© 2008 The Authors. Journal compilation © 2008 Blackwell Publishing Ltd 213 Review Article Keywords canine, hypoxia, resistance, tumour Correspondence address: Dr Marlene Hauck Department of Clinical Sciences College of Veterinary Medicine North Carolina State University Box 8401, 4700 Hillsborough Street Raleigh NC 27606 USA e-mail: marlene_hauck@ncsu. edu Introduction Hypoxia has been a suspected cause for treatment failure in human oncology since the 1950s. The study of hypoxia in human medicine over the past 50 years has revealed that it is, in fact, a cause of treatment resistance for both radiation and che- motherapy. Pivotal work by Gray in 1953 and Thomlinson and Gray in 1955 lead to the subse- quent in-depth study of the role of hypoxia in radi- ation therapy. 1,2 These investigators found large regions of necrosis in human lung tumours and discovered that a thin ring of viable tumour cells consistently surrounded the necrosis. They calcu- lated the diffusion distance of oxygen and con- cluded that lack of oxygen was the cause of the necrosis. Additionally, they concluded that the de- creasing oxygen concentration from the vessel wall out through the tissue would leave cells at different oxygen tensions depending on their distance from the vessel. This gradient implied that near the ne- crotic edge, there might be residual hypoxic, but viable cells that could give rise to tumour regrowth after radiation. Reasons for hypoxia-induced radioresistance are lack of reactive oxygen species (ROS), low prolifer- ation rate of hypoxic cells compared with aerobic cells and upregulation of hypoxia responsive genes that promote growth and survival of cells, metasta- sis and a more aggressive phenotype. 1, 3–6 Hypoxic cells are also more resistant to chemotherapy. One reason for chemotherapy resistance is that hypoxic cells are farther from the vasculature and may not be exposed to lethal drug concentrations. 7 Low rates of cell proliferation also have fewer cells in the stage of the cell cycle most susceptible to these drugs. Even drugs that are classified as hypoxic cy- totoxins are less efficacious because of diffusion limitations. 8 Since Thomlinson and Gray ’s seminal work, tu- mour hypoxia has been demonstrated to exist in numerous tumour types and has been well docu- mented as a significant cause of treatment failure. 9–13 A variety of clinical studies have shown that hypoxic human tumours are: (1) more likely to fail locally after radiotherapy; (2) more invasive and likely to develop metastases; and (3) a negative prognostic indicator of disease free and overall The role of hypoxia in canine cancer S. A. Snyder 1 , M. W. Dewhirst 2 and M. L. Hauck 1 1 Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, USA 2 Department of Radiation Oncology, Duke University Medical Center, Durham, NC, USA Abstract Human oncology has clearly demonstrated the existence of hypoxic tumours and the problematic nature of those tumours. Hypoxia is a significant problem in the treatment of all types of solid tumours and a common reason for treatment failure. Hypoxia is a negative prognostic indicator of survival and is correlated with the development of metastatic disease. Resistance to radiation therapy and chemother- apy can be because of hypoxia. There are two dominant types of hypoxia recognized in tumours, static and intermittent. Both types of hypoxia are important in terms of resistance. A variety of physiological factors cause hypoxia, and in turn, hypoxia can induce genetic and physiological changes. A limited number of studies have documented that hypoxia exists in spontaneous canine tumours. The knowl- edge from the human literature of problematic nature of hypoxic tumours combined with the rapid growth of veterinary oncology has necessitated a better understanding of hypoxia in canine tumours.