Tumoral invasion in the central nervous system

  • Yves A. De Clerck
  • Hiroyuki Shimada
  • Ignacio Gonzalez-Gomez
  • Corey Raffel


During growth, migration and differentiation, cells closely interact with the extracellular matrix (ECM). The harmony between cells and their environment is a key factor that maintains the normal architecture of tissues. Loss of growth control is not the only characteristic of oncogenesis, loss of control by the ECM is an important event that allows malignant cells to further progress toward invasion and metastasis. Changes in cell adhesion, proteolytic degradation of the ECM and cell migration have all been described during invasion of most tissues by tumor cells. However little is known of these changes in tumors of the central nervous system (CNS). Although brain tumor cells may share some of the invasive characteristics of tumors that arise outside the CNS, the particular structure and composition of the brain ECM suggest the existence of unique invasive mechanisms in these tumors. Furthermore, the interaction between brain tumor cells and their ECM may explain the intriguing observation that despite their highly invasive behavior, these cells remain poorly metastatic. This review focuses on biochemical mechanisms essential for tumor invasion and how they relate to invasion of tumors that arise in the CNS.

Key words

tumor invasion extracellular matrix metastasis central nervous system brain tumor 


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  1. 1.
    Folkman J, Shing Y: Angiogenesis. J Biol Chem 267: 10931–10934, 1992PubMedGoogle Scholar
  2. 2.
    Liotta LA, Steeg PS, Stetler Stevenson WG: Cancer metastasis and angiogenesis: an imbalance of positive and negative regulation. Cell 64: 327–336, 1991PubMedCrossRefGoogle Scholar
  3. 3.
    Yagel S, Parhar RS, Jeffrey JJ, Lala PK: Normal nonmeta-static human trophoblast cells share in vitro invasive properties of malignant cells. J Cell Physiol 136: 455–462, 1988PubMedCrossRefGoogle Scholar
  4. 4.
    Liotta LA, Stetler Stevenson WG, Steeg PS: Cancer invasion and metastasis: positive and negative regulatory elements. Cancer Invest 9: 543–551, 1991PubMedCrossRefGoogle Scholar
  5. 5.
    Liotta LA: Tumor invasion and metastases — role of the extracellular matrix: Rhoads Memorial Award lecture. Cancer Res 46: 1–7, 1986PubMedCrossRefGoogle Scholar
  6. 6.
    Dedhar S: Integrins and tumor invasion. Bioessays 12: 583–590, 1990PubMedCrossRefGoogle Scholar
  7. 7.
    Dedhar S, Saulnier R: Alterations in integrin receptor expression on chemically transformed human cells: specific enhancement of laminin and collagen receptor complexes. J Cell Biol 100: 481–489, 1990CrossRefGoogle Scholar
  8. 8.
    Horan HP, Thor A, Scholm J, Rao CN, Liotta LA: Expression of laminin receptor in normal and carcinomatous human tissues as defined by a monoclonal antibody. Cancer Res 45: 2713–2719, 1985Google Scholar
  9. 9.
    Hirst R, Horwitz R, Buck C, Rohrschreider L: Phosphorylation of the fibronectin receptor complex in cells transformed by oncogenes that encode tyrosine kinases. Proc Natl Acad Sci USA 70: 3170–3174, 1986Google Scholar
  10. 10.
    Werb Z, Tremble PM, Behrendtsen O, Crowley E, Damsky CH: Signal transduction through the fibronectin receptor induces collagenase and stromelysin gene expression. J Cell Biol 109: 877–889, 1989PubMedCrossRefGoogle Scholar
  11. 11.
    Seftor RB, Seftor EA, Gehlsen KR, Stetler Stevenson WG, Brown PD, Ruoslahti E, Hendrix MJC: Role of the α vβ3 integrin in human melanoma invasion. Proc Natl Acad Sci USA 89: 1557–1561, 1992PubMedCrossRefGoogle Scholar
