Obesity and prostate cancer progression : determining the role of macrophages in the tumor microenvironment

Obesity is associated with a greater risk of prostate cancer mortality. However, the mechanisms connecting obesity to the progression of prostate cancer remain unknown. This study determined the impact of obesity on the prostate tumor microenvironment (TME) by looking at macrophage recruitment and tumor-associated macrophage (TAM) polarization. Results from the study showed that obese mice had higher macrophage and TAM infiltration into the TME compared to normal weight mice in a PTEN knockout mouse model. To answer mechanistic questions, an in vitro model in which adipose stromal cells, prostate cancer cells, and macrophages were exposed to sera from obese or non-obese men, or conditioned media generated under obese or non-obese conditions was utilized. Obese conditions increased expression of recruiting and polarizing molecules in adipose and prostate cancer cells, and of TAM markers in macrophages. Since a high concentration of TAMS in tumors has been linked to progression in prostate cancer, the effects of obesity-induced TAMs on prostate cancer cells were observed by looking at characteristics of an invasive phenotype in vitro. Furthermore, the potential of targeting TAMs with rapamycin was studied, given that mTOR has been shown to be important for macrophage polarization and stabilization. Rapamycin selectively decreased viability of obesity-stimulated TAM-like macrophages compared to M1 macrophages in this model. Data suggest that obesity promotes macrophage infiltration into the prostate tumor microenvironment, and induces TAM polarization through the COX-2/PGE2 pathway. Additionally, the mTOR pathway appears to be involved in the survival of TAMs. This study offers a novel mechanistic approach to treat obese patients with prostate cancer.