CYTOKINE REPERTOIRE DURING MATURATION OF MONOCYTES TO MACROPHAGES WITHIN SPHEROIDS OF MALIGNANT AND NONMALIGNANT UROTHELIAL CELL-LINES

Terminal maturation of human blood monocytes to macrophages (MAC) in v ivo is believed to be important for the morphology, antigen expression and functional activity of the resulting MAC population. This process is modulated by the specific tissue micro-environment to which blood monocytes migrate upon leaving the vasculature. Tumor-associated macro phages (TAM) are a special type of NAG, and little is known about the modulating capacity of the tumor environment on monocyte-to-MAC differ entiation. By co-culturing 8-dimensional multicellular spheroids (MCS) of the urothelial-bladder-carcinoma cell fines J82 and RT4 with human monocytes/MAC we generated TAM in vitro. For comparison, monocytes/MA C were co-cultured with the non-tumorigenic urothelial cell line HCV29 . The effects on monocyte differentiation were analyzed, particularly with respect to cytokine release. Monocyte maturation was modulated wi thin the tumor spheroid dependent upon the tumor cell type. Monocytes co-cultured with MCS of the poorly differentiated J82 carcinoma sponta neously produced high amounts of IL-IP and IL-6, but only low amounts of TNF-alpha, which could be Further increased by the addition of LPS. This cytokine pattern is characteristic for monocytes and remained co nstant for up to 8 days in J82-MCS co-cultures, However; in RT4-MCS an d HCV29-MCS co-cultures, the initial cytokine pattern changed and afte r 8 days corresponded well to that of MAC differentiated in vitro with out tumor contact. In addition to functional parameters, we analyzed t he morphology of J82-MCS-TAM and found that they displayed a monocytel ike morphology. Our data indicate that (1) tumor cells can influence m onocyte-to-MAC differentiation, giving rise to TAM with monocyte-speci fic phenotypic properties; and (2) this capacity is dependent on the t ype of tumor cell. (C) 1998 Wiley-Liss, Inc.