Research press release



Metabolism: Tumour-promoting metabolite found in ageing blood

タンパク質と脂質の代謝副産物の一種が、がん細胞の悪性特性(例えば、薬剤耐性や転移)を誘導し、そうした物質の血清濃度が、60歳以上の高齢者で高くなることを明らかにした論文が、今週、Nature に掲載される。この知見から、老化に関連した代謝調節の異常が、高齢者の発がんリスクとがん死リスクが高いことに関与している可能性が示唆された。

今回、John Blenisたちの研究チームは、ヒトがん細胞株を30歳以下の健康なドナー30人と60歳以上のドナー30人の血清で処理した。その結果、高齢ドナーの血清で処理したがん細胞が、遊走、浸潤、生存、転移の能力を獲得したことが明らかになった。また、高齢ドナーの血清で処理したがん細胞は、悪性がんに関連するタンパク質の濃度が上昇し、広く用いられている化学療法薬に対して抵抗性を示した。



A by-product of protein and fat metabolism that is elevated in people aged 60 years and over induces aggressive traits such as drug resistance and metastasis in cancer cells. The findings, reported in Nature this week, suggest that ageing-related deregulation of metabolism may have a role in the increased risk of cancer development and death in older people.

John Blenis and colleagues treated human cancer cell lines with serum from 30 healthy donors who were 30 years old or younger and 30 more who were 60 years old or older. The authors found that cancer cells treated with serum from the older donors gained the ability to migrate, invade, survive and metastasize. The cells also showed increases in levels of proteins associated with aggressive cancer, as well as resistance to widely used chemotherapeutic drugs.

Analysing the metabolites in the sera from old and young donors, the authors found significantly higher concentrations of methylmalonic acid (MMA), a metabolite of proteins and fats, in samples from older donors. Subsequent genetic analyses revealed that higher concentrations of MMA were associated with increased expression of the SOX4 gene, which contributes to tumour progression and metastasis formation and is present at high levels in aggressive cancers. When SOX4 activity was blocked, MMA did not increase migratory and invasive properties or resistance to chemotherapeutic drugs in cancer cells.

Taken together, the findings suggest that ageing promotes increased MMA levels in the blood, which in turn enables cancer cells to migrate, invade, survive and metastasize. Accumulation of MMA represents a novel link between ageing and cancer progression, and is a potential target for new cancer therapies.

doi: 10.1038/s41586-020-2630-0

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