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

The growth of solid tumors in vivo beyond 1-2 mm in diameter requires induction and maintenance of an angiogenic response. This can occur through the release of various angiogenic growth factors from tumor cells. One such factor is vascular endothelial growth factor/vascular permeability factor (VEGF/VPF), a secreted and specific mitogen for vascular endothelial cells. We show that one of the most commonly encountered genetic changes detected in human cancer, i.e., expression of mutant ras oncogenes, is associated with marked up-regulation of VEGF/VPF in transformed epithelial cells. Thus, elevation of the levels of both VEGF/VPF mRNA and secreted functional protein were detected in human and rodent tumor cell lines expressing mutant K-ras or H-ras oncogenes, respectively. Genetic disruption of the mutant K-ras allele in human colon carcinoma cells was associated with a reduction in VEGF/VPF activity. Furthermore, pharmacological disruption of mutant RAS protein function in H-ras transformed rat intestinal epithelial cells by treatment with L-739,749 (a protein farnesyltransferase inhibitor) caused a significant suppression of VEGF/VPF. The results suggest that dominantly acting ras oncogenes may contribute to the growth of solid tumors in vivo not only by a direct effect on tumor cell proliferation but also indirectly, i.e., by facilitating tumor angiogenesis. Hence, pharmacologically targeting mutant ras oncogenes could conceivably suppress solid tumor growth in vivo, in part, by inhibiting tumor-induced angiogenesis.
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PMID:Mutant ras oncogenes upregulate VEGF/VPF expression: implications for induction and inhibition of tumor angiogenesis. 755 32

The growth and metastatic spread of cancer is directly related to tumor angiogenesis, and the driving factors need to be understood to exploit this process therapeutically. However, tumor cells and their normal stroma express a multitude of candidate angiogenic factors, and very few specific inhibitors have been generated to assess which of these gene products are only innocent bystanders and which contribute significantly to tumor angiogenesis and metastasis. Here we investigated whether the expression in tumors of a secreted fibroblast growth factor (FGF)-binding protein (FGF-BP) that mobilizes and activates locally stored FGFs (ref. 11) can serve as an angiogenic switch molecule. Developmental expression of the retinoid-regulated FGF-BP gene is prominent in the skin and intestine during the perinatal phase and is down-modulated in the adult. The gene is, however, upregulated in carcinogen-induced skin tumors, in squamous cell carcinoma (SCC) and in some colon cancer cell lines and tumor samples. To assess the significance of FGF-BP expression in tumors, we depleted human SCC (ME-180) and colon carcinoma (LS174T) cell lines of their endogenous FGF-BP by targeting with specific ribozymes. We found that the reduction of FGF-BP reduced the release of biologically active basic FGF (bFGF) from cells in culture. Furthermore, the growth and angiogenesis of xenograft tumors in mice was decreased in parallel with the reduction of FGF-BP. This suggests that human tumors can utilize FGF-BP as an angiogenic switch molecule.
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PMID:A secreted FGF-binding protein can serve as the angiogenic switch in human cancer. 933 15

Angiogenesis is required for tumor formation. Several studies have demonstrated that tumor angiogenesis is regulated by a balance between proangiogenesis and antiangiogenesis factors and that this balance varies in different organ environments. To investigate whether expression of an angiogenesis inhibitor by cancer cells could alter this balance and prevent tumor formation in different organ environments, we engineered stable transfectants from RenCa mouse renal carcinoma cells and SW620 human colon carcinoma cells to constitutively secrete a mouse endostatin protein with c-myc and polyhistidine (His) tags. Production and secretion of the endostatin-c-myc-His fusion protein by endostatin-transfected cells were confirmed by immunofluorescence staining and Western blot analysis. The endostatin transfectants and control transfectants, stably transfected with a control plasmid, had similar in vitro growth rates compared with their parental cell lines. Conditioned medium from endostatin-transfected cells inhibited human umbilical vein endothelial cell proliferation by 36-51% compared with conditioned medium from control cells. After inoculation into mice, flank tumors from endostatin-transfected cells were 73-91% smaller than flank tumors from control cells after 3 weeks. Inoculation of a cell mixture containing 25% endostatin-transfected cells and 75% control cells resulted in inhibition of flank tumor formation as effective as after inoculation of 100% endostatin-transfected cells. Formation of lung metastases by RenCa endostatin-transfected cells and formation of liver metastases by SW620 endostatin-transfected cells were dramatically inhibited compared with formation of metastases by control cells. These findings demonstrate that endostatin can inhibit tumor formation in different organ environments and that gene delivery of endostatin into even a minority of tumor cells may be an effective strategy to prevent progression of micrometastases to macroscopic disease.
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PMID:Mouse endostatin inhibits the formation of lung and liver metastases. 1062 20

