The Role of Snail Signaling in Prostate Cancer Metastasis

描述（由申请人提供）：Snail转录因子在发育早期和癌细胞中是重要的，并通过诱导上皮间质转化（EMT）促进癌细胞迁移和进展。我们已经观察到Snail在前列腺癌骨转移人类患者样品中的表达增加。我们最近产生了一个EMT前列腺癌模型，利用ARCaP人前列腺癌细胞过度表达蜗牛，并确定增加NF？B配体（RANKL）和组织蛋白酶-L（Cat L）。这些细胞在体外和体内均能诱导破骨细胞的生成。非洲裔美国人的骨密度比其他任何种族都高，而且比其他任何种族都更容易患上前列腺癌。我们假设Snail可以介导EMT介导的前列腺癌向高骨密度骨迁移，并通过钙、Cat L和RANKL信号传导介导肿瘤-肿瘤微环境相互作用的恶性循环，导致肿瘤生长和破骨细胞生成增加。首先，将分析Snail介导的Cat L表达在前列腺肿瘤进展中的作用和机制（具体目的1）。其次，将检查Snail在向高骨矿物质密度迁移中的作用，以及骨降解释放的钙是否刺激更多的RANKL和Cat L表达/活性和肿瘤生长（具体目的2）。由于Snail不是成年细胞所必需的，除非在损伤期间，靶向主要由癌细胞表达的Snail可以拮抗骨中的转移性病变，而不会影响身体其他区域的正常骨。

DESCRIPTION (provided by applicant): Snail transcription factor is important early in development and in cancer cells and promotes cancer cell migration and progression by inducing epithelial mesenchymal transition (EMT). We have observed increased expression of Snail in prostate cancer bone metastatic human patient samples. We recently generated an EMT model for prostate cancer utilizing the ARCaP human prostate cancer cells overexpressing Snail and identified increased receptor activator for NF?B ligand (RANKL) and cathepsin-L (Cat L). These cells could induce osteoclastogenesis both in vitro and in vivo. African American men have higher bone mineral density than any other race and also present with more aggressive prostate cancer than any other race. We hypothesize that Snail can mediate EMT-mediated prostate cancer migration towards bone of high bone mineral density and mediate the vicious cycle of tumor-tumor microenvironment reciprocal interactions through calcium, Cat L, and RANKL signaling, resulting in tumor growth and increased osteoclastogenesis. Firstly, the role and mechanism of Snail-mediated Cat L expression in prostate tumor progression will be analyzed (Specific Aim 1). Secondly, the role of Snail in migration towards high bone mineral density will be examined and whether calcium release from bone degradation stimulates more RANKL and Cat L expression/activity and tumor growth (Specific Aim 2). Since Snail is not required by adult cells except during injury, targeting Snail that is mainly expressed by cancer cells may antagonize metastatic lesions in bone without affecting normal bone in other areas of the body.