Collagen XV as a tumor and metastasis suppressor.

描述(申请人提供)：XV胶原蛋白是一种蛋白多糖，存在于许多组织的基底膜区域，但其确切功能尚不清楚。我们有初步的数据支持这样的假设，即人的XV胶原蛋白是一种剂量依赖的致瘤性抑制因子，并通过限制迁移到基底膜而在防止上皮细胞从分化的上皮细胞中逃逸方面发挥关键作用。这些数据来自于对宫颈癌上皮细胞的实验，我们预测它们也将适用于其他上皮性肿瘤。我们建议在胰管上皮细胞中验证我们的假设。胰腺癌通常是高度转移性的，与许多其他癌症相比，预后极差。胰腺癌细胞通过胰管基底膜从导管上皮细胞的起源部位逃逸的始动事件是胰腺癌发生发展的基础。阐明这次逃逸涉及的关键分子事件，是这个项目的中心焦点，在这个项目中，我们将追求两个特定的目标。首先，我们将检验一种假设，即在维持胰管上皮基底膜的完整性中，XV胶原起着关键作用，并且导管上皮细胞中XV胶原蛋白的丢失有助于胰腺癌的转移。同时，我们将研究XV胶原蛋白抑制宫颈癌细胞恶性的机制。我们将确定负责这一活性的蛋白质结构域，并确定在基底膜和非恶性上皮细胞表面的XV胶原蛋白的功能伙伴。这些实验可能确定细胞外胶原XV向导管上皮细胞传递信号以影响其生长和分化的途径。通过鉴定XV型胶原与其他分子的直接分子相互作用，我们将确定受其丢失影响的信号通路。这一系列的实验可能会为胰腺癌和其他上皮性癌症的治疗干预提供新的途径，这些癌症的靶标是XV胶原蛋白多糖。

DESCRIPTION (provided by applicant): Collagen XV is a proteoglycan found in the basement membrane zones of a number of tissues but its precise functions remain to be elucidated. We have preliminary data that supports the hypothesis that human collagen XV is a dose-dependent suppressor of tumorigenicity and plays a key role in preventing the escape of epithelial cells from the differentiated epithelium by restricting migration into the basement membrane. These data derive from experiments on cervical cancer epithelial cells, and we predict that they will be applicable to other epithelial tumors. We propose test our hypothesis in the epithelium of the pancreatic duct. Pancreatic adenocarcinomas are generally highly metastatic and are associated with an extremely poor prognosis in comparison to many other cancers. The initiating events that underlie the escape of a pancreatic tumor cell, from its site of origin in the ductal epithelium, through the basement membrane of the pancreatic duct are fundamental to the progression of the pancreatic adenocarcinoma. Elucidation of the key molecular events involved in this escape, are a central focus of this project in which we will pursue the two specific aims. First, we will test the hypothesis that collagen XV plays a key role in maintaining the integrity of the epithelium basement membrane in the pancreatic duct and that loss of collagen XV from ductal epithelial cells contributes to metastasis of pancreatic adenocarcinoma. Concurrently we will investigate the mechanism whereby collagen XV suppresses malignancy in cervical carcinoma cells. We will define the domains of the protein responsible for this activity and identify the functional partners of collagen XV at the basement membrane and on the surface of non-malignant epithelial cells. These experiments may identify pathways for extra-cellular collagen XV to transmit signals to ductal epithelial cells to influence their growth and differentiation. Through the identification of direct molecular interactions of type XV collagen with other molecules we will define the signaling pathways that are influenced by its loss. This series of experiments may generate new avenues for therapeutic intervention in pancreatic cancer, and other cancers of epithelial origin, that target the collagen XV proteoglycan.