  12. 12.
    Guirguis R, Margulies I, Taraboletti G, Schiffmann E, Liotta L: Cytokine-induced pseudopodial protrusion is coupled to tumour cell migration. Nature 329: 261–263, 1987PubMedCrossRefGoogle Scholar
  13. 13.
    Gottesman MM: The role of proteases in cancer. Seminars in Cancer Biology. W.B. Saunders. Philadelphia. 1990. pp. 97–160Google Scholar
  14. 14.
    Murphy G, Cockett MI, Ward RV, Docherty AJ: Matrix metalloproteinase degradation of elastin, type IV collagen and proteoglycan. A quantitative comparison of the activities of 95 kDa and 72 kDa gelatinases, stromelysins-1 and -2 and punctuated metalloproteinase (PUMP). Biochem J 277: 277–279, 1991PubMedGoogle Scholar
  15. 15.
    Matrisian LM: The matrix degrading metalloproteinases. Bioessays 14: 455–463, 1992PubMedCrossRefGoogle Scholar
  16. 16.
    Goldfarb RH, Liotta LA: Proteolytic enzymes in cancer invasion and metastasis. Semin Thromb Hemost 12: 294–307, 1986PubMedCrossRefGoogle Scholar
  17. 17.
    Blasi F: Surface receptors for urokinase plasminogen activator. Fibrinolysis 2: 73–84, 1988Google Scholar
  18. 18.
    Miles LA, Plow EP: Plasminogen receptors: ubiquitous sites for cellular regulation of fibrinolysis. Fibrinolysis 2: 61–71, 1988Google Scholar
  19. 19.
    Sloane BF: Cathepsin B and cystatins: evidence for a role in cancer progression. Semin Cancer Biol 1: 137–152, 1990PubMedGoogle Scholar
  20. 20.
    Rochefort H, Capony F, Garcia M: Cathepsin D: a protease involved in breast cancer metastasis. Cancer Metast Rev 9: 321–331, 1990CrossRefGoogle Scholar
  21. 21.
    De Clerck YA, Laug WE: The role of the extracellular matrix in tumor invasion, metastasis and angiogenesis. Teicher BA. Drug Resistance in Oncology. Marcel Dekker. NY. 1993. pp. 121–163Google Scholar
  22. 22.
    Liotta LA, Mandler R, Murano G, Katz DA, Gordon RK, Chiang PK, Schiffmann E: Tumor cell autocrine motility factor. Proc Natl Acad Sci USA 83: 3302–3306, 1986PubMedCrossRefGoogle Scholar
  23. 23.
    Barsky SH, Rao CN, Williams JE, Liotta LA: Laminin molecular domains which alter metastasis in a murine model. Lab Invest 74: 843–848, 1984Google Scholar
  24. 24.
    Humphries MJ, Olden K, Yamada KM: A synthetic peptide from fibronectin inhibits experimental metastasis of murine melanoma cells. Science 233: 467–470, 1986PubMedCrossRefGoogle Scholar
  25. 25.
    Vollmers HP, Birchmeier W: Cell adhesion and metastasis: a monoclonal antibody approach. Trend Biochem Sci 376: 452–455, 1983CrossRefGoogle Scholar
  26. 26.
    Reich R, Thompson EW, Iwamoto Y, Martin GR, Deason JR, Fuller GC, Miskin R: Effects of inhibitors of plasminogen activator, serine proteinases, and collagenase IV on the invasion of basement membranes by metastatic cells. Cancer Res 48: 3307–3312, 1988PubMedGoogle Scholar
  27. 27.
    Yagel S, Warner AH, Nellans HN, Lala PK, Waghorne C, Denhardt DT: Suppression by cathepsin L inhibitors of the invasion of amnion membranes by murine cancer cells. Cancer Res 49: 3553–3557, 1989PubMedGoogle Scholar
  28. 28.
    Albini A, Melchiori A, Santi L, Liotta LA, Brown PD, Stetler Stevenson WG: Tumor cell invasion inhibited by TIMP-2. J Natl Cancer Inst 83: 775–779, 1991PubMedCrossRefGoogle Scholar
  29. 29.
    Alvarez OA, Carmichael DF, DeClerck YA: Inhibition of collagenolytic activity and metastasis of tumor cells by a recombinant human tissue inhibitor of metalloproteinases. J Natl Cancer Inst 82: 589–595, 1990PubMedCrossRefGoogle Scholar
  30. 30.