Tumor angiogenesis is a critical step for the growth and metastasis of solid tumors. Vascular endothelial growth factor (VEGF) is a specific and potent angiogenic factor and contributes to the development of solid tumors by promoting tumor angiogenesis. Therefore, it is a prime therapeutic target for the development of antagonists for treatment of cancer. We identified from peptide libraries arginine-rich hexapeptides that inhibit the interaction of VEGF(165) with VEGF receptor (IC(50) = 2-4 micrometer). They have no effect on binding of basic fibroblast growth factor to cellular receptor. The hexapeptides inhibit the proliferation of human umbilical vein endothelial cells induced by VEGF(165) without toxicity. The peptides bind to VEGF and inhibit binding of both VEGF(165) and VEGF(121), suggesting that the peptides interact with the main body of VEGF but not the heparin-binding domain that is absent in VEGF(121). The identified peptides block the angiogenesis induced by VEGF(165) in vivo in the chick chorioallantoic membrane and the rabbit cornea. Furthermore, one of the hexapeptides, RRKRRR, blocks the growth and metastasis of VEGF-secreting HM7 human colon carcinoma cells in nude mice. Based on our results, the arginine-rich hexapeptides may be effective for the treatment of various human tumors and other angiogenesis-dependent diseases that are related to the action of VEGF and could also serve as leads for development of more effective drugs.
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PMID:Arginine-rich anti-vascular endothelial growth factor peptides inhibit tumor growth and metastasis by blocking angiogenesis. 1078 75

Mechanisms that regulate the transition of micrometastases from clinically undetectable and dormant to progressively growing are critically important but poorly understood in cancer biology. Here we examined the effect of a primary tumor on the growth of solitary tumor cells in the mouse liver, as well as on the development of tumor angiogenesis in a dorsal skin-fold chamber. s.c. placement of a CT-26 (BALB/c-derived mouse colon carcinoma) primary tumor markedly inhibited development of liver metastasis in BALB/c mice after subsequent intraportal injection of tumor cells. Dorsal skin-fold chamber experiments showed that this growth inhibition paralleled a strong antiangiogenic effect by the primary tumor. Furthermore, intravital microscopy of the liver after intraportal injection of green fluorescent protein-expressing tumor cells showed that primary tumors promoted dormancy of single tumor cells for up to 7 days. Immunohistological staining for Ki-67 confirmed that these solitary cells were indeed dormant. In contrast, in the absence of a primary tumor, GFP-expressing tumor cells quickly developed into micrometastases. Thus, primary CT-26 tumor implants nearly abrogated tumor metastasis by inhibition of angiogenesis and by promoting a state of single-cell dormancy. Knowledge of the mechanism underlying this dormancy state could result in the development of new therapeutic tools to fight cancer.
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PMID:A primary tumor promotes dormancy of solitary tumor cells before inhibiting angiogenesis. 1145 10

