Abstract 2356: Pro-inflammatory macrophages promote prostate cancer initiation and progression via NOX2-mediated oxidative stress
Authors: Jones Kia J. , Bryant Latoya K. , Hinton Cimona V. 
Published: August 2015

In recent years, the causal relationship between inflammation and cancer has gained wider acceptance; however, many of the molecular and cellular mechanisms mediating this relationship remain unresolved. A key regulator of the link between inflammation and cancer are tumor-associated macrophages (TAMs). Derived primarily from circulating peripheral blood monocytes, TAMs form the major leukocytic infiltrate found within the stroma of many tumor types. Their interaction with neoplastic cells shape their differentiation and functional orientation into two phenotypically distinct subsets: the “classically” activated M1 macrophages and the “alternatively” activated M2 macrophages. Macrophages within the tumor microenvironment are thought to acquire an M2 phenotype characterized by production of pro-angiogenic factors, ECM degrading enzymes and up-regulation of anti-inflammatory responses, thereby promoting tumor progression. In contrast, M1 macrophages are regarded as anti-microbial and anti-tumorigenic due to their efficient production of pro-inflammatory cytokines, and reactive oxygen species (ROS).

While the generation of ROS during pro-inflammatory immune responses is an important aspect of host defense, excessive ROS production has also been implicated in the pathogenesis of various degenerative diseases, including cancer. However, despite the well-established role of M1 macrophages in generating high levels of reactive oxygen intermediates, they are still largely viewed as anti-tumorigenic. Interestingly, the membrane-associated enzymes, NADPH oxidases (NOXs), are major sources of ROS in macrophages. Thus, the goals of the current study is to aid in understanding the complex interaction between tumor cells and TAMs, and to investigate a potentially novel function of M1 macrophages in promoting prostate tumorigenesis. We hypothesize that prostate cancer (PCa) cells promote a pro-tumor microenvironment, characterized by increased inflammation and oxidative stress, in part, through M1 macrophage-mediated NOX-derived ROS production. Accordingly, our lab observed that PCa cell conditioned media efficiently recruited monocytes with increased recruitment ability directly proportional to increasing PCa cell line aggressiveness. Secondly, when compared with PCa cells cultured alone, PCa cells co-cultured with M1 macrophages exhibited significantly higher oxidative stress levels. Furthermore, upon silencing of NOX2 in M1 macrophages, we noted a decrease in fluorescent ROS staining when compared to control siRNA treated macrophages, suggesting the involvement of NOX2 in M1 macrophage-mediated ROS production. Lastly, we observed that M1-mediated ROS generation through NOX enzymes promotes prostate cancer cell invasiveness. Taken together, our results suggest a potentially novel pro-tumorigenic function of M1 macrophages in PCa, with specific regard to NOX2.

Citation Format: Kia J. Jones, Latoya K. Bryant, Cimona V. Hinton. Pro-inflammatory macrophages promote prostate cancer initiation and progression via NOX2-mediated oxidative stress. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2356. doi:10.1158/1538-7445.AM2015-2356