Testosterone strongly enhances azoxymethane/dextran sulfate sodium-induced colorectal cancer development in C57BL/6 mice

Abstract

Colorectal cancer (CRC) is known to occur more frequently in males than in females, with sex hormones reportedly influencing the development. The purpose of the study was to investigate whether orchiectomy in C57BL/6 male mice reduces colorectal tumorigenesis and whether testosterone administration increases tumorigenesis after orchiectomy in an azoxymethane (AOM)/dextran sulfate sodium (DSS) mouse model. Clinical symptoms, including colitis and tumor incidence, were evaluated in the absence or presence of testosterone in AOM/DSS-treated male, as well as orchiectomized (ORX) male and female mice. The levels of serum testosterone and colonic myeloperoxidase, interleukin (IL)-1 beta, and IL-6 were measured by ELISA. Target mRNA expression was assessed by quantitative real-time PCR. Orchiectomy significantly diminished the AOM/DSS-induced colitis indices, including disease activity index, colon shortening, and histological severity at week 2, and decreased tumor numbers and incidence rates in the distal part of the colon increased following AOM/DSS administration at week 13; this reduction was reversed by testosterone supplementation. Furthermore, it was confirmed that the ELISA level (MPO and IL-1 beta) and the mRNA expression of the inflammatory mediators (COX-2 and iNOS) were maintained at high levels in the tumors of the testosterone-treated group compared with AOM/DSS groups. Interestingly, both endogenous and exogenous testosterone administrations were associated with tumor development (> 2 mm in size) and submucosal invasive cancer. Based on multivariate logistic regression analysis, testosterone was identified as a reasonable hazard factor for the progression of submucosal invasive cancer of the distal colon. In conclusion, endogenous and exogenous testosterone presented a stimulating effect on AOM/DSS-induced colitis and carcinogenicity.