Quantitative analysis of the process of tumor angiogenesis was performed in a new animal model of tumor microcirculation, in which colon carcinoma cells were inoculated into the peritoneal cavity of rats. Time-dependent changes in the microvascular architecture of mesenteric microvessels of tumor-bearing rats were visualized using an intravital microscope. Simultaneously, the expression of vascular endothelial growth factor (VEGF) by the tumor cells and VEGF secretion into ascites were analyzed. The results showed that VEGF increases microvascular permeability and stimulates the growth of microvessels into the tumor and that the spatial and temporal concentration of VEGF is strongly correlated. Such a correlation was stronger in the early angiogenic stages of tumor growth than in the subsequently occurring multiple metastatic stage, when VEGF was still observed at a high level in tumor surroundings. Thus, VEGF is suggested to be primarily involved in the pathophysiological control of angiogenesis accompanying tumor progression.
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PMID:Vascular endothelial growth factor (VEGF) expression regulates angiogenesis accompanying tumor growth in a peritoneal disseminated tumor model. 1149 Oct 18

The compound 317615 x 2HCl, a selective protein kinase Cbeta inhibitor, was not very cytotoxic toward human CaKi1 renal cell carcinoma cells or human HT-29 colon carcinoma cells in monolayer culture. Isobologram analysis was used to determine additivity or synergy of the combination regimens. Exposure of CaKi1 cells to 317615 x 2HCl (10 or 100 mM) along with gemcitabine or 5-fluorouracil for 24 hours resulted in cytotoxicity that appeared to be less-than-additive to additive for the two agents. Exposure of HT-29 cells to gemcitabine along with 317615 x 2HCl (10 mM or 100 mM) resulted in a synergistic cytotoxicity while combinations with 5-fluorouracil resulted in additive to greater-than-additive cytotoxicity for the agents. After treatment of CaKi1 or HT-29 xenograft-bearing mice with 317615 x 2HCl, immunohistochemical staining for expression of endothelial specific markers, either CD31 or CD105, was used to quantify the number of intratumoral vessels in the samples. CaKi1 tumor angiogenesis was very responsive to treatment with 317615 x 2HCl such that the number of intratumoral vessels stained by CD31 or CD105 was decreased to 20% of the control. The HT-29 colon carcinoma angiogenesis was also responsive to 317615 x 2HCl, such that the number of intratumoral vessels stained by CD31 or CD105 was decreased to 40% to 50% of the controL 5-fluorouracil, cisplatin or fractionated radiation therapy was combined with treatment with 317615 x 2HCl in the simultaneous combination treatment regimen in animals bearing HT-29 colon carcinoma xenografts. The resulting tumor growth delays indicated that administration of 317615 x 2HCl increased the effects of the cytotoxic therapy. Both a simultaneous or an overlapping treatment regimen and a sequential treatment regimen were used to assess 317615 x 2HCl alone and along with fractionated radiation therapy or gemcitabine against the human CaKi1 renal cell carcinoma xenograft. The CaKi1 tumor was quite sensitive to fractionated radiation therapy and to gemcitabine and, although 317615 x 2HCl was an effective single agent in this tumor, the combination regimens did not reach additivity for the combination regimens in vivo. 317615 x 2HCl is in early clinical testing.
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PMID:Antiangiogenic and antitumor effects of a protein kinase Cbeta inhibitor in human HT-29 colon carcinoma and human CaKi1 renal cell carcinoma xenografts. 1184 70

Hypoxia-inducible factor 1 (HIF-1) transactivates genes the products of which mediate tumor angiogenesis and glycolytic metabolism. Overexpression of the HIF-1 alpha subunit, resulting from intratumoral hypoxia and genetic alterations, has been demonstrated in common human cancers and is correlated with tumor angiogenesis and patient mortality. Here we demonstrate that hypoxia or HIF-1 alpha overexpression stimulates Matrigel invasion by HCT116 human colon carcinoma cells, whereas this process is inhibited by a small interfering RNA directed against HIF-1 alpha. We show that HIF-1 regulates the expression of genes encoding cathepsin D; matrix metalloproteinase 2; urokinase plasminogen activator receptor (uPAR); fibronectin 1; keratins 14, 18, and 19; vimentin; transforming growth factor alpha; and autocrine motility factor, which are proteins that play established roles in the pathophysiology of invasion. Neutralizing antibodies against uPAR block tumor cell invasion induced by hypoxia or HIF-1 alpha overexpression. These results provide a molecular basis for promotion of the invasive cancer phenotype by hypoxia and/or HIF-1 alpha overexpression.
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PMID:Regulation of colon carcinoma cell invasion by hypoxia-inducible factor 1. 1261 33

