Steroid Sulfatase Inhibitor Reduces Proliferation of Ishikawa Endometrial Cancer Cells in Co-Culture Systems  

作　　者：Mitsuo Nishimoto Masafumi Toyoshima Naomi Shiga Hiroki Utsunomiya Fumihiko Suzuki Satoru Nagase Hidekazu Nishigori Takashi Suzuki Hironobu Sasano Kiyoshi Ito Nobuo Yaegashi Mitsuo Nishimoto;Masafumi Toyoshima;Naomi Shiga;Hiroki Utsunomiya;Fumihiko Suzuki;Satoru Nagase;Hidekazu Nishigori;Takashi Suzuki;Hironobu Sasano;Kiyoshi Ito;Nobuo Yaegashi(Department of Obstetrics and Gynecology, Tohoku University School of Medicine, Sendai, Japan;Department of Obstetrics and Gynecology, Iwate Prefectural Iwai Hospital, Iwate, Japan;Department of Obstetrics and Gynecology, Yamagata University School of Medicine, Yamagata, Japan;Department of Pathology, Tohoku University School of Medicine, Sendai, Japan;Department of Disaster Obstetrics and Gynecology, International Research Institute of Disaster Science, Tohoku University, Sendai, Japan)

机构地区：[1]Department of Obstetrics and Gynecology, Tohoku University School of Medicine, Sendai, Japan [2]Department of Obstetrics and Gynecology, Iwate Prefectural Iwai Hospital, Iwate, Japan [3]Department of Obstetrics and Gynecology, Yamagata University School of Medicine, Yamagata, Japan [4]Department of Pathology, Tohoku University School of Medicine, Sendai, Japan [5]Department of Disaster Obstetrics and Gynecology, International Research Institute of Disaster Science, Tohoku University, Sendai, Japan

出　　处：《Open Journal of Endocrine and Metabolic Diseases》2016年第9期193-204,共12页内分泌与新陈代谢疾病期刊（英文）

摘　　要：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 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

关 键 词：Aromatase Inhibitors Co-Culture System Endometrial Cancer ESTROGEN Estrogen Sulfatase Inhibitor 

分 类 号：R73[医药卫生—肿瘤]