Cancer hijacks the microbiome to glut itself on glucose

September 28, 2018 by Garth Sundem, CU Anschutz Medical Campus
Cancer hijacks the microbiome to glut itself on glucose
Haobin Ye, PhD. Credit: CU Anschutz Medical Campus

Cancer needs energy to drive its out-of-control growth. It gets energy in the form of glucose, in fact consuming so much glucose that one method for imaging cancer simply looks for areas of extreme glucose consumption—where there is consumption, there is cancer. But how does cancer get this glucose? A University of Colorado Cancer Center study published today in the journal Cancer Cell shows that leukemia undercuts the ability of normal cells to consume glucose, thus leaving more glucose available to feed its own growth.

"Leukemia create a diabetic-like condition that reduces going to , and as a consequence, there is more glucose available for the . Literally, they are stealing glucose from normal cells to drive growth of the tumor," says Craig Jordan, Ph.D., investigator at University of Colorado Cancer Center, division chief of the Division of Hematology and the Nancy Carroll Allen Professor of Hematology at the University of Colorado School of Medicine.

Like diabetes, 's strategies depend on . Healthy cells need insulin to use glucose. In diabetes, either the pancreas under-produces insulin or tissues cannot not respond to insulin and so cells are left starved for energy while glucose builds up in the blood. The current study shows that goes about creating similar conditions of glucose buildup in two ways.

First, tumor cells trick fat cells into over-producing a protein called IGFBP1. This protein makes less sensitive to insulin, meaning that when IGFBP1 is high, it takes more insulin to use glucose than it does when IGFBP1 is low. Unless the supply of insulin goes up, high IGFBP1 means that the glucose consumption of healthy cells goes down. (This protein may also be a link in the chain connecting cancer and obesity: The more fat cells, the more IGFBP1, and the more glucose is available to the cancer.)

Of course, cancer has a second strategy that ensures insulin production does not go up to meet the need created by increased IGFBP1. In fact, cancers turn insulin production down. In large part, they do this in the gut.

"In the course of doing this systemic analysis, we realized that some of the factors that help regulate glucose are made by the gut or bacteria in the gut. We looked there and found that the composition of the microbiome in leukemic animals was different than in control mice," Jordan says.

One major difference in the guts of leukemic mice was the lack of a specific kind of bacteria known as bacteroids. These bacteroids produce short-chain fatty acids that in turn feed the health of cells lining your gut. Without bacteroids, gut health suffers. And the current study shows that without bacteroids, gut health suffers in ways that specifically aid cancer.

One way is the loss of hormones called incretins. When blood glucose gets high, for example after you eat, your gut releases incretins, which tamp down blood glucose, reducing it back into the normal range. Working through the gut, leukemia inactivates these incretins, allowing to remain higher than it should. Leukemia also nixes the activity of serotonin. Serotonin is well-known as a "feel good" chemical that helps to regulate mood and is found in many antidepressants. But serotonin is also essential for the manufacture of insulin in the pancreas, and by attacking serotonin, leukemia reduces (and thus, down the line, glucose use).

The result of less insulin secretion and less insulin sensitivity is that cancer undercuts healthy cells' use of insulin from both sides: Healthy cells need more insulin, just as there is less insulin available. Less insulin use by healthy cells leaves more glucose for the cancer.

"It's a classic parasite trick: Take advantage of something the host does and subvert it for your own purposes," Jordan says.

Interestingly, just as a parasite might eat a host's food leading to malnourishment, cancer's energy theft may play a role in the fatigue and weight loss common in cancer patients.

"The fairly prevalent observation is that cancer patients have a condition called cachexia, basically wasting away—you lose weight. If cancers are inducing systemic changes that result in depletion of normal energy stores, this could be part of that story," Jordan says.

However, Jordan and colleagues including first author Haobin Ye, Ph.D., not only showed how leukemia dysregulates healthy cells' glucose consumption, but also showed how to "re-regulate" this consumption.

"When we administered agents to recalibrate the glucose system, we found that we could restore glucose regulation and slow the growth of leukemia cells," Ye says.

These "agents" were surprisingly low-tech. One was serotonin. Another was tributyrin, a fatty acid found in butter and other foods. Serotonin supplementation replaced the serotonin nixed by leukemia and tributyrin helped to replace the short-chain fatty acids that were absent due to loss of bacteroids.

The group calls the combination Ser-Tri therapy. And they show that it is more than a theory. Ser-Tri therapy led to the recovery of insulin levels and reduction of IGFPB1. And leukemic mice treated with Ser-Tri therapy lived longer than those without. Twenty-two days after leukemia was introduced in mice, all of the untreated mice had died, while more than half of the mice treated with Ser-Tri were still alive.

