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International Journal of Colorectal Disease

, Volume 23, Issue 11, pp 1049–1055 | Cite as

The role of hypoxia in recurrence following resection of Dukes’ B colorectal cancer

  • R. Rajaganeshan
  • R. Prasad
  • P. J. Guillou
  • G. Poston
  • N. Scott
  • D. G. Jayne
Original Article

Abstract

Goals

Tumour hypoxia has been shown to be a predictor of early distant relapse in node-negative breast and cervical cancer. The purpose of the present study was to determine the role of hypoxia in predicting patients who are at high risk of disease recurrence in Dukes B colorectal cancers.

Materials and methods

Archival tissue was retrieved from 52 patients who had undergone surgical resection for primary colorectal cancer. Tissue micro-arrays were constructed using tissue from the margin and the centre of the tumour. Hypoxia markers hypoxia-inducible factor (Hif)-1α, vascular endothelial growth factor (VEGF), carbonic anhydrase (CA)-9 and glucose transporter (Glut)-1 were visualised using immunohistochemical detection and quantified using semi-quantitative analysis of the digitised images. Clinical details and outcome data were retrieved by case note review and collated with hypoxia markers data in a statistical database.

Results

Primary colorectal cancers with a high Hif-1α expression tended to have a significantly worse disease-free survival (log rank p < 0.001) and overall survival (log rank p = 0.012). VEGF was also a significant predictor of disease recurrence in primary colorectal cancers (p = 0.015). Significant correlations were also noted between Hif-1α and VEGF (Pearson’s p = 0.009). Glut-1 and CA-9 did not show a similar pattern with no differences in the expression pattern and no correlation observed with any of the markers. Multivariate analysis of prognostic factors showed vascular invasion (p < 0.001) and Hif-1α at the tumour margin (p < 0.001) to be independent predictors for the development of liver metastases.

Conclusion

These results suggest an important role for Hif-1α and VEGF in colorectal cancer progression, with both markers biological mechanisms directly interlinked through the hypoxic pathway. Identification of high-risk patients using the above factors will improve treatment strategies in node-negative disease and help improve patient outcome.

Keywords

Colorectal cancer Liver metastases Hypoxia 

Notes

Acknowledgments

We thank Mr. T. Andrews for helpful suggestions and technical support.

