VEGF Signaling in Mammary Tumorigenesis

描述（由申请人提供）：该提案将研究新的假设，即VEGF/Neuropilin-2 （NRP2）信号通过增强肿瘤启动细胞的功能，与致癌刺激合作，驱动乳腺癌，特别是三阴性肿瘤的形成。提出的机制是VEGF/NRP2信号传导促进整合素6？1/focal adhesion kinase （FAK）介导的Hedgehog效应子Gli1的诱导，Gli1通过促进Bmi-1和其他靶基因的转录激活，有助于肿瘤启动细胞的功能。为了验证这一机制，提出了三个具体目标。第一个目标将明确NRP2在三阴性肿瘤形成、维持和治疗中的作用，并提出VEGF/NRP2信号通路增强肿瘤启动细胞功能的假设。这一目标将涉及转基因和原位小鼠模型，以及

DESCRIPTION (provided by applicant): This proposal will examine the novel hypothesis that VEGF/Neuropilin-2 (NRP2) signaling cooperates with oncogenic stimuli to drive the formation of mammary cancers, especially triple-negative tumors, by potentiating the function of tumor-initiating cells. The mechanism proposed is that VEGF/NRP2 signaling promotes integrin ?6?1/focal adhesion kinase (FAK)-mediated induction of the Hedgehog effector Gli1, which contributes to the function of tumor initiating cells by promoting the transcriptional activation o Bmi-1 and other target genes. To validate this mechanism, three specific aims are proposed. The first aim will define the role of NRP2 in the formation, maintenance and therapy of triple-negative tumors, and address the hypothesis that VEGF/NRP2 signaling enhances the function of tumor initiating cells. This aim will involve transgenic and orthotopic mouse models, as well as tumor cells isolated from freshly resected tumors. The second aim is based on the finding that NRP2 interacts specifically with the ?6?1 integrin (CD49f), which is a functional marker of tumor initiating cells. This aim will examine the hypothesis that VEGF/NRP2 signaling contributes to the regulation of Bmi-1, a polycomb group transcriptional repressor important for the function of tumor stem cells, by a FAK- dependent mechanism. The third aim will establish that VEGF/NRP2 signaling promotes activation of the Hedgehog pathway in tumor initiating cells, and that the contribution of VEGF/NRP2 to tumorigenesis is dependent on Gli1. More specifically, the hypothesis will be evaluated that VEGF/NRP2 signaling induces Gli1 and Gli1-mediated Bmi-1 expression in tumor initiating cells and that loss of NRP2 can be compensated for by Gli1 expression. The proposed work will provide an integrated mechanism for how VEGF/NRP2 signaling, integrin ?6?1 and FAK interface with the Hedgehog pathway to regulate the function of tumor initiating cells. At a translational level, these studies will highlight the feasibility of targeting NRP2 on tumor cells for therapy of aggressive breast cancers. This issue is timely because the FDA has recommended discontinuing the use of Avastin (bevacizumab), which does not inhibit the VEGF/NRP2 interaction, for treating breast cancer because it has not been shown to be effective. These findings strengthen the rationale for targeting NRP2 directly especially given the preferential expression and critical function of NRP2 in tumor-initiating cell.