HIF-1α is a crucial factor in the development of peritoneal dissemination via natural metastatic routes in scirrhous gastric cancer

  • Authors:
    • Shuusuke Miyake
    • Yoshihiko Kitajima
    • Jun Nakamura
    • Keita Kai
    • Kazuyoshi Yanagihara
    • Tomokazu Tanaka
    • Masatsugu Hiraki
    • Kohji Miyazaki
    • Hirokazu Noshiro
  • View Affiliations

  • Published online on: August 21, 2013     https://doi.org/10.3892/ijo.2013.2068
  • Pages: 1431-1440
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

The molecular mechanisms underlying the peritoneal dissemination of gastric cancer remain unclear. Using in vivo metastatic models, this study attempted to clarify the role of hypoxia inducible factor (HIF)-1α in the development of peritoneal dissemination of gastric cancer. HIF-1α knockdown (KD) cells were established in the scirrhous gastric cancer cell line 58As9. Using KD and control (SC) cells, the presence of peritoneal dissemination was assessed in orthotopic implantation (o.i.) and intraperitoneal injection (i.p.) models. A series of in vitro analyses were also conducted. Finally, tumor angiogenesis was immunohistochemically analyzed. In the o.i. model, peritoneal dissemination was more frequently observed in the SC mice (93%) compared to the KD mice (13%) (P<0.001). In the i.p. model, peritoneal dissemination occurred at a high rate in both types of mice; however, a greater number of nodules was observed in the KD mice (P=0.017). The in vitro assays showed that HIF-1α exerts unfavorable effects on anoikis resistance and adhesion to extracellular matrix. Angiogenesis and vascular invasion were more aggressive in the SC gastric tumors. Vascular invasion was present in the intratumoral regions of the disseminated nodules in the SC o.i., but not the i.p., mice. HIF-1α was found to be crucial for the development of peritoneal dissemination in o.i. model, which mimics natural metastasis. In contrast, HIF-1α played an inhibitory role in suppressing peritoneal dissemination in the i.p. model. These results indicate that peritoneal dissemination in o.i. mice may not act through a seeding mechanism. An immunohistochemical analysis demonstrated HIF-1α-activated angiogenesis and vascular invasion in stomach tumors. Furthermore, the results showed that the disseminated nodules observed in SC o.i. mice were formed via extravasation of cancer cells. We provide a possible mechanism in which peritoneal dissemination of gastric cancer develops via a vascular network whereby HIF-1α activates tumor angiogenesis.
View Figures
View References

Related Articles

Journal Cover

November 2013
Volume 43 Issue 5

Print ISSN: 1019-6439
Online ISSN:1791-2423

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
APA
Miyake, S., Kitajima, Y., Nakamura, J., Kai, K., Yanagihara, K., Tanaka, T. ... Noshiro, H. (2013). HIF-1α is a crucial factor in the development of peritoneal dissemination via natural metastatic routes in scirrhous gastric cancer. International Journal of Oncology, 43, 1431-1440. https://doi.org/10.3892/ijo.2013.2068
MLA
Miyake, S., Kitajima, Y., Nakamura, J., Kai, K., Yanagihara, K., Tanaka, T., Hiraki, M., Miyazaki, K., Noshiro, H."HIF-1α is a crucial factor in the development of peritoneal dissemination via natural metastatic routes in scirrhous gastric cancer". International Journal of Oncology 43.5 (2013): 1431-1440.
Chicago
Miyake, S., Kitajima, Y., Nakamura, J., Kai, K., Yanagihara, K., Tanaka, T., Hiraki, M., Miyazaki, K., Noshiro, H."HIF-1α is a crucial factor in the development of peritoneal dissemination via natural metastatic routes in scirrhous gastric cancer". International Journal of Oncology 43, no. 5 (2013): 1431-1440. https://doi.org/10.3892/ijo.2013.2068