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

Melanoma cells produce growth factors for autocrine growth control and for stimulating fibroblasts and endothelial cells in the tumor stroma. Activated stromal fibroblasts can in turn secrete growth factors that support tumor growth. We studied this feedback from fibroblasts to melanoma cells by overexpressing insulin-like growth factor 1 (IGF-1) with an adenoviral vector. Melanoma cells do not produce IGF-1. IGF-1 enhanced survival, migration, and growth of cells from biologically early lesions, but not from biologically late primary or metastatic lesions. Early melanoma cells were activated by IGF-1 to phosphorylate Erk1 and -2 of the mitogen-activated protein kinase pathway. IGF-1 also activated Akt, inhibited its down-stream effector GSK3-β, and stabilized β-catenin. Late primary and metastatic melanoma cells did not respond to growth stimulation by IGF-1 because of a constitutive activation of the mitogen-activated protein kinase pathway and a higher level of stabilized β-catenin. These studies demonstrate that fibroblast-derived growth factors from the tumor environment can provide the malignant cells with a positive feedback through multiple mechanisms but that this stimulation is required only for cells from early and not late stages of tumor progression.