Integrins and bone matrix in prostate cancer

前列腺癌中的整合素和骨基质

• 批准号: 6708390
• 负责人: Tatiana V Byzova
• 金额: $ 26.93万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-03-01 至 2006-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6708390
• 关键词: Integrins; bone; matrix; prostate; cancer

DESCRIPTION (provided by applicant): This proposal centers on the mechanisms of the functional communications between a major family of cell surface adhesion receptors, the integrins, and a subset of its ligands, the bone matrix proteins, with an emphasis on osteonectin (SPARC) and a major family of angiogenic growth factors, the VEGFs and its receptors. The context in which these relationships will be examined is prostate cancer. The central hypothesis to be tested in this proposal is that the process of integrin activation preferentially enhances recognition of bone matrix ligands, thereby selectively increasing the metastasis of prostate cancer cells to bone. One of the mechanisms of regulation of integrin activation is via VEGFdependent autocrine loop. The corollary to this hypothesis that the bone matrix ligands alter the VEGF/VEGFR2 expression and further amplify proposed VEGF autocrine loop will also be tested. Our Specific Aims are: Aim I. How does integrin activation influence recognition of the bone matrix? We will introduce wild-type and mutant forms of integrin into prostate cancer cells which result in a resting, constitutively activated state or a non-activatable receptor and determine how these states influence recognition of bone matrix ligands. The emphasis of our studies will be the bone protein that is responsible for prostate cancer - bone interactions, SPARC (osteonectin). We will then determine the mechanisms of SPARC interactions with integrins on prostate cancer cells that are known to metastasize to bone relative to those with low metastatic potential. We will determine whether activation or neutralization of the V-ALIA pathway alters integrin function and SPARC recognition on these cells. Aim II. What is the role of newly identified regulatory circuits in the V-ALIA pathway in prostate cancer? We will assess how the bone matrix protein SPARC influences the expression of VEGFs and VEGFRs. We will use purified protein as well as bone extracts from normal and SPARC (-/-) mice. Aim III. What is the role of the V-ALIA pathway in vivo? We will determine the integrin activation states of human prostate tumors that have metastasized to bone as compared to tumors localized to the prostate. We will compare the growth characteristics in bone environment of cell lines expressing inactive and active integrins. We will compare the tumor growth characteristics within the bones of WT and SPARC (-/-) mice. Our efforts to determine how the recognition of bone specific matrix proteins by prostate tumor cells occurs and what mechanisms regulate this recognition will provide insights into a basic and potentially important process operative in the growth and metastasis of prostate cancer.

描述（由申请人提供）：该提案集中于主要的细胞表面粘附受体家族之间的功能通信机制，整联蛋白和其配体的子集，骨基质蛋白，重点是骨质蛋白（SPARC）（SPARC）和主要的血管生长系列，是血管生长因素的主要家庭。研究这些关系的背景是前列腺癌。在该提案中要检验的中心假设是整联蛋白激活的过程优先增强对骨基质配体的识别，从而选择性地增加了前列腺癌细胞向骨骼的转移。整联蛋白激活调节的机制之一是通过VEGFDECTICENT自分泌环。这一假设的推论是，骨基质配体改变了VEGF/VEGFR2的表达，并进一步放大了所提出的VEGF自分泌环。我们的具体目的是：目标I。整联蛋白激活如何影响骨基质的识别？我们将将整合素的野生型和突变形式引入前列腺癌细胞中，从而导致静止，组成型活化的状态或不可活化的受体，并确定这些状态如何影响骨基质配体的识别。我们研究的重点将是负责前列腺癌的骨蛋白 - 骨骼相互作用，SPARC（ostocelectin）。然后，我们将确定SPARC相互作用在前列腺癌细胞上的机制，这些机制相对于具有低转移性潜能的骨骼转移到骨骼。我们将确定V-ALIA途径的激活或中和是否会在这些细胞上改变整合素的功能和SPARC识别。目标II。新确定的调节回路在前列腺癌中的V-Alia途径中的作用是什么？我们将评估骨基质蛋白SPARC如何影响VEGF和VEGFR的表达。我们将使用纯化的蛋白质以及来自正常和SPARC（ - / - ）小鼠的骨骼提取物。目标三。体内V-Alia途径的作用是什么？我们将确定与位于前列腺的肿瘤相比，已转移到骨骼的人类前列腺肿瘤的整合素激活态。我们将比较表达不活跃和活性整合素的细胞系的骨骼环境中的生长特征。我们将比较WT和SPARC（ - / - ）小鼠骨骼内的肿瘤生长特征。我们为确定前列腺肿瘤细胞对骨骼特异性基质蛋白的识别的努力以及哪些机制调节这种识别将为前列腺癌生长和转移的基本且潜在的重要过程操作提供见解。