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  • Writer's pictureRyan Allen

How tumors flip the switch

Cancer cells are fundamentally different from normal cells. They originate from our own tissue, yet they become almost a separate entity living among us. Their genetic code is rewired, optimized for a simple goal: to grow and proliferate.

One seemingly important ”switch” that cancer cells make is metabolic. As explained in my most recent post, these cells completely deviate from the norm by voluntarily opting for inefficiency. The tumor cells preferentially perform glycolysis in the cytosol rather than utilizing their mitochondria, even in the presence of sufficient oxygen. This phenomenon, known as the Warburg effect, might seem inexplicable and counter-evolutionary. However, we know cancer to be a highly advanced and adapted beast, capable of overcoming all the obstacles we put in its path. It seems quite unlikely that such a major energetic weakness would keep showing up in tumors. So, seeking to understand how we might fundamentally reframe our view of this disease, a few hypotheses have been put forth to make sense of this aerobic glycolysis observation.

1. Impaired mitochondria

The original theory put forth by Otto Warburg–the German scientist behind the discovery–was that cancer resulted from some sort of damage to the mitochondria. According to Warburg, as a result of the newfound mitochondrial dysfunction, cancer cells have no choice but to undergo glycolysis as it is the only available path to producing ATP. In the face of more evidence, this hypothesis has largely fallen out of favor. As has now been noted, even in the presence of seemingly healthy mitochondria, the cancer cells would rather use this inefficient glycolytic mechanism. The decision appears not obligatory, but voluntary.

Figure 1: Branching anabolic pathways from glycolysis. Once again, do not fear: the fine details of this diagram are not important. Note that glycolysis (in blue) occurs in the cytosol, outside the mitochondria. Significantly for hypothesis #2, several intermediates of glycolysis are capable of leaving this pathway and entering others for the synthesis of things like lipids and triglycerides (fats), serine, glycine, and other amino acids (proteins), ribose and nucleic acids (DNA and genetic material). For this reason, glycolysis may allow cancer cells to expedite different synthesis processes for rapid cell growth and division. (Image: Zhang et al., 2021)

2. Rapid anabolic demand

An intriguing idea started to gain traction in the late 2000s supported by Dr. Lewis Cantley at Weill Cornell Medicine, among others. He and his colleagues proposed that tumors would prefer to shunt their glucose fuel into glycolysis as a way to fulfill the need for significant, accelerated growth. You can think of cancer cells as constantly screaming at themselves to grow, grow, grow and divide, divide, divide. One problem with this is that they simply lack the biomass to keep creating new cells, yet they continue signaling to do so. In order to accomplish this, they need to incorporate biomass at a much faster rate.

Glycolysis allows them to do exactly that. The process of glycolysis, like many pathways in the cell, involves numerous steps and intermediates. It is rather unique, though, in that its intermediates can diverge into several other different anabolic pathways. Recall that an anabolic process, or anabolism, implies building up, while catabolic (or catabolism) means breaking down. In the case of glycolysis, carbon molecules at different steps along the way can go into the synthesis of amino acids for proteins, fatty acids for lipids, nucleic acids for genetic material, etc. instead of continuing on to produce ATP. The increasing use of glycolysis amplifies the cell’s demand for fuel, causing it to take in more and more glucose. By this theory, the cancer cell then uses early steps of glycolysis to assimilate as much carbon as possible into these different synthesis pathways, allowing it to have the necessary amount of material to keep dividing at this pace.

3. Lactate signaling

The avid Zone 7 followers may remember that I actually brought this hypothesis up in a newsletter segment back in November, just because I find it so intriguing and am still actively trying to investigate it further. In my last post, I showed that lactate was a key byproduct of glycolysis. Well, as detailed in the newsletter, it turns out that lactate may serve a crucial role as a signaling molecule for cancer. Some evidence has emerged to suggest that it may take a genetic approach, regulating the expression of numerous oncogenes involved in breast cancer development.

This gets even more interesting, though. Most of us actually know of the molecule lactate by another name: lactic acid. That’s because it’s commonly found in this acidic form, and as a result the accumulation of lactate outside cells will lower the pH of the surroundings (make them more acidic). The acidity of the tumor microenvironment is an established observation (I’ve seen it remarkably clearly in the lab myself), but as far as I know it remains unclear why the cancer cells favor this. If the other aspects of these hypotheses are any indication, though, it strikes me as unlikely that this acidity is just due to “waste product accumulation” from the tumors; I think it too must be doing something to favor tumor growth, aiding or signaling in some way to the cells.

Now, this post is not necessarily all-encompassing. These are the most established hypotheses that I am currently aware of in the scientific literature, and I would imagine more will emerge. The likely truth is also that the Warburg effect is due to a combination of hypotheses; the adaptation may provide numerous benefits to the cancer. Perhaps that is why it has been so strongly preserved and prioritized evolutionarily. Though none are clearly confirmed, these hypotheses offer insights that allow us to rethink our perspective of this malady, and perhaps even metabolism in general. Could it be possible that the complex processes of metabolism may not solely serve to produce energy at the cellular level? Could it be that metabolites play a wide variety of roles we are yet to understand, and are very rarely just “byproducts” or “intermediates?” In my opinion, the answer is not just possible, but likely.


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