Role of Slit in CXCR4-Mediated Breast Cancer Metastasis

Slit 在 CXCR4 介导的乳腺癌转移中的作用

• 批准号: 6921012
• 负责人: Ramesh K. Ganju
• 金额: $ 26.86万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-11 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6921012
• 关键词: SCID mouse; antineoplastics; biological signal transduction; breast neoplasms; cell adhesion; cellular oncology; chemokine receptor; chemotaxis; clinical research; cytoskeleton; drug design /synthesis /production; drug screening /evaluation; enzyme induction /repression; gene expression; human tissue; metalloendopeptidases; metastasis; neoplasm /cancer pharmacology; neoplastic cell; neoplastic process

DESCRIPTION (provided by applicant): The chemokine receptor CXCR4 and its ligand CXCL12 play a critical role in breast cancer metastasis. Our preliminary work indicates that CXCR4 mediates novel signaling pathways that regulate the CXCL12-induced chemotaxis, chemoinvasion, and adhesion of breast cancer cells. Given the importance of metastasis as the major cause of increased morbidity and eventual mortality in breast cancer patients, understanding of how signaling molecules control the events that lead to metastasis is of fundamental importance. We have shown that a key regulatory signaling molecule linked to CXCR4-mediated breast cancer cell chemotaxis and chemoinvasion is Cbl. The first specific aim of this proposal is to characterize the interaction between Cbl and the CXCR4 receptor. We will also characterize the role of Cbl in modulating CXCR4-mediated chemotactic signaling pathways. Moreover, we are developing innovative strategies to block the CXCR4-mediated metastasis of breast cancer cells. In this regard, we have shown that a novel biological molecule that binds to the Robo receptor, called Slit, blocks CXCL12-induced chemotaxis, chemoinvasion and adhesion, the fundamental components that promote the metastasis of breast cancer cells. The main objective of this project is to analyze the role of Slit as an anti-metastatic factor in breast cancer cells. We hypothesize that: 1) Slit treatment will inhibit breast cancer cell metastasis to the lungs and lymph nodes; 2) Slit induces cross-talk between Robo and the CXCR4 receptor; and 3) Slit inhibits metalloproteinase secretion by blocking the functions of RAFTK/Pyk2 and beta-catenin. To test these hypotheses, we will analyze the regulatory region within the Slit and Robo molecules that mediate anti-metastatic functions. In Aim 2, we will study the effects of different truncated Slit molecules in the chemotaxis, chemoinvasion, and adhesive properties of various breast cancer cells. After in vitro characterization, we will study the in vivo effects of Slit and its truncated form on the pathogenesis of breast cancer metastasis in an in vivo model system. In Aim 3, we will define the domain on the cytoplasmic tail of this Robo receptor that interacts with the CXCR4 receptor. We will also study the effect of the truncated form of the Robo receptor on breast cancer metastasis. In this aim, we will also define the role of RAFTK/Pyk2 and beta-catenin on the Slit-mediated downregulation of matrix-metalloproteinase 2 and 9 secretion and other anti-chemotactic and chemoinvasive mechanisms. These studies will help us to identify CXCL12-induced and Slit-mediated chemotactic/chemoinvasive pathways that may become novel targets for the treatment of breast cancer metastasis. Furthermore, innovative therapeutic strategies to prevent breast cancer metastasis can be anticipated based on these studies of Slit/Robo function.

描述（由申请人提供）：趋化因子受体CXCR4及其配体CXCL12在乳腺癌转移中起关键作用。 我们的初步工作表明，CXCR4介导了调节CXCL12诱导的趋化性，化学侵袭和乳腺癌细胞粘附的新型信号通路。 鉴于转移是乳腺癌患者发病率和最终死亡率增加的主要原因，因此了解信号分子如何控制导致转移的事件的重要性至关重要。 我们已经表明，与CXCR4介导的乳腺癌细胞趋化性和化学浸泡相关的关键调节信号分子是CBL。 该提案的第一个具体目的是表征CBL和CXCR4受体之间的相互作用。 我们还将表征CBL在调节CXCR4介导的趋化信号通路中的作用。 此外，我们正在制定创新策略，以阻止乳腺癌细胞的CXCR4介导的转移。 在这方面，我们已经表明，与机器人受体结合的新型生物分子（称为缝隙）阻止了CXCL12诱导的趋化性，化学浸润和粘附，这是促进乳腺癌细胞转移的基本成分。 该项目的主要目的是分析狭缝作为乳腺癌细胞中抗转移性因子的作用。 我们假设：1）狭缝治疗将抑制乳腺癌细胞转移到肺和淋巴结； 2）缝隙在Robo和CXCR4受体之间引起串扰； 3）缝隙通过阻断Raftk/pyk2和β-catenin的功能来抑制金属蛋白酶分泌。 为了检验这些假设，我们将分析介导抗转移功能的缝隙和机器人分子中的调节区域。 在AIM 2中，我们将研究各种乳腺癌细胞的趋化性裂片分子在趋化性，化学侵袭和粘合特性中的影响。 在体外表征之后，我们将研究狭缝的体内效应及其对体内模型系统中乳腺癌转移发病机理的截短形式。 在AIM 3中，我们将在与CXCR4受体相互作用的该机器人受体的细胞质尾部上定义结构域。 我们还将研究机器人受体截短形式对乳腺癌转移的影响。 在此目标中，我们还将定义RAFTK/PYK2和β-catenin在缝隙介导的基质 - 甲甲基蛋白酶2和9分泌以及其他抗化学和化学活化机制的缝隙介导的下调中的作用。 这些研究将有助于我们鉴定CXCL12诱导的和裂缝介导的趋化性/化学侵袭性途径，这些途径可能成为治疗乳腺癌转移的新靶标。 此外，根据这些缝隙/机器人功能的研究，可以预期预防乳腺癌转移的创新治疗策略。