Continue my summary on Dr. Thomas Seyfried's talk - 'Cancer as a Metabolic Disease: Implications for Novel Therapies' . Let's resume applying the scientific method to his talk from step 6.
To refresh our memory first: the scientific method is a problem-solving approach at the core of biology and other sciences. It has five basic steps, plus one feedback step:
Make an observation.
Ask a question.
Form a hypothesis, or testable explanation.
Make a prediction based on the hypothesis.
Test the prediction.
Iterate: use the results to make new hypotheses or predictions.
Now apply step 6 to his talk:
6. Iterate: He used the experimental results to make new hypotheses on how cancer cells arise.
The metabolic theory of cancer is based on the work of Otto Warburg, who defined cancer as a metabolic problem back in the 1920s. Cancer develops from damage to mitochondrion and cancer cells are unable to generate energy through the use of oxygen, through oxidative phosphorylation, but only through the use of glucose for energy. Normal cells can produce energy anaerobically using glucose, such as while sprinting, and can produce energy aerobically using oxygen, such as while jogging. Due to damage to the mitochondria of the cancer cells, they are locked into producing energy through the fermentation process. Even in the presence of oxygen, cancer cells continue to ferment lactate acid. This is referred to as the Warburg Effect. Dr. Seyfried believes the last part is not accurate because cells should not continue to ferment lactate acid when oxygen is present. They should shift back to oxidative phosphorylation. However, since the mitochondria are damaged, oxidative phosphorylation becomes almost impossible. There must exist an alternative way. So he made a further hypothesis that the cancer cells can also ferment succinic acid derived from glutamine inside of the mitochondria. He and his colleague named it the "Q-Effect" to distinguish it from the Warburg Effect. The letter Q in Q-Effect is the single letter for glutamine. This enhanced fermentation is the signature metabolic malady of all cancer cells.
The two figures below show Dr. Seyfried's view of the difference of energy metabolism in normal cells and in cancer cells at the presence of oxygen. You can see that the normal cells generate most of the ATPs in the mitochondria through oxidative phosphorylation, with the waste products of carbon dioxide and water. Whereas the cancer cells generate very few ATPs in the mitochondria through oxidative phosphorylation due to the respiration damage. Instead cancer cells generate most of the ATPs through substrate-level phosphorylation, both inside and outside of the mitochondria, with the waste products of succinic acid and lactic acid, respectively. What was missing, in his view, in the Warburg theory is not considering ATP generation through the Krebs cycle.
Then he further explained his hypothesis why the mutations in the nucleus are downstream epipharise as downstream epiphenomena of the damage to the mitochondria. In the figure below, surrounded by the blue line, which indicates the oncogenic paradox box, there exist many risk factors that can damage the mitochondria, including RAS oncogene, rare mutations, inflammation, viruses, aging, and so on. All these mitochondrial damage leads to the generation of reactive oxygen species (ROS). The ROS damage the nuclear genome, lipids and proteins in the cell. So the mutation that we seen in cancer come as the result of damage from ROS. The mutations are the effect, but not the cause of cancer. So the majority of studies on cancer have really been focusing on downstream epiphenomena, where the real origin of the disease is related to the function of the mitochondria.
ROS also damage oxidative phosphorylation - OxPhos. The cell sends a signal to the nucleus that the organelle is incapable of providing enough energy to maintain the life of the cell. This signaling system then turn on the genes in the nucleus that up-regulate substrate-level phosphorylation (SLP) (see the red line in the plot at the bottom of the figure below). In order to run SLP, you need to bring in to the cell fermentable fuels, which are glucose and glutamine. At the meantime, the mitochondria continue to suffer damage, and gradually lose their ability to produce energy through OxPhos (the green line in the plot at the bottom of the figure below). It is this transition from OxPhos to SLP that ultimately leads to the development dysregulated cell growth. In addition, the damaged mitochondria is unable to control apoptosis, or programmed cell death. So the cancer cells can bypass the natural process of programmed cell death. And therefore, go on to proliferate.
Now comes to the biggest part of the hypothesis. Metastasis the the primary cause of morbidity and mortality for cancer patients. How to link metastasis to disturbed energy metabolism? First, we need to look at the metastatic cascade. Metastatic cascade is a typical series of events that underlie the origin of any tissue. Breast cancer, colon cancer, bladder cancer, all of these different cancers to spread around the body go through the same cascade:
local invasion - green tumor cell on the upper left enters local tissue
intravasation - green tumor cells enter blood vessel
immune system survival - avoid and suppress immune system, travel along blood vessel
Extravasation - leave bloodstream
secondary tumor formation - form tumor in distant organs
This is so called cancer spreader metastasis. How can the accumulation of random somatic mutations cause a non-random metastatic cascade. It does not make sense.
Now the question is how to explain these based on the mitochondrial metabolic theory of cancer. He linked it to the macrophage fusion hypothesis, see figure below. Macrophages, these cells are guardians of our body. They are wound-healing cells. They patrol our entire body. They enter and exit bloodstream. They work with the immune system. They are part of the immune system. In the figure below:
Step 1. Here are some epithelial cells (in blue). Many cancers arise from epithelial cells.
Step 2. They become destabilized by any one of the provocative agents. They have destabilized energy metabolism, and are entering their default state. But they are not capable of spreading around the body.
Step 3. Our immune cells (in orange) come into this micro environment, recognizing cancer as an unhealed wound and they begin to throw out growth factors in cytokines, which is like putting gasoline on the fire. It stimulates these incipient cancer cells to grow even more disorganized and dysregulated.
Step 4. The immune cells will fuse to heal the wound. They will either fuse together or fuse with these incipient cancer cells by diluting the cytoplasm with abnormal mitochondria.
Step 5. Now what you have is these rogue macrophages (in purple), former immune cells. They are already genetically programmed to spread throughout the body. That is what they do in their normal function. But now they are metabolically destabilized with a genetic architecture to spread around the body, and that's what they do.
Step 6. They intravasate and they suppress the immune system. They are the tumor cells that will be the most deadly. These deadly tumor cells are heavily dependent on glutamine and glucose for their survival.
Step 7. They extravasate and form tumor elsewhere.
Loop back to scientific method step 4, Dr. Seyfried made a new prediction based on the new hypothesis. Recognizing that all cancer cells require glutamine and glucose to obtain energy through fermentation, especially the metastatic cell, what will be the effective therapies for managing and preventing tumors?
- To be continued.