The Role of Snail Signaling in Prostate Cancer Metastasis

描述(申请人提供)：蜗牛转录因子在早期发育和癌细胞中很重要，通过诱导上皮间充质转化(EMT)促进癌细胞迁移和进展。我们观察到Snail在前列腺癌骨转移患者样本中的表达增加。我们最近利用过表达Snail的人前列腺癌ARCaP细胞建立了前列腺癌的EMT模型，并发现了增加的核因子？B配体受体激活剂(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生成。非裔美国人的骨密度比其他任何种族都高，也比其他任何种族都患有更具侵袭性的前列腺癌。我们推测，Snail可能通过钙、Cat L和RANKL信号途径，介导前列腺癌向高骨密度骨的迁移，并介导肿瘤-肿瘤微环境相互作用的恶性循环，从而促进肿瘤生长和促进破骨细胞生成。首先，我们将分析Snail介导的Cat L在前列腺癌进展中的作用和机制(特定目标1)。其次，将研究蜗牛在向高骨密度迁移中的作用，以及骨降解释放的钙是否会刺激更多的RANKL和Cat L的表达/活性和肿瘤生长(特定目标2)。由于除损伤外，成体细胞不需要Snail，靶向主要由癌细胞表达的Snail可能拮抗骨转移病变，而不影响身体其他部位的正常骨。

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.