alphaV integrin promotes in vitro and in vivo survival of cells in metastatic melanoma.
The expression of integrin alphaV subunit on 4 melanoma-derived cell lines (A2058, SK-mel-5, WM-115 and WM-266-4) was analyzed. WM-115 cells, which originate from a primary tumor, were negative, whereas all 3 metastasis-derived lines had high levels of alphaV. To study alphaV integrins in the survival of melanoma cells, we developed a novel strategy that is exempt from extracellular inhibitors of ligand binding, which can activate integrin signaling and have integrin-independent effects on apoptosis. A recombinant adenovirus was used to transfer cDNA coding for a single-chain intracellular anti-alphaV integrin antibody into the melanoma cells. Anti-alphaV integrin adenovirus effectively inhibited the cell surface expression of alphaV integrins. In cell culture experiments, the depletion of alphaV integrins detached cells from extracellular matrix and induced apoptosis. Moreover, it prevented WM-266-4 cells from forming tumors in severe combined immunodeficiency mice but it could not prevent the growth of tumors that were formed by alphaV-negative WM-115 cells. Our results indicate that in primary melanomas there are cells that survive without alphaV integrins, whereas during the progression of disease cells can develop a dependency on these receptors. Furthermore, the data oppose the possibility that in melanoma cells apoptosis could occur due to direct activation of caspases by ligand-free alphaV integrins on the cell surface.
MediCity Research Laboratory, University of Turku, Turku, Finland.
Pekka
P
Koistinen
Matti
M
Ahonen
Veli-Matti
VM
Kähäri
Jyrki
J
Heino
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017209:Apoptosis; D002448:Cell Adhesion; D002470:Cell Survival; D018450:Disease Progression; D005109:Extracellular Matrix / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D039564:Integrin alphaV / Q000235:genetics / Q000378:metabolism*; D008207:Lymphatic Metastasis / Q000473:pathology; D008545:Melanoma / Q000378:metabolism / Q000473:pathology / Q000556:secondary; D051379:Mice; D016513:Mice, SCID; D012878:Skin Neoplasms / Q000378:metabolism / Q000473:pathology / Q000556:secondary; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000637:transplantation
D039564:Integrin alphaV