Antitumor activity of ALK1 in pancreatic carcinoma cells

In this study, the authors investigated the expression of activin receptor‐like kinase 1 (ALK1) in pancreatic carcinoma and evaluated its potential role as a tumor suppressor in vitro and in vivo. Endogenous ALK1 expression was demonstrated by immunohistochemistry in both pancreatic tumor tissue and peritumoral normal tissue from 6 patients and by RT‐PCR in 8/12 established pancreatic cancer cell lines. Ectopic expression of a constitutively active (ca) ALK1 mutant in TGF‐β sensitive PANC‐1 and COLO‐357 cells augmented transcriptional activation of a Smad2/3 responsive reporter, and slowed down basal growth in vitro. Both effects were further enhanced by TGF‐β/ALK5 stimulation, suggesting largely independent nuclear Smad signaling by both type I receptors. Upon orthotopic transplantation of PANC‐1‐caALK1 into immunodeficient mice, tumor size was strongly reduced and was associated with a lower microvessel density in the PANC‐1‐caALK1‐derived tumors. In vitro, this mutant efficiently blocked TGF‐β‐induced epithelial‐to‐mesenchymal transdifferentiation and suppressed TGF‐β/ALK5‐mediated activation of the p38 MAPK pathway. Mechanistically, caALK1 silenced MyD118, an immediate TGF‐β target gene whose protein product, GADD45β, couples Smad signaling to p38 activation. These results show that ALK1 activation in pancreatic tumor cells is antioncogenic by inducing ALK5‐independent growth inhibition and by blocking TGF‐β/ALK5‐mediated epithelial‐to‐mesenchymal transdifferentiation and, possibly, invasion and metastatic progression. © 2007 Wiley‐Liss, Inc.