The role of human peritoneal mesothelial cells in the fibrosis and progression of gastric cancer

Abstract

Peritoneal dissemination is the most frequent metastatic pattern of scirrhous gastric cancer. However, despite extensive research effort, disease outcomes have not improved sufficiently. Tumor progression and metastasis result from interactions between cancer and various cells in the stroma, including endothelial cells, immune cells and fibroblasts. Fibroblasts have been particularly well studied; they are known to change into carcinoma-associated fibroblasts (CAFs) and produce transforming growth factor β (TGF-β), which mediates cancer-stroma interactions. Here, we investigated whether TGF-β derived from cancer cells in the peritoneal microenvironment activates human peritoneal mesothelial cells (HPMCs), leading to the progression and fibrosis of gastric cancer. We found that activated HPMCs (a-HPMCs) took on a spindle shape formation, decreased the expression of E-cadherin and increased that of α-SMA. Furthermore, a-HPMCs became more invasive and upregulated proliferation of human gastric cancer-derived MKN45 cells following direct cell-cell contact. Notably, MKN45 cells co-cultured with a-HPMCs also acquired anchorage-independent cell growth and decreased expression of E-cadherin in vitro. To measure the effects of the co-culture in vivo, we developed a mouse xenograft model into which different culture products were subcutaneously injected. The largest tumors were observed in mice that had been given MKN45 cells co-cultured with a-HPMCs. Furthermore, these tumors contained HPMC-derived fibrous tissue. Thus, the epithelial-mesenchymal transition (EMT) of HPMCs appears to drive peritoneal dissemination and tumor fibrosis.

Mechanisms of peritoneal dissemination in gastric cancer (Review)

“…These results indicated that CAFs have a crucial role in the growth and invasion of gastric cancer cells (58). Another previous study verified that HPMCs are one source of CAFs (25). HPMCs have a spindle-shaped morphology following the stimulation of TGF-β and these activated HPMCs are more invasive.…”

“…Taken together, CAFs in gastric cancer originate from orthotopic fibroblasts, HPMCs and bone marrow-derived cells, and they promote the progression of gastric cancer in a number of ways (25,58,60). The CXCL12/CXCR4 axis may be required in the migration of CAFs.…”

“…Regarding gastric cancer, TGF-β1 levels detected using an ELISA with peritoneal wash fluid samples are associated with peritoneal dissemination and depth of invasion (18). Furthermore, TGF-β1 induces the EMT of HPMCs in vitro and in vivo (25). Subsequent previous studies have further demonstrated that TGF-β1 increases the expression of collagen I in rat peritoneal mesothelial cells via the c-Jun N-terminal kinase (JNK)/Smad3 signalling pathway, and of collagen III and fibronectin of HPMCs via Smad2 (26,27).…”

The Importance of Controlling the TGF-β Signaling Pathway in the Gastric Cancer Microenvironment

“…For example, bone marrow-derived mesenchymal stem cells, hematopoietic stem cells, epithelial cells that undergo the EMT, and endothelial cells that undergo the endothelial-mesenchymal transition are considered possible predecessors of CAFs (Figure 2). In gastric cancer, human peritoneal mesothelial cells (HPMCs) transform into myofibroblast-like cells following exposure to TGF-β, and these cells contribute to stromal fibrosis in a mouse xenograft model when coinoculated with MKN45 gastric cancer cells [66]. Moreover, in vivo experiment demonstrate that bone marrow-derived cells (fibrocytes) migrate and enhance tumor proliferation and fibrosis via the SDF-1/CXCR4 system [67].…”

Peritoneal myofibroblasts at metastatic foci promote dissemination of pancreatic cancer

“…Although myofibroblasts have been reported to derive from resident peritoneal fibroblasts, human peritoneal mesothelial cells (hPMCs) (16,17), bone marrow progenitor cells or the primary tumor itself (18,19), the origin of these myofibroblasts has not been clearly established. Also, during the initial stages of peritoneal (20)(21)(22)(23).…”