Skip to main content
SpringerLink
Log in

The role of endothelial cells in tumor invasion and metastasis

  • Published:
Journal of Neuro-Oncology Aims and scope Submit manuscript

Summary

Metastasis is one of the most devastating aspects of cancer. It is a complex multistep processes that results in spread of tumorigenic cells to secondary sites in various organs. The actual events that are involved in metastasis are the subject of several recent reviews [1–3].

Upon growth of neoplastic cells beyond a certain mass (2 mm in diameter) an extensive vascularization through angiogenesis occurs. The new capillary network provides a supply of nutrients and gas exchange that allows further growth and development of the tumor mass. The network of the blood vessels also provides an entry site into the circulation for the neoplastic cells that detach from the tumor mass. Only a small percentage of circulating tumor cells (< 0.01%) survive travel in the circulation and arrest in the capillary beds of distant organs, extravasate and proliferate within the organ parenchyma producing a successful metastasis [1].

Vasculature plays an important role in several steps of the metastatic process; 1) at the site of metastasis, vessels capture the cancer cell and provide the entry route into the secondary organ, and 2) through angiogenesis, vascular endothelial cells provide the supply of nutrients for the growth of the primary tumor mass and the route of intravasation. The lining of all blood vessels are covered with endothelial cells which play an active role in both processes. The metastatic properties of cancer cells have been extensively studied. Here, we will discuss the role of endothelial cells in the metastatic process with focus on their interaction with cancer cells at the site of extravasation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Fidler IJ: Cancer metastasis. British Medical Bulletin 47: 157–177, 1991

    PubMed  Google Scholar 

  2. Zetter BR: The cellular basis of site-specific tumor metastasis. New England J Med 322: 605–611, 1990

    Google Scholar 

  3. Weiss L: Principles of metastasis. Academic Press, Orlando, 1985

    Google Scholar 

  4. Liotta LA, Steeg PS, Stetler-Stevenson WG: Cancer metastasis and angiogenesis: an imbalance of positive and negative regulation. Cell 64: 327–336, 1991

    Google Scholar 

  5. Leibovich SI, Polverini PJ, Shepard HM, Wiseman DM, Shively V, Nuseir N: Macrophage-induced angiogenesis is mediated by tumor necrosis factor alpha. Nature 329(6140): 630–632, 1987

    PubMed  Google Scholar 

  6. Pepper MS, Belin D, Montesano R, Orci J-D, Vassalli: Transforming growth factor-beta 1 modulates basic fibroblast growth factor-induced proteolytic and angiogenic properties of endothelial cellsin vitro. J Cell Biol 111: 743–755, 1990

    PubMed  Google Scholar 

  7. Bellusci S, Moens G, Gaudino G, Comoglio P, Nakamura T, Theiry J-P, Thiery J, Jouanneau: Creation of an hepatocyte growth factor/scatter factor autocrine loop in carcinoma cells induces invasive properties associated with increased tumorigenicity. Oncogene 9: 1091–1099, 1994

    PubMed  Google Scholar 

  8. Ausprunk DH, Knighton DR, Folkman J: Vascularization of normal and neoplastic tissues grafted to the chick chorioal-lantois. Role of host and preexisting graft blood vessels. American J Pathology 79(3): 597–628, 1975

    Google Scholar 

  9. Mignatti P, Robbins E, Rifkin DB: Tumor invasion through the human amniotic membrane: requirement for a proteinase cascade. Cell 47: 487–498, 1986

    PubMed  Google Scholar 

  10. Herron GS, Banda MJ, Clark EJ, Gavrilovic J, Werb Z: Secretion of metalloproteinases by stimulated capillary endothelial cells. II. Expression of collagenase and stromelysin activities is regulated by endogenous inhibitors. J Biol Chem 261: 2814–2818, 1986

    PubMed  Google Scholar 

  11. Montesano R, Pepper MS, Mohle-Steinlein U, Risau W, Wagner EF, Orci L: Increased proteolytic activity is responsible for the aberrant morphogenetic behavior of endothelial cells expressing the middle T oncogene. Cell 62: 435–445, 1990

    PubMed  Google Scholar 

  12. Mignatti P, Robbins E, Tsuboi R, Rifkin DB:In vitro angiogenesis on the human amniotic membrane: requirement for basic fibroblast growth factor-induced proteinases. J Cell Biol 108: 671–682, 1989

