Contact with fibrillar collagen inhibits melanoma cell proliferation by up-regulating p27(KIP1)

It is known that the extracellular matrix regulates normal cell proliferati on, and it is assumed that anchorage-independent malignant cells escape thi s regulatory function. Here we demonstrate that human M24met melanoma cells remain responsive to growth regulatory signals that result from contact wi th type I collagen and that the effect on proliferation depends on the phys ical structure of the collagen. On polymerized fibrillar collagen, M24met c ells are growth arrested at the G(1)/S checkpoint and maintain high levels of p27(KIP1) mRNA and protein. In contrast, on nonfibrillar (denatured) col lagen, the cells enter the cell cycle, and p27(KIP1) is downregulated. Thes e growth regulatory effects involve contact between type I collagen and the collagen-binding integrin alpha(2)beta(1) which appears restricted in the presence of fibrillar collagen. Thus melanoma cells remain sensitive to neg ative growth regulatory signals originating from fibrillar collagen, and th e proteolytic degradation of fibrils is a mechanism allowing tumor cells to escape these restrictive signals.