Pro‐tumoral behavior of omental adipocyte‐derived fibroblasts in tumor microenvironment at the metastatic site of ovarian cancer. Issue 11 (16th September 2021)

• Record Type: Journal Article
• Authors: Iyoshi, Shohei; Yoshihara, Masato; Nakamura, Kae; Sugiyama, Mai; Koya, Yoshihiro; Kitami, Kazuhisa; Uno, Kaname; Mogi, Kazumasa; Tano, Sho; Tomita, Hiroyuki; Kajiwara, Keiji; Taki, Masayasu; Yamaguchi, Shigehiro; Nawa, Akihiro; Kajiyama, Hiroaki
• Is Part Of: International journal of cancer. Volume 149:Issue 11(2021)
• Page Start: 1961
• Page End: 1972
• Publication Date: 2021-09-16
• Subjects: adipocyte -- dedifferentiation -- ovarian cancer -- tumor microenvironment; Cancer -- Periodicals; Cancer -- Prevention -- Periodicals; 616.994
• DOI: 10.1002/ijc.33770
• Languages: English
• ISSNs: 0020-7136

Abstract

Abstract: Adipocyte‐rich omentum offers "good soil" for disseminating ovarian cancer (OvCa), contributing to therapeutic difficulty. However, little is understood about the association between adipocytes and tumor growth at peritoneal dissemination site. Herein, we report the induction of adipocyte dedifferentiation by OvCa cells and pro‐tumorigenic effects of resulted adipocyte‐derived fibroblasts. We confirmed that malignant ascites promoted the dedifferentiation of the primary human adipocytes obtained from surgical omental specimen into omental adipocyte‐derived fibroblast (O‐ADF) that possess both mesenchymal stem cell and myofibroblast‐like features. This promotion of dedifferentiation by malignant ascites was blocked by addition of Wnt signaling inhibitor. The effects of dedifferentiated adipocytes in proliferation and migration of OvCa cells were analyzed with in vitro coculturing experimental models and in vivo mice model, and we demonstrated that OvCa cell lines showed enhanced proliferative characteristics, as well as increased migratory abilities upon coculturing with O‐ADF. Additionally, exogenous transforming growth factor‐β1 augmented desmoplastic morphological change of O‐ADF, leading to higher proliferative ability. Our results suggest that OvCa cells promote dedifferentiation of peritoneal adipocytes by activating Wnt/β‐catenin signaling, and generated O‐ADFs exhibit pro‐tumoral hallmarks. Abstract : What's new? Adipocyte‐rich omentum offers a fertile ground for disseminating ovarian cancer. However, the association between adipocytes and tumour growth at the peritoneal dissemination site remains poorly understood. Here, the authors show that ovarian cancer cells promote the dedifferentiation of peritoneal adipocytes into fibroblasts by activating the Wnt/β‐catenin signalling pathway. The generated omental adipocyte‐derived fibroblasts were able to boost the proliferation of ovarian cancer cells in their vicinity. The study sheds light on the possibility that ovarian cancer not only uses omental adipocytes as a fuel source but also turns them into cancer‐associated fibroblast‐like supporters with pro‐tumour functionalities.