Fibroblasts in omentum activated by tumor cells promote ovarian cancer growth, adhesion and invasiveness

Abstract

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.

Revisiting the Complexity of the Ovarian Cancer Microenvironment—Clinical Implications for Treatment Strategies

“…For example, it was showed that cytokines present within medium conditioned by an ovarian clear cell carcinoma cell line, ES-2, induced urokinase-type plasminogen activator (uPA) mRNA transcription in fibroblast cells, which is a protease implicated in cancer invasion and migration (45). Moreover, a recent study suggested that a premetastatic niche is created in the omentum through the activation and proliferation of NFs that are stimulated by the release of TGF-b1 from cancer cells (46). The establishment of the premetastatic niche would provide an altered microenvironment that enhances tumor invasion and implantation on peritoneal surfaces, through the secretion of hepatocyte growth factor (HGF) and MMP-2 (MMP2; ref.…”

“…The establishment of the premetastatic niche would provide an altered microenvironment that enhances tumor invasion and implantation on peritoneal surfaces, through the secretion of hepatocyte growth factor (HGF) and MMP-2 (MMP2; ref. 46). An inhibitor of the TGF-b type I receptor, A83-01, abrogated TGF-b1 signaling and reduced the proliferation and activation of NFs, as well as reduced a-SMA and MMP-2 expression in SKOV3/NF tumors (46).…”

“…46). An inhibitor of the TGF-b type I receptor, A83-01, abrogated TGF-b1 signaling and reduced the proliferation and activation of NFs, as well as reduced a-SMA and MMP-2 expression in SKOV3/NF tumors (46). Such interventions should be considered for further development, as targeting elements of signal transduction pathways between cancer and stromal cells will lead to reduced levels of EOC metastasis.…”

Peritoneal myofibroblasts at metastatic foci promote dissemination of pancreatic cancer

“…Moreover, stromal components were shown to promote the malignant behavior of pancreatic cancer cells, with myofibroblasts being the especially associated with cancer-stromal cell interactions in primary tumors (7,(9)(10)(11)(12). Few studies, however, assessed cancer-stromal cell interactions at peritoneally disseminated sites (13)(14)(15).…”

“…Thus, the interactions between cancer cells derived from the primary tumor and submesothelium layer components such as myofibroblasts may be a key to peritoneal dissemination (24). Hepatocyte growth factors (HGF) produced by human peritoneal myofibroblasts have been found to promote the peritoneal dissemination of gastric cancer (25), and myofibroblasts in omentum were shown to be activated by tumor cells and to promote the growth, adhesion and invasiveness of ovarian cancer (14). However, the roles of peritoneal myofibroblasts and their matrices in the peritoneal dissemination of pancreatic cancer remain unclear.…”