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Role of collagenases in tumor cell invasion

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Summary

Collagenases are a family of metalloproteinases which may play a role in facilitating tumor cell invasion of the extracellular matrix. Tumor cells traverse two types of extracellular matrix: basement membranes and interstitial stroma, at multiple stages of the metastatic process. The matrix is a dense meshwork of collagen, proteoglycans, elastin and glycoproteins. Normally the matrix does not contain open spaces large enough for cell movement. Therefore numerous investigators have postulated that collagenolytic proteases, secreted by tumor cells or associated host cells, breakdown the extracellular matrix during tumor cell invasion. A large number of animal and human tumors have been shown to contain collagenase at a higher level than corresponding benign tissues. Separate collagenolytic metalloproteinases have been identified which degrade specific types of collagen. A basement membrane collagenolytic protease was shown to be elevated in a series of metastatic murine tumor cells. Immunologic studies using antibodies specific for collagenase have demonstrated that in vivo, tumor cells can produce collagenase. Therefore identification of collagenase in cultured lines of tumor cells is not an artifact of in vitro cultivation. In some cases, tumor cells may induce host cells to produce collagenase. The best evidence to date that collagenases actually play a role in invasion is derived from experiments in which natural collagenase inhibitors block tumor cell invasion of extracellular matrix in vitro.

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References

  1. Hay ED: Cell biology of extracellular matrix. Plenum, New York, 1982

    Google Scholar 

  2. Kleinman HK, Klebe RJ, Martin GR: Role of collagenous matrices in the adhesion and growth of cells. J Cell Biol 88: 473–485, 1981.

    Google Scholar 

  3. Vracko R: Basal lamina scaffold-anatomy and significance for maintenance of orderly tissue structures. Am J Pathol 77: 313–338, 1974.

    Google Scholar 

  4. Bornstein P, Sage H: Structurally distinct collagen types. Ann Rev Biochem 49: 957–1003, 1980.

    Google Scholar 

  5. Bernfield MR, Banerjee SD, Cohn RH: Dependence of salivary epithelial morphology and branching morphogenesis upon acid mucopolysaccharide protein at the epithelial surface. J Cell Biol 52: 675, 1972.

    Google Scholar 

  6. Kanwar Y, Farquhar MG: Isolation of glycosaminoglycans (heparan sulfate) from glomerular basement membranes. Proc Natl Acad Sci USA 76: 4493–4497, 1979.

    Google Scholar 

  7. Gospodarowicz D, Greenburg G, Birdwell CR: Determination of cellular shape by the extracellular matrix and its correlation with the control of cellular growth. Cancer Res 38: 4155–4171, 1978.

    Google Scholar 

  8. Hascall VC, Hascall GK: Proteoglycans. In: Hay EC, (ed) Cell biology of extracellular matrix. Plenum, New York, pp. 39–63, 1982.

    Google Scholar 

  9. Kefalides NA, Alper R, Clark CC: Biochemistry and metabolism of basement membranes. Int Rev Cytol 61: 167–228, 1979.

    Google Scholar 

  10. Hassell JR, Gehron Robey P, Barrach H-J, Wilczek J, Rennard SI, Martin GR: Isolation of a heparan sulfate-containing proteoglycan from basement membrane. Proc Natl. Acad Sci USA 77: 4494, 1980.

    Google Scholar 

  11. Carlin B, Jaffee R, Bender B, Chung EE: Entactin, a novel basal lamina-associated sulfated glycoprotein. J Biol Chem 256: 5209–5214, 1981.

    Google Scholar 

  12. Timpl R, Rhode H, Gehron Robey P, Rennard SI, Foidart JM, Martin GR: Laminin — a glycoprotein from basement membranes. J Biol Chem 254: 9933–9937, 1979.

    Google Scholar 

  13. Martinez-Hernandez A, Gay S, Miller EJ: Ultrastructural localization type V collagen in rat kidney. J Cell Biol 92: 343–349, 1982.

