VEGF Signaling in Mammary Tumorigenesis

乳腺肿瘤发生中的 VEGF 信号转导

基本信息

批准号：
8406744
负责人：
Arthur M Mercurio
金额：
$ 34.45万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-09 至 2017-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8406744
关键词：
Address Avastin Blocking Antibodies Breast Carcinoma Cell Therapy Cells Clinical Trials Data Epithelial Erinaceidae Focal Adhesion Kinase 1 Gene Targeting Genes Growth Integrins Link Maintenance Therapy Malignant Epithelial Cell Malignant Neoplasms Mammary Neoplasms Mammary Tumorigenesis Mediating Modeling NRP1 gene Neurons Neuropilin-2 Neuropilins Oncogenes Oncogenic Outcome Pathway interactions Polycomb Property Regulation Resected Role Semaphorins Signal Transduction Stimulus Therapeutic Intervention Transcription Repressor/Corepressor Transcriptional Activation Transgenic Organisms Tumor Markers Tumor Stem Cells Vascular Endothelial Growth Factor Receptor Vascular Endothelial Growth Factors Woman Work angiogenesis base bevacizumab breast tumorigenesis interest malignant breast neoplasm mouse model neoplastic cell novel receptor self-renewal therapeutic angiogenesis transcription factor triple-negative invasive breast carcinoma tumor tumor initiation tumorigenesis

项目摘要

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. PUBLIC HEALTH RELEVANCE: This proposal seeks to understand mechanisms that contribute to the formation and growth of breast cancers. We propose to investigate a network of molecules that cooperate with oncogenes to initiate the formation of breast tumors, and evaluate whether these molecules are potential targets for the treatment of these tumors.

描述（由申请人提供）：该提案将检查新的假设，即VEGF/Neuropilin-2（NRP2）信号传导与致癌刺激合作，以促进乳腺癌的形成，尤其是三分为肿瘤，尤其是通过增强肿瘤发射细胞的功能。提出的机制是VEGF/NRP2信号传导促进整联蛋白？6？1/局灶性粘附激酶（FAK）介导的刺猬效应GLI1的诱导，这通过促进转录激活O BMI-1和其他靶基因来促进肿瘤启动细胞的功能。为了验证这种机制，提出了三个具体目标。第一个目的将定义NRP2在三阴性肿瘤的形成，维持和治疗中的作用，并解决了VEGF/NRP2信号传导增强肿瘤启动细胞功能的假设。此目标将涉及转基因和原位小鼠模型，以及从新鲜切除的肿瘤中分离出来的肿瘤细胞。第二个目的是基于发现NRP2专门与？6？1整合素（CD49F）相互作用的发现，哪个是肿瘤启动细胞的功能标记。该目的将检验以下假设：VEGF/NRP2信号传导通过FAK依赖性机制促进BMI-1的调节，BMI-1是Polycomb组转录阻遏物对肿瘤干细胞功能重要的重要性。第三个目标将确定VEGF/NRP2信号传导促进肿瘤启动细胞中刺猬途径的激活，并且VEGF/NRP2对肿瘤发生的贡献取决于GLI1。更具体地说，将评估该假设，即VEGF/NRP2信号传导在肿瘤引发的细胞中诱导GLI1和GLI1介导的BMI-1表达，并且可以通过GLI1表达来补偿NRP2的丧失。所提出的工作将提供一种综合机制，以供VEGF/NRP2信号传导，整联蛋白？1？1以及与刺猬途径的FAK接口，以调节肿瘤启动细胞的功能。在翻译水平上，这些研究将强调将NRP2靶向肿瘤细胞以治疗侵袭性乳腺癌的可行性。此问题之所以及时，是因为FDA建议停止使用Avastin（bevacizumab），而不会抑制VEGF/NRP2相互作用，以治疗乳腺癌，因为它尚未证明是有效的。这些发现加强了直接靶向NRP2的基本原理，特别是考虑到NRP2在肿瘤发射细胞中的优先表达和关键功能。公共卫生相关性：该提案旨在了解有助于乳腺癌的形成和生长的机制。我们建议研究与肿瘤基因合作以启动乳腺肿瘤形成的分子网络，并评估这些分子是否是治疗这些肿瘤的潜在靶标。