Twitter isn’t all bad. This week I was scrolling through my feed and came upon a post from Inigo San Millan, an Assistant Professor at the University of Colorado School of Medicine and the Director of the Sports Performance Program at the CU Sports Medicine and Performance Center in Boulder, Colorado. The headline that caught my eye read: “Lactate May Be Key For Cancer Development”.
My immediate thought was: That can’t be good.
Athletes get worried when headlines imply a connection between exercise and an increased risk of injury, illness, or death. At 56 years old, I’m one of them. When I clicked on the link to Medical News Today, what I read compelled to me go find the full research paper.
What The Study Does NOT Say
Athletes could interpret the article’s title to imply strenuous exercise increases the risk of developing cancer. When strenuous exercise increases the demand for energy and the mitochondria in muscle cells reach the limit for how quickly they can break down carbohydrate and fat through aerobic metabolism, carbohydrate can be partially broken down using the metabolic shortcut of glycolysis. This liberates the much-needed energy and produces lactate.
If producing a lot of lactate caused cancer, Olympians would die very young. In fact, there would be an epidemic of cancer among amateur, elite, and even recreational athletes. Everybody produces lactate, every minute of every day. Athletes produce even more of it. Thankfully, despite how the title can be interpreted, the article does not assert any increase in cancer risk in connection with strenuous exercise.
The Lactate and Cancer Connection: The Warburg Effect
I’m sure I won’t do Dr. San Millan’s study justice in my simplified explanation, but he and his colleagues took a novel approach to an old mystery. Back in the 1920s, Otto Warburg discovered cancer cells consume a lot more glucose and produce a lot more lactate – even when there is sufficient oxygen available for aerobic metabolism – compared to healthy cells. Known as the Warburg Effect, this may be initiated by changes that hinder the function of a cell’s mitochondria.
As Dr. San Millan points out, much of the ensuing research focused on the glucose end of the equation, with the goal of slowing or reversing the growth of cancerous tissues by disrupting the exchange of lactate between and within cells. Advocates of nutritional ketosis (fueling the body with ketone bodies derived from fat) often point to slowing or stopping the growth of cancer cells through starvation (reduced availability of glucose) as one of the biggest health benefits of the high fat, very low carbohydrate nutritional strategy. According to San Millan, however, “oncogenes” (genes with the potential to cause cancer) are the driving force behind the dramatic increase in glucose metabolism by cancer cells, not the carbohydrate you eat. Even without consuming carbohydrate, a triad of oncogenes (HIF-1, c-MYC and p53) can feed aggressive cancers by stimulating the breakdown of protein from skeletal muscle and converting it to glucose through gluconeogenesis. This is part of the reason cancer patients suffer muscle wasting (cachexia); protein is being converted to glucose to feed cancer cells.
A Novel Look at the Warburg Effect
One of the mysteries of the Warburg Effect is that it doesn’t make evolutionary sense. Evolution moves toward greater efficiency, not the other way around. Compared to aerobic metabolism, glycolysis is a far less efficient way to produce energy from carbohydrate. If you think of cancer as a parasite, overconsumption of glucose contributes to substantial weight loss, weakens its host, and hastens its own death. Again, that is contrary to the normal process of evolution.
What if dysregulated lactate production is the purpose of cancer?
Dr. San Millan and other researchers looking at the lactate production side of the Warburg Effect hypothesize that dysregulated lactate production sets the stage for cancer cells to thrive, multiply, spread, and metastasize. Cancerous tumors establish a acidic microenvironment around them. This may help protect cancer cells from the body’s immune system, as well as create an environment conducive to the growth and spread of new cancer cells. The release of lactate into the bloodstream causes a chronic exposure to lactate throughout the body, as opposed to short-term spikes in blood lactate from strenuous exercise. Normally, the presence of lactate causes the up-regulation of mitochondrial activity in order to break it down for fuel. According to the abnormal lactate metabolism theory of cancer, cancer may spread when an anomaly causes a down-regulation of mitochondrial activity in the presence of lactate, thus increasing that cell’s glycolytic activity, producing more lactate, and establishing an environment conducive to the growth of more highly-glycolytic cancer cells.