    Google Scholar 

  14. Roll RJ, Madri JA, Alberta J, Furthmayr H: Codistribution of collagen types IV and AB2 in basement membranes and mesangium of the kidney. J Cell Biol 85: 597–616, 1980.

    Google Scholar 

  15. Miller EJ, Lunde L: Isolation and characterization of the cyanogen bromide peptides from the α1 (II) chain of bovine and human cartilage collagen. Biochemistry 12: 3153–3159, 1973.

    Google Scholar 

  16. Liotta LA, Wicha MS, Foidart JM, Rennard SI, Garbisa S, Kidwell WR: Hormonal requirements for basement membrane collagen deposition by cultured rat mammary epithelium. Lab Invest 41: 511–518, 1979.

    Google Scholar 

  17. Stenman S, Vaheri AL: Distribution of a major connective tissue protein, fibronectin, in normal human tissue. J Exp Med 147: 1054–1064, 1978.

    Google Scholar 

  18. Alitalo K, Keski-Oja J, Waheri A: Extracellular matrix proteins characterize human tumor cell lines. Int J Cancer 27: 733–741, 1981.

    Google Scholar 

  19. Al-Adnani MS, Kirrane JA, McGee JO'D: Inappropriate production of collagen and prolyl hydroxyproline by human breast cancer cells in vivo. Br J Cancer 31: 653–660, 1975.

    Google Scholar 

  20. Jackson JG, Orr JW: The ducts of carcinomatous breasts with particular reference to connective tissue changes. J Pathol Bacteriol 74: 265–273, 1957.

    Google Scholar 

  21. Azzopardi JG: Problems in breast pathology. WB Saunders, Philadelphia, pp. 242–393, 1979.

    Google Scholar 

  22. Barsky SH, Rao CN, Grotendorst GR, Liotta LA: Increased content of type V collagen in desmoplasia of human breast carcinoma. Am J Pathol 108: 276–283, 1982.

    Google Scholar 

  23. Dvorak HF, Dickersin GR, Dvorak AM, Manseau EJ, Pyne K: Human breast carcinoma: fibrin deposits and desmoplasia. Inflammatory cell type and distribution. Microvasculature and infarction. J Natl Cancer Inst 67: 335, 1981.

    Google Scholar 

  24. Siegal GP, Barsky SH, Terranova VP, Liotta LA: Stages of neoplastic transformation of human breast tissue as monitored by dissolution of basement membrane components. Invasion Metastasis 1: 54–70, 1981.

    Google Scholar 

  25. Woolley DE, Tetlow LC, Mooney CJ, Evanson JM: Human collagenase and its extracellular inhibitors in relation to tumor invasiveness. In: Strand P, Barrett AJ, Baiei A (eds) Proteinases and tumor invasion. Raven Press, New York, p. 97–113, 1980.

    Google Scholar 

  26. Pearce RH, Laurent TC: Exlusion of dextrans by meshworks of collagenous fibers. Biochem J 163: 617–625, 1977.

    Google Scholar 

  27. Timpl R, Wiedemann H, Van Delden V, Furthmayr H, Kuhn K: A network model for the organization of type IV collagen molecules in basement membranes. Eur J Biochem 120: 203–211, 1981.

    Google Scholar 

  28. Garbisa S, Liotta LA, Tryggvason K, Siegal GP: Antibodies to collagenase resistant terminal regions of protype IV collagen recognize whole basement membrane and 7-S collagen. FEBS Lett 127: 257–262, 1981.

    Google Scholar 

  29. Rao CN, Margulies IMK, Tralka TS, Terranova VP, Madri JA, Liotta LA: Isolation of a subunit of laminin and its role in tumor cell attachment. J Biol Chem 257: 9740–9744, 1982.

    Google Scholar 

  30. Terranova VP, Rohrbach DH, Martin GR: Role of laminin in the attachment of PAM 212 (epithelial) cells to basement membrane collagen. Cell 22: 719–726, 1980.

    Google Scholar 

  31. Terranova VP, Liotta LA, Russo RG, Martin GR: Role of laminin in the attachment and metastasis of murine tumor cells. Cancer Res 42: 2265–2269, 1982.

