Transforming growth factor-β1 induces connective tissue growth factor expression and promotes peritoneal metastasis of gastric cancer

Abstract

Transforming Growth Factor-β1 (TGF-β1) is involved in human cancer development and progression. Nonetheless, the role of TGF-β1 as regards peritoneal metastasis of gastric cancer has not been completely characterized. In this study, we investigated the exact role of TGF-β1 on peritoneal metastasis of gastric cancer. The results indicated that human peritoneal mesothelial cells (HPMCs) exposed to TGF-β1 or serum free conditional medium (SF-CM) of SGC7901 which produced a large amount of TGF-β1 became exfoliated, apoptosis and exhibited signs of injury, and the tumor-mesothelial cell adhesion significantly increased. Connective tissue growth factor (CTGF) expression was also increased when HPMCs were exposed to TGF-β1 or SF-CM of SGC7901. However, these effects were significantly decreased when HPMCs were exposed to SF-CM of SGC7901- TGFβS, a TGF-β1 knockdown stable cell line. Animal studies revealed that nude mice injected with SGC7901- TGFβS cells featured a smaller number of peritoneal seeding nodules and lower expression of CTGF in ascites than the control cell lines. These findings suggest that TGF-β1 promotes peritoneal metastasis of gastric cancer and induces CTGF expression. Therefore, blockage of TGF-β1 or TGF-β1 signaling pathway might prevent and treat peritoneal metastasis of gastric cancer.

The role of transforming growth factor β in upper gastrointestinal cancers: A systematic review

“…[43] In two studies, TGF-β inhibition significantly reduced the number of peritoneal nodules in tumors grown from SGC-7901 cells. [34,56] Another study showed the same effect in tumors grown from HSC-39 cells. [52] The effect of TGF-β on non-tumor cells Several studies investigated the effect of TGF-β addition on mesothelial cells, fibroblasts, endothelial cells and immune cells.…”

“…[43][44][45][46][47][48][49][50] Thirteen studies assessed adhesion to either a fibronectin membrane or peritoneal mesothelial cells. [34,43,46,[51][52][53][54][55][56][57][58][59][60] Additionally, 11 studies tested invasion capacity by allowing cells to migrate toward a serum gradient for an extended period of time. [36,37,[43][44][45][46][47][48] Green = increased apoptosis or decreased proliferation, Grey = no effect, Red = increased proliferation.…”

“…Three studies injected BALB/c nude mice with cancer cells that were pretreated with 10 ng/mL TGF-β [43,46] or were miR-193b inhibited, [45] and measured the number of liver nodules after four weeks. Three studies used TGF-β knockdown cells [56] or treated BALB/c nude mice with TGF-β inhibitors [34,52] and measured the number of disseminated nodules on the peritoneum after four weeks. A summary of the results can be found in Fig.…”

“…[52,53] Additionally, TGF-β induced apoptosis in peritoneal mesothelial cells in three different studies. [51,55,56] Both Na et al and Gu et al reported that SGC-7901 cells induced migration in HPMCs, which was blocked by TβR inhibition (5.1 vs. 21.3% apoptotic cells, p < 0.05 [55]; 56.0 vs. 103.0 apoptotic cells per field, p < 0.01 [63]). Lastly, TGF-β and gastric cancer cells induced morphological changes in HPMCs, which became more spindle-like, had reduced cytoplasm volume and had reduced cell-to-cell adhesion.…”

“…Lastly, TGF-β and gastric cancer cells induced morphological changes in HPMCs, which became more spindle-like, had reduced cytoplasm volume and had reduced cell-to-cell adhesion. [55,56] When treated with TGF-β inhibition, gastric cancer cells could not induce these changes.…”