S100A10 FACILITATES THE TUMOR PROMOTING ASSOCIATION OF MACROPHAGES WITH TUMOR CELLS

Abstract

Hematopoietic cells are recruited to and co-opted by the growing tumor making expansive tumor growth possible. Although several cell types become associated with the growing tumor, macrophages play a fundamental role. The movement of macrophages across the basement membrane and through the extracellular matrix to the tumor site requires the activation of proteases, such as plasmin, at their cell surface. The proteolytic aspect of macrophage recruitment may represent an exploitable aspect of tumor growth in terms of therapeutic strategies. Here I show that the S100A10 protein facilitates the infiltration of macrophages into the site of tumor growth by stimulating the generation of the protease plasmin at their surface. Using a mouse model in which wild-type (WT) and S100A10-null mice are inoculated with tumor cells, a decrease in tumor-associated macrophages (TAMs) and greatly diminished tumor growth in tumors grown in S100A10-null mice was observed. Although tumor growth in S100A10-null mice could be restored by intraperitoneal injection of WT macrophages, S100A10-null macrophages only restored tumor growth when directly injected into the tumor. Lastly, selective depletion of macrophages from a WT mouse by liposome encapsulated clodronate treatment resulted in similar tumor growth deficits as in the S100A10-null mouse. These results highlight a new role for the S100A10 protein in the recruitment of TAMs to the tumor site and demonstrate a potential therapeutic strategy in which the tumor associated cells may be targeted.