The warburg effect is the seventh hallmark of cancer

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There are more than 100 distinct types of cancer and subtypes of tumors detected within different organs. A variety of cancer cell genotypes are results of manifestation of six essential alterations in cell phenotypes that express malignancy: self-sufficiency in growth signals, insensitivity to growth-inhibitory (antigrowth) signals, evasion of programmed cell death (apoptosis), limitless replicative potential, sustained angiogenesis and tissue invasion and metastasis. Hanahan and Weinberg discussed the phenotypic differences between healthy and cancerous cells in a paper titled "The Hallmarks of Cancer". The authors introduced six phenotypic alterations at the cellular level as the essential hallmarks of cancer. In 1924, Biochemist Otto Warburg brought about the observation of how cancer cells displayed high rates of glycolysis and produced lactic acid even in the presence of oxygen He therefore proposed that the primary cause of cancer is the replacement of the aerobic respiration in normal body cells by glycolysis and this was termed the 'Warburg effect', the seventh hallmark of cancer. The Warburg hypothesis in cancer cells, however, has been controversial. Aerobic glycolysis was proposed by Otto Warburg as a secondary effect to impaired or damaged respiration in cancer cell physiology. Warburg's theory, however, was opposed as being too simplistic and inconsistent with studies done on normal respiratory process in tumor cells. The theory did not discuss the role of cancer-associated mutations, the phenomenon of metastasis and did not associate the molecular mechanisms displayed in cancer cell proliferation directly to cell respiratory defects. Glycolysis was observed as only a symptom of cancer and not the cause itself. Instead, the prime cause of cancer was related to defects in genetic expression. On the other hand, newer studies have discussed on the genetic origin of cancer and have proposed that cancer is primarily a metabolic disease.

There are more than 100 distinct types of cancer and subtypes of tumors detected within different organs. The term 'Hallmarks of Cancer' refers to the distinct characteristics that attribute to the formation of cancer. In other words, they can be also described as biological alterations acquired by a cell to turn it cancerous. In a landmark review, Hanahan and Weinberg discussed six significant changes in cell physiology that could bring about malignancy in cells. These six changes were referred to as the hallmarks of cancer and they are namely self-sufficiency in growth signals, insensitivity to antigrowth signals, apoptosis, limitless replicative potential, angiogenesis and tissue invasion and metastasis (Figure 1). The paths that cells take on to turn cancerous can vary highly. In a particular cancer types, mutations in oncogenes such as p53 tumor suppressor gene or ras protein can be only found in a certain subset of morphologically similar tumors. Also, mutations in certain oncogenes can take place earlier in certain tumors and later in other tumor types. Therefore, cancer cells acquire the above mentioned biological alterations at different stages of a tumor progression. The pattern by which these changes are attained can differ tumor to tumor or within the same tumor type itself. A cell may acquire a single or more than one biological alteration to become cancerous. Nonetheless, however independent each and every step in tumorogenesis progresses with these changes, the biological endpoints are eventually reached in bringing about cancer, characterized by the various hallmarks (Figure 2).

Genome instability, resulting in increased mutability was observed as the main trigger to these cancer manifestations. A cell is considered to be cancerous when it has acquired these six capabilities .

