J Cancer 2017; 8(10):1818-1825. doi:10.7150/jca.19057

Research Paper

Hypoxia-inducible factor-1 alpha Correlates with Tumor-Associated Macrophages Infiltration, Influences Survival of Gastric Cancer Patients

Wei-jie Zhang1,2#, Cheng Chen6#, Zhi-hua Zhou7#, Shan-ting Gao2, Teong Jin Tee3, Liu-qing Yang4, Yuan-yuan Xu4, Tao-hong Pang4, Xin-yun Xu5, Qi Sun5, Min Feng1, 2, Hao Wang1, 2, Chun-lei Lu8, Guo-zhong Wu8, Sheng Wu8, Wen-xian Guan1, 2✉, Gui-fang Xu4✉

1. Department of General surgery, Drum Tower Clinical College of Nanjing Medical University, Nanjing, Jiangsu Province, China;
2. Department of General surgery, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu Province, China;
3. Department of Medical, Gastroenterology unit, Nilai Medical Center, Nilai, Negeri Sembilan, Malaysia.
4. Department of Gastroenterology, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu Province, China;
5. Department of Pathology, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu Province, China;
6. Department of Radiotherapy, Jiangsu Cancer Hospital Affiliated to Nanjing Medical University, Nanjing, Jiangsu Province, China;
7. Department of Pathology, 101th Hospital of PLA, Wuxi, Jiangsu Providence, China;
8. Department of General surgery, 101th Hospital of PLA, Wuxi, Jiangsu Providence, China;
# Wei-jie Zhang, Cheng Chen and Zhi-hua Zhou equally contributed to this study.

Abstract

Background: Hypoxia was a common feature for accelerating tumor metastasis by both inducting epithelial-mesenchymal transition (EMT) of tumor cells and polarization of tumor-associated macrophages (TAMs). The association and roles between hypoxia, EMT and TAMs in the biological behavior of gastric cancer (GC) for the time being recurrence is unclear.

Material and methods: hypoixa by expression of hypoxia-inducible factor-1 alpha (HIF-1α), polarized functional status of infiltrated TAMs by immunohistochemical staining of CD68 and CD163, and the expression of E-cadherin as EMT property had been evaluated in 236 patients consecutive with histologically confirmed GC. Clinical significance was assessed for all these patients.

Results: High expression of HIF-1α was found in patients with aggressive features, especially for recurrent patients. High infiltration of TAMs and abnormal expression of EMT-marker were also related to aggressive characteristics and predicted poor prognosis in GC. Meanwwhile, there existed a significant correlation among expression of HIF-1α, infiltration of TAMs and EMT marker in GC tissues. Multivariate Cox analysis revealed that high expression of HIF-1α combined TAMs infiltration were independent prognostic factors for disease-specific survival rate.

Conclusion: HIF-1α is an unfavorable indicator for prognosis, may promote tumor progression through the induction of EMT and establishment of a pro-tumor immunosuppressive microenvironment. Further investigation into the therapeutic effects of blocking hypoxia is possible a potential strategy for GC treatment.

Keywords: Gastric cancer, hypoxia-inducible factor-1 alpha, tumor-associated macrophages, epithelial-mesenchymal transition, prognosis

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How to cite this article:
Zhang Wj, Chen C, Zhou Zh, Gao St, Tee TJ, Yang Lq, Xu Yy, Pang Th, Xu Xy, Sun Q, Feng M, Wang H, Lu Cl, Wu Gz, Wu S, Guan Wx, Xu Gf. Hypoxia-inducible factor-1 alpha Correlates with Tumor-Associated Macrophages Infiltration, Influences Survival of Gastric Cancer Patients. J Cancer 2017; 8(10):1818-1825. doi:10.7150/jca.19057. Available from http://www.jcancer.org/v08p1818.htm