the full oxidation of one glucose molecule ( oxidative phosphorylation ) within a cell in the presence of oxygen produces 38 molecules of adenosine - three - phosphate ( atp ) , which in turn represents the essential cellular fuel ( figure 1.a ) .
the first step ( glycolysis , occurring in cytoplasm ) of glucose cellular respiration produces only 2 atp molecules and ends up with production of two molecules of pyruvic acid .
if a given cell has access to oxygen , the pyruvic acid will be converted to acetyl - coenzyme a , which enters the krebs cycle ( citric acid cycle , occurring within mitochondria ) followed by the electron transport chain process ( occurring on the inner mitochondrial membrane ) that creates most of the atp molecules .
it is the very last step within electron transport chain that needs oxygen to collect the terminal electron from the last cytochrome ( cyt a3 ) and become a nascent o to pick up 2 h and create one of the byproducts of aerobic cellular respiration - a water molecule . on the other hand ,
if the cells reside under hypoxic conditions , the pyruvic acid is not converted into acetyl - coenzyme a , but into a lactic acid - the process termed anaerobic cellular respiration ( lactic acid cycle ) . in the latter case , the net energy balance is only two atp molecules making the anaerobic glucose metabolism energetically highly inefficient process . while the lack of oxygen at the cellular level can occur at times of excessive physical activity ( resulting in subsequent muscle pain ) , it also represents a hallmark of highly invasive and fast - growing cancers [ ] . as the cancer cells multiply
, their fast multiplication rate outgrows the angiogenesis so much so that while the glucose access to fast - growing cells could be sufficient the lack of blood vessels disrupts the level of oxygen needed for the full glucose oxidation .
such a microscopic picture defines one of the fundamental properties of the cancer microenvironment that forces malignant cells to metabolize glucose through the lactic acid cycle .
looking at chemical equations between aerobic and anaerobic glucose metabolism ( figure 1 ) one may conclude that cancer cells ( as well as healthy ones ) under hypoxic condition would need 19 times higher uptake of glucose to maintain the same metabolic level as well - oxygenated cells .
this would , in turn , mean that the appropriate quantitative analysis of fdg - based pet images could help in pinpointing hypoxic segments ( by abundance only [ ] ) of the tumor by solely looking into very high uptake values , which would eventually be some 20 times greater than in well - oxygenated cancer cells .
however , the isolation of the hypoxic target volumes is far from being that simple .
apart from the fact that acute hypoxia in tumors develop as soon as one moves few hundred microns from the blood vessels , yet another important fact prevents fdg being an ideal hypoxia marker - the warburg effect .
recently , interest in tumor metabolism has been revived partly as a result of the widespread clinical application of pet using fdg .
fdg - based pet imaging has confirmed that most primary and metastatic cancers show a significant increase in the glucose uptake when compared to normal tissues .
glycolysis involves the conversion of glucose to pyruvate and then to lactic acid , the waste product . in non - cancerous cells ,
mitochondria oxidize pyruvate to carbon dioxide and water in the presence of oxygen ( figure 2.a ) , and the glycolytic reaction is inhibited ( pasteur effect [ ] ) .
conversion of glucose to lactic acid , even in the presence of oxygen is known as aerobic glycolysis ( figure 2.b ) or the warburg effect [ , ] . in one of his seminal papers [ ]
the second phase of cancer formation represents a long struggle for existence by the injured cells to maintain their structure , in which a part of the cells die from lack of energy while another part succeeds in replacing the irretrievably lost respiration energy by fermentation energy ( from lactic acid cycle ) .
warburg 's initial hypothesis that cancer results from impaired mitochondrial metabolism has been shown to be incorrect , but the observation of augmented glycolysis in tumors , even in the presence of oxygen , has been continually proven [ ] . while cancer cells do carry oxidative phosphorylation , the majority of glucose molecules taken by cancer cells ( 66% ) are metabolized through fermentation [ ] , a process that is ten times faster than full glucose oxidation .
in addition to being energetically highly inefficient process glycolysis ( either anaerobic or aerobic ) , with its metabolic products ( such as hydrogen ions ) , cause constant acidification of the extracellular space , which might result in increased local toxicity [ , ]
. nevertheless , despite these drawbacks , cancer cells consistently progress towards the wasteful and potentially toxic glycolytic phenotype .
gatenby and gillies [ ] proposed that the consistent expression of up - regulated glycolysis is not accidental but represents a solution to the environmental growth constraints during tumor development .