Hallmark One: Self-Sufficiency in Growth Signals

Acquired Growth signal autonomy was introduced as the 1st hallmark of cancer. It met the criteria of a hallmark due to the prevalence of the dominant levels of oncogenes regulating this growth signal autonomy. Normal cells need mitogenic growth signals in order to activate proliferation. In the absence of such growth signals, proliferation would not occur. However, oncogenes found in cancer cells tend to mimick normal growth signals which lead to their proliferative growth when the growth was not necessary. Also, cancer cells are found to be less responsive to exogenous growth signals. They are believed to generate their own growth factors to which they are responsive to. This prevents them from being dependent on growth signals from other cells in the same tissue. Three molecular aspects present were proved to express cell malignancy such as changes in the exogenous growth signals received, transcellular transducers or intracellular mechanisms that facilitate the downstream signalling cascade. For instance, glioblastomas and sarcomas produce PDGF (platelet derived growth factor) and TGFα (tumor growth factor α). During cancer pathogenesis, cell surface receptors which facilitate growth signals into the cell are prone to deregulation. These receptors are overexpressed in many cancers causing the tumour cell to become hyperresponsive to growth factors that induce proliferation (Fedi et al., 1997). For instance, the epidermal GF receptor (EGF-R/erbB) is upregulated in stomach, brain, and breast tumors while the HER2/neu receptor is overexpressed in stomach and mammary tumorogenesis ; . Cancer cells are also those that have acquired the ability to interact with their neighbouring cell components to bring about the abnormal increase in growth signals leading to their proliferative state .

Hallmark Two: Insensitivity to Anti-growth signals

Antigrowth signals in cells block cell proliferation via two mechanisms. Cells may be transferred from the active proliferative cycle into the quiescent state or they may lose their ability to proliferate by being converted into postmitotic state by acquiring traits that aid them in differentiation. Cancer cells bypass this antiproliferative signals to flourish. The decision whether a cell moves from the G1 state to the S state is determined by the antiproliferative signals mitigated though the retinoblastoma protein (pRb). In a cell's hyposphosphorylated state, pRb inhibits proliferation by altering E2f transcription factors. However, in tumor cells, this pRb signalling pathway is disrupted by factors such as downregulated or mutant or dysfunctioning TGFβ receptors

Hallmark Three: Evading Apoptosis

A cell is not only classified as cancer due to its high rate of proliferation. Acquired resistance to apoptosis is also a mounting hallmark of many cancers. The apoptotic mechanism is in the dormant state till it is triggered by a many types of cellular signals. Cell membranes are disrupted, chromosomes are degraded etc. This happens all in a span of 30-120mins . The apoptotic circuit consists of the sensors and the effectors. The sensors aid in monitoring the internal and external conditions of the cell by evaluating whether they are normal or abnormal to influence the decision of the cell to go through apoptosis. The effectors respond to the signals sent out by the sensors to carry out the apoptosis. The triggering abnormalities include cell DNA defect, inadequate survival factor etc. The possibility that evading cell apoptosis led to cancer was raised in 1972 by Kerr, Wyllie and Currie when they described high rate of apoptosis in the cells. When the components in the apoptotic circuit are altered or dysfunctional, apoptosis fails to occur and hence, cancer cells are able to prosper without any disruption of their proliferative state. The loss of a apoptotic regulator most commonly derives from the mutation associated with the p53 tumor suppressor gene. The p53 protein suffers a loss of function and this is evident in more than 50% of cancers. This results in the elimination of a vital component of the apoptotic sensor for DNA damage. Hypoxia and overexpression of oncogenes also interact with the p53 in the apoptotic circuit. P53 function is lost and apoptosis is not activated. Cancer cells continue proliferation .

