Tks5 activation in mesothelial cells creates invasion front of peritoneal carcinomatosis.

Scirrhous gastric cancer is frequently associated with peritoneal dissemination, and the interaction of cancer cells with peritoneal mesothelial cells (PMCs) is crucial for the establishment of the metastasis in the peritoneum. Although cells derived from PMCs are detected within tumors of peritoneal carcinomatosis, how PMCs are incorporated into tumor architecture is not understood. The present study shows that PMCs create the invasion front of peritoneal carcinomatosis, which depends on activation of Tks5 in PMCs. In peritoneal tumor implants, PMCs represent majority of cells located at the invasive edge of the cancer tissue. Exogenously implanted PMCs and host PMCs aggressively invade into abdominal wall upon the peritoneal inoculation of cancer cells, and PMCs locate ahead of cancer cells in the direction of invasion. Tks5, a substrate of Src kinase, is predominantly expressed in the PMCs of cancer tissue, and promotes the invasion of PMCs and cancer cells. Expression and activation of Tks5 was induced in PMCs following their exposure to gastric cancer cells, and increased Tks5 expression was detected in PMCs located at the invasion front. Reduced Tks5 expression in PMCs blocked PMC invasion, which in turn prevents cancer cell invasion both in vitro and in vivo. The peritoneal dissemination of gastric cancer was significantly increased by mixing cancer cells and PMCs, and was suppressed by knockdown of Tks5 in PMCs. These results suggest that cancer-activated PMCs create invasion front by guiding cancer cells. Signaling leading to Tks5 activation in PMCs may be a suitable therapeutic target for prevention of peritoneal carcinomatosis.

Asporin activates coordinated invasion of scirrhous gastric cancer and cancer-associated fibroblasts.

Scirrhous gastric cancer, which has the worst prognosis among the various types of gastric cancer, is highly invasive and associated with abundant stromal fibroblasts. Although cancer-associated fibroblasts (CAFs) have been proposed to generate a tumor-supportive extracellular matrix that promotes the expansion of this type of cancer, the molecular mechanisms by which CAFs assist cancer cells are not yet fully understood. Here, we show for the first time that Asporin, a small leucine-rich proteoglycan (SLRP), is predominantly expressed in CAFs, and has essential roles in promoting co-invasion of CAFs and cancer cells. CAFs of scirrhous gastric cancer possess high potential for invasion, and invasion by CAFs frequently proceeded invasion by cancer cells, both in vitro and in vivo. Expression of Asporin was induced in fibroblasts by exposure to gastric cancer cells. Asporin secreted from CAFs activates Rac1 via an interaction with CD44 and promotes invasion by CAFs themselves. Moreover, Asporin promoted invasion by neighboring cancer cells, via paracrine effects mediated by activation of the CD44-Rac1 pathway. These results suggest that Asporin is a unique SLRP that promotes progression of scirrhous gastric cancer and is required for coordinated invasion by CAFs and cancer cells. Therefore, Asporin may represent a new therapeutic target molecule for the development of drugs aimed at manipulating the cancer microenvironment.