Skip to main content
SpringerLink
Log in

The effects of oxygen radical — mediated pulmonary endothelial damage on cancer metastasis

  • Invited Paper
  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Summary

The vascular bed of the lung is susceptible to environmental and host-mediated injury from free radicals. The lung is also a frequent site for the formation of cancer metastases. Since the circulation is important for the spread of cancer and because the endothelium is a barrier between the circulation and extravascular tissue, we have postulated that free radical damage to the pulmonary microvasculature enhances the formation of metastases. Pulmonary endothelial injury was induced in mice by bleomycin (120 mg/kg i.v.) or by exposure to 90% oxygen for 2–4 days. In rats, damage was elicited by intravenous injection of cobra venom factor which activates the circulating leukocytes. Endothelial damage was demonstrated by morphology and by measurement, in lung lavage fluids, of increased protein and/or leakage of 125I-albumin, previously injected intravenously. When radiolabeled cancer cells were injected into the tail vein during periods of pulmonary endothelial damage, there was a 3–36 fold increase in the numbers of these cells located in the lung after 24 hours. Subsequently more metastatic tumors formed in the animals with injured lungs. In rats, the enhanced localization was prevented by pretreatment of the animals with catalase or with antineutrophil antibodies. We have also demonstrated that stimulation of rat cancer cells by the chemotactic peptide N-fMLP is followed by chemiluminescence, amplified in the presence of luminol. Evidence for the generation of oxygen radicals by these cells includes inhibition of the response in the absence of oxygen or in the presence of superoxide dismutase, catalase, and mannitol, and dose-dependent reduction of acetylated cytochrome C. We conclude that free radical-mediated damage to the pulmonary endothelium significantly increases the metastasis of circulating tumor cells and we postulate that some cancer cells may directly facilitate their spread by generating free radicals.

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. Weiss L: Principles of Metastasis. Orlando, Academic Press, 1985

    Google Scholar 

  2. Schirrmacher V: Cancer Metastasis: experimental approaches, theoretical concepts, and impacts for treatment strategies. Adv Cancer Res 43:1–74, 1985

    Google Scholar 

  3. Fidler IJ, Balch CM: The biology of cancer metastasis and implications for therapy. Curr Prob Surg XXIV:130–209, 1987

    Google Scholar 

  4. Liotta LA: Tumor invasion and metastases — Role of the extracellular matrix: Rhoads memorial award lecture. Cancer Research 46:1–7, 1986

    Google Scholar 

  5. Weiss L, Orr FW Honn KV: Interactions of cancer cells with the microvasculature during metastasis. FASEB Journal (in press)

  6. Dennis JW, Laferte S, Waghorne C, Breitman JL, Kerbel RS: Beta 1–6 branching of ASN-linked oligosaccharides is directly associated with metastasis. Science 236:582–585, 1987

    Google Scholar 

  7. Nicolson GL: Metastatic tumor cell attachment and invasion assay utilizing vascular endothelial cell monolayers. J Histochem Cytochem. 30:214–220, 1982

    Google Scholar 

  8. Auerbach R, Wei Cheng L, Pardon E, Gumkowski F, Kaminska G, Kaminski M: Specificity of adhesion between tumor cells and capillary endothelium: an in vitro correlate of preferential metastasis in vivo. Cancer Res 47:1492–1496, 1987

    Google Scholar 

  9. Bevilacqua MP, Pober JS, Wheeler ME, Cotran RS, Gimbrone Jr MA: Interleukin-1 acts on cultured human vascular endothelium to increase the adhesion of polymorphonuclear leukocytes, monocytes, and related leukocyte cell lines. J Clin Invest 76:2003–2011, 1985

    Google Scholar 

  10. Liotta LA, Thorgeirsson UP, Garbisa S: Role of collagenases in tumor cell invasion. Cancer Metastasis Reviews 1:277–288, 1982

    Google Scholar 

  11. McCarthy J, Hagen ST, Furcht LT: Fibronectin contains distinct adhesion and motility-promoting domains for metastatic melanoma cells. J Cell Biol 102:179–188, 1986

    Google Scholar 

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

    Google Scholar 

  13. 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 

  14. Vlodavsky I, Atzmon AR, Fuks Z: Tumor cell attachment to the vascular endothelium and subsequent degradation of the subendothelial extracellular matrix. Exp Cell Res 140:149–159, 1982

