Effects of Obesity on the Regulation of Macrophage Population in the Prostate Tumor Microenvironment

Abstract

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 macrophage recruitment and tumor-associated macrophage (TAM) polarization in the prostate tumor microenvironment, since a high concentration of TAMs in tumors has been linked to progression in prostate cancer. We utilized an in vitro model in which pre-adipocytes, prostate cancer cells, and macrophages were exposed to sera from obese or nonobese men, or conditioned media generated under obese or nonobese conditions. Matrigel invasion chambers were used to assess macrophage recruitment in vitro, and immunohistochemical analysis evaluated recruitment in a PTEN knockout mouse model. qPCR was used to measure mRNA levels of CCL2, COX-2, IL-10, TGF-beta, VEGF-A, arginase-1, and MMP-9. PGE2 production was measured by ELISA. Obesity increased macrophage and TAM recruitment, and increased mRNA levels of TAM markers in macrophages. Similarly, obese conditions increased CCL2 and COX-2 expression, as well as PGE2 levels in prostate cancer cells. COX-2 inhibition resulted in lower expression of obesity-induced TAM markers. Our data suggest that obesity promotes macrophage infiltration into the prostate tumor microenvironment, and induces TAM polarization through the COX-2/PGE2 pathway.

Myeloid-derived suppressor cells coming of age

“…In vitro, macrophages coming from obese subjects or exposed to conditions mimicking the obese microenvironment showed increases in migration and upregulation of markers of TAM. In the same study, it was also demonstrated that obesity promoted macrophages infiltration in the prostate tumor microenvironment, and induced TAM polarization through the COX2-PGE2 pathway 155 .…”

Role of systemic inflammatory response markers in urological malignancy

“…Among these risk factors, obesity is associated with the development of kidney and PCs . A recent in vitro study regarding PC showed that obesity promotes macrophage infiltration into the prostate tumor microenvironment, inducing tumor‐associated macrophage polarization through the COX‐2/PGE2 pathway . In contrast, cancer cells per se elicit inflammation by recruitment and activation of inflammatory cells in the tumor microenvironment …”

“…2 A recent in vitro study regarding PC showed that obesity promotes macrophage infiltration into the prostate tumor microenvironment, inducing tumor-associated macrophage polarization through the COX-2/PGE2 pathway. 3 In contrast, cancer cells per se elicit inflammation by recruitment and activation of inflammatory cells in the tumor microenvironment. 4 In the urological cancer research field, several studies have shown an association among infiltration of inflammatory cells, such as neutrophils and macrophages, tumor aggressiveness, and poor prognosis.…”

Polarization of M2 Macrophages by Interaction between Prostate Cancer Cells Treated with Trichomonas vaginalis and Adipocytes

“…CCL2 is one of the key chemokines involved in attracting monocytes and macrophages, and it has been found to circulate at higher levels in obesity. Moreover, adipose cells are major contributors to CCL2 levels [30,31], and expression of CCL2 along with numbers of macrophages increases in the prostate cancer tissue of obese mice [32]. In this study, CCL2 produced from adipocyte activated by TCM attracted macrophages more strongly than ACM, which contained less CCL2 (Fig.…”