DESCRIPTON: (provided by application) Pancreatic ductal adenocarcinomas (PDACs) exhibit a plethora of molecular alterations that include mutations in the K-ras, p53, p16 and Smad4 genes, and overexpress multiple mitogenic growth factors and their tyrosine kinase receptors. PDACs also express high levels of transforming growth factor-beta (TGF-beta) isoforms, but are resistant to TGF-beta-mediated growth inhibition because they harbor Smad4 mutations, overexpress Smad6 or Smad7, and under-express the type I TGF-beta receptor (TbetaRI). The net result of these alterations is enhanced mitogenic signaling in conjunction with loss of negative growth constraints. The existence of redundant mechanisms for inducing resistance to TGF-beta-mediated growth inhibition : about together with our finding that overexpression of either TGF-beta ligands or the type II TGF-beta receptor (TbetaRII) in PDAC correlates with shortened patient survival, underscore the importance of TGF-beta-mediated events in PDAC. However, the mechanisms whereby TGF-betas may confer a growth advantage to pancreatic cancer cells are not known. In this proposal we will use subcutaneous and orthotopic nude mouse models of PDAC in order to test the hypothesis that cancer cell derived TGF-betas act in vivo to promote cancer growth via two distinct pathways. We will assess whether TGF-betas act via paracrine pathways on adjoining cellular elements by studying the effects of a soluble TbetaRII construct. We will also determine whether TGF-betas act directly on the cancer cells to enhance invasion and metastasis, using dominant-negative and full length TbetaRII constructs, and a constitutively active TbetaRI construct. Because Smad7 enhances pancreatic cancer cell tumorigenicity and blocks the growth suppressive actions of TGF-betal without attenuating its ability to promote the expression of genes implicated in cancer spread, we will assess the contribution of Smad7 overexpression to the biological aggressiveness of PDAC. To this end we will investigate the role of specific genes that are regulated by TGF-beta1 in a setting in which Smad7 is overexpressed by assessing their function in cultured pancreatic cancer cells and their expression in PDAC samples.
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