DYSREGULATION OF TGF-BETA ACTIONS IN PANCREATIC CANCER

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DESCRIPTION: (adapted from the investigator's abstract) The cellular and molecular mechanisms that contribute to the biological aggressiveness of pancreatic ductal adenocarcinomas are not known. However, it is established that these cancers have a high incidence of mutations in the K-ras oncogene, harbor a number of mutated tumor suppressor genes, and overexpress several growth factors and their corresponding transmembrane tyrosine kinase receptors that are positive modulators of cell growth. The investigators reported that human pancreatic cancers also express high levels of the three mammalian transforming growth factor beta (TGF-b) isoforms and that their presence in the cancers is associated with disease progression. TGF-bs inhibit the growth of epithelial cell types but enhance angiogenesis, contribute to extracellular matrix formation, regulate cell migration and adhesion and modulate immune functions. It is conceivable, therefore, that TGF-bs act via paracrine mechanisms to enhance the growth of pancreatic cancer cells in vivo. This implies that cancer-directed TGF-b inhibitor pathways may be inoperative in this disorder. In theory, this loss of negative growth regulation could be due to alterations at the level of the TGF-b receptors or to post-receptor defects. In the present proposal they will test the hypothesis that aberrant expression and altered function of TGF-b receptors in pancreatic cancer cells results in perturbations in autocrine growth suppressive mechanisms while concomitant TGF-b overexpression enhances cell growth via paracrine mechanisms. Two approaches will be used to test this hypothesis. First, they will determine whether and how TGF-b receptor expression is altered in pancreatic cancer and establish the clinical significance of these alterations. This analysis will be performed using the appropriate specific antibodies, molecular probes and oligonucleotides. Control tissues will consist of normal human pancreatic samples obtained through an organ donor program. Second, they will elucidate the reasons for pancreatic cancer cell resistance to TGF-b1-mediated growth inhibition by examining the potential roles of TGF-b receptor and post-receptor defects. They will also determine how TGF-b ligand overexpression in pancreatic cancer contributes to disease progression and devise approaches that have the potential to restore cancer cell inhibitory responsiveness and suppress the paracrine actions of TGF-bs.