Hallmark Four: Limitless Replicative Potential

Research done over the past 30 years found that acquired disruption of cell-to-cell signalling as mentioned in the three hallmarks above, on its own, does not ascertain the prevalence of macroscopic tumors. A cell also contains a cell-autonomous program that controls its extent of multiplication. It is believed to work independently of the cell-to-cell signalling and has to be disrupted to bring about tumor cell proliferation. Generally, cells have a finite life span. They enter senescence after a specific number of doubling. For instance, the senescence of cultured human fibroflasts can be prevented by inactivating their pRb and p53 tumor suppressor genes, facilitating the cells to continue multiplying until they enter into a crisis described as massive cell death and the occasional formation of a variant that gives the cell the ability to multiply infinitely and become immortal . Most types of cancer cells that are cultured are found to be immortalized. This proves that the acquired capability, limitless replicative potential is a physiological aspect acquired in vivo during tumor progression and this brings about cell malignancy . This finding also suggests that during tumor progression, cells go through the maximum number of doublings before atttaining immortality to complete the tumorogenesis process by acquiring infinite replicative potential. The gradual shortening of the telomerase prevents the DNA polymerases from replicating the 3' ends of chromosomal DNA during each S phase. As a result, the chromosomal DNA ends are not protected and this leads to the cascade of actions that end in the death of the cell . However, telomere maintenance is present in all types of tumor cells. The gene encoding the telomerase gene is upregulated when hexanucleotide repeats are added onto the ends of the telomeric DNA. This occurs in 85%-90% of cancer cells . The rest of the cells have come up with a mechanism whereby their telomeres are maintained through recombination-based interchromosomal exchanges of sequence information via a method termed as 'ALT' . When the telomeres are maintained at a length beyond the critical threshold, infinite multiplication of the descendant cells occurs.

Hallmark Five: Sustained Angiogenesis

Blood vessels supply oxygen and nutrients that are vital for cell survival. This causes cells in a tissue to propagate within a short distance away from a network of capillary blood vessels to be able to access the oxygen and nutrients. Once a tissue is formed, angiogenesis, a process involving the formation of new blood vessels is critically regulated. However, cells within proliferating region are a found to lack angiogenic ability. In order to proliferate and expand, they have to develop angiogenic ability . All cancerous tumors release angiogenic growth factor proteins to stimulate blood vessels to grow within the proliferative region to tap sufficient oxygen and nutrients . Such ability is induced step by step in tumorogenesis via a switch to an angiogenic state from vascular quiescence. Hanahan and Folkman studied three transgenic mouse models and found them to undergo angiogenesis leading to the formation of a tumor .

Hence, this acquired ability promotes tumorogenesis and becomes suitable to be a hallmark of cancer.

Hallmark Six: Tissue Invasion and Metastasis

Metastases are the cause for 90% of human cancer deaths . Cancer cells acquire this capability to get out from their primary tumor lesion to invade the surrounding cells where there more nutrients and oxygen available for their survival. The body has many mechanisms to prevent this from happening. However, tumor cells have acquired the ability to overcome these barriers. In tumor cells, the cell adhesion molecules (CAM) are altered or misplaced. Hence, the cancer cells are able to detach from their primary site and spread to the secondary sites. Mutation, loss or decrease of cadherins would have led to this state.

Figure 1: Six Acquired capabilities of Cancer cells

According to Hanahan and Weinberg, six cellular changes transform normal cells into tumor cells. These six hallmarks of cancer are: 1) self-sufficiency in growth signals, 2) insensitivity to antigrowth signals, 3) evasion of apoptosis, 4) limitless replicative potential, 5) sustained angiogenesis, and 6) tissue invasion and metastasis .

Figure 2: Somatic evolution of carcinogenesis.

Normal cells become hyperproliferative due to molecular biological alterations. Oxygen diffusion limit is reached when cells hyperproliferate and they become hypoxic leading to apoptosis and/or autophagy or adapt as a glycolytic phenotype (bioenergetic alteration), which allows cells to survive. As a consequence of increased glycolysis, lesions become acidotic, which selects for immortal cells that eventually breach the basement membrane and cause malignancy. As cancer progression proceeds, mutations cause further molecular and bio-energetic alterations .

The Seventh Hallmark of Cancer- The Warburg Effect

In 1930, Otto Warburg, a biochemist discovered that defects in oxidative phosphorylation (OXPHOS) or aerobic respiration in the mitochondria caused cancer and the cell to switch to anaerobic glycolytic energy metabolism even in aerobic conditions. He also proposed that cancer cells have consistently higher rates of glycolysis than normal cells . Normal cell proliferation and survival requires ATP and this comes from two sources. The first is glycolysis, which is a cascade of reactions that metabolizes glucose to pyruvate in the cytoplasm to produce a net of 2 ATP from each glucose molecule. The other is the Krebs cycle, which uses pyruvate generated from glycolysis in a cascade of reactions and donates electrons via NADH and FADH2 to the respiratory chain complexes in the mitochondria. In muscles, which have encountered prolonged exercise and experience limited oxygen supply, pyruvate is not used in the Krebs cycle and is converted into lactic acid by lactate dehydrogenase (LDH) via anaerobic glycolysis.

