Collagen XV as a tumor and metastasis suppressor.

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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.