Tumors consume glucose at high rates, but a team of Vanderbilt researchers discovered that cancer cells themselves are not the culprits, which has altered cancer metabolism models that have been developed and refined over the past 100 years.
Instead, the non-cancer cells in the tumor – primarily immune cells called macrophages – have the highest glucose uptake, the group reported April 7 in the journal. Temperate nature. The investigators said the findings that different cells in the tumor microenvironment use distinct nutrients according to their metabolic programs could be exploited to develop new therapies and imaging strategies.
“The field of cancer metabolism has really spread over the past 20 years, but it was based on this observation published by Otto Warburg in 1922 – that cancer cells can consume glucose at a very high rate,” said Geoffrey Rathmell, Ph.D., Cornelius. Vanderbilt Professor of Immunobiology and Director of the Vanderbilt Center for Immunobiology. “We now know that tumors include many types of cells, and it is surprising that non-cancer cells are actually the main consumers of glucose in a tumor.”
Warburg’s observation is also the basis for tumor imaging by positron emission tomography (PET), which uses a radioactive glucose tracer (FDG) to “illuminate” cancer cells based on glucose metabolism. But FDG-PET doesn’t always give the results doctors expect.
“I was curious about why the PET scans were ‘hot’ or ‘not hot’ for many years because the type of kidney cancer that I’m studying, from what we understand about biology, should be lit up on the PET scanner and often not,” Saeed W. Kimrin Rathmell, MD, PhD, Hugh Morgan Professor and Chair of the Department of Medicine. Jeff and I have had many conversations about cells that use glucose: Are they cancer cells? Is it immune cells? How does it all fit together? You can only imagine our dinner table. ”
Two MD students – Bradley Reinfeld of the Kimrin Rathmell Group and Matthew Madden in the Geoff Rathmell Group – took upon themselves the challenge of answering these questions. Conceptually, their approach was straightforward: administering PET tracers to mice with tumors, isolating tumors, separating tumors into different cell types using proteins and cell surface markers and cytometry, and measuring radioactivity in cells.
The team used two different PET trackers, one to track glucose and one to the nutrient glutamine, and six different tumor models including colorectal, kidney and breast cancer. In each case, they found that myeloid immune cells (mainly macrophages) had the highest glucose uptake, followed by T cells and cancer cells. In contrast, cancer cells had the highest absorption of glutamine.
“We think this is a general phenomenon that spans across cancers,” Madden said.
The researchers showed that it was specific cellular signaling pathways rather than nutrient limitation that led to the differences in glucose and glutamine absorption.
The results contradict the prevailing view of metabolic competition in the tumor microenvironment where cancer cells “win” to deplete nutrients and inhibit immune cells.
“The idea was that cancer cells eat up all the glucose, and therefore, the immune cells cannot get enough glucose and they cannot do their job,” Madden said. “Our data indicates that nutrients do not limit. Instead, cells are programmed to consume some nutrients, and there is a division of nutrients between cells: Cancer cells capture glutamine and fatty acids. Immune cells capture glucose.”
Knowing that cells in a tumor microenvironment use different nutrients “may allow certain types of cells to be specifically targeted – for new treatments or for imaging people’s tumors,” said Reinfeld.
Kimryn Rathmell added, “We are now in a good place to have more advanced PET scanners. It is time to think about fluorinated glutamine testing or other nutrient investigations in patients.”
She said the results are also important for interpreting the results of the FDG-PET imaging. “We order FDG-PET scans all the time, and we need a good understanding of what this information provides us. We use it to judge a tumor response, but it might tell us about the inflammatory response and not the tumor response.”
Geoff Rathmell said the collaborative project involved Rainfield and Madden in each trial, noting that the students reached out to fellow students in the Medical Scientist Training Program to explore additional tumor models. “It was a very dynamic and interesting collaboration,” he said.
Other Vanderbilt groups participating in the studies included those of Charles Manning, David Merryman, Rachel Johnson, Matthew Wilson and Christopher Williams. The work also included close collaboration with the Alexander Muir Laboratory groups at the University of Chicago and Matthew Vander Hayden, who was recently appointed as the new director of the Koch Institute for Integrative Cancer Research at MIT.
The research was supported by the National Institutes of Health (Grants CA239367, CA247202, DK120149, CA217987, GM007753, DK105550, GM007347, CA090625, CA234920), American Heart Association, Veterans Affairs America Department, Crohn’s and Colitis Foundation, Vanderbilt Cancer Research and American Association -Incyte.