Journal
INTERNATIONAL JOURNAL OF CANCER
Volume 149, Issue 11, Pages 1961-1972Publisher
WILEY
DOI: 10.1002/ijc.33770
Keywords
adipocyte; dedifferentiation; ovarian cancer; tumor microenvironment
Categories
Funding
- Japan Society for the Promotion of Science [17H04338, 19H03797, 20H03824]
- Grants-in-Aid for Scientific Research [19H03797, 20H03824, 17H04338] Funding Source: KAKEN
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The study demonstrated that OvCa cells induce dedifferentiation of peritoneal adipocytes, resulting in the generation of O-ADFs with pro-tumoral characteristics. Inhibition of Wnt signaling pathway blocked the dedifferentiation effect of malignant ascites on adipocytes.
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-beta 1 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/beta-catenin signaling, and generated O-ADFs exhibit pro-tumoral hallmarks.
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