Basic fibroblast growth factor and ultraviolet B transform melanocytes in human skin

Ultraviolet (UV) light is an epidemiological risk factor for melanoma, but its specific contribution to melanoma induction is not known. The first cri tical step of melanoma development, ie, the uncontrolled proliferation of m elanocytes, may be induced by a combination of UV damage and an imbalance o f growth factor production by cells in the immediate area of the melanocyte . Among several candidates, basic fibroblast growth factor (bFGF) is the ma jor autocrine growth factor in melanoma and associated with tumor progressi on. Overexpression of bFGF via adenoviral gene transfer in human skin xenog rafted to severe combined immunodeficiency mice led to black-pigmented macu les within 3 weeks of treatment. Immunofluorescence analysis demonstrated p athological hyperpigmentation, proliferation and hyperplasia of activated m elanocytes, but no malignant transformation. Similar changes were observed in skin reconstructs. When bFGF was combined with UVB, pigmented lesions wi th hyperplastic melanocytic cells were detected, including a lesion with hi gh-grade atypia resembling lentiginous forms of malignant melanoma. Donor-m atched control grafts revealed no melanocytic changes. bFGF was overexpress ed in dermal fibroblasts demonstrating the cocarcinogenic influence of para crine-acting growth factors by cells of the microenvironment. This is the f irst report suggesting that an imbalance of physiological growth factor pro duction in the skin may cause melanoma in combination with UVB.