鑽石舞台

Interviewer: Benjamin Thompson

Cancer cells are gluttons for glucose – burning through buckets of the stuff to make the energy and metabolites they need to thrive. And this insatiable appetite for sugar could represent something of an opportunity. What if you could starve tumours of glucose? For inspiration, Yihai turned to another type of glucose-loving tissue – brown fat.

Interviewee: Yihai Cao

What it does actually is help us keep our body temperature when the environment is getting cold. So, brown fat is, in our body, like a radiator to produce a lot of heat.

Interviewer: Benjamin Thompson

When we’re cold, brown fat burns through blood glucose and lipid molecules to help keep our body temperature up, and this gave Yihai an idea.

Interviewee: Yihai Cao

I was curious to know, what if we put experimental animals that have tumours into the cold to activate brown fat, let the brown fat take a lot of glucose, and then create a competitive scenario and maybe the tumour will not have much glucose to take.

Interviewer: Benjamin Thompson

So, that’s what Yihai and his colleagues did. They turned to mice engineered to grow various types of solid human tumour. Then they kept the mice at a cool 4 °C to activate their brown fat and monitored their tumour growth.

Interviewee: Yihai Cao

We tested many different types of cancers, especially those ones that are very difficult to treat, like pancreatic cancer and liver cancer. So, by putting animals into cold, that is +4 °C, after a few weeks we saw very potent anti-tumour effects. Tumours grew more slower and they seem to be less invasive as well. It’s a very good sign. And they live longer, by the way.

Interviewer: Benjamin Thompson

The team showed that cold exposure inhibited growth in the different tumour types and for one type of cancer – colorectal cancer – the survival of the mice almost doubled compared to mice that were kept at warmer temperatures. And it wasn’t just the cold. The brown fat definitely seemed to be playing a role, as the same tumour suppression effect wasn’t seen in mice that』d had their brown fat removed or inactivated. In fact, Yihai’s team tested the role of brown fat in a variety of ways. They showed that mice in the cold had lower blood sugar levels, and that the activated brown fat was taking up much more glucose than the tumours. Increasing overall blood sugar levels in the mice reversed the anticancer effects.

Interviewee: Yihai Cao

Indeed, when we gave a high-glucose drinking water to the mice, tumour growth was largely restored, so that’s really supporting the hypothesis that reducing blood glucose is one of the mechanisms.

Interviewer: Benjamin Thompson

But potentially not the only mechanism. For example, the team showed that in some cases, genes involved in glucose uptake were downregulated in the cold-mice tumours, suggesting it might be a tandem effect of the brown fat using up available blood glucose and the tumours not being as efficient at taking it up in the first place. Yihai says there are other things to investigate too.

Interviewee: Yihai Cao

Because when fat breaks down and produces heat, you also have a lot of metabolites and lots of other growth factors. Cytokines required for tumour growth also get changed. For now, I can only see the competition as a mechanism, but maybe future studies will actually discover many more mechanisms behind.

Interviewer: Benjamin Thompson

But although the exact mechanism is unclear, Yihai was keen to see if he could reproduce the effect he saw in mice in a human cancer patient. And so, he enrolled a person with Hodgkin’s lymphoma who was between chemotherapy cycles in a pilot study, and asked her to spend time in a warm room, and a room kept at 22 °C which, according to Yihai, should be cool enough to activate brown fat. She was then scanned to see what effect this had on her brown fat and tumour tissue.

Interviewee: Yihai Cao

In the warm environments, she did have actually brown fat activation. Maybe some other mechanisms of cancer activated the brown fat. However, when she moved to the cold environment, her tumour glucose uptake was much more reduced, and the brown fat signals became even more boosted. So, that was of course one patient. We cannot make any conclusions. But we want to relate that this thing really exists in humans. That’s the point we’re trying to make.

Interviewer: Benjamin Thompson

Mariia Yuneva, who researches cancer biology and metabolism at the Francis Crick Institute in the UK and who wasn’t involved in this work, was intrigued by the study, but pointed out that it raises a number of questions too.

Interviewee: Mariia Yuneva

So, first of all, all tumours are different, so it would be very interesting to see how these tumours that they saw an effect on, do they switch to other types of nutrition, right? So, do they use more amino acids, for example? Do they use more lipids? What happens to the tumours who originally rely on other sources more than glucose, and we know those exist, right. And how deep in human patients do you need to go with lowering down the temperature and for how long to have an effect on tumours, given the fact they already don’t have much fat perhaps, and that the condition of their body is already affected.

Interviewer: Benjamin Thompson

Mariia also wants to know how this method compares to attempts to starve tumours of glucose using calorie-limited diets, which has attracted a lot of research.

Interviewee: Mariia Yuneva

They don’t compare this, but perhaps it’s a more efficient way to lower glucose levels down, than using the calorie restriction, for example. And so, there are recent studies demonstrating that, indeed, decreasing glucose levels in the diet and calorie restriction can have an effect on tumour progression, but it’s still not a very clear picture. The picture is quite complicated because different tumours can respond differently.

Interviewer: Benjamin Thompson

It’s clear that metabolism is complicated, and there’s lots to learn about how lab efforts to starve tumours of glucose could translate into the clinic. But Yihai thinks that with proper testing, if the effect that he’s shown is found to be relevant in humans, it could form a simple and useful extra weapon in the arsenal against cancer.

Interviewee: Yihai Cao

In this study, we want to present a concept for a new cancer therapy. We want to make sure this has human relevance. For the future, it does need to be carefully studies by recruiting a large number of patients to see cold, in combination with what kind of therapy, would produce the most beneficial effects. And to see which type of cancer is much more suitable for this type of therapy. And we have no idea at this moment, so we want to do that together with clinical oncologists.

Interviewer: Benjamin Thompson

That was Yihai Cao from the Karolinska Institute in Sweden. You also heard from Mariia Yuneva from the Francis Crick Institute here in the UK. To read Yihai’s paper, look out for a link in this week’s show notes.

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