Involvement of tumor cell integrin alpha v beta 3 in hematogenous metastasis of human melanoma cells.
Early metastasis is the primary cause of death in melanoma patients. The adhesion receptor integrin alpha v beta 3 contributes to tumor cell functions that are potentially involved in melanoma growth and metastasis. We tested whether integrin alpha v beta 3 supports metastasis of human melanoma cells when injected into the bloodstream of immune deficient mice. Comparing variants of the same melanoma cell type that expressed either alpha v beta 3, alpha IIb beta 3 or no beta 3 integrin, we found that only alpha v beta 3 strongly supported metastasis. Inhibition of tumor cell alpha v beta 3 function reduced melanoma metastasis significantly and prolonged animal survival. To understand mechanisms that allow alpha v beta 3, but not alpha IIb beta 3 to support melanoma metastasis, we analyzed proteolytic and migratory activities of the melanoma cell variants. Melanoma cells expressing alpha v beta 3, but not those expressing alpha IIb beta 3 or no beta 3 integrin, produced the active form of metalloproteinase MMP-2 and expressed elevated mRNA levels of MT1-MMP and TIMP-2. This indicates an association between alpha v beta 3 expression and protease processing. Furthermore, alpha v beta 3 expression was required for efficient melanoma cell migration toward the matrix proteins fibronectin and vitronectin. The results suggest that expression of integrin alpha v beta 3 promotes the metastatic phenotype in human melanoma by supporting specific adhesive, invasive and migratory properties of the tumor cells and that the related integrin alpha IIb beta 3 cannot substitute for alpha v beta 3 in this respect.
Department of Molecular and Experimental Medicine, Scripps Research Institute, Mail MEM 175, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA. brunie@scripps.edu
Brunhilde
B
Felding-Habermann
Emilia
E
Fransvea
Timothy E
TE
O'Toole
Lisa
L
Manzuk
Barbara
B
Faha
Mary
M
Hensler
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D005353:Fibronectins / Q000378:metabolism; D006801:Humans; D007275:Injections, Intravenous; D008175:Lung Neoplasms / Q000556:secondary*; D053511:Matrix Metalloproteinase 14; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis / Q000235:genetics; D053504:Matrix Metalloproteinases, Membrane-Associated; D008545:Melanoma / Q000378:metabolism / Q000473:pathology*; D008546:Melanoma, Experimental / Q000556:secondary* / Q000628:therapy; D008666:Metalloendopeptidases / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D009368:Neoplasm Transplantation; D009360:Neoplastic Cells, Circulating; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000502:physiology; D012333:RNA, Messenger / Q000032:analysis; D012334:RNA, Neoplasm / Q000032:analysis; D019030:Receptors, Vitronectin / Q000276:immunology / Q000502:physiology*; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000235:genetics; D014407:Tumor Cells, Cultured / Q000637:transplantation; D019096:Vitronectin / Q000378:metabolism
D000911:Antibodies, Monoclonal; D005353:Fibronectins; C507096:Mmp14 protein, mouse; D009363:Neoplasm Proteins; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D019030:Receptors, Vitronectin; D019096:Vitronectin; D019716:Tissue Inhibitor of Metalloproteinase-2; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2; D053511:Matrix Metalloproteinase 14