Theories about cancer have been changing in recent years. The conventional collective wisdom points to the “somatic mutation theory,” suggesting that cancer results from DNA damage. A series of mutations leads to oncogenes, which is genetic material that is capable of inducing cancer. Then the cancer follows a typical path to development. This theory has been accepted in established circles for many years.
In 2006, the U.S. launched The Cancer Genome Atlas (TCGA) as part of the sixteen-nation International Cancer Genome Consortium. The objective was to map out all the genes in thousands of cancer cells to pinpoint which mutations were associated with cancers. Then the endeavor was to develop therapies that targeted specific mutations.
While there was considerable excitement at first, years later the results are creating confusion. As summarized in 2015 in the journal Nature, “most mutations formed a bewildering hodgepodge of genetic oddities, with little commonality between tumours.” The reporter further observed, “cancers are often quick to become resistant, typically by activating different genes to bypass whatever cellular process is blocked by the treatment.”
In other words, the group found no consistent mutations that connected to various types of cancers. And when specific targets were identified and therapies developed to block them, the cancer cells bypassed the process. The result has been multiple failures of very costly biologic and targeted therapies.
Thus, the genome project has added skepticism over the conventional somatic mutation theory. Some researchers have concluded that cancer is too complex to understand. Others are working on developing other theories of cancer leading to effective therapeutic alternatives.
Otto Warburg and His Effect on Understanding Cancer
Otto Warburg’s research has been gaining revived attention recently. Beginning in the 1930s, Warburg identified one quality of cancer cells that appeared to be consistent in every cancer cell type he examined.
Discussing this in a 1956 paper published in Science, Warburg put forth that cancer has four basic tenets: “Cancer arises from damage to cellular respiration; energy through fermentation gradually compensates for insufficient respiration; cancer cells continue to ferment lactate in the presence of oxygen; [and] enhanced fermentation is the signature metabolic malady of all cancer cells.”
While conventional science accepted this as a property of cancer, (now known as the “Warburg Effect”), it considered the finding to be quirky as something cancer cells do as a result of mutations. However, Warburg asserted that “damaged cellular respiration” and “energy through fermentation” defined cancer cells and how they originate.
Support for Warburg’s theory came from studies conducted in the late 1980s at several American Universities. Newer technologies enabled experiments that Warburg could not do with the technology of the 1930s.
One experiment involved taking the nucleus from a cancer cell and transferring it to the cytoplasm of a healthy cell. This generally resulted in extinguishing the “tumorigenic phenotype,” meaning that the new cell behaved as a non-cancerous cell. The researchers then performed the reverse, transferring the nucleus of a normal cell to the cytoplasm of a cancer cell. This usually resulted in the cell behaving as a cancer cell. This suggested that a cell nucleus had little effect on the malignancy of a cell.
More work was conducted with electron microscopes, which enable a view into the internal structures of cells. The scientists found that cancer cells had fewer mitochondria, and the mitochondria had abnormal internal architecture. This finding supported Warburg’s theory. Because the mitochondria are the source of the primary metabolic activity of a cell, the malfunctioning mitochondria reflected the damaged cellular respiration on a biochemical level that Warburg had discovered decades prior.
Mitochondrial Damage and Cancer
How does mitochondrial damage lead to cancer? A paper published in 2005 in the journal Medical Hypotheses suggested that signaling pathways from malfunctioning mitochondria to the nucleus could alter cellular metabolism, tumor progression, proliferation, and resistance to apoptosis.
In 2012, Thomas Seyfield and a coauthor published a paper in the journal Nutrition and Metabolism. In it, the stated: “Emerging evidence indicates that impaired cellular energy metabolism is the defining characteristic of nearly all cancers regardless of cellular or tissue origin.” The hypothesis that Seyfried developed was that “genomic instability and essentially all hallmarks of cancer, including aerobic glycolysis (Warburg effect), can be linked to impaired mitochondrial function and energy metabolism.”
In 1986, The New England Journal of Medicine published a paper that suggested another issue regarding cancer. Titled “Tumors: wounds that do not heal,” the paper argued that cancer behaves much like a healing wound, activating many of the same cellular mechanisms such as growth factors, inflammation, angiogenic factors, and enzymes. But unlike a normal wound, the cancer healing process is never completed and continues on.
Pulling this data together gives a picture of initial damage to mitochondria that leads to known cancer risk factors like hypoxia, oxidative stress, radiation, and certain infectious agents. The mitochondria send out signals to the nucleus to activate genes in an attempt to repair the damage.
Then a simultaneous shift in metabolism happens in which the normal oxidative phosphorylation (the process in which ATP is formed) in mitochondria becomes replaced with glycolysis in the cytoplasm. This results in two goals. First, an alternative energy source must replace the damaged metabolism. However, glycolysis is a less efficient way to produce energy than oxidative phosphorylation; only a tiny percent of the ATP that is generated by the mitochondria per molecule of glucose is produced from glycolysis. Thus, a much larger supply of glucose is necessary to meet the energy requirements. Secondly, this enhanced glycolysis provides material for production of nucleic acids needed for increased cell division.
