The Role of Glycolysis in Tumorigenesis—The Many Unresolved Issues

The upregulation of glycolysis and resultant lactate production (hereafter referred to as fermentative glycolysis) even under normoxic conditions has been considered a hallmark of cancer. In recent years, however, it has become clear that fermentative glycolysis in tumors is not as all-inclusive as originally thought. Nevertheless, many tumor types at different stages of progression are characterized by a predominantly glycolytic metabolism. Fermentative glycolysis in tumors supports several different functions: energy production in the form of adenosine triphosphate molecules, the maintenance and amplification of glycolytic metabolism itself, the feeding of oxidative metabolism through the production of lactate, the generation of metabolic intermediates for biomass production, and the execution of non-metabolic, non-canonical, so-called moonlighting functions. This knowledge, however, raises a number of different questions which, by and large, are still unanswered today. Are there different degrees of glycolysis upregulation in order to support the different functions? How is fermentative glycolysis maintained even under normoxic conditions? Why do moonlighting functions exist, given that they are unrelated to the metabolic steps of glycolysis? Moonlighting functions are generally discussed in the context of tumorigenesis, but do they exist also in non-transformed cells? Do they occur in a coordinated manner in all tumor cells or are they activated selectively depending on the tumor type, tumor stage, or on the inducing stimulus? While these issues are mostly unresolved, in this article we propose some tentative answers which, we hope, may promote new research directions which may further our understanding in this field.