Many cancer models fail to accurately replicate human cancers, particularly metastasis.

Cancer models serve as crucial instruments in comprehending disease mechanisms and formulating new treatments. However, a significant number of these models fall short in accurately replicating crucial aspects of human cancers, particularly metastasis. One of the issues with common cancer models is that metastatic models seldom display the systemic spread observed in human cancers. This is because the direct injection of cells into the circulation sidesteps the natural metastatic process. Another issue arises with human xenografts in mice, which over time, start to adopt mouse characteristics, thereby altering their behavior. The mice used as hosts also exhibit abnormal immune systems and metabolism. Genetic models also present problems as they involve multiple simultaneous mutations that are rarely seen in human cancers. Moreover, these models seldom metastasize outside the affected tissue. Cell culture assays, on the other hand, only provide an approximation of invasive behavior in an artificial environment. The most effective models are those that naturally arise and grow orthotopically in syngeneic hosts, such as the VM mouse model. This model displays the full spectrum of metastatic cancer traits. The biological behavior of these models is more crucial than histological classification, which often proves to be ambiguous. However, the high costs associated with animals and the regulations surrounding their use discourage the utilization of good in vivo models. Despite these challenges, animal studies remain indispensable in translating therapies to the clinic. It's important to note that cancer is fundamentally a disease of energy metabolism, irrespective of the tissue origin. Therefore, targeting the energy of tumor cells can serve as an effective therapy across different types of cancers.

Cancer cells, due to their faulty mitochondria and impaired respiration, rely heavily on inefficient fermentation for energy.

Cancer cells operate differently from normal cells, particularly in how they produce energy. They have faulty mitochondria - the powerhouses of the cell - and struggle with cellular respiration, the process of converting nutrients into energy. This forces them to depend more on a less efficient process called fermentation. This observation was first made by Otto Warburg in the 1920s when he noticed that cancer tissues were fermenting at high rates, even when there was plenty of oxygen available. Over time, more and more evidence has backed up this theory of impaired respiration in cancer cells. The mitochondria in cancer cells are not just dysfunctional, they're also abnormal in their number, size, shape, and structure. The inner membrane of these mitochondria, which houses the essential components for oxidative phosphorylation (OxPhos) - a key process in cellular respiration - is often damaged and has fewer folds or cristae. This damage hinders the electron transport chain (ETC) complexes, which are crucial for OxPhos. Moreover, the protein composition in cancer cell mitochondria is altered, and there's an abnormal presence of cardiolipin, a lipid that's vital for ETC function. All these abnormalities lead to reduced activities of ETC enzymes and less ATP synthesis via OxPhos. To make up for this energy deficit, cancer cells increase their reliance on fermentation pathways like glycolysis, which allows them to produce ATP through a process called substrate-level phosphorylation. This switch to fermentation is crucial for cancer cells to survive and multiply. It's also believed that this impaired respiration is what triggers the genomic instability seen in cancer cells. This supports Warburg's original theory that respiratory insufficiency is a fundamental defect in cancer cells. Therefore, finding ways to target these fermentation pathways could be a promising strategy in the fight against cancer.

Some scientists suggest that oxidative phosphorylation may still function in cancer cells, necessitating more rigorous experiments to clarify this issue.

Otto Warburg's theory was met with skepticism by Sidney Weinhouse and Alan Aisenberg, who believed that there was insufficient evidence to prove that respiration in cancer cells was impaired. Many of the experiments that supported Warburg's theory were flawed due to improper comparisons between tumor and normal cells. To truly highlight the metabolic differences, appropriate controls are necessary. Dean Burk, another scientist, demonstrated that malignant cells, which are derived from normal fibroblasts, had a higher rate of glycolysis than their nonmalignant counterparts. Warburg remained steadfast in his belief that defects in a process called oxidative phosphorylation resulted in inefficient energy production in cancer cells. Warburg's theory, though it lost some of its significance in the 20th century, has seen a resurgence due to mounting evidence of mitochondrial abnormalities in cancer. Factors like carcinogens and radiation can damage mitochondria. Unlike normal cells, cancer cells are unable to switch from fermentation to using ketones for respiration. It is unlikely that a resolution for cancer will be found until the evidence for respiratory insufficiency is acknowledged. Once this happens, therapies that target tumor cell metabolism could emerge as effective strategies.