    DeClerck YA, Yean TD, Chan D, Shimada H, Langley KE: Inhibition of tumor invasion of smooth muscle cell layers by recombinant human metalloproteinase inhibitor. Cancer Res 51: 2151–2157, 1991Google Scholar
  31. 31.
    Schultz RM, Silberman S, Persky B, Bajkowski AS, Carmichael DF: Inhibition by human recombinant tissue inhibitor of metalloproteinases of human amnion invasion and lung colonization by murine B16-F10 melanoma cells. Cancer Res 48: 5539–5545, 1988PubMedGoogle Scholar
  32. 32.
    DeClerck YA, Perez N, Shimada H, Boone TC, Langley KE, Taylor SM: Inhibition of invasion and metastasis in cells transfected with an inhibitor of metalloproteinases. Cancer Res 52: 701–708, 1992Google Scholar
  33. 33.
    Powell WC, Knox JD, Navre M, Grogan TM, Kittelson J, Nagle RB, Bowden GT: Expression of the metalloproteinase matrilysin in DU-145 cells increases their invasive potential in severe combined immunodeficient mice. Cancer Res 53: 417-422, 1993PubMedGoogle Scholar
  34. 34.
    Khokha R, Zimmer MJ, Wilson SM, Chambers AF: Up-regulation of TIMP-1 expression in B16-F10 melanoma cells suppresses their metastatic ability in chick embryo. Clin Exp Metastasis 10: 365–370, 1992PubMedCrossRefGoogle Scholar
  35. 35.
    Axelrod JH, Reich R, Miskin R: Expression of human recombinant plasminogen activators enhances invasion and experimental metastasis of H-ras-transformed NIH 3T3 cells. Mol Cell Biol 9: 2133–2141, 1989PubMedGoogle Scholar
  36. 36.
    Cajot JF, Schleuning WD, Medcalf RL, Bamat J, Testuz J, Liebermann L, Sordat B: Mouse L cells expressing human prourokinase-type plasminogen activator: effects on extracellular matrix degradation and invasion. J Cell Biol 109: 915–925, 1989PubMedCrossRefGoogle Scholar
  37. 37.
    Yu H, Schultz RM: Relationship between secreted urokinase plasminogen activator activity and metastatic potential in murine B16 cells transfected with human urokinase sense and antisense genes. Cancer Res 50: 7623–7633, 1990PubMedGoogle Scholar
  38. 38.
    Rutka JT, Apodaca G, Stern R, Rosenblum M: The extracellular matrix of the central and peripheral nervous systems: structure and function. J Neurosurg 69: 155–170, 1988PubMedCrossRefGoogle Scholar
  39. 39.
    Bignami A, Asher R: Some observations on the localization of hyaluronic acid in adult, newborn and embryonal rat brain. Int J Dev Neurosci 10: 45–57, 1992PubMedCrossRefGoogle Scholar
  40. 40.
    Giordana MT, Bertolotto A, Mauro A, Migheli A, Pezzotta S, Racagni G, Schiffer D: Glycosaminoglycans in human cerebral tumors. Part II. Histochemical findings and correlations. Acta Neuropathol Berl 57: 299–305, 1982PubMedCrossRefGoogle Scholar
  41. 41.
    Iwata M, Wight TN, Carlson SS: A brain extracellular matrix proteoglycan forms aggregates with hyaluronan. J Biol Chem 268: 15061–15069, 1993PubMedGoogle Scholar
  42. 42.
    Aquino DA, Margolis RU, Margolis RK: Immunocytochemical localization of a chondroitin sulfate proteoglycan in nervous tissue. I. Adult brain, retina, and peripheral nerve. J Cell Biol 99: 1117–1129, 1984PubMedCrossRefGoogle Scholar
  43. 43.
    Perides G, Rahemtulla F, Lane WS, Asher RA, Bignami A: Isolation of a large aggregating proteoglycan from human brain. J Biol Chem 267: 23883–23887, 1992PubMedGoogle Scholar
  44. 44.
    Zisch AH, D Alessandri L, Ranscht B, Falchetto R, Winterhalter KH, Vaughan L: Neuronal cell adhesion molecule contactin/F11 binds to tenascin via its immunoglobulin-like domains. J Cell Biol 119: 203–213, 1992PubMedCrossRefGoogle Scholar
  45. 45.
    Bignami A, Dahl D: Brain-specific hyaluronate-binding protein. A product of white matter astrocytes? J Neurocytol 15: 671–679, 1986PubMedCrossRefGoogle Scholar
