CONSTITUTIVE OR INDUCIBLE OVEREXPRESSION OF THE IGF-2 GENE IN CELLS OF A HUMAN COLON-CARCINOMA CELL-LINE

Two types of clones have been isolated from the SW613-S human colon ca rcinoma cell line. Clones with a high level of amplification of the c- myc gene are tumorigenic in nude mice and can proliferate in chemicall y defined, serum-free medium, whereas clones with a low level of ampli fication are nontumorigenic and cannot multiply in defined medium. The expression level of the insulin-like growth factor type 1 (IGF-1) gen e is low in tumorigenic clones and undetectable in nontumorigenic clon es. Tumorigenic clones produce high levels of IGF-2 (and IGF-binding p roteins), compared to nontumorigenic clones. This is the consequence o f a differential transcriptional regulation of the IGF-2 gene between the two types of clones. This regulation consists of a modulation of t he activity of promoters P3 and P4. Overexpression of the IGF-2 gene i s constitutive in tumorigenic clones: it is stably maintained during i n vitro propagation of the cells. Tumorigenic cell lines obtained afte r transfer of c-myc gene copies into the cells of nontumorigenic clone s exhibit a high level of expression of the IGF-2 gene when they are g rown in vivo, as subcutaneous tumors in nude mice. This high level of expression is lost in most of these cell lines when they are returned to in vitro culture conditions indicating that, in these cells, IGF-2 overexpression is not constitutive but inducible by in vivo growth con ditions. We had previously shown that tumorigenic clones use the overp roduced IGF-2 as an autocrine growth factor. The results reported here suggest than IGF-2 overexpression has an important role in the tumori genic phenotype of these cells. (C) 1995 Academic Press, Inc.