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If most people get infected with HPV at some point, why do just a few of them develop cancer?

This entry is part 5 of 5 in the series Cancer and Infections

The fifth post in our Cancer and Infections series looks at a widespread virus called human papillomavirus (HPV).

Most of us will be infected with human papillomavirus at some point in our lives. There are more than 100 different types of the virus, most of which cause no symptoms and go away by themselves without treatment. Other types cause harmless growths such as verrucas and warts.

But the virus also has a more sinister side. It causes nearly all cases of cervical cancer, and HPV infections also increase the risk of developing cancers of the genitals, anus, mouth and throat.

Together, these add up to more than 5,000 new cases of cancer every year in the UK.

Yet there’s an important question: if most people get infected with HPV at some point, why do just a few of them develop cancer?

And how exactly can a viral infection cause the disease?

To answer this, we need to go on a journey back in time to see how scientists first discovered this link. Along the way we’ll find out how research has made a huge impact in reducing the number of women losing their lives to cervical cancer, and see what the future holds for preventing and treating HPV-linked cancers.

Tales from the boudoir

The potential link between a viral infection and cervical cancer was first noticed in the 50s and 60s by scientists searching for clues to things that might trigger cervical cancer. To do this, they compared the lifestyles of women with cervical cancer to those without the disease.

They came up with a surprising observation: cervical cancer seemed to be more common among women who started having sex at a younger age or who had multiple sexual partners.

This seemed odd. Cancer itself isn’t contagious, but the pattern the scientists observed was similar to that of a sexually transmitted infection.

This piqued the interest of German virologist Harold zur Hausen, who’d worked on a cancer-causing virus called EBV. Zur Hausen had read reports from doctors about women with genital warts also developing cervical cancer, and had also heard about the work of US researcher Richard Shope from the 1930s, showing that infection with a type of papillomavirus could cause warts and cancers in rabbits. He figured that a similar virus might be responsible for human cancers, and set out to find it.

The human papillomavirus

The human papillomavirus

Zur Hausen began his quest by looking for viruses in human genital warts, leading to the discovery of a new type of papillomavirus, which he called HPV-6 (versions one to five had already been discovered). Much to his disappointment, his team couldn’t find HPV-6 in any cervical cancer samples, but it did lead him to a closely related papillomavirus, ultimately named HPV-11. In 1983 zur Hausen published evidence that HPV-11 was present in three out of 24 cervical cancer samples he tested.

And now he and his team were on a roll. It became apparent that there were many different types of HPV. They continued their search and discovered HPV-16, which was detected in about half of cervical cancers, then HPV-18, present in around one in five cervical cancer samples.

It was becoming clear that infection with these two types was closely linked to cervical cancer – a discovery that eventually won zur Hausen a Nobel Prize.

Over the next decade more evidence began to pour in, linking more types of the virus to cervical cancer. To join all the dots together, in 1995 the International Biological Study on Cervical Cancer group was set up to look at the bigger picture. Using samples from 22 countries, they found HPV in more than nine out of every ten cervical cancer samples (93 per cent), and this figure was consistent across the globe.

But even this turned out to be an underestimate. In 1999, a group of scientists, including Cancer Research UK scientist Professor Julian Peto, diligently re-tested the samples and found that virtually all cervical cancer samples (99.7 per cent) contained the virus. They showed HPV infection is the trigger for cervical cancer – this was, and remains to this day, the strongest link between a single ’cause’ and a specific cancer.

Researchers have now identified more than a hundred different types of HPV. Luckily, only around a dozen – known as ‘high risk’ types – are linked to cancer,

But even among women infected with high risk HPV, it’s unlikely they will develop cancer – most will not. Instead, they’ll either carry it without noticing any symptoms, or their immune system will get rid of the virus.

But for some women, a persistent, long-lasting HPV infection causes problems. During this period HPV makes proteins that target cervical cells’ machinery to allow the virus to reproduce. This can lead to the cells growing out of control and gradually picking up more genetic faults along the way, eventually developing into a cancer.

And this delay between becoming infected with HPV and developing cancer offered a promising opportunity. Could doctors spot women with early changes that could lead to cervical cancer during this period, and pre-emptively strike to get rid of the danger?

