There would appear to be overwhelming evidence that OXYGEN Tension is the PRIMARY differentiating factor, ie that which determines at what stage of development or differentiation (going forward) that cells are at or what stage of DEDIFFERENTIATION (going backward) that cancer cells are at.  What if, after transformation of epithelial cells, angiogenesis (the growth of blood vessels) is PROGRAMMED to lag behind tumor growth, so that as oxygen tension goes down in the tumor, it's cells increasingly DEDIFFERENTIATE, those furthest from the blood vessels and thus exposed to the LEAST oxygen tension. undergoing EMT (epithelial to mesenchymal transfer) to become cancer stem cells.  Then as these cells with a mesenchymal phenotype crawl toward the blood vessels to metastasise they are exposed to increased oxygen tension and revert to an epithelial phenotype?  The question is why all this order?  HIF (hypoxia inducable factor) proteins affect 800 genes, 1/13 of all coding genes.  That an AWFUL lot of genes for something that is supposed to be a stuff up, eh.