UMLS:C0677930 - FACTA Search

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Query: UMLS:C0677930 (primary tumor)
20,210 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We reported that NK4, composed of the N-terminal hairpin and subsequent four kringle domains of hepatocyte growth factor (HGF), acts as the competitive antagonist for HGF. We now provide the first evidence that NK4 inhibits tumor growth and metastasis as an angiogenesis inhibitor as well as an HGF antagonist. Administration of NK4 suppressed primary tumor growth and lung metastasis of Lewis lung carcinoma and Jyg-MC(A) mammary carcinoma s.c. implanted into mice, although neither HGF nor NK4 affected proliferation and survival of these tumor cells in vitro. NK4 treatment resulted in a remarkable decrease in microvessel density and an increase of apoptotic tumor cells in primary tumors, which suggests that the inhibition of primary tumor growth by NK4 may be achieved by suppression of tumor angiogenesis. In vivo, NK4 inhibited angiogenesis in chick chorioallantoic membranes and in rabbit corneal neovascularization induced by basic fibroblast growth factor (bFGF). In vitro, NK4 inhibited growth and migration of human microvascular endothelial cells induced by bFGF and vascular endothelial growth factor (VEGF) as well as by HGF. HGF and VEGF activated the Met/HGF receptor and the KDR/VEGF receptor, respectively, whereas NK4 inhibited HGF-induced Met tyrosine phosphorylation but not VEGF-induced KDR phosphorylation. NK4 inhibited HGF-induced ERK1/2 (p44/42 mitogen-activated protein kinase) activation, but allowed for bFGF- and VEGF-induced ERK1/2 activation. These results indicate that NK4 is an angiogenesis inhibitor as well as an HGF antagonist, and that the antiangiogenic action of NK4 is independent of its activity as HGF antagonist. The bifunctional properties of NK4 to act as an angiogenesis inhibitor and as an HGF antagonist raises the possibility that NK4 may prove therapeutic for cancer patients.
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PMID:HGF/NK4, a four-kringle antagonist of hepatocyte growth factor, is an angiogenesis inhibitor that suppresses tumor growth and metastasis in mice. 1111 60

We have reported that particle-mediated interleukin 12 (IL-12) gene transfer into the skin overlying the local tumor inhibits systemic metastases. To further characterize this effect, we compared the antitumor and antimetastatic effects of IL-12 cDNA delivered at the local tumor site versus at a site distant from the primary tumor, in a spontaneous metastasis model of LLC-F5 tumor. Local IL-12 gene delivery into the skin overlying the intradermal tumor (local IL-12 treatment) on days 7, 9, and 11 after tumor implantation resulted in the most suppression of the growth of the primary LLC-F5 tumor, whereas IL-12 gene transfer into the skin distant from the tumor (distant IL-12 treatment) was less effective. In contrast, both local IL-12 and distant IL-12 treatment, followed by tumor excision, inhibited lung metastases to a similar extent, resulting in significantly extended survival of test mice. The results of in vivo studies using depleting anti-asialo GM1 antibody and anti-CD4/anti-CD8 monoclonal antibodies, or neutralizing anti-interferon gamma (IFN-gamma) monoclonal antibody demonstrated that natural killer (NK) cells, CD8(+) T cells, and IFN-gamma contributed to the antimetastatic effects in both treatment groups. Furthermore, the levels of mRNA expression of vascular endothelial growth factor and matrix methalloproteinase 9 at the tumor microenvironment were suppressed after both local and distant IL-12 treatment. These results suggest that the current particle-mediated IL-12 gene delivery in the spontaneous LLC-F5 metastasis model can confer antimetastatic activities, irrespective of the gene transfection site, via a combination of several mechanisms involving CD8(+) T cells, NK cells, IFN-gamma, and antiangiogenesis.
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PMID:Interleukin 12 gene transfer into skin distant from the tumor site elicits antimetastatic effects equivalent to local gene transfer. 1117 52

In brain, breast, and other common human tumors there is a correlation between expression of the transcriptional activator hypoxia-inducible factor 1 (HIF-1) and tumor grade and vascularization. HIF-1 stimulates angiogenesis by activating transcription of the gene encoding vascular endothelial growth factor (VEGF). HIF-1 is a heterodimer consisting of a constitutively-expressed HIF-1beta subunit and an O2- and growth factor-regulated HIF-1alpha subunit. Recent studies have demonstrated that HIF-1alpha expression is increased in tumor relative to normal tissue by two mechanisms. First, decreased intratumoral O2 concentrations provide a physiological stimulus. Second, genetic alterations that activate oncogene products or inactivate tumor suppressor gene products increase HIF- 1alpha expression and/or HIF-1 transcriptional activity independent of the O2 concentration. Taken together, these recent data suggest that increased HIF-1 activity provides a molecular basis for VEGF-induced angiogenesis and other adaptations of cancer cells to hypoxia that are critical for establishment of a primary tumor and its progression to the lethal phenotype.
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PMID:HIF-1: using two hands to flip the angiogenic switch. 1119 Oct 64

