International Journal of Clinical Oncology

, Volume 18, Issue 2, pp 293–304 | Cite as

Clinicopathological significance of hypoxia-inducible factor-1 alpha (HIF-1α) expression in gastric cancer

  • Taro Isobe
  • Keishiro Aoyagi
  • Kikuo Koufuji
  • Kazuo Shirouzu
  • Akihiro Kawahara
  • Tomoki Taira
  • Masayoshi Kage
Original Article



Hypoxia is a common feature of rapidly growing solid tumors. Therefore, cellular adaptation to hypoxia and altered glucose metabolism are fundamental to the biology of cancer cells. Hypoxia-inducible factor-1α (HIF-1α) is a transcription factor for more than 60 genes recognized to control the delivery of oxygen and nutrients through the induction of angiogenesis and glycolysis under hypoxic conditions. Therefore, inhibition of the expression of HIF-1α can be expected to be potentially tumor-specific molecular target-based therapy. In this study, we evaluated the significance of HIF-1α expression in relationship to clinicopathological factors, prognosis, vascular endothelial growth factor (VEGF) expression, and microvessel density (MVD).


Paraffin-embedded tumor specimens from 128 patients who underwent gastrectomy at Kurume University from 2004 to 2005 were used to assess the clinical significance of HIF-1α expression. We used the ABC method to perform an immunohistochemical analysis of the HIF-1α and VEGF expression.


Eighty-four (65.6%) of gastric cancer specimens were positive for HIF-1α expression. Multivariate analysis showed that histology, depth of invasion, VEGF expression, and MVD were significantly associated with HIF-1α expression. On relapse-free and overall survival curves, the HIF-1α-negative group was significantly higher than the HIF-1α-positive group. Moreover, HIF-1α(+)/VEGF(+) patients had the worst prognosis. HIF-1α expression was identified as a significant predictor of relapse-free survival and overall survival by multivariate Cox’s proportional hazard analyses.


Overexpression of HIF-1α was found to be an indicator of poor prognosis for patients with gastric cancer and was significantly correlated with histology, depth of invasion, VEGF, and MVD.


