In a recent study published in Cancer Cell, researchers in Colorado found that leukemia cells may hijack glucose metabolism to soak up as much energy as they need to rapidly grow and divide. In doing so, they also deprive healthy tissues of glucose. Leukemia cells appear to promote insulin resistance in healthy tissue and suppress insulin secretion from the pancreas.

The research project started with a relatively simple but unanswered question: How does cancer tissue compete with the rest of the body for a limited amount of glucose, to fuel its rapid growth?

“If you think about it, the amount of cancer or tumor tissue in the body of a cancer patient, compared with the amount of normal tissue, is very small,” said Haobin Ye, first author of the study and a researcher in the Division of Hematology at the University of Colorado Anschutz Medical Campus. “But cancer cells require a lot of energy for proliferation. In this way they are like parasites. But how does such a small parasite as a cancer cell compete with the rest of the body for precious nutrients like glucose?”

Ye and colleagues had a hint. Cancer cells, in the case of leukemia, might impair glucose uptake and utilization by healthy tissues in the body, leaving more glucose for use by themselves. For example, Ye has observed that leukemia cells can deplete glucose so that less is available for muscle, one of the most demanding tissues when it comes to energy consumption of glucose. Ye and colleagues reasoned that cancer cells must somehow be hijacking the body’s glucose metabolism pathways. There are other signs that cancer cells may hijack glucose metabolism to support their exorbitant energy needs. Obesity and diabetes, conditions in which glucose uptake and metabolism in healthy tissues are impaired, are associated with the spread and survival of tumors.

Ye and colleagues tested their “glucose hijacking” hypothesis in a leukemia mouse model. They found, as they suspected, that mice with leukemia have diabetes-like conditions including insulin resistance in various healthy tissues.

“Studies have mainly focused on cell intrinsic mechanisms by which glucose is preferentially utilized, such as activation of glucose transporters and glycolysis. In the present study, we sought to approach glucose metabolism from a holistic perspective and to consider how cancer cells manage their need for glucose in the context of an entire mammalian organism.”  – Ye et al., 2018

“We found that the cancer tissue could inhibit glucose utilization in normal tissue through induction of insulin resistance,” Ye said. “This process involves multiple tissues, including adipose tissue, colon tissue and even microbiota [microbes in the gut].”

Immunoflourescence of a smooth muscle cell. Credit: Beano5.
Immunoflourescence of a smooth muscle cell. Credit: Beano5.

How Leukemia Cells Hijack the Host’s Glucose Metabolism

Ye and colleagues uncovered several mechanisms by which leukemia cells appear to promote insulin resistance in non-cancerous tissues. They found that leukemia cells infiltrate fat, where they promote inflammation. The leukemia cells induce otherwise normal adipose tissue to produce an adipokine [a cytokine secreted by adipose tissue] called IGFBP1, which binds insulin-like growth factor 1 (IGF-1). IGF-1 has similar effects on glucose metabolism as insulin does and is not available for cell signaling when bound to IGFBP-1. IGF binding proteins have also been found to inhibit insulin receptor activity. Ye found that IGFBP1 directly inhibits the signaling functions of insulin and IGF-1 and therefore inhibits glucose uptake in various tissues.

While IGFBP1 is normally produced at very low levels in the human body, its production is increased in obese individuals. Ye and colleagues found that its production is also increased nearly 100-fold in leukemia mice as opposed to normal mice. By infiltrating fat tissue, causing inflammation and promoting an abnormally high production of IGFBP1, leukemia cells cause other tissues like muscles to become insulin resistant. As these tissues are impaired in their ability to take up glucose, more glucose is available in the bloodstream to leukemia cells.

“Data suggest that leukemic tumors induce high-level production of IGFBP1 from adipose tissue, which in turn acts to impair insulin/IGF1 function and induce an insulin-resistant condition.” – Ye et al., 2018

Ye and colleagues also found that in mice, leukemia impairs the secretion of insulin from the pancreas. They stumbled upon the underlying mechanism when they observed that mice with leukemia had abnormally low levels of serotonin. Serotonin, which you may know as the “relax and be happy” brain chemical that gets a boost when you metabolize carbspromotes insulin secretion from the pancreas. But you might not have known that the production of serotonin is partly regulated by microbes in your gut. Seeing changes in serotonin levels in mice with leukemia prompted Ye and colleagues to investigate the role of the microbiota in the progression of this cancer. They found that leukemia mice have different gut microbe compositions as compared to healthy mice, particularly a lack of “good” gut microbes that produce butyrate. This short-chain fatty acid has many health benefits when produced by our gut microbes – it can improve insulin sensitivity and energy expenditure, promote brain health and help reduce oxidative stress.

“We compared the composition of the microbiota between the leukemia model and normal mice, and we found that the species of gut bacteria in these two different types of mice were very different,” Ye said. “We don’t know which types of bacteria exactly are responsible for promoting serotonin production in the gut, but we know that certain types of gut bacteria produce short chain fatty acids, like butyrate, and these short chain fatty acids regulate the production of serotonin and insulin.”

Leukemia cells thus cause a reduction in serotonin produced in the gut by colon cells, through changes in the gut microbiome, and impair insulin production and secretion from the pancreas.

