The Role of ADAM15 in Prostate Tumor Intravazation and Metastasis

描述（由申请人提供）：我们一直在研究ADAM 15去整合素在人前列腺癌转移进展中的功能。这项工作是基于人前列腺肿瘤生长，前列腺肿瘤细胞/血管内皮相互作用，血管生成，血管侵袭和明显转移的生物模型，这表明了一个明确的，但未表征的作用，ADAM 15在前列腺癌的进展。我们的初步研究支持了一个中心假设，即在前列腺肿瘤细胞中异常的ADAM 15功能不仅支持原发性肿瘤的生长，而且介导前列腺肿瘤细胞和血管内皮之间的相互作用，促进血管内流和转移。本提案的主要目标将试图描绘在这些恶性过程中的特定功能的ADAM 15。我们所描述的机械聚焦实验应该证实，ADAM 15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ADAM 15可以被验证为前列腺癌转移进展的介导物，那么治疗靶向ADAM 15的理由将是合理的。ADAM家族的几个成员，包括ADAM 15正在成为肿瘤微环境的调节剂，并且对它们作为抗癌剂开发靶点的潜力的兴趣正在上升。考虑到ADAM 15功能结构域的多样性，这种去整合素被认为影响癌症及其转移扩散固有的几个重要细胞过程。旨在抑制ADAM 15金属蛋白酶活性或其EGF同源性或去整合素结构域的细胞外活化的方法可以证明对转移性前列腺癌的治疗有益。

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.