Selectin-Mediated Recruitment of Leukocytes Contributes to Metastatic Niche Formation and Chemokines Orchestrate this Process

Metastasis is the primary cause of cancer-related mortality and the adopted metastatic microenvironment significantly contributes this process. During hematogenous metastasis tumor cells interact with blood constituents and these contacts enhance the capacity to colonize distant organs. Selectins are vascular receptors that facilitate tumor cell interactions with platelets, leukocytes and the endothelium. At sites of metastatic initiation activated endothelium is always detected, which is associated with E-selectin expression. Here we provide evidence that E-selectin contributes to the recruitment of leukocytes and thereby promotes metastasis. We observed reduced metastasis in the absence of E-selectin using several mouse models. Tumor cell extravasation was dependent on endothelial activation, which in turn contributed to increased chemokine levels in metastatic tissues. Next we tested the hypothesis that local inhibition of chemokine CCL2 at metastatic sites can interfere with tumor cell extravasation and thereby reduce metastasis. The use of two different targeting strategies to the lungs showed an effective inhibition of metastatic seeding and thereby metastasis. Taken together, we present a new mechanism how selectin promotes early metastatic niche formation and thereby metastasis.