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Metabolic theory of cancer starts with the Warburg Effect.
  • The story starts in the first decades of the 20th century with Otto Heinrich Warburg, who won the Nobel Prize in Medicine/Physiology in 1931 for his ‘discovery of the nature and mode of action of the respiratory enzyme‘ (The Nobel Prize in Physiology or Medicine 1931).
  • Through the process of oxidative phosphorylation (OXPHOS), mitochondria are the cell’s source of ATP (adenosine triphosphate), the necessary source of cellular fuel.
    • Cell derives its energy through respiration.
    • Respiration requires the combustion of glucose.
    • Aerobic respiration means in presence of oxygen.
    • Anaerobic respiration (fermentation) is obviously in the absence of oxygen.
    • Normally, the latter is much more inefficient. Pyruvate—> lactate/lactic acid generates 2 ATP molecules while Pyruvate —> aerobic respiration yields ~30 ATP molecules.
    • Also, more lactate —> more acidic the cell, subsequently found to be a hallmark of tumor cells.
  • In 1927, Warburg observed that rather than relying on oxygen-dependent OXPHOS, cancer cells tend to use glycolysis for ATP production, even in the presence of oxygen. This phenomenon is called the Warburg effect or aerobic glycolysis (fermentation) (1).
  • In his experiments on slices of living tissues, Warburg found that through the weird process of aerobic glycolysis (fermentation), tumor cells had surmounted the inherent energy limitation of glycolysis. While normal tissue slices switched to lactate production when deprived of oxygen (Warburg called this the Pasteur effect), tumor slices continued this process even in the presence of oxygen (2).
  • Warburg wrote, ‘When the respiration of body cells has been irreversibly damaged, cancer cells by no means immediately result. For cancer formation there is necessary not only an irreversible damaging of the respiration but also an increase in the fermentation-…’ (3).
  • Though technological improvements over the subsequent decades uncovered some technical flaws in Warburg’s experiments, nevertheless his data have withstood the test of time.
  • In more modern terms, this implies a necessary metabolic inflection point on the road to cancer. When a cell suffers respiratory damage, i.e., some kind of damage to mitochondrial function, it will try to adapt by increasing glycolysis. If it doesn’t it will die.
  • Warburg proposed that cancer cells have undergone respiratory damage and successfully emerged from the ensuing bottleneck by adapting and switching to aerobic glycolysis (fermentation) (4).
  • Warburg’s hypothesis was that defective mitochondria and/or the resulting respiratory injury was a critical driver of cancer initiation. In other words, Warburg proposed defective mitochondria as the root cause of cancer (5).
  • Tumors are frequently observed to produce high levels of mitochondrial ROS (Reactive Oxygen Species). In the Warburg model, this is posited to provoke genetic instability and thereby drive further tumor generation (tumorigenesis) (6, 7).
  • Cell respiration and death are key functions that are highly dysfunctional in cancer cells. Ancient remnants of an ancestral bacterial symbiont, mitochondria are the key organelle involved in both processes.
  • As the primary consumer of oxygen inside cells, mitochondria are the cell’s engine, generating high levels of ROS through their key role in cellular energy metabolism.
Rekindled interest in Warburg’s theory
  • Originally popular, Warburg’s theory was then sidelined once oncogenes and tumor suppressor genes began to be discovered in the late 1970s. With them, the genetic theory of cancer took shape and has dominated ever since.
  • Technological advances led to data that rekindled interest in Warburg’s idea.
  • For one, nearly all tumors, regardless of origin, perform aerobic glycolysis (fermentation).
  • In fact, tumor’s insatiable thirst for glucose is the basis for one of the most commonly used tests to diagnose and stage tumors. Called FDG-PET (18Fluoro-deoxy-glucose-Positron Emission Tomography) (8).
    • In this test, FDG substitutes for glucose in the 1st step of glycolysis.
    • Taken up by the cell, it stays in it because the fluorine atom prevents its further modification by enzymes.
    • The FDG-PET test is very sensitive and relatively easily picks up increased uptake of glucose by cancer cells.
    • It’s used for cancers ranging from breast, colorectal, lung to melanoma, i.e., increased glucose uptake by cancers is a generalizable feature.
  • For another, over-expression of genes involved in glycolysis is also a generalizable feature of cancers, being found in 24 different kinds of cancer that represent >70% of human cancers (9).
Observational data support Warburg’s idea of mitochondrial involvement in cancer (few e.g.)
  • Many, not all, cancer cells have abnormalities in their mitochondria, ranging from altered cristae (folds of the inner mitochondrial membrane), changes in membrane composition and membrane potential (10, 11).
  • Aggressive and rapidly growing tumors show signs of mitochondrial dysfunction (12, 13).
  • Degree of mitochondrial changes depend on the type of tumor and its milieu such as hypoxia (low oxygen levels) and hormones (14, 15, 16).
Mechanistic data support Warburg’s idea of mitochondrial involvement in cancer (few e.g.)
  • Some experimental models have shown that mitochondrial metabolism is required/essential for tumor growth (17, 18, 19).
  • Localized in the mitochondrial membrane, the proto-oncogene Bcl-2 prevents cell death. Bcl-2’s mitochondrial location implies integral role for mitochondria in oncogenesis.
  • Mutations in mitochondrial genes, succinate dehydrogenase (SDH) and fumarate hydratase (FH), predispose to cancer (20).
