The article here discusses the interesting possibility that comparatively simple differences in circulating factors may be at the root of the higher risk of cancer metastasis in older people. Metastasis is the process by which cancer cells migrate from the primary tumor to form new tumors elsewhere. It is what makes cancers in much of the body hard to treat and ultimately fatal rather than merely harmful, problematic, but manageable. Thus targets that might potentially interfere in metastasis are of interest.

As we get older, the risk that we will develop cancer increases, because we accumulate genetic mutations and are continually exposed to cancer-causing substances. Most cancer-causing agents are found in the environment, but some are produced by our own bodies. Researchers now report that methylmalonic acid (MMA) – a by-product of protein and fat digestion – can accumulate in the blood with age, and might promote the spread of tumours. Methylmalonic acid is produced in cells in very small amounts. Usually, it becomes linked to the molecule coenzyme A to form methylmalonyl-CoA, and is converted to succinyl-CoA in a reaction that involves vitamin B12 as a cofactor. Succinyl-CoA subsequently enters the TCA cycle – a series of chemical reactions that are a key part of energy production in the cell.

Researchers report that MMA levels are significantly higher in the blood of healthy people over the age of 60 than in those under 30. The elevated level of MMA had not caused ill health in the individuals studied. However, the authors found that treating human cancer cells with serum from the blood of the older group, or with high concentrations of MMA, led them to adopt characteristics of metastatic cancer cells – those that can spread from a primary tumour to seed cancers elsewhere in the body. These characteristics include a loss of cell-cell attachment and an increase in mobility. When injected into mice, the cells formed metastatic tumours in the lungs.

The authors examined the gene-expression profiles of cells treated with MMA, and compared them with those of untreated cells. One of the genes most highly upregulated in response to MMA was SOX4, which encodes a transcription factor involved in the regulation of embryonic development and cancer progression. The authors demonstrated that repressing SOX4 expression blocked the cancer-cell response to MMA, and prevented the formation of metastatic tumours in mice that received injections of cancer cells treated with old serum. Thus, MMA indirectly induces an increase in the expression of SOX4, which in turn elicits broad reprogramming of gene expression and subsequent transformation of cells into a metastatic state.