Abstract
Objectives: Estrogens significantly contribute toward the growth and development of endometrial cancers. Two principal pathways have been implicated in the final steps of estrogen synthesis: the steroid sulfatase (STS) and aromatase pathways. In this study, we aimed to evaluate the possible effects of tumor-stromal interactions on local estrogen biosynthesis in endometrial cancer. We also assessed the biological effects of inhibitors of steroid sulfatase and aromatase in the co-culture system compared with usual monocultures. Methods/Materials: We isolated stromal cells from endometrial cancer patients to examine local biosynthesis of estrogens and tumor-stromal interactions. Next we examined the effects of steroid sulfatase inhibitor and aromatase inhibitor in monoculture of endometrial cancer cell line (Ishikawa) and in a co-culture system involving an Ishikawa cells and stromal cells. Results: Estrogen receptor and steroid sulfatase mRNA levels in cancer cells were significantly higher in the co-cultures compared with the monocultures of endometrial cancer cells. Estradiol and androstenediol concentrations were also significantly higher in the co-cultured cells. Proliferation of the cancer cells was significantly increased through the steroid sulfatase pathway, which metabolizes androgens, estrone sulfate, and estradiol sulfate as its substrates. However, its proliferation was significantly decreased by the treatment of steroid sulfatase or aromatase inhibitors. The significant growth inhibition by the steroid sulfatase and aromatase inhibitors were also observed in the co-culture system. Conclusions: We evaluated the effects of STS inhibitor and aromatase inhibitors on the proliferation of estrogen-dependent endometrial cancer cells. Considering that intratumoral estrogen metabolism plays an important role, our co-culture systems provide an environment similar to that of the tumor in living patients in terms of metabolism and synthesis of intratumoral estrogens. The results of this study may aid in achieving improved clinical responses from patients treated with STS inhibitors.
Highlights
The incidence of endometrial cancer has increased rapidly, and it is one of the most common gynecologic malignancies in developed countries [1]
We aimed to evaluate the possible effects of tumor-stromal interactions on local estrogen biosynthesis in endometrial cancer
We aimed to evaluate the possible effects of tumor-stromal interactions on local estrogen biosynthesis in endometrial cancer and to assess the biological effects of inhibitors of STS and aromatase in the co-culture system compared with usual monocultures
Summary
The incidence of endometrial cancer has increased rapidly, and it is one of the most common gynecologic malignancies in developed countries [1]. Several studies have focused on intratumoral estrogen metabolism and biosynthesis and reported that estradiol (E2), estrone (E1), and testosterone levels are several times higher in tumor tissues than in serum [2]-[4]. This finding indicates that in situ estrogen metabolism, including its biosynthesis and degradation, plays a very important role in the development of endometrial proliferative disorders, such as endometrial hyperplasia [5], and in furthering the progression to endometrial cancer [2] [3] [6]-[13]. It has been reported that in situ estrogen activity may be regulated primarily by intratumoral STS [15] [16]
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