  • In some cases, mitochondrial dysfunction is even sufficient to drive cancer (21).
  • Ingenious mitochondria transplant experiment from normal mammary cell to breast cancer cells inhibited their proliferation and increased drug sensitivity (22).
Data that contradict the theory or aren’t explained by it
  • High rate of glycolysis isn’t a unique attribute of tumor cells since it’s also observed in normal cells.
  • Data in the 1950s showed that tumor cells effectively oxidized the fatty acid palmitate (23, 24), similar to normal cells such as liver cells.
  • Mitochondrial TCA (Tricarboxylic acid) cycle enzyme activities were similar between tumor and healthy cells (25).
  • Many tumor cell lines show normal respiratory function (4).
  • Theory doesn’t explain the how and why of tumor-associated mutations.
  • Theory doesn’t explain how a cancer’s damaged respiration links to its uncontrolled proliferation.
  • Theory doesn’t explain tumor metastases.
Metabolic reprogramming reconciles the contradictions to derive a consensus role for mitochondria in tumorigenesis
  • Though many, if not most, tumor cells have fully functional mitochondria, pockets of them have mitochondrial gene mutations (26, 27), especially in TCA cycle enzymes
  • Such tumor cells are glycolysis-dependent and their mitochondria display outlandishly altered metabolic features such as ‘reductive carboxylation‘, i.e., glutamine—>alpha-ketoglutarate (28) and increased ROS (29, 30, 31).
  • This is in contrast to the ‘Warburg effect’, i.e., aerobic glycolysis, where the TCA cycle results in lactate.
  • In 1951, Feodor Lynne suggested tumor cell mitochondria undergo uncoupling rather than permanent damage (32).
  • The mitochondrial uncoupling hypothesis (33, see figure below) suggests that cancer cells are more dependent on glycolysis not because they can’t reduce oxygen but because they’re unable to synthesize ATP in response to changes in the Mitochondrial Proton Gradient (MTP).
    • Such mitochondria undergo a metabolic shift and start using non-glucose carbon sources such as fatty acids and glutamine to maintain their function, i.e., metabolic pathway uncoupled from glucose consumption.
    • This mitochondrial uncoupling process is similar to that in Brown Adipose Tissue (BAT) during cold acclimation.
    • Genes involved in BAT mitochondrial uncoupling are over-expressed in some human cancer cell lines and primary human colon cancer (34).
As Samudio et al explain, ‘recent investigations into the mechanisms that underlie the Warburg effect suggest that (a) mitochondrial uncoupling can promote aerobic glycolysis in the absence of permanent and transmissible alterations to the oxidative capacity of cells, (b) aerobic glycolysis may represent a shift to the oxidative metabolism of non glucose carbon sources, and (c) mitochondrial uncoupling may be associated with increased resistance to chemotherapeutic insults‘. (33).
  • One key feature of this metabolic reprogramming is flexibility, a tumor cell’s capacity for and flexible use of aerobic glycolysis (fermentation) being an emblematic example.
  • Thus, modern revision of Warburg’s idea is that cancer cells are metabolically flexible, switching from one state, say aerobic glycolysis, to another, say OXPHOS, to adapt to different micro-environments as they grow.
  • Metabolic reprogramming is a key feature of tumorigenesis and mitochondria are key players in this process.
  • There is still no satisfactory consensus on how metabolic reprogramming supports/drives metastases though there are some hypotheses.
  • According to one (35; see figure below), some attributes of malignancy such as independence from extracellular matrix (ECM), aka anoikis, trigger metabolic and oxidative stress.
  • Since these are the purview of mitochondria, their responses would thus shape metastatic potential.
  • According to others (36, 37; see figure below), not all cancer cells undergo metabolic reprogramming.
  • Rather, only some, for e.g., cancer stem cells (CSC) or quiescent/slow-cycling tumor cells, do so.
  • Difficult to test since there aren’t reliable methods to identify such cells.
Another way of conceptualizing the problem of cancer genesis is to consider who drives it, the nucleus or the mitochondria.
  • Classic chicken-and-egg.
  • Is impaired cellular respiration manifested as aerobic glycolysis (fermentation) the cause of cancer or a result of it?
  • Does genomic instability cause aerobic glycolysis (fermentation) or result from it?
  • A more nuanced picture suggests metabolic reprogramming sculpts the tumor program with both the nucleus and mitochondria driving the process synchronously (38; see figures below).
  • In such a scenario, mitochondrial dysfunctions trigger a feed-back loop that drives tumorigenesis.
  • Mitochondria dysfunction —> oncometabolites, small molecule metabolites, accumulate —> induce genetic and epigenetic changes that drive tumorigenesis (27).
Bibliography
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  2. Warburg, O. “KP, and E. Negelein.” On the Metabolism of Cancer Cells (1924): 319-344.
  3. Warburg, Otto. “On the origin of cancer cells.” Science 123.3191 (1956): 309-314. Page on mosao2.org
  4. Seyfried, Thomas N., and Laura M. Shelton. “Cancer as a metabolic disease.” Nutr Metab (Lond) 7.7 (2010): 269-70. Cancer as a metabolic disease
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https://www.quora.com/What-is-the-metabolic-theory-of-cancer/answer/Tirumalai-Kamala

 

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