UMLS:C0178874 - FACTA Search

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

Menstrual cycle activity predisposes to ovarian epithelial tumors based on numerous epidemiological studies. We showed that the hormones involved in menstrual cycle regulation modulate cell cycle activity in these tumors in an accompanying paper. We investigated whether such hormones could also influence angiogenesis, an important determinant of tumor progression, in the same tumors. Treatment with progesterone (P4) stimulated VEGF protein secretion in 4 of 5 ovarian carcinoma cell lines examined. Northern blot analyses performed in MCV50 cells showed that this effect was accompanied by increased VEGF mRNA levels. P4 also stimulated VEGF promoter activity in these cells. Estradiol (E2) showed a similar, but substantially smaller effect on VEGF secretion which was additive to that of P4. Conditioned medium from P4-treated cells strongly stimulated angiogenesis on chicken chorio-allantoic membranes. Incubating the conditioned medium with a neutralizing anti-VEGF antibody, but not with non-specific immunoglobulins abolished this effect. Angiogenic activity was not altered by treatment of the membranes with P4 directly. We conclude that P4 can stimulate angiogenic activity via induction of VEGF secretion in some ovarian epithelial tumors. Therapeutic use of progestins may be most effective when administered in combination with an anti-angiogenic agent, at least against a subset of ovarian carcinomas.
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PMID:Effect of reproductive hormones on ovarian epithelial tumors: II. Effect on angiogenic activity. 1243 84

HIF-1 is reported to transactivate expression of VEGF, which is an important angiogenic factor. To determine whether HIF-1alpha plays a role in angiogenesis through its regulation of VEGF, we examined expression of HIF-1alpha and its relation to clinicopathologic features, VEGF expression and prognosis of patients with colorectal carcinoma. Expression of HIF-1alpha and VEGF was examined in 4 colorectal carcinoma cell lines (COLO320DM, COLO201, DLD-1, WiDr) and 149 colorectal carcinoma tissues (10 fresh specimens, 139 archival, paraffin-embedded specimens). HIF-1alpha protein levels were increased by hypoxia in 3 of 4 colorectal carcinoma cell lines (COLO201, DLD-1, WiDr), and VEGF mRNA levels were also increased by hypoxia in the same cell lines. In 8 of 10 patients with colorectal cancer, expression of HIF-1alpha and VEGF was increased in tumor tissues compared to corresponding normal mucosa. Of 139 archival specimens of colorectal carcinoma, 81 (58.3%) expressed HIF-1alpha protein at a high level. HIF-1alpha expression was correlated with tumor invasion, tumor stage, lymphatic invasion, venous invasion and liver metastasis. Moreover, HIF-1alpha expression was correlated significantly with VEGF expression and microvessel density. Although there was a tendency for poorer prognosis in patients with high HIF-1alpha-expressing tumors, this correlation was not statistically significant. These findings suggest that HIF-1alpha may play a role in angiogenesis and tumor progression via regulation of VEGF in human colorectal carcinoma.
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PMID:Expression of hypoxia-inducible factor-1alpha is associated with tumor vascularization in human colorectal carcinoma. 1267 75

Angiogenesis, neovascularization from pre-existing vasculature, is necessary to supply oxygen and nutrition for tumor growth in both primary and distant organs. It consists of sprouting and non-sprouting (the enlargement, splitting, and fusion of pre-existing vessels) processes, and both can occur concurrently. Growth of solid tumors, including non-small cell lung cancer (NSCLC), is usually dependent on angiogenesis, which is regulated by complex mechanisms involving various angiogenesis-related molecules. Vascular endothelial growth factor (VEGF), also known as vascular permeability factor (VPF), one of the most potent angiogenic molecules, regulates both angiogenesis and vascular permeability, and hence promotes tumor progression and development of malignant pleural effusions in NSCLC. Signals via epidermal growth factor receptor (EGFR) promote not only the tumor cell cycle, but also the process of angiogenesis. Therefore, these molecules are potential targets for anti-tumor vasculature therapy. Many agents targeting tumor vasculature have been developed, and several compounds have shown anti-tumor potential in preclinical studies. Their efficacy against NSCLC is currently being evaluated in clinical trials.
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PMID:Molecular mechanisms of angiogenesis in non-small cell lung cancer, and therapeutics targeting related molecules. 1282 70