    PubMed  Google Scholar 

  13. Levin EG, Santel L: Association of a plasminogen activator inhibitor (PAI-1) with the growth substratum and membrane of human endothelial cells. J Cell Biol 105: 2543–2649, 1987

    PubMed  Google Scholar 

  14. Gottesman M: The role of proteases in cancer. Sem Cancer Biol 1: 97–160, 1990

    Google Scholar 

  15. Schultz RM, Silberman S, Perski B, Bajowski AS, Carmichael DF: Inhibition by recombinant tissue inhibitor of metalloproteinases of human amnion invasion and lung colonization by murine B16-F10 melanoma cells. Cancer Research 48: 5539–5545, 1988

    PubMed  Google Scholar 

  16. Alvarez OA. Carmichael DF, DeClerk 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, 1990

    PubMed  Google Scholar 

  17. Heuser LS, Miller FN: Differential macromolecular leakage from the vasculature of tumors. Cancer 57: 461–464, 1986

    PubMed  Google Scholar 

  18. Gerlowski LE, Jain RK: Microvascular permeability of normal and neoplastic tissues. Microvasc Res 31: 288–305, 1986

    PubMed  Google Scholar 

  19. Hori K, Suzuki M, Tanda S, Saito S:In vitro analysis of tumor vascularization in the rat. Jpn J Cancer Res 81: 279–288, 1990

    PubMed  Google Scholar 

  20. Willis RA: The spread of tumors in the human body. Butterworth. London, 1972

    Google Scholar 

  21. Osborn L: Leukocyte adhesion to endothelium in inflammation. Cell 62: 3–6, 1990

    PubMed  Google Scholar 

  22. Abbassi O, Kishimoto TK, Mcintire LV, Smith CW: Neutrophil adhesion to endothelial cells. Blood Cells 19: 245–260, 1993

    PubMed  Google Scholar 

  23. Bevilacqua MP, Nelson RM: Selectins. J Clin Invest 91: 379–387, 1993

    PubMed  Google Scholar 

  24. Larsen E, Celli A, Gilbert GE, Furie BC, Erban JK. Bonfanti R, Wagner DD, Furie B: PADGEM protein: A receptor that mediates the interaction of activated platelets with neutrophils and monocytes. Cell 59: 305–312, 1989

    PubMed  Google Scholar 

  25. Bevilacqua MP, Pober JS, Mendrick DL, Cotran RS, Gimbrone Jr MA: Identification of an inducible endothelial-Ieu-Locyte adhesion molecule. Proc Natl Acad Sci 84: 9238–9242, 1987

    PubMed  Google Scholar 

  26. Hattori R, Hamilton KK, Fugate RD, McEver RP, Sims PJ: Stimulated secretion of endothelial von Willibrand factor is accompanied by rapid redistribution to the cell surface of the intracellular granule membrane protein GMP-140. J Biol Chem 264(14): 7768–7771, 1989

    PubMed  Google Scholar 

  27. Dejana E, Bertocchi F, Bortolami MC, Regonesi A, Tonta A, Breviario F, Giavazzi R: Interleukin 1 promotes tumor cell adhesion to cultured human endothelial cells. J Clin Invest 82: 1466–1470, 1988

    PubMed  Google Scholar 

  28. Rice GE, Bevilacqua MP: An inducible endothelial cell surface glycoprotein mediates melanoma adhesion. Science 246: 1303–1305, 1989

    PubMed  Google Scholar 

  29. Lenter M, Levinovitz A, Isenmann S. Vestweber D: Monospecific and common glycoprotein ligands for E- and P-Selectin on myeloid cells. J Cell Biol 125: 471–481, 1944

    Google Scholar 

  30. Lowe JB, Stoolman LM, Nair RP, Larsen RD, Berhend TL, Marks RM: ELAM-1-dependent cell adhesion to vasculature endothelium by a transfected human fucosyltransferase cDNA. Cell 63: 475–484, 1990

    PubMed  Google Scholar 

  31. Pauli BU, Johnson RC, Widom J, Cheng CF: Endothelial cell adhesion molecules and their role in organ preference of metastasis. TIG (Trends Glycosci Glycothec) 4: 405–414, 1992

    Google Scholar 

  32. Pauli BU, Augustin-Voss HG, El-Sabban ME, Johnson RC, Hammer DA: Organ preference of metastasis: the role of endothelial cell adhesion molecules. Cancer Metastasis Rev 9: 175–189, 1990

