There are over 200 different types of cancer that affect virtually every organ in the body. They can seem bewilderingly different but all cancers share certain features that make them… well, cancer.
In January 2000, US cancer experts Doug Hanahan and Bob Weinberg published a seminal paper called “The Hallmarks of Cancer”, which outlined six of these common features. The article appeared in the Millennium issue of the journal Cell, and it went on to influence a generation of cancer researchers.
Nowadays, their ideas are regarded as established fact. The paper has since been referenced by others over 10,000 times, and was downloaded 20,000 times a year between 2004 and 2007.
Ten years later, at the 2010 NCRI Cancer Conference, Doug Hanahan flew in from Switzerland to give us his thoughts about how our understanding has progressed in the intervening years and – crucially – what this means for developing more effective ways to treat cancer. He even added a couple of new hallmarks.
In their original review, Hanahan and Weinberg proposed the following ‘hallmarks’ – features that cells acquire as they become cancerous:
The cells of our bodies are, in effect, members of a huge support group. They constantly supply each other with encouraging messages, telling their neighbours that “everything’s OK” and to stay where they are.
In contrast, cancer cells behave like arrogant, self-important egomaniacs. They only listen to their own internal voice, and despite all evidence that they’re behaving in an anti-social manner, carry on regardless.
Needless to say, when a cell starts misbehaving, its neighbours kick up a fuss, sending messages telling it to play nicely with the rest of the group. A second hallmark of cancer is that, metaphorically speaking, it can stick its fingers in its ears and ignore the clamour from next door telling it to cease and desist.
Perhaps the most well-known feature of cancer cells is their wanderlust. Unlike healthy cells, which generally stay in one place, cancer cells acquire the ability to roam around the body to find new homes. This ability to invade and spread – known as metastasis - is actually what makes cancer a deadly disease.
Each time a cell divides, it picks up a few tiny errors in its DNA. The more times it divides, the more errors it accumulates. This acts like a molecular ‘clock’, limiting the number of times that most cells can divide in a lifetime. Cancer cells bypass these mechanisms, and can divide again and again, becoming more and more error-strewn and abnormal as they do so.
We all need oxygen and nutrients to keep us going, and cancer cells are no exception. They’re masters at subverting the body’s pipelines – our blood vessels – for their own purposes. This particular hallmark of cancer – the ability to grow new blood vessels, or angiogenesis – is so important that it’s become a major focus of efforts to target the disease, as we’ve written about before.
6. Cheating death
‘Apoptosis’, also called ‘programmed cell death’ or cell suicide, is another one of nature’s anti-cancer tricks. Cells that become damaged or dysfunctional have a number of internal trip-wires that cause them to self-destruct, but – as you might expect – cancer cells manage to defuse these booby traps and carry on growing.
A decade on – new insights
Since their article appeared in 2000, research – and our understanding of cancer – has moved on. Hanahan and Weinberg have been writing an update, and Hanahan shared some of the pair’s latest thinking with us. They’ve now added four more characteristics to their list:
7. Deregulated energy supplies
The idea that cancer cells generate energy differently from normal cells has been around since the 1920s, and there’s now a substantial body of evidence that this is the case. This unusual mode of energy production is a hot topic in cancer research, and scientists are trying to exploit it to develop more effective treatments.
8. Masters of disguise
We now know that our immune system plays an important role in protecting us against cancer, by spotting rogue cancer cells and nipping them in the bud. So for a cancer to develop, its cells need to escape detection by the immune system.
How they do this, how to prevent it, and how we can use the power of the immune system to destroy cancers is another major focus of research around the world.
Cancers have unstable DNA – a fact that’s been known for several decades. Tumour cells are continually mutating and evolving, scrambling their DNA into an almost unrecognisable state.
Hanahan admitted that there’d been some debate about whether this was in fact a ‘hallmark’ of cancer, or a feature that enabled cancer cells to acquire other characteristics. But to recognise the importance of genetic instability and mutations, they decided to include it in their revised list.
We’ve blogged many times about the importance of inflammation in the development of cancer, and Weinberg and Hanahan felt it important enough to include as a hallmark of the disease. They added the caveat that it’s not a feature of cancer cells themselves, but an effect they have on their surrounding environment.
Hanahan also mentioned three other aspects of cancer that have gained in importance over the last decade. Firstly is the view that a tumour is not a uniform ‘bag of cancer cells’ – it’s more akin to a small ‘rogue organ’, made up from many different types of cell – stem cells, immune cells, supporting cells and blood vessels – all working together to sustain the tumour.
Secondly, he emphasised the importance of what’s becoming known as ‘systems biology’ – the study of an entire system rather than its component parts. This involves understanding the messages produced by cancer cells and their surrounding neighbours, the signals that are sent within these cells, and how all of these join together to form a ‘molecular circuit board’.
Finally he spoke about the recognition that cancer doesn’t develop down a single, linear path. Cancers aren’t static, they’re dynamic, living entities that grow, retreat, speed up, slow down, and constantly change. Unfortunately, this makes them much harder to target than was optimistically thought ten years ago. But it’s an important realisation that’s now guiding cancer researchers.
What does it mean for patients?
Hanahan and Weinberg’s insights are hugely influential in the cancer research community, but have they actually achieved anything concrete for people with the disease? The answer to this is a resounding ‘yes’ – and their new ideas will undoubtedly influence future cancer treatment.
Hanahan took the blocking of new blood vessel growth, or angiogenesis, as an example. This is an important hallmark identified in their original paper, and subsequently a key focus of recent drug development research.
Several anti-angiogenesis drugs have now been developed (for example, bevacizumab), but even though they seem to work as they’re supposed to in the lab, they haven’t had the clinical impact that many predicted. Hanahan thinks that their ‘hallmarks’ approach could explain why.
Several lines of evidence suggest that targeting one ‘hallmark’ in a tumour can cause it to re-emphasise another. Hanahan highlighted data from animal studies showing that blocking cancer’s ability to grow a new blood supply encouraged it to develop wanderlust and invade the surrounding tissue in search of a new energy supply. And he pointed to research hinting that patients treated with anti-angiogenesis drugs could – worryingly – be making the cancer spread further down the line.
In the face of it this is a rather worrying prospect – not only might the drugs not work, they could even make things worse. But Hanahan pointed to the positive prospect that, once we’ve developed drugs (or drug combinations) that can target multiple hallmarks at the same time, this would bring these new treatments back into play . And he spoke of exciting new data presented at recent conferences showing that this was indeed the case.
Far from ending on a dispiriting note, Hanahan showed that, by combining the lessons learned from the last decade with these new insights, we may just be on the cusp of one of the most exciting periods of cancer research in history. It’s one where cancer’s hallmarks, and our ability to exploit them, lead to real benefits for patients and ultimately save lives.
Hanahan, D., & Weinberg, R. (2000). The Hallmarks of Cancer Cell, 100 (1), 57-70 DOI: 10.1016/S0092-8674(00)81683-9