by Lara Roach
figures by Aparna Nathan

There are trillions of cells in the human body, and each one needs nutrient molecules they can convert into energy or useful chemicals to survive, grow, and divide. Cells can get their “fuel” from a variety of sources, but the most common is the sugar glucose, which is abundant in foods like fruit and honey. When cells transform glucose into more useful molecules and energy, a common by-product is a molecule called lactate, which was considered to be an unimportant waste product for many years.

Recent studies, however, have shown that certain types of cells have found a role for lactate. Last fall, two research articles were the first to provide direct evidence that cancer cells use lactate as fuel to grow and divide. Remarkably, this basic research finding that improves our understanding of how cancer cells use nutrients could also inform the design of our next batch of cancer drugs.

Breaking down sugar and making lactate

Sugars like glucose are collections of carbon atoms, among other things. Just as the same planks of wood can be used to make different kinds of furniture, carbon atoms can be used to make different molecules. A process called a metabolic pathway describes the way that our body breaks apart sugar and re-purposes its carbon atoms. As cells consume glucose, they can change it through a metabolic pathway called glycolysis into a different carbon-based molecule called pyruvate (Figure 1). Pyruvate serves multiple roles: 1) it can be used to support a pathway called the citric acid cycle that produces energy and other important molecules, or 2) it can be converted to the molecule lactate.

Figure 1: A basic overview of glucose metabolism in human cells. Glucose (purple) is taken up by a cell where it is changed to pyruvate (pink) via glycolysis. Pyruvate can then be used by the citric acid cycle to make energy, or it can be converted to lactate (green) and released from the cell.

Lactate (not to be confused with the sugar in milk called lactose) is mostly studied in the context of the liver, where lactate can be converted back into glucose by the reverse of glycolysis. Outside of the liver, lactate can serve many useful functions, such fueling the heart, brain, and skeletal muscles (Figure 2). However, nobody had shown that cancer cells, which create and release lactate in large amounts, actually use it as fuel.

Figure 2: Lactate plays many roles in the body. Lactate has already been shown to be used by organs like the heart, brain, and musculoskeletal system.

Healthy cells and cancer cells use sugar differently

Though healthy cells consume their fair share of glucose, cancer cells are particularly known for their sweet tooth, gobbling up glucose at an astounding rate. In fact, this phenomenon can be exploited in cancer diagnostics. Patients are given a special type of glucose that can be imaged using a medical test called a PET scan (positron emission tomography). Similar to how doctors can see bones from an X-ray, tumors can be seen as bright masses (Figure 3) because they collect such a large amount of the specialized glucose.

So why does it matter that cancer cells are sugar addicts? By better understanding their preferences and dependencies (i.e. how they work) and by determining how they’re different from healthy cells, researchers are one step closer to developing better treatments for cancer patients. While much of what scientists understand about glucose’s role in supporting cell growth applies to both healthy and cancerous cells, there are some important differences.

Figure 3: Positron emission tomography (PET) can be used to detect cancer. The PET scan on the left is showing the abdomen of a patient looking down from the top of their head. The bright spot indicated by the arrows is a tumor.

Cancer is defined by uncontrollable cell growth and division, so cancer cells need the building blocks and energy to make new cells much faster than healthy cells do. Therefore, they rely heavily on the glucose and rapidly convert it to pyruvate via glycolysis. Back in the 1920s, it was discovered that cancer cells prefer not to rely on the citric acid cycle like healthy cells do. Instead, they turn most of their pyruvate into lactate, which they then release. And because cancer cells consume so much glucose, they end up producing a lot of lactate.

New studies show cancer cells use lactate

Two independent research teams were recently the first scientists to show that cancer cells use lactate to grow. One team, led by Dr. Ralph DeBerardinis at the University of Texas Southwestern Medical Center, looked at lung cancer patients and their surgically removed tumors. The team found that the lung tumor cells took lactate from the blood and turned it back into pyruvate to support the main metabolic pathway preferred by healthy cells: the citric acid cycle (Figure 4). These studies were the first to show that lactate, not just glucose, can be used as a source of fuel for the citric acid cycle.

Figure 4: Tumors both release and capture lactate. In a tumor, pyruvate (red) is converted to lactate (green) and released from cells. At the same time, lactate is taken from the blood stream and turned back to pyruvate inside the cells. The pyruvate is then used in the citric acid cycle to make energy.

In a separate set of experiments, a team led by Dr. Joshua Rabinowitz at Princeton University took an in-depth look at how cells, both healthy and cancerous, could use lactate. While studying both healthy mice and mice with lung and pancreatic cancer, they observed that lactate was collected from the environment to make the same types of molecules that were seen in the DeBerardinis experiments. This result suggests that lactate taken from the blood is being used in the citric acid cycle. The researchers also claim that almost 40% of glucose is first converted to lactate and released into the blood. That lactate is then consumed by other cells in the body to be changed back to pyruvate to be used in the citric acid cycle. It may seem counter-intuitive that lactate is released just to be taken up again, but converting pyruvate into lactate allows cancer cells to focus solely on glycolysis. Notably, in addition to producing pyruvate as an end-product, glycolysis also generates many other molecules along the way that are important to the cell, which may be one of many reasons why cells simultaneously excrete lactate and sequester it from the blood.

