Galván G C, Johnson C B, Price R S, Liss M A, Jolly C A, deGraffenried L A
a Department of Nutritional Sciences , The University of Texas at Austin , Austin , Texas , USA.
b School of Family and Consumer Sciences, Nutrition and Foods Program , Texas State University , San Marcos , Texas , USA.
Nutr Cancer. 2017 Oct;69(7):996-1002. doi: 10.1080/01635581.2017.1359320. Epub 2017 Sep 25.
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.
肥胖与前列腺癌死亡风险增加相关。然而，将肥胖与前列腺癌进展联系起来的机制仍不清楚。本研究确定了肥胖对前列腺肿瘤微环境中巨噬细胞募集和肿瘤相关巨噬细胞（TAM）极化的影响，因为肿瘤中高浓度的TAM与前列腺癌进展有关。我们利用了一种体外模型，其中前脂肪细胞、前列腺癌细胞和巨噬细胞暴露于肥胖或非肥胖男性的血清中，或暴露于在肥胖或非肥胖条件下产生的条件培养基中。使用基质胶侵袭小室评估体外巨噬细胞募集，免疫组化分析评估PTEN基因敲除小鼠模型中的募集情况。qPCR用于测量CCL2、COX-2、IL-10、TGF-β、VEGF-A、精氨酸酶-1和MMP-9的mRNA水平。通过ELISA测量PGE2的产生。肥胖增加了巨噬细胞和TAM的募集，并增加了巨噬细胞中TAM标志物的mRNA水平。同样，肥胖条件增加了前列腺癌细胞中CCL2和COX-2的表达以及PGE2水平。COX-2抑制导致肥胖诱导的TAM标志物表达降低。我们的数据表明，肥胖促进巨噬细胞浸润到前列腺肿瘤微环境中，并通过COX-2/PGE2途径诱导TAM极化。
