Amos-Landgraf James M, Heijmans Jarom, Wielenga Mattheus C B, Dunkin Elisa, Krentz Kathy J, Clipson Linda, Ederveen Antwan G, Groothuis Patrick G, Mosselman Sietse, Muncan Vanesa, Hommes Daniel W, Shedlovsky Alexandra, Dove William F, van den Brink Gijs R
McArdle Laboratory for Cancer Research, Department of Oncology and Laboratory of Genetics, University of Wisconsin-Madison, Madison, WI 53706;
Tytgat Institute for Liver and Intestinal Research and Department of Gastroenterology and Hepatology, Academic Medical Center, 1105 AZ, Amsterdam, The Netherlands;
Proc Natl Acad Sci U S A. 2014 Nov 18;111(46):16514-9. doi: 10.1073/pnas.1323064111. Epub 2014 Nov 3.
It recently has been recognized that men develop colonic adenomas and carcinomas at an earlier age and at a higher rate than women. In the Apc(Pirc/+) (Pirc) rat model of early colonic cancer, this sex susceptibility was recapitulated, with male Pirc rats developing twice as many adenomas as females. Analysis of large datasets revealed that the Apc(Min/+) mouse also shows enhanced male susceptibility to adenomagenesis, but only in the colon. In addition, WT mice treated with injections of the carcinogen azoxymethane (AOM) showed increased numbers of colonic adenomas in males. The mechanism underlying these observations was investigated by manipulation of hormonal status. The preponderance of colonic adenomas in the Pirc rat model allowed a statistically significant investigation in vivo of the mechanism of sex hormone action on the development of colonic adenomas. Females depleted of endogenous hormones by ovariectomy did not exhibit a change in prevalence of adenomas, nor was any effect observed with replacement of one or a combination of female hormones. In contrast, depletion of male hormones by orchidectomy (castration) markedly protected the Pirc rat from adenoma development, whereas supplementation with testosterone reversed that effect. These observations were recapitulated in the AOM mouse model. Androgen receptor was undetectable in the colon or adenomas, making it likely that testosterone acts indirectly on the tumor lineage. Our findings suggest that indirect tumor-promoting effects of testosterone likely explain the disparity between the sexes in the development of colonic adenomas.
最近人们认识到，男性患结肠腺瘤和结肠癌的年龄比女性更早，发病率也更高。在早期结肠癌的Apc(Pirc/+)（Pirc）大鼠模型中，这种性别易感性得到了重现，雄性Pirc大鼠发生的腺瘤数量是雌性的两倍。对大型数据集的分析表明，Apc(Min/+)小鼠在腺瘤发生方面也表现出雄性易感性增强，但仅在结肠中如此。此外，用致癌物氧化偶氮甲烷（AOM）注射处理的野生型小鼠，雄性的结肠腺瘤数量增加。通过操纵激素状态来研究这些观察结果背后的机制。在Pirc大鼠模型中，结肠腺瘤占优势，这使得能够在体内对性激素作用于结肠腺瘤发生的机制进行具有统计学意义的研究。通过卵巢切除术使内源性激素耗竭的雌性，腺瘤患病率没有变化，补充一种或多种雌性激素也未观察到任何效果。相比之下，通过睾丸切除术（阉割）使雄性激素耗竭，可显著保护Pirc大鼠不发生腺瘤，而补充睾酮则会逆转这种效果。这些观察结果在AOM小鼠模型中得到了重现。在结肠或腺瘤中未检测到雄激素受体，这使得睾酮可能间接作用于肿瘤谱系。我们的研究结果表明，睾酮的间接促肿瘤作用可能解释了结肠腺瘤发生中两性之间的差异。
