Environmental restrictions within tumor ecosystems select for a convergent, hypoxia-resistant phenotype of cancer stem cells

Tumors are ecosystems which develop from stem cells endowed with unlimited self-renewal and genetic instability, under the effects of mutagenesis and natural selection imposed by environmental changes. While changes and variations made possible by genetic instability are practically unlimited, the microenvironment progressively reduces those possibilities in the struggle for life imposed by hypoxia and nutrient shortage typical of tumor environments. This entails the tendency to evolve a convergent phenotype resistant to microenvironmental restrictions (first of all hypoxia), which progressively dominates the clonal selection. It is shown that adaptation to hypoxia, rather than being a peculiarity of cancer stem cells, is also a characteristic of normal hematopoietic stem cells, and may thus be described as a general feature of the stem cell phenotype. The metabolic orientation of this phenotype closely resembles the orientation of highly anaplastic ascites hepatomas, showing that, in restricted environments, stem cell recruitment to growth is limited by mitochondrial reoxidation of reducing equivalents produced in folate redox steps connected with purine synthesis. Finally, a review of earlier research into glucose metabolism in cancer leads to the reinterpretation of Warburg's aerobic glycolysis as a defence mechanism which disposes of glycolytic products able to negatively interfere with the crucial role of mitochondrial respiration in cell recruitment for growth.