Angiogenesis is increased in various human cancers, including head and neck squamous cell carcinoma (HNSCC), and correlates with tumor progression and metastasis. Vascular endothelial growth factor (VEGF) has been shown to be a key regulator of angiogenesis. We determined whether VEGF antisense oligonucleotide treatment can decrease angiogenic activity of HNSCC cell lines in vitro and of HNSCC xenografts in vivo. Established human HNSCC cell lines were screened for VEGF expression at both mRNA and protein levels. By using a 21-mer antisense phosphorothioate oligonucleotide targeting the translation start site of human VEGF mRNA, we examined modulation of VEGF expression in cell line supernatants by capture ELISA, and in cell lysates by Western blotting. Human umbilica vein endothelial cells (HUVEC) were grown in conditioned medium produced from the treated tumor cells. Endothelial cell (EC) proliferation was determined by cell count and EC migration was measured using a modified Boyden chamber. Mice with HNSCC xenografts were treated with PBS, VEGF antisense or sense oligonucleotides (10 mg/kg; i.p. injection), respectively and tumor volumes were measured for 5 weeks. VEGF antisense oligonucleotide treatment resulted in a significant reduction of VEGF protein expression compared to sense control. Although the growth rate of the tumor cell lines was not affected, addition of conditioned medium from VEGF antisense-treated tumor cells resulted in decrease of endothelial cell proliferation and migration. VEGF antisense oligonucleotide treatment of HNSCC xenografts resulted in a significant tumor growth suppression. These results suggest that downmodulation of VEGF using antisense oligonucleotides may be a potential therapy for the inhibition of angiogenesis in HNSCC.
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PMID:Abrogation of VEGF expression in human head and neck squamous cell carcinoma decreases angiogenic activity in vitro and in vivo. 1288 90

Angiogenesis, the formation of blood vessels, is a major factor influencing tumor growth and metastatic capacity, and VEGF is the prototype angiogenic factor. VEGF expression is also found in the dermis and tumor stroma during the course of melanoma progression. Various oncogenes such as c-Src, v-Raf, and Ras, and multiple environmental stimuli, including hypoxia and ultraviolet radiation (UVR), can regulate VEGF expression under certain conditions. We have constructed several cell lines from a radial growth phase, primary human melanoma cell line, WM35. We have stably transfected WM35 cells with mutant activated H-ras, N-ras, dominant negative p53, or empty vector. In this report, we determined how VEGF expression and release from these melanoma cell lines were affected by the following important factors associated with melanoma initiation and progression: hypoxia, UVR, activated Ras, dominant negative p53, and culture conditions mimicking radial growth phase melanoma (monolayer culture) and vertical growth phase melanoma (spheroid culture). We found that hypoxia, but not UVR, up-regulates VEGF mRNA expression and protein release in these melanoma cells. In addition, activated Ras and dominant negative p53 enhances the hypoxia-induced VEGF protein release. We propose that hypoxia-induced VEGF release promotes tumor progression, especially in melanomas with Ras or p53 mutations.
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PMID:Release of vascular endothelial growth factor from a human melanoma cell line, WM35, is induced by hypoxia but not ultraviolet radiation and is potentiated by activated Ras mutation. 1463 12

