Abstract 1532: The role of Arg-1+iNOS+ tumor-associated macrophages and nitric oxide on tumor microenviroment after high-dose irradiation.
Authors: Hong Ji-Hong , Fu Sheng-Yung , Chen Fang-Hsin , Wang Chun-Chieh , Chiang Chi-Shiun 
Published: August 2014

Tumor-associated macrophages (TAMs) are a major non-cancer component in solid tumors and actively participate in remodeling tumor microenvironment after a variety of treatment; however their functions in irradiated tumors are not fully clarified. Our previous studies showed that high-dose irradiation to TRAMP-C1 tumor (a mouse prostate cancer cell line) decreased micro-vascular density (MVD) and induced CD68+ TAMs aggregation at avascular hypoxia region. These findings drive us to examine if these aggregated CD68+ TAMs promote regrowth of irradiated tumors. The TRAMP-C1 tumor cells were i.m. injection into shank muscle and irradiated with single-dose 25Gy at size of 4mm diameter. Sutent, a tyrosine kinase inhibitor, was i.p. injected (20mg/kg per day) to some mice and served as a model for hypoxia induced by anti-angiogenesis treatment. Tumors treated with Sutent alone also had decreased MVD and large amount of avascular hypoxia, but the aggregation of CD68+ TAMs in avascular hypoxia region was only observed in irradiated tumors, not in sutent-treated tumors; this finding suggests this aggregation of CD68+ TAMs in hypoxic region is not a universal finding and could be specific for irradiated tumor microenvironment. The phenotype of TAMs in regions with and without aggregation was studied and the differences existed. Arg-1+iNOS− TAMs were the dominant phenotype outside the avascular hypoxia regions and randomly distributed, but presence and accumulation of Arg-1+iNOS+ TAMs in avascular hypoxia regions was detected. The NOS inhibitor, L-NAME (500mg/L in drinking water), was therefore used to block the effects of nitric oxide produced from specific Arg-1+iNOS+ TAMs accumulated in avascular hypoxia region. The blockade of nitric oxide delayed tumor regrowth in irradiated but not in control tumors. Aggregation of TAMs and presence of Arg-1+ iNOS+ TAMs in avascular hypoxia regions were totally vanished in tumors treated with NOS inhibitor. In addition, the MVD was further decreased and percentages of avascular hypoxia regions were increased in the irradiated tumor treated with NOS inhibitor. These findings suggested that Arg-1+iNOS+TAMs accumulated in avascular hypoxia regions promote tumor regrowth after irradiation, and nitric oxide blockage is a potential strategy to improve the effects of radiotherapy. (This work is supported by grants 101-2314-B-182A-129-MY3 from National Science Council, Taiwan, CMRPG390943 from Chang Gung Memorial Hospital)

Citation Format: Ji-Hong Hong, Sheng-Yung Fu, Fang-Hsin Chen, Chun-Chieh Wang, Chi-Shiun Chiang. The role of Arg-1+iNOS+ tumor-associated macrophages and nitric oxide on tumor microenviroment after high-dose irradiation. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1532. doi:10.1158/1538-7445.AM2013-1532