UMLS:C1519670 - FACTA Search

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

Vulvar intraepithelial neoplasia (VIN) has been reported to be a precursor of invasive vulvar cancer. Switching to the angiogenic phenotype is considered a key step in tumor growth. Microvessel density (MVD) and vascular endothelial growth factor (VEGF), a highly angiogenic peptide, are important parameters of tumor angiogenesis. Forty-three histologic slides with 38 VIN I-III lesions were immunohistochemically stained for factor VIII-related antigen (F8-RA) and 44 slides with 37 VIN I-III for VEGF, since F8-RA reliably highlights tumor microvessels. Determination of MVD and VEGF expression was done by counting microvessels and VEGF-positive cells at a magnification of 200x and 400x. The highest concentration of F8-RA-stained MVD and VEGF expression was found at a small subepithelial area at the border of the VIN lesion to the stroma underneath but concentrations were low in all specimens of normal epithelium. High VEGF expression was significantly correlated to high MVD. For both MVD and VEGF expression the differences between VIN I and VIN III and between VIN II and VIN III were statistically significant (P < 0.0001). VIN III lesions are the clinical relevant precursors of invasive cancer of the vulva, as outlined by intense expression of VEGF protein and a highly dense network of microvessels underlying the dysplastic epithelium.
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PMID:Angiogenesis in vulvar intraepithelial neoplasia. 906 59

Neovascularization promotes tumor growth by facilitating nutrient exchange and by the paracrine effect. To investigate the relationship between tumor angiogenesis and patient outcome in colorectal cancer, 133 primary tumors were immunostained for CD34 antigen. Blood vessels within five microscopic fields at x200 were counted, and the mean was assigned. Mean patient age was 62.9 years, mean follow-up was 56.4 months, and mean vessel count was 112 (range, 23-298). Cox proportional hazards model and multivariate logistic regression analyses showed that the vessel count was the most important prognostic factor and correlated significantly with hematogenous, but not peritoneal or lymph node, metastasis.
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PMID:Tumor angiogenesis and mode of metastasis in patients with colorectal cancer. 906 67

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

The regulation of tumor growth by cytokine-induced alterations in host effector cell recruitment and activation is intimately associated with leukocyte adhesion and angiogenic modulation. In the present study, we have developed a novel tumor model to investigate this complex series of events in response to cytokine administration. Gelatin sponges containing recombinant human basic fibroblast growth factor (rhFGFb) and B16F10 melanoma cells were implanted onto the serosal surface of the left lateral hepatic lobe in syngeneic C57BL/6 mice. The tumor model was characterized by progressive tumor growth initially localized within the sponge and the subsequent development of peritoneal carcinomatosis. Microscopic examination of the sponge matrix revealed well developed tumor-associated vascular structures and areas of endothelial cell activation as evidenced by leukocyte margination. Treatment of mice 3 days after sponge implantation with a therapeutic regimen consisting of pulse recombinant human interleukin-2 (rhIL-2) combined with recombinant murine interleukin-12 (rmIL-12) resulted in a marked hepatic mononuclear infiltrate and inhibition of tumor growth. In contrast to the control group, sponges from mice treated with rhIL-2/rmIL-12 demonstrated an overall lack of cellularity and vascular structure. The regimen of rhIL-2 in combination with rmIL-12 was equally effective against gelatin sponge implants of rhFGFb/B16F10 melanoma in SCID mice treated with anti-asialo-GM1 in the absence of a mononuclear infiltration, suggesting that T, B, and/or NK cells were not the principal mediators of the anti-tumor response in this tumor model. The absence of vascularity within the sponge after treatment suggests that a potential mechanism of rhIL-2/rmIL-12 anti-tumor activity is the inhibition of neovascular growth associated with the establishment of tumor lesions. This potential mechanism could be dissociated from the known activities of these two cytokines to induce the recruitment and activation of host effector cells. Moreover, this model provides a unique opportunity to study the cellular and molecular mechanism(s) underlying both tumor angiogenesis and leukocyte recruitment to metastatic lesions.
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PMID:Regulation of local host-mediated anti-tumor mechanisms by cytokines: direct and indirect effects on leukocyte recruitment and angiogenesis. 913 9

