TITLE:
Steroid Sulfatase Inhibitor Reduces Proliferation of Ishikawa Endometrial Cancer Cells in Co-Culture Systems
AUTHORS:
Mitsuo Nishimoto, Masafumi Toyoshima, Naomi Shiga, Hiroki Utsunomiya, Fumihiko Suzuki, Satoru Nagase, Hidekazu Nishigori, Takashi Suzuki, Hironobu Sasano, Kiyoshi Ito, Nobuo Yaegashi
KEYWORDS:
Aromatase Inhibitors, Co-Culture System, Endometrial Cancer, Estrogen, Estrogen Sulfatase Inhibitor
JOURNAL NAME:
Open Journal of Endocrine and Metabolic Diseases,
Vol.6 No.9,
September
16,
2016
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.