Integrins and Melanoma Progression

  • E. H. J. Danen
  • G. N. P. van Muijen
  • P. J. M. ten Berge
  • D. J. Ruiter
Part of the Recent Results in Cancer Research book series (RECENTCANCER, volume 128)


Tumor (or neoplastic) progression is one of the crucial events in the development of cancer. It is defined as the acquisition of permanent, irreversible, and qualitative changes of one or more characteristics in a neoplasm and its precursor lesions (Nowell 1986). Confronted with selective pressure imposed by host defense and/or therapy, tumor progression favors relentless emergence of new subpopulations with enhanced growth and metastatic capacities, creating tumor heterogeneity (Fidler 1988). Tumor heterogeneity is based on both genetic and epigenetic changes and on differences in development and maturation of the tumor cell population. A better understanding of the pathogenesis of neoplastic progression is likely to provide new clues for diagnosis and therapy aimed at the aggressive tumor cell populations.


Epidermal Growth Factor Receptor Integrin Expression Melanoma Progression Fibronectin Receptor Cell BioI 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. Akiyama S, Yamada SS, Chen W, Yamada KM (1989) Analysis of fibronectin receptor function with monoclonal antibodies: roles in cell adhesion, migration, matrix assembly, and cytoskeletal organization. J Cell Biol 109: 863–875PubMedCrossRefGoogle Scholar
  2. Akiyama SK, Nagata K, Yamada KM (1990) Cell surface receptors for extracellular matrix components. Biochim Biophys Acta 1031: 91–110PubMedGoogle Scholar
  3. Albelda SM, Mette SA, Elder DE, Stewart R, Damjanovich L, Herlyn M, Buck CA (1990) Integrin distribution in malignant melanoma: association of the β3 subunit with tumor progression. Cancer Res 50: 6757–6764PubMedGoogle Scholar
  4. Anichini A, Mortarini R, Berti E, Parmiani G (1990a) Multiple VLA antigens on a subset of melanoma clones. Hum Immunol 28: 119–122PubMedCrossRefGoogle Scholar
  5. Anichini A, Mortarini R, Supino R, Parmiani G (1990b) Human melanoma cells with high susceptibility to cell-mediated lysis can be identified on the basis of ICAM-1 phenotype, VLA profile and invasive ability. Int J Cancer 46: 508–515PubMedCrossRefGoogle Scholar
  6. Aresu O, Nicolò G, Allavena G, Melchiori A, Schmidt J, Kopp JB, d’Amore E, Chader GJ, Albini A (1991) Invasive activity, spreading on and chemotactic response to laminin are properties of high but not low metastatic mouse osteosarcoma cells. Invest Metastasis 11: 2–13Google Scholar
  7. Bröcker EB, Suter L, Brüggen J, Ruiter DJ, Macher E, Sorg C (1985) Phenotypic dynamics of tumor progression in human malignant melanoma. Int J Cancer 36: 29–35PubMedCrossRefGoogle Scholar
  8. Burn P, Kupfer A, Singer J (1988) Dynamic membrane-cytoskeletal interactions: specific association of integrin and talin arises after phorbol ester treatment of peripheral blood lymphocytes. Proc Natl Acad Sci USA 85: 497–501PubMedCrossRefGoogle Scholar
  9. Burridge K, Fath K, Kelly T, Nuckolls G, Turner C (1988) Focal adhesions: transmembrane junctions between the extracellular matrix and the cytoskeleton. Ann Rev Cell Biol 4: 487–525PubMedCrossRefGoogle Scholar
  10. Carter WG, Wayner EA, Bouchard TS, Kaur P (1990) The role of integrins α2β1 and α3β1 in cell-cell and cell-substrate adhesion of human epidermal cells. J Cell Biol 110: 1387–1404PubMedCrossRefGoogle Scholar
