They question the cancer metabolism models that have been developed


Tumors consume glucose at a high rate, but a team of researchers at Vanderbilt University Medical Center, in the United States, has discovered that cancer cells are not responsible, which calls into question the cancer metabolism models that have been developed and perfected over the last 100 years. On the contrary, the non-cancerous cells of a tumor (mainly the immune cells called macrophages) are the ones that absorb the most glucose, according to the group in the journal ‘Nature’.

According to the researchers, the discovery that different cells in the tumor microenvironment use different nutrients according to their own metabolic programs could be used to develop new therapies and imaging strategies.

“The field of cancer metabolism has exploded in the last 20 years, but it has been based on the observation that Otto Warburg published in 1922: that cancer cells can consume glucose at a very high rate,” says Dr. Jeffrey Rathmell, 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-cancerous cells are actually the main glucose consumers in the tumor. “

Warburg’s observation is also the basis for tumor imaging using positron emission tomography (PET), which uses a radioactive glucose tracer (FDG) to “light up” cancer cells based on their glucose metabolism. But FDG-PET does not always give the results that doctors expect.

“I had been curious for many years why PET scans are ‘hot’ or ‘not hot’, because the type of kidney cancer I study, based on what we understand from biology, should be hot on PET and often not It is, “says W. Kimryn Rathmell, professor and chair of the Department of Medicine.” Jeff and I have had many conversations about which cells are using glucose: are they cancer cells, are they immune cells, how does it all fit together? Imagine our table. “

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Two doctoral students – Bradley Reinfeld, from Kimryn Rathmell’s group, and Matthew Madden, from Jeff Rathmell’s group – took on the challenge of answering these questions. In principle, their approach was straightforward: administer PET tracers to mice with tumors, isolate the tumors, separate the tumors into various cell types using cell surface marker proteins and flow cytometry, and measure the radioactivity in the cells.

The team used two different PET tracers, one for tracking glucose and one for 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) were the ones that took up glucose the most, followed by T cells and cancer cells. In contrast, cancer cells had the highest glutamine uptake.

“We think this is a general phenomenon that extends to all types of cancer,” says Madden.

The researchers showed that the differences in glucose and glutamine uptake were due to certain cell signaling pathways and not to limiting nutrients.

The results contrast with the prevailing view of a metabolic competition in the tumor microenvironment in which cancer cells “win” to deplete nutrients and suppress immune cells.

“The idea has been that cancer cells gobble up all the glucose, and as a result, immune cells can’t get enough glucose and can’t do their job,” Madden says. “Our data suggest that nutrients are not limiting. Instead, cells are programmed to consume certain nutrients, and there is a partition of nutrients between cells: Cancer cells collect glutamine and fatty acids; immune cells collect glucose. “

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Knowing that cells in the tumor microenvironment use different nutrients “may allow them to target specific cell types, for new therapies or to obtain images of people’s tumors,” Reinfeld points out.

In this sense, Kimryn Rathmell adds that “now is a good time to have more sophisticated PET radiotracers. It is time to think about testing fluorinated glutamine or other nutritional probes in patients.”

The findings are also important for interpreting the results of FDG-PET images, he says. “We ask for FDG-PET scans all the time, and we need to have a good sense of what that information is giving us,” he explains. We use it to judge the tumor response, but it may be talking about the inflammatory response and not about the tumor response. “

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