Fibroblasts in omentum activated by tumor cells promote ovarian cancer growth, adhesion and invasiveness.
Omentum metastasis is a common occurrence in epithelial ovarian cancer (EOC), which is often accompanied by ascites that facilitates the spread of EOC cells. A subpopulation of fibroblasts-the cancer-associated fibroblasts (CAFs) are important promoters of tumor progression. We have shown previously that CAFs exist not only in omentum with EOC metastasis but also in omentum without metastasis. In the present study, using primary human fibroblasts isolated from normal omentum (NFs) and omentum with ovarian cancer metastasis (CAFs), we established in vitro coculture models and a 3D culture model mimicking human omentum structure for investigation of interactions between fibroblasts and cancer cells. We demonstrate that EOC cells activate NFs and promote their proliferation via transforming growth factor-β1 (TGF-β1) signaling, and the activated fibroblasts contribute to the invasion and adhesion of EOC cells. Moreover, EOC cells and NFs coculture led to overexpression of hepatocyte growth factor (HGF) and matrix metalloproteinase-2 (MMP-2) and adhesion and invasion of EOC cells could be partially suppressed by blocking the function of HGF or MMP-2. Additionally, mouse peritoneal dissemination models of EOC confirmed the activation of fibroblasts by cancer cells and the tumor growth- and metastasis-promoting effects of activated fibroblasts in vivo. Our findings indicate that activated fibroblasts in omentum form a congenial environment to promote EOC cells implantation. It is an intriguing concept that targeting the activation of omentum fibroblast through the inhibition of TGF-β1 signaling can be used as a new therapeutic strategy against ovarian cancer omentum metastases, which needs further study.
Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022 Wuhan, China.
Jing
J
Cai
Huijuan
H
Tang
Linjuan
L
Xu
Xiaoyi
X
Wang
Chun
C
Yang
Shasha
S
Ruan
Jianfeng
J
Guo
Sha
S
Hu
Zehua
Z
Wang
D000818:Animals; D000077216:Carcinoma, Ovarian Epithelial; D002448:Cell Adhesion; D002478:Cells, Cultured; D005260:Female; D005347:Fibroblasts / Q000502:physiology*; D017228:Hepatocyte Growth Factor / Q000502:physiology; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009375:Neoplasms, Glandular and Epithelial / Q000473:pathology*; D009852:Omentum / Q000473:pathology*; D010051:Ovarian Neoplasms / Q000473:pathology*; D053773:Transforming Growth Factor beta1 / Q000502:physiology
D053773:Transforming Growth Factor beta1; D017228:Hepatocyte Growth Factor; D020778:Matrix Metalloproteinase 2