Clinical & Experimental Metastasis

, Volume 25, Issue 4, pp 305–324 | Cite as

Stepping out of the flow: capillary extravasation in cancer metastasis

  • Fayth L. Miles
  • Freddie L. Pruitt
  • Kenneth L. van Golen
  • Carlton R. CooperEmail author
Review Paper


In order for cancer cells to successfully colonize a metastatic site, they must detach from the primary tumor using extracellular matrix-degrading proteases, intravasate and survive in the circulation, evade the immune response, and extravasate the vasculature to invade the target tissue parenchyma, where metastatic foci are established. Though many of the steps of metastasis are widely studied, the precise cellular interactions and molecular alterations associated with extravasation are unknown, and further study is needed to elucidate the mechanisms inherent to this process. Studies of leukocytes localized to inflamed tissue during the immune response may be used to elucidate the process of cancer extravasation, since leukocyte diapedesis through the vasculature involves critical adhesive interactions with endothelial cells, and both leukocytes and cancer cells express similar surface receptors capable of binding endothelial adhesion molecules. Thus, leukocyte extravasation during the inflammatory response has provided a model for transendothelial migration (TEM) of cancer cells. Leukocyte extravasation is characterized by a process whereby rolling mediated by cytokine-activated endothelial selectins is followed by firmer adhesions with β1 and β2 integrin subunits to an activated endothelium and subsequent diapedesis, which most likely involves activation of Rho GTPases, regulators of cytoskeletal rearrangements and motility. It is controversial whether such selectin-mediated rolling is necessary for TEM of cancer cells. However, it has been established that similar stable adhesions between tumor and endothelial cells precede cancer cell transmigration through the endothelium. Additionally, there is support for the preferential attachment of tumor cells to the endothelium and, accordingly, site-specific metastasis of cancer cells. Rho GTPases are critical to TEM of cancer cells as well, and some progress has been made in understanding the specific roles of the Rho GTPase family, though much is still unknown. As the mechanisms of cancer TEM are elucidated, new approaches to study and target metastasis may be utilized and developed.


Invasion Extravasation Endothelial Neoplasm Leukocytes 



We are very grateful to Dr. Robert A. Sikes for helpful discussion, suggestions and editorial assistance for this manuscript. Also, we are grateful to the editorial contributions provided by Dr. Mary C. Farach-Carson. Dr. Cooper and Ms. Miles were supported by a DoD hypothesis development award PC050554, as well as the NIH-K22 Career-Transition Award, 5K22CA971117-3 (CRC). Dr. van Golen is supported by a start-up package provided by the University of Delaware. All authors are, in part, supported by the Center for Translational Cancer Research provided by the state of Delaware.


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Copyright information

© Springer Science+Business Media B.V. 2007

Authors and Affiliations

  • Fayth L. Miles
    • 1
  • Freddie L. Pruitt
    • 1
  • Kenneth L. van Golen
    • 1
  • Carlton R. Cooper
    • 1
    • 2
    Email author
  1. 1.Department of Biological Sciences, Center for Translational Cancer ResearchUniversity of DelawareNewarkUSA
  2. 2.Department of Biological Sciences, Center for Translational Cancer ResearchUniversity of DelawareNewarkUSA

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