor activity by transfection with PTN-targeted ribozymes and generated cell lines expressing different levels of PTN. We found that the reduction of PTN does not affect growth of the melanoma cells in vitro. In nude mice, however, tumor growth and angiogenesis were decreased in parallel with the reduced PTN levels and apoptosis in the tumors was increased. Concomitantly, the metastatic spread of the tumors from the subcutaneous site to the lungs was prevented. These studies support a direct link between tumor angiogenesis and metastasis through a secreted growth factor and identify PTN as a candidate factor that may be rate-limiting for human melanoma metastasis.
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PMID:Melanoma angiogenesis and metastasis modulated by ribozyme targeting of the secreted growth factor pleiotrophin. 896 27

Scatter factor (SF) (also known as hepatocyte growth factor) is a plasminogen-related growth factor that induces tumor cell motility, invasion, and angiogenesis. Its receptor is a tyrosine kinase encoded by c-met, a protooncogene. Human breast cancer cells express SF and c-met in vivo; but human breast cancer cell lines do not produce SF in vitro. To determine whether SF can modulate the in vivo growth of human breast cancers within a natural mammary environment, we studied the orthotopic growth of SF-transfected (SF+) versus control (SF-) clones of MDAMB231 human mammary carcinoma cells in the mammary fat pads of athymic nude mice. SF+ clones expressed SF mRNA and produced very high titers of SF protein, whereas SF- clones did not express SF mRNA or produce detectable SF protein. Two SF+ clones (21 and 29) showed significantly increased tumor growth rates, reaching 3- to 4-fold larger primary tumor volumes and weights by time of killing (p < 0.001), as well as higher rates of axillary lymph node metastasis (p < 0.02), as compared with two SF- clones (32 and 34). In contrast, in vitro proliferation rates, two-dimensional colony formation, and soft agar colony formation were no greater in SF+ than in SF- clones. We performed further studies to investigate the discrepancy between the in vivo and in vitro growth results. Tumor extracts from SF+ clone (21 + 29) tumors had 50-fold higher SF content than did SF- clone (32 + 34) tumors, confirming high-level SF expression in vivo in SF+ tumors. Immunostaining of tumor sections for proliferating cell nuclear antigen revealed only a modest increase in the proportion of cycling cells in SF+ versus SF- tumors (70% versus 60%, respectively). The terminal deoxytransferase-labeling index was equally low (approximately 1%) in SF+ and SF- tumors, suggesting that apoptosis was not responsible for the slower growth of SF- tumors. However, SF+ tumors had significantly higher tumor microvessel densities than SF- tumors (p < 0.001). Moreover, there were much higher titers of chemotactic activity for microvascular endothelial cells in cell-conditioned media and primary tumor extracts from SF+ clones as compared with SF- clones. As demonstrated using the rat cornea assay, there was more angiogenic activity in SF+ tumor extracts than in SF- extracts. The increased chemotactic and angiogenic activities in SF+ tumor extracts were not explained by secondary alterations in the content of the angiogenic mediator, vascular endothelial growth factor, or the antiangiogenic glycoprotein, thrombospondin-1; and those activities were neutralized using an anti-SF monoclonal antibody. These findings suggest that SF promotes the orthotopic growth of human breast cancers, at least in part, by stimulating tumor angiogenesis.
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PMID:Scatter factor stimulates tumor growth and tumor angiogenesis in human breast cancers in the mammary fat pads of nude mice. 912 Nov 17