Intestinal villi, small finger-like projections that extend into the lumen of the small intestine, and gut bacteria. Credit: ChrisChrisW.

Fecal Transplants for the Win

In order to demonstrate the importance of microbiota changes with leukemia, Ye and colleagues performed an elegant experiment in which they transferred microbiota between different types of mice through fecal implants. They collected fecal materials from both normal mice and mice with leukemia, and transferred these materials into recipient leukemia mice that had been treated with strong antibiotics to eliminate their original gut microbes. What they found highlights just how much changes in our gut microbes may impact our health and even cancer risk.

“Interestingly, the recipient mice that get the microbiota from leukemia donor mice demonstrate a faster progression of leukemia than recipient mice that get microbiota from normal mice,” Ye said. This finding suggests a causal relationship between gut microbiota composition and cancer cell proliferation.

Ye and colleagues confirmed their findings by giving leukemia mice butyrate and serotonin supplements. When they did so, they found that the mice had a lowered leukemia cell burden and slowed disease progression. Why did this happen? Serotonin promotes the secretion of insulin from the pancreas, helping to promote glucose uptake in healthy tissues. Butyrate, a short chain fatty acid produced by certain gut microbes, further increases the production of serotonin in the gut and also increases the insulin sensitivity of various tissues. Serotonin and butyrate together help to suppress leukemia progression by limiting how much glucose leukemia cells can get their hands on. When given to leukemia model mice, these compounds have the effect of increasing glucose uptake in normal tissue while decreasing glucose uptake in leukemia tissues, the opposite of what normally happens in leukemia mice. To demonstrate this outcome, Ye and colleagues took PET CT scans of the study mice. The scans of mice treated with serotonin and butyrate were less “bright” (indicating lowered glucose metabolism or less glucose uptake) in areas where leukemia tissue was present, when compared to the scans of untreated mice.

“In the future, we want to investigate the microbiome changes that occur in leukemia, and explore whether we can restore a healthy microbiota in mice with leukemia, for example,” Ye said. “This might help restore insulin sensitivity of healthy tissues.”

Diet Connections

All the mice in Ye’s study were fed the same diet. However, he and colleagues are currently conducting a follow-up study to investigate how high-fat and other diets impact leukemia metabolism and progression. So far, their preliminary results indicate that mice fed a high-fat diet have a faster progression of leukemia. This may be because with high-fat diets, the insulin sensitivity of normal tissues is decreased and glucose levels in the blood remain high as the body works to take up and metabolize free fatty acids floating around in the blood. [This effect in humans may be different depending on the type of fat consumed.] This means more glucose is available for growing leukemia cells. Also, leukemia stem cells may use fatty acids as an energy source when available – they tend to be very adaptable in their energy sources.

“Our findings strongly suggest that tumor progression can be significantly affected by systemic glucose metabolism… [and] management of systemic glucose metabolism provides significant survival benefits.” – Ye et al., 2018

Takeaways

What can we learn from Ye and colleagues’ findings to slow the growth and proliferation of leukemia cells in human patients? Ye mostly conducts his research in animal models, but has worked with collaborators to translate findings from mouse models to humans.

For example, we now know that people with leukemia often have high serum levels of IGFBP1 and fatty acids, indicating there may be an insulin resistant phenotype in leukemia patients.  Patients and survivors with certain types of leukemia often suffer from metabolic syndrome. Leukemia cells have been found to infiltrate adipose tissue, where they are highly inflammatory. This inflammation can cause lipolysis in adipose tissue, an enzymatic process that converts triglycerides in adipocytes to fatty acids. These free fatty acids, once released into the bloodstream, are a strong inducer of insulin resistance in other tissues, by impairing the function of insulin on other tissues.

“Our results suggest that human leukemia induces an insulin-resistant phenotype through production of inflammatory mediators, IGFBP1, and FFAs [free fatty acids] to support tumor growth.” – Ye et al., 2018

“Our results from mouse studies suggest that increased exercise and healthy, anti-inflammatory diets that can reduce insulin resistance might potentially be helpful for patients with certain types of leukemia,” Ye said. Ye and colleagues are currently exploring how various diets may play a role in the progression of leukemia.

Olive oil and foods rich in omega-3 fatty acids are associated with lowered levels of inflammation. Credit: autumnhoverter.

Drugs that can increase tissue sensitivity to insulin are also being investigated for potential use as a treatment for patients with certain types of leukemia. While other nutrient interventions based on caloric restriction, such as intermittent fasting, have been shown to increase insulin sensitivity in overweight individuals, these interventions may be contraindicated in leukemia patients who suffer from undernutrition and malnutrition.

Another possible translatable finding from Ye’s study is the use of IGFBP1 as a biomarker of biomarker for leukemia. Ye and colleagues found that this the amount of this cytokine in the serum is correlated with leukemia cell burden in an organism. They found that serum IGFBP1 levels are high in diagnosed leukemia patients, but lowered upon remission. Patients who’ve relapse also have higher levels of serum IGFBP1.

“I think this protein could function as a biomarker for leukemia patients,” Ye said.

Learn more about managing your risks for insulin resistance, diabetes and certain cancers here. How does Ye apply his research to his own health? He tries to exercise every day, eat a balanced diet and get consistent, healthy levels of sleep.