Cancer cells adapt to low oxygen environments by using mitochondrial amino acid fermentation, particularly of glutamine, for energy production.

Cancer cells have a unique ability to adapt to low oxygen environments by using amino acid fermentation in addition to glycolysis to make up for insufficient respiration. This process, known as mitochondrial amino acid fermentation, helps to maintain a stable metabolic state under hypoxic conditions, similar to what is observed in some diving animals. Specifically, cancer cells can ferment glutamine and its metabolites, glutamate and α-ketoglutarate, to produce energy when oxygen levels are low. The fermentation of glutamine results in the production of succinate, alanine, and aspartate. Studies on metastatic mouse cells have shown that these cells can use glutamine fermentation as a source of energy. These cells are capable of producing a significant amount of ATP and remain viable when using either glutamine or glucose alone. However, the production of ATP is higher when both glucose and glutamine are used, suggesting a synergistic relationship between the two fuels. Interestingly, it is glutamine, not aspartate or alanine, that drives this synergy. Nuclear Magnetic Resonance (NMR) analysis of these mouse cells confirms that glutamine is metabolized through the Tricarboxylic Acid (TCA) cycle. However, the observed synergy under anoxic conditions or in the presence of cyanide points towards fermentation, rather than oxidative phosphorylation. Cancer cells can survive in low oxygen environments by using linked fermentation pathways in the cytoplasm and mitochondria. The malate-aspartate and glycerol 3-phosphate shuttles serve as connections between the cytoplasmic and mitochondrial redox reactions. In this scenario, ATP production occurs through substrate-level phosphorylation, not oxidative phosphorylation. Therefore, targeting glucose and glutamine metabolism could be an effective strategy to disrupt energy production in cancers that rely on these fuels. Incorporating the concept of mitochondrial amino acid fermentation into our understanding of cancer metabolism provides valuable insights into how cells adapt to insufficient respiration. This viewpoint not only supports Warburg's theory that impaired respiration is a fundamental characteristic of cancer, but also explains the metabolic flexibility of cancer cells.

Impaired cellular respiration triggers a stress response that, while initially protective, can lead to genomic instability and cancer development in the long term.

When cells are unable to respire properly, they trigger a stress response known as the retrograde (RTG) response. This is an adaptive mechanism that attempts to make up for the lack of respiration by increasing the production of genes required for fermentation pathways. However, if the RTG response is activated for an extended period, it can lead to genomic instability, an abnormal number of chromosomes (aneuploidy), and a mutation-prone state. There are several reasons why cells might struggle with respiration. These include genetic defects, inflammation, or exposure to environmental toxins. Inflammation can harm respiration through the production of nitric oxide and TGF-beta signaling. Similarly, toxic particles can disrupt the function of mitochondria, the powerhouses of the cell. When respiration is impaired, it also disrupts the balance of calcium within the cell, leading to defects in cell division and aneuploidy. Another consequence of insufficient respiration is the production of reactive oxygen species. These molecules can damage DNA repair enzymes like p53 and APE1, leading to loss of genetic diversity and the occurrence of somatic mutations. In response to impaired respiration, a protein called HIF-1alpha stabilizes and increases the rate of glycolysis to compensate. While the RTG response can protect cell viability in the short term, its long-term activation can promote the development of cancer. The sustained process of glycolysis allows cells to tolerate these genomic defects. The progression of cancer can be seen as a harmful cycle of respiratory damage, RTG response, genomic instability, and compensatory fermentation. Therefore, most traits associated with cancer are a result of impaired respiration, rather than being the initial cause of cancer. As such, a key strategy in the fight against cancer could be to target fermentation metabolism.