    Google Scholar 

  15. Thorgeirsson UP, Liotta LA, Kalebic T, Margulies IM, Thomas K, Rios-Candelore M, Russo RG: Effect of natural protease inhibitors and a chemoattractant on tumor cell invasion in vitro. JNCI 69:1049–1054, 1982

    Google Scholar 

  16. Crissman J, Hatfield J, Schaldenbrand M, Sloane B, Hohn KV: Arrest and extravasation of B16 amelanotic melanoma in murine lungs. A light and electron microscopic study. Laboratory Investigations 53:470–478, 1985

    Google Scholar 

  17. Dao TL, Yogo H: Enhancement of pulmonary metastases by X-irradiation in rats bearing mammary cancer. Cancer 20:2020–2025, 1967

    Google Scholar 

  18. Hirata H, Tanaka K: Artificial metastases and decrease of fibrinolysis in the nude mouse lung after hemithoracic irradiation. Clin Exp Met 2:311–319, 1984

    Google Scholar 

  19. Milas L, Malenica B, Allegretti N: Enhancement of artificial lung metastases in mice caused by cyclophosphamide. I. Participation of impairment of host antitumor resistance. Cancer Immunol Immunother 6:191–196, 1979

    Google Scholar 

  20. Moore JV, Dixon B: Metastasis of a transplantable mammary tumour in rats treated with cyclophosphamide and/or irradiation. Br J Cancer 36:221–226, 1977

    Google Scholar 

  21. Poupon MF, Pauwels C, Jasmin C, Antoine E, Lascaux V, Rose B: Amplified pulmonary metastases of a rat rhabdomyosarcoma in respone to nitrosourea treatment. Cancer Treat Rep 68:749–758, 1984

    Google Scholar 

  22. Steel GG, Adams K: Enhancement by cytotoxic agents of artificial pulmonary metastasis. Br J Cancer 36:653–658, 1977

    Google Scholar 

  23. Hecht SM: DNA strand scission by activated bleomycin group antibiotics. Fed Proc 45:2784–2791, 1986

    Google Scholar 

  24. Kanofsky JR: Singlet oxygen production by bleomycin. A comparison with heme-containing compounds. J Biol Chem 261:13546–13550, 1986

    Google Scholar 

  25. Pepin JM, Langer RO: Effects of dimethyl sulfoxide (DMSO) on bleomycin-induced pulmonary fibrosis. Biochem Pharmacol 34:2386–2389, 1985

    Google Scholar 

  26. Adamson IYR, Bowden DH: The pathogenesis of bleomycin induced pulmonary fibrosis in mice. Am J Pathol 77:185–198, 1974

    Google Scholar 

  27. Adamson IYR, Bowden DH: Bleomycin-induced injury and metaplasia of alveolar Type 2 cells. Am J Pathol 96:531–544, 1979

    Google Scholar 

  28. Orr FW, Adamson IYR, Young L: Promotion of pulmonary metastasis by bleomycin-induced endothelial injury. Cancer Res 46:891–897, 1986

    Google Scholar 

  29. Davis WB, Rennard SJ, Bitterman PB, Crystal R: Pulmonary oxygen toxicity. N Eng J Med 309:878–883, 1983

    Google Scholar 

  30. Bowden DH, Adamson IYR: Endothelial regeneration as a marker of the differential vascular responses in oxygen-induced pulmonary edema. Lab Invest 30:350, 1974

    Google Scholar 

  31. Adamson IYR, Young L, Orr FW: Tumor metastasis after hyperoxic injury and repair of the pulmonary endothelium. Lab Invest 57:71–77, 1987

    Google Scholar 

  32. Orr FW, Adamson IYR, Young L: Quantification of metastasic tumor growth in bleomycin-injured lungs. Clin Exp Met 4:105–116, 1986

    Google Scholar 

  33. Adamson IYR: Drug-induced pulmonary fibrosis. Envir Health Pers 55:25–36, 1984

    Google Scholar 

  34. Adamson IYR, Orr FW, Young L: Effects of injury and repair of the pulmonary endothelium on lung metastasis after bleomycin. J Pathology 150:279–287, 1986

