A Common Sugar May Help Cancer Cells Spread Through The Body

Cancer can resemble the villain in a horror film: the hero appears to have defeated him for good, only for him to return and cause more terror.

Chemotherapy is likewise intended to destroy cancer cells, yet some endure treatment by entering a state called cellular senescence.

Rather than becoming inactive, these cells stay metabolically active. They release a blend of proteins, fats and other molecules that can alter a tumour and its surroundings by sending signals to neighbouring cells.

New research published in Nature Aging has found that one of these signals may be a substance found in kitchen cupboards – and that it could be telling cancer cells to spread.

“Our study is among the first to show that a nutrient – in this case, fructose – can act as one of those signals,” says Aidan Cole, a molecular biologist at The Wistar Institute in Philadelphia.

Fructose and ovarian cancer spread

The team investigated ovarian cancers treated with cisplatin, a potent platinum-based chemotherapy drug that often causes cellular senescence.

Although most patients initially respond favourably to treatment, recurrence is frequent. The tumours can then spread across the abdominal cavity.

What makes these cells move around?

Answering that question could offer clues to preventing cancer recurrence, which is how 90 percent of people who die from the disease are killed.

To identify the cellular process involved, the researchers first used cisplatin to induce senescence in laboratory-grown ovarian cancer cells. They then gathered the growth medium, containing every molecule released by the cells over two days.

When untreated ovarian cancer cells were exposed to this medium, they did not divide more rapidly or become more resistant to cell death.

Instead, the researchers found that the cells were far more likely to release their hold on neighbouring cells and detach from three-dimensional tumour-like spheroids. This is the first crucial stage in ovarian cancer’s characteristic pattern of spread.

How fructose affects cancer cell adhesion

The effect remained after the team heat-inactivated and filtered out suspected proteins. They could therefore rule out recognised signalling molecules, including cytokines and growth factors, both of which are proteins.

The responsible substance had to be a considerably smaller molecule.

Metabolic analysis identified fructose. Senescent cells used up glucose while releasing increased quantities of fructose.

Adding physiological concentrations of fructose to otherwise normal conditioned medium alone replicated the increase in cell detachment. Reintroducing glucose, meanwhile, largely reversed the result.

The researchers next traced the metabolic cascade set off by fructose. It did more than provide fuel: fructose changed mitochondrial metabolism, eventually lowering cholesterol production.

This cholesterol reduction had a significant effect. Cholesterol helps to stabilise cell membranes and secure cells both to each other and to nearby tissue. With less cholesterol in their membranes, cancer cells were less adhesive and more prone to breaking away.

The researchers initially observed this detachment in cell cultures, but they also examined the process in mice.

Mice implanted with ovarian cancer cells developed substantially more metastatic tumours after receiving material from senescent cells than after treatment with the same material from normal cells. This occurred despite no increase in cancer cell proliferation.

Another important result was that mice on a high-fructose diet developed more widespread metastatic disease than animals given glucose.

When the researchers disabled the cancer cells’ ability to metabolise fructose, they observed fewer cancer cells moving around.

This indicates that an animal’s diet could affect how cancer progresses.

“As far as we know, this is the first time anyone has shown, in a preclinical model rather than just a dish, that it's the molecules these cells release – not the cells themselves – that drive the cancer's spread,” Cole says.

What the preclinical findings mean

It is important to stress that these are preclinical findings from experiments in mice and cells. They should not be interpreted as showing that dietary fructose on its own causes ovarian cancer metastasis in humans.

Nevertheless, people consume considerably more sugar than they once did. In the US, a third of teenagers obtain 15 percent or more of their calories from sugar, particularly high-fructose corn syrup, so the findings warrant further study.

Related: Gut Bacteria May Reveal How a Western Diet Fuels Colon Cancer

The work indicates that chemotherapy-induced senescent cells actively reshape the tumour’s metabolic environment in ways that promote the spread of surviving cancer cells.

The researchers propose that future treatments combining senolytic drugs, which selectively remove senescent cells, with specifically designed dietary interventions could help limit this unintended consequence of chemotherapy for ovarian cancer and improve outcomes.

“Fructose may play an underappreciated role in modulating tumor cell behavior,” the researchers conclude.

“This raises the possibility that restricting fructose intake could be a promising dietary intervention to assist in treatment response.”

The study was published in Nature Aging.

This article was fact-checked and edited by Clare Watson. Although we take pride in our process, we are only human. If you spot an error, please let us know.