In this study we investigated the effects of the angiogenesis inhibitor TNP-470 on human pancreatic cancer cells in vitro and in vivo. The action of TNP-470 on vascular endothelial growth factor (VEGF) was also assessed. In vitro human pancreatic cancer cells (MIAPaCa-2, AsPC-1, and Capan-1), and human umbilical vein endothelial cells (HUVEC) were exposed to increasing concentrations (1 pg/ml to 100 microg/ml) of TNP-470. Cell proliferation was assessed after 3 days by cell count and MTT assay. In vivo, 5 x 10(6) pancreatic cancer cells were injected subcutaneously into nude mice. Four weeks later, 1 mm3 fragments of the resulting tumors were implanted into the pancreas of other mice. Animals received either TNP-470 (30 mg/kg every other day) or vehicle subcutaneously for 14 weeks. The volume of the primary tumor and metastatic spread were determined at autopsy. Concentrations of VEGF were determined in serum (VEGF(S)) and ascites (VEGF(A)) by enzyme-linked immunosorbent assay. Microvessel density was analyzed by immunohistochemistry in CD31-stained tumor sections. In vitro, proliferation and viability of the human pancreatic cancer cell lines were significantly inhibited at high concentrations of TNP-470 (> 1 microg/ml). In contrast, TNP-470 effectively decreased the growth of HUVEC at 100 pg/ml. In vivo, tumor volume and dissemination scores were significantly lower in all three pancreatic cancer cell lines. VEGF(S) and VEGF(A) were not different between treated groups. Treatment with TNP-470 significantly reduced neoangiogenesis in tumors of all three human pancreatic cancer cell lines: MIAPaCa-2 = 74.8 +/- 7.8/0.74 mm2 vs. 24.8 +/- 3.7/0.74 mm2; AsPC-1 = 65.3 +/- 5.0/0.74 mm2 vs. 26.0 +/- 3.4/0.74 mm2; and Capan-1 = 82.2 +/- 5.8/0.74 mm2 vs. 26.9 +/- 2.5/0.74 mm2 (P < 0.001). However, survival was not statistically different between groups. TNP-470 reduced tumor growth and metastatic spread of pancreatic cancer in vivo. This was probably due to the antiproliferative effect of the agent on endothelial cells rather than to the direct inhibition of pancreatic cancer cell growth. TNP-470 activity was not associated with alteration of VEGF secretion.
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PMID:Angiogenesis inhibitor TNP-470 reduces human pancreatic cancer growth. 1133 74

The vascular endothelial growth factor (VEGF) plays a central role in promoting angiogenesis, and it is the target of innovative anti-cancer therapies. In colorectal carcinomas, differences in the VEGF expression have been found between the primary tumor and its metastases. We postulated that differences in the VEGF expression may also exist between liver and abdominal metastases from colon cancer. Consecutive colon cancer patients with liver or abdominal metastases were considered eligible for the study. Biopsies had to be performed before chemotherapy and the VEGF analysis were conducted through immunohistochemistry. The staining results were correlated to the metastatic pattern. The study population consisted of 41 patients with a metastatic site in the liver in 19 patients and the abdomen in 22 patients. A positive VEGF staining was found in 19 of the 41 metastatic samples (46%). Cases with positive VEGF expression were found more frequently in abdominal (15 out of 22 patients; 68%) than in liver metastases (4 out of 19 patients; 21%). Also, the degree of VEGF immunoreactivity was significantly higher in abdominal than in liver metastases. Evidence is supported that the VEGF expression may be different between colon cancer metastatic sites. The efficacy of anti-VEGF treatments may depend on the VEGF expression status, and this finding deserves further investigation.
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PMID:Differences of vascular endothelial growth factor (VEGF) expression between liver and abdominal metastases from colon cancer. Implications for the treatment with VEGF inhibitors. 1182 68

