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Tks5 activation in mesothelial cells creates invasion front of peritoneal carcinomatosis

Oncogene volume 34, pages 3176–3187 (2015)Cite this article

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Abstract

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.

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Acknowledgements

We thank Murata K (Department of Environmental Health Sciences, Akita University School of Medicine) for advice and discussion about statistics. This work was supported by JSPS KAKENHI (Grant Nos 25290042 and 26640068 to MT) Takeda Science Foundation (MT) and the National Cancer Center Research and Development Fund (Grant No. 23-A-9 to MT).

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Authors and Affiliations

  1. Department of Molecular Medicine and Biochemistry, Akita University Graduate School of Medicine, Akita, Japan

    R Satoyoshi, N Aiba & M Tanaka

  2. Division of Translational Research, Exploratory Oncology and Clinical Trial Center, National Cancer Center, Chiba, Japan

    K Yanagihara

  3. Department of Surgical Oncology, Osaka City University Graduate School of Medicine, Osaka, Japan

    M Yashiro

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  1. R Satoyoshi
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  2. N Aiba
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Correspondence to M Tanaka.

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Satoyoshi, R., Aiba, N., Yanagihara, K. et al. Tks5 activation in mesothelial cells creates invasion front of peritoneal carcinomatosis. Oncogene 34, 3176–3187 (2015). https://doi.org/10.1038/onc.2014.246

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