Cancer esearch oenvironment and Immunology luronan Deficiency in Tumor Stroma Impairs Macrophage R fficking and Tumor Neovascularization

Downlo pite the importance of stromal cells in tumor progression, our overall understanding of the molecular s that regulate the complex cellular interactions within tumor stroma is limited. Here, we provide le lines of evidence that tumor-associated macrophages (TAM) preferentially traffic to stromal areas d within tumors in a manner dependent on a hyaluronan (HA)–rich tumor microenvironment. To s the role of stroma-derived HA in macrophage recruitment, we disrupted the HA synthase 2 (Has2) n stromal fibroblasts using conditional gene targeting. The Has2 null fibroblasts showed severe ment in recruiting macrophages when inoculated with tumor cells into nude mice, which shows the bution of stroma-derived HA in intratumoral macrophage mobilization. Furthermore, a deficiency in al HA attenuated tumor angiogenesis and lymphangiogenesis concomitantly with impaired macrophage tment. Taken together, our results suggest that stromal HA serves as a microenvironmental signal for recrui the recruitment of TAMs, which are key regulatory cells involved in tumor neovascularization. Cancer Res; 70(18); 7073–83. ©2010 AACR.