To be brutally honest, cancer is a concept that the scientific community has long struggled to comprehend. Progress, particularly in the clinical setting, has been hard to come by over the last several decades. While improvements have been made, most have been somewhat minor in the grand scheme of things, and virtually none have fundamentally changed the way we view the disease. In fact, arguably the last critical observation of a fundamental distinction between normal cells and cancer cells came in the 1920s by German scientist Otto Warburg. Strangely, he found that cancer cells voluntarily opted for a less efficient, glycolytic pathway of metabolism, even in the presence of oxygen. Now, let’s dissect exactly what that means.
Figure 1: Overview of mitochondrial metabolism. Do not fear: the fine details of this diagram are not important. The key aspects from this post include: glycolysis outside the mitochondria (top), generation of loaded electron carriers inside the mitochondria (highlighted in yellow), and subsequent utilization of these electrons in the electron transport chain to produce ATP with ATP synthase (left). (Image: Haigis and Spinelli, 2018)
In our normal cellular metabolism, we burn largely macronutrient fuels (carbohydrates, fats, and even amino acids from proteins) through various processes to produce adenosine triphosphate (ATP), our cells’ energy currency. Generally speaking, inside the cell, each of these fuels can be broken down to a form in which they can enter the mitochondria. In this organelle, through various processes, they can pass electrons to carrier molecules. These carriers (such as NADH and FADH2) will then pass the electrons down something called the electron transport chain (ETC), where a resulting charge gradient forms from passing down all these negative electrons. A complex enzyme called ATP synthase then engages in something called oxidative phosphorylation, generating vast amounts of ATP by pumping protons from this gradient. All of this is the most efficient mechanism of energy production that evolution has designed for us. It takes place in the mitochondria, and it’s called aerobic metabolism.
Some may recall from their high school biology textbooks that “aerobic” means “in the presence of oxygen.” This is generally the case, as oxygen is often the final molecule to “accept” the electrons at the end of the electron transport chain. However, circumstances can exist in which sufficient oxygen is not present, or just not used. For example, as we’ve previously discussed with cardiorespiratory exercise and Zone 2 training, sometimes we may pass the threshold of physical exertion under which we can use the mitochondria. While the mitochondria is very efficient at making energy from fuel sources, it’s not the fastest mechanism. We would prefer to use it whenever possible, but when we need energy quickly, we may opt for the rapid short-term solution of glycolysis.
Glycolysis (literally meaning “breaking glucose”) does not occur in the mitochondria; it takes place in the cytosol, the cell’s big pool of solution in which all the organelles float around. We would typically categorize it as anaerobic metabolism, as it does not require oxygen to proceed. It’s also not nearly as productive as standard mitochondrial metabolism. For reference, glycolysis produces 2 ATP from each molecule of glucose, whereas oxidative phosphorylation would give you an estimated 32-38 total ATP.
Imagine driving a hybrid or electric car. You get incredible gas mileage, but maybe you can’t go all that fast. So, when you go to the racetrack and need to optimize for speed, you wouldn’t drive your Prius. You’d maybe switch over to a gas-guzzling racecar, that can give you quick bursts of speed despite its fuel inefficiency. Roughly speaking, this is a metaphor for metabolism: the Prius is your mitochondrial metabolism, and the racecar is glycolysis. Most of the time, we don’t need a racecar if we’re just driving on the street, so we’ll default to using our mitochondria to produce energy from fuels with maximum efficiency. Why is it, then, that cancer cells would rather drive a wasteful racecar on the street?
Figure 2: Generalized depiction of the Warburg effect. In a normal cell, metabolism favors use of the mitochondria (red), whereas in the cancer cell it is largely reserved to the cytosolic processes (cytosol=cytoplasm) of glycolysis and fermentation to lactate. Note the typo: the Warburg effect is referred to as aerobic glycolysis, not anaerobic, due to the irrelevance of sufficient oxygen. (Image: Baek and Kim, 2021)
As Warburg noted, tumors preferentially utilize glycolysis as their dominant pathway of energy production, even when there’s clearly sufficient cellular oxygen for mitochondrial respiration. Avoiding the mitochondria, the glycolytic product of pyruvate undergoes fermentation to produce lactate. This odd concept, termed aerobic glycolysis or the Warburg effect, may strike you as illogical and counterintuitive. After all, it seems like overkill to drive a racecar through your neighborhood every day. Nevertheless, this observation has remained consistent over the last century of research in cancer metabolism, and it can only be assumed that it is evolutionarily favorable for tumor growth. Several questions emerge. Among them, why does this happen? How can this give us more insight into the fundamental nature of cancer? Can it change the way we view this disease? And of course, can there be clinical, therapeutic implications? Stay tuned for a follow-up post where I will attempt to address the various perspectives in the scientific community on these outstanding questions.
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