References

  1. 1.
    Brizel DM et al (1996) Tumor oxygenation predicts for the likelihood of distant metastases in human soft tissue sarcoma. Cancer Res 56(5):941–943PubMedGoogle Scholar
  2. 2.
    Zhong H et al (1999) Overexpression of hypoxia-inducible factor 1alpha in common human cancers and their metastases. Cancer Res 59(22):5830–5835PubMedGoogle Scholar
  3. 3.
    Subarsky P, Hill RP (2003) The hypoxic tumour microenvironment and metastatic progression. Clin Exp Metastasis 20:237–250PubMedCrossRefGoogle Scholar
  4. 4.
    Thews O, Wolloscheck T, Dillenburg W, Kraus S, Kelleher DK, Konerding MA et al (2004) Microenvironmental adaptation of experimental tumours to chronic vs acute hypoxia. Br J Cancer 91(6):1181–1189PubMedGoogle Scholar
  5. 5.
    Semenza GL (2000) Hypoxia, clonal selection, and the role of Hif-1 in tumour progression. Crit Rev Biochem Mol Biol 35(2):71–103PubMedCrossRefGoogle Scholar
  6. 6.
    Harris AL (2002) Hypoxia—a key regulatory factor in tumour growth. [Review] Nat Rev Cancer 2(1):38–47PubMedCrossRefGoogle Scholar
  7. 7.
    Krishnamachary B et al (2003) Regulation of colon carcinoma cell invasion by hypoxia-inducible factor 1. Cancer Res 63(5):1138–1143PubMedGoogle Scholar
  8. 8.
    Quintero M, Mackenzie N, Brennan PA (2004) Hypoxia-inducible factor 1 (HIF-1) in cancer. Eur J Surg Oncol 30(5):465–468PubMedCrossRefGoogle Scholar
  9. 9.
    Poston GJ (2004) Surgical strategies for colorectal liver metastases. Surg Oncol 13(2–3):125–136PubMedCrossRefGoogle Scholar
  10. 10.
    De Quay N, Cerrottini J, Albe X, Saraga E, Caplin S (1999) Prognosis in Dukes' B colorectal carcinoma: The Jass classification revisited. Eur J Surg 165:588–592PubMedCrossRefGoogle Scholar
  11. 11.
    Cianchi F, Palomba A, Messerini L, Boddi V, Asirelli G, Perigli G, Bechi P, Taddei A, Pucciani F, Cortesini C (2002) Tumor angiogenesis in lymph node-negative rectal cancer: correlation with clinicopathological parameters and prognosis. Ann Surg Oncol 9(1):20–26PubMedCrossRefGoogle Scholar
  12. 12.
    Takahashi Y, Tucker SL, Kitadai Y, Koura AN, Bucana CD, Cleary KR, Ellis LM (1997) Vessel counts and expression of vascular endothelial growth factor as prognostic factors in node-negative colon cancer. Arch Surg 132(5):541–546PubMedGoogle Scholar
  13. 13.
    Waterworth A, Horgan K, Speirs V, Hanby AM (2004) Tissue microarrays—big potential from small samples. Int J Oncol 25(1):167–171PubMedGoogle Scholar
  14. 14.
    Newland RC et al (1995) Survival after curative resection of lymph node negative colorectal carcinoma. A prospective study of 910 patients. Cancer 76(4):564–571PubMedCrossRefGoogle Scholar
  15. 15.
    Ratto C et al (1999) Accurate lymph-node detection in colorectal specimens resected for cancer is of prognostic significance. Dis Colon Rectum 42(2):143–154PubMedCrossRefGoogle Scholar
  16. 16.
    Sobrero A, Kohne C (2006) Should adjuvant chemotherapy become standard treatment for patients with stage II colon cancer? Lancet Oncol 7:515–517PubMedCrossRefGoogle Scholar
  17. 17.
    Colpaert C, Vermulen P, van Beest P, Goovaerts G et al (2001) Intratumoural hypoxia resulting in the presence of a fibrotic focus is an independent predictor of early distant relapse in lymph node-negative breast cancer patients. Histopathology 39(4):416–425PubMedCrossRefGoogle Scholar
  18. 18.
    Fyles A, Milosevic M, Hedley D, Pintillie M, Levin W, Manchul L, Hill RP (2002) Tumour hypoxia has independent predictor impact only in patients with node negative cervix cancer. J Clin Oncol 20(3):680–687PubMedCrossRefGoogle Scholar
  19. 19.
    Midgley R, Kerr D (2005) Bevacizumab—current status and future directions. Ann Oncol 16(7):999–1004PubMedCrossRefGoogle Scholar
  20. 20.
    Benjamin LE, Keshet E (1997) Conditional switching of vascular endothelial growth factor (VEGF) expression in tumors: induction of endothelial cell shedding and regression of hemangioblastoma-like vessels by VEGF withdrawal. Proc Natl Acad Sci U S A 94(16):8761–8766PubMedCrossRefGoogle Scholar
  21. 21.
    Mizukami Y et al (2005) Induction of interleukin-8 preserves the angiogenic response in HIF-1alpha-deficient colon cancer cells. Nat Med 11(9):992–997PubMedGoogle Scholar
  22. 22.
    An WG et al (1998) Stabilization of wild-type p53 by hypoxia-inducible factor 1alpha. Nature 392(6674):405–408PubMedCrossRefGoogle Scholar
  23. 23.
    Airley RE et al (2003) GLUT-1 and CAIX as intrinsic markers of hypoxia in carcinoma of the cervix: relationship to pimonidazole binding. Int J Cancer 104(1):85–91PubMedCrossRefGoogle Scholar
  24. 24.
    Kivela AJ et al (2005) Carbonic anhydrases in normal gastrointestinal tract and gastrointestinal tumours. World J Gastroenterol 11(2):155–163PubMedGoogle Scholar
  25. 25.
    Medina RA et al (2004) Differential regulation of glucose transporter expression by estrogen and progesterone in Ishikawa endometrial cancer cells. J Endocrinol 182(3):467–478PubMedCrossRefGoogle Scholar
  26. 26.
    Hakimian J, Ismail-Beigi F (1991) Enhancement of glucose transport in clone 9 cells by exposure to alkaline pH: studies on potential mechanisms. J Membr Biol 120(1):29–39PubMedCrossRefGoogle Scholar
  27. 27.
    Klip A et al (1994) Regulation of expression of glucose transporters by glucose: a review of studies in vivo and in cell cultures. FASEB J 8(1):43–53PubMedGoogle Scholar
  28. 28.
    Hedley D et al (2003) Carbonic anhydrase IX expression, hypoxia, and prognosis in patients with uterine cervical carcinomas. Clin Cancer Res 9(15):5666–5674PubMedGoogle Scholar
  29. 29.
    Gatenby RA, Gillies RJ (2004) Why do cancers have high aerobic glycolysis? Nature Rev Cancer 4(11):891–899CrossRefGoogle Scholar
  30. 30.
    Zu XL, Guppy M (2004) Cancer metabolism: facts, fantasy, and fiction. Biochem Biophys Res Commun 313(3):459–465PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • R. Rajaganeshan
    • 1
  • R. Prasad
    • 2
  • P. J. Guillou
    • 1
  • G. Poston
    • 3
  • N. Scott
    • 4
  • D. G. Jayne
    • 1
  1. 1.Academic Surgical UnitSt James’s University HospitalLeedsUK
  2. 2.Department of Hepatobiliary and Transplant SurgerySt. James’s University HospitalLeedsUK
  3. 3.Liverpool Hepatobiliary CentreUniversity Hospital AintreeLiverpoolUK
  4. 4.Department of PathologySt. James’s University HospitalLeedsUK

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