Collagen XV as a tumor and metastasis suppressor.

描述（由申请人提供）：胶原蛋白XV是一种蛋白聚糖，存在于许多组织的基底膜区，但其确切功能仍有待阐明。我们有初步的数据支持这一假设，即人胶原XV是一种剂量依赖性的肿瘤抑制剂，并在防止上皮细胞从分化的上皮细胞中逃逸，限制迁移到基底膜中发挥关键作用。这些数据来自宫颈癌上皮细胞的实验，我们预测它们将适用于其他上皮肿瘤。我们建议在胰管上皮中检验我们的假设。胰腺腺癌通常是高度转移性的，并且与许多其他癌症相比与极差的预后相关。胰腺肿瘤细胞从其导管上皮起源部位通过胰管基底膜逃逸的起始事件是胰腺癌进展的基础。阐明参与这种逃逸的关键分子事件，是这个项目的中心焦点，我们将追求两个特定的目标。首先，我们将测试的假设，胶原蛋白XV在维持胰腺导管上皮基底膜的完整性中起着关键作用，并从导管上皮细胞的胶原蛋白XV的损失有助于胰腺癌的转移。同时，我们将研究胶原XV抑制宫颈癌细胞恶性的机制。我们将定义负责这种活性的蛋白质的结构域，并确定胶原XV在基底膜和非恶性上皮细胞表面的功能伙伴。这些实验可以识别细胞外胶原XV将信号传递到导管上皮细胞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，我们将确定受其损失影响的信号传导途径。这一系列的实验可能会产生新的途径，治疗干预胰腺癌，和其他上皮来源的癌症，靶向胶原蛋白XV蛋白聚糖。

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.