Advertisement

Tumor Biology

, Volume 35, Issue 6, pp 6105–6111 | Cite as

Tumor-associated mesothelial cells are negative prognostic factors in gastric cancer and promote peritoneal dissemination of adherent gastric cancer cells by chemotaxis

  • Zhi-Feng Miao
  • Ting-Ting Zhao
  • Zhen-Ning Wang
  • Feng Miao
  • Ying-Ying Xu
  • Xiao-Yun Mao
  • Jian Gao
  • Hui-Mian Xu
Research Article

Abstract

Peritoneal dissemination is highly frequent in gastric cancer. Damage to human peritoneal mesothelial cell (HPMC) barriers provokes gastric cancer peritoneal dissemination (GCPD), the key events during GCPD, is characterized by fibroblastic development. In this study, we have studied the association between fibroblast activation protein (FAP) expression in peritoneum and the pathological features of the primary tumor. The clinical prognosis of gastric cancer patients was evaluated according to FAP expression. In a gastric cancer cell-HPMC co-culture system, expression of E-cadherin, α-smooth muscle actin, and FAP were evaluated by Western blotting. Gastric cancer cell migration and adhesion to HPMC were also assayed. Our results showed positive peritoneal staining of FAP in 36/86 cases (41.9 %), which was associated with a higher TNM stage in primary gastric cancer and higher incidence of GCPD (both p < 0.05). Survival analysis showed FAP expression was an independent prognostic factor of poor survival (p = 0.02). Peritoneum of FAP-positive expression exhibited a distinct fibrotic development and expressed higher level of the mesenchymal marker α-SMA, which was confirmed by the in vitro Western blot assay. In HPMC and gastric cancer cell adherence assay, SGC-7901 cells preferentially adhered to TA-HPMC at different cell densities (both p < 0.05). Additionally, SGC-7901 cells were more prone to chemotaxis by FAP-expressed tumor-associated–human peritoneal mesothelial cells (TA-HPMC) compared with HPMC co-cultured with normal gastric glandular epithelial cells in a time-dependent manner (both p < 0.05). Our study indicated a positive correlation between peritoneum FAP expression and GCPD. FAP-expressed TA-HPMC might be an important cellular component and instigator of GCPD.

Keywords

Peritoneal carcinomatosis Stomach cancer Tumor-associated human peritoneal mesothelial cell Prognosis Fibrotic disease 

Notes

Acknowledgments

We thank Prof. Feng Li for the excellent technical guidance and assistance. This work was support by the National Science Foundation of China (no. 81272718 and no. 81302125)

