Induction of scattering and cellular invasion by trefoil peptides in src- and RhoA-transformed kidney and colonic epithelial cells

Trefoil factors (TFFs) are protease-resistant peptides that promote epithel ial cell migration and mucosal restitution during inflammatory conditions a nd wound healing in the gastrointestinal tract. To date, the molecular mech anism of TFFs action and their possible role in tumor progression are uncle ar. In the present study, we observed that premalignant human colonic PC/AA /C1 and canine kidney MDCK epithelial cells are not competent to invade col lagen gels in response to exogenously added TFFs (pS2, spasmolytic polypept ide, and intestinal trefoil factor). In contrast, activated src and RhoA ex ert permissive induction of invasion by the TFFs that produce similar paral lel dose-response curves in src-transformed MDCKts.src and PCmsrc cells (EC 50=20-40 nM). Cell scattering is also induced by TFFs in MDCKts.src cells. Stable expression of the pS2 cDNA promotes constitutive invasiveness in MDC Kts.src-pS2 cells and human colonic HCT8/S11-pS2 cells established from a s poradic tumor. Furthermore, we found that TEE-mediated cellular invasion is dependent of several signaling pathways implicated in cell transformation and survival, including phosphoinositide PI3'-kinase, phospholipase C, prot ein kinase C, and the rapamycin target TOR. Constitutive and intense expres sion of pS2 was revealed by Western blot analyses and immunohistochemistry in human colorectal tumors and their adjacent control mucosa during the neo plastic progression, from the adenoma to the liver metastases. Our studies indicated that TFFs can be involved in cell scattering and tumor invasion v ia autocrine loops and may serve as potential targets in the control of col on cancer progression.