Advertisement

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

  • Brunhilde Felding-Habermann
  • Emilia Fransvea
  • Timothy E. O'Toole
  • Lisa Manzuk
  • Barbara Faha
  • Mary Hensler
Article

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.

αvβ3 αIIbβ3 integrin melanoma metastasis MMP-2 

References

  1. 1.
    Ruoslahti E. Integrins as signaling molecules and targets for tumor therapy. Kidney Int 1997; 51: 1413–7.PubMedGoogle Scholar
  2. 2.
    Li G, Herlyn M. Dynamis of intercellular communication during melanoma development. Mol Med Today 2000; 6: 163–9.PubMedCrossRefGoogle Scholar
  3. 3.
    Becker JC, Kampgen E, Brocker E. Classical chemotherapy for metastatic melanoma. Clin Exp Dermatol 2000; 25: 503–8.PubMedCrossRefGoogle Scholar
  4. 4.
    Albelda SM, Mette SA, Elder DE et al. Integrin distribution in malignant melanoma: Association of the beta 3 subunit with tumor progression. Cancer Res 1990; 50: 6757–64.PubMedGoogle Scholar
  5. 5.
    Natali PG, Hamby CV, Felding-Habermann B et al. Clinical significance of alpha(v)beta3 integrin and intercellular adhesion molecule-1 expression in cutaneous malignant melanoma lesions. Cancer Res 1997; 57: 1554–60.PubMedGoogle Scholar
  6. 6.
    Danen EH, Ten Berge PJ, Van Muijen GN et al. Emergence of alpha 5 beta 1 fibronectin-and alpha v beta 3 vitronectin-receptor expression in melanocytic tumour progression. Histopathology 1994; 24: 249–56.PubMedGoogle Scholar
  7. 7.
    Felding-Habermann B, Mueller BM, Romerdahl CA et al. Involvement of integrin alpha V gene expression in human melanoma tumorigenicity. J Clin Invest 1992; 89: 2018-22.PubMedCrossRefGoogle Scholar
  8. 8.
    Montgomery AM, Reisfeld RA, Cheresh DA. Integrin alpha v beta 3 rescues melanoma cells from apoptosis in three-dimensional dermal collagen. Proc Natl Acad Sci USA 1994; 91: 8856–60.PubMedCrossRefGoogle Scholar
  9. 9.
    Seftor RE, Seftor EA, Hendrix MJ, Molecular role(s) for integrins in human melanoma invasion. Cancer Metastasis Rev 1999; 18: 359–75.PubMedCrossRefGoogle Scholar
  10. 10.
    Felding-Habermann B, Ruggeri ZM, Cheresh DA. Distinct biological consequences of integrin alpha v beta 3-mediated melanoma cell adhesion to fibrinogen and its plasmic fragments. J Biol Chem 1992; 267: 5070–7.PubMedGoogle Scholar
  11. 11.
    Felding-Habermann B, Habermann R, Saldivar E et al. Role of beta3 integrins in melanoma cell adhesion to activated platelets under flow. J Biol Chem 1996; 271: 5892–900.PubMedCrossRefGoogle Scholar
  12. 12.
    Cheresh DA, Spiro RC. Biosynthetic and functional properties of an Arg-Gly-Asp-directed receptor involved in human melanoma cell attachment to vitronectin, fibrinogen, and von Willebrand factor. J Biol Chem 1987; 262: 17703–11.PubMedGoogle Scholar
  13. 13.
    Wong H, Anderson WD, Cheng T et al. Monitoring mRNA expression by polymerase chain reaction: The 'primer-dropping' method. Anal Biochem 1994; 223: 251–8.PubMedCrossRefGoogle Scholar
  14. 14.
    Frelinger AL, Du X, Plow EF et al., Monoclonal antibodies to ligand-occupied conformers of integrin αIIb β 3 (glycoprotein IIb-IIIa) alter receptor affinity, specificity, and function. J Biol Chem 1991; 266: 17106–11.PubMedGoogle Scholar
