Good News! Cancer Cells are Metabolically Handicapped

Being free of normal restraints can make a killer or a thief seem powerful. But it doesn't mean the killer is an evil genius like those so common in movies and on TV. My Dad, a criminal law professor, often told me stories about how stupid criminals are; he even cowrote a book about it in honor of one of his colleagues: Criminals are Stupid: A Tribute to Woody Deem

Being free of normal restraints can make cancer cells seem powerful. But the damage they have suffered that makes them go rogue is likely to handicap them in some way. There are mechanisms that keep cells on the straight and narrow. It would be hard for something to damage those good-behavior mechanisms without damaging something else as well.  

Thomas Seyfried, in his book Cancer as a Metabolic Disease: On the Origin, Management, and Prevention of Cancer argues persuasively that metabolic damage is a common path for a cell to break free of normal restraints. In Chapter 15, he writes:

According to my view, cancer cells proliferate and survive not because of their genomic instability, but because of their respiratory insufficiency. Respiratory insufficiency enhances fermentation, destabilizes the genome, and causes entry into the default state of unbridled proliferation [15]. ...

Fermentation energy is primal energy. Fermentation is linked to unbridled proliferation [15, 20]. ...

Unbridled proliferation is the default state of metazoan cells when released from active negative control [33–35].

Active respiration maintains the differentiated state and genome integrity through the RTG signaling system (Chapter 10).

To understand this passage, it is important to know how Thomas Seyfried is using the technical terms "respiration" and "fermentation." The current version of the Wikipedia article "Cellular respiration" explains:

Most of the ATP produced by aerobic cellular respiration is made by oxidative phosphorylation. This works by the energy released in the consumption of pyruvate being used to create a chemiosmotic potential by pumping protons across a membrane.

Thomas Seyfried uses the term "respiration" to refer to oxidative phosphorylation, or OxPhos. OXPHOS depends on pumping protons across the inner mitochondrial membrane, which is a delicate structure that must be constructed carefully and can easily be damaged. 

Fermentation is a similar chemical process in yeast, bacteria, and eukaryotes.  (All animals are "eukaryotes," including us). The current version of the Wikipedia article "Fermentation" describes it as follows: 

Fermentation is a metabolic process that consumes sugar in the absence of oxygen. ...

Along with photosynthesis and aerobic respiration, fermentation is a way of extracting energy from molecules, but it is the only one common to all bacteria and eukaryotes. It is therefore considered the oldest metabolic pathway, suitable for an environment that did not yet have oxygen.

Fermentation normally occurs in an anaerobic environment. In the presence of O2, NADH and pyruvate are used to generate ATP in respiration. This is called oxidative phosphorylation, and it generates much more ATP than glycolysis alone. For that reason, fermentation is rarely utilized when oxygen is available.

If Thomas Seyfried is right that cancer cells often have a damaged capability for OxPhos, then cancer cells can't extract as much energy from a given amount of nutrients as normal cells can. If there is plenty of sugar available, cancer cells will be able to do fine by taking in sugar and fermenting it. If there is less sugar available within the body, then it puts cancer cells at more of a disadvantage, since cells that can do OxPhos can wring more energy from each sugar molecule than is possible for a cell that can't do OxPhos and can only manage fermentation.

Thomas Seyfried is far from alone in thinking that many cancer cells are metabolically handicapped. A lot of research, including randomized clinical trials, are being conducted on the basis of this hypothesis, as I discuss in "How Fasting Can Starve Cancer Cells, While Leaving Normal Cells Unharmed." 

A key part of Thomas Seyfried's argument is that metabolizing glutamine and possibly other amino acids without OxPhos can mimic some of the indicators that many investigators use to judge whether OxPhos is intact or not. The following passage from Chapter 4 is important, but heavy going. The two main claims are

  • Metabolizing glutamine without OxPhos can create the illusion for a lab analyst of OxPhos.
  • Glutamine is a major energy source for cells of the immune system, which, when they become cancerous, are capable of being metastatic, spreading cancer far and wide in the body. (I added emphasis with bold italics to the two sentences on this.)

