IGF‐2 autocrine stimulation in tumorigenic clones of a human colon‐carcinoma cell line

Abstract

Clonal analysis has shown that the SW613-S human colon-carcinoma cell line is heterogeneous: some cell clones display a high level of amplification of the c-myc gene and are tumorigenic in nude mice, whereas others have a small number of copies of this gene and are non-tumorigenic. Tumorigenic clones can proliferate in a chemically defined serum-free medium, whereas non-tumorigenic clones cannot. Suramin, like anti-insulin-like growth factor (IGF) or anti-IGF-I receptor antibodies, efficiently inhibits the growth of tumorigenic clones in defined medium. Inhibition by suramin or by anti-IGF antibodies can be reversed by pure IGF-I or IGF-2. Pure IGF-1 or IGF-2 or culture medium conditioned by tumorigenic clones can stimulate DNA synthesis in cells of non-tumorigenic clones. Co-culture with cells of tumorigenic clones sustains the growth of non-tumorigenic clones in defined medium. Cells of both tumorigenic and non-tumorigenic clones express high-affinity IGF-1 receptors at their surface but tumorigenic clones produce on average 5 times more IGF-1 and 25 times more IGF-2 than non-tumorigenic ones. These results indicate that autocrine growth stimulation of tumorigenic clones by IGFs through the IGF-1 receptor is essential for their ability to grow in defined medium. Since cells of tumorigenic clones produce IGF-2 at levels 80 times higher than IGF-1 and since an antibody strictly specific for IGF-1 has no effect on DNA synthesis in cells of tumorigenic clones grown in defined medium, IGF-2 is very likely the main effector in the autocrine loop.

Apoptosis-prone phenotype of human colon carcinoma cells with a high level amplification of the c-myc gene

“…Harrington et al (1994a) demonstrated that some cytokines, including the IGFs and PDGF, may act as survival factors and block c-myc-induced apoptosis. Previous work on tumorigenic and non-tumorigenic SW613-S-derived clones proved that 12A1 cells overexpress the genes of several growth factors, including PDGF-A and IGF-2, as compared to B3 cells (Galdemard et al, 1995;Lamonerie et al, 1995;Lavialle et al, 1989;Modjtahedi et al, 1992). In addition, it was shown that tumorigenic 12A1 cells can proliferate in a chemically de®ned, serum-free medium containing only transferrin as a proteinaceous component, whereas non-tumorigenic B3 cells cannot.…”

“…In addition, it was shown that tumorigenic 12A1 cells can proliferate in a chemically de®ned, serum-free medium containing only transferrin as a proteinaceous component, whereas non-tumorigenic B3 cells cannot. Moreover, we have previously reported that IGF-2 acts through an autocrine pathway that is essential for the growth of tumorigenic cells under these serum-free culture conditions (Lamonerie et al, 1995). Since tumorigenic cells cannot grow in de®ned medium devoid of transferrin and since none of the growth factors overproduced by tumorigenic cells is apparently su cient by itself to suppress c-myc-induced apoptosis in the absence of transferrin, we conclude that transferrin is a likely candidate as a survival factor for these cells.…”

Allelic imbalance of insulin-like growth factor II gene expression in cancerous and precancerous lesions of the liver

“…The IGF II is speculated to serve as an autocrine growth factor in various cancers, because they often coexpress the IGF II and the IGF I receptor. [1][2][3][4] The IGF II gene expression is monoallelic in all the normal tissues other than the liver because of the imprinting of the maternal allele. However, interestingly, most of the cancers arising in these tissues, such as lung cancers, breast cancers, esophageal cancers, Wilms' tumor, and cervical cancers, are reported to show biallelic expression (relaxation) of the IGF II gene.…”

Expression of the wild-type insulin-like growth factor II receptor gene suppresses growth and causes death in colorectal carcinoma cells

“…This is a potent growth stimulant which is expressed at high levels in colorectal carcinoma, hepatoblastoma, breast cancer, rhabdomyosarcoma, and Wilm's tumor, among other cancer types (Guo et al, 1995;Lamonerie et al, 1995;Rainier et al, 1995;Manni et al, 1994;Minniti et al, 1994;Yun et al, 1993). Furthermore, conditioned media from human colon cancer cell lines contain elevated levels of IGFII prohormone, a more biologically potent form of IGFII (Culouscou et al, 1990).…”