ALTERED EXPRESSION OF INSULIN-LIKE GROWTH-FACTOR-I AND ITS RECEPTOR DURING MULTISTAGE CARCINOGENESIS IN MOUSE SKIN

We examined the possible role of insulin-like growth factor-1 (IGF-I) and IGF-I receptor (IGF-Ir) during multi-stage carcinogenesis in mouse skin. For th is purpose, the expression of both IGF-I and IGF-Ir was investigated in mouse skin during tumor promoter treatment and in prim ary papillomas and squamous cell carcinomas (SCCs) obtained from SENCA R mice treated with standard initiation-promotion regimens. ICF-I tran scripts were not detectable or only weakly detectable in normal SENCAR mouse epidermis by northern or reverse transcription (RT)-polymerase chain reaction (PCR) analysis, respectively, whereas IGF-I-transcripts (primarily a 7.0-kb transcript) were readily detected in RNA preparat ions from the dermis by both northern blot analysis and RT-PCR analysi s. in contrast, IGF-Ir transcripts were observed in RNA samples from b oth epidermis and dermis of control SENCAR mice. Single and multiple t opical treatments with 3.4 nmol of 12-O-tetradecanoylphorbol-13-acetat e (TPA) had no effect on dermal or epidermal IGF-I and IGF-Ir mRNA lev els. In contrast, the levels of IGF-I transcripts were elevated (2.5- to 15-fold) in a significant number of mouse skin tumors (71% of all t umors examined). Transcripts of 7.0, 2.5, and 1.3 kb were more consist ently overexpressed in skin tumors compared with epidermis, whereas th e two smaller transcripts were most consistently overexpressed compare d with the dermis. The levels of an 11.0-kb IGF-Ir transcript were als o elevated (2.5- to 8-fold) in some papillomas (20%) and SCCs (55%), b ut the percentage of tumors exhibiting this property (32% of all tumor s examined) was lower than the percentage overexpressing IGF-I. These data suggest that altered expression of ICF-I and IGF-Ir may play a ro le in multistage carcinogenesis in the mouse skin model, The inability of TPA to induce elevated IGF-I or IGF-Ir expression suggests that th ese changes in skin tumors are coincident with tumor formation and not a direct result of altered epidermal proliferation per se. Altered ex pression of IGF-I in a high percentage of papillomas may indicate that IGF-I has an important role in the development of autonomous growth i n these tumors. The higher percentage of SCCs with altered levels of I GF-Ir mRNA may indicate a role for these changes in the later stages ( i.e., tumor progression) of carcinogenesis in this model system. (C) 1 996 Wiley-Liss, Inc.