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The Peter Attia Drive
#30 - Thomas Seyfried, Ph.D.: Controversial discussion—cancer as a mitochondrial metabolic disease?
Nov 26, 2018
02:48:06
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Quick takeaways
- Cancer is caused by a defect in the respiratory system of cells, not solely genetic mutations.
- Cancer cells rely on fermentation for energy production due to defective mitochondria.
- Upregulation of the glycolytic pathway provides both energy and building blocks for tumor growth.
- Structural integrity of mitochondria is compromised in cancer cells, leading to deficient ATP production.
- Macrophage fusion with cancer cells promotes metastasis and enhanced invasive behavior.
Deep dives
The Warburg Effect and Defective Respiration
The Warburg effect, named after Otto Warburg, refers to the observation that cancer cells continue to undergo fermentation metabolism, producing lactic acid, even in the presence of oxygen. Warburg hypothesized that this was due to a defect in respiration, specifically in the mitochondria. Numerous studies have shown that cancer cells indeed have defective mitochondria, whether in terms of structure, number, or function. This impairment of respiration forces cancer cells to rely on fermentation for energy production, leading to the Warburg effect.
Genetic Factors and Cancer Risk
Inherited mutations account for a small percentage (around 5-6%) of human cancers. Mutations in genes such as BRCA1 and BRCA2 have been identified as increasing the risk of breast and ovarian cancer. However, not all individuals with these mutations develop cancer, suggesting that other factors play a role. It is now understood that the primary cause of cancer is the damage to the respiratory system within cells, rather than solely genetic mutations. Cells with healthy mitochondria are less likely to develop cancer.
Building Blocks and Energy for Tumor Growth
Another proposed explanation for the Warburg effect is the need for building blocks for tumor growth. Tumors require not only energy but also the necessary components to rapidly proliferate. The up-regulation of the glycolytic pathway can provide both energy and building blocks, contributing to tumor growth. While this explanation adds another aspect to the understanding of the Warburg effect, it does not negate the fact that cancer cells have defective respiration and rely on fermentation for their energy needs.
Cancer cells rely on fermentation for energy production
Cancer cells, including those in brain and heart, have a compromised respiratory system and rely heavily on fermentation for energy production. They upregulate pathways that allow them to ferment glucose and glutamine, generating the necessary building blocks and ATP for rapid cell division. This shift from oxidative phosphorylation to substrate-level phosphorylation is crucial for the survival and growth of cancer cells.
Structural defects in mitochondria contribute to cancer cell behavior
The structural integrity of mitochondria is compromised in cancer cells, leading to a deficiency in oxidative phosphorylation and ATP production. This defect is associated with mutations in essential genes and lipid abnormalities in the mitochondria. Additionally, the damaged respiratory system results in the production of reactive oxygen species, contributing to the mutagenesis and carcinogenic behavior of cancer cells.
Macrophage involvement in cancer metastasis
There is evidence suggesting that macrophages can fuse with cancer cells, resulting in more aggressive and metastatic behavior. The fusion of macrophages and neoplastic cells gives rise to hybrid cells with enhanced invasive and dispersal capabilities. These findings highlight the role of macrophages in promoting cancer metastasis.
Macrophages and Wound Healing
Macrophages play a crucial role in wound healing by recognizing acute wounds and facilitating the healing process. They release growth factors and cytokines to promote the repair of damaged tissue. However, in cases of neoplastic cells, such as cancer cells, macrophages can unintentionally stimulate the growth of these abnormal cells due to the release of the same growth factors. The abnormal cells, which do not have the capacity to grow outside the local area, are not recognized as foreign invaders by macrophages and are not promptly eliminated. The release of lactic acid by the neoplastic cells creates a hypoxic microenvironment, signaling damage, but the macrophages fail to recognize the abnormality. The fusion of macrophages with stem cells that have defective respiratory systems can dilute the normal mitochondria in the macrophages and lead to cells with dysregulated growth properties.
Metastasis and Needle Biopsy
Metastasis, the spread of cancer cells from the primary tumor to distant organs, can occur as a result of various factors. One of the debated factors is the role of needle biopsies in increasing the risk of metastasis. Needle biopsies can create an inflammatory environment in the tumor microenvironment, promoting the fusion of cells and potentially facilitating the spread of cells to other areas. The inflammatory ancotaxis induced by needle biopsies can provoke the invasion of cells into the local environment, leading to metastatic behavior over time. While it is important to diagnose and understand the genetic profile of tumors, the potential risk of needle biopsies in promoting metastasis calls for caution and strategic management. Alternative approaches, such as metabolic therapy and reducing inflammation, may offer potential avenues for reducing the mortality rate of cancer.
Metabolic therapy offers a less toxic approach to treating cancer
Metabolic therapy, specifically the ketogenic diet, can significantly reduce the toxicity of certain drugs used to treat cancer. This means lower doses of drugs can be used to achieve more effective results. The current approach of relying on new drugs to target cancer versus exploring alternative methods of making existing drugs less toxic ultimately leads to the same outcome: improved effectiveness in treating cancer. However, the strategy of treating cancer as a metabolic disease is not widely adopted and requires more clinics to embrace this approach.
The importance of reevaluating the standard of care for brain cancer
Radiation therapy, a key component of the standard of care for brain cancer, may actually lead to more harm than good. Irradiating the brain can cause a release of glutamine, a fuel source for tumor cells, while corticosteroids used to reduce edema can elevate blood sugar levels. This combination creates a bigger problem and potentially leads to the demise of patients. By reconsidering the standard of care and embracing metabolic therapy, such as the ketogenic diet, there is potential to greatly extend overall survival, improve quality of life, and offer a less toxic treatment approach for brain cancer patients.
24.
Do You Think There Is a Better Explanation for Why These Hypotheses Aren't Being Investigated?
2min
In this episode, Thomas Seyfried, a cancer researcher and professor of biology at Boston College, discusses a controversial view of cancer as a mitochondrial metabolic disease. Many topics related to the causes, treatments, and prevention of cancer are covered in this in-depth conversation.
We discuss:
- How Tom got interested in cancer research [9:00];
- Calorie-restricted ketogenic diets, fasting, and epileptic seizures [18:30];
- Otto Warburg and the Warburg effect [30:45];
- Germline mutations, somatic mutations, and no mutations [42:00];
- Mitochondrial substrate level phosphorylation: Warburg’s missing link [51:30];
- What is the structural defect in the mitochondria in cancer? [1:02:00];
- Peter’s near-death experience with the insulin suppression test while in ketosis [1:06:30];
- Insulin potentiation therapy and glutamine inhibition [1:13:15];
- The macrophage fusion-hybrid theory of metastasis [1:39:30];
- How are cancer cells growth dysregulated without a mutation? [1:47:00];
- What is the dream clinical trial to test the hypothesis that we can reduce the death rates of cancer by 50%? [2:03:15];
- How can the hypothesis be tested rigorously that structural abnormalities in the mitochondria impair respiration and lead to compensatory fermentation? [2:26:30];
- Case studies of GBM survivors [2:32:45]; and
- More.
Learn more at www.PeterAttiaMD.com
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