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

Miyake,Shuusuke; Kitajima,Yoshihiko; Nakamura,Jun; Kai,Keita; Yanagihara,Kazuyoshi; Tanaka,Tomokazu; Hiraki,Masatsugu; Miyazaki,Kohji; Noshiro,Hirokazu

doi:10.3892/ijo.2013.2068

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

Affiliations: Department of Surgery, Saga University Faculty of Medicine, Saga 849-8501, Japan, Department of Pathology and Biodefense, Saga University Faculty of Medicine, Saga 849-8501, Japan, Division of Genetics, National Cancer Center Research Institute, Chuo-ku, Tokyo 104-0045, Japan, Saga University Faculty of Medicine, Saga 849-8501, Japan
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: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

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

1.	Garcia M, Jemal A, Ward EM, Center MM, Hao Y, Siegel RL and Thun MJ: Global Cancer Facts and Figures 2007. American Cancer Society; Atlanta, GA: 2007
2.	Chu DZ, Lang NP, Thompson C, Osteen PK and Westbrook KC: Peritoneal carcinomatosis in non gynecologic malignancy. A prospective study of prognostic factors. Cancer. 63:364–367. 1989. View Article : Google Scholar : PubMed/NCBI
3.	Yonemura Y, Kawamura T, Bandou E, Tsukiyama G, Endou Y and Miura M: The natural history of free cancer cells in the peritoneal cavity. Advances in Peritoneal Surface Oncology. Gonzalez-Moreno S: Springer; Berlin: pp. 11–23. 2007, View Article : Google Scholar
4.	Kotanagi H, Saito Y, Shiozawa N and Koyama K: Establishment of a human cancer cell line with high potential for peritoneal dissemination. J Gastroenterol. 30:437–438. 1995. View Article : Google Scholar : PubMed/NCBI
5.	Yanagihara K, Takigahira M, Tanaka H, et al: Development and biological analysis of peritoneal metastasis mouse models for human scirrhous stomach cancer. Cancer Sci. 96:323–332. 2005. View Article : Google Scholar : PubMed/NCBI
6.	Takei Y, Takigahira M, Mihara K, Tarumi Y and Yanagihara K: The metastasis-associated microRNA miR-516a-3p is a novel therapeutic target for inhibiting peritoneal dissemination of human scirrhous gastric cancer. Cancer Res. 71:1442–1453. 2010. View Article : Google Scholar
7.	Wang GL and Semenza GL: General involvement of hypoxiainducible factor 1 in transcriptional response to hypoxia. Proc Natl Acad Sci USA. 90:4304–4308. 1993. View Article : Google Scholar : PubMed/NCBI
8.	Semenza GL: HIF-1 and tumor progression: pathophysiology and therapeutics. Trends Mol Med. 8:S62–7. 2002. View Article : Google Scholar : PubMed/NCBI
9.	Semenza GL: Targeting HIF-1 for cancer therapy. Nat Rev Cancer. 3:721–732. 2003. View Article : Google Scholar
10.	Kitajima Y and Miyazaki K: The critical impact of HIF-1α on gastric cancer biology. Cancers. 5:15–26. 2013.
11.	Sumiyoshi Y, Kakeji Y, Egashira A, Mizokami K, Orita H and Maehara Y: Overexpression of hypoxia-inducible factor 1α and p53 is a marker for an unfavorable prognosis in gastric cancer. Clin Cancer Res. 12:5112–5117. 2006.
12.	Koukourakis MI, Giatromanolaki A, Skarlatos J, et al: Hypoxia inducible factor (HIF-1α and HIF-2α) expression in early esophageal cancer and response to photodynamic therapy and radiotherapy. Cancer Res. 61:1830–1832. 2001.
13.	Bos R, van der Groep P, Greijer AE, et al: Levels of hypoxiainducible factor-1α independently predict prognosis in patients with lymph node negative breast carcinoma. Cancer. 97:1573–1581. 2003.
14.	Nakanishi K, Hiroi S, Tominaga S, et al: Expression of hypoxiainducible factor-1α protein predicts survival in patients with tranitional cell carcinoma of the upper urinary tract. Clin Cancer Res. 11:2583–2590. 2005.
