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Involvement of tumor cell integrin αvβ3 in hematogenous metastasis of human melanoma cells

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Abstract

Early metastasis is the primary cause of death in melanoma patients. The adhesion receptor integrin αvβ3 contributes to tumor cell functions that are potentially involved in melanoma growth and metastasis. We tested whether integrin αvβ3 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 αvβ3, αIIbβ3 or no β3 integrin, we found that only αvβ3 strongly supported metastasis. Inhibition of tumor cell αvβ3 function reduced melanoma metastasis significantly and prolonged animal survival. To understand mechanisms that allow αvβ3, but not αIIbβ3 to support melanoma metastasis, we analyzed proteolytic and migratory activities of the melanoma cell variants. Melanoma cells expressing αvβ3, but not those expressing αIIbβ3 or no β3 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 αvβ3 expression and protease processing. Furthermore, αvβ3 expression was required for efficient melanoma cell migration toward the matrix proteins fibronectin and vitronectin. The results suggest that expression of integrin αvβ3 promotes the metastatic phenotype in human melanoma by supporting specific adhesive, invasive and migratory properties of the tumor cells and that the related integrin αIIbβ3 cannot substitute for αvβ3 in this respect.

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Author notes

  1. Emilia Fransvea

    Present address: Clinica Medica II, Bari, Italy

  2. Timothy E. O'Toole

    Present address: Department of Molecular Cardiology, Cleveland Clinic Foundation, Ohio, USA

  3. Lisa Manzuk

    Present address: Biosite Diagnostics, San Diego, California, USA

  4. Barbara Faha

    Present address: Canji, Inc., San Diego, California, USA

  5. Mary Hensler

    Present address: Nereus Pharmaceuticals, San Diego, California, USA

Authors and Affiliations

  1. Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California, USA

    Brunhilde Felding-Habermann, Emilia Fransvea & Timothy E. O'Toole

  2. IXSYS Inc., San Diego, California, USA

    Lisa Manzuk, Barbara Faha & Mary Hensler

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  1. Brunhilde Felding-Habermann
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  4. Lisa Manzuk
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Felding-Habermann, B., Fransvea, E., O'Toole, T.E. et al. Involvement of tumor cell integrin αvβ3 in hematogenous metastasis of human melanoma cells. Clin Exp Metastasis 19, 427–436 (2002). https://doi.org/10.1023/A:1016377114119

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