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

Vascular endothelial growth factor (VEGF) is critical for vascularization of tissues, including tumors, making it an attractive target for controlling angiogenesis. An important first step towards the goal of effectively blocking tumor angiogenesis is to understand the relationships among tumor-promoting molecules. Whereas little is known about developmental regulation of VEGF, pathological regulation of VEGF during disease states and tumorigenesis is better understood. This review focuses on transcriptional regulation of VEGF expression in cancer. Understanding how VEGF is regulated in tumors cells may provide the basis for future treatments that target both the tumor and its vascular supply.
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PMID:Transcriptional regulation of vascular endothelial growth factor in cancer. 1573 33

Prostate cancer is the most common non-skin cancer affecting men in United States and the second leading cause of death after lung cancer. The clinical course of patients after given diagnosis of prostate cancer is highly variable and the underlying reasons for such variability remain elusive. To better understand the pathophysiology of prostate cancer, there has been a push to elucidate the molecular mechanisms that mediate the development and progression of prostate cancer. Recent literature has pointed that a complex interplay between various cytokines, growth factors, and androgen receptors regulate the growth and functions of the prostate gland. Amongst the currently implicated anomalous pathways involved in prostate oncogenesis, the IGF-IGFBP axis has been demonstrated to play a very important role, although the precise molecular events regulated by IGF remain to be elucidated. The tumor promoting functions of VEGF has been defined in tumor angiogenesis and currently remains the central focus of anti-angiogenesis therapy in prostate cancer. Another key cytokine, TGF-beta has tumor-suppressor functions in normal prostate gland, but its pleiotropic functions in prostate cancer are influenced by the hormonal state of the disease. In partnership with other deregulated growth factor signaling, the TGF-beta cascade has also been implicated in the spread of prostate cancer. Lastly, members of the EGFR family, particularly the HER2 receptor, have also been recognized as crucial elements of aberrant signal transduction pathways, which induce activation of downstream signaling, involved in cellular proliferation, cell survival, and angiogenesis. The abnormal function of a number of growth factors in prostate cancer biology explains the heterogeneity of its histologic grade, mode of presentation and disease prognosis. At the same time, continued research in this field allows for the potential development of drug therapies against a diverse pool of cancer causing targets.
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PMID:Growth factors involved in prostate carcinogenesis. 1576 31

This study focused on the screening of small-molecule inhibitors that target signal transducers and activators of transcription 3 (Stat3) in human breast carcinoma. The constitutive activation of Stat3 is frequently detected in human breast cancer cell lines as well as clinical breast cancer specimens and may play an important role in the oncogenesis of breast carcinoma. Activated Stat3 may participate in oncogenesis by stimulating cell proliferation, promoting tumor angiogenesis, and resisting apoptosis. Because a variety of human cancers are associated with constitutively active Stat3, Stat3 represents an attractive target for cancer therapy. In this study, of the nearly 429,000 compounds screened by virtual database screening, chemical samples of top 100 compounds identified as candidate small-molecule inhibitors of Stat3 were evaluated by using Stat3-dependent luciferase reporter as well as other cell-based assays. Through serial functional evaluation based on our established cell-based assays, one compound, termed STA-21, was identified as the best match for our selection criteria. Further investigation demonstrated that STA-21 inhibits Stat3 DNA binding activity, Stat3 dimerization, and Stat3-dependent luciferase activity. Moreover, STA-21 reduces the survival of breast carcinoma cells with constitutive Stat3 signaling but has minimal effect on the cells in which constitutive Stat3 signaling is absent. Together, these results demonstrate that STA-21 inhibits breast cancer cells that express constitutively active Stat3.
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PMID:A low-molecular-weight compound discovered through virtual database screening inhibits Stat3 function in breast cancer cells. 1578 62

Heparan sulfate proteoglycans are integral components of the extracellular matrix that surrounds all mammalian cells. In addition to providing structural integrity, they act as a storage depot for a variety of heparan sulfate (HS)-binding proteins, including growth factors and chemokines. Heparanase is a matrix-degrading enzyme that cleaves heparan sulfate side chains from the core proteoglycans, thus liberating such HS-binding proteins, as well as potentially contributing to extracellular matrix degradation. Here, we report that heparanase mRNA and protein expression are increased in the neoplastic stages progressively unfolding in a mouse model of multistage pancreatic islet carcinogenesis. Notably, heparanase is delivered to the neoplastic lesions in large part by infiltrating Gr1+/Mac1+ innate immune cells. A sulfated oligosaccharide mimetic of heparan sulfate, PI-88, was used to inhibit simultaneously both heparanase activity and HS effector functions. PI-88 had significant effects at distinct stages of tumorigenesis, producing a reduction in the number of early progenitor lesions and an impairment of tumor growth at later stages. These responses were associated with decreased cell proliferation, increased apoptosis, impaired angiogenesis, and a substantive reduction in the number of invasive carcinomas. In addition, we show that the reduction in tumor angiogenesis is correlated with a reduced association of VEGF-A with its receptor VEGF-R2 on the tumor endothelium, implicating heparanase in the mobilization of matrix-associated VEGF. These data encourage clinical applications of inhibitors such as PI-88 for the many human cancers where heparanase expression is elevated or mobilization of HS-binding regulatory factors is implicated.
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PMID:A functional heparan sulfate mimetic implicates both heparanase and heparan sulfate in tumor angiogenesis and invasion in a mouse model of multistage cancer. 1580 57