  11. Chammas R, Veiga SS, Line S, Potocnjak P, Brentani RR (1991) Asn-linked oligosacharide-dependent interaction between laminin and gp 120/140. J Biol Chem 266: 3349–3355PubMedGoogle Scholar
  12. Chan BMC, Matsuura N, Takada Y, Zetter BR, Hemler ME (1991) In vitro and in vivo consequences of VLA-2 expression on rhabdomyosarcoma cells. Science 251: 1600–1602PubMedCrossRefGoogle Scholar
  13. Chen YQ, Nelson KK, Fitzgerald LA, Honn KV (1991) Detection of αllbβ3 integrin in melanoma cells and its correlation with tumor cell metastasis. Proc Am Assoc Cancer Res 32: 3–3Google Scholar
  14. Cheresh DA, Spiro RC (1987) Biosynthetic and functional properties of an Arg-GlyAsp-directed receptor involved in human cell attachment to vitronectin, fibrinogen, and von Willebrand factor. J Biol Chem 262: 17703–17711PubMedGoogle Scholar
  15. Cheresh DA, Smith JW, Cooper HM, Quaranta V (1989) A novel vitronectin receptor integrin (αvβx) is responsible for distinct adhesive properties of carcinoma cells. Cell 57: 59–69PubMedCrossRefGoogle Scholar
  16. Clark WH Jr, Elder DE, Guerry D, Epstein ME, Greene MH, Van Horn MH (1984) A study of tumor progression. The precursor lesions of superficial spreading and nodular melanoma. Hum Pathol 15: 1147–1156PubMedCrossRefGoogle Scholar
  17. Darribère T, Guida K, Larjava H, Johnsos KE, Yamada KM, Thiery J, Boucaut J (1990) In vivo analysis of integrin β1 subunit function in fibronectin matrix assembly. J Cell Biol 110: 1813–1823PubMedCrossRefGoogle Scholar
  18. Dedhar S, Saulnier R (1990) Alterations in integrin receptor expression on chemically transformed human cells: specific enhancement of laminin and collagen receptor complexes. J Cell Biol 110: 481–489PubMedCrossRefGoogle Scholar
  19. DeWit PEJ, Moretti S, Koenders PE, Weterman MAJ, Van Muijen GNP, Gianotti B, Ruiter DJ (1992) Increasing epidermal growth factor receptor expression in human melanocytic tumor progression. J Invest Dermatol 99: 168–173CrossRefGoogle Scholar
  20. Diamond MS, Staunton DE, Martin SD, Springer TA (1991) Binding of the integrin Mac-1 (CD11b/CD18) to the third immunoglobulin-like domain of ICAM-1 (CD54) and its regulation by glycosylation. Cell 65: 961–971PubMedCrossRefGoogle Scholar
  21. Elices MJ, Osborn L, Takada Y, Crouse C, Lubkowskyi S, Hemler ME, Lobb RR (1990) VCAM-1 on activated endothelium interacts with the leucocyte integrin VLA-4 at a site distinct from the VLA-4/fibronectin binding site. Cell 60: 577–584PubMedCrossRefGoogle Scholar
  22. Erle DJ, Ruegg C, Sheppard D, Pytela R (1990) Complete amino acid sequence of an integrin β subunit (β7) identified in leucocytes. J Biol Chem 266: 11009–11016Google Scholar
  23. Fearon ER, Cho KR, Nigro JM, Kern SE, Simons JW, Ruppert JM, Hamilton SR, Preisinger AC, Thomas G, Kinzler KW, Vogelstein B (1990) Identification of a Chromosone 18q gene that is altered in colorectal cancers. Science 247: 49–56PubMedCrossRefGoogle Scholar
  24. Fidler IJ (1988) The biology of melanoma metastasis. J Dermatol Surg Oncol 14: 875–881PubMedGoogle Scholar
  25. Geiger B, Ginsberg D (1991) The cytoplasmic domain of adherens type junctions. Cell Motil Cytoskeleton 20: 1–6PubMedCrossRefGoogle Scholar
  26. Giancotti FG, Ruoslahti E (1990) Elevated levels of the α5β1 fibronectin receptor supress the transformed phenotype of chinese hamster ovary cells. Cell 60: 849–859PubMedCrossRefGoogle Scholar
  27. Ginsberg MH, Loftus JC, Plow EF (1988) Cytoadhesins, integrins, and platelets. Thromb Haemost 59: 1–6PubMedGoogle Scholar