  46. 46.
    Giordana MT, Germano I, Giaccone G, Mauro A, Migheli A, Schiffer D: The distribution of laminin in human brain tumors: an immunohistochemical study. Acta Neuropathol 67: 51–57, 1985PubMedCrossRefGoogle Scholar
  47. 47.
    Schiffer D, Giordana MT, Mauro A, Migheli A: GFAP, F VIII/RAg, laminin, and fibronectin in gliosarcomas: an immunohistochemical study. Acta Neuropathol Berl 63: 108–116, 1984PubMedCrossRefGoogle Scholar
  48. 48.
    McComb RD, Bigner DD: Immunolocalization of laminin in neoplasms of the central and peripheral nervous systems. J Neuropathol Exp Neurol 44: 242–253, 1985PubMedCrossRefGoogle Scholar
  49. 49.
    Rutka JT, Hyatt CA, Giblin JR: Distribution of extracellular matrix proteins in primary human brain tumours: an immunohistochemical analysis. Can J Neurol Sci 14: 25–30, 1987PubMedGoogle Scholar
  50. 50.
    Schachner M, Schoonmaker G, Hynes RO: Cellular and subcellular localization of LETS protein in the nervous system. Brain Res 158: 149–158, 1978PubMedCrossRefGoogle Scholar
  51. 51.
    Gladson CL, Cheresh DA: Glioblastoma expression of vitronectin and the alpha v beta 3 integrin. Adhesion mechanism for transformed glial cells. J Clin Invest 88: 1924–1932, 1991PubMedCrossRefGoogle Scholar
  52. 52.
    Bertolotto A, Giordana MT, Magrassi ML, Mauro A, Schiffer D: Glycosaminoglycans (GAGs) in human cerebral tumors. Part 1. Biochemical findings. Acta Neuropathol Berl 58: 115–119, 1982PubMedCrossRefGoogle Scholar
  53. 53.
    Glimelius B, Norling B, Westermark B, Wasteson A: Composition and distribution of glycosaminoglycans in cultures of human normal and malignant glial cells. Biochem J 172: 443–456, 1978PubMedGoogle Scholar
  54. 54.
    Iozzo RV: Proteoglycans and neoplastic-mesenchymal cell interactions. Hum Pathol 15: 2–10, 1984PubMedCrossRefGoogle Scholar
  55. 55.
    Pilkington GJ, Akinwunmi J, Ognjenovic N, Rogers JP: Differential binding of anti-CD44 on human gliomas in vitro. Neuroreport 4: 259–262, 1993PubMedCrossRefGoogle Scholar
  56. 56.
    Apodaca G, Rutka JT, Bouhana K, Berens ME, Giblin JR, Rosenblum ML, McKerrow JH, Banda MJ: Expression of metalloproteinases and metalloproteinase inhibitors by fetal astrocytes and glioma cells. Cancer Res 50: 2322–2329, 1990PubMedGoogle Scholar
  57. 57.
    Rao JS, Steck PA, Mohanam S, Stetler Stevenson WG, Liotta LA, Sawaya R: Elevated levels of M(r) 92, 000 type IV collagenase in human brain tumors. Cancer Res 53: 2208–2211, 1993Google Scholar
  58. 58.
    Paganetti PA, Caroni P, Schwab ME: Glioblastoma infiltration into central nervous system tissue in vitro: involvement of a metalloprotease. J Cell Biol 107: 2281–2291, 1988PubMedCrossRefGoogle Scholar
  59. 59.
    Rosenberg GA, Kornfeld M, Estrada E, Kelley RO, Liotta LA, Stetler Stevenson WG: TIMP-2 reduces proteolytic opening of blood-brain barrier by type IV collagenase. Brain Res 576: 203–207, 1992PubMedCrossRefGoogle Scholar
  60. 60.
    Landau B, Kwaan H, Verrusio E, Engelhard H, Brem S: Urokinase-type plasminogen activator and plasminogen activator inhibitors in human brain tumors. (Abstract) Proc Amer Assn Cancer Res 34: 80, 1993Google Scholar
  61. 61.
    Gately S, Takano S, Brem S: Immunohistochemical identification of plasminogen in human brain tumors. (Abstract) Proc Amer Assn Cancer Res 34: 78, 1993Google Scholar
  62. 62.
    McCormick D: Secretion of cathepsin B by human gliomas in vitro. Neuropathol and Applied Neurobiol 19: 146–151, 1993CrossRefGoogle Scholar
  63. 63.