The constitutive activation of signal transducer and activator of transcription 3 (Stat3) is frequently detected in breast cancer tissues and cell lines. Stat3 has been classified as a proto-oncogene, because an activated form of Stat3 can mediate oncogenic transformation in cultured cells and tumor formation in nude mice. Since Stat3 may play an important role in breast cancer, it is of interest to investigate the expression of phosphorylated Stat3, an activated form of Stat3, and its downstream mediators specifically in breast cancer, and to explore the possible mechanisms of Stat3 signaling pathway in oncogenesis of breast cancer. We analyzed Stat3 phosphorylation and expression of Stat3-regulated genes in breast cancer cell lines as well as invasive breast cancer tissues using tissue microarray slides. Our results showed that elevated levels of phosphorylation of Stat3 protein (Tyr705) were detected in 48 out of total 136 invasive breast tumors (35%) whereas normal breast tissues express much lower levels of Stat3 phosphorylation. The increased levels of Stat3 phosphorylation were associated with the metastasis in regional lymph nodes (P=0.042) and the expression of progesterone receptor (P=0.028) but not with distant metastasis, nor the expression of estrogen receptor. Our results also indicate that elevated levels of Stat3 phosphorylation were significantly associated with increased expression of potential downstream targets of Stat3 which include apoptosis inhibitors (Survivin, Mcl-1, HSP27, Adrenomedullin, and Bcl-xL), cell-cycle regulators (c-Fos, MEK5, and c-Myc), and inducer of tumor angiogenesis (VEGF, COX-2, MMP-2, MMP-10, and MMP-1) in invasive breast cancer tissues. Therefore, our findings suggest that constitutive Stat3 signaling may be one of the key upstream regulators to induce these downstream proteins, which may play important roles in Stat3-mediated oncogenesis in breast cancer.
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PMID:Evaluation of potential Stat3-regulated genes in human breast cancer. 1608 Oct 48

It is widely accepted that angiogenesis is required for tumor progression. Vascular endothelial growth factor (VEGF) is a key molecule for tumor angiogenesis; however, its expressional regulation is not well understood during all stages of tumorigenesis. Using cell lines and surgical specimens of human non-small cell lung cancers (NSCLCs), we here show that platelet-derived growth factor-AA (PDGF-AA) is an essential autocrine regulator for VEGF expression. To directly assess the expression of PDGF-AA-dependent VEGF and its roles in tumorigenesis, we stably transfected established cell lines with their antisense genes. In addition, the levels of PDGF-AA and VEGF expression in surgical sections were measured and compared with clinicopathologic findings such as tumor size and patient prognosis. PDGF-AA tightly regulated VEGF expression and had a greater effect on tumor size and patient prognosis than did VEGF in both cell lines and surgical sections. PDGF-AA expression was not seen in the atypical adenomatous hyperplasia at all, whereas VEGF was occasionally seen. Furthermore, the frequency of VEGF expression was higher in advanced NSCLCs than in precancerous lesions, which was tightly correspondent to the results for PDGF-AA. These results indicate that PDGF-AA is an important regulator of the frequency and level of VEGF expression during the transition from a precancerous lesion to advanced cancer. The PDGF-AA/VEGF axis, therefore, may be a ubiquitous autocrine system for enhancing angiogenic signals, and PDGF-AA, and its related pathways could be a more efficient target of antiangiogenic therapy for cancers than VEGF and its pathways.
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PMID:Platelet-derived growth factor-AA is an essential and autocrine regulator of vascular endothelial growth factor expression in non-small cell lung carcinomas. 1610 75