It is observed that many cancer cells have a high level of glucose consumption and they produce lactic acid rather than breaking down glucose via the Krebs cycle that generates ATP in non-hypoxic cells. Normal cells go through low rates of glycolysis and source their energy from pyruvate oxidation in their mitochondria. Warburg observed that thin slices of human and animal tumors ex vivo expressed high levels of glucose uptake and lactate formation. This shift towards lactate production in cancers, even in the presence of sufficient oxygen is known as the Warburg effect or aerobic glycolysis. Aerobic glycolysis occurs in carcinomas due to activation of oncogenes or loss of tumor suppressors, which are further stimulated by stabilization of the hypoxia-inducible factor (HIF) (Figure 3) via adaptation to a hypoxic microenvironment or through pathways which stabilize HIF under non-hypoxic conditions .

Figure 3. HIF-1 and O2 Regulatory mechanism

Right: Under normoxic conditions, HIF-1α is hydroxylated by PHD2, using O2, and binds to VHL, which recruits a ubiquitin-protein ligase complex comprising of the proteins elongin C (EC), elongin B (EB), cullin 2 (C2), ring box protein 1 (R1) and a ubiquitin conjugating enzyme (UCE). Ubiquitinated HIF-1α is degraded by the proteasome.

Left: Under hypoxic conditions, PHD2 activity is inhibited, HIF-1α accumulates, dimerizes with HIF-1β, binds to DNA and activates the transcription of target genes whose protein products play critical roles in physiological responses to hypoxia (Oxygen Homeostasis in Health and Disease .

The underlying mechanisms leading to the Warburg effect include alterations in the mitochondria, upregulation of rate-limiting enzymes and proteins in glycolysis and intracellular pH regulation, shift to anaerobic metabolism after hypoxia induction and metabolic reprogramming. Glycolytic metabolism, in other words, the Warburg Effect has been, thus, discussed as a potential seventh hallmark or sign of cancer .

Emerging evidence also signifies that impaired cellular energy metabolism is the main characteristic of almost all cancers regardless of cellular or tissue origin. In contrast to normal cells, which derive most of their energy from oxidative phosphorylation, most cancer cells become highly dependent on substrate level phosphorylation to meet their energy demands .

Aerobic glycolysis was proposed by Otto Warburg as a secondary effect to impaired or damaged respiration in cancer cell physiology . This triggers an elevated glycolytic flux to compensate for the loss of energy production to keep the cancer cells viable. Although lactic acid is formed in both aerobic and anaerobic glycolysis, aerobic glycolysis can take place in tumor cells as a result of damaged respiration while anaerobic glycolysis takes place in the absence of oxygen. As oxygen will decrease the rate anaerobic glycolysis and lactic acid production in most normal cells, the continuous formation of lactic acid in the presence of oxygen can represent an abnormal effect. This condition is evident in most cancers. If cells are able to increase glycolysis following respiratory damage, they are considered capable of bringing about tumors . On the other hand, cells that are not able to elevate glycolysis during respiratory insults, the cells would die as a result of energy failure. Therefore, tumorogenic cells can form from normal body cells in response to a gradual and irreversible damage to their respiratory capacity.