  15. 15.
    Niiya K, Hodson E, Bader R et al. Increased surface expression of the membrane glycoprotein IIb/IIIa complex induced by platelet activation. Relationship to the binding of fibrinogen and platelet aggregation. Blood 1987; 70: 475–83.PubMedGoogle Scholar
  16. 16.
    Stetler-Stevenson WG. The role of matrix metalloproteinases in tumor invasion, metastasis, and angiogenesis. Surg Oncol Clin N Am 2001; 10: 383–92, x.PubMedGoogle Scholar
  17. 17.
    Murphy G, Stanton H, Cowell S et al. Mechanisms for pro matrix metalloproteinase activation. APMIS 1999; 107: 38–44.PubMedGoogle Scholar
  18. 18.
    Hart IR, Birch M, Marshall JF. Cell adhesion receptor expression during melanoma progression and metastasis. Cancer Metastasis Rev 1991; 10: 115–28.PubMedCrossRefGoogle Scholar
  19. 19.
    Smith JW, Piotrowicz RS, Mathis D. A mechanism for divalent cation regulation of beta 3-integrins. J Biol Chem 1994; 269: 960–7.PubMedGoogle Scholar
  20. 20.
    Timar J, Raso E, Fazakas ZS et al. Multiple use of a signal transduction pathway in tumor cell invasion. Anticancer Res 1996; 16: 3299–306.PubMedGoogle Scholar
  21. 21.
    Tang DG, Honn KV. Adhesion molecules and tumor metastasis: An update. Invasion Metastasis 1994; 14: 109–22.PubMedGoogle Scholar
  22. 22.
    Brooks PC, Montgomery AM, Rosenfeld M et al. Integrin alpha v beta 3 antagonists promote tumor regression by inducing apoptosis of angiogenic blood vessels. Cell 1994; 79: 1157–64.PubMedCrossRefGoogle Scholar
  23. 23.
    Curran S, Murray GI. Matrix metalloproteinases in tumour invasion and metastasis. J Pathol 1999; 189: 300–8.PubMedCrossRefGoogle Scholar
  24. 24.
    Seiki M. Membrane-type matrix metalloproteinases. APMIS 1999; 107: 137–43.PubMedCrossRefGoogle Scholar
  25. 25.
    Hofmann UB, Westphal JR, Waas ET et al. Coexpression of integrin alpha(v)beta3 and matrix metalloproteinase-2 (MMP-2) coincides with MMP-2 activation: Correlation with melanoma progression. J Invest Dermatol 2000; 115: 625–32.PubMedCrossRefGoogle Scholar
  26. 26.
    Morrison CJ, Butler GS, Bigg HF et al. Cellular Activation of MMP-2 (Gelatinase A) by MT2-MMP Occurs via a TIMP-2-independent Pathway. J Biol Chem 2001; 276: 47402–10.PubMedCrossRefGoogle Scholar
  27. 27.
    Pekovich SR, Bock PE, Hoover RL. Thrombin-thrombomodulin activation of protein C facilitates the activation of progelatinase A. FEBS Lett 2001; 494: 129–32.PubMedCrossRefGoogle Scholar
  28. 28.
    Brooks PC, Stromblad S, Sanders LC et al. Localization of matrix metalloproteinase MMP-2 to the surface of invasive cells by interaction with integrin alpha v beta 3. Cell 1996; 85: 683-93.PubMedCrossRefGoogle Scholar
  29. 29.
    Brooks PC, Silletti S, von Schalscha TL et al. Disruption of angiogenesis by PEX, a noncatalytie metalloproteinase fragment with integrin binding activity. Cell 1998; 92: 391–400.PubMedCrossRefGoogle Scholar
  30. 30.
    Silletti S, Kessler T, Goldberg J et al. Disruption of matrix metalloproteinase 2 binding to integrin alpha vbeta 3 by an organic molecule inhibits angiogenesis and tumor growth in vivo. Proc Natl Acad Sci USA 2001; 98: 119–24.PubMedCrossRefGoogle Scholar
  31. 31.
