Human pancreatic cancers overexpress a number of important tyrosine growth factor receptors and their ligands. These include the epidermal growth factor (EGF) receptor (EGFR) and related receptors, multiple ligands that bind to EGFR, certain fibroblast growth factors (FGF) receptors (FGFR) and ligands, and insulin-like growth factor I (IGF-I) and its receptor. The excessive activation of mitogenic signaling cascades that are modulated by these overexpressed ligands and receptors is compounded by the presence of mutations in the K-ras oncogene. Pancreatic cancers also overexpress transforming growth factor betas (TGF-β) that usually inhibit the growth of epithelial cells. Pancreatic cancers, however, underexpress the type 1 TGF- β receptor and harbor mutations in the smad4 gene, alterations that prevent TGF-βs from inhibiting cancer cell growth that do not confer onto pancreatic actions that promote cancer growth in vivo. Together, these perturbations confer onto pancreatic cancer cells a tremendous growth advantage.
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