HIF-1α VEGF Gastric cancer Clinicopathological factors 


  1. 1.
    Parkin DM (2001) Global cancer statistics in the year 2000. Lancet Oncol 2:533–543PubMedCrossRefGoogle Scholar
  2. 2.
    Liao D, Johnson RS (2007) Hypoxia: a key regulator of angiogenesis in cancer. Cancer Metastasis Rev 26:281–290PubMedCrossRefGoogle Scholar
  3. 3.
    Folkman J (1971) Tumor angiogenesis: therapeutic implications. N Engl J Med 285:1182–1186PubMedCrossRefGoogle Scholar
  4. 4.
    Gatenby RA, Kessler HB, Rosenblum JS et al (1988) Oxygen distribution in squamous cell carcinoma metastasis and its relationship to outcome of radiation therapy. Int J Radiat Oncol Biol Phys 14:531–538CrossRefGoogle Scholar
  5. 5.
    Takahashi R, Tanaka S, Hiyama T et al (2003) Hypoxia-inducible factor 1 alpha expression and angiogenesis in gastrointestinal stromal tumor of stomach. Oncol Rep 10:797–802PubMedGoogle Scholar
  6. 6.
    Zhong H, Agani F, Baccala AA et al (1998) Increased expression of hypoxia-inducible factor 1 alpha in rat and human prostate cancer. Cancer Res 58:5280–5284PubMedGoogle Scholar
  7. 7.
    Chen WT, Huang CJ, Wu MT et al (2005) Hypoxia-inducible factor 1 alpha is associated with risk of aggressive behavior and tumor angiogenesis in gastrointestinal stromal tumor. Jpn J Clin Oncol 35:207–213PubMedCrossRefGoogle Scholar
  8. 8.
    Mizokami K, Kakeji Y, Oda S et al (2006) Clinicopathological significance of hypoxia-inducible factor 1 alpha overexpression in gastric carcinomas. J Surg Oncol 94:149–154PubMedCrossRefGoogle Scholar
  9. 9.
    Yoshikawa T, Tsuburaya A, Miyagi Y et al (2006) Up-regulation of hypoxia-inducible factor 1 alpha and VEGF mRNAs in peritoneal dissemination of patients with gastric cancer. Anticancer Res 63:3849–3854Google Scholar
  10. 10.
    Sumiyoshi Y, Kakeji Y, Egashira A et al (2006) Overexpression of hypoxia-inducible factor 1 alpha and p53 is a marker for an unfavorable prognosis in gastric cancer. Clin Cancer Res 12:5112–5117PubMedCrossRefGoogle Scholar
  11. 11.
    Stoeltzing O, McCarty MF, Wey JS et al (2004) Role of hypoxia-inducible factor 1 alpha in gastric cancer cell growth, angiogenesis, and vessel maturation. J Natl Cancer Inst 96:946–956PubMedCrossRefGoogle Scholar
  12. 12.
    Fukuda R, Kelly B, Semenza GL (2003) Vascular endothelial growth factor gene expression in colon cancer cells exposed to prostaglandin E2 is mediated by hypoxia-inducible factor 1. Cancer Res 63:2330–2334PubMedGoogle Scholar
  13. 13.
    Koshikawa N, Iyozumi A, Gassmann M (2003) Constitutive upregulation of hypoxia-inducible factor 1 alpha mRNA occurring in highly metastatic lung carcinoma cells leads to vascular endothelial growth factor overexpression upon hypoxic exposure. Oncogene 22:6717–6724PubMedCrossRefGoogle Scholar
  14. 14.
    Semenza GL (2001) Hypoxia-inducible factor 1: oxygen homeostasis and disease pathophysiology. Trends Mol Med 7:345–350PubMedCrossRefGoogle Scholar
  15. 15.
    Saramaki OR, Savinainen KJ, Nupponen NN et al (2001) Amplification of hypoxia-inducible factor 1 alpha gene in prostate cancer. Cancer Genet Cytogenet 128:31–34PubMedCrossRefGoogle Scholar
  16. 16.
    Ravi R, Mookerjee B, Bhujwalla ZM et al (2000) Regulation of tumor angiogenesis by p53 induced degradation of hypoxia-inducible factor 1α. Genes Dev 14:34–44PubMedGoogle Scholar
  17. 17.
    Kung AL, Wang S, Klco JM et al (2000) Suppression of tumor growth through disruption of hypoxia inducible transcription. Nat Med 6:1335–1340PubMedCrossRefGoogle Scholar
  18. 18.
    Akakura N, Kobayashi M, Horiuchi I et al (2001) Constitutive expression of hypoxia-inducible factor-1 alpha renders pancreatic cancer cells resistant to apoptosis induced by hypoxia and nutrient deprivation. Cancer Res 61:6548–6554PubMedGoogle Scholar
  19. 19.
