The remarkable yin and yang of tumour hypoxia

Abstract

Purpose: To honour perhaps the most influential man in the radiation sciences, Henry S. Kaplan, by reviewing the field of tumour hypoxia, one of his many interests.

Results: It was postulated over 50 years ago by Thomlinson and Gray that human solid tumours would contain hypoxic cells and that they would exert a negative influence on the outcome of radiotherapy, a prediction that has been amply validated. In addition to the ‘chronic’ hypoxia that they proposed we know that tumours also have ‘acute’ hypoxia produced by the unstable nature of tumour blood flow. The most hypoxic cells in the tumour are the key mediators of the response to large radiation doses (such as are given in stereotactic body radiotherapy), whereas cells at intermediate levels of hypoxia are the most important for standard fractionated radiotherapy. But tumour hypoxia can be exploited to preferentially activate anti-cancer drugs such as tirapazamine in tumours. In addition, hypoxia, through the transcription factor hypoxia inducible factor 1(HIF-1), drives both local angiogenesis and vasculogenesis from circulating cells. We have shown that local tumour irradiation can inhibit angiogenesis, making growth of tumours from surviving cancer cells dependent on vasculogenesis, and that inhibiting key steps in vasculogenesis can markedly sensitize tumours to irradiation.

Keywords:

• angiogenesis
• hypoxia
• macrophages
• radiosensitizers
• tumour physiology
• vascular system

Acknowledgements

Many talented people both in my laboratory and as collaborators performed the work that I have described. There are too many to mention them all. However, I would like to thank a few in particular: Bill Lee of SRI international who was instrumental in creating both etanidazole and tirapazamine, Bill Denny and Bill Wilson in Auckland NZ, who have been long-term collaborators on hypoxic cytotoxins, former lab members including Norman Coleman, Elaine Zeman, Amato Giaccia, Jim Evans, Mary Jo Dorie, Katy Peters and Brad Wouters, and current lab members Sophia Chernikova, Shie-chau Liu, Mitomu Kioi and G-one Ahn. The work described was funded by NIH grants CA15201, CA25990, CA067166, CA082566, CA128873 and grants from the Accelerate Brain Cancer Cure and the James McDonnell Foundation.

Declaration of interest: The author reports no conflicts of interest. The author alone is responsible for the content and writing of the paper.