Normal mitochondrial respiration can suppress cancer development, suggesting that mitochondrial dysfunction, not nuclear mutations, is the primary cause of cancer.

Mitochondria, the powerhouses of cells, can play a significant role in suppressing the development of cancer. This concept is rooted in Warburg's theory, which suggests that cancer develops due to insufficient respiration, or energy production, within mitochondria. If the damaged mitochondria in cancer cells are replaced with normal, functioning ones, the theory proposes that this should restore the cell's normal respiration process and halt the progression of cancer. This idea has been supported by various experiments involving cell hybrids, also known as cybrids. These are created by combining normal cells with cancer cells. The results showed that when these cybrids contained normal cytoplasm, they were able to suppress the development of cancer, even when the cell's nucleus contained mutations. This suggests that mutations in the nucleus alone are not enough to cause cancer, and that normal mitochondria in the cytoplasm play a crucial role in preventing the disease. This concept has also been demonstrated in animal studies. For example, when nuclei from frog and mouse tumors were transplanted into normal egg cytoplasm that contained healthy mitochondria, the cells developed normally. Despite the presence of genomic defects in the nuclei, tumors did not form. This further supports the idea that nuclear mutations alone cannot cause cancer without the presence of dysfunctional mitochondria.

The metabolic switch to fermentation is a survival strategy for cancer cells, allowing them to avoid apoptosis and achieve limitless replication.

Impaired cellular energy metabolism, particularly a deficiency in oxidative phosphorylation (OxPhos), is a key factor contributing to abnormal cell growth and cancer. When cells can't generate enough energy through their usual respiration processes, they undergo metabolic shifts to use fermentation pathways as an alternative. This shift involves the activation of oncogenes and growth signaling pathways such as MYC, Ras, and Akt, which stimulate glycolysis and glutaminolysis. At the same time, tumor suppressors like p53, which would typically initiate apoptosis, or programmed cell death, are suppressed. This metabolic switch to fermentation is a survival strategy for cancer cells, allowing them to avoid apoptosis and achieve limitless replication. They increase their telomerase activity, which helps maintain telomeres, the protective ends of chromosomes, allowing for unlimited cell divisions. The process of angiogenesis, the formation of new blood vessels, ensures a steady supply of blood to fuel the fermentation process. These characteristics, known as the hallmarks of cancer, are adaptations to insufficient respiration. They allow cells to continue proliferating and surviving, despite the defective OxPhos. Therefore, the abnormal growth seen in cancer can be traced back to mitochondrial dysfunction. The potential solution to reversing the cancer phenotype could lie in restoring normal respiration.

Metastasis, the spread of cancer cells, may be driven by mitochondrial dysfunction in myeloid immune cells, specifically macrophages.

Metastasis refers to the process where cancer cells spread from the original or primary tumor to other parts of the body. This is the leading cause of death in cancer patients. The process involves several steps: cancer cells detach from the primary tumor, enter the bloodstream, exit the bloodstream at different locations, evade the immune system, and start growing in these new locations. Traditionally, it has been believed that this process is driven by genetic mutations that cause epithelial cells (the cells that line the body's surfaces) to transform into mesenchymal cells (cells that can move easily and spread to other parts of the body). Another theory suggests that tissue stem cells, which naturally have the ability to move and grow in new locations, could be the source of metastatic cells. However, recent evidence is pointing towards a different origin for metastatic cancers: myeloid immune cells, specifically macrophages. Macrophages are cells that naturally have the ability to move around the body, engulf and digest cellular debris and foreign substances, merge with other cells, and enter and exit the bloodstream. These abilities could explain how metastatic cancers behave without the need for complex genetic mutations. Research has shown that metastatic tumor cells share many characteristics with macrophages. They express the same biomarkers, have the ability to engulf other cells, can merge with host cells, show signs of having merged with other cells, share the same lipid composition, and in some cases, have even been shown to originate from normal macrophage cell lines. This theory, known as the myeloid fusion theory, also supports the "seed and soil" hypothesis. This hypothesis suggests that cancer cells (the "seeds") are more likely to grow in certain parts of the body (the "soil") because these areas are more conducive to their growth. Macrophages naturally migrate to these areas, which are common sites for metastasis. The theory suggests that metastasis is likely caused by mitochondrial dysfunction in myeloid cells or in the cells that result from their fusion with other cells. This dysfunction leads to uncontrolled cell growth. This theory provides a metabolic explanation for metastasis, without the need for stepwise genetic mutations. Understanding cancer as a disease caused by mitochondrial dysfunction could lead to new ways of treating metastasis. This perspective could pave the way for new treatments that target the metabolic processes involved in metastasis, rather than focusing solely on genetic mutations.