    Google Scholar 

  32. Thorgeirsson UP, Liotta LA, Kalebic T, Margulies IM, Thomas K, Riescandelore M, Russo RG: Effect of natural protease inhibitors and a chemoattractant on tumor cell invasion in vitro. J Natl Cancer Inst, Nov 1982.

  33. Jones PA, DeClark YA: Destruction of extracellular matrices containing glycoproteins, elastin and collagen by metastatic human tumor cells. Cancer Res 40: 3222–3227, 1980.

    Google Scholar 

  34. Kramer RH, Nicolson GL: Invasion of vascular endothelial cell monolayers and underlying matrix by metastatic human cancer cells. In: Schweiger HG (ed). Int Cell Biol. Springer-Verlag, Berlin, pp. 794–799, 1981.

    Google Scholar 

  35. Kramer RH, Gonzalez R, Nicolson GL: Metastatic tumor cells adhere preferentially to the extracellular matrix underlying vascular endothelial cells. Int J Cancer 26: 639–645, 1980.

    Google Scholar 

  36. Nicolson GL: Cancer metastasis: organ colonization and the cell surface properties of malignant cells. Biochem Biophys Acta Rev Cancer (in press).

  37. Russo RG, Thorgeirsson UP, Liotta LA: In vitro quantitative assay of invasion using human amnion. In: Liotta LA, Hart IR (eds) Tumor invasion and metastases. Martinus Nijhoff, The Hague, pp. 173–187, 1982.

    Google Scholar 

  38. Russo RG, Liotta LA, Thorgeirsson UP, Brundage R, Schiffmann E: Polymorphonuclear leukocyte migration through human amnion membrane. J Cell Biol 91: 459–467, 1981.

    Google Scholar 

  39. Russo RG, Thorgeirsson UP, Schiffmann E, Liotta LA: Human amnion assay: a new method for quantitating cell invasiveness in vitro. J Cell Biol (91) (2,Pt.2): 152a (abstr), 1981.

  40. Garbisa S, Kniska K, Tryggvason K, Foltz C, Liotta LA: Quantitation of basement membrane collagen degradation by tumor cells in vitro. Cancer Lett 9: 359–366, 1980.

    Google Scholar 

  41. Birbeck MSC, Wheatley DN: An electron microscopic study of the invasion of ascites tumour cells into the abdominal wall. Cancer Res 25: 490–497, 1965.

    Google Scholar 

  42. Robertson DM, Williams DC: In vitro evidence of neutral collagenase activity in an invasive mammalian tumor. Nature London 221: 259–260, 1969.

    Google Scholar 

  43. Taylor AC, Levy BM, Simpson JW: Collagenolytic activity of sarcoma tissues in culture. Nature London 228: 366–367, 1970.

    Google Scholar 

  44. Dresden MH, Heilman SA, Schmidt JD: Collagenolytic enzymes in human neoplasms. Cancer Res 32: 993–996, 1972.

    Google Scholar 

  45. Bauer EA, Gordon JM, Reddick ME, Eisen AZ: Quantitation and immunocytochemical localization of human skin collagenase in basal cell carcinoma. J Invest Dermatol 69: 363–367, 1977.

    Google Scholar 

  46. Harris EDJr, Faulkner CS, Wood SJr: Collagenase in carcinoma cells. Biochem Biophys Res Commun 48: 1247–1253, 1972.

    Google Scholar 

  47. Hashimoto K, Yamanishi Y, Maeyens E, Dabbous MK, Kanzaki T: Collageolytic activities of squamous-cell carcinoma of skin. Cancer Res 33: 2790–2801, 1973.

    Google Scholar 

  48. Kuettner KE, Soble L, Croxen RL, Marczynska B, Hiti J, Harper E: Tumour cell collagenase and its inhibition by a cartilage-derived protease inhibitor. Science 196: 653–654, 1977.

    Google Scholar 

  49. Liotta LA, Kleinerman J, Catanzaro P, Rynbrandt D: Degradation of basement membrane collagen by murine tumor cells. J Natl Cancer Inst 58: 1427–1431, 1977.