Previous reports suggest that tissue factor (TF) may play an essential role in embryonic vascular development and tumor angiogenesis. To further examine this relationship, the morphology of fully developed TF-deficient embryos and the growth of TF-deficient teratomas and teratocarcinomas were analyzed. In a 129/Sv genetic background, TF null embryos do not survive beyond mid-gestation. In contrast, 14% of 129/Sv x C57BL/6 TF-deficient embryos escape this early mortality and survive to birth. On gross and microscopic inspection, these late gestation, TF-deficient embryos appear normal. The growth and vascularity of TF(+/+), TF(+/-), and TF(-/-) teratomas and teratocarcinomas are indistinguishable. Thus, tumor-derived TF is not required for tumor growth and angiogenesis and the combined data do not support an essential role for TF in embryonic vascular development.
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PMID:Effect of tissue factor deficiency on mouse and tumor development. 919 67

Abundant literature exists demonstrating that tumors are dependent on angiogenesis for both tumor growth and invasion. The extent of angiogenesis in primary tumors has been demonstrated to be associated with a negative prognosis in several tumors including non-small cell lung carcinoma, prostate cancer, and in node-negative breast cancer, where angiogenesis is an independent negative prognostic factor. These data demonstrate the significance of angiogenesis in tumor biology and indicate that it can be utilized as a target for novel therapeutic strategies. The recent expansion of knowledge into the specific pathways of tumor angiogenesis has provided reagents which can now be utilized to provide markers of efficacy of antiangiogenic agents in cancer patients. A critical part of the development of angiogenesis inhibitors for cancer therapy is the clinical trial strategy. Since these agents are primarily thought to be cytostatic, carefully designed trials must be conducted which focus on appropriate endpoints and integrate relevant biologic markers to support efficacy.
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PMID:Development of angiogenesis inhibitors for cancer therapy. 919 84

Binding of the serine protease urokinase (u-PA) to its receptor on tumor cell surfaces facilitates proteolysis and tumor invasion. We undertook this study to determine whether the role of u-PA in prostate cancer induced angiogenesis and secondary tumor growth by developing a homologous, immunocompetent in vivo model in which the tumors cells secrete an inhibitor of the murine u-PA receptor. A mutant recombinant murine u-PA that retains receptor binding but not proteolytic activity was made by PCR mutagenesis. Mutant u-PA and a reporter gene pRK luciferase were transfected and stably expressed in the highly metastatic rat Dunning MAT-LyLu prostate cancer cell line. Several clones expressing mutant u-PA and luciferase were identified by Western blotting, plasminogen zymography, and reverse transcription-PCR. One of these clones, 5C4, was injected s.c. into Copenhagen rats. Compared to animals injected with clones expressing pRK luciferase alone, tumors in animals injected with 5C4 cells were significantly smaller. Moreover, there were fewer lung micrometastases in the 5C4 animals. Primary tumor angiogenesis was measured by microvessel quantification of tissue stained with antibodies against von Willebrand factor. Mean microvessel density in 5C4 tumors was 4.3-fold lower than that in animals with tumors derived from the control tumor cell line (P < 0.0001). Significant inhibition of tumor growth was also observed for two additional MAT-LyLu cell lines expressing mutant u-PA. These findings suggest that cell surface u-PA contributes to prostate cancer growth by enhancing angiogenesis.
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PMID:Inhibition of prostate cancer neovascularization and growth by urokinase-plasminogen activator receptor blockade. 927 33

Angiogenesis is crucial for tumor growth and metastasis. Hepatocellular carcinoma (HCC) is a typical hypervascular tumor. However, the relationship between tumor vascularity and the outcome of patients with HCC has not been evaluated. To clarify whether tumor angiogenesis is related to the prognosis of patients, immunohistochemical staining, using anti-von Willebrand factor (vWF) and anti-CD34, was applied in resected specimens from 43 cases of HCC. In nonmalignant tissue, staining was confined to vessels in the portal tract and to a few periportal sinusoids with both of the endothelial markers applied. In tumor tissue, however, sinusoid-like vessels reacted intensively with anti-CD34 but not with anti-vWF. The intratumor microvessel density (MVD) highlighted by anti-CD34 was 297 +/- 88 (per 0.74 mm2), which was significantly higher than that highlighted by anti-vWF (4 +/- 7). When only the MVD highlighted by anti-CD34 was analyzed, tumor diameter larger than 2 cm, poor differentiation (Edmondson's II to IV), and portal invasion were significantly related to the subgroup with MVD > or = 290. Overall survival curves of patients with MVD < 290 were better, and these patients were more likely to remain tumor free. Cox hazards model revealed intratumor MVD and Edmondson's grade to be independent prognostic factors for the overall survival of patients. These results demonstrated for the first time that tumor angiogenesis assessed by anti-CD34 was correlated with the outcome of patients with HCC, suggesting a potential role for anti-CD34 in the diagnosis and treatment of HCC.
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PMID:Quantitation of sinusoid-like vessels in hepatocellular carcinoma: its clinical and prognostic significance. 936 65