Cancer progression appears to align more with Lamarck's theory of acquired inheritance than Darwin's natural selection, and should be treated as a metabolic disease, not a genetic one.

Looking at the development of cancer, it's possible to use various evolutionary theories as a lens. One such theory is Darwin's, which suggests that natural selection favors beneficial traits. However, cancer cells seem to contradict this theory as they amass mutations that are generally considered harmful. This goes against Darwin's idea that natural selection should weed out these detrimental variations. Therefore, the progression of cancer doesn't seem to align with Darwin's theory. Another evolutionary theory comes from Lamarck, who suggested that traits acquired during an organism's lifetime can be passed on to its offspring. This theory seems to fit better with the behavior of cancer cells. For instance, cancer cells can pass on defective mitochondria to their daughter cells. This causes a shift from respiration to fermentation, which allows the cells to multiply without control. This process of cancer progression seems to embody Lamarck's concept of acquired inheritance. However, it's important to note that cancer doesn't have a purposeful agenda. Some might try to apply teleological explanations, which assume that cancer cells are purposefully motivated. But these explanations don't really shed light on the mechanistic origins of cancer. A more accurate understanding of cancer is that it's a metabolic disease, rather than a genetic one. Therefore, when developing therapies, the focus should be on targeting the metabolism of tumor cells, rather than their mutations.

Current cancer treatments are limited in effectiveness and often have severe side effects, but targeting tumor cell energy metabolism offers a promising, less toxic alternative.

The effectiveness of current cancer treatment strategies is limited, particularly in controlling many advanced metastatic cancers. While surgery, chemotherapy, and radiation therapy can manage some benign or non-metastatic tumors in the short term, they are less successful against many invasive, metastatic cancers over a longer period. This is evident in the yearly death rates from cancer, which have remained static for decades, suggesting that many new therapies, despite their advanced claims, are not as effective as hoped. Moreover, many of these current cancer therapies come with severe side effects that can actually exacerbate the progression of the disease. For instance, radiation and chemotherapy can induce inflammation and cell death, which ironically provide fuel for tumor growth. Similarly, high dose steroids, which are administered to reduce swelling, can increase blood sugar levels, thereby feeding tumor growth. Even new immunotherapy drugs are not without their toxic effects, with some studies indicating higher death rates from treatment than cure rates. The reliance on these toxic therapies often results in a reduced quality of life without a corresponding increase in survival. However, there is a promising alternative approach in the form of non-toxic therapies that target tumor cell energy metabolism. Unlike normal cells, cancer cells rely heavily on glucose and glutamine as metabolic fuels. By limiting these fuels, it is possible to selectively target cancer cells while leaving normal cells largely unaffected. Such metabolic therapies can manage cancer effectively without the negative side effects of standard care that often speed up disease progression. By viewing cancer as a metabolic disease, it opens up the possibility for less toxic, more effective long-term treatment strategies.

Non-toxic dietary and metabolic therapies, such as the calorie-restricted ketogenic diet, effectively manage cancer progression and metastasis.