  28. Guan J, Hynes RO (1990) Lymphoid cells recognize an alternatively spliced segment of fibronectin via the integrin receptor α4β1. Cell 60: 53–61PubMedCrossRefGoogle Scholar
  29. Hemler ME (1988) Adhesive protein receptors on hematopoietic cells. Immunol Today 41: 109–113CrossRefGoogle Scholar
  30. Hemler ME (1990) VLA proteins in the integrin family: structures, functions, and their role on leucocytes. Ann Rev Immunol 8: 365–400CrossRefGoogle Scholar
  31. Hemler ME, Huang C, Schwarz L (1987) The VLA protein family: characterization of five distinct cell surface heterodimers each with a common 130,000 molecular weight β subunit. J Biol Chem 262: 3300–3309PubMedGoogle Scholar
  32. Hemler ME, Crouse C, Sonnenberg A (1989) Association of the VLA α6 subunit with a novel protein: a possible alternative to the common VLA β1 subunit on certain cell lines. J Biol Chem 264: 6529–6535PubMedGoogle Scholar
  33. Herlyn M, Clark WH Jr, Rodeck U, Mancianti ML, Jambrosic J, Koprowski H (1987) Biology of tumor progression in human melanocytes. Lab Invest 66: 461–474Google Scholar
  34. Holzmann B, Johnson JP, Kaudewitz P, Riethmuller G (1985) In situ analysis of antigens on malignant and benign cells of the melanocytic lineage. J Exp Med 161: 366–377PubMedCrossRefGoogle Scholar
  35. Holzmann B, Bröcker E-B, Lehmann J, Ruiter DJ, Sorg C, Riethmuller G, Johnson JP (1987) Tumor progression in human malignant melanoma: four sequential progression stages defined by their antigenic phenotypes. Int J Cancer 39: 466–471PubMedCrossRefGoogle Scholar
  36. Holzmann B, McIntyre BW, Weissman IL (1989) Identification of a murine Peyers Patch-specific lymphocyte homing receptor as an integrin molecule with an α chain homologous to human VLA-4α. Cell 56: 37–46PubMedCrossRefGoogle Scholar
  37. Hynes RO (1987) Integrins: a family of cell surface receptors. Cell 48: 549–554PubMedCrossRefGoogle Scholar
  38. Johnson JP, Stade BG, Holzmann B, Schwable W, Riethmuller G (1989) De novo expression of intercellular-adhesion molecule 1 in melanoma correlates with increased risk of metastasis. Proc Natl Acad Sci USA 86: 641–644PubMedCrossRefGoogle Scholar
  39. Kaufmann R, Frosch D, Westphal C, Weber L, Klein CE (1989) Integrin VLA-3: ultrastructural localization at cell-cell contact sites of human cell cultures. J Cell Biol 109: 1807–1815PubMedCrossRefGoogle Scholar
  40. Kirchhofer D, Languino LR, Ruoslahti E, Pierschbacher MD (1990) α2β1 Integrins from different cell types show different binding specificities. J Biol Chem 265:615–618PubMedGoogle Scholar
  41. Kishimoto TK, Larson RS, Corbi AL, Dustin ML, Staunton DE, Springer TA (1989) The leucocyte integrins. Adv Immunol 46: 149–182PubMedCrossRefGoogle Scholar
  42. Klein CE, Steinmeyer T, Mattes J, Kaufmann R, Weber L (1990) Integrins of normal human epidermis: differential expression, synthesis and molecular structure. Br J Dermatol 123: 171–178PubMedCrossRefGoogle Scholar
  43. Klein CE, Steinmeyer T, Kaufmann D, Weber L, Brocker EB (1991) Identification of a melanoma progression antigen as integrin VLA-2. J Invest Dermatol 96: 281–284PubMedCrossRefGoogle Scholar
  44. Komoriya A, Green LJ, Mervic M, Yamada SS, Yamada KM, Humphries MJ (1991) The minimal essential sequence for a major cell type-specific adhesion site (CS1) within the alternatively spliced type III connecting segment domain of fibronectin is leucine-aspartic acid-valine. J Biol Chem 266: 15075–15079PubMedGoogle Scholar
