Angiogenesis

About: Angiogenesis is a research topic. Over the lifetime, 58248 publications have been published within this topic receiving 3290129 citations. The topic is also known as: blood vessel formation from pre-existing blood vessels & GO:0001525.

Stem cell-like glioma cells promote tumor angiogenesis through vascular endothelial growth factor

Abstract: Malignant gliomas are highly lethal cancers dependent on angiogenesis. Critical tumor subpopulations within gliomas share characteristics with neural stem cells. We examined the potential of stem cell-like glioma cells (SCLGC) to support tumor angiogenesis. SCLGC isolated from human glioblastoma biopsy specimens and xenografts potently generated tumors when implanted into the brains of immunocompromised mice, whereas non-SCLGC tumor cells isolated from only a few tumors formed secondary tumors when xenotransplanted. Tumors derived from SCLGC were morphologically distinguishable from non-SCLGC tumor populations by widespread tumor angiogenesis, necrosis, and hemorrhage. To determine a potential molecular mechanism for SCLGC in angiogenesis, we measured the expression of a panel of angiogenic factors secreted by SCLGC. In comparison with matched non-SCLGC populations, SCLGC consistently secreted markedly elevated levels of vascular endothelial growth factor (VEGF), which were further induced by hypoxia. In an in vitro model of angiogenesis, SCLGC-conditioned medium significantly increased endothelial cell migration and tube formation compared with non-SCLGC tumor cell-conditioned medium. The proangiogenic effects of glioma SCLGC on endothelial cells were specifically abolished by the anti-VEGF neutralizing antibody bevacizumab, which is in clinical use for cancer therapy. Furthermore, bevacizumab displayed potent antiangiogenic efficacy in vivo and suppressed growth of xenografts derived from SCLGC but limited efficacy against xenografts derived from a matched non-SCLGC population. Together these data indicate that stem cell-like tumor cells can be a crucial source of key angiogenic factors in cancers and that targeting proangiogenic factors from stem cell-like tumor populations may be critical for patient therapy.

Vascular Endothelial Growth Factor

Abstract: Vascular endothelial growth factor (VEGF, VEGF-A) is a major regulator of physiological and pathological angiogenesis. Several VEGF inhibitors have been approved by the FDA for the treatment of advanced cancer and neovascular age-related macular degeneration. This brief review provides a historic account of the challenges associated with the discovery of VEGF and the early steps in elucidating the role of this molecule in the regulation of angiogenesis.

HER2 (neu) Signaling Increases the Rate of Hypoxia-Inducible Factor 1α (HIF-1α) Synthesis: Novel Mechanism for HIF-1-Mediated Vascular Endothelial Growth Factor Expression

Abstract: Angiogenesis is essential for tumorigenesis as well as metastasis (11, 16, 64), and vascular density is an important prognostic factor in breast cancer (19, 27, 58, 59). Vascular endothelial growth factor (VEGF) plays a major role in tumor angiogenesis (10), and its expression in breast cancer is inversely correlated with patient survival (29, 30). VEGF expression can be induced by exposure of tumor cells to hypoxia or growth factors and, in both cases, this expression is due in part to increased VEGF gene transcription that is mediated by hypoxia-inducible factor 1 (HIF-1) (6, 9, 12, 22, 44, 63, 65). HIF-1 is a heterodimer composed of HIF-1α and HIF-1β subunits (56, 57). Whereas HIF-1β is constitutively expressed, the expression and activity of the HIF-1α subunit are induced by exposure of cells to hypoxia or growth factors (reviewed in reference 49). HIF-1 activates the transcription of genes whose products are required for critical aspects of tumor progression including angiogenesis (plasminogen activator inhibitor 1 and VEGF), iron homeostasis (transferrin and transferrin receptor), and metabolic adaptation (glucose transporters and glycolytic enzymes), as well as several factors that affect tumor cell survival or proliferation (endothelin 1, inducible nitric oxide synthase, and insulin-like growth factor 2). HIF-1α is overexpressed in primary and metastatic human tumors (1, 4, 5, 53, 62, 66). In breast cancer, HIF-1α overexpression can be detected in ductal carcinoma in situ but not in benign ductal hyperplasia (5), i.e., in early-stage cancer prior to invasion but concomitant with increased angiogenesis (15). HIF-1 activity is increased both by intratumoral hypoxia and by genetic alterations, including loss-of-function mutations in the tumor suppressor genes encoding p53, PTEN, and VHL (von Hippel-Lindau protein) as well as gain-of-function mutations in oncogenes that activate the phosphatidylinositol 3-kinase (PI3K), SRC, and mitogen-activated protein (MAP) kinase signal-transduction pathways (24, 34, 40, 41, 47, 48, 65, 66, 68). Loss or gain of HIF-1 activity is negatively and positively correlated, respectively, with tumor growth and angiogenesis in xenograft assays (6, 24, 28, 33, 40, 44, 45). Among the genetic alterations identified in human breast cancer, one of the most important is the increased activity of the HER2 receptor tyrosine kinase encoded by the ERBB2 gene on chromosome 17q21, which occurs in approximately one-third of breast tumors and is associated with increased tumor grade, chemotherapy resistance, and decreased rates of patient survival (36, 43, 50, 51). Overexpression of HER2 transforms human mammary epithelial and mouse 3T3 cells and imparts resistance against the chemotherapeutic agents tamoxifen and Taxol (32, 39, 61). Treatment of breast cancer cells with a neutralizing antibody against HER2 results in a dose-dependent inhibition of VEGF expression (38). A humanized monoclonal antibody to HER2 inhibits breast cancer growth and has been approved for treatment of HER2-overexpressing tumors (35). Unlike other members of the epidermal growth factor receptor (EGFR) family, HER2 has tyrosine kinase activity in the absence of any known ligand. HER2 heterodimerizes with the EGFR family members HER3 and HER4, which bind the ligand heregulin (55). In breast cancer cells, heregulin activates AKT (also known as protein kinase B) via the PI3K pathway (31). HER2 overexpression is also associated with increased AKT activity (67). Recently, HER2 overexpression or heregulin stimulation has been shown to induce VEGF mRNA and protein expression in cancer cell lines (3, 60). Because HIF-1 has been shown to lie downstream of EGFR and PI3K-AKT signaling and upstream of VEGF expression in tumor cells (9, 65, 68), we have analyzed HIF-1 activity in HER2-overexpressing 3T3 cells and heregulin-stimulated MCF-7 cells. Our results indicate that HIF-1 contributes to the induction of VEGF expression in these cells. Because hypoxia (52) and mutations in the tumor suppressor genes VHL (7, 54) and p53 (40) induce HIF-1 activity by inhibiting the ubiquitination and proteasomal degradation of HIF-1α (20, 26, 46), it was assumed that receptor tyrosine kinase signaling induced HIF-1α expression by the same mechanism. However, our results demonstrate that HER2 signaling induces HIF-1α protein synthesis rather than inhibiting its degradation, thus representing a novel mechanism for the regulation of HIF-1 and VEGF expression.