Cancer progression and metastasis can be effectively managed by therapies that focus on cancer cell fermentation. One such therapy that is non-toxic is known as dietary energy reduction (DER). This method works by lowering the levels of circulating glucose while increasing ketone bodies. This shift in metabolism from glucose to ketones specifically targets tumor cells that are genetically defective and have impaired respiration. On the other hand, normal cells can easily adapt to using ketones as fuel, thus they are protected. DER has the ability to inhibit several cancer characteristics including cell proliferation, evasion of apoptosis, angiogenesis, and inflammation. It achieves this by reducing signaling through growth pathways like IGF-1/PI3K/Akt and downregulating genes related to glycolysis. DER also enhances apoptosis through dephosphorylation of BAD and cleavage of caspase-9/-3. The anti-inflammatory effects of DER are achieved through the inhibition of NF-kB and downstream targets like COX-2. Additionally, DER targets abnormal tumor vasculature while promoting vessel maturation. The ketogenic diet, when given in restricted amounts to limit the availability of glucose, can mimic the anticancer effects of DER. This restricted ketogenic diet works in synergy with glycolysis inhibitors like 2-deoxyglucose for even greater therapeutic efficacy. Targeting glutamine is also proving to be an effective strategy, particularly for metastatic cancers. The calorie-restricted ketogenic diet (KD-R) works by reducing blood glucose while increasing ketone bodies. This metabolic environment puts stress on the energy metabolism of tumor cells while improving the health of normal cells. The KD-R protocol is implemented in 3 phases. Phase 1 starts the metabolic therapy by limiting carbohydrates and proteins while increasing fats. This results in lower blood glucose and higher ketone levels within days. Phase 2 may involve the surgical removal of the tumor, which is easier when the tumor is smaller and less inflamed. Phase 3 continues to put metabolic pressure on any remaining tumor cells with the KD-R and drugs that target glucose and glutamine metabolism. While this approach can be challenging to adhere to, it has been successful in managing malignant cancers. Even though radiation and chemotherapy are still commonly used, the KD-R offers an alternative metabolic strategy for cancer patients. In conclusion, non-toxic dietary and metabolic therapies take advantage of the metabolic flexibility of normal cells to target tumor cells that are genetically defective and metabolically challenged. Therapy that enhances mitochondrial function through glucose reduction and ketone elevation can effectively manage cancer progression and metastasis.

Lifestyle modifications that reduce chronic inflammation and boost mitochondrial energy metabolism, including dietary changes and weight management, can prevent most types of cancer.

Cancer prevention often hinges on steering clear of elements that harm cellular respiration. One of the primary culprits behind respiratory damage and consequently, cancer, is chronic inflammation. This inflammation disrupts the microenvironments within tissues, setting the stage for the onset of cancer. Obesity is another factor that amplifies inflammation and, by extension, the risk of cancer. Interestingly, individuals with Alzheimer's disease tend to have a lower risk of cancer. This is attributed to their hypometabolic state, which is characterized by reduced metabolic activity. The role of diet in cancer prevention is significant. A diet that restricts energy intake can boost mitochondrial function and lower the risk of cancer. This is achieved by reducing inflammation and reactive oxygen species, which are harmful molecules that can damage cells. Therapeutic fasting and ketogenic diets, which are low in carbohydrates and high in fats, are potent strategies for cancer prevention. These dietary approaches work by depriving the body of glucose, a type of sugar. This deprivation enhances mitochondrial function and targets tumor cells specifically. Moreover, fasting and ketogenic diets promote autophagy, a process where the body cleans out damaged cells, and autolytic cannibalism, where precancerous cells are destroyed. The primary aim of cancer prevention is to enhance mitochondrial respiration over fermentation, a process that can lead to cancer. In conclusion, lifestyle modifications that minimize chronic inflammation and enhance mitochondrial energy metabolism can prevent most types of cancer. These changes can range from dietary adjustments to weight management, all of which contribute to a healthier, cancer-resistant body.

