Cross-talk between human monocytes and cancer cells during reactive oxygen intermediates generation: the essential role of hyaluronan.

Abstract

Human monocytes exhibit considerable cytocidal activity against tumor (but not normal cells) associated, at least partly, with the generation of reactive oxygen intermediates (ROIs). The present study examined the role of surface determinants and hyaluronan (HA) in the induction of ROI production by human monocytes stimulated with cancer cells, as measured by luminol-enhanced chemiluminescence (CL). The inhibitory effect of monoclonal antibodies (MAbs) indicated the engagement of CD18, CD29 and CD44 adhesion molecules. Preincubation of monocytes and tumor cells, expressing CD44 determinants, with either anti-CD44 MAb or HA inhibited CL generation. Addition of HA to monocytes decreased the expression of CD44 and induced CL response. Supernatants from the cultures of tumor cells stimulated CL response of monocytes, an effect that was abolished by treatment of the supernatants with hyaluronidase (HAase) or by preincubation of monocytes with an anti-CD44 MAb. These results indicate that several surface molecules of monocytes, including CD44, are required to trigger the generation of ROI after their contact with tumor cells, whereas HA overexpressed on some cancer cells may allow monocytes (via CD44) to distinguish between transformed and normal cells. However, blocking of CD44 on monocytes by free HA dampens their response to tumor cells. Taken together, these observations suggest that the presence of HA in the tumor stroma may modulate effector functions of infiltrating macrophages and their interactions with cancer cells in situ.