Insulin-like growth factor-1 induces survival and growth of biologically early melanoma cells through both the mitogen-activated protein kinase and beta-catenin pathways

Melanoma cells produce growth factors for autocrine growth control and for stimulating fibroblasts and endothelial cells in the tumor stroma. Activate d stromal fibroblasts can in turn secrete growth factors that support tumor growth. We studied this feedback from fibroblasts to melanoma cells by ove rexpressing insulin-like growth factor 1 (IGF-1) with an adenoviral vector. Melanoma cells do not produce IGF-1. IGF-1 enhanced survival, migration, a nd growth of cells from biologically early lesions, but not from biological ly late primary or metastatic lesions. Early melanoma cells were activated by IGF-1 to phosphorylate Erk1 and -2 of the mitogen-activated protein kina se pathway. IGF-1 also activated Akt, inhibited its down-stream effector GS K3-beta, and stabilized beta -catenin. Late primary and metastatic melanoma cells did not respond to growth stimulation by IGF-1 because of a constitu tive activation of the mitogen-activated protein kinase pathway and a highe r level of stabilized beta -catenin. These studies demonstrate that fibrobl ast-derived growth factors from the tumor environment can provide the malig nant cells with a positive feedback through multiple mechanisms but that th is stimulation is required only for cells from early and not late stages of tumor progression.