Identification of Hyal2-expressing tumor-associated myeloid cells in cancer: implications for cancer-related inflammation through enhanced hyaluronan degradation

Increased presence of myeloid derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) in tumor tissue has been extensively reported. These cells represent a major constituent of tumor infiltrate and exhibit a distinct phenotype with immunosuppressive and tolerogenic functions. However, their role in the regulation of hyaluronan (HA) metabolism in the tumor microenvironment has not been established. Here we describe a novel function of tumor-associated myeloid cells related to the enhanced breakdown of extracellular HA in human bladder cancer tissue leading to accumulation of small HA fragments with MW <20 kDa. Increased fragmentation of extracellular HA and accumulation of low molecular weight HA (LMW-HA) in tumor tissue was associated with elevated production of multiple inflammatory cytokines, chemokines, and angiogenic factors. The fragmentation of HA by myeloid cells was mediated by the membrane-bound enzyme hyaluronidase 2 (Hyal2). The increased numbers of Hyal2+CD11b+ myeloid cells were detected in the tumor tissue as well as in the peripheral blood of bladder cancer patients. Co-expression of CD33 suggests that these cells belong to monocytic myeloid-derived suppressor cells. HA-degrading function of Hyal2-expressing MDSCs could be enhanced by exposure to tumor-conditioned medium, and IL-1{beta} was identified as one of factors involved in the stimulation of Hyal2 activity. CD44-mediated signaling plays an important role in the regulation of HA-degrading activity of Hyal2-expressing myeloid cells, since engagement of CD44 receptor with specific monoclonal antibody triggered translocation of Hyal2 enzyme to the cellular surface and also stimulated secretion of IL-1{beta}. Taken together, this work identifies the Hyal2-expressing tumor-associated myeloid cells, and links these cells to the accumulation of LMW-HA in the tumor microenvironment and cancer-related inflammation and angiogenesis.