Hypoxia-inducible factor 1 (HIF-1) is a heterodimeric basic helix-loop-helix transcription factor composed of HIF-1alpha and HIF-1beta subunits. HIF-1 expression is induced by hypoxia, growth factors, and activation of oncogenes. HIF-1 activates downstream target genes such as vascular endothelial growth factor A (VEGF-A), which plays an important role in tumor progression and angiogenesis. Estrogen exposure is considered to be the major risk factor for ovarian cancer. Estradiol (E2) is usually metabolized by CYP1A1/1A2 and CYP3A4 to the 2-hydroxy estradiol (2-OHE2) and 4-hydroxy estradiol (4-OHE2) in human liver. Many reports have suggested that the formation of 4-OHE2 is important for mammary carcinogenesis. However, the formation of 2-OHE2 may play an important role in exhibiting anticarcinogenic effects. In the present study, we have demonstrated that one of the catechol estrogen metabolites of E2, 4-OHE2, induces HIF-1alpha and VEGF-A expression at protein level in two human ovarian cancer cell lines, OVCAR-3 and A2780-CP70 cells, in dose- and time-dependent manners, whereas the other catechol estrogen metabolite of E2, 2-OHE2, does not alter HIF-1alpha and VEGF-A expression. To explore the mechanism of 4-OHE2-induced HIF-1alpha and VEGF-A expression, we studied whether phosphatidylinositol 3-kinase (PI3K) or mitogen-activated protein kinase (MAPK) signaling pathways are involved in 4-OHE2-induced HIF-1alpha and VEGF-A expression. Our findings indicate that PI3K inhibitors, LY294002 and wortmannin, inhibited HIF-1alpha and VEGF-A expression, whereas MAPK inhibitor, PD98059, did not alter HIF-1alpha and VEGF-A expression induced by 4-OHE2. 4-OHE2, but not 2-OHE2, also induced Akt phosphorylation at Ser473 in dose- and time-dependent manners, and LY294002 and wortmannin inhibited Akt phosphorylation at Ser473 induced by 4-OHE2. Our results also indicated that the mTOR/FRAP inhibitor, rapamycin, inhibited 4-OHE2-induced HIF-1alpha and VEGF-A expression. These results suggest that the PI3K/Akt/FRAP signaling pathway is required for HIF-1alpha and VEGF-A expression induced by 4-OHE2, whereas the MAPK pathway is not required. The finding that induction of HIF-1alpha and VEGF-A expression occurs via the activation of the PI3K/Akt/FRAP signaling pathway could be an important mechanism of 4-OHE2-induced carcinogenesis.
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PMID:4-Hydroxy estradiol but not 2-hydroxy estradiol induces expression of hypoxia-inducible factor 1alpha and vascular endothelial growth factor A through phosphatidylinositol 3-kinase/Akt/FRAP pathway in OVCAR-3 and A2780-CP70 human ovarian carcinoma cells. 1505 Apr 14

The p53 tumor-suppressor gene is one of the most frequently mutated genes in human cancers, and its genetic alterations may play critical roles in oncogenesis, tumor progression, and angiogenesis. To clarify the influence of the p53 status on hypoxia-inducible gene expression, we first performed transfection assays with a hypoxia-responsive vector carrying 5 hypoxia-responsive elements upstream of the human CMV minimal promoter driving transcription of the luciferase gene in various human tumor cell lines with wild-type (wt) or mutant (mut) p53. As a result, hypoxia responsiveness considerably varied between cell lines, and we could not obtain clear evidence that the hypoxia-inducible factor-1 (HIF-1) mediated gene expression in the wt-p53 cells was lower than that in cells with mut-p53. It is interesting that SaOS2 cells (p53 null) showed the highest luciferase activities under both aerobic and hypoxic conditions among tested cells. Next, to elucidate the effects of endogenous wt- and mut-p53s, a transfection assay and Northern blot analysis for VEGF transcription under hypoxia were performed by using isogenic variants of HT1080 cells differing in their p53 status. The luciferase and the endogenous VEGF mRNA expression were apparently lower in a variant carrying mutations in both p53 alleles than in a parental line harboring wt-p53, implying that some types of mutant p53 constitutively accumulated in cells can decrease both the basal and the hypoxia-induced expressions in addition to wt-p53.
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PMID:Influences of the p53 status on hypoxia-induced gene expression. 1530 78

Angiogenesis is increased in various human cancers, including head and neck squamous cell carcinoma (HNSCC), and correlates with tumor progression and metastasis. Vascular endothelial growth factor (VEGF) has been shown to be a key regulator of angiogenesis. We determined whether VEGF antisense oligonucleotide treatment can decrease the angiogenic activity of HNSCC cell lines in vitro and of HNSCC xenografts in vivo. Established human HNSCC cell lines were screened for VEGF expression at both mRNA and protein levels. By using a 21-mer antisense phosphorothioate oligonucleotide targeting the translation start site of human VEGF mRNA, we examined the modulation of VEGF expression in cell line supernatants by capture ELISA and in cell lysates by Western blotting. Human endothelial cells were grown in conditioned medium produced from the treated tumor cells. Endothelial cell proliferation was determined by cell count, and endothelial cell migration was measured using a modified Boyden chamber. Mice with HNSCC xenografts were treated with PBS, VEGF antisense or sense oligonucleotides (10 mg/kg i.p. injection, 3 times/week), respectively, and tumor volumes were measured for 5 weeks. VEGF antisense oligonucleotide treatment resulted in a significant reduction of VEGF protein expression compared to treatment with the sense control. Although the growth rate of the tumor cell lines was not affected, the addition of conditioned medium from VEGF antisense-treated tumor cells resulted in decreased endothelial cell proliferation and migration. VEGF antisense oligonucleotide treatment of HNSCC xenografts resulted in a significant tumor growth suppression. These results suggest that downmodulation of VEGF using antisense oligonucleotides may be a potential therapy for the inhibition of angiogenesis in HNSCC.
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PMID:Antiangiogenic therapy of head and neck squamous cell carcinoma by vascular endothelial growth factor antisense therapy. 1560 22