15.	Birner P, Schindl M, Obermair A, Breitenecker G and Oberhuber G: Expression of hypoxia-inducible factor 1α in epithelial ovarian tumors: its impact on prognosis and on response to chemotherapy. Clin Cancer Res. 7:1661–1668. 2001.
16.	Nakamura J, Kitajima Y, Kai K, Hashiguchi K, Hiraki M, Noshiro H and Miyazaki K: HIF-1alpha is an unfavorable determinant of relapse in gastric cancer patients who underwent curative surgery followed by adjuvant 5-FU chemotherapy. Int J Cancer. 127:1158–1171. 2010. View Article : Google Scholar
17.	Ide T, Kitajima Y, Miyoshi A, et al: Tumor-stromal cell interaction under hypoxia increases the invasiveness of pancreatic cancer cells through the hepatocyte growth factor/c-Met pathway. Int J Cancer. 119:2750–2759. 2006. View Article : Google Scholar : PubMed/NCBI
18.	Kitajima Y, Ide T, Ohtsuka T and Miyazaki K: Induction of hepatocyte growth factor activator gene expression under hypoxia activates the hepatocyte growth factor/c-Met system via hypoxia inducible factor-1 in pancreatic cancer. Cancer Sci. 99:1341–1347. 2008. View Article : Google Scholar
19.	Liu L, Sun L, Zhang H, et al: Hypoxia-mediated up-regulation of MGr1-Ag/37LRP in gastric cancers occurs via hypoxiainducible-factor 1-dependent mechanism and contributes to drug resistance. Int J Cancer. 124:1707–1715. 2009. View Article : Google Scholar : PubMed/NCBI
20.	Song IS, Wang AG, Yoon SY, Kim JM, Kim JH, Lee DS and Kim NS: Regulation of glucose metabolism-related genes and VEGF by HIF-1α and HIF-1β, but not HIF-2α, in gastric cancer. Exp Mol Med. 41:51–58. 2009.
21.	Zhang R, Fu H, Chen D, Hua J, Hu Y, Sun K and Sun X: Subcellular distribution of S100A4 and its transcriptional regulation under hypoxic conditions in gastric cancer cell line BGC823. Cancer Sci. 101:1141–1146. 2010. View Article : Google Scholar : PubMed/NCBI
22.	Liu L, Ning X, Sun L, et al: Hypoxia-inducible factor-1α contributes to hypoxia-induced chemoresistance in gastric cancer. Cancer Sci. 99:121–128. 2008.
23.	Miyoshi A, Kitajima Y, Ide T, et al: Hypoxia accelerates cancer invasion of hepatoma cells by upregulating MMP expression in an HIF-1α-independent manner. Int J Oncol. 29:1533–1539. 2006.PubMed/NCBI
24.	Xin L and Yibin K: Hypoxia and hypoxia-inducible factors: master regulators of metastasis. Clin Cancer Res. 16:5928–5935. 2010. View Article : Google Scholar : PubMed/NCBI
25.	Hiraki M, Kitajima Y, Kai K, Nakamura J, Hashiguchi K, Noshiro H and Miyazaki K: Knockdown of hypoxia-inducible factor-1a accelerates peritoneal dissemination via the upregulation of MMP-1 expression in gastric cancer cell lines. Exp Ther Med. 4:355–362. 2012.PubMed/NCBI
26.	Liotta LY: Tumor invasion and metastases - role of the extra-cellular matirix: Rhoads Memorial Award lecture. Cancer Res. 46:1–7. 1986.PubMed/NCBI
27.	Kawamura T, Endo Y, Yonemura Y, et al: Significance of integrin alpha2/beta1 in peritoneal dissemination of a human gastric cancer xenograft model. Int J Oncol. 18:809–815. 2001.PubMed/NCBI
28.	Stoeltzing O, McCarty MF, Wey JS, et al: Role of hypoxiainducible factor 1alpha in gastric cancer cell growth, angiogenesis and vessel maturation. J Natl Cancer Inst. 96:946–956. 2004. View Article : Google Scholar : PubMed/NCBI
29.	Albrecht I and Christofori G: Molecular mechanisms of lymphangiogenesis in development and cancer. Int J Dev Biol. 55:483–494. 2011. View Article : Google Scholar : PubMed/NCBI
30.	Silverman MP: The subperitoneal space: mechanisms of tumor spread in the peritoneal cavity, mesentery and omentum. Cancer Imaging. 4:25–29. 2003. View Article : Google Scholar : PubMed/NCBI