  45. Krissansen GW, Elliot MJ, Lucas CM, Stomski FC, Berndt MC, Cheresh DA, Lopez AF, Burns GF (1990) Identification of a novel integrin β subunit expressed on cultured monocytes (macrophages). J Biol Chem 265: 823–830PubMedGoogle Scholar
  46. Kupfer A, Singer J (1989) Cell biology of cell couples. Ann Rev Immunol 7: 309–337CrossRefGoogle Scholar
  47. Larjava H, Peltonen J, Akiyama SK, Yamada SS, Gralnick HR, Uitto J, Yamada KM (1990) Novel function for β1 integrins in keratinocyte cell-cell interactions. J Cell Biol 110: 803–815PubMedCrossRefGoogle Scholar
  48. McDonald JA (1989) Receptors for extracellular matrix components. Am J Physiol 257: L331 - L337PubMedGoogle Scholar
  49. McDonald JA, Quade BJ, Broekelmann TJ, LaChance R, Forsman K, Hasegawa E, Akiyama S (1987) Fibronectin’s cell-ahesive domain and an amino-terminal matrix assembly domain participate in its assembly into fibroblast pericellular matrix. J Biol Chem 262: 2957–2967PubMedGoogle Scholar
  50. McGregor BC, McGregor JL, Weiss LM, Wood GS, Hu C, Boukerche H, Warnke R (1989) Presence of cytoadhesins ( IIb IIIa like glycoproteins) on human metastatic melanomas but not on benign melanocytes. Am J Clin Pathol 92: 495–499PubMedGoogle Scholar
  51. Mortarini R, Anichini A, Parmiani G (1991) Heterogeneity for integrin expression and cytokine-mediated VLA modulation can influence the adhesion of human melanoma cells to extracellular matrix proteins. Int J Cancer 47: 551–559PubMedCrossRefGoogle Scholar
  52. Natali P, Nicotra M, Cavaliere R, Bigotti A, Romano G, Temponi M, Ferrone S (1990) Differential expression of intercellular adhesion molecule 1 in primary and metastatic melanoma lesions. Cancer Res 50: 1271–1278PubMedGoogle Scholar
  53. Nowell PC (1986) Mechanisms of tumor progression. Cancer Res 46: 2203–2207PubMedGoogle Scholar
  54. Osborn L, Hession C, Tizard R, Vassallo C, Luhowskyj S, Chi-Rosso G, Lobb RR (1989) Direct cloning of vascular cell adhesion molecule-1, a cytokine induced endothelial protein that binds to lymphocytes. Cell 59: 1203–1211PubMedCrossRefGoogle Scholar
  55. Perrotti D, Cimino L, Tibursi RFG, Gentileschi MP, Sacchi A (1990) Metastatic phenotype: growth factor dependence and integrin expression. Anticancer Res 10: 1587–1598PubMedGoogle Scholar
  56. Plantefaber LC, Hynes R (1989) Changes in integrin receptors on oncogenically transformed cells. Cell 56: 281–290PubMedCrossRefGoogle Scholar
  57. Pytela R (1988) Amino acid sequence of the murine Mac-1 α chain reveals homology with the integrin family and an additional domain related to von Willebrand factor. EMBO J 7: 1371–1378PubMedGoogle Scholar
  58. Quaranta V, Jones JCR (1991) The internal affairs of an integrin. Trends Cell Biol 1: 2–4PubMedCrossRefGoogle Scholar
  59. Real FX, Rettig WJ, Garin Chesa P, Melamed MR, Old LJ, Mendelsohn J (1986) Expression of epidermal growth factor receptor in human cultured cells and tissues. Cancer Res 46: 4726–4731PubMedGoogle Scholar
  60. Ruiter DJ, Dingjan GM, Steylen PM, Van Beveren-Hooijer M, De Graaff-Reitsma CB, Bergman W, Van Muyen GNP, Warnaar SO (1985) Monoclonal antibodies selected to discriminate between malignant melanomas and nevocellular nevi. J Invest Dermatol 85: 4–8PubMedCrossRefGoogle Scholar
  61. Ruoslahti E, Pierschbacher MD (1987) New perspectives in cell adhesion. Science 283: 491–497CrossRefGoogle Scholar