Tumor growth and metastasis are angiogenesis dependent. Previously, we reported that angiostatin, a potent angiogenesis inhibitor, produced by a primary Lewis lung carcinoma suppressed its growth of lung metastases (O'Reilly, M.S., L. Holmgren, Y. Shing, C. Chen, R.A. Rosenthal, M. Moses, W.S. Lane, Y. Cao, E.H. Sage, and J. Folkman. 1994. Cell. 79:315-328). Now we show that a shift of balance of tumor angiogenesis by gene transfer of a cDNA coding for mouse angiostatin into murine T241 fibrosarcoma cells suppresses primary and metastatic tumor growth in vivo. Implantation of stable clones expressing mouse angiostatin in C57Bl6/J mice inhibits primary tumor growth by an average of 77%. After removal of primary tumors, the pulmonary micrometastases in approximately 70% of mice remain in a microscopic dormant and avascular state for the duration of the experiments, e.g., 2-5 mo. The tumor cells in the dormant micrometastases exhibit a high rate of apoptosis balanced by a high proliferation rate. Our study, to our knowledge, for the first time shows the diminished growth of lung metastases after removal of the primary tumor, suggesting that metastases are self-inhibitory by halting angiogenesis. Our data may also provide a novel approach for cancer therapy by antiangiogenic gene therapy with a specific angiogenesis inhibitor.
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PMID:Expression of angiostatin cDNA in a murine fibrosarcoma suppresses primary tumor growth and produces long-term dormancy of metastases. 948 76

Human uveal melanoma disseminates initially and preferentially to the liver. This study describes the relationship between the expression of the c-met proto-oncogene (receptor for hepatocyte growth factor/scatter factor (HGF/SF)) in interconverted uveal melanoma cells (co-expressing vimentin and keratin intermediate filaments) and the regulation of their motogenic response to HGF/SF, a key step in local invasion and targeted dissemination to the liver. Expression of c-met in uveal melanoma cell lines correlates with both the appearance of an interconverted phenotype and invasive ability (measured in vitro). Using chemotactic checkerboard analysis, the greatest motogenic response to HGF/SF was achieved by invasive, interconverted, c-met-positive uveal melanoma cells. C-met was observed histologically in a uveal melanoma containing interconverted cells but was absent in a tumor composed of non-interconverted cells (vimentin positive/keratin negative). The c-met ligand, HGF/SF, although not expressed by uveal melanoma cell lines, was localized in tissue sections of primary uveal melanomas and metastatic melanoma to the liver. In the primary tumor, staining for HGF/SF was most intense at the level of the choriocapillaris, a finding that is significant because 1) highly remodeled neovascular loops and networks, which appear in tumors likely to disseminate, can be traced to the choriocapillaris and the draining vortex veins and 2) HGF/SF plays a role in tumor angiogenesis. Foci of metastatic melanoma to the liver stain diffusely for HGF/SF. Regulation of the uveal melanoma interconverted phenotype by HGF/SF may play an important role in the dissemination of this tumor.
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PMID:Regulation of uveal melanoma interconverted phenotype by hepatocyte growth factor/scatter factor (HGF/SF). 954 44

Concomitant resistance (CR), the phenomenon by which tumor-bearing hosts are able to inhibit secondary implants of the same tumor at distant sites of the body, has been previously observed by us and others in different murine tumor models. Here, we verified the generation of CR in nude mice by tumors induced by SC inoculation of Calu-6, a human lung carcinoma cell line. Histological analysis of secondary tumors subject to CR did not reveal macrophage infiltration nor cytotoxic signs. Although serum from tumor-bearing mice inhibited in vitro [3H]thymidine uptake by Calu-6 cells, no significant differences in [3H]thymidine labeling index of tumors implanted in the right flank of mice with and without a primary tumor in the left flank were detected. In our model, the presence of a primary tumor hindered remote tumor angiogenesis, as well as serum from tumor-bearing mice inhibited in vitro proliferation of an endothelial cell line derived from a murine hemangioendothelioma. Conversely, an enhancement of the apoptotic index was observed in secondary tumor implants carried out in tumor-bearing mice. The results reported herein show that human tumor cells are capable of inducing CR, and that this phenomenon would be a consequence of an impaired neovascularization as well as an increased programmed cell death at sites distant from the primary tumor.
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PMID:Antiangiogenesis and apoptosis as mediators of concomitant tumor resistance induced by Calu-6, a human lung carcinoma cell line, in nude mice. 961 53


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