An ounce of prevention is worth a pound of cure

The answer is yes, thanks to Dr Georgios Papanicolaou’s discovery that these early changes could be spotted by collecting cells from the cervix, smearing them on a glass slide then examining them under a microscope, to see whether any of the cells look unusual or abnormal.

Smear tests can spot abnormal cells

Smear tests can spot abnormal cells

Doctors started offering this simple test, also known as the smear test (Pap test in the US) to women in the UK during routine appointments in the 1960s. But offering the test to people already going to their doctor meant women at greatest risk from cervical cancer were often missed out, and there were no follow up procedures to ensure women were screened regularly or called back if there were concerns.

To overcome these issues, in 1988 the UK government decided to make the cervical screening test a national screening programme, something our researchers played a big role in. It meant organising the programme centrally, systematically inviting women for screening every few years, and contacting them if further tests are needed.

The organised programme has played a huge role in substantially reducing rates of cervical cancer over the last 30 years and our researchers have provided the proof of just how effective it is: calculating the number of lives saved (around 5,000 every year) and the proportion of cancers prevented (about three-quarters).

But even when cells in the cervix show up as abnormal, it doesn’t necessarily mean they’ll lead to cancer – sometimes, abnormal cells can disappear of their own accord and don’t need treating. So researchers wondered whether there was a way to predict which abnormal cells were at higher risk of developing into cancer, and which were more likely to vanish.

Again, our researchers were involved. Professors Jack Cuzick and Anne Szarewski discovered they could re-test some abnormal cervical samples for the HPV virus to help answer this question. Women with borderline or mildly abnormal cells in their cervix who are also infected with high risk HPV types are at higher risk of cancer, and should be referred for further testing and possible treatment, while women not infected are less likely to develop cancer, so can safely go back to having normal screening every 3 years. This ‘HPV triage’ is now a routine part of cervical screening.

So can the programme be improved further? The next big step is to swap around the order of the tests, so cells collected from women are tested for HPV first, and then examined under a microscope as a follow up. This seemingly small change could have a large impact: research has shown that it could save even more lives than the current test. And it would also mean that women would only need screening every five or six years (instead of three years as in the current programme). This approach is being piloted at the moment, and we’re campaigning to make this a reality for the future.

But while the national screening programme has dramatically reduced the number of women with cervical cancer in the UK, the bigger picture tells us there’s still a lot more to be done.

Worldwide, cervical cancer is the fourth most common cancer in women, and disproportionally affects lower and middle income countries – around 85 per cent of women diagnosed live in regions such as Africa and Latin America where there is little (if any) cervical screening available and poor access to healthcare in general.

HPV is also linked to cancers of the mouth and throat, anus, vagina, vulva and penis. Despite the fact that only a small percentage of people infected with HPV go on to develop cancer, because the virus is so widespread it still accounts for a large number of cancer cases, causing around five in every 100 cases of cancer globally.

But because these cancers are caused by a virus, this brings hope for prevention – through vaccination.

Protecting the next generation

The HPV vaccine had unusual, and agricultural, beginnings. In the 1950s, vets were looking for a vaccine for cattle to protect them from bovine papilloma virus, which can cause tumours in cows.

This research turned out to be relevant to human disease too – our researchers in the Beatson Institute in Glasgow proved that a vaccine containing a molecule very similar to one made by HPV-16 (the commonest cancer causing type) protected calves from infection, providing a robust rationale for developing a human version.

Vaccine

HPV vaccines are now being rolled out across the world

The two scientists widely credited with developing the HPV vaccine are Professor Ian Frazer and Dr Jian Zhou (although there is some dispute over this). The pair came up with the basis of the vaccine in Queensland, Australia, but they met and began their studies on an HPV vaccine in Cambridge while they were working in Professor Lionel Crawford’s lab – Crawford was a Cancer Research UK scientist and an expert on cancer and virology (most famous for his partnership with Professor David Lane and their discovery of p53, the “guardian of the genome”).

Companies bought the rights to produce vaccines commercially and, after trials proved they were effective in preventing the disease. In 2008 the HPV vaccination programme was rolled out across the UK in schools. Now, all girls aged 12-13 are offered a vaccine to protect them against the types of HPV that cause most cases of cervical cancer.

