The Role of ADAM15 in Prostate Tumor Intravazation and Metastasis

描述(申请人提供)：我们一直在研究ADAM15去整合素在人类前列腺癌转移进展中的作用。这项工作基于人类前列腺癌生长、前列腺癌细胞/血管内皮细胞相互作用、血管生成、血管侵袭和显性转移的生物学模型，表明ADAM15在前列腺癌进展中扮演着明确但尚未确定的角色。我们的初步研究支持这一中心假设，即前列腺肿瘤细胞中异常的ADAM15功能不仅支持原发肿瘤的生长，而且介导了前列腺肿瘤细胞和血管内皮细胞之间的相互作用，促进了血管内皮细胞的生长和转移。这项提案的主要目标将试图描绘ADAM15在这些恶性过程中的具体功能。我们描述的机械聚焦实验应该证实ADAM15在与人类前列腺癌相关的转移过程中发挥作用。因此，该项目与人类健康直接相关。如果ADAM15可以被确认为前列腺癌转移进展的媒介，那么在治疗上靶向ADAM15的理由将是合理的。ADAM家族的几个成员，包括ADAM15，正在成为肿瘤微环境的调节者，人们对它们作为抗癌药物开发靶点的兴趣正在上升。鉴于ADAM15功能域的多样性，这种去整合素被认为影响了癌症及其转移扩散所固有的几个重要的细胞过程。旨在抑制ADAM15金属蛋白酶活性或其EGF同源或去整合素结构域的细胞外激活的方法可能被证明对转移性前列腺癌的治疗有利。

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.