Double burden: older people not only develop cancer more often, their tumors are also often more aggressive. The reason for this lies in the “old” blood, as a study has now revealed. Because it contains a metabolic product that stimulates cancer cells to form metastases. In addition, this methylmalonic acid makes the tumors resistant to common chemotherapies, as the researchers report in the specialist journal “Nature”. This knowledge could now lead to new therapies.
The risk of cancer increases with age – that much seems clear. Because in the course of life carcinogenic environmental influences accumulate, at the same time the cell’s own DNA repair can no longer do it, all Mutations and Genetic damage to eliminate. As a result, cells degenerate more frequently and thus cancer. In addition, however, tumors in older people also grow more aggressively and form metastases. Why, however, has so far remained unclear.
Cancer cells react differently to the blood of old and young people
Researchers working with Ana Gomes from Weill Cornell Medical College in New York may have found an answer – in our blood. The starting point of their study was a simple experiment: They took over 60 blood samples from 30 young people under the age of 30 and 30 healthy older people. They then cultivated two cancer cell lines in a nutrient solution mixed with the subjects’ blood sera.
The result: the tumor cells cultivated with young blood hardly changed. But the cancer cells that grew in the serum of the older test subjects showed clear signs of change: They became more aggressive and penetrated the surrounding tissue, developed mobile settlements and became resistant to two common chemotherapeutic agents, carboplatin and paclitaxel.
More metastases in “old” blood
This change to increased aggressiveness was also confirmed in animal experiments: When mice were injected with breast cancer cells cultivated with old serum, they soon developed metastases in the lungs, as Gomes and her team report. In contrast, this was not the case in the animals that received the cancer cells pretreated with young serum.
“This shows that there are factors circulating in the blood that give the tumor cells aggressive properties – and that are related to age,” the scientists state. But what are these factors? To find out, they compared the levels of 179 metabolic products in old and young blood. It was found that three metabolites in particular were significantly increased in the sera of the older participants.
Methylmalonic acid is to blame
When the researchers tested these three substances separately on cancer cells, only one of them triggered the aggressive change: methylmalonic acid (MMS). This molecule is produced when proteins and fats are broken down and is found in the blood of older people in ten to 100 times higher concentrations than in young people, as Gomes and her colleagues found.
More detailed analyzes revealed: In the blood, methylmalonic acid accumulates in blood lipids and is then taken up with these by tumor cells. There the substance acts on the gene activity of the cancer cell and primarily activates the SOX4 gene. “SOX4 is considered a marker for a poor prognosis because it contributes to tumor growth and metastasis,” the researchers report. “This gene is abnormally expressed in many aggressive cancers.”
New starting points for therapy
This makes it clear: aging not only favors the development of cancerous tumors, it also increasingly releases a metabolic product that makes cancer cells that have once formed more aggressive. Under the influence of the methylmalonic acid circulating in the blood, the tumor cells become more invasive, more mobile and more difficult to fight.
The good news, however, is that because the mechanism that drives tumors to metastasize and develop resistance has now been identified, this also offers new approaches for medicine. “Methymalonic acid accumulation links aging with cancer growth – and this suggests that MMA could also be a promising target for therapies in advanced cancer,” the researchers say. (Nature, 2020; doi: 10.1038 / s41586-020-2630-0)
What: Nature
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