The hypoxic core: a possible answer to the cancer paradox

There are many differences, at all levels of organization, between cancerous and normal cells. Two of these (oxygen delivery and glucose metabolism) are related and manifest as low intercellular oxygen tensions (pO(2)) and a glycolytic metabolic profile in tumours and/or cancer cells. It is becoming increasingly apparent that these characteristics of cancer combine to enhance both the survival and aggressiveness of cancer cells, and that they can adversely impact on some forms of treatment. But they are also exploited in current strategies of detection and monitoring of cancers. These are therefore characteristics with important implications for the crucial balance between the aggression and growth characteristics of a tumour, and our ability to detect and treat it. The interactions and the hierarchy of events leading to these manifestations are complex, not fully understood, and involve a pivotal and intriguing paradox. This paradox results in a seemingly contradictory state in which the most dangerous tumours are those that are the most hypoxic, but also those that are the most angiogenic. This review is a synthesis of the available data into a feasible hypothesis which offers a possible resolution of this paradox and provides a testable paradigm for tumour behaviour.