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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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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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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