VARYING PATTERNS OF EXPRESSION OF INSULIN-LIKE-GROWTH-FACTOR-I AND INSULIN-LIKE-GROWTH-FACTOR-II AND THEIR RECEPTORS IN MURINE MAMMARY ADENOCARCINOMAS OF DIFFERENT METASTASIZING ABILITY

We studied the expression of insulin-like growth factors I (IGF-I) and II (IGF-II) and their receptors (IGF-R) in 2 related murine mammary a denocarcinoma in vivo lines, M3 and MM3, with different metastasizing ability. We further investigated the effects of IGFs on the secretion of a key enzyme in the metastatic cascade, the urokinase-type plasmino gen activator (uPA) in M3 and MM3 cells. M3 is a spontaneous mammary t umor originated in BALB/c mice, with a 40% incidence of lung metastase s. MM3 variant, obtained by successive s.c. implants of M3 lung metast ases into syngeneic mice, shows a 95% incidence of lung metastases. Si milar levels of expression of IGF-I protein were found in M3 and MM3 t umors, whereas IGF-II expression was 4-fold higher in MM3. RNAse prote ction assays showed similar levels of IGF-I mRNA in M3 and MM3 tumors and revealed a 4-fold increase in IGF-II transcripts in MM3 tumors com pared with M3. Authentic IGF-I and II messages were also found in prim ary cultures of M3 and MM3 cells. IGF-I mRNA levels were similar in bo th cultures and, as described for solid tumors a Ei-fold increase in I GF-II message was detected in MM3 cells. The presence of type I and ma nnose-6-phosphate (Man-6P)/type II IGF-R was demonstrated in both M3 a nd MM3 tumors. A 2-fold increase of type I IGF-R was detected in MM3 t umors compared with M3. Man-6P/type II IGF-R levels were 2-fold lower in MM3 tumors than in M3. As observed in tumor membranes, type I IGF-R concentrations were higher and Man-6P/type II IGF-R lower in cultures of MM3 epithelial cells compared with MM3 cells. In addition, we foun d that IGF-I enhanced secreted uPA activity in both M3 and MM3 cells w hile IGF-II only stimulated uPA secretion in MM3 cells. (C) 1996 Wiley -Liss, Inc.