Pro‐tumoral behavior of omental adipocyte‐derived fibroblasts in tumor microenvironment at the metastatic site of ovarian cancer

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 protumorigenic 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.

Cancer-Associated Fibroblasts Influence the Biological Properties of Malignant Tumours via Paracrine Secretion and Exosome Production

“…Other candidate cell types hypothesised as precursors of CAFs and factors stimulating their formation [59][60][61][62][63][64][65] are included in Table 1. Members of the TGF-β family seem to be the most frequently discussed in this context as inducers of the transition of precursor cells to myofibroblasts [66].…”

Etiopathogenesis of ovarian cancer. An inflamm-aging entity?

“…Therefore, it has been suggested that organs rich in adipocytes, such as the omentum, may be sites of both metastasis and origin. That is, they may serve as a site of the initial seeding and transformation of malignant precursor cells that originate in other parts of the abdomen ( Iyoshi et al, 2021 ). This could explain why apparently cancer-free women are diagnosed with advanced-stage disease within a few months.…”

The recent advances of cancer associated fibroblasts in cancer progression and therapy

“…Though precise lineage tracing study has shown the origin of fibroblasts in healthy or injured tissues, the origins and specific activation processes of CAFs are still lacking ( 6 , 7 ). Several cells may be predecessors of CAFs, such as normal fibroblasts ( 8 ), mesenchymal stem cells (MSCs) ( 9 ), pancreatic stellate cells (PSCs) ( 10 ), epithelial cells ( 11 ), endothelial cells ( 12 ), adipocytes ( 13 ), pericytes ( 14 ), hematopoietic stem cells ( 15 ) and cancer stem cells (CSCs) ( 16 ). The changes in the microenvironment where these precursor cells exist in may be a primary inducer of CAF transition ( 3 ).…”