The Warburg hypothesis (), sometimes known as the Warburg theory of cancer, postulates that the driver of

tumorigenesis Carcinogenesis, also called oncogenesis or tumorigenesis, is the formation of a cancer, whereby normal cells are transformed into cancer cells. The process is characterized by changes at the cellular, genetic, and epigenetic levels and abnor ...

is an insufficient cellular respiration caused by insult to mitochondria. The term '' Warburg effect'' in oncology describes the observation that

cancer Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...

cell Cell most often refers to: * Cell (biology), the functional basic unit of life Cell may also refer to: Locations * Monastic cell, a small room, hut, or cave in which a religious recluse lives, alternatively the small precursor of a monastery ...

s, and many cells grown ''

in vitro ''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called " test-tube experiments", these studies in biology ...

'', exhibit

glucose Glucose is a simple sugar with the molecular formula . Glucose is overall the most abundant monosaccharide, a subcategory of carbohydrates. Glucose is mainly made by plants and most algae during photosynthesis from water and carbon dioxide, u ...

fermentation even when enough

oxygen Oxygen is the chemical element with the symbol O and atomic number 8. It is a member of the chalcogen group in the periodic table, a highly reactive nonmetal, and an oxidizing agent that readily forms oxides with most elements as ...

is present to properly respire. In other words, instead of fully respiring in the presence of adequate oxygen, cancer cells ferment. The Warburg hypothesis was that the Warburg effect was the root cause of cancer. The current popular opinion is that cancer cells ferment glucose while keeping up the same level of respiration that was present before the process of

carcinogenesis Carcinogenesis, also called oncogenesis or tumorigenesis, is the formation of a cancer, whereby normal cells are transformed into cancer cells. The process is characterized by changes at the cellular, genetic, and epigenetic levels and abno ...

, and thus the Warburg effect would be defined as the observation that cancer cells exhibit glycolysis with lactate production and mitochondrial respiration even in the presence of oxygen.

Hypothesis

The

hypothesis A hypothesis (plural hypotheses) is a proposed explanation for a phenomenon. For a hypothesis to be a scientific hypothesis, the scientific method requires that one can test it. Scientists generally base scientific hypotheses on previous obse ...

was postulated by the Nobel laureate

Otto Heinrich Warburg Otto Heinrich Warburg (, ; 8 October 1883 – 1 August 1970), son of physicist Emil Warburg, was a German physiologist, medical doctor, and Nobel laureate. He served as an officer in the elite Uhlan (cavalry regiment) during the First World War, ...

in 1924. He hypothesized that

, malignant growth, and

tumor A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...

growth are caused by the fact that

cells mainly generate

energy In physics, energy (from Ancient Greek: ἐνέργεια, ''enérgeia'', “activity”) is the quantitative property that is transferred to a body or to a physical system, recognizable in the performance of work and in the form of hea ...

(as e.g.,

adenosine triphosphate Adenosine triphosphate (ATP) is an organic compound that provides energy to drive many processes in living cells, such as muscle contraction, nerve impulse propagation, condensate dissolution, and chemical synthesis. Found in all known forms o ...

/ ATP) by non-oxidative breakdown of

(a process called glycolysis). This is in contrast to healthy cells which mainly generate energy from oxidative breakdown of pyruvate. Pyruvate is an end-product of glycolysis, and is

oxidized Redox (reduction–oxidation, , ) is a type of chemical reaction in which the oxidation states of substrate change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is the gain of electrons or a ...

within the mitochondria. Hence, according to Warburg,

stems from the lowering of mitochondrial respiration. Warburg regarded the fundamental difference between normal and cancerous cells to be the ratio of glycolysis to respiration; this observation is also known as the Warburg effect. In the somatic mutation theory of cancer, malignant proliferation is caused by

mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA replication, DNA or viral repl ...

s and altered gene expression, in a process called

malignant transformation Malignant transformation is the process by which cells acquire the properties of cancer. This may occur as a primary process in normal tissue, or secondarily as ''malignant degeneration'' of a previously existing benign tumor. Causes There are ...

, resulting in an uncontrolled growth of cells. The metabolic difference observed by Warburg adapts cancer cells to the

hypoxic Hypoxia means a lower than normal level of oxygen, and may refer to: Reduced or insufficient oxygen * Hypoxia (environmental), abnormally low oxygen content of the specific environment * Hypoxia (medical), abnormally low level of oxygen in the t ...

(oxygen-deficient) conditions inside solid tumors, and results largely from the same mutations in oncogenes and tumor suppressor genes that cause the other abnormal characteristics of cancer cells. Therefore, the metabolic change observed by Warburg is not so much the cause of cancer, as he claimed, but rather, it is one of the characteristic effects of cancer-causing mutations. Warburg articulated his hypothesis in a paper entitled ''The Prime Cause and Prevention of Cancer'' which he presented in lecture at the meeting of the Nobel-Laureates on June 30, 1966 at

Lindau Lindau (german: Lindau (Bodensee), ''Lindau am Bodensee''; ; Low Alemannic: ''Lindou'') is a major town and island on the eastern side of Lake Constance (''Bodensee'' in German) in Bavaria, Germany. It is the capital of the county (''Landkreis' ...

, Lake Constance, Germany. In this speech, Warburg presented additional evidence supporting his theory that the elevated anaerobiosis seen in cancer cells was a consequence of damaged or insufficient respiration. Put in his own words, "the prime cause of cancer is the replacement of the respiration of oxygen in normal body cells by a fermentation of sugar." The body often kills damaged cells by apoptosis, a mechanism of self-destruction that involves mitochondria, but this mechanism fails in cancer cells where the mitochondria are shut down. The reactivation of mitochondria in cancer cells restarts their apoptosis program.

Continuing research and interest

A large number of researchers have dedicated and are dedicating their efforts to the study of the Warburg effect that is intimately associated with the Warburg hypothesis. In oncology, the Warburg effect is the observation that most

cells predominantly produce energy by a high rate of glycolysis followed by

lactic acid fermentation Lactic acid fermentation is a metabolic process by which glucose or other six-carbon sugars (also, disaccharides of six-carbon sugars, e.g. sucrose or lactose) are converted into cellular energy and the metabolite lactate, which is lactic acid i ...

in the

cytosol The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cells ( intracellular fluid (ICF)). It is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondri ...

, rather than by a comparatively low rate of glycolysis followed by oxidation of pyruvate in mitochondria as in most normal cells. Interestingly, researchers found that under

obesity Obesity is a medical condition, sometimes considered a disease, in which excess body fat has accumulated to such an extent that it may negatively affect health. People are classified as obese when their body mass index (BMI)—a person's ...

, tumor cells invert the metabolic flow by producing

by gluconeogenesis using

lactic acid Lactic acid is an organic acid. It has a molecular formula . It is white in the solid state and it is miscible with water. When in the dissolved state, it forms a colorless solution. Production includes both artificial synthesis as well as nat ...

and other metabolic sources as substrates. This process in known as Warburg effect inversion. In particular, almost 18,000 publications have been published on the matter of ATP and the Warburg effect in the period 2000 to 2015. Most of the functions of the Warburg Effect have been the object of study.The Warburg Effect: How Does it Benefit Cancer Cells?
Trends in Biochemical Sciences- M.V. Liberti, J.W. Locasale. January 2016 Thousands of publications claim to have determined its functions or causes.

Hypothesis

Continuing research and interest

See also

References

Further reading