Targeting Tumor Cell-Platelet Interaction in Breast Cancer Metastasis

Metastatic cells often use the bloodstream to colonize distant target organs. To do this, tumor cells must detach from the primary tumor, gain access to blood vessels, and survive and manage the unique conditions in the vasculature. In this environment, tumor cells are confronted with plasma proteins, erythrocytes, leukocytes and platelets. The metastatic cells are further exposed to shear forces that are generated by blood flow and physically oppose cell attachment. It is generally accepted that fairly large numbers of cells from a primary tumor enter the circulation. However, only few will give rise to metastases [1]. To colonize their target organs successfully, tumor cells must attach to vascular endothelial cells or components of the vessel wall. This is mediated by specific adhesive functions of tumor cell receptors, including integrins. In the live host, it is not clear whether tumor cells attach directly to the endothelium. They may require crosslinking plasma protein ligands and support by platelets and/or leukocytes to adhere to the vessel wall in the presence of flow dependent shear forces [2]. Tumor cells that fail to attach are rapidly cleared from the circulation. Metastatic cells that manage to arrest within microvessels of their target organs either extravasate, or start to proliferate at the attachment site [3]. Cells that cannot proliferate within the vasculature undergo rapid apoptosis [4]. Non-proliferating extravasated cells may remain dormant for extended periods of time [5]. Failure to proliferate within target organs of metastasis is mediated, at least in part, by metastasis suppressor genes [6]. Interestingly, these genes do not affect primary tumor growth [7]. Their mechanism of action and relation to the functionality of adhesion molecules are still unclear [8]. However, integrin supported adhesion of circulating tumor cells, and their interaction with platelets within the vasculature not only represents the first critical step toward target organ colonization, but also contributes to tumor cell survival and proliferation at the secondary site [9] (fig. 1).