    Huhtala P, Humphries MJ, McCarthy JB et al. Cooperative signaling by alpha 5 beta 1 and alpha 4 beta 1 integrins regulates metalloproteinase gene expression in fibroblasts adhering to fibronectin. J Cell Biol 1995; 129: 867–79.PubMedCrossRefGoogle Scholar
  32. 32.
    Philip S, Bulbule A, Kundu GC, Osteopontin stimulates tumor growth and activation of promatrix metalloproteinase-2 through nuclear factor-kappa B-mediated induction of membrane type 1 matrix metalloproteinase in murine melanoma cells. J Biol Chem 2001; 276: 44926–35.PubMedCrossRefGoogle Scholar
  33. 33.
    Hofmann UB, Westphal JR, van Kraats AA et al. Expression of integrin alpha(v)beta(3) correlates with activation of membrane-type matrix metalloproteinase-1 (MT1-MMP) and matrix metalloproteinase-2 (MMP-2) in human melanoma cells in vitro and in vivo. Int J Cancer 2000; 87: 12–9.PubMedCrossRefGoogle Scholar
  34. 34.
    Deryugina EI, Bourdon MA, Jungwirth K, Smith JW, Strongin AY. Functional activation of integrin alpha V beta 3 in tumor cells expressing membrane-type 1 matrix metalloproteinase. Int J Cancer 2000; 86: 15–23.PubMedCrossRefGoogle Scholar
  35. 35.
    Deryugina EI, Ratnikov B, Monosov E et al. MT1-MMP initiates activation of pro-MMP-2 and integrin alphavbeta3 promotes maturation of MMP-2 in breast carcinoma cells. Exp Cell Res 2001; 263: 209–23.PubMedCrossRefGoogle Scholar
  36. 36.
    Thiagarajan P, Le A, Snuggs MB et al. The role of carboxy-terminal glycosaminoglycan-binding domain of vitronectin in cytoskeletal organization and migration of endothelial cells. Cell Adhes Commun 1996; 4: 317–25.PubMedGoogle Scholar
  37. 37.
    Kanse SM, Kost C, Wilhelm OG et al. The urokinase receptor is a major vitronectin-binding protein on endothelial cells. Exp Cell Res 1996; 224: 344–53.PubMedCrossRefGoogle Scholar
  38. 38.
    Honn KV, Tang DG. Adhesion molecules and tumor cell interaction with endothelium and subendothelial matrix. Cancer Metastasis Rev. 1992; 11: 353–75.PubMedCrossRefGoogle Scholar
  39. 39.
    Seiffert D. Constitutive and regulated expression of vitronectin. Histol Histopathol 1997; 12: 787–97.PubMedGoogle Scholar
  40. 40.
    Clyman RI, Mauray F, Kramer RH. Beta 1 and beta 3 integrins have different roles in the adhesion and migration of vascular smooth muscle cells on extracellular matrix. Exp Cell Res 1992; 200: 272–84.PubMedCrossRefGoogle Scholar
  41. 41.
    Belkin AM, Akimov SS, Zaritskaya LS et al. Matrix-dependent proteolysis of surface transglutaminase by membrane-type metalloproteinase regulates cancer cell adhesion and locomotion. J Biol Chem 2001; 276: 18415–22.PubMedCrossRefGoogle Scholar
  42. 42.
    Bendeck MP, Irvin C, Reidy M et al. Smooth muscle cell matrix metalloproteinase production is stimulated via alpha(v)beta(3) integrin. Arterioscler Thromb Vasc Biol 2000; 20: 1467–72.PubMedGoogle Scholar

Copyright information

© Kluwer Academic Publishers 2002

Authors and Affiliations

  • Brunhilde Felding-Habermann
    • 1
  • Emilia Fransvea
    • 1
  • Timothy E. O'Toole
    • 1
  • Lisa Manzuk
    • 2
  • Barbara Faha
    • 2
  • Mary Hensler
    • 2
  1. 1.Department of Molecular and Experimental MedicineThe Scripps Research InstituteLa JollaUSA
  2. 2.IXSYS Inc.San DiegoUSA

Personalised recommendations