Vascular endothelial growth factor (VEGF) is a leading candidate for an endogenous mediator of tumor angiogenesis. Recently, two endothelial cell surface receptors, flk-1 and flt-1, have been shown to mediate the angiogenic activities of VEGF. In this study, we have evaluated whether a soluble VEGF receptor could suppress tumor angiogenesis and thereby inhibit tumor growth. A soluble VEGF receptor was constructed by fusing the entire extracellular domain of murine flk-1 to a six-histidine tag at the COOH terminus (ExFlk.6His). In vitro, recombinant ExFlk.6His protein bound VEGF with high affinity (Kd, 16 nM) and blocked receptor activation in a dose-dependent manner and inhibited VEGF-induced endothelial cell proliferation and migration. ExFlk.6His bound to endothelial cells only in the presence of VEGF, and cell surface cross-linking yielded a high molecular weight complex consistent with the VEGF-mediated formation of a heterodimer between ExFlk.6His and the endogenous VEGF receptor. In vivo, ExFlk.6His potently inhibited corneal neovascularization induced by conditioned media from a rat mammary carcinoma cell line (R3230AC). Moreover, when ExFlk.6His protein was administered into a cutaneous tumor window chamber concomitantly with R3230AC carcinoma transplants, tumor growth was inhibited by 75% (P < 0.005) and vascular density was reduced by 50% (P < 0.002) compared with control-treated tumors. These results demonstrate the potential of ExFlk.6His to inhibit VEGF action by a potent "dominant-negative" mechanism and suggest that targeting VEGF action using a soluble receptor may be an effective antiangiogenic therapy for cancer and other "angiogenic" diseases.
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PMID:Inhibition of tumor growth by targeting tumor endothelium using a soluble vascular endothelial growth factor receptor. 943 88

Recent studies have shown that urokinase (uPA) is an independent prognostic marker in breast cancer. uPA plays a key role in the degradation of tumor matrix and promotes tumor progression. Macrophage expression of uPA appears to be important in this context. Our objective in the present study was to provide evidence that tumor growth factor-beta (TGF-beta) released from breast cancer cells markedly up-regulates uPA expression in tumor-associated macrophages (TAMs). TAMs from 32 breast carcinomas were cultured. Blood monocytes from healthy donors and breast cancer patients as well as tissue macrophages from patients with fibrocystic changes of the breast were also examined. After TGF-beta incubation, uPA levels were tested by ELISA, and uPA mRNA levels were determined by Northern blot analysis. TGF-beta receptor and uPA cell surface fluorescence intensities were determined by flow cytometry; TGF-beta receptors were determined by Western blot analysis. Protein kinase-C dependence was also examined, and immunohistochemical stainings for uPA and TGF-beta were performed. We have demonstrated that TGF-beta markedly up-regulates basal uPA expression (mRNA and protein) in TAMs but only modestly increases uPA production in blood monocytes and tissue macrophages. Exposure of macrophages to TGF-beta1 led to a rapid and sustained increase in uPA mRNA levels, which was independent of de novo protein synthesis and completely inhibited by actinomycin D. H7 markedly reduced the ability of TGF-beta to stimulate uPA expression. Likewise, okadaic acid potentiated the ability of TGF-beta to up-regulate macrophage uPA expression. We suggest that TAMs are more responsive to TGF-beta stimulation than are blood monocytes and tissue macrophages because of different TGF-beta receptor densities. TGF-beta stimulates transcription of the uPA gene, increases uPA-mRNA stability, and activates uPA expression via protein kinase-C-dependent mechanisms. The ability of TGF-beta to induce macrophage uPA expression may provide an indirect mechanism by which this growth factor stimulates angiogenesis. It may be, therefore, that TAMs promote tumor progression and tumor angiogenesis.
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PMID:Transforming growth factor-beta stimulates urokinase expression in tumor-associated macrophages of the breast. 946 Nov 22

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