PROJECT 4:MECHANISMS FACILITATING GROWTH & METASTASIS OF PANCREATIC CANCER

这个子项目是利用这些资源的众多研究子项目之一

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Pancreatic cancer is the fourth most frequent cause of cancer-related death in the U.S., and only about 5% of patients with this disease survive. Improved comprehension of how pancreatic tumors grow and metastasize is necessary in order for better therapies to be developed. In some systems, principally the nervous system, amyloid precursor protein (APP) and amyloid precursor-like-protein 2 (APLP2) have been associated with cellular growth and migration. Recent studies have shown over-expression of APP and APLP2 in human cancer, including pancreatic cancer, and in some cancers higher APP expression has been shown to correlate with a worse survival rate. APP secreted by prostate and pancreatic cancer cell lines increases proliferation by binding to an unidentified cell surface receptor, and both APP and APLP2 contribute to adhesion and motility in several cell types. There is evidence that APP and APLP2 have novel roles in pancreatic cancer, but the mechanisms for how they contribute to this disease are not known. In this project, our overall objective is to gain understanding of mechanisms underlying pancreatic cancer growth and spread. Our central hypothesis is that APP and APLP2 stimulate the proliferation and metastasis of pancreatic cancer cells. To accomplish this objective, our Aims are, first, to ascertain mechanisms mediated by APP and APLP2 that facilitate pancreatic cancer cell growth. Our working hypothesis for this aim is that secreted APLP2 and APP trigger the proliferation of pancreatic cancer cells via a NF-¿B pathway. The second aim is to determine mechanisms mediated by APP and APLP2 that increase the spread of pancreatic cancer cells. The working hypothesis that will be tested in this aim is that transmembrane APP and APLP2 are key regulators of the adhesion and dissemination of pancreatic cancer cells. Our results from these studies will provide a novel perspective on the regulation of cellular growth and motility, with relevance to normal and cancer cells and particularly to pancreatic cancer cells. Furthermore, results from this study are expected to support the use of novel treatments for pancreatic cancer that target APP and APLP2.