In addition, mitochondria regulate apoptosis. When a cell is sufficiently damaged, the mitochondria send signals telling them to self-destruct. However, impaired mitochondria will ultimately lose this process thereby allowing damaged cells to continue living, which is another quality of cancer.
Once it receives this direction from the mitochondria, a cell seeks to reestablish healthy functioning. This response is typically temporary. However, the cancer cell operates autonomously and is concerned only with its own survival rather than the overall health of the entire body.
Another developing hypothesis is the cancer stem cell theory. This hypothesis states that with cancer, some cells cannot initiate new tumors. Other cells, cancer stem cells, can initiate, promote, and spread neoplastic growth. The CSCs are difficult to kill, not responsive to traditional cytotoxic therapies, and responsible for relapses. In addition, cancer stem cells are more primitive in the functioning. For instance, they rely on a more primitive form of metabolism, glycolysis. This may be another aspect of the disruption of normal mitochondrial respiration and regression.
Does Diet Matter?
Do any of these hypotheses and new data lead to new methods of managing cancer? Now that a difference between the functions of healthy and cancer cells in metabolism, science may be able to target this quality.
One direction may be through diet. Because cancer is dependent on large volumes of glucose, it makes sense to limit the supply. One idea is known as the ketogenic diet for cancer, which has some encouraging initial results. It is a diet low in carbohydrates and high in fats with moderate proteins. With the significant reduction in carbohydrates, the body will break down fats into ketones as a replacement energy source. However, because ketones are metabolized in the mitochondria, cancer cells, which have malfunctioning mitochondria, cannot make use of the ketones. It appears that higher levels of ketones, even with regular glucose levels, may create an impediment to cancer growth.
In laboratory and preclinical animal studies, case reports, and small clinical trials, researchers have observed improved outcomes, especially when a ketogenic diet is used in combination with conventional therapies. They note benefits from reduced toxicity to healthy issues from cytotoxic treatments and improved tumor responses. These results have led to a number of clinical trials that combine the ketogenic diet with conventional treatments.
Other Types of Interventions
Other types of interventions may target the amplified glycolysis pathways in cancer cells. Several compounds have inhibited various enzymes in cancer metabolism and weaken or even kill cancer cells. A few have progressed through basic research, animal studies, and small clinical trials. One of these substances is dichloroacetate (DCA), which is actually an old drug used for treating a rare metabolic disease in children. A 2014 review paper suggested that DCA may prompt “two fundamental changes in tumor metabolism.” First, the review noted an “anti-proliferative” effect whereby DCA “reverses” the Warburg effect by “redirect[ing] glucose metabolism from glycolysis to oxidation.” Second, the review described a “pro-apoptotic” effect, with DCA reestablishing apoptotic function of the mitochondria. Citing preclinical and small clinical trials, the authors suggest that DCA has “additive or synergistic effects when used in combination with standard agents.”
One enzyme, hexokinase-2 (HK2) is a key compound in glycolysis and is significantly overexpressed in cancer cells exhibiting the Warburg effect. Another substance, 3-bromopyruvate (3BP) is a powerful blocker of this enzyme. Some animal studies and several case reports have shown positive results.
Melatonin has shown some anticancer mechanisms in the past, with positive effects in a number of clinical trials. A recent paper described the use of melatonin in preclinical research for leiomyosarcoma (LMS), a highly malignant, soft tissue sarcoma. In summary, the scientists stated, “These results demonstrate that nocturnal melatonin directly inhibited tumour growth and invasion of human LMS via suppression of the Warburg effect, lactic acid uptake and other related signalling mechanisms.” Eventually, science may find that natural substances can be helpful in cancer management.
A clinical trial published in 2014 addressed cancer metabolism. The researchers assessed twenty-seven compounds known to affect glucose metabolism. After in vitro testing, they narrowed the list down to seven combinations and tested the pairs to find the most effective combination, which they determined to be alpha-lipoic acid (α-LA) and hydroxycitrate, which is also known as garcinia.
Then they initiated a clinical trial with forty advanced cancer patients with a life expectancy of two to six months. A combination of the two identified compounds, α-LA and hydroxycitrate, were given along with low-dose naltrexone. One group received only the metabolic therapy and a second group additionally received chemotherapy. The one-year survival was approximately the same (68 to 70 percent) in both groups. This study supported the potential of metabolic therapy, which hopefully can be further enhanced by combinations with other promising substances.
Final Thoughts
The metabolic approach may be effective at improving quality of life. It may improve the length of life in some cancer patients, including long-term survivors in complete remission. However, the disease is complex, and science has much to discover in terms of dealing with cancer, in particular more advanced cancers. In addition, cancer cells have more ways to obtain energy than just dietary carbohydrates. They can use the amino acid glutamine through the analogous pathway of glutaminolysis. The liver can produce glucose through gluconeogenesis, a process that many cancers promote. Thus the challenge remains to cut off the methods that cancer cells use to bypass interventions.
Of course, preventing cancer is the ideal objective. This is where a diet that is nutrient dense with low toxicity plays a role. Addressing inflammation, oxidative stress, and immune balance helps to protect the mitochondria and prevent the results of neglecting them, including cancer. However, if damage has already occured, then the same dietary approach becomes that much more important to assist in damage control, repair damaged cells, and support apoptosis.
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