Endoglin (CD105) has been shown to be a more useful marker to identify proliferating endothelium involved in tumor angiogenesis than panendothelial markers such as CD31. We investigated endoglin and vascular endothelial growth factor expression as possible prognostic markers in colorectal cancer. Surgical specimens from 150 patients with resected colorectal carcinomas were immunostained for endoglin, CD31 and vascular endothelial growth factor. Colorectal carcinoma cases consisted of 50 cases without lymph node metastases, 50 cases with only lymph node metastases and 50 cases with liver metastases (38 cases also had positive lymph nodes). Positively stained microvessels were counted in densely vascular foci (hot spots) at x 400 fields in each specimen. For vascular endothelial growth factor, intensity of staining was scored on a three-tiered scale. Results were correlated with other prognostic parameters. Endoglin demonstrated significantly more proliferating neoplastic microvessels than CD31 (31+/-10 vs 19+/-8/0.15 mm2 field, P<0.001). Low vascular endothelial growth factor expression within tumor cells was seen in 49 (33%) and high expression in 101 cases (67%). There was a positive correlation of endoglin, CD31 counts and vascular endothelial growth factor overexpression with the presence of angiolymphatic invasion and lymph node metastases (P<0.05). Only endoglin counts correlated significantly with liver metastases and positive vascular pedicle lymph nodes (P<0.05), while vascular endothelial growth factor showed significant correlation with the depth of invasion (P<0.01). Endoglin, by staining higher numbers of the proliferating vessels in colon carcinoma, is a more specific and sensitive marker for tumor angiogenesis than the commonly used panendothelial markers. Endoglin staining also showed prognostic significance with positive correlation with angiolymphatic invasion and metastases to lymph nodes and liver.
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PMID:Endoglin (CD105) and vascular endothelial growth factor as prognostic markers in colorectal cancer. 1465 50

Identification of appropriate models for in vivo and in vitro preclinical testing of inhibitors of tumor angiogenesis and progression is vital to the successful development of anticancer therapeutics. Although the focus is on human molecular targets, most preclinical in vivo efficacy testing occurs in mice. The goal of the current studies was to identify a murine endothelial cell line to model tumor endothelium for studying the antiangiogenic activity of therapeutic compounds in vitro. In situ hybridization was performed on three s.c. grown syngeneic murine tumors (B16 melanoma, Lewis lung carcinoma, and CT26 colon carcinoma) to assess expression of murine homologs of human tumor endothelial cell markers in the vasculature of these tumor models. Seven murine endothelial cell lines were characterized for expression of the murine homologs of recognized endothelial cell surface markers as well as for tumor endothelial cell surface markers. The seven murine endothelial cell lines had similar generation times and five of the seven lines were able to form tubes on Matrigel. Real-time-PCR and flow cytometry analysis were used to evaluate relative mRNA and protein expression of murine homologs of several recognized endothelial cell surface markers in the seven cell lines. The expression of the mRNA for the murine homologs of five tumor endothelial cell surface markers was also evaluated. The 2H11 cell line expressed all five of the tumor endothelial cell surface markers as well as several well-recognized endothelial cells markers. The 2H11 cell line responds to known and novel antiangiogenic agents by inhibition of proliferation and tube formation. These cells can be used in in vitro angiogenesis assays for evaluating the potential antiangiogenic properties and interspecies cross-reactivity of novel compounds.
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PMID:Murine endothelial cell lines as models of tumor endothelial cells. 1504 39


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