    Google Scholar 

  50. Murphy G, Sellers A: The extracellular regulation of collagenase activity. In: Woolley DE, Evanson JM, (eds) Collagenase in normal and pathological connective tissues. Wileys, Chichester, pp. 65–81, 1980.

    Google Scholar 

  51. Reynolds JJ, Sellers A, Murphy G, Cartwright E: New factor that may control collagen resorption. Lancet 2: 333–335, 1977.

    Google Scholar 

  52. Riley WB, Peacock EEJr: Identification, distribution, and significance of a collagenolytic enzyme in human tissues. Proc Soc Exp Biol Med 124: 207–210, 1977.

    Google Scholar 

  53. Tane N, Hashimoto K, Kanzaki T, Ohyama H: Collagenolytic activities of cultured human malignant melanoma cells. J Biochem 84: 1171–1176, 1978.

    Google Scholar 

  54. Yamanishi Y, Dabbous MK, Hashimoto K: Effect of collagenolytic activity in basal cell epithelioma of the skin on reconstituted collagen and physical properties and kinetics of the crude enzyme. Cancer Res 32: 2551–2560, 1972.

    Google Scholar 

  55. McCroskery PA, Richards JF, Harris EDJr: Purification and characterisation of a collagenase extracted from rabbit tumours. Biochem J 152: 131–142, 1975.

    Google Scholar 

  56. Biswas C, Moran WP, Bloch KJ, Gross J: Collagenolytic activity of rabbit V2-carcinoma growing at multiple sites. Biochem Biophys Res Commun 80: 33–38, 1978.

    Google Scholar 

  57. Wirl G: Extractable collagenase and carcinogenesis of the mouse skin. Connect Tissue Res 5: 171–178, 1977.

    Google Scholar 

  58. Abramson M, Schilling RW, Huang CC, Salome RG: Collagenase activity in epidermoid carcinoma of the oral cavity and larynx. Ann Otol Rhinol Laryngol 84: 158–162, 1975.

    Google Scholar 

  59. Hashimoto K, Yamanishi Y, Dabbous MK: Electron microscopic observations of collagenolytic activity of basal cell epithelioma of the skin in vivo and in vitro. Cancer Res 32: 2561–2567, 1972.

    Google Scholar 

  60. Ohyama H, Hashimoto K: Collagenase of human skin basal cell epithelioma. J Biochem 82: 175–184, 1977.

    Google Scholar 

  61. Yamanishi Y, Maeyens E, Dabbous MK, Ohyama H, Hashimoto K: Collagenolytic activity in a malignant melanoma: physiochemical studies. Cancer Res 33: 2507–2512, 1973.

    Google Scholar 

  62. Gross J, Nagai Y: Specific degradation of the collagen molecule by tadpole collagenolytic enzyme. Proc Natl Acad Sci USA 54: 1197–1204, 1965.

    Google Scholar 

  63. Eisen AZ, Jeffrey JJ, Gross J: Human skin collagenase isolation and mechanism at attack on the collagen molecule. Biochem Biophys Acta 151: 637–645, 1968.

    Google Scholar 

  64. Woolley DE, Glanville RW, Roberts DR, Evanson JM: Purification, characterization and inhibition of human skin collagenase. Biochem J 169: 265–276, 1978.

    Google Scholar 

  65. McCroskery PA, Richards JF, Harris EDJr: Gelatin: a poor substrate for mammalian collagenase. Science 182: 70–71, 1975.

    Google Scholar 

  66. Woolley DE, Glanville RW, Crossley MJ, Evanson JM: Purification of rheumatoid synovial collagenase and its action on soluble and insoluble collagen. Eur J Biochem 54: 611–622, 1975.

    Google Scholar 

  67. Woolley DE, Glanville RW, Evanson JM: Differences in the physical properties of collagenases isolated from rheumatoid synovium and human skin. Biochem Biophys Res Commun 51: 729–734, 1973.

