Blockade of the insulin-like growth-factor-I receptor inhibits growth of human colorectal cancer cells: evidence of a functional IGF-II-mediated autocrine loop.
Insulin-like growth factors (IGFs) are potent proliferation stimulators for numerous tumor cells and often function as autocrine growth factors. We have previously shown that exogenous IGF-I and IGF-II enhance proliferation of colorectal carcinoma cells. The biological signal of both factors is transmitted through the IGF-I receptor (IGF-I-R). This receptor was expressed in 12/12 colorectal carcinoma cell lines tested. alpha IR3, a neutralizing monoclonal antibody (MAb) directed against the human IGF-I-R, inhibited proliferation in 7/12 lines (Caco-2, HT-29, LS411N, LS513, LS1034, WiDr and SW620), as reflected by a reduction of MTT conversion (19 to 42%), a decrease in cell number (39 to 72%) and an increase in doubling time (up to 2-fold). In addition, in 4 cell lines (Caco-2, LS513, LS1034, WiDr) alpha IR3 suppressed colony formation in methylcellulose (40 to 84%). Excess of exogenous IGF completely neutralized alpha IR3-mediated inhibitory effects. Northern blot analysis revealed abundant expression of 2 IGF-II transcripts of 5.0 and 4.3 kb in LS1034 cells. In addition, we observed that growth inhibition by alpha IR3 was correlated with a more differentiated phenotype. Our results suggest that growth of many colorectal carcinoma cell lines is regulated by autocrine IGF-II-mediated stimulation of the IGF-I-R.
Lahm
H
H
Department of Cellular Biology, Swiss Institute for Experimental Cancer Research, Chemin des Boveresses 155, Epalinges.
Amstad
P
P
Wyniger
J
J
Yilmaz
A
A
Fischer
J R
JR
Schreyer
M
M
Givel
J C
JC
D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D015152:Blotting, Northern; D002448:Cell Adhesion; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D015179:Colorectal Neoplasms / Q000473:pathology* / Q000648:ultrastructure*; D003470:Culture Media; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000096:biosynthesis / Q000494:pharmacology; D007335:Insulin-Like Growth Factor II / Q000096:biosynthesis / Q000502:physiology*; D008747:Methylcellulose; D014411:Neoplastic Stem Cells / Q000187:drug effects; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors* / Q000276:immunology; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D003470:Culture Media; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; D008747:Methylcellulose; D017526:Receptor, IGF Type 1