BACKGROUND: Detection of micrometastasis is an important problem of clinical significance for a better understanding and control of tumor progression, which will improve patients' survival time.METHODS: To identify micrometastases in bone marrow, an immunocytochemical assay for epithelial cytokeratin protein was performed in 106 patients with primary gastric cancer. Also, in 40 of the 106 patients, vascular endothelial growth factor (VEGF) expression and intratumoral vessel density were examined by an immunohistochemical staining method.RESULTS: Of the 106 patients, 22 (20.8%) presented with cytokeratin-positive cells in bone marrow at the time of primary surgery. The positive findings were related to depth of invasion, peritoneal dissemination, and liver metastasis. Patients with cytokeratin-positivity in bone marrow had a higher VEGF positive rate (73%; 8/11) than did cytokeratin-negative patients (48%; 14/29). Intratumoral vessel density in VEGF-positive patients was 26.9 +/- 10.3, which was significantly higher than that in VEGF-negative patients (13.2 +/- 8.7, P < 0.05). Thus, the presence of cytokeratin-positive cells in bone marrow was closely related to angiogenesis in the primary tumor.CONCLUSIONS: Cytokeratin staining can be useful for identifying patients at high risk for metastasis. Prophylactic lymph node dissection, adjuvant chemotherapy, and antiangiogenic treatment may be necessary for patients with micrometastasis.
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PMID:Clinical significance of micrometastasis in bone marrow of patients with gastric cancer and its relation to angiogenesis. 1195 70

The role of vascular endothelial growth factor (VEGF) during peritoneal dissemination of ovarian carcinoma and the association with tumor microvessel density (MVD) and matrix metalloproteinase (MMP) activity was investigated. To this end, MVD, tumor tissue and ascitic fluid levels of VEGF, and MMP activity of ascitic fluid were examined in patients with ovarian cancer and benign ovarian tumor. The effect of ascites on cell growth, cell invasion activity and angiogenesis was investigated in vitro. Ascitic fluid and tumor tissue samples were obtained from 15 patients with benign ovarian tumor and 24 patients with ovarian carcinoma. Tissue extract and ascitic fluid levels of VEGF were measured using enzyme immunoassay. Tumor microvessels were detected immunohistochemically. MMP activity was measured by gelatin zymography. For the in vitro experiment, the SKOV-3 human ovarian carcinoma cell line was utilized. Cell growth was examined using MTT-assay, cell invasion activity was measured by Matrigel in vitro invasion assay, and neovascularization was assessed using an angiogenesis kit. VEGF levels in tissue extract and ascitic fluid, MVD, expression of active form MMP-2 in ascitic fluid and ascites volume were higher in ovarian cancer patients than in benign ovarian tumor patients. In addition, these were elevated in stage III and IV diseases compared to stage I and II diseases in ovarian cancer patients. MVD and expression of active form MMP-2 in ascitic fluid were closely correlated with VEGF level in tissue extracts, and MVD and ascites volume were closely correlated with VEGF level in ascitic fluid. Cell invasive activity and angiogenesis activity increased when cells were exposed to ascites. These increases were apparent when exposed to ascites obtained from ovarian cancer patients and were related to VEGF concentrations of ascitic fluid and expression of active form MMP-2 in ascitic fluid. The increased VEGF secreted from tumor cells is suggested to enhance tumor growth through angiogenesis, to produce ascites and to elevate ascitic VEGF concentrations and expression of active form MMP-2. The progression of peritoneal involvement may be induced by elevated VEGF and expression of active form MMP-2, followed by increased VEGF in the primary tumor. Control of VEGF in the primary tumor may become an effective strategy against peritoneal dissemination of ovarian carcinoma.
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PMID:Vascular endothelial growth factor activating matrix metalloproteinase in ascitic fluid during peritoneal dissemination of ovarian cancer. 1246 50

