Intravascular origin of metastasis from the proliferation of endothelium-attached tumor cells: a new model for metastasis (original) (raw)

Nature Medicine volume 6, pages 100–102 (2000)Cite this article

Abstract

Metastasis is a frequent complication of cancer, yet the process through which circulating tumor cells form distant colonies is poorly understood. We have been able to observe the steps in early hematogenous metastasis by epifluorescence microscopy of tumor cells expressing green fluorescent protein in subpleural microvessels in intact, perfused mouse and rat lungs. Metastatic tumor cells attached to the endothelia of pulmonary pre-capillary arterioles and capillaries. Extravasation of tumor cells was rare, and it seemed that the transmigrated cells were cleared quickly by the lung, leaving only the endothelium-attached cells as the seeds of secondary tumors. Early colonies were entirely within the blood vessels. Although most models of metastasis include an extravasation step early in the process1, here we show that in the lung, metastasis is initiated by attachment of tumor cells to the vascular endothelium and that hematogenous metastasis originates from the proliferation of attached intravascular tumor cells rather than from extravasated ones. Intravascular metastasis formation would make early colonies especially vulnerable to intravascular drugs, and this possibility has potential for the prevention of tumor cell attachment to the endothelium.

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References

  1. Luzzi, K.J. et al. Multistep nature of metastatic inefficiency: dormancy of solitary cells after successful extravasation and limited survival of early micrometastases . Am. J. Pathol. 153, 865– 873 (1998).
    Article CAS Google Scholar
  2. Al-Mehdi, A. B. et al. Endothelial NADPH oxidase as the source of oxidants with lung ischemia or high K+. Circ. Res. 83, 730–737 (1998).
    Article CAS Google Scholar
  3. Voyta, J.C., Via, D.P., Butterfield, C.E. & Zetter, B.R. Identification and isolation of endothelial cells based on their increased uptake of acetylated-low density lipoprotein. J. Cell Biol. 99, 2034–2040 (1984).
    Article CAS Google Scholar
  4. Bernhard, E.J., Gruber, S.B. & Muschel, R.J. Direct evidence linking expression of matrix metalloproteinase 9 (92-kDa gelatinase/collagenase) to the metastatic phenotype in transformed rat embryo cells. Proc. Natl. Acad. Sci. USA 91, 4293–4297 (1994).
    Article CAS Google Scholar
  5. Hua, J. & Muschel, R.J. Inhibition of matrix metalloproteinase 9 expression by a ribozyme blocks metastasis in a rat sarcoma model system . Cancer Res. 56, 5279– 5284 (1996).
    CAS PubMed Google Scholar
  6. Frisch, S.M. et al. Adenovirus E1A represses protease gene expression and inhibits metastasis of human tumor cells. Oncogene 5, 75–83 (1990).
    CAS Google Scholar
  7. Liotta, L A, Steeg, P.S. & Stetler-Stevenson, W.G. Cancer metastasis and angiogenesis: an imbalance of positive and negative regulation. Cell 64, 327–336 (1991).
    Article CAS Google Scholar
  8. Fidler, I.J. Metastasis: quantitative analysis of distribution and fate of tumor emboli labeled with 125I-5-iodo-2′-deoxyuridine. J. Natl. Cancer Inst. 45, 773–782 (1970).
    CAS PubMed Google Scholar
  9. Fidler, I.J. & Nicolson, G.L. Brief communication: Organ selectivity for implantation survival and growth of B16 melanoma variant tumor lines. J. Natl. Cancer Inst. 57, 1199–1202 (1976).
    Article CAS Google Scholar
  10. Chen, W.T. Proteolytic activity of specialized surface protrusions formed at rosette contact sites of transformed cells. J. Exp. Zool. 251 , 167–185 (1989).
    Article CAS Google Scholar
  11. Crissman, J.D., Hatfield, J., Schaldenbrand, M., Sloane, B.F. & Honn, K.V. Arrest and extravasation of B16 amelanotic melanoma in murine lungs. A light and electron microscopic study. Lab. Invest. 53, 470–478 (1985).
    CAS PubMed Google Scholar
  12. Roos, E. Dingemans, K.P. Mechanisms of metastasis. Biochim. Biophys. Acta. 560, 135–166 (1979).
    CAS PubMed Google Scholar
  13. Dingemans, K.P. Behavior of intravenously injected malignant lymphoma cells. A morphologic study. J. Natl. Cancer Inst. 51, 1883– 1895 (1973).
    Article CAS Google Scholar
  14. Lapis, K. Paku, S., Liotta, LA . Endothelialization of embolized tumor cells during metastasis formation. Clin. Exp. Metastasis 6, 73–89 (1988).
    Article CAS Google Scholar
  15. Hangan, D. et al. Integrin VLA-2 (α2β1) function in postextravasation movement of human rhabdomyosarcoma RD cells in the liver . Cancer Res. 56, 3142– 3149( 1996).
    CAS PubMed Google Scholar
  16. Scherbarth, S. & Orr, F.W. Intravital videomicroscopic evidence for regulation of metastasis by the hepatic microvasculature: effects of interleukin-1alpha on metastasis and the location of B16F1 melanoma cell arrest. Cancer Res. 57, 4105– 4110 (1997).
    CAS PubMed Google Scholar
  17. Boudreau, N., Sympson, C.J., Werb, Z. & Bissell, M.J. Suppression of ICE and apoptosis in mammary epithelial cells by extracellular matrix. Science 267, 891–893 ( 1995).
    Article CAS Google Scholar
  18. Frisch, S.M. & Francis, H. Disruption of epithelial cell-matrix interactions induces apoptosis. J. Cell Biol. 124, 619–626 (1994).
    Article CAS Google Scholar
  19. Nikiforov M.A. et al. p53 modulation of anchorage independent growth and experimental metastasis. Oncogene 13, 1709– 1719 (1996).
    CAS PubMed Google Scholar
  20. Hauser, P.J., Agrawal, D. & Pledger, W.J. Primary keratinocytes have an adhesion dependent S phase checkpoint that is absent in immortalized cell lines. Oncogene 17, 3083–3092 ( 1998).
    Article CAS Google Scholar

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Acknowledgements

We thank Y. Dong and M. Meuler for technical assistance and W.G. Mckenna and E.J. Bernhard for reading the manuscript. This work was supported by a Parker B. Francis fellowship (A.B.A.), National Institutes of Health RO1 CA46830-09 (R.J.M.) and SCOR P50-HL60290 (A.B.F.), and a Merck Research fellowship (L.S.).

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Authors and Affiliations

  1. Institute for Environmental Medicine, University of Pennsylvania, 269a John Morgan Building, 3620 Hamilton Walk, Philadelphia, 19104, Pennsylvania, USA
    A.B. Al-Mehdi, K. Tozawa & A.B. Fisher
  2. Department of Pathology and Laboratory Medicine, University of Pennsylvania, 269a John Morgan Building, 3620 Hamilton Walk, Philadelphia, 19104, Pennsylvania, USA
    L. Shientag, A. Lee & R.J. Muschel

Authors

  1. A.B. Al-Mehdi
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  2. K. Tozawa
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  3. A.B. Fisher
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  4. L. Shientag
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  5. A. Lee
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  6. R.J. Muschel
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Correspondence toR.J. Muschel.

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Al-Mehdi, A., Tozawa, K., Fisher, A. et al. Intravascular origin of metastasis from the proliferation of endothelium-attached tumor cells: a new model for metastasis.Nat Med 6, 100–102 (2000). https://doi.org/10.1038/71429

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