Home

Cancer as a Metabolic Disease - Book Summary (2024)

Thomas Seyfried

"Cancer as a Metabolic Disease" is a comprehensive treatise that presents the argument that cancer is primarily a metabolic disease, not a genetic one. The author, a biochemical geneticist, discusses the role of energy metabolism in cancer's origin and progression, and proposes that targeting the defective energy metabolism of tumors could lead to more effective and less toxic treatment strategies.

Key Ideas

Despite years of extensive research, cancer continues to pose a significant health challenge, primarily due to the lack of a comprehensive theory that brings together the various observations about the disease. This book aims to shed light on the evidence that suggests cancer is predominantly a metabolic disease, rather than a genetic one.

Regardless of their cellular or tissue origin, cancer cells display common metabolic abnormalities. One of these is the increased uptake of glucose and its fermentation into lactate, even in the presence of oxygen. This phenomenon, known as the Warburg effect, suggests that the mitochondria in these cells are not functioning properly.

The somatic mutation theory suggests that cancer develops from accumulated mutations in oncogenes and tumor suppressor genes. However, this theory is challenged by the fact that most cancers show significant genetic diversity within the same tumor, which contradicts the idea that specific mutations are the primary cause. Furthermore, while gene mutations are rare, cancer cells often exhibit extensive mutations.

The Warburg effect, a common metabolic characteristic of cancer cells, points to impaired respiration as the root cause of cancer. Warburg's hypothesis suggests that an irreversible injury to cellular respiration is the primary cause of cancer, forcing cells to depend on fermentation for energy. While subsequent research has focused more on gene mutations as the cause of cancer, emerging evidence supports Warburg's original hypothesis.

It is likely that mitochondrial dysfunction occurs first and then leads to the genome instability that accompanies tumorigenesis. Therefore, restoring normal respiration could be an effective strategy for preventing and treating cancer. By focusing on cancer metabolism, a unifying theory can be developed to integrate the diverse observations about cancer, which could potentially lead to the defeat of this disease.

"Cancer as a Metabolic Disease" by Thomas Seyfried presents a comprehensive argument that cancer should be viewed primarily as a metabolic disease rather than a genetic one. Seyfried argues that the root cause of cancer is a defect in cellular energy production due to damaged respiration in the mitochondria, leading to increased fermentation for energy production. This shift in energy metabolism is a fundamental aspect of cancer that is common across various types of the disease. Seyfried suggests that by understanding and targeting this metabolic dysfunction, more effective and less toxic cancer treatments can be developed.

The book also highlights the potential of dietary interventions, particularly the ketogenic diet, in managing and preventing cancer. The ketogenic diet, which is high in fats and low in carbohydrates, can starve cancer cells of glucose, their primary fuel for fermentation, and potentially inhibit tumor growth.

Here are 10 specific actions that can be taken to implement the learnings from the book:

Adopt a ketogenic diet: This diet is high in fats and low in carbohydrates, which can potentially starve cancer cells of their primary fuel, glucose.
Regular exercise: Exercise improves overall metabolic health and can enhance the efficiency of mitochondria, the energy-producing structures in cells.
Regular medical check-ups: Early detection of cancer can lead to more effective treatment.
Limit exposure to environmental toxins: Many toxins can damage mitochondria and contribute to the metabolic dysfunction seen in cancer.
Limit consumption of processed foods and sugars: These can contribute to metabolic dysfunction and feed cancer cells.
Maintain a healthy weight: Obesity is a risk factor for many types of cancer and can contribute to metabolic dysfunction.
Avoid smoking and limit alcohol consumption: Both of these can damage mitochondria and contribute to cancer risk.
Consider intermittent fasting: Fasting can enhance mitochondrial health and metabolism.
Stay informed about new research: The field of cancer metabolism is rapidly evolving, and new treatments and prevention strategies are continually being developed.
Advocate for a metabolic perspective in cancer research and treatment: This can help shift the focus of cancer research and treatment towards targeting the metabolic dysfunction at the root of the disease.