Contact with fibrillar collagen inhibits melanoma cell proliferation by up-regulating p27KIP1.
It is known that the extracellular matrix regulates normal cell proliferation, and it is assumed that anchorage-independent malignant cells escape this regulatory function. Here we demonstrate that human M24met melanoma cells remain responsive to growth regulatory signals that result from contact with type I collagen and that the effect on proliferation depends on the physical structure of the collagen. On polymerized fibrillar collagen, M24met cells are growth arrested at the G(1)/S checkpoint and maintain high levels of p27(KIP1) mRNA and protein. In contrast, on nonfibrillar (denatured) collagen, the cells enter the cell cycle, and p27(KIP1) is down-regulated. These 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 negative growth regulatory signals originating from fibrillar collagen, and the proteolytic degradation of fibrils is a mechanism allowing tumor cells to escape these restrictive signals.
Henriet
P
P
Division of Hematology-Oncology, Department of Pediatrics, Childrens Hospital Los Angeles, California 90027, USA.
Zhong
Z D
ZD
Brooks
P C
PC
Weinberg
K I
KI
DeClerck
Y A
YA
D017209:Apoptosis; D002453:Cell Cycle / Q000502:physiology*; D018797:Cell Cycle Proteins; D002455:Cell Division / Q000187:drug effects / Q000502:physiology*; D003094:Collagen / Q000494:pharmacology / Q000502:physiology*; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors; D016326:Extracellular Matrix Proteins / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016023:Integrins / Q000235:genetics / Q000502:physiology; D007700:Kinetics; D008545:Melanoma; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins
D018797:Cell Cycle Proteins; D016326:Extracellular Matrix Proteins; D016023:Integrins; D008869:Microtubule-Associated Proteins; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D003094:Collagen; D018844:Cyclin-Dependent Kinases