  62. Sheppard D, Rozzo C, Starr L, Quaranta V, Erie DJ, Pytela R (1990) Complete amino acid sequence of a novel integrin β subunit (β6) identified in epithelial cells using the polymerase chain reaction. J Biol Chem 265: 11502–11507PubMedGoogle Scholar
  63. Springer TA (1990) Adhesion receptors of the immune system. Nature 346: 425–434PubMedCrossRefGoogle Scholar
  64. Takeichi M (1991) Cadherin cell adhesion receptors as a morphogenetic regulator. Science 251: 1451–1455PubMedCrossRefGoogle Scholar
  65. Tamkun JW, DeSimone DW, Fonda D, Patel RS, Buck C, Horwitz AF, Hynes RO (1986) Structure of integrin, a glycoprotein involved in the transmembrane linkage between fibronectin and actin. Cell 46: 271–282PubMedCrossRefGoogle Scholar
  66. Terranova VP, Liotta LA, Russo RG, Martin GR (1982) Role of laminin in the attachment and metastasis of murine tumor cells. Cancer Res 42: 2265–2269PubMedGoogle Scholar
  67. Terranova VP, Rao CN, Kalebic T, Margulies IMK, Liotta LA (1983) Laminin receptor on human breast carcinoma cells. Proc Natl Acad Sci USA 80: 444–451PubMedCrossRefGoogle Scholar
  68. Tetteroo PAT, Lansdorp PM, Leeksma OC, Von dem Borne AEG (1983) Monoclonal antibodies against human platelet glycoprotein IIIa. Br J Haematol 55: 509PubMedCrossRefGoogle Scholar
  69. Van Kooyk Y, van de Wiel-van Kemenade P, Weder P, Kuijpers TW, Figdor CG (1989) Enhancement of LFA-1-mediated cell adhesion by triggering through CD2 or CD2 on T lymphocytes. Nature 342: 811–813PubMedCrossRefGoogle Scholar
  70. Van Muijen GNP, Ruiter DJ, Hoefakker S, Johnson JP (1990) Monoclonal antibody PAL-M1 recognizes the transferrin receptor and is a progression marker in melanocytic lesions. J Invest Dermatol 95: 65–69PubMedCrossRefGoogle Scholar
  71. Van Muijen GNP, Cornelissen LMHA, Jansen CFJ, Figdor CG, Johnson JP, Bröcker E, Ruiter DJ (1991) Antigen expression of metastasizing and non-metastasizing human melanoma cells xenografted into nude mice. Clin Exp Metastasis 9: 259–272PubMedCrossRefGoogle Scholar
  72. Van Waes C, Kozarsky KF, Warren AB, Kidd L, Paugh D, Liebert M, Carey TE (1991) The A9 antigen associated with aggressive human squamous carcinoma is structurally and functionally similar to newly defined integrin α6β4. Cancer Res 51: 2395–2402PubMedGoogle Scholar
  73. Vleminckx K, Vakaet L, Mareel M, Fiers W, Van Roy F (1991) Genetic manipulation of E-cadherin expression by epithelial tumor cells reveals an invasion supressor role. Cell 66: 107–119PubMedCrossRefGoogle Scholar
  74. Vogel BE, Tarone G, Giancotti FG, Gailit J, Ruoslahti E (1990) A novel fibronectin receptor with an unexpected subunit composition (αvβ1). J Biol Chem 265: 5934–5937PubMedGoogle Scholar
  75. Wayner EA, Garcia-Pardo A, Humphries MJ, McDonald JA, Carter WG (1989) Identification and characterization of the T-lymphocyte adhesion receptor for an alternative cell attachment domain (CS-1) in plasma fibronectin. J Cell Biol 109: 1321–1330PubMedCrossRefGoogle Scholar
  76. Zutter MM, Mazouijan G, Santoro SA (1990) Decreased expression of integrin adhesive receptors in adenocarcinoma of the breast. Am J Pathol 137: 863–870PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin · Heidelberg 1993

Authors and Affiliations

  • E. H. J. Danen
    • 1
  • G. N. P. van Muijen
    • 1
  • P. J. M. ten Berge
    • 1
  • D. J. Ruiter
    • 1
  1. 1.Department of PathologyUniversity Hospital NijmegenNijmegenThe Netherlands

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