Here is the passage:

Although many tumor cells have active TCA cycles and might appear to respire, in that they consume oxygen and produce CO2 and ATP in the mitochondria, I will present data showing that this is pseudo respiration in some cases. In other words, pseudo respiration has all the characteristics of respiration, but does not involve ATP synthesis through OxPhos. I propose that this apparent respiratory energy is derived from amino acid fermentation. Just as tumor cells ferment glucose in the presence of O2, some tumor cells also ferment glutamine and possibly other amino acids in the presence of elevated glucose and O2. ...

The neutral amino acid glutamine is readily taken up into cells through simple uniport mechanisms [15, 18]. Glutamine can serve as a major source of metabolic fuel for generating ATP through TCA cycle, substrate-level phosphorylation when OxPhos is deficient [42, 44]. Glutamine is also anapleurotic in replenishing metabolites for the TCA cycle [59, 65]. We recently described how cancer cells could generate energy through mitochondrial fermentation and substrate-level phosphorylation in the TCA cycle using glutamine as a substrate [44, 58, 66] (Fig. 4.8). Glutamine is also a major energy fuel for cells of the immune system [67]. As myeloid cells can be the origin of many metastatic cancers following fusion hybridizations, glutamine becomes an important fuel for driving metastasis [66, 68] (Chapter 13). Indeed, targeting glutamine can significantly inhibit systemic metastasis as we have shown [69] (Chapter 17). ...

It is well documented that glutamine enters the mitochondria where it is rapidly metabolized to glutamate by mitochondrial glutaminase [18, 83]. Glutamate is then metabolized to α-ketoglutarate through either a transamination reactions with aspartate or alanine as products or through the action of glutamate dehydrogenase [15, 18, 65, 83].

The bottom line is that plenty of amino acids, like plenty of sugar, can keep cells that can't do OxPhos well-fed. Protein is made of amino acids. My hypothesis to be tested is that the sudden bursts of sugar-abundance in the body generated by eating easily-digestible carbohydrates and the sudden bursts of amino-acid abundance generated by eating the concentrated protein in meat and other animal products can improve the environment for cancer cells. In my own practice, I have quit eating sugar and other easily-digestible carbohydrates, which have many other bad effects as well, and have cut back on milk and meat without eliminating them.

Thomas Seyfried makes another important claim: that cancer cells will have trouble metabolizing fats and the ketone bodies made from body fat during fasting, especially given the low blood-sugar levels during fasting. Again from Chapter 15:

Because tumor cells ferment rather than respire, they are dependent on the availability of fermentable fuels (glucose and glutamine). Normal cells shift metabolism from glucose to ketone bodies and fats when placed under energy stress. ...

Ketone bodies and fats are nonfermentable fuels in mammalian cells. Tumor cells have difficulty in using ketone bodies and fats for fuel when glucose is reduced.


Conclusion: Races that Cancer Can Win and Races Cancer Can't Win

If cancer cells have already made the adjustments to switch over to fermentation, injuries that deprive cells of oxygen by interrupting blood flow could give cancer cells an advantage. But fasting, which shifts the nutrients available to cells toward fats and ketone bodies, should give an advantage to normal cells. 

More generally, eating less should be harder on cancer cells than normal cells. Many people bemoan the fact that when they lose weight, their metabolism becomes more efficient, so that they burn fewer calories in a normal day. But there is a silver lining to an efficient metabolism: if normal cells are running their metabolism at maximum efficiency, getting a lot of energy from a relatively small amount of food, cancer cells that can't do OxPhos won't be able to keep up. And if cancer cells die because they can't keep up, the day you die can be put off. 


Don't miss these other posts on diet and health and on fighting obesity:

Also see the last section of "Five Books That Have Changed My Life."