10.1038/nrc1478 10.1038/nrc1478-c1

We thank Ger Bongaerts and Theo Wagener for their comments. It appears that they have misunderstood some components of our article. We completely agree with the biochemical pathways of glucose metabolism that they outline. We also agree that in the absence of oxygen, tumour cells, like normal cells, will generate energy by metabolized glucose to lactic acid (a process they term 'fermentative'). The question we address is the observation that tumour cells, unlike normal cells, use fermentative processes even in the presence of oxygen. We describe this as 'aerobic glycolysis' — a term they appear to misconstrue as meaning the oxidative metabolism of glucose. In any case, our main point is that metabolism of glucose to lactic acid provides a proliferative advantage to tumour populations if they evolve resistance to the resulting extracellular acidosis. In other words, during carcinogenesis some tumour populations gain a competitive advantage by using fermentative processes to create an environment that is toxic (through creation of extracellular acidosis) to their competitors but harmless to themselves. We hypothesize that this advantage explains the observation that tumour cells use anaerobic metabolism of glucose even in the presence of oxygen.

Finally we agree with their conclusion that tumour growth will probably be generally dependent on ATP production. Under anaerobic conditions, we agree with their statement that “...the faster solid tumours will ferment, the faster they will grow.” However, this again misses the point of our article. Our focus was not on solid tumour growth but on somatic evolution in premalignant lesions that ultimately leads to the invasive phenotype. In fact, critical to our hypothesis is that premalignant somatic evolution occurs in an area confined by the basement membrane and, therefore, not in contact with blood vessels. As stated in the article, we completely agree that the glycolytic phenotype is probably initially induced by the absence of oxygen. Indeed, this induction is a crucial component of our hypothetical model of carcinogenesis. However, the observation that tumour cells use fermentative processes even in the presence of oxygen indicates that, ultimately, a constitutive upregulation of the anaerobic pathways must occur.