    PubMed  Google Scholar 

  33. Berlin C, Berg EL, Briskin MJ, Andrew DP, Kilshaw PJ, Holzman B, Weissman IL, Hamann A, Butcher EC: a4b7 integrin mediates lymphocyte binding to the mucosal vascular addressin MAdCAM-1. Cell 74: 185–195, 1993

    PubMed  Google Scholar 

  34. Doussis-Anagnostopoulou I, Kaklamanis L, Cordeil J, Jones M. Turley H, Pulford K, Simmons D, Mason D, Gatter K: ICAM-3 expression on endothelium in lymphoid malignancy. American J Pathology 143: 1040–1043, 1993

    Google Scholar 

  35. Rice Ge, Gimbrone Jr MA, Bevilacqua MP: Tumor cell-en-dothelial interactions. American J Pathology 133: 204–210, 1988

    Google Scholar 

  36. Totsuka T, Tanimoto H, Yamaguchi T, Inoue H, Saito I, Miyasaka N: Invasive human T lymphoma cells produce a novel factor that upregulates expression of adhesion molecules on endothelial cells. Experimental Hematology 21: 1544–1549, 1993

    PubMed  Google Scholar 

  37. Nicolson GL: Organ specificity of tumor metastasis: role of preferential adhesion, invasion and growth of malignant cells at specific secondary sites. Cancer Metastasis Rev 7: 143–188, 1988

    PubMed  Google Scholar 

  38. Nicholson GL, Dulski K, Basson C, Welch DR: Preferential organ attachment and invasionin vitro by B16 melanoma cells selected for differing metastatic colonization and invasive properties. Invasion & Metastasis 5(3): 144–158, 1985

    Google Scholar 

  39. Auerbach R, Lu WC, Pardon E, Gumkowski F, Kaminska G, Kaminski M: Specificity of adhesion between murine tumor cells and capillary endothelium: Anin vitro correlate of preferential metastasisin vivo. Cancer Research 47: 1492–1496, 1987

    PubMed  Google Scholar 

  40. Zhu D, Cheng C-F. Pauli BU: Mediation of lung metastasis of murine melanomas by a lung-specific endothelial cell adhesion molecule. Proc Natl Acad Sci 88: 9568–9572, 1991

    PubMed  Google Scholar 

  41. Johnson RC. Zhu D. Augustin-Voss HG, Pauli BU: Lung endothelial dipeptidyl peptidase IV is an adhesion molecule for lung-metastatic rat breast and prostate carcinoma cells. J Cell Biol 121: 1423–1432, 1993

    PubMed  Google Scholar 

  42. Smyth SS. Joneckis CC, Parise LV: Regulation of vascular integrins. Blood 81: 2827–2843, 1993

    PubMed  Google Scholar 

  43. Ruoslahti E: Integrins. J Clin Invest 87: 1–5, 1991

    PubMed  Google Scholar 

  44. Brook PC, Clark RAF, Cheresh DA: Requirement of vascular αvβ3 for angiogenesis. Science 264: 569–571, 1994

    PubMed  Google Scholar 

  45. Tang DC, Diglio CA, Honn KV: Activation of microvasculature endothelium by Eicosanoid 12(S)-Hydroxyeicosate-traenoic Acid leads to enhanced tumor cell adhesion via up-regulation of surface expression of avb3 integrin: A post-transcriptional, protein kinase C and cytoskeleton-dependent process. Cancer Research 54: 1119–1129, 1994

    PubMed  Google Scholar 

  46. Lafrenie RM, Podor TJ, Buchanan MR, Orr FW: Up-regu-lated biosynthesis and expression of endothelial cell vitronectin receptor enhances cancer cell adhesion. Cancer Research 52: 2202–2208, 1992

    PubMed  Google Scholar 

  47. Larson RS, Springer TA: Structure and function of leukocyte integrins. Immunol Rev 114: 181, 1990

    PubMed  Google Scholar 

  48. Ginsberg MH, Loftus JC, Plow EF: Cytoadhesions, integrins, and platelets. Thromb Haemostasis 59: 1–6, 1988

    Google Scholar 

  49. Phillips DR, Charo IF, Parise LV, Fitzgerald LA: The platelet membrane glycoprotein IIb-IIIa complex. Blood 71: 831, 1988