    Google Scholar 

  68. Stricklin GP, Bauer EA, Jeffrey JJ, Eisen AZ: Human skin collagenase: isolation of precursor and active forms from both fibroblast and organ cultures. Biochem 16: 1607–1615, 1977.

    Google Scholar 

  69. Birkedal-Hansen H, Cobb CM, Taylor RE, Fullmer HM: Procollagenase from bovine gingiva. Biochem Biophys Acta 429: 229–238, 1976.

    Google Scholar 

  70. Huang HC, Wu CH, Abramson M: Collagenase activity in cultures of rat prostate carcinoma. Biochem Biophys Acta 570: 149–156, 1979.

    Google Scholar 

  71. Liotta LA, Abe S, Gehron-Robey P, Martin GR: Preferential digestion of basement membrane collagen by an enzyme derived from a metastatic murine tumor. Proc Natl Acad Sci USA 76: 2268–2272, 1979.

    Google Scholar 

  72. Welgus HG, Jeffrey JJ, Eisen AE: The collagen substrate specificity of human skin fibroblast collagenase. J Biol Chem 256: 9511–9515, 1981.

    Google Scholar 

  73. Liotta LA, Tryggvason K, Garbisa S, Gehron-Robey P, Abe S: Partial purification and characterization of a neutral protease which cleaves type IV collagen. Biochemistry 20: 100–104, 1981.

    Google Scholar 

  74. Liotta LA, Tryggvason K, Garbisa S, Hart I, Foltz CM, Shafie S: Metastatic potential correlates with enzymatic degradation of basement membrane collagen. Nature London 284: 67–68, 1980.

    Google Scholar 

  75. Liotta LA, Lanzer WL, Garbisa S: Identification of a type V collagenolytic enzyme. Biochem Biophys Res Commun 98: 184–190, 1981.

    Google Scholar 

  76. Liotta LA, Kalebic T, Reese CA, Mayne R: Protease susceptibilities of HMW, 1α, 2α, but not 3α cartilage collagens are similar to type V collagen. Biochem Biophys Res Commun 104: 500–505, 1982.

    Google Scholar 

  77. Mainardi LL, Seyer JM, Kang AH: Type specific collagenolysis: identification of a type V degrading activity in alveolar macrophages. Biochem Biophys Res Commun 97: 1108–1115, 1980.

    Google Scholar 

  78. Vaes G: The release of collagenase as an inactive proenzyme by bone explants in culture. Biochem J 126: 275–289, 1972.

    Google Scholar 

  79. Harper E, Gross J: Collagenase, procollagenase and activator relationships in tadpole tissue cultures. Biochem Biophys Res Commu 48: 1147–1152, 1972.

    Google Scholar 

  80. Sellers A, Cartwright E, Murphy G, Reynolds JJ: Evidence that latent collagenases are enzyme-inhibitor complexes. Biochem J 163: 303–307, 1977.

    Google Scholar 

  81. Harper E, Block KJ, Gross J: The zymogen of tadpole collagenase. Biochem J 10: 3035–3041, 1971.

    Google Scholar 

  82. Vater CA, Mainardi LL, Harris EDJr: Binding of latent rheumatoid synovial collagenase to collagen fibrils. Biochem Biophys Acta 539: 238–247, 1978.

    Google Scholar 

  83. Werb Z, Burleigh MC, Barrett AJ, Starkey PM: The interactions of 288–1 with proteinases. Binding and inhibition of mammalian collagenases and other metal proteinases. Biochem J 139: 359–368, 1974.

    Google Scholar 

  84. Woolley DE, Roberts DR, Evanson JM: Small molecular weight 288–2 serum protein which specifically inhibits human collagenases. Nature London 261: 325–327, 1976.

    Google Scholar 

  85. Kuettner KE, Hiti J, Eisenstein R, Harper E: Collagenase inhibition by cationic proteins derived from cartilage and aorta. Biochem Biophys Res Commun 72: 40–47, 1976.