    Google Scholar 

  35. Till GO, Johnson KJ, Kunkel R, Ward PA: Intravascular activation of complement and acute lung injury. J Clin Invest 69:1126–1135, 1982

    Google Scholar 

  36. Morgamoth ML, Till GO, Kunkel RG, Ward PA: Complement and neutrophil-mediated injury of perfused rat lungs. Lab Invest 54:507–514, 1986

    Google Scholar 

  37. Thommasen HV: The role of the polymorphonuclear leukocyte in the pathogenesis of the adult respiratory distress syndrome. Clin Invest Med 8:185–194, 1985

    Google Scholar 

  38. Orr FW, Warner DJA: Effects of neutrophil-mediated pulmonary endothelial injury on the localization and metastasis of circulating Walker carcinosarcoma cells. Invasion Metastasis 7:183–196, 1987

    Google Scholar 

  39. Orr FW, Mokashi S, Delikatny J: Generation of a complement-derived chemotactic factor for tumor cells in experimentally induced peritoneal exudates and its effect on the local metastasis of circulating tumor cells. Am J Pathol 108:112–118, 1982

    Google Scholar 

  40. Ozaki T, Yoshida K, Ushijima K, Hayashi H: Studies on the mechanisms of invasion in cancer. II. In Vivo effects of a factor chemotactic for cancer cells. Int J Cancer 7:93–100, 1971

    Google Scholar 

  41. Rayner DC, Orr FW, Shin RPC: Binding of formyl peptides to Walker 256 carcinosarcoma cells and their chemotactic response. Cancer Research 45:2288–2293, 1985

    Google Scholar 

  42. Clarke PRH, Varani J: Phorbol ester binding to chemotactically responding and non-responding Walker 256 carcinosarcoma cells. Cancer Res 44:4967–4971, 1984

    Google Scholar 

  43. Mokashi S, Delikatny J, Orr FW: Relationships between chemotaxis, chemotactic modulators and cyclic nucleotide levels in tumor cells. Cancer Res 43:1980–1983, 1983

    Google Scholar 

  44. Varani J, Fantone JC: Phorbot myristae acetate-induced adherence of Walker 256 carcinosarcoma cells. Cancer Res 42:190–197, 1982

    Google Scholar 

  45. Wass JA, Varani J, Ward PA: Size increase induced in Walker ascites cells by chemotactic factors. Cancer Lett 9:313–318, 1980

    Google Scholar 

  46. Leroyer V, Werner L, Shaughnessy S, Goddard G, Orr W: Chemiluminescence and oxygen radical generation by Walker carcinosarcoma cells after chemotactic stimulation. Cancer Research 47:4771–4775, 1987

    Google Scholar 

  47. Weiss SJ, Peppin G, Ortiz X, Ragsdale C, Test ST: Oxidative autoactivation of latent collagenase by human neutrophils. Science 227:747–749, 1985

    Google Scholar 

  48. Shah SV, Baricos WH, Basci A: Degradation of human glomerular basement membrane by stimulated neutrophils. Activation of a metalloproteinase(s) by reactive oxygen metabolites. J Clin Invest 79:25–31, 1987

    Google Scholar 

  49. Clark RA, Stone PJ, El Hag A, Calore JD, Franzblau C: Myeloperoxidase-catalyzed inactivation of alpha 1-protease inhibitor by human neutrophils. J Biol Chem 256:3348–3353, 1981

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pathology and Oncology Research Group, McMaster University, Hamilton, Ontario

    F. W. Orr, D. Warner & S. Shaughnessy

  2. The Department of Pathology, University of Manitoba, Winnipeg, Manitoba, Canada

    I. Y. R. Adamson, V. Leroyer, L. Werner & L. Young

Authors
  1. F. W. Orr
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. I. Y. R. Adamson
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. D. Warner
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. V. Leroyer
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. L. Werner
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. S. Shaughnessy
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. L. Young
    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

Orr, F.W., Adamson, I.Y.R., Warner, D. et al. The effects of oxygen radical — mediated pulmonary endothelial damage on cancer metastasis. Mol Cell Biochem 84, 189–198 (1988). https://doi.org/10.1007/BF00421054

Download citation

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00421054

Key words

Search

Navigation