How Cancer Cells Fuel Their Growth

    Cancer cells are notorious for their ability to divide uncontrollably and generate hordes of new tumor cells. Most of the fuel consumed by these rapidly proliferating cells is glucose, a type of sugar.

    Scientists had believed that most of the cell mass that makes up new cells, including cancer cells, comes from that glucose. However, MIT biologists have now found, to their surprise, that the largest source for new cell material is amino acids, which cells consume in much smaller quantities.

    The MIT research suggests that cell biologists and cancer researchers need to be more careful about when they think about the ways cancer cells “fuel” their growth. Also, separate research, from Rice University, indicates that cancer cells have yet another energy pathway surprise. Specifically, some cancer cells get 30–60% of their fuel from eating their neighbor’s “words.”

    The Rice researchers also used labeled atoms, in this case carbon-13 atoms, to elucidate that exosomes supply amino acids to nutrient-deprived cancer cells. This work was detailed February 27 in eLife, in an article entitled, “Tumor Microenvironment Derived Exosomes Pleiotropically Modulate Cancer Cell Metabolism.”

    “Using intra-exosomal metabolomics,” the article’s authors wrote, “we provide compelling evidence that CDEs [cancer-associated fibroblast-derived exosomes] contain intact metabolites, including amino acids, lipids, and TCA-cycle [tricarboxylic acid cycle] intermediates that are avidly utilized by cancer cells for central carbon metabolism and promoting tumor growth under nutrient deprivation or nutrient stressed conditions.”

    The results from the MIT study appeared more recently, on March 7, in Developmental Cell. According to this study—“Amino Acids Rather than Glucose Account for the Majority of Cell Mass in Proliferating Mammalian Cells”—rates of nutrient consumption are only indirectly associated with mass accumulation. “High rates of glucose and glutamine consumption,” wrote the study’s authors, “support rapid cell proliferation beyond providing carbon for biosynthesis.”

    Since the 1920s, scientists have known that cancer cells generate energy differently than normal cells, a phenomenon dubbed the “Warburg effect” after its discoverer, German biochemist Otto Warburg. Human cells normally use glucose as an energy source, breaking it down through a series of complex chemical reactions requiring oxygen. Warburg discovered that tumor cells switch to a less efficient metabolic strategy known as fermentation, which does not require oxygen and produces much less energy.

    More recently, scientists have theorized that cancer cells use this alternative pathway to create building blocks for new cells. However, one strike against this hypothesis is that much of the glucose is converted into lactate, a waste product that is not useful to cells. Furthermore, there has been very little research on exactly what goes into the composition of new cancer cells or any kind of rapidly dividing mammalian cells.

    “Because mammals eat such a diversity of foods, it seemed like an unanswered question about which foods contribute to what parts of mass,” said Matthew Vander Heiden, M.D., Ph.D., the scientist who led the MIT study.

    The MIT researchers found that glucose accounts for just 10–15% of the carbon found in cancer cells, whereas glutamine contributes about 10% of the carbon. Instead, the researchers found that as a group, amino acids (excluding glutamine) contribute the majority of the carbon atoms found in new cells and 20–40% of the total mass.

    Although initially surprising, the findings make sense, Dr. Vander Heiden noted, because cells are made mostly of protein.

    “There’s some economy in utilizing the simpler, more direct route to build what you’re made out of,” he explained. “If you want to build a house out of bricks, it’s easier if you have a pile of bricks around and use those bricks than to start with mud and make new bricks.”

    Dr. Vander Heiden’s lab is now pursuing a more comprehensive understanding of how the Warburg effect may help cells reproduce. “It refocuses the question,” he commented. “It isn’t necessarily about how the Warburg effect helps cells put glucose into cell mass, but more about why does glucose-to-lactate conversion help cells use amino acids to build more cells.”

    Like the MIT researchers, the Rice University researchers referenced the Warburg effect. “Our results show that not only do exosomes enhance the phenomenon of the ‘Warburg effect’ in tumors, but exosomes also contain ‘off-the-shelf’ metabolites within their cargo that cancer cells use directly in their metabolic processes,” said Rice University’s Hongyun Zhao, the first author of the eLife study.

    Some of Zhao’s follow-up tests also suggest possible new treatment regimes. For example, Zhao exposed cancer cell cultures to drugs that were known to block the uptake of exosomal signals. The tests, which showed that the cancer cell’s metabolic activity dropped significantly, helped prove that the tumors were using the exosomes as fuel. The fact that four of the drugs used in the tests—heparin, cytochalasin D, ethyl-isopropyl amiloride, and choloroquine—are already approved by the FDA for other uses suggests that they may also be useful as chemotherapeutic agents.

In other words, disruption of the exosomal metabolic adaptation of cancer cells could provide a novel therapeutic avenue for exploitation.