Prostaglandins promote colon cancer cell invasion; signaling by cross-talk between two distinct growth factor receptors

Colorectal cancer is the second most frequent cancer in the Western world, often lethal when invasion and/or metastasis occur. In addition to hepatocyte growth factor (HGF), colon cancer invasion may be driven by prostaglandins, especially the E₂ series (PGE₂), generated by the cyclooxygenase-2 (Cox-2) enzyme. While concentration of PGE₂ as well as expression of Cox-2, HGF receptor (c-Met-R), epidermal growth factor receptor (EGFR), and β-catenin are all dramatically increased in colon cancers and implicated in their growth and invasion, the precise role of PGE₂ in the latter process remains unclear. Here we provide evidence that PGE₂ transactivates c-Met-R (contingent upon functional EGFR), increases tyrosine phosphorylation and nuclear accumulation of β-catenin, and induces urokinase-type plasminogen activator receptor (uPAR) mRNA expression. This is accompanied by increased β-catenin association with c-Met-R and enhanced colon cancer cell invasiveness. Inactivation of EGFR and c-Met-R significantly reduced PGE₂-induced cancer cell invasiveness. Clinical relevance of these findings is confirmed by our immunohistochemical studies demonstrating that cancer cells in the invasive front overexpress Cox-2, c-Met-R, and β-catenin. Our findings explain a functional relationship between prostaglandins, EGFR, and c-Met-R in colon cancer growth and invasion.