Novel function for VEGF in breast carcinoma survival

描述（由申请人提供）：已知血管内皮生长因子（VEGF）通过促进血管生成促进乳腺癌进展。目前的研究表明VEGF在促进乳腺癌细胞侵袭和迁移中的新功能。具体来说，这一提议提出了一个假设，即乳腺癌细胞分泌VEGF通过与相同或邻近肿瘤细胞上的VEGF受体结合来促进其侵袭。此外，据推测，这种VEGF自分泌信号通过促进这些细胞的pi3激酶依赖性迁移来促进乳腺癌的侵袭。采用反义策略，探讨抑制VEGF表达对体外乳腺癌细胞侵袭和迁移的影响。此外，这种自分泌信号通过维持这些细胞中组成性升高的pi3激酶活性水平来驱动乳腺癌侵袭和迁移的假设将被探索。最后，VEGF受体neuropilin在VEGF自分泌功能中的作用将被检查。具体来说，neuropilin抑制抗体以及抑制内源性neuropilin功能的缺失构建体对乳腺癌侵袭和迁移的影响将被研究。最后，我将评估特异性抑制乳腺癌细胞中VEGF自分泌信号传导对免疫缺陷小鼠乳腺癌细胞生长和转移的影响。这种新的VEGF功能的表征将对拓宽我们对乳腺癌进展的多个步骤的认识至关重要。

DESCRIPTION (provided by applicant): The vascular endothelial growth factor (VEGF) is known to contribute to breast carcinoma progression by promoting angiogenesis. The current studies address a novel function for VEGF in promoting the invasion and migration of breast carcinoma cells. Specifically, this proposal addresses the hypothesis that VEGF secretion by breast carcinoma cells promotes their invasion by binding to VEGF receptors on the same or neighboring tumor cells. Moreover, it is hypothesized that this VEGF autocrine signaling contributes to breast carcinoma invasion by promoting the PI3-kinase-dependent migration of these cells. Using an antisense strategy, the effects of inhibiting VEGF expression on the invasion and migration of breast carcinoma cells in vitro will be explored. Moreover, the hypothesis that this autocrine signaling drives breast carcinoma invasion and migration by maintaining constitutively elevated levels of PI3-kinase activity in these cells will be explored. Finally, a role for the VEGF receptor neuropilin in this VEGF autocrine function will be examined. Specifically, the effects of neuropilin inhibitory antibodies, as well as deletion constructs that inhibit endogenous neuropilin function on breast carcinoma invasion and migration will be investigated. Finally, I will assess the effects of specifically inhibiting VEGF autocrine signaling in breast carcinoma cells on their growth and metastasis in immunodeficient mice. The characterization of this novel VEGF function will be critical in broadening our knowledge of the multiple steps involved in breast carcinoma progression.