Heparanase is an endoglycosidase that degrades heparan sulfate (HS) in the extracellular matrix (ECM) and cell surfaces, and fulfills a significant role in cancer metastasis and angiogenesis. We evaluated the expression of heparanase and its possible association with the expression of angiogenic molecules in malignant mesothelioma (MM), and analyzed whether expression of these proteins is site-related (pleural vs peritoneal MM, solid lesions vs effusions). Sections from 80 MM (56 biopsies, 24 effusions) were analyzed for heparanase protein expression using immunohistochemistry (IHC). Sixty MM were of pleural origin, and 20 were peritoneal. Effusion specimens consisted of 6 peritoneal and 18 pleural effusions, while biopsies consisted of 14 peritoneal and 42 pleural lesions. Fifty-four specimens were additionally evaluated for expression of basic fibroblast growth factor (bFGF), interleukin-8 (IL-8) and vascular endothelial growth factor (VEGF) proteins using IHC. Microvessel density (MVD) was studied in 28 biopsies using an anti-CD31 antibody. mRNA expression of heparanase (HPSE-1), VEGF and the VEGF receptor KDR was analyzed in 23 effusions using RT-PCR. Heparanase protein expression was seen in 69/80 (86%) tumors. Of these, 35 showed combined membrane and cytoplasmic expression, 30 cytoplasmic expression, and four exclusively membrane expression. Both total (P = 0.001) and cytoplasmic (P = 0.002) expression was significantly higher in solid tumors compared to effusions. Protein expression of VEGF, IL-8 and bFGF was seen in 21/54 (39%), 22/54 (41%) and 44/54 (81%) specimens, respectively. Protein expression of bFGF was significantly higher in solid tumors (P < 0.001) and correlated with heparanase expression (P = 0.005). HPSE-1 and VEGF mRNA expression was detected in all 23 effusions using RT-PCR, while KDR mRNA was found in 12/23 MM. KDR mRNA expression correlated with that of both HPSE-1 (P = 0.005) and VEGF (P = 0.001). Our results document frequent expression of heparanase in MM, in agreement with the biological aggressiveness of this tumor. The co-expression of heparanase with bFGF is in agreement with the role of the former in releasing bFGF from the ECM. The concomitant reduction in protein expression of both molecules in effusions as compared to solid tumors, supports the hypothesis of a reduced need for pro-angiogenic stimuli in effusions, and may aid in defining tumor progression in this setting.
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PMID:Heparanase and basic fibroblast growth factor are co-expressed in malignant mesothelioma. 1567 72

Tissue factor (TF), an initiator of the extrinsic coagulation cascade, is expressed in a wide range of cancer cells and plays important roles in cancer progression and metastasis. We demonstrated between TF and vascular endothelial growth factor (VEGF) production differences in four human gastric cell lines. One of these cell lines, SGC-7901, a high TF and VEGF producer, was grown subcutaneously in severe combined immuno-deficient (SCID) mice. The SCID mice generated solid tumors characterized by intense vascularity. In contrast, SGC-7901 cells transfected with antisense TF cDNA generated relatively avascular tumors in SCID mice, as determined by immunohistochemical staining of tumor vascular endothelial cells with anti-VIII factor antibody. To investigate the structure-function relationship between TF and VEGF, the SGC-7901 cell line was transfected with antisense a full-length TF cDNA, a cytoplasmic deletion mutant lacking the distal three serine residues (potential substrates for protein kinase C), or an extracellular domain mutant, which has markedly diminished function for activation of factor X. Cells transfected with the full-length antisense TF sequence produced decreased levels of both TF and VEGF. Transfectants with the extracellular domain mutant produced high levels of VEGF mRNA. However, cells transfected with the cytoplasmic deletion mutant construct produced increased levels of TF, but little or no VEGF. Thus, the cytoplasmic tail of TF may signal VEGF expression in some tumor cells.
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PMID:Regulation of vascular endothelial growth factor (VEGF) production and angiogenesis by tissue Factor (TF) in SGC-7901 gastric cancer cells. 1584 7

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