The continuing line of work shows that cancer may depend on the ability to out-compete healthy cells for limited energy. Healthy tissues have strategies to regulate insulin, glucose and other factors controlling energy consumption; cancer cells have strategies to subvert this regulation with the goal of making more energy available for their own use.

"We now have evidence that what we observed in our mouse models is also true for leukemia patients." Ye says.

Understanding these mechanisms that cancer uses to unbalance the body's system of energy in their favor is helping doctors and researchers learn to thumb the scale in favor of healthy cells.

"This furthers the notion that you can do things systemically to disfavor leukemia cells and favor normal tissue," Jordan says. "This could be part of limiting growth of tumors."

Explore further: New potential target for treatment of diabetes

More information: Haobin Ye et al, Subversion of Systemic Glucose Metabolism as a Mechanism to Support the Growth of Leukemia Cells, Cancer Cell (2018). DOI: 10.1016/j.ccell.2018.08.016

Related Stories

New potential target for treatment of diabetes

July 25, 2018
Researchers at Karolinska Institutet have discovered that one of the building blocks in the calcium channels in the pancreatic beta cells play an important role in regulating our blood glucose values. Treatments aimed at ...

Culprit in reducing effectiveness of insulin identified

April 26, 2018
Scientists at Osaka University have discovered that Stromal derived factor-1 (SDF-1) secreted from adipocytes reduces the effectiveness of insulin in adipocytes and decreased insulin-induced glucose uptake.

Beta cell-seeded implant restores insulin production in type 1 diabetes mouse model

March 19, 2018
Researchers have successfully created a novel biomaterial that can be seeded with insulin-producing beta cells. Implantation of the beta cell-seeded biomaterial reversed diabetes in a mouse model by effectively normalizing ...

How obesity drives colon cancer in mice

July 4, 2018
Obesity, which is on the rise worldwide, has been linked to colon cancer but the mechanism has been a mystery. In a new study, Yale researchers and their co-authors have uncovered how obesity drives tumor growth in mice, ...

Kidney cells engineered to produce insulin when caffeine is present in the body

June 22, 2018
A team of researchers from ETH Zurich and the University of Basel in Switzerland and Institut Universitaire de Technologie in France has that found that embryonic kidney cells engineered to produce insulin when exposed to ...

Normal insulin rhythm restored in mouse pancreas cells by glucose pulse

October 27, 2016
Pulses of the sugar glucose can restore normal insulin release in mouse pancreas cells that have been exposed to excess glucose, according to a study published in PLOS Computational Biology. This finding could improve understanding ...

Recommended for you

Two ways cancer resists treatment are actually connected, with one activating the other

December 18, 2018
Drugs that target BRAF and MEK in cancer have shown promise in treating a subset of melanoma that carries a mutation in the BRAF gene, but drug resistance usually emerges, reversing the benefit of these drugs and limiting ...

HPV discovery raises hope for new cervical cancer treatments

December 18, 2018
Researchers at the University of Virginia School of Medicine have made a discovery about human papillomavirus (HPV) that could lead to new treatments for cervical cancer and other cancers caused by the virus.

Vaccine, checkpoint drugs combination shows promise for pancreatic cancers

December 18, 2018
Researchers at the Johns Hopkins Kimmel Cancer Center discovered a combination of a cancer vaccine with two checkpoint drugs reduced pancreatic cancer tumors in mice, demonstrating a possible pathway for treatment of people ...

Researchers identify ways breast cancer avoids immune system detection

December 18, 2018
Recent breakthroughs in immunotherapy are making a huge difference in treating some forms of cancer, especially metastatic cancer. But breast cancer has proven a tricky foe for this new therapy, and an interdisciplinary team ...

Metal chemotherapy drugs boost the impact of immunotherapy in cancer

December 18, 2018
Due to their powerful tumour-killing effect, metal-based chemotherapies are frequently used in cancer treatment. However, it was hitherto assumed that they damaged the immune system, because of their cytotoxic (cell-damaging) ...

10-year follow-up after negative colonoscopies linked to lower colorectal cancer risk

December 17, 2018
Ten years after a negative colonoscopy, Kaiser Permanente members had 46 percent lower risk of being diagnosed with and were 88 percent less likely to die from colorectal cancer compared with those who did not undergo colorectal ...

1 comment

Adjust slider to filter visible comments by rank

Display comments: newest first

Jay1212
5 / 5 (1) Sep 29, 2018
Could explain why Metformin seems to have anti-cancer properties.

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.