    Rosenblum ML, Eisenberg AO, Norman D: Brain tumor invasion: clinical patterns of malignant astrocytoma spread. J Neurosurg 76: 338, 1992Google Scholar
  64. 64.
    Monod L, Diserens AC, Jongeneel CV, de Tribolet N: Human glioma cell lines expressing the common acute lymphoblastic leukemia antigen (cALLa) have neutral endopeptidase activity. Int J Cancer 44: 948–951, 1989PubMedCrossRefGoogle Scholar
  65. 65.
    Pratt RM, Larsen MA, Johnston MC: Migration of cranial neural crest cells in a cell-free hyaluronate-rich matrix. Dev Biol 44: 298–305, 1975PubMedCrossRefGoogle Scholar
  66. 66.
    Sanes JR: Roles of extracellular matrix in neural development. Annu Rev Physiol 45: 581–600, 1983PubMedCrossRefGoogle Scholar
  67. 67.
    Toole BP, Biswas C, Gross J: Hyaluronate and invasiveness of the rabbit V2 carcinoma. Proc Natl Acad Sci USA 76: 6299–6303, 1979PubMedCrossRefGoogle Scholar
  68. 68.
    Pansera F, Pansera E: An explanation for the rarity of extra-axial metastases in brain tumors. Medical Hypotheses 39: 88–89, 1992PubMedCrossRefGoogle Scholar
  69. 69.
    Daumas Duport C, Scheithauer BW, Kelly PJ: A histologic and cytologic method for the spatial definition of gliomas. Mayo Clin Proc 62: 435–449, 1987Google Scholar
  70. 70.
    Gehan ER, Walker MD: Prognostic factors for patients with brain tumors. Natl Cancer Inst Monogr 46: 189–195, 1977PubMedGoogle Scholar
  71. 71.
    Burger PC, Heinz ER, Shibata T, Kleihues P: Topographic anatomy and CT correlations in the untreated glioblastoma multiforme. J Neurosurg 68: 698–704, 1988PubMedCrossRefGoogle Scholar
  72. 72.
    Matsukado Y, MacCarty CS, Kernohan JW: The growth of glioblastoma multiforme (astrocytomas, grade 3 and 4) in neurosurgical practice. J Neurosurg 18: 636–644, 1961PubMedCrossRefGoogle Scholar
  73. 73.
    Maxwell HP: The incidence of interhemispheric extension of glioblastoma multiforme through the corpus callosum. J Neurosurg 3: 54–57, 1946PubMedCrossRefGoogle Scholar
  74. 74.
    Rosenblum ML, Eisenberg AD, Norman D: Brain tumor invasion: clinical patterns of malignant astrocytoma spread. J Neurosurg 76: 383A, 1992Google Scholar
  75. 75.
    Grabb PA, Albright AL, Pang D: Dissemination of supratentorial malignant gliomas via the cerebrospinal fluid in children. Neurosurgery 30: 64–71, 1992PubMedCrossRefGoogle Scholar
  76. 76.
    Berger MS, Baumeister B, Geyer JR, Hilstein J, Kanev PM, Leroux PD: The risk of metastases from shunting in children with primary central nervous system tumors. J Neurosurg 74: 872–877, 1991PubMedCrossRefGoogle Scholar
  77. 77.
    Gralich JH, Sundaresan N: Metastatic brain tumors. Wilkins RH and Rengachary SS. Neurosurgery. McGraw-Hill. New York, NY. 1985Google Scholar
  78. 78.
    Posner JB, Chernik NL: Intracranial masses from systemic cancer. Adv Neurol 19: 579–592, 1978PubMedGoogle Scholar
  79. 79.
    Takakura K, Sano K, Hojo S, Hirano A: Metastatic Tumors of the Central Nervous System. Imku-shoin. Tokyo. 1982Google Scholar

Copyright information

© Springer Science+Business Media Dordrecht 1994

Authors and Affiliations

  • Yves A. De Clerck
    • 1
  • Hiroyuki Shimada
    • 2
  • Ignacio Gonzalez-Gomez
    • 2
  • Corey Raffel
    • 3
  1. 1.Division of Hematology-Oncology, Department of PediatricsChildrens Hospital Los Angeles, University of Southern CaliforniaLos AngelesUSA
  2. 2.Department of PathologyChildrens Hospital Los Angeles, University of Southern CaliforniaLos AngelesUSA
  3. 3.Division of Neurosurgery, Department of SurgeryChildrens Hospital Los Angeles, University of Southern CaliforniaLos AngelesUSA

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