“To Stop Cancer You Have To Stop Lactate”
In the Medical News Today article, Dr. Millan is quoted as saying, “to stop cancer you have to stop lactate” because the presence of lactate is required for five essential steps of cancer development: angiogenesis (creation of new blood vessels inside tumors), immune escape (how cancer cells outmaneuver the immune system) cell migration (how cancer spreads), metastasis (development of additional tumors), and self-sufficient metabolism. Going back to the evolutionary conundrum, dysregulated lactate production starts to make sense if lactate is essential for creating the conditions necessary for an organism to thrive, replicate, and spread.
You’re probably still thinking this sounds pretty bad for athletes who chronically produce a lot of lactate, right?
Here’s where we get to the good news.
The Protective Effect of Exercise
Endurance exercise has been repeatedly shown to increase an athlete’s ability to produce energy via glycolysis. Exercise also accelerates the rate at which the resulting lactate gets reintegrated into aerobic metabolism and broken down for energy. To quote Dr. San Millan’s paper:
“[O]ne of the most impressive adaptations to metabolic stress in mammalian biology is doubling of mass of the muscle mitochondrial reticulum due to endurance exercise training. Increased muscle mitochondrial density due to endurance training allows for increased respiratory control, increased fat metabolism and greater lactate clearance in muscles working at a given exercise power output. As well, by increasing lactate clearance via oxidation and gluconeogenesis, high muscle mitochondrial density and other physiological and metabolic adaptations allow for high rates of muscle glycolysis to be tolerated because of correspondingly high lactate clearance rates. However, while high mitochondrial density provides a metabolic underpinning for exercise capacity, mitochondrial dysfunction is disastrous for lactate clearance in cancer.”
Stopping lactate production in healthy people as a means of preventing cancer would be difficult because lactate production is a normal process in cells throughout the body. However, increased aerobic fitness increases your ability to produce energy through aerobic metabolism and reduces reliance on glycolysis. Fitness also boosts the rate and amount of lactate you can break down for fuel, thereby burning up the precursor required for each of the 5 key steps in cancer’s development. In other words, when abnormal lactate metabolism happens somewhere in your body, increased fitness may be key to preventing that anomaly from establishing an environment in which cancer cells can survive, multiply, and reach a critical mass necessary to support a tumor.
Dr. San Millan also points out that cells communicate by releasing exosomes (vesicles containing cellular material). Cancer cells release exosomes that facilitate the spread of cancer. Increased aerobic fitness may counteract this communication by increasing the exosomal communication coming from healthy skeletal muscle cells, and since there are so many more skeletal muscle cells compared to cancer cells, the effect may be akin to a large crowd drowning out the speech of a small but vocal hate group.
To take these ideas a step further (and into the land of speculation), if increased ability to break down lactate for energy has a protective effect against the development of cancer, then perhaps lack of fitness (can’t process lactate quickly) and an overabundance of available glucose (lots of tumor-friendly fuel) could partly explain why sedentary people who consume lots of sugar have a higher incidence of cancer than athletes (some of whom also consume a lot of sugar). It may also help explain why the incidence of cancer increases as societies and nations develop technologies that reduce the energy expenditure required for activities of daily living. At some level, fitness is fitness, whether it’s the result of carrying water from the river or training for a triathlon.
Summary: Exercise is neither the cure nor cause of cancer
I think the medical profession would agree with the statement that it’s unlikely there is a unifying cause of all cancers (not even genetics), but rather that it is a class of diseases caused by a multifactorial process. Exercising is good for your health for a wide range of reasons and the increased ability to process lactate might be one of them. As Dr. San Millan’s study concludes, a greater research emphasis on the lactate-cancer connection, including the role exercise can play in the prevention and treatment of cancer, could open the doors to both exciting new medical treatments and public health policies!
CEO/Head Coach of CTS
San-Millan, Inigo, and George A. Brooks. “Reexamining Cancer Metabolism: Lactate Production for Carcinogenesis Could Be the Purpose and Explanation of the Warburg Effect.” Carcinogenesis (2017) 38 (2): 119-133.