    Dalgard CL, Lu H, Mohyedin A et al (2004) Endogenous 2-oxoacids differentially regulate expression of oxygen sensors. Biochem J 380:419–424PubMedCrossRefGoogle Scholar
  20. 20.
    Huang LE, Gu J, Schau M (1998) Regulation of hypoxia-inducible factor 1 alpha is mediated by O2-dependent degradation domain via the ubiquitin-proteasome pathway. Proc Natl Acad Sci USA 95:7987–7992PubMedCrossRefGoogle Scholar
  21. 21.
    Talks KL, Turley H, Gatter KC et al (2000) The expression and distribution of the hypoxia-inducible factors HIF-1alpha and HIF-2alpha in normal human tissues, cancers, and tumor-associated macrophages. Am J Pathol 157:411–421PubMedCrossRefGoogle Scholar
  22. 22.
    Chun YS, Kim MS, Park JW (2002) Oxygen-dependent and -independent regulation of HIF-1alpha. J Korean Med Sci 17:581–588PubMedGoogle Scholar
  23. 23.
    Shi YH, Fang WG (2004) Hypoxia-inducible factor-1 in tumor angiogenesis. World J Gastroenterol 10:1082–1087PubMedGoogle Scholar
  24. 24.
    Stroka DM, Burkhardt T, Desbaillets I et al (2001) HIF-1 is expressed in normoxic tissue and displays an organ-specific regulation under systemic hypoxia. FASEB J 15:2445–2453PubMedGoogle Scholar
  25. 25.
    Zagzag D, Zhong H, Scalzitti JM et al (2000) Expression of hypoxia-inducible factor 1 alpha in brain tumors: association with angiogenesis, invasion, and progression. Cancer (Phila) 88:2606–2618CrossRefGoogle Scholar
  26. 26.
    Theodoropoulos VE, Lazaris A, Sofras F et al (2004) Hypoxia-inducible factor 1 alpha expression correlates with angiogenesis and unfavorable prognosis in bladder cancer. Eur Urol 46:200–208PubMedCrossRefGoogle Scholar
  27. 27.
    Bos R, Zhong H, Hanrahan CF et al (2001) Levels of hypoxia-inducible factor 1 alpha during breast carcinogenesis. J Natl Cancer Inst 93:309–314PubMedCrossRefGoogle Scholar
  28. 28.
    Kuwa T, Kitada Y, Tanaka S et al (2003) Expression of hypoxia-inducible factor 1 alpha is associated with tumor vascularization in human colorectal carcinoma. Int J Cancer 105:176–181CrossRefGoogle Scholar
  29. 29.
    Wiesener MS, Munchenhagen PM, Berger I et al (2001) Constitutive activation of hypoxia-inducible factor-1 alpha in clear cell renal carcinomas. Cancer Res 61:5215–5222PubMedGoogle Scholar
  30. 30.
    Birner P, Schindl M, Obermair A et al (2001) Expression of hypoxia-inducible factor 1 alpha in epithelial ovarian tumors: its impact on prognosis and on response to chemotherapy. Clin Cancer Res 7:1661–1668PubMedGoogle Scholar
  31. 31.
    Buchler P, Reber HA, Buchler M et al (2003) Hypoxia-inducible factor 1 regulates vascular endothelial growth factor expression in human pancreatic cancer. Pancreas 26:56–64PubMedCrossRefGoogle Scholar
  32. 32.
    Japanese Gastric Cancer Association (2010) Japanese classification of gastric carcinoma, 14th edn. Kanehara, TokyoGoogle Scholar
  33. 33.
    Livingston DM, Shivdasani R (2001) Toward mechanism-based cancer care. JAMA 285:588–593PubMedCrossRefGoogle Scholar
  34. 34.
    Oskoski R Jr (2007) Vascular endothelial growth factor (VEGF) signaling in tumor progression. Crit Rev Oncol Hematol 62:179–213CrossRefGoogle Scholar
  35. 35.
    Senger DR, Galli SJ, Dvorak AM et al (1983) Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science 219:983–985PubMedCrossRefGoogle Scholar
  36. 36.
    Dvorak HF, Brown LF, Detmar M et al (1995) Vascular permeability factor/vascular endothelial growth factor, microvascular hyperpermeability, and angiogenesis. Am J Pathol 146:1029–1039PubMedGoogle Scholar
  37. 37.
    Nagy JA, Masse EM, Herzberg KT et al (1995) Pathogenesis of ascites tumor growth: vascular permeability factor, vascular hyperpermeability, and ascites fluid accumulation. Cancer Res 55:360–368PubMedGoogle Scholar
  38. 38.