Therefore, aerobic glycolysis triggered by damaged respiration, is found to be the single most common phenomenon found in cancer . Transcription factors such as c-MYC, HIF-1 and p53 play a vital role in regulating the energy metabolism. Using the database of Expressed Sequence Tags (dbEST) for expression of genes and expressed sequence tags, studies have discovered that genes involved in glycolysis are overexpressed in 24 different kinds of cancers representing more than 70% of human cancer cases . The cellular energy level as measured by the nucleotide triphosphate/inorganic phosphate (NTP/Pi) ratio of malignant tumors remains relatively unaffected by hypoxia but is reduced when there is a lack in glucose. As what Warburg proposed, this shift from oxidative phosphorylation to glycolysis may not be essential for malignant transformation but it is a secondary effect to transformation characterized by high metastatic tendency and survival advantage .

Metabolites are essential for cancer cell proliferation. Sufficient supply of building blocks for DNA, RNA, protein, lipid and complex carbohydrate is needed to prepare for cell division . Glycolysis, glutaminolysis and de novo lipid biosynthesis are essential platforms for cancer cell proliferation . Cancer cells have higher glucose, lactate and glutamine production rate and an upregulated pentose phosphate pathway activity than normal cells . Fatty acid synthase (FASN), a key regulator of de novo lipid biosynthesis and a gene highly expressed in most cancers, is regulated by glucose via the carbohydrate responsive element binding protein (ChREBP), by glucocorticoids via sterol regulatory element binding protein-1 (SREBP-1), and by AKT/hypoxia-induced factor-1 (HIF-1) signaling inducing the SREBP-1 gene . Elevated rates of glycolysis are consistently observed in cancers malignant cells and these are due to upregulation of enzymes in glycolysis namely hexokinase 2 (HK2), glyceraldehyde-3- phosphate dehydrogenase (GAPDH), 6-phosphofructo-1-kinase (PFK1), triose-phosphate isomerase (TPI), phosphoglycerate kinase 1 (PGK1), and enolase 1 (ENO1), and pyruvate kinase (PK) and a reduction in some enzymes in gluconeogenesis and mitochondrial respiration . The high expression of genes involved in glycolysis aid in ensuring a high throughput of supply materials and bio-energy from glucose for biosynthetic processes and cellular functions . As a result of glycolytic metabolism, tumor cells are able to gain survival advantages such as independence from oxygen supply, ability to detoxify chemotherapy drugs and ability to repair DNA damage. The glycolytic metabolic pathway is also linked to generating NAD(P)H to break down other redox reactions . NAD(P)H aids in helping cancer cells survive chemotherapy by detoxifying drugs via the cytochrome P-450 system. In response to a DNA damage, poly(ADP-ribose) polymerase(PARP-1) is activated at the sites of DNA damage. PARP-1 breaks NAD+ into nicotinamide and ADP-ribose, polymerizes ADP-ribose and transfers ADP-ribose moieties to carboxyl groups of PARP-1, consuming a large quantity of NAD+/ATP. PARP-1 activation leads to rapid depletion of the cytosolic NAD+ pool and renders the cells unable to utilize glucose as a metabolic substrate . The tumor metabolome also suggests a vulnerability of the cancer cells to a reduction of NAD+ after DNA damage .

Discussion- The Warburg Effect hypothesis as a seventh hallmark of cancer

The Warburg Hypothesis

Damage to cellular respiration as a result of genomic instability is the main key to tumor progression. This hypothesis is based on evidence that cell growth and proliferation is primarily based on mitochondrial energy and that all cells require a constant level of energy to maintain viability. The Warburg effect is known to be an adaptation of cancer cells to the hypoxic conditions inside solid tumors and hence not the cause but an effect of cancer. Although no specific mutation or acquired cell abnormality is common to all cancers, almost all cancers are known to display aerobic glycolysis in regardless to their biological origin. In order for cancer cells to remain viable, an increase in glycolysis rate was observed. Even though lactic acid is produced in both aerobic and anaerobic glycolytic pathways, a damaged respiratory pathway brings about aerobic glycolysis in cancer cells while mere absence of oxygen brings about anaerobic glycolysis. In normal cells, the presence of oxygen will reduce the need for anaerobic glycolysis and lactic acid production. This is termed as the 'Pasteur' effect. However, in most tumor cells, even with oxygen around, lactic acid is still continued to be produced and this forms an abnormal 'Pasteur' effect. If normal cells could still continue tapping energy (via aerobic glycolysis) even though the respiratory pathway is damaged, they are identified as potential cancer cells the other cells that are not able to increase their level of glycolysis to survive would go through cell apoptosis . Therefore, aerobic glycolysis as a result of a defective respiratory pathway forms as a fundamental phenotype in cancer. This surviving capability they have acquired proves that the Warburg effect is suitable to be a hallmark of cancer.

