Abstract
Previous epidemiologic and in vitro studies have indicated a potential involvement of estrogens in the pathogenesis of human colon carcinoma, but the precise roles of estrogens have remained largely unknown. Therefore, in this study, we first measured intratumoral concentrations of estrogens in 53 colon carcinomas using liquid chromatography-electrospray ionization tandem mass spectrometry (LC-ESI-MS). Tissue concentrations of total estrogen [estrone (E(1)) + estradiol] and E(1) were significantly (2.0- and 2.4-fold, respectively) higher in colon carcinoma tissues than in nonneoplastic colonic mucosa (n = 31), and higher intratumoral concentrations of total estrogen and E(1) were significantly associated with adverse clinical outcome. Intratumoral concentration of total estrogen was significantly associated with the combined status of steroid sulfatase (STS) and estrogen sulfotransferase (EST), but not with that of aromatase. Thus, we subsequently examined the STS/EST status in 328 colon carcinomas using immunohistochemistry. Immunoreactivities for STS and EST were detected in 61% and 44% of the cases, respectively. The -/+ group of the STS/EST status was inversely associated with Dukes' stage, depth of invasion, lymph node metastasis, and distant metastasis and positively correlated with Ki-67 labeling index of the carcinomas. In addition, this -/+ group had significantly longer survival, and a multivariate analysis revealed the STS/EST status as an independent prognostic factor. Results from our present study showed that the STS/EST status of carcinoma tissue determined intratumoral estrogen levels and could be a significant prognostic factor in colon carcinoma, suggesting that estrogens are locally produced mainly through the sulfatase pathway and play important roles in the progression of the disease.
Highlights
Colon cancer is the third leading cause of cancer-related deaths in both men and women in the United States [1]
When the cases were divided into À/+ and others, the STS/estrogen sulfotransferase (EST) status was significantly associated with the intratumoral concentrations of total estrogen (P < 0.001), E1 (P < 0.001), and E2 (P = 0.002) in the 53 colon carcinoma tissues examined (Fig. 3C)
Previous study in breast carcinoma showed that tissue concentration of total estrogen was 1.9-fold higher in breast carcinoma than in corresponding nonneoplastic breast tissue in postmenopausal women [27], whereas the plasma levels of E1 and E2 were similar in normal women and breast carcinoma patients both before and after menopause [28]
Summary
Colon cancer is the third leading cause of cancer-related deaths in both men and women in the United States [1]. 9), and some colon carcinoma cells are responsive to estrogens [10,11,12]. It is well known that estrogens are locally produced from circulating inactive steroids in estrogen-dependent tumors, such as breast carcinoma, through sulfatase and aromatase pathways In this study, we first measured tissue concentrations of estrogens in 53 colon carcinoma tissues and correlated these findings with immunoreactivities for STS, EST, and aromatase. The result showed a strong association between the intratumoral estrogen concentrations and STS/EST status, so we subsequently examined the STS/EST status in 328 colon carcinomas to obtain better understanding of the role and significance of estrogenic actions in colon carcinoma
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