References

  1. 1.
    Zhang ZY, Ge HY. Micrometastasis in gastric cancer. Cancer Lett. 2013;336:34–45.CrossRefPubMedGoogle Scholar
  2. 2.
    Qiu MZ, Wang ZQ, Zhang DS, et al. Clinicopathological characteristics and prognostic analysis of gastric cancer in the young adult in China. Tumour Biol. 2011;32:509–14.CrossRefPubMedGoogle Scholar
  3. 3.
    Jayne D. Molecular biology of peritoneal carcinomatosis. Cancer Treat Res. 2007;134:21–33.PubMedGoogle Scholar
  4. 4.
    Glockzin G, Piso P. Current status and future directions in gastric cancer with peritoneal dissemination. Surg Oncol Clin N Am. 2012;21:625–33.CrossRefPubMedGoogle Scholar
  5. 5.
    Yashiro M, Chung YS, Nishimura S, et al. Fibrosis in the peritoneum induced by scirrhous gastric cancer cells may act as “soil” for peritoneal dissemination. Cancer. 1996;77:1668–75.CrossRefPubMedGoogle Scholar
  6. 6.
    Na D, Lv ZD, Liu FN, et al. Gastric cancer cell supernatant causes apoptosis and fibrosis in the peritoneal tissues and results in an environment favorable to peritoneal metastases, in vitro and in vivo. BMC Gastroenterol. 2012;12:34.PubMedCentralCrossRefPubMedGoogle Scholar
  7. 7.
    Wagner BJ, Löb S, Lindau D, et al. Simvastatin reduces tumor cell adhesion to human peritoneal mesothelial cells by decreased expression of VCAM-1 and β1 integrin. Int J Oncol. 2011;39:1593–600.PubMedGoogle Scholar
  8. 8.
    Ksiazek K, Mikuła-Pietrasik J, Catar R, et al. Oxidative stress-dependent increase in ICAM-1 expression promotes adhesion of colorectal and pancreatic cancers to the senescent peritoneal mesothelium. Int J Cancer. 2010;127:293–303.PubMedGoogle Scholar
  9. 9.
    Iwasa S, Okada K, Chen WT, et al. Increased expression of seprase, a membrane-type serine protease, is associated with lymph node metastasis in human colorectal cancer. Cancer Lett. 2005;227:229–36.CrossRefPubMedGoogle Scholar
  10. 10.
    Kraman M, Bambrough PJ, Arnold JN, et al. Suppression of antitumor immunity by stromal cells expressing fibroblast activation protein-alpha. Science. 2010;330:827–30.CrossRefPubMedGoogle Scholar
  11. 11.
    Lai D, Ma L, Wang F. Fibroblast activation protein regulates tumor-associated fibroblasts and epithelial ovarian cancer cells. Int J Oncol. 2012;41:541–50.PubMedGoogle Scholar
  12. 12.
    Lv ZD, Wang HB, Dong Q, et al. Mesothelial cells differentiate into fibroblast-like cells under the scirrhous gastric cancer microenvironment and promote peritoneal carcinomatosis in vitro and in vivo. Mol Cell Biochem. 2013;377:177–85.CrossRefPubMedGoogle Scholar
  13. 13.
    Lv ZD, Wang HB, Li FN, et al. TGF-ß1 induces peritoneal fibrosis by activating the Smad2 pathway in mesothelial cells and promotes peritoneal carcinomatosis. Int J Mol Med. 2012;29:373–9.PubMedGoogle Scholar
  14. 14.
    Zhou F, Li GY, Gao ZZ, et al. The TGF-ß1/Smad/CTGF pathway and corpus cavernosum fibrous-muscular alterations in rats with streptozotocin-induced diabetes. J Androl. 2012;33:651–9.CrossRefPubMedGoogle Scholar
  15. 15.
    Lv ZD, Na D, Liu FN, et al. Induction of gastric cancer cell adhesion through transforming growthfactor-beta1-mediated peritoneal fibrosis. J Exp Clin Cancer Res. 2010;29:139.PubMedCentralCrossRefPubMedGoogle Scholar
  16. 16.
    Tsukada T, Fushida S, Harada S, et al. The role of human peritoneal mesothelial cells in the fibrosis and progression of gastric cancer. Int J Oncol. 2012;41:476–82.PubMedCentralPubMedGoogle Scholar
  17. 17.
    Comen EA. Tracking the seed and tending the soil: evolving concepts in metastatic breast cancer. Discov Med. 2012;14:97–104.PubMedGoogle Scholar
  18. 18.
    Jiang CG, Lv L, Liu FR, et al. Downregulation of connective tissue growth factor inhibits the growth and invasion of gastric cancer cells and attenuates peritoneal dissemination. Mol Cancer. 2011;10:122.PubMedCentralCrossRefPubMedGoogle Scholar
  19. 19.
    Na D, Liu FN, Miao ZF, et al. Astragalus extract inhibits destruction of gastric cancer cells to mesothelial cells by anti-apoptosis. World J Gastroenterol. 2009;15:570–7.PubMedCentralCrossRefPubMedGoogle Scholar
  20. 20.
    Liu M, Xu J, Deng H. Tangled fibroblasts in tumor-stroma interactions. Int J Cancer. 2011;129:1795–805.CrossRefPubMedGoogle Scholar
  21. 21.
    Otranto M, Sarrazy V, Bonté F, et al. The role of the myofibroblast in tumor stroma remodeling. Cell Adhes Migr. 2012;6:203–19.CrossRefGoogle Scholar
  22. 22.
    Zhuang Z, Zhou R, Xu X, et al. Clinical significance of integrin αvβ6 expression effects on gastric carcinoma invasiveness and progression via cancer-associated fibroblasts. Med Oncol. 2013;30:580.CrossRefPubMedGoogle Scholar
  23. 23.
    Hu C, Wang Z, Zhai L, et al. Effects of cancer-associated fibroblasts on the migration and invasion abilities of SGC-7901 gastric cancer cells. Oncol Lett. 2013;5:609–12.PubMedCentralPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2014

Authors and Affiliations

  • Zhi-Feng Miao
    • 1
  • Ting-Ting Zhao
    • 2
  • Zhen-Ning Wang
    • 1
  • Feng Miao
    • 3
  • Ying-Ying Xu
    • 2
  • Xiao-Yun Mao
    • 2
  • Jian Gao
    • 4
  • Hui-Mian Xu
    • 1
  1. 1.Department of Surgical OncologyThe First Affiliated Hospital of China Medical UniversityShenyangChina
  2. 2.Department of Breast SurgeryThe First Affiliated Hospital of China Medical UniversityShenyangChina
  3. 3.Department of DigestionThe Fourth Affiliated Hospital of China Medical UniversityShenyangChina
  4. 4.Center of Laboratory Technology and Experimental MedicineChina Medical UniversityShenyangChina

Personalised recommendations