    PubMed  Google Scholar 

  50. Dedhar S: Integrins and tumor invasion. BioEssays 12: 583–590, 1990

    PubMed  Google Scholar 

  51. Takenaga K, Takahashi K: Effects of 12-O-tetradecanoyl-phorbol-13-acetate on adhesiveness and lung colonizing ability of Lewis lung carcinoma cells. Cancer Research 46: 375–380, 1986

    PubMed  Google Scholar 

  52. Gopalakrishna R, Barsky SH: Tumor promoter-induced membrane bound protein kinase C regulates hematogenous metastasis. Proc Natl Acad Sci USA 85: 612–616, 1988

    PubMed  Google Scholar 

  53. Korczak B, Whale C, Kerbel RS: Possible involvement of Ca2 + mobilization and protein kinase C activation in the induction of spontaneous metastasis by mouse mammary adenocarcinoma cells. Cancer research 49: 2597–2602, 1989

    PubMed  Google Scholar 

  54. Nishizuka Y: Studies and perspectives of protein kinase C. Science 233: 305–312, 1986

    PubMed  Google Scholar 

  55. Dumont JA, Jones Jr WD, Bitonti AJ: Inhibition of experimental metastasis and cell adhesion of B16F1 melanoma cells by inhibitors of protein kinase C. Cancer research 52: 1195–1200, 1992

    PubMed  Google Scholar 

  56. Chan BMC, Matsuura N, Takada Y, Zetter BR, Hemler ME:In vitro andin vivo consequences of VLA-2 expression of rhabdomyosarcoma cells. Science 251: 1600–1602, 1991

    PubMed  Google Scholar 

  57. Elices MJ, Osborn L, Takada Y, Crouse C, Luhowskyj S, Hemler ME, Lobb RR: VCAM-1 on activated endothelium interacts with the leukocyte integrin VLA-4 at a site distinct from the VLA-4/fibronectin binding site. Cell 60: 577–584, 1990

    PubMed  Google Scholar 

  58. Guan JL, Hynes RO: Lymphoid cells recognize an alternatively spliced segment of fibronectin via the integrin receptor a4bl. Cell 60: 53–61, 1990

    PubMed  Google Scholar 

  59. Ruoslahti E, Pierschbacher MD: New perspectives in cell adhesion: RGD and integrins. Science 238(4826): 491–497, 1987

    PubMed  Google Scholar 

  60. Humphries MJ, Olden K, Yamada KM: A synthetic peptide from fibronectin inhibits experimental metastasis of murine melanoma cells. Science 233: 467–470, 1986

    PubMed  Google Scholar 

  61. Ruoslahti E, Giancotti FG: Integrins and tumor cell dissemination. Cancer Cells 1: 119–126, 1989

    PubMed  Google Scholar 

  62. Qian F, Vaux DL, Weissman IL: Expression of the integrin α4πl on melanoma cells can inhibit the invasive stage of metastasis formation. Cell 77: 335–347, 1994

    PubMed  Google Scholar 

  63. Juliano RL: Membrane receptors for extracellular matrix macromolecules: relationship to cell adhesion and tumor metastasis. Biochem Biophys Acta 907: 261–278, 1987

    PubMed  Google Scholar 

  64. Auerbach R, Alby L, Morrissey LW, Tu M, Joseph J: Expression of organ-specific antigens on capillary endothelial cells. Microvasc 29: 401–411, 1985

    Google Scholar 

  65. Felgner PL, Gadek TR, Holm M, Roman R, Chan HW, Wenz M, Northrop JP, Ringold GM, Danielsen M: Lipofection: a highly efficient lipid-mediating DNA-transfection procedure. Proc Natl Acad Sci USA 84: 7413–7417, 1987

    PubMed  Google Scholar 

  66. Jahroudi N, Lynch DC: Endothelial specific regulation of von Willibrand factor gene expression. Mol Cell Biol 14: 999–1008, 1994

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Radiation Oncology, University of Pittsburgh, Pittsburgh, PA, USA

    Nadia Jahroudi & Joel S. Greenberger

Authors
  1. Nadia Jahroudi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Joel S. Greenberger
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Jahroudi, N., Greenberger, J.S. The role of endothelial cells in tumor invasion and metastasis. J Neuro-Oncol 23, 99–108 (1995). https://doi.org/10.1007/BF01053415

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF01053415

Key words

Search

Navigation