Normal aerobic respiration provides the ATP energy for a successful and continual DNA repair and also to control gene expression. Warburg's hypothesis, indicates that there is a relatively lesser ATP production via anaerobic glycolysis and therefore the lesser ability to maintain normal DNA repair and protein expression . Recent studies have shown that the high levels of lactate production has aided the cancer cells in carrying out the production of amino acids, nucleic acids and phospholipids and that the low amounts of ATP production is not a limiting factor for cancer cell survival (Figure 4). Thus the cell switch to aerobic glycolysis promotes tumor cell proliferation and this supports the Warburg hypothesis (Figure 5).

In recent years, Warburg's hypothesis has been relooked at in response to several studies associating both defective mitochondrial function and defective cell respiration cancer progression. Subsequent work has shown that the Warburg effect might lead to a promising approach in the treatment of carcinomas .

Figure 4. The altered metabolic pathway in cancer cells

A defective respiratory pathway forms an environment of low oxygen levels. This leads to an altered metabolic pathway and the Warburg effect. HIF reduces the cell's reliability on oxygen while genes Ras, Myk and Akt aid in upregulating glycolysis. This furnishes the tumor cells with additional survival advantages such as increased biosynthesis, apoptosis avoidance and metabolite signaling. However, the altered metabolic pathway leaves the cells with liabilities such as toxic and lactate accumulation or a high energetic demand .

Figure 5. Distinction between oxidative phosphorylation, anaerobic glycolysis, and aerobic glycolysis (Warburg effect) (Mathew G et al., 2009;

In normal differentiated cells, glucose is converted into carbon dioxide by pyruvate oxidation in the TCA cycle. There is minimal production of lactate and a high level of ATP produced. High levels of lactate is produced under anaerobic conditions. In contrast, tumor cells produce high levels of lactate in regardless to the availability of oxygen .

2.2 Cell Energy Production

Warburg also proved that the total energy production in normal kidney and liver cells was astonishingly similar to that produced in proliferating tumor cells . Glycolysis or glutaminolysis must increase in cells experiencing mitochondrial impairment in order to maintain adequate ATP for viability (Figure 4).

A major difference between normal cells and cancer cells is in the origin of the energy produced rather than in the amount of energy produced. It is critical to recognize that a prolonged reliance on substrate level phosphorylation for energy production brings about genomic instability and cellular disorder which characterizes further cancer development and hence, this warrants the Warburg effect to be a suitable hallmark of cancer.

2.3 Mitochondrial Dysfunction in Cancer Cells

Numerous discoveries prove that tumor mitochondria are structurally and functionally abnormal and not able to generate normal levels of energy . Changes in mitochondrial membrane lipids and especially the inner membrane enriched lipid, cardiolipin disrupt the mitochondrial proton motive gradient hence, inducing protein-independent uncoupling with a fall in respiratory energy production. Cancer cells contain abnormalities in cardiolipin content or composition that are linked to electron transport impairment . This alters the function of most electron transport chain complexes such as the F1-ATPase and also prevents uptake of ADP through the adenine nucleotide transporter thus affecting the efficiency of oxidative phosphorylation. This can also inhibit oxidation of the coenzyme Q couple, hence, producing reactive oxygen species during cancer progression . Elevated ROS production can adversely affect genomic stability, tumor suppressor gene function and control over cell proliferation . Therefore, cancer cell respiration is altered in several ways in tumor cells, bringing about the need for aerobic glycolysis.