Societal and therapeutic impact

By better understanding how cancer cells use nutrients to support tumor growth, new therapies could be generated in the future against the pathways on which cancer cells depend most. For example, studies have shown that specific types of cancers rely upon a molecule called glutamine as a nutrient source, making glutamine breakdown a very important pathway in cancer cells. Researchers exploited this finding to develop drugs that are now showing promising preliminary results in clinical trials. Though the use of lactate is not specific to cancer cells, the idea that cancer cells can reuse molecules that had previously been considered waste products is significant. In fact, another recent study looking at another “waste” molecule that can be recycled to support breast cancer growth was recently published. Finally, this line of research could also extend beyond cancer to metabolic diseases like diabetes in which there is too much sugar in the blood. By continuing to learn more about how cancer cells use available nutrients like glucose and lactate to support tumor growth, researchers can better serve cancer patients in the future.

Lara Roach is a second-year Ph.D. student in the Biological and Biomedical Sciences program at Harvard University.

For more information:

  • The primary research paper from the DeBerardinis group, published in the journal Cell
  • The primary research paper from the Rabinowitz group, published in the journal Nature
  • A longform article from The New York Times Magazine that discusses the history of “starving cancer to death” as a treatment strategy
  • A video that describes more of the biochemical details behind glycolysis, the citric acid cycle, and the ways that cells make energy

10 thoughts on “The Circle of Lactate: How cancer cells can reuse their own waste

  1. Very interesting, thank you.
    It seems to be quite a bit related to the ongoing research in deuterium/hydrogen and how a high deuterium load, or inability to keep the gradient in check, will lead to the negative cascade of cellular adaptions.
    A lot of work has been done on heavy water and the opposite, light water, with a low concentration of deuterium and on how deuterium depleted light water impacts metabolism and cancer.
    Here is a list of some relevant studies that you might find interesting: https://DeuteriumDepletedWaterResearch.com

  2. How do the cancerous cell ferment the lactate in order to use it as an energy source? That seems like a delicate process that could easily be interrupted causing a major reduction of ATP in the cancerous cell.

    Do the cells bring the lactate back in via osmosis? If so, can you lower the hydrostatic pressure of the fluid that holds the lactate making it hard for the cell to acquire enough lactate, as well as, lower the osmotic pressure, which in return stops the cancerous cell from reproducing due to a lack of energy and osmotic pressure needed.

    Seems like nitric oxide could be a huge factor in the situation. Is there a way to lower the hydrostatic pressure of the fluid in and around a tumor, introduce cold temperature, remove glucose levels (via metformin or another therapy maybe directly at the tumor site), add nitric acid, healthy white blood cells and a glutamine inhibitor. My goal here is to get rid of the energy sources; glucose, lactate and glutamine. Increase hydrostatic pressure to lower osmotic pressure to interrupt the reproduction process.

    1. The cold temperature is an assumption that cold could freeze the cytoplasm or if not that cold at least slow down the metabolic rate of a cancer cell. I would also think after introducing the cold temperature I would then go to a high temperature just over what the body produces when sick. So 110-120 degrees Fahrenheit. It might be smart to actually do the heat first followed by the cold temperature. Both extremes would kill the cancerous cell but only the cold would affect healthy cells as well. The 110-120 would only affect the cancer cells I would imagine.

    2. How would the hydrostatic pressure affect the cancer cells. Didn’t think of that but I completely agreed with disrupting its energy source. There has to be a connection as to why these cells prefer lactate for ATP production.

  3. Great post really got the wheel turning on interrupting the metabolism on cancerous cells thus stopping reproduction. Thank you for the time and effort you put into the article.

  4. Warburg effect started all of this. Why doesn’t science find a way to block what the cancer cell needs to grow if we know it needs the waste product Lactate !
    It seems like we know what makes the tumor grow, can we ever find a way to trick the cell and interrupt the growth and stop the tumor.
    I am not a medical person but this is my opinion.
    My dad died of cancer and my friends wife has lung cancer end stage.
    It seems we are getting closer to the answers I pray one day we will have the right sequence
    To stop a tumor from growing out of control. ( Maybe there is a way that only the cancer cell would reject the lactate and not be able to grow.)

    1. I believe that cancer research should seek to develop a therapeutic agent that mimics the biological pathway of McArdle’s disease as this will act as a switch on lactic acid/lactate to prevent the cancer cells from recycling this to form cellular growth. I believe that this will restore acid/base homeostasis as the necessary biological pause will have been previously produced at the cellular level. I believe that McArdle’s disease provides us with a cellular map to produce healthy levels of ATP and its derivatives to overcome improper ATP development inherent in cancer cells. I have limited university science courses however I was told by the Holy Spirit that the words of Christ in Matthew 5:13 that when salt loses its saltiness (acid/base imbalance occurs) subsequent steps in ATP formation go awry and cancer ensues. Scripture says “Let your light be single” (formation of the mono-phosphates in the pathways from ATP to cAMP, etc.). All this follows Isaiah 40 ‘Those who wait on the Lord will renew their strength, they will run and not be faint. In science, this can be mapped biochemically as the formation of glycolysis before the necessary phosphorylation linked to the Kreb’s cycle. Have researchers considered using the biochemical pathways of McArdle’s disease as a template for a cure for cancer? I pray they will and ask anyone reading this to propose this paradigm to your medical research teams even if you are skeptical.

  5. Can we help the body by pushing the pH of the bloodstream to be slightly greater than the 7.0 which it strives to maintain ? In this way, lactic acidosis can be somewhat neutralized, thus depriving cancer cells of the lactate they need for fuel. For example, eat more foods which metabolize to alkalais.

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