The Role of ADAM15 in Prostate Tumor Intravazation and Metastasis

ADAM15 在前列腺肿瘤浸润和转移中的作用

基本信息

批准号：
8256675
负责人：
MARK L DAY
金额：
$ 39.71万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-06-21 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8256675
关键词：
Address Affect Angioinvasion Antineoplastic Agents Binding Biological Markers Biological Models Blood Vessels Cadherins Cancer Patient Cell Adhesion Cell Adhesion Molecules Cell physiology Cells Clinical Data Development Disease Progression Disintegrin Domain Disintegrins Distant E-Cadherin EGF gene EGF-Like Domain Environment Epithelium Extracellular Domain Extracellular Matrix Extracellular Matrix Proteins Family Family member Goals Growth Growth Factor Health Human Integrin Binding Laboratories Liver Lung Malignant - descriptor Malignant Neoplasms Malignant neoplasm of prostate Mediating Mediator of activation protein Membrane Membrane Proteins Messenger RNA Metalloproteases Metastatic Prostate Cancer Modality N-Cadherin Neoplasm Metastasis Peptide Hydrolases Primary Neoplasm Process Prostate Prostatic Neoplasms Proteins Publishing Regulation Regulation of Proteolysis Research Role Serum Signal Pathway Signal Transduction Solid Stem cells Tumor Angiogenesis Vascular Endothelium Vascular blood supply Work angiogenesis base bone extracellular in vivo interest member men metastatic process neoplastic cell novel diagnostics prognostic public health relevance research study therapeutic target tumor tumor growth tumor progression

项目摘要

DESCRIPTION (provided by applicant): We have been investigating the function of the ADAM15 disintegrin in the metastatic progression of human prostate cancer. This work is based on biological models of human prostate tumor growth, prostate tumor cell/vascular endothelial interactions, angiogenesis, angioinvasion and overt metastasis, which demonstrates a clear, but uncharacterized role for ADAM15 in prostate cancer progression. Our preliminary studies supports the central hypothesis that aberrant ADAM15 function in prostate tumor cells not only supports primary tumor growth, but also mediates interactions between prostate tumor cells and vascular endothelium promoting vascular intravazation and metastasis. The primary goals of this proposal will attempt to delineate the specific function of ADAM15 in these malignant processes. The mechanistically focused experiments we describe should confirm that ADAM15 functions in metastatic processes that are relevant to human prostate cancer. Consequently, this project is of direct relevance to human health. If ADAM15 can be validated as a mediator of metastatic progression of prostate cancer, then a rationale for targeting ADAM15 therapeutically would be justified. Several members of the ADAM family, including ADAM15 are emerging as regulators of the tumor microenvironment and interest in their potential as targets for the development of anticancer agents is rising. Given the diversity of ADAM15 functional domains, this disintegrin is thought to affect several important cellular processes that are intrinsic to cancer and its metastatic spread. Modalities aimed at inhibiting the extracellular activation of ADAM15 metalloproteinase activity or its EGF-homology or disintegrin domains could prove beneficial for the treatment of metastatic prostate cancer. PUBLIC HEALTH RELEVANCE: Given the diversity of ADAM15 functional domains, this disintegrin is thought to effect several important cellular processes that are intrinsic to prostate cancer and its metastatic spread. Modalities aimed at inhibiting the extracellular metalloproteinase domain, the EGF-homology domain or the disintegrin domain could prove beneficial for the treatment of metastatic prostate cancer.

描述（由申请人提供）：我们一直在研究ADAM15解体蛋白在人前列腺癌转移性进展中的功能。这项工作基于人类前列腺肿瘤生长，前列腺肿瘤细胞/血管内皮相互作用，血管生成，血管浸泡和明显转移的生物学模型，这些模型表现出ADAM15在前列腺癌进展中的明确但未表征的作用。我们的初步研究支持了以下假设，即异常ADAM15在前列腺肿瘤细胞中起作用不仅支持原发性肿瘤的生长，而且还介导了前列腺肿瘤细胞与促进血管内皮的血管内皮之间的相互作用，从而促进血管内皮和转移。该提案的主要目标将试图在这些恶性过程中描述ADAM15的特定功能。我们描述的机械集中的实验应确认与人类前列腺癌相关的转移过程中的ADAM15功能。因此，该项目与人类健康有直接相关。如果可以将ADAM15验证为前列腺癌转移性进展的介体，则可以证明对ADAM15进行靶向ADAM15的理由是合理的。亚当家族（包括亚当15）的几个成员正在成为肿瘤微环境的调节因子，并且对它们作为抗癌药物发展目标的潜力的兴趣正在上升。鉴于ADAM15功能结构域的多样性，该解体蛋白被认为会影响癌症及其转移性植物固有的几种重要细胞过程。旨在抑制ADAM15金属蛋白酶活性或其EGF - 同学或解体蛋白结构域的细胞外激活的模态可能对治疗转移性前列腺癌有益。公共卫生相关性：鉴于ADAM15功能域的多样性，这种解体被认为会影响几个重要的细胞过程，这些过程对前列腺癌及其转移性蔓延是固有的。旨在抑制细胞外金属蛋白酶结构域，EGF - 同源域或解体蛋白结构域的模态可能对治疗转移性前列腺癌有益。