Fat fuels liver cancer cells
Obesity may explain a dramatic rise in liver cancer – and obesity treatments might just offer a solution. Elizabeth Finkel reports.
Cancer cells are bad-ass marathoners, outpacing the growth of surrounding cells and going the distance to colonise far-flung parts of the body.
So, what’s the fuel of choice for these long-distance foes? Much attention has been paid to sugars, but fats are also favourites. It’s not about what we eat – there’s no evidence that cutting carbs, for instance, will starve cancer cells – it’s more about how the cells themselves are producing these fuels.
Now a group led by researchers at the University of Basel in Switzerland has figured out how liver cancer cells acquire their supply of fat.
The findings published in Cancer Cell also suggest that drugs that stop fat synthesis could be useful additions to liver cancer therapy.
“This is an awesome paper,” says Andrew Hoy, who heads the lipid metabolism laboratory at the Charles Perkins Centre in Sydney. “We’ve known since the 1930s that cancer cells change their glucose metabolism; this shows that lipids are important, too.”
In the US, rates of liver cancer are rising faster than any other type, tripling since the mid-1970s.
More than 90% of liver cancer is the type known as hepatocellular carcinoma (HCC). Traditional risk factors for HCC are infection with hepatitis B or C viruses, alcohol consumption and exposure to aflatoxin B1, a toxin common in mouldy corn or peanuts.
But the dramatic rise in the US likely owes its cause to rising obesity. Studies show a clear correlation between increasing body mass index and liver cancer.
The Basel team wanted to drill down into the mechanisms that drive the disease.
They knew that HCC often appears to be preceded by a stage called non-alcoholic fatty liver disease (NAFLD), where the liver is crammed with droplets of fats known as triglycerides.
But how exactly does fat drive the development of the cancer?
One clue is that a signalling protein called mTOR is often overactive in liver cancers.
Could the two be connected?
To find out, the team turned to mice that had an overactive form of mTOR. As the mice grew older, two things happened. They increased their synthesis of lipids and subsequently their immune systems started cranking up, evidenced by higher numbers of immune cells in the bloodstream and higher levels of inflammatory factors like IL-6. Chronic inflammation is a well-established risk factor for cancer (which is why infection with hepatitis A and B viruses often leads to liver cancer).
Sure enough, the mice went on to develop liver cancer. “The time sequence is the real strength of our paper; it allowed us to identify a key event required for cancer development,” explained Yakir Guri, a clinician-scientist and the first author.
The team drilled down into the mechanism at play and found that mTOR joined forces with other proteins to formed a molecular machine called mTORC2.
Not all fats are equal. It turns out this machine was turning other fats into building blocks needed for making cell membranes known as glucosylceramide and cardiolipin. Fuelled by these fats, the cancer cells would have what they needed to multiply. When the team used drugs such as obesity treatment Orlistat to specifically shut down the synthesis of those fats, the cancers’ growth was stymied.
Finding that mTOR was involved in the synthesis of these fatty cellular building blocks was new. But the involvement of mTOR in cancer was not. It had long been known to occupy a key position in our metabolic circuitry by acting as a nutrient sensor. The head of the Basel lab, Michael Hall, first discovered the TOR gene played this role in yeast.
Blocking mTOR with drugs such as Rapamycin – a drug used to prevent organ transplant rejection – appears to replicate some of the beneficial effects of fasting like cancer prevention and slowing aging.
When the team examined liver tissue samples from human patients with liver cancer, they also found mTORC2 was raised, as was the synthesis of lipids.
So, putting mTORC2 into overdrive raises the production of lipids that fuels the cancer.
The question remains: what triggers mTOR in the first place? One possible, but yet to be proven, explanation is that the excessive intake of nutrients that leads to obesity puts the nutrient sensor mTOR into overdrive, which in turn triggers mTORC2.
Overall, nailing the exact chain of events between obesity and cancer remains a challenge, says Hoy. Fats appear to provide a general ecosystem that is favourable to cancer, among other things by triggering inflammation. The new findings add to the picture by showing that fats also provide a reservoir for mTORC2 to generate specific fatty building blocks for cellular growth.
The findings point the way to desperately needed new treatments for liver cancer, which has a dismal 20% survival rate after five years.
Trials are currently under way using drugs that inhibit lipid synthesis. Guri suggests that even before the cancer has developed, interventions should begin for people who have a fatty liver. “Early medical intervention in NAFLD patients for instance should be considered.”
But an ounce of prevention is best. Bottom line: keep the weight off.