Acid produced during digestion helps explain why cancer worsens with age

This is an Inside Science story.

Many forms of cancer become more common and deadlier as we get older. There are several reasons behind this, including a weakening immune system and an accumulation of potentially dangerous mutations in our genes. Now a new culprit has been uncovered.

That culprit is methylmalonic acid (MMA), a byproduct of protein and fat digestion that is elevated in the blood of older people. A study published Wednesday in the journal Nature reports that MMA can induce aggressive metastasis and drug resistance in cancer cells, both in the test tube and in mice.

John Blenis, a cancer biologist at Weill Cornell Medicine in New York, and his colleague Ana Gomes treated human cancer cells with blood serum samples from people who were either under 30 or over 60. The cells exposed to older serum showed signs typical of cancer cells that had gained the ability to metastasize and spread to other parts of the body, and showed increased levels of proteins associated with aggressive cancer, as well as resistance to common chemotherapy drugs. When injected into mice, the cells quickly migrated to the lungs and started new tumors.

When the researchers analyzed the serum used to treat the cancer cells, they found that MMA was elevated in all of the samples that were able to induce metastasis. And when cancer cells were exposed just to elevated levels of MMA, the same changes were seen -- including the ability to induce new tumors in mice.

The researchers also analyzed the genetic changes in the cancer cells and found that higher levels of MMA were associated with increased expression of the SOX4 gene, which contributes to tumor progression and is highly active in aggressive cancers. Blocking the expression of SOX4 stopped MMA from inducing metastasis and drug resistance.

It is not yet clear how exactly all this works, but Blenis said it raises interesting new questions about how aging interacts with cancer, as well as potential new ways to prevent or treat it. The metabolic pathway that leads to MMA, for example, is known to be associated with certain fatty acids, so there could be implications for how diet affects cancer risk.

"This is one of those major observations that opens up a whole new field," said Blenis. "It's very exciting."

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