A study published in Nature has explored the role of age-induced accumulation of methylmalonic acid in cancer progression.
Disease of old age
There is growing evidence to support that cancer cell-extrinsic factors are key in modulating tumour progression. Society often considers cancer to be a disease of old age, with the risk of cancer and associated mortality increasing with age. Nevertheless, our understanding of the complex relationship between ageing and cancer is still not fully understand. Researchers often attribute this link to the accumulation of mutagens over time. However, this does not consider the established role of diet, exercise and small molecules impacting the pace of metabolic ageing.
Ageing and cancer progression
In the study researchers hypothesised that ageing may produce an environment that enables tumour progressiveness. Specifically, they evaluated the role of metabolic alterations that occur with age. To test this hypothesis, they cultured human cancer A549 and HCC1806 cells in 10% human serum from 30 young (age ≤30 years) and 30 old (age ≥60 years) healthy donors.
They found that injecting cultured cells into mice, aged sera potentiated the ability of the cells to colonise the lung and form metastatic lesions. This highlighted that ageing and age-induced factors help promote the acquisition of aggressive cancer properties.
To investigate what was underpinning these aggressive properties, the team examined the metabolic compositions of the donor sera. Out of the three metabolites that were consistently increased in the sera of aged donors, methylmalonic acid (MMA) was the only one found to induce a complete pro-aggressive epithelial-to-mesenchymal transition (EMT)-like phenotype.
MMA is a dicarboxylic acid that is primarily a by-product of propionate metabolism. The analyses revealed that MMA levels were higher in the sera of old donors than in young donors. To further understand the progressive properties of MMA, the team treated cells with MMA. They found that MMA concentrations of 1mM were sufficient to induce an EMT-like phenotype and the expression of pro-aggressive proteins. Interestingly, MMA also induced resistance to common chemotherapy drugs – carboplatin and paclitaxel.
From gene set enrichment analysis (GSEA), the team showed that MMA positively regulates transcription. SOX4 was one of the most upregulated transcription factor genes found. This gene is often a marker of poor prognosis that contributes to tumour progression and metastatic formation. It has been found to be aberrantly expressed in a wide variety of aggressive cancers. The team found that depletion of SOX4 abrogated the ability of MMA to induce migratory and invasive properties or resistance to chemotherapeutic drugs.
These results have shown that metabolic deregulation due to aging plays a central role in the acquisition of aggressive properties that contribute to tumour progression. In particular, ageing increases the circulation of MMA, which creates an environment for cancer cells to migrate, invade, survive and thrive as metastatic lesions. As a result, this suggests that MMA may be a promising therapeutic target for advanced carcinomas.
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