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

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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Localization of tumor cells in the subpleural pulmonary microvessels.
Figure 2: Fate of tumor cells in the pulmonary circulation.

References

  1. 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).

  2. 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).

  3. 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).

  4. 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).

  5. 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).

  6. 6

    Frisch, S.M. et al. Adenovirus E1A represses protease gene expression and inhibits metastasis of human tumor cells. Oncogene 5, 75–83 (1990).

  7. 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).

  8. 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).

  9. 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).

  10. 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).

  11. 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).

  12. 12

    Roos, E. Dingemans, K.P. Mechanisms of metastasis. Biochim. Biophys. Acta. 560, 135–166 (1979).

  13. 13

    Dingemans, K.P. Behavior of intravenously injected malignant lymphoma cells. A morphologic study. J. Natl. Cancer Inst. 51, 1883– 1895 (1973).

  14. 14

    Lapis, K. Paku, S., Liotta, LA . Endothelialization of embolized tumor cells during metastasis formation. Clin. Exp. Metastasis 6, 73–89 (1988).

  15. 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).

  16. 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).

  17. 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).

  18. 18

    Frisch, S.M. & Francis, H. Disruption of epithelial cell-matrix interactions induces apoptosis. J. Cell Biol. 124, 619–626 (1994).

  19. 19

    Nikiforov M.A. et al. p53 modulation of anchorage independent growth and experimental metastasis. Oncogene 13, 1709– 1719 (1996).

  20. 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).

Download references

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.).

Author information

Correspondence to R.J. Muschel.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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

Download citation

Further reading