DISRUPTION OF THE ANTIPROLIFERATIVE TGF-BETA SIGNALING PATHWAYS IN HUMAN PANCREATIC-CANCER CELLS

Resistance to TGF-beta 1 occurred in pancreatic cancer cells suggestin g that inactivation of TGF-beta inhibitory signaling pathways may play an important role in human pancreatic cancer. The aim of our study wa s to determine the presence of alterations in the main putative compon ents of the TGF-beta inhibitory signaling pathways (p15, Smad4, Smad2, TGF beta-RII, CDC25A). A panel of human carcinomas of the exocrine pa ncreas orthotopically implanted and perpetuated in nude mice and pancr eatic cancer cell lines were studied. p15 gene alterations, mainly hom ozygous deletions that involved exons 1 and/or 2, were found in the 62 .5% (5 of 8) of pancreatic xenografts whereas Smad4 gene aberrations w ere found in one of eight xenografts and in two of seven cell lines, A dditional aberrations in these genes were acquired during in vivo perp etuation and distal dissemination. Paradoxically, TGF beta-RII overexp ression and a decrease in CDC25A protein levels were found in all tumo rs and cell lines. In one cell line, resistance to TGF-beta 1 occurred in the absence of alterations in the genes analysed so far. We conclu de that all human pancreatic tumor cells analysed herein have non-func tional TGF-beta pathways. The majority of cells harbor alterations in at least one of the putative components of TGF-beta pathways, mainly i n p15 and Smad4 genes. These results suggest that inactivation of TGF- beta signaling pathways plays an important role in human pancreatic tu morigenesis.