INCREASED TUMORIGENICITY IN THE HUMAN PANCREATIC-CELL LINE MIA PACA-2IS ASSOCIATED WITH AN ABERRANT REGULATION OF AN IGF-1 AUTOCRINE LOOP AND LACK OF EXPRESSION OF THE TGF-BETA TYPE RII RECEPTOR

The growth characteristics associated with tumorigenicity were determi ned in clones of MIA PaCa-2 and PANC-1 pancreatic carcinoma cells. MIA PaCa-2 cells differed from PANC-1 cells in that they rapidly formed t umors in nude mice, formed colonies more rapidly and formed larger col onies in soft agar, and were cloned more efficiently when seeded at lo w density. MIA PaCa-2 cells but not PANC-1 cells were stimulated to es cape quiescence and undergo DNA synthesis with nutrient media lacking growth factors. Both cell lines were stimulated to proliferate with se rum-free media containing EGF, transferrin, and insulin. Antibody neut ralization assays indicated that an IGF-1 autocrine loop was required for the nutrient stimulation of growth in MIA PaCa-2 cells and for the growth-factor stimulation in both MIA PaCa-2 and PANC-1 cells. Both c ell lines were stimulated to proliferate with exogenous IGF-1 in basal media; this stimulation was specifically blocked by antibodies to IGF -1 or its receptor. MIA PaCa-2 and PANC-1 cells expressed similar leve ls of IGF-1 receptor mRNA and showed similar binding kinetics in recep tor binding assays. In contrast to PANC-1 cells, MIA PaCa-2 cells were insensitive to TGF-beta 1 and did not express TGF-beta receptor type II. The results suggest that the growth-factor independence is represe ntative of a more tumorigenic phenotype. We hypothesize that growth-fa ctor independence of MIA PaCa-2 cells is mediated by an aberrant regul ation of an IGF-1 autocrine loop. A decreased regulation of this IGF-1 loop may be potentiated by loss of response to TGF-beta. (C) 1995 Wil ey-Liss, Inc.