Receptor tyrosine kinases of the Eph family are upregulated in several different types of cancer. One family member in particular, the EphA2 receptor, has been linked to breast, prostate, lung and colon cancer, as well as melanoma. However, mechanisms by which EphA2 contributes to tumor progression are far from clear. In certain tumor cell lines, EphA2 receptor is underphosphorylated, raising the question of whether ligand-induced receptor phosphorylation and its kinase activity play a role in oncogenesis. To test directly the role of EphA2 receptor phosphorylation/kinase activity in tumor progression, we generated EphA2 receptor variants that were either lacking the cytoplasmic domain or carrying a point mutation that inhibits its kinase activity. Expression of these EphA2 mutants in breast cancer cells resulted in decreased tumor volume and increased tumor apoptosis in primary tumors. In addition, the numbers of lung metastases were significantly reduced in both experimental and spontaneous metastasis models. Reduced tumor volume and metastasis are not due to defects in tumor angiogenesis, as there is no significant difference in tumor vessel density between wild-type tumors and tumors expressing EphA2-signaling-defective mutants. In contrast, tumor cells expressing the EphA2 mutants are defective in RhoA GTPase activation and cell migration. Taken together, these results suggest that receptor phosphorylation and kinase activity of the EphA2 receptor, at least in part, contribute to tumor malignancy.
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PMID:A kinase-dependent role for EphA2 receptor in promoting tumor growth and metastasis. 1610 80

PTEN is an important tumor suppressor gene. Hereditary mutation of PTEN causes tumor-susceptibility diseases such as Cowden disease. We used the Cre-loxP system to generate an endothelial cell-specific mutation of Pten (Tie2CrePten) in mice. Tie2CrePten(flox/+) mice displayed enhanced tumorigenesis due to an increase in angiogenesis driven by vascular growth factors. This effect was partially dependent on the PI3K subunits p85alpha and p110gamma. In vitro, Tie2CrePten(flox/+) endothelial cells showed enhanced proliferation/migration. Tie2CrePten(flox/flox) mice died before embryonic day 11.5 (E11.5) due to bleeding and cardiac failure caused by impaired recruitment of pericytes and vascular smooth muscle cells to blood vessels, and of cardiomyocytes to the endocardium. These phenotypes depend strongly on p110gamma rather than on p85alpha and were associated with decreased expression of Ang-1, VCAM-1, connexin 40, and ephrinB2 but increased expression of Ang-2, VEGF-A, VEGFR1, and VEGFR2. Pten is thus indispensable for normal cardiovascular morphogenesis and post-natal angiogenesis, including tumor angiogenesis.
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PMID:The PTEN/PI3K pathway governs normal vascular development and tumor angiogenesis. 1610 12

The von Hippel-Lindau tumor suppressor protein (pVHL) suppresses tumor formation by binding the alpha subunits of hypoxia-inducible-factors responsible for stimulating tumor angiogenesis and glycolysis, and targeting them for ubiquitination and proteasomal destruction. Loss of pVHL leads to tumorigenesis and development of sporadic renal cell carcinomas and central nervous system hemangioblastomas. In the present study, we investigated whether engineered overexpression of pVHL in C6 glioma cells, which already express endogenous pVHL, would suppress the tumorigenicity of this particular tumor cell type. C6 cells overexpressing VHL displayed a reduced growth rate (70% inhibition) compared to the parental cell line when subcutaneously implanted in athymic (nu/nu) mice. Growth inhibition was associated with a 50% reduction in the number of tumor vessels and a 60% increase in tumor cell apoptosis, due in part to downregulation of HIF-1, VEGF, and the antiapoptotic factor Bcl-2, respectively. Gene transfer of VHL suppressed the growth of established C6 gliomas, and synergized with antisense HIF-1 to completely eradicate tumors. The data suggest that VHL gene therapy and/or agents that increase VHL expression could have utility in the treatment of gliomas, particularly when combined with agents that inhibit the expression or function of HIF-1.
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PMID:Overexpression of von Hippel-Lindau tumor suppressor protein and antisense HIF-1alpha eradicates gliomas. 1621 Oct 89

Farnesyltransferase (FTase) inhibitors (FTI) have broad antineoplastic actions targeting both cancer cells and mesenchymal cells involved in tumor angiogenesis. The small GTPases H-Ras, Rheb, and RhoB and the centromere proteins CENP-E and CENP-F are relevant targets of farnesylation inhibition; however, their relative importance in the antineoplastic effect of FTIs may vary in different cell types at different stages of the cell cycle and at different stages in oncogenesis. Three recent studies argue that Ras-independent and perhaps even FTase-independent properties are important to the antineoplastic action of this class of drugs. In mice, genetic ablation of FTase does not abolish the oncogenic activity of Ras, limiting the original conception of FTIs as an effective means to target Ras in cancer cells. FTase may not be the sole molecular target of these agents, and one study has suggested that FTIs act by targeting geranylgeranyl transferase II. Lastly, we have obtained evidence that induction of reactive oxygen species and reactive oxygen species-mediated DNA damage by FTIs may be critical for their antineoplastic action as a class. Together, these findings may alter thinking about how to apply FTIs in the clinic.
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PMID:Recent advances in understanding the antineoplastic mechanisms of farnesyltransferase inhibitors. 1623 Mar 62


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