    Boocock CA, Charnock-Jones DS, Sharkey AM et al (1995) Expression of vascular endothelial growth factor and its receptors flt and KDR in ovarian carcinoma. J Natl Cancer Inst 87:506–516PubMedCrossRefGoogle Scholar
  39. 39.
    Aoyagi K, Kouhuji K, Takeda J et al (2005) VEGF significance in peritoneal recurrence from gastric cancer. Gastric Cancer 8:155–163PubMedCrossRefGoogle Scholar
  40. 40.
    Imaizumi T, Aoyagi K, Shirouzu K et al (2010) Suppressive effect of bevacizumab on peritoneal dissemination from gastric cancer in a peritoneal metastasis model. Surg Today 40:851–857PubMedCrossRefGoogle Scholar
  41. 41.
    Chen C, Pore N, Behrooz A et al (2001) Regulation of glut1 mRNA by hypoxia-inducible factor-1. Interaction between H-ras and hypoxia. J Biol Chem 276:9519–9525PubMedCrossRefGoogle Scholar
  42. 42.
    Jiang BH, Agani F, Passaniti A et al (1997) V-SRC induces expression of hypoxia-inducible factor 1(HIF-1) and transcription of genes encoding vascular endothelial growth factor and enolase 1: involvement of HIF-1 in tumor progression. Cancer Res 57:5328–5335PubMedGoogle Scholar
  43. 43.
    Laughner E, Taghavi P, Chiles K et al (2001) HER2 (neu) signaling increases the rate of hypoxia-inducible factor 1alpha (HIF-1alpha) synthesis: novel mechanism for HIF-1-mediated vascular endothelial growth factor expression. Mol Cell Biol 21:3995–4004PubMedCrossRefGoogle Scholar
  44. 44.
    Mazure NM, Chen EY, Laderoute KR et al (1997) Induction of vascular endothelial growth factor by hypoxia is modulated by a phosphatidylinositol 3-kinase/Akt signaling pathway in Ha-ras-transformed cells through a hypoxia inducible factor-1 transcriptional element. Blood 90:3322–3331PubMedGoogle Scholar
  45. 45.
    Aebersold DM, Burri P, Beer KT et al (2001) Expression of hypoxia-inducible factor 1 alpha: a novel predictive and prognostic parameter in the radiotherapy of oropharyngeal cancer. Cancer Res 61:2911–2916PubMedGoogle Scholar
  46. 46.
    Matuyama T, Nakanishi K, Hayashi T et al (2005) Expression of hypoxia-inducible factor 1α in esophageal squamous cell carcinoma. Cancer Sci 96:176–182CrossRefGoogle Scholar
  47. 47.
    Koukourakis MI, Giatromanolaki A, Skarlatos J et al (2001) Hypoxia-inducible factor (HIF-1α and HIF-2α) expression in early esophageal cancer and response to photodynamic therapy and radiotherapy. Cancer Res 61:1830–1832PubMedGoogle Scholar
  48. 48.
    Beasley NJP, Leek R, Alam M et al (2002) Hypoxia-inducible factor HIF-1α and HIF-2α in head and neck cancer: relationship to tumor biology and treatment outcome in surgically resected patients. Cancer Res 62:2493–2497PubMedGoogle Scholar
  49. 49.
    Griffiths EA, Pritchard SA, Valentine HR et al (2007) Hypoxia-inducible factor 1 alpha expression in the gastric carcinogenesis sequence and its prognostic role in gastric and gastroesophageal adenocarcinomas. Br J Cancer 96:95–103PubMedCrossRefGoogle Scholar
  50. 50.
    Krishnamachary B, Berg-Dixon S, Kelly B et al (2003) Regulation of colon carcinoma cell invasion by hypoxia-inducible factor 1. Cancer Res 63:1138–1143PubMedGoogle Scholar
  51. 51.
    Yuri K, Qun L, Daniel Z et al (2009) Hypoxia-regulated delta-like 1 homologue enhances cancer cell stemness and tumorigenicity. Cancer Res 69:9271–9280CrossRefGoogle Scholar
  52. 52.
    Wen WM, Alex AA (2009) Novel agents on the horizon for cancer therapy. CA Cancer 59:111–137CrossRefGoogle Scholar

Copyright information

© Japan Society of Clinical Oncology 2012

Authors and Affiliations

  • Taro Isobe
    • 1
  • Keishiro Aoyagi
    • 1
  • Kikuo Koufuji
    • 1
  • Kazuo Shirouzu
    • 1
  • Akihiro Kawahara
    • 2
  • Tomoki Taira
    • 2
  • Masayoshi Kage
    • 2
  1. 1.Department of SurgeryKurume University School of MedicineKurumeJapan
  2. 2.Department of Diagnostic PathologyKurume University HospitalKurumeJapan

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