Blockade of vascular endothelial growth factor (VEGF) and inhibition of matrix metalloproteinases (MMP) are promising therapies for cancer. This study assessed the effects of a neutralizing anti-VEGF antibody (A4.6.1) and an MMP inhibitor (BB-94) on pancreatic cancer (PaCa) in vivo. Five million cells of two human PaCa cell lines (AsPC-1 and HPAF-2) were injected subcutaneously into nude mice; 1 mm(3) fragments of the resulting tumors were implanted into the pancreas of other mice. Animals were randomized into a control group and three treatment groups: A4.6.1 (100 microg intraperitoneally twice weekly); BB-94 (50 mg/kg every other day); and combination (A4.6.1 plus BB-94). Treatment was started after 3 days and continued for 14 weeks. Tumor volume, local and distant spread (score), and ascites were determined at autopsy. Microvessel density as a parameter of neoangiogenesis was analyzed in CD31-stained tumor sections. Both monotherapies reduced tumor volume (HPAF-2: -89% by A4.6.1 and -75% by BB-94; AsPC-1: -48% by A4.6.1 and -72% by BB-94), spread (HPAF-2: -76% by A4.6.1 and -58% by BB-94; AsPC-1: -32% by A4.6.1 and -54% by BB-94), and microvessel density (HPAF-2: -75% by A4.6.1 and -30% by BB-94; AsPC-1: -59% by A4.6.1 and -30% by BB-94), resulting in a tendency toward increased survival (HPAF-2: 8 of 8 animals by A4.6.1 or BB-94 vs. 4 of 8; AsPC-1: 3 of 8 by A4.6.1, 4 of 8 by BB-94 vs. 1 of 8). Combination therapy yielded additional effects in the HPAF-2 group with regard to tumor volume (-95%) and development of ascites (0 of 8 vs. 2 of 8 by A4.6.1 or BB-94 vs. 5 of 8 control mice). Both VEGF blockade and MMP inhibition reduce primary tumor size, metastasis, and angiogenesis, thereby increasing survival in experimental pancreatic cancer. Combination treatment results in additive effects in moderately differentiated HPAF-2 tumors.
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PMID:Evaluation of vascular endothelial growth factor blockade and matrix metalloproteinase inhibition as a combination therapy for experimental human pancreatic cancer. 1260 Apr 46

Contortrostatin, a 13.5 kDa disulfide-linked homodimeric polypeptide possessing an Arg-Gly-Asp sequence, was isolated from venom of the southern copperhead snake. Daily injection of contortrostatin into the primary tumor of human breast cancer MDA-MB-435 carried in nude mice significantly inhibited tumor growth and neovascularization of the tumor tissue. On the chick embryo chorioallantoic membrane, contortrostatin inhibited angiogenesis induced by MDA-MB-435 cells, basic fibroblast growth factor, and vascular endothelial growth factor. In addition, contortrostatin effectively blocked adhesion of human umbilical vein endothelial cells (HUVEC) to immobilized vitronectin and significantly inhibited invasion of HUVEC through a Matrigel barrier. Competitive binding assays and adhesion assays with different integrin antibodies suggested that integrin alpha(v)beta3 is a binding site for contortrostatin on vascular endothelial cells. Detachment of HUVEC from vitronectin by contortrostatin induced apoptosis. HUVEC adhered and spread well on immobilized contortrostatin without undergoing apoptosis, suggesting that it is the inhibition of adhesion and spreading of HUVEC on extracellular matrix proteins, rather than binding of contortrostatin to integrins per se, that triggers apoptosis. We conclude that contortrostatin binds to alpha(v)beta3, and interferes with the anchorage-dependent survival mechanism of the vascular endothelial cells, and the mobility of the cells. The consequent suppression of angiogenesis is an important component of the antineoplastic activity of contortrostatin.
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PMID:Contortrostatin, a dimeric disintegrin from Agkistrodon contortrix contortrix, inhibits angiogenesis. 1451 25

Early stage primary human cutaneous melanoma is known to remain relatively avascular and dormant for up to a decade, after which it may give rise to more rapidly growing, vascular and metastatically- competent primary tumor. Clinical dormancy of early stage human melanomas can be recapitulated experimentally by injection of cell lines established from such tumors into nude mice. For example, WM1341B cells, which were isolated from a thin vertical growth phase (VGP) human melanoma, are non-tumorigenic in nude mice even though some of the cells remain viable for at least three weeks at the site of orthotopic injection. These cells produce little or no vascular endothelial growth factor/vascular permeability factor (VEGF/VPF), a potent stimulator of angiogenesis. In order to determine whether their in vivo dormant behaviour may therefore be related to an inability to induce tumor angiogenesis, subpopulations of WM1341B cells were engineered to constitutively overexpress the VEGF/VPF121 isoform. This apparently single modification was sufficient to induce overt and progressively growing tumors by several independent VEGF/VPF121 producing clones, which could be largely blocked by systemic treatment of mice with a monoclonal anti-VEGF neutralizing antibody (A 4.6.1). No evidence for an autocrine mechanism of growth stimulation by VEGF was found. Taken together, these results support the notion that defective angiogenesis may, at least in part, account for dormant phenotype of some early stage primary melanomas. Since the induction of an overt tumorigenic phenotype in several VEGF/VPF transfected WM1341B clones appears to depend exclusively on their expression of VEGF/VPF, such sublines should be useful for screening the activity of known or potential VEGF/VPF ligand or VEGF/VPF receptor antagonists in an in vivo context.
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PMID:The dormant in vivo phenotype of early stage primary human melanoma: termination by overexpression of vascular endothelial growth factor. 1451 61

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