Smad4/TGF-β Signaling Pathways in Pancreatic Cancer Pathogenesis

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is an extremely aggressive disease with dismal survival statistics. Extensive research efforts have focused on the elucidation of the specific molecular alterations behind pancreatic cancer, with the goals of understanding PDAC pathobiology and devising new and effective targeted therapies. These studies have yielded surprisingly consistent results, indicating that key genetic alterations include a high frequency of mutations in the K-ras, p53, p16 and Smad4 genes. In addition, there is excessive activation of mitogenic pathways, overexpression of TGF-$β$ isoforms, and an intense desmoplastic reaction that is driven, in part, by the proliferation of pancreatic stellate cells, and marked apoptosis resistance. This chapter focuses on the potential role of the TGF-$β$ signaling pathway in PDAC progression and metastasis while highlighting the importance of Smad4 in TGF-$β$ signal transduction.