    Google Scholar 

  86. Cawston TE, Galloway WA, Merger E, Murphy G, Reynolds JJ: Purification of rabbit bone inhibiton of collagenase. Biochem J 195: 159–165, 1981.

    Google Scholar 

  87. Murphy G, Cawston TE, Reynolds JJ: An inhibitor of collagenase from human amniotic fluid. Biochem J 195: 167–170, 1981.

    Google Scholar 

  88. Nolan JC, Ridge S, Oronsky AL, Klakey LL, Kerwar SS: Synthesis of a collagenase inhibitor by smooth muscle cells in culture. Biochem Biophys Res Commun 83: 1183–1190, 1978.

    Google Scholar 

  89. Pauli BU, Memoli VH, Kuettner KE: In vitro determination of tumor invasiveness using extracted hyaline cartilage. Cancer Res 41: 2084–2091, 1981.

    Google Scholar 

  90. DeVore DP, Houchens DP, Ovejera AA, Dill GS, Hutson TB: Collagenase inhibitors retarding invasion of a human tumor in nude mice. Expl Cell Biol 48: 367–373, 1980.

    Google Scholar 

  91. Woolley DE: Collagenase immunologicalization studies of human tumours. Liotta LA, Hart IR (eds) Tumor invasion and metastasis. Martinus Nijhoff, The Hague, 1982.

    Google Scholar 

  92. Biswas C: Host-tumor cell interactions and collagenase activity. Liotta LA, Hart IR (eds) Tumor invasion and metastasis. Martinus Nijhoff, The Hague, pp. 405–425, 1982.

    Google Scholar 

  93. Gadek JE, Fells GA, Wright DG, Crystal RG: Human neutrophil elastase functions as a type III collagen ‘collagenase’. Biochem Biophys Res Commun 95: 1815–1822, 1980.

    Google Scholar 

  94. Mainardi CL, Hasty DL, Seyer JM, Kang AH: Specific cleavage of human type III collagen by human polymorphonuclear leukocyte elastase. J Biol Chem 255: 2006–2010, 1981.

    Google Scholar 

  95. Uitto V-J, Schwartz D, Veis A: Degradation of basement membrane collagen by neutral proteases from human granulocytes. Eur J Biochem 105: 409–417, 1980.

    Google Scholar 

  96. Mainardi CL, Dixit SN, Kang AH: Degradation of (type IV) basement membrane collagen by a proteinase isolated from human polymorphonuclear leucocyte granules. J Biol Chem 255: 5435–5441, 1980.

    Google Scholar 

  97. Horwitz AL, Hance AJ, Crystal RG: Granulocyte collagenase: selective digestion of type I relative to type III collagen. Proc Natl Acad Sci USA 74: 897–901, 1977.

    Google Scholar 

  98. Liotta LA, Goldfarb RH, Brundage R, Siegal GP, Terranova V, Garbisa S: Effect of plasminogen activator (urokinase), plasmin, and thrombin on glycoprotein and collagenous components of basement membrane. Cancer Res 41: 4629–4636, 1981.

    Google Scholar 

  99. Sage H, Bornstein P: Characterization of a novel collagen chain in human placenta and its relation to AB collagen. Biochemistry 18: 3815–3822, 1979.

    Google Scholar 

  100. Fidler IJ, Gersten DM, Hart IR: The biology of cancer invasion and metastasis. Adv Cancer Res 28: 149–250, 1978.

    Google Scholar 

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Authors and Affiliations

  1. Laboratory of Pathology, Section of Tumor Invasion and Metastases, NCI, NIH, 20205, Bethesda, Maryland, USA

    Lance A. Liotta & Unnur P. Thorgeirsson

  2. Histology and General Embryology Institute, Padova University, Italy

    Spiridione Garbisa

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  1. Lance A. Liotta
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  2. Unnur P. Thorgeirsson
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  3. Spiridione Garbisa
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Liotta, L.A., Thorgeirsson, U.P. & Garbisa, S. Role of collagenases in tumor cell invasion. Cancer Metast Rev 1, 277–288 (1982). https://doi.org/10.1007/BF00124213

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