they suggest that increased glycolysis is an essential component of the malignant phenotype and , therefore , a hallmark of invasive cancers .
transport enzymes of the glut and hexokinase families are up - regulated in tumor cells expressing the glycolytic phenotype , and the level of glut-1 glucose transporter expression has been shown to correlate with [ 18f ] fdg uptake in non - small cell lung cancer , for example [ ] .
gatenby and gillies 11 describe the concept of carcinogenesis as a process that occurs by cellular evolution implying that common characteristics of malignant phenotypes , such as upregulation of glycolysis , are the result of active selection processes .
they further argue that upregulation of glycolysis is likely to be an adjustment to hypoxia developing as pre - malignant tissue grows gradually further away from their blood supply .
also , an augmented acid production from glycolysis upregulation leads to microenvironmental acidosis and requires further adjustments through somatic evolution to phenotypes resistant to acid - induced toxicity .
finally , they conclude that cell populations that emerge from this evolutionary sequence have a compelling growth advantage , as they alter their environment through increased glycolysis in a way that is toxic to other phenotypes , but harmless to themselves . to further support the attempt by gatenby and gillies 11 in explaining the cause of warburg effect in aggressive tumors as a response to harsh environmental conditions
know  a priori they will encounter severe conditions in the future . consequently , they 
decide  to switch their glucose metabolism to highly inefficient but the only possible ( and highly toxic ) metabolic pathway . to make their explanation more sounded ,
gatenby and gillies 11 speculate that :   intuitively , it would seem that the darwinian forces prevailing during the somatic evolution of invasive cancers would select against a metabolic phenotype that is more than an order of magnitude less efficient than its competitors and that is environmentally poisonous . in other words , the accepted tenet of  survival of the fittest  would seem to generally favour populations with more efficient and sophisticated substrate metabolism . 
consequently , they suggest that glycolytic phenotype in cancers is directly governed by the evolutive mechanisms , over the relatively short time frame during which tumors develop .
figure 3 illustrates the very point within a cellular glucose metabolism where the fate of the pyruvic acid is decided . in the presence of oxygen
, the pyruvic acid will be converted into acetyl group and attached to coenzyme a , a process mediated by the so - called pyruvate dehydrogenase complex ( pdc ) .
the complex consists of three enzymes : pyruvate dehydrogenase , dihydrolipoyl transacetylase , and dihydrolipoyl dehydrogenase . on the other hand , conversion of pyruvic acid to lactic acid requires one enzyme only - lactate dehydrogenase ( ldha ) . from the cellular kinetics point of view
, one may ask a simple question : what is the probability that something goes wrong with either of the two possible metabolic pathways depicted in figure 3 ?
synthesis of three enzymes , needed to provide conversion of pyruvic acid to acetyl coenzyme a , even in the presence of oxygen will be ( notably three times ) more prone to the errors than a transcription of only one ( competing ) enzyme .
it was reported that many human cancers have higher ldha levels than normal tissues [ ] , but the correlation between oncogenes and glycolysis was poorly understood .
the question could be then raised whether the warburg effect is only a consequence , or could it be at the root of the very cause of carcinogenesis ?
a new hypothesis could be staged that the switch from aerobic cellular respiration to aerobic glycolysis leads to carcinogenesis , and the cell begins to develop the cancerous phenotype [ , ] at the point where the fate of pyruvic acid is decided .
such a switch could be governed by the lack of complete pdc ( at least one of the enzymes is missing ) .
while at this very moment the question whether warburg effect is a hen , or an egg remains at the level of pure hypothesis , several clinical observations might be called upon to support such proposition indirectly . while there is no apparent relation between type 1 diabetes mellitus patients and incidence of cancer to this date [ ] ,
several publications argue that there could be a lower cancer rate in patients with insulin - dependent diabetes . in 2003 , zendehdel et al .
[ ] published results on cancer incidence in patients with type 1 ( insulin - dependent ) diabetes mellitus on a cohort of 29 187 patients , followed over a period of 30 years , during which they observed 355 incidences of cancer .
such a low frequency ( 1% over 30 years , or 0.04% per year ) appears negligible when compared to 1.66 million cases of new cancer cases per year in the us ( 0.52% per year [ ] ) .
