AACR 2015

Incidences of liver cancer rising in the USA

Dr Anna Mae Diehl - Duke University Medical Center, Durham, USA

We know that liver cancer is one of the few cancers in the world that’s rising in incidence. It’s becoming one of the most common cancers, even in the United States. It has been long known to be very common in parts of the world where liver disease is common, so particularly viral hepatitis, hepatitis B, hepatitis C. So liver cancer used to be a problem of the third world – Asia, Africa. But what’s in the third world? Viral hepatitis. But it didn’t really hit home until this disease began to become more prevalent in places where we live, in Europe and in the United States, and why was that happening? I think part of it is the diversification of the populations with an influx of immigrants from parts of the world where liver cancer was endemic and liver disease was endemic but also we know that the rising epidemic of obesity and metabolic liver disease and that’s contributing to cirrhosis and a rising incidence of cancer related with cirrhosis.

What lessons do the processes surrounding cirrhosis teach us about the origins of primary liver cancer?

What we learned is that cirrhosis occurs because the liver is trying to regenerate and replace cells that are killed from various things, viruses, toxins, alcohol. Normally the liver does that extraordinarily well and you don’t get cirrhosis and you don’t get cancer. But sometimes the process becomes deregulated and it’s as if it’s stalled. The liver keeps trying to replace the cells that died but the process is defective. So we’re looking into what are the characteristics of this defective regenerative response and in the process we’ve identified lots of cells that accumulate in the liver and how they talk to each other by different signalling pathways. Lo and behold it turns out that they are communicating using many of the pathways that are known to be activated in other kinds of cancers. So we think that the cirrhotic microenvironment is creating a very comfortable place for cells with cancerous malignancies to reside, sort of selecting for them.

Does this open the door to using, perhaps, targeted therapies that antagonise some of those pathways?

I would think so. I would think so. A number of pathways that have become famous for regulating growth in other cancers, like the hedgehog pathway, one we’ve studied, but Wnt, Notch, Hippo. Pathways that are very famous in developmental biology and also in other cancers are now known to be activated as part of liver repair. This might open the opportunities to use drugs that intervene in those pathways as new treatments for liver cancer.

In terms of present day medicine, what should busy cancer doctors be thinking about when trying to understand what’s happening in the liver to cause liver cancer?

I think one of the most important things is to recognise this association between liver disease and liver cancer. One of the reasons we’ve been unsuccessful in treating liver cancer is that we don’t screen people who are at risk for liver disease. The CDC now recommends that all baby boomers be tested for hepatitis C because hepatitis C is actually endemic in our generation. If you don’t know that you have hepatitis C, you don’t know that you might have hepatitis C related chronic liver disease. And if you don’t know you have hepatitis C related chronic liver disease, you don’t know you’re at risk for cancer. So screening is very important because we know if we detect these tumours when they’re small they can be taken out locally with radiologic approaches that are minimally invasive. However, when they become large or disseminated then we have very few therapies. So the most important thing is early diagnosis and screening.

So screening is one important message. Finally, what would you leave cancer doctors with as the message coming out of your very fascinating research on the causes of liver cancer?

If we find somebody who has liver disease and we understand the pathways that become deregulated when you get cirrhosis, those same pathways will be deregulated when you get cancer. So we need to develop better biomarkers so that we can identify who is at risk for developing these things, try to intervene early, and use drugs that would interrupt those aberrant signalling pathways.