BMP signaling is a therapeutic target in ovarian cancer

Tomohiko Fukuda,Ryo Tanabe,Hiroo Koyama,Risa Fukuda,Daizo Koinuma,Carl-Henrik Heldin,Aristidis Moustakas,Kohei Miyazono,Yoshinobu Hashizume

doi:10.1038/s41420-020-00377-w

Abstract

BMP signaling has been found to have tumor-promoting as well as tumor-suppressing effects in different types of tumors. In this study, we investigated the effects of BMP signaling and of BMP inhibitors on ovarian cancer (OC) cells in vitro and in vivo. High expression of BMP receptor 2 (BMPR2) correlated with poor overall survival of OC patients in the TCGA dataset. Both BMP2 and BMPR2 enhanced OC cell proliferation, whereas BMP receptor kinase inhibitors inhibited OC cell growth in cell culture as well as in a mouse model. BMP2 also augmented sphere formation, migration, and invasion of OC cells, and induced EMT. High BMP2 expression was observed after chemotherapy of OC patients in the GSE109934 dataset. In accordance, carboplatin, used for the treatment of OC patients, increased BMP2 secretion from OC cells, and induced EMT partially via activation of BMP signaling. Our data suggest that BMP signaling has tumor-promoting effects in OC, and that BMP inhibitors might be useful therapeutic agents for OC patients. Considering that carboplatin treatment augmented BMP2 secretion, the possibility to use a combination of BMP inhibitors and carboplatin in the treatment of OC patients, would be worth exploring.

Highlights

Ovarian cancer (OC) is the most lethal gynecologic cancer with an increasing incidence; 295,414 new cases and 184,799 deaths worldwide were reported in 20181
The Bone morphogenetic proteins (BMPs) signaling pathway is activated in OC The expression of mRNA for most BMP ligands and receptors was found to be frequently increased in OC by analysis of the TCGA OC database[23] (Fig. 1a)
To investigate the growth-promoting effect of BMP signaling further, OC cell lines were treated with the BMP receptor kinase inhibitors LDN193189 and RK78324

Summary

Introduction

Ovarian cancer (OC) is the most lethal gynecologic cancer with an increasing incidence; 295,414 new cases and 184,799 deaths worldwide were reported in 20181. Epithelial OC is the most common type, 70% of which consists of high-grade serous carcinoma[2]. Because OC disseminates intraperitoneally, many OC patients are diagnosed at advanced stages. Combination of surgery and chemotherapy is a standard treatment. OC often recurs even if patients show complete response to initial treatment. Cancer stem cells and epithelial-mesenchymal transition (EMT) are likely to be

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