Blood Journal
Leading the way in experimental and clinical research in hematology

Selectin-mediated activation of endothelial cells induces expression of CCL5 and promotes metastasis through recruitment of monocytes

  1. Heinz Läubli1,2,
  2. Katharina-Susanne Spanaus3, and
  3. Lubor Borsig1,2
  1. 1Institute of Physiology, University of Zürich, Zürich;
  2. 2Zürich Center for Integrative Human Physiology, Zürich; and
  3. 3Institute of Clinical Chemistry, University Hospital Zürich, Zürich, Switzerland

Abstract

Hematogenous metastasis is promoted by interactions of tumor cells with leukocytes, platelets, and the endothelium in the local intravascular microenvironment. Here we show that the activation of the microvascular endothelium results in recruitment of monocytes to metastatic tumor cells and promotes the establishment of the metastatic microenvironment. This inflammatory-like endothelial response was observed in microvascular endothelial cells only. Microarray analysis of microvascular endothelial cells cocultured with tumor cells in the presence of leukocytes and platelets revealed a specific gene expression profile. Selectin-mediated interactions of tumor cells with platelets and leukocytes activated endothelial cells and induced production of C-C chemokine ligand 5 (CCL5). Inhibition of CCL5-dependent monocyte recruitment during the early phase of metastasis by a CCL5 receptor antagonist strongly reduced tumor cell survival and attenuated metastasis. Collectively, these findings demonstrate that the endothelial expression of CCL5 contributes to the formation of a permissive metastatic microenvironment.

  • Submitted October 28, 2008.
  • Accepted August 24, 2009.
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