VEGF Signaling in Mammary Tumorigenesis

乳腺肿瘤发生中的 VEGF 信号转导

• 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
• 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

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）：该提案将检验新的假设，即 VEGF/Neuropilin-2 (NRP2) 信号传导与致癌刺激协同作用，通过增强肿瘤起始细胞的功能来驱动乳腺癌，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/粘着斑激酶(FAK)介导的Hedgehog效应器Gli1的诱导，Gli1通过促进Bmi-1和其他靶基因的转录激活来促进肿瘤起始细胞的功能。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 在三阴性肿瘤的形成、维持和治疗中的作用，并解决 VEGF/NRP2 信号传导增强肿瘤起始细胞功能的假设。这一目标将涉及转基因和原位小鼠模型，以及 从刚切除的肿瘤中分离出的肿瘤细胞。第二个目标是基于 NRP2 与 ?6?1 整合素 (CD49f) 特异性相互作用的发现，后者是肿瘤起始细胞的功能标记。该目标将检验以下假设：VEGF/NRP2 信号传导有助于通过 FAK 依赖性机制调节 Bmi-1，Bmi-1 是一种对肿瘤干细胞功能很重要的多梳组转录抑制因子。第三个目标是确定 VEGF/NRP2 信号传导促进肿瘤起始细胞中 Hedgehog 通路的激活，并且 VEGF/NRP2 对肿瘤发生的贡献依赖于 Gli1。更具体地说，将评估以下假设：VEGF/NRP2 信号传导诱导肿瘤起始细胞中的 Gli1 和 Gli1 介导的 Bmi-1 表达，并且 NRP2 的损失可以通过 Gli1 表达来补偿。拟议的工作将为 VEGF/NRP2 信号传导、整合素 ?6?1 和 FAK 如何与 Hedgehog 通路相互作用以调节肿瘤起始细胞的功能提供一个综合机制。在转化水平上，这些研究将强调靶向肿瘤细胞上的 NRP2 来治疗侵袭性乳腺癌的可行性。这个问题很及时，因为 FDA 已建议停止使用阿瓦斯汀（贝伐珠单抗）来治疗乳腺癌，因为阿瓦斯汀（贝伐单抗）不会抑制 VEGF/NRP2 相互作用，但尚未被证明有效。这些发现强化了直接靶向 NRP2 的基本原理，特别是考虑到 NRP2 在肿瘤起始细胞中的优先表达和关键功能。 公共卫生相关性：该提案旨在了解导致乳腺癌形成和生长的机制。我们建议研究与癌基因合作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。