[ ] reported on the lower incidence of cancer death mortality in diabetic patients ( 6.7% , both type 1 and 2 ) when compared to non - diabetic patients ( 13.4% ) using a cohort of 39 811 patients with the end - stage renal disease .
it might be argued that cells in diabetic patients ( generally deprived of normal glucose uptake due to lacking insulin ) become  trained  ( to use rhetoric by blagosklonny [ ] ) by the microenvironment and well  prepared  as soon as glucose becomes available .
once the glucose is phosphorylated by hexokinase and enters the glucose oxidation process , the cell is  prepared  not to waste the opportunity and gets the maximum out of the relatively  scars glucose supplies .
 one could further argue that diabetic patient cells are making sure that the synthesis of the pdc is up and running flawlessly , to avoid wasteful pathway of cellular glucose metabolism . on the other hand , despite a relatively small amount of data published it appears that the incidence of cancer is also correlated with the increased intake of carbohydrates [ , , ] .
one may argue that normal cells , exposed to increased supply of glucose would quickly switch towards the energetically inefficient pathway ( lactic acid cycle ) of burning glucose even in the presence of oxygen ( warburg effect ) since the source of energy ( glucose - atp ) are virtually inexhaustible .
in addition , the atp production via fermentation is much faster ( as mentioned above ) , albeit highly ineficient , when compared to full oxydation .
it is also of note that contrary to type 1 ( insulin - dependent ) , patients with type 2 diabetes mellitus have higher probability for cancer incidence [ ] .
yet another detail deserves attention : type 1 diabetes is commonly regarded as a juvenile - onset diabetes as it often begins in childhood while the type 2 diabetes was considered an adult - onset diabetes .
however , type 2 diabetes is becoming increasingly common in children [ ] who are more obese or overweight that could be correlated with carbohydrates rich diets . finally
, the possible triggering of carcinogenesis by aerobic glycolysis , accompanied by increased glucose uptake , can be further supported by studies demonstrating increased glucose uptake observed to coincide with the transition from premalignant lesions to invasive cancer [ , ] .
unlike warburg 's initial hypothesis that cancer cells metabolize glucose through aerobic glycolysis due to impaired mitochondrial function a new hypothesis was presented that the normal cell becomes cancerous at the point when it switches its glucose metabolism from oxidative phosphorylation to aerobic glycolysis . the new hypothesis that warburg effect corresponds to the very beginning of carcinogenesis
such failure could be mediated by one ( or multiple ) of the well - known carcinogenic factors in synergy with an excessive supply of glucose in carbohydrates rich diets .
the new hypothesis revolves around a point within cellular glucose oxidation at which the fate of pyruvic acid is decided .
several observations have been presented to support such hypothesis : lower incidence of cancer in insulin - dependent type 1 diabetes mellitus patients ; increased cancer incidence in societies consuming high quantities of carbohydrates ; and the increased probability of synthesis failure of the pyruvate dehydrogenase complex consisting of three enzymes when compared to the synthesis of a single lactate dehydrogenase enzyme .
contemporary agreement in explaining why tumor cells opt for aerobic glycolysis ( warburg effect ) that is far less efficient than oxidative phosphorylation at producing atp , is that it represents evolutionary adaptation to harsh microenvironmental conditions by using the carbon chains ( from the lactic acid ) as building blocks for synthesis of biomolecules ( nucleic acids , proteins , and lipids ) , which are essential for cell proliferation .
however , even the acceptance of the aerobic glycolysis being a more adequate glucose metabolism pathway for cancer cells , the question of a hen or an egg remains : is the warburg effect just a consequence , or could it be the very cause of carcinogenesis ( figure 4 ) ?
 ever since its discovery ( 1924 ) the warburg effect ( aerobic glycolysis ) remains an unresolved puzzle : why the aggressive cancer cells  prefer  to use the energetically highly inefficient method of burning the glucose at the cellular level ? while in the course of the last 90 years several hypotheses have been suggested , to this date there is no clear explanation of this rather unusual effect . 
 even though it is commonly assumed that warburg effect is a consequence of carcinogenesis , yet another hypothesis could be brought up that the cellular switch to aerobic glycolysis may represent the very point in time when a normal cell becomes cancerous . 
 furthermore , this switch may happen at the point where the fate of pyruvic acid is determined , caused by the inadequate supply of enzymes that promote citric as opposed to lactic acid cycle . 
 currently , few clinical observations , like low cancer incidence in type 1 diabetes mellitus and increased cancer incidence in people on high carbohydrate diets might be called upon to support such hypothesis . 
Economy of cellular energy balance
Warburg effect, or aerobic glycolysis - hallmark of invasive cancers
Contemporary explanation of the Warburg effect
A new hypothesis
Conclusion