In addition to the lipidomic evidence supporting the Warburg cancer theory, recent studies show proteomic evidence supporting the theory . The results displayed a reduction in the ß-F1-ATPase/Hsp60 ratio concurrent with an upregulation of the glyceraldehyde-3-phosphate dehydrogenase potential in most common human cancers. These and other studies reflect that the bioenergetic capacity of tumor cells is largely defective and concludes that mitochondria structure and function is abnormal in cancer cells . Hence, mitochondrial dysfunction will cause cancer cells to be more heavily dependent on substrate level phosphorylation or glycolysis for energy production than normal and healthy cells in order to maintain cell survival, energy production and cell viability.

2.4 Genome Instability and Mitochondrial Dysfunction

Metabolic studies in several human cancers previously showed that that loss of mitochondrial function preceded the appearance of malignancy and aerobic glycolysis . Over the last 50 years, the general view has been that gene mutations and chromosomal abnormalities underlie most aspects of tumor initiation and progression which includes the Warburg effect. Although mitochondrial function and oxidative phosphorylation is defective in cancer cells, it remains unclear how these defects are linked to tumorogenesis . Most inherited metabolic defects do not specifically compromise mitochondrial function or lead to cancer formation. Nevertheless, there are some exceptions such as germ-line mutations in genes that encode TCA cycle proteins which can pose an increased risk to certain human cancers. For instance, the risk for paraganglioma consists of mutations in the succinate dehydrogenase gene while the risk for leiomyomatosis and renal cell carcinoma involves mutations in the fumarase gene . These mutations directly impair mitochondrial energy production causing an elevated glycolysis and hence, the Warburg effect .

2.5 Implications of the Warburg effect on Cancer Management

As cancer is considered to be a metabolic disease as discussed above, cancer therapy would specifically target energy metabolism. For instance, mitochondrial replacement therapy could possibly restore a more normal energy metabolism and differentiated state to cancer cells . However, several studies have shown that dietary energy restriction is a general metabolic therapy that naturally reduces circulating glucose levels and significantly reduces growth and progression of numerous cancers . The influence of energy restriction on tumor growth relies on the cell host background and cancer growth site. In a study, it was observed that energy restriction is effective in reducing the U87 human glioma when grown orthotopically in the brain of immunodeficient SCID mice but not when grown outside the brain in non-obese diabetic SCID mice . However, there is strong evidence that proves that dietary energy restriction can slow down the growth rate of many tumors regardless of the specific genetic defects expressed within the tumor . As such, activation of aerobic glycolysis induces an environment for cancer cells to survive without oxygen dependency for ATP production, particularly in the hypoxic tumor microenvironment. This liberation, however, could be exploited for therapeutic purposes. For example, inhibition of ATP citrate lyase can suppress tumor cell growth . Inhibition of glycolysis can overcome tumor drug resistance . Furthermore, inhibition of HIF-1 or PDK1, which leads to a higher mitochondrial oxygen depletion, renders cells more susceptible to anoxia-induced cell death or sensitivity to tirapazamine, a chemotherapeutic agent which is activated in a hypoxic state

3. Conclusion

The general view in the past 50 years has been that a defective respiratory pathway and the Warburg effect along with gene mutations and chromosomal abnormality form as a strong foundation in tumorogenesis. The key components in the Warburg effect such as increased glucose consumption, reduced oxidative phosphorylation and large amounts of lactate production form distinguishing acquired capabilities in forming a cancer cell. In this review, evidence reveals that all forms of cancer derive from the defective mitochondrial function and hence, the mitochondrial defect leads to the Warburg effect that characterizes cancer formation, making it an apt hallmark of cancer.

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