Cancer has an insatiable appetite for the body’s nutrients. Most of the time, sugar is its preferred source of energy, but in some rare instances, cancer appears to favor fat over sugar. And now, scientists at the Harvard Medical School are beginning to understand exactly how this happens. The results have the potential to broaden therapies against these fat-loving cancer types.
Most tumors rely on glucose and other sugar forms as their main fuel for growth. Only when the sugar supply runs low does cancer turn to fat instead. But for a few cancers, scientists were perplexed at how cancer cells were able to use fat instead of sugar. Fat-loving cancers include acute myeloid leukemia and prostate cancer – two of the more common cancer types that can’t be starved by cutting the glucose supply.
Led by Marcia Haigis, the Harvard team identified a key protein that regulates when fat cells get burned for cancer’s consumption. The protein is known as prolyl hydroxylase 3 (PHD3). As it turns out, PHD3 blocks fat metabolism, which promotes glucose breakdown for energy. Higher PHD3, then, should be found in tumors that love sugar, whereas PHD3 levels should be low in tumors that love fat.
Indeed, by combing through databases of human cancers, Haigis’ team found exactly what they were looking for. In prostate cancer and acute myeloid leukemia, levels of PHD3 were significantly lower than that of other typical sugar-loving cancers.
"This really represents a new frontier in looking at the metabolism of cancer," said Haigis, associate professor of cell biology at Harvard, and senior author of the paper. "Understanding the molecular handle of this pathway is the first step toward translating the basic work into therapy."
To further prove PHD3’s role in cancer’s propensity for fat as fuel, the team tinkered with the levels of PHD3. By increasing the amount of PHD3, the cancer cells could not metabolize fat and promptly died.
"That was really exciting," Haigis said. "We've altered a lot of metabolic pathways in cancer, and this is one of the few pathways we've modulated where we really see the tumors die. They are so dependent on fat oxidation that they die."
Now that the results show how these cancers burn fat for fuel, the next question is why. "What do fats provide to tumors that other fuels don't? That's one open question, and this is only the first chapter in the story,” Haigis said. In particular, she hopes the study will begin to unravel more ways to effectively starve cancers, like prostate and leukemia, to improve patient outcomes.
Additional sources: Harvard Medical School