HPV vaccines are now being rolled out across the world. Although it’s too early to show that vaccination has cut cancer rates, promising early results from Scotland, Australia and Denmark show that fewer vaccinated women have abnormal cervical cells (which can turn into cancer) detected during cervical screening compared to unvaccinated women.

Not the end of the story

So vaccination could significantly reduce the number of HPV-related cancers in the future. But not everyone receives the vaccine, so there are still plenty of people who aren’t protected. Furthermore, the vaccine doesn’t offer protection against all the types of HPV that cause cancer. So we urgently need to carry on work to make sure treatments for people who develop HPV-linked cancers are the best they can be.

In fact, it’s possible that vaccines – but not the ones we use at the moment to prevent infection – could help treat people with HPV-linked cancer. A vaccine could help boost an immune response against cancer by targeting molecules made by the virus – similar to an approach being tested for cancers linked to another virus, EBV. We’re supporting researchers in Southampton to work out which HPV molecules are the most potent activators of the immune system – these could form the basis of future treatments.

Another observation that could lead to new treatments is the fact that patients with mouth and throat cancers caused by HPV tend to respond better to therapy than those with similar cancers which aren’t caused by the virus. The increasing numbers of people being diagnosed with mouth and throat cancers raises two questions – firstly, is there a way of testing people for oral HPV infection? And, because people with HPV-linked oral cancer respond well to treatment, could they receive less intensive therapy to spare them some of the side effects, while still keeping the treatment as effective as possible? Trials are underway at the moment to test whether this could be an option.

We’ve come a long way since HPV and its links to cancer were discovered. Thanks to the NHS Screening Programme, thousands fewer women in the UK every year are losing their lives to cervical cancer – something that urgently needs to be addressed in lower and middle income countries. And the introduction of the vaccine will save many more lives in future, protecting people against many types of cancer.

All of these life-saving advances were brought about by years of dedicated work around the world.

And although there’s still a lot to be done before we can say we’ve truly beaten HPV-linked cancers, there’s no doubting how far we’ve come.

Emma

Key references:

  • Dürst M, et al. (1983). A papillomavirus DNA from a cervical carcinoma and its prevalence in cancer biopsy samples from different geographic regions. Proceedings of the National Academy of Sciences of the United States of America, 80 (12), 3812-5 PMID: 6304740
  • Boshart M, et al. (1984). A new type of papillomavirus DNA, its presence in genital cancer biopsies and in cell lines derived from cervical cancer. The EMBO journal, 3 (5), 1151-7 PMID: 6329740
  • Walboomers JM, et al. (1999). Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. The Journal of pathology, 189 (1), 12-9 PMID: 10451482

Image credits: Computer virus image from Flickr and smear test image from Wikimedia Commons

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Emma Smith November 10, 2014

Thanks everyone for your comments and for the points you raised. Here are some responses:

Karen – our nurses might be able to help you with your question – feel free to give them a ring on 0808 800 4040 or via our website https://www.cancerresearchuk.org/about-cancer/utilities/contact-us/send-a-question

Anne – we have another post discussing the age limits set for cervical screening, you can read more about the evidence here http://scienceblog.cancerresearchuk.org/2014/06/09/cervical-screening-is-age-the-only-debate/. We don’t know if screening older women would save more lives, but it’s something one of our researchers, Professor Peter Sasieni is researching currently http://www.cancerresearchuk.org/science/research/who-and-what-we-fund/browse-by-location/london/queen-mary-university-of-london/peter-sasieni-8162.

Susanne and Barry – thanks for your thoughts. We do emphasise elsewhere – e.g. on our website and in our health leaflets – that smoking is a risk factor for cervical cancer. This particular post is a historical look-back at how HPV was linked to cancer and what impact this discovery has made. We still don’t know the reasons why a minority of women develop cervical cancer (or why smoking exacerbates this risk), but it’s something scientists are working hard to understand. The fact that viruses, and cancer cells, can evade the immune system is a very interesting topic and one we might look at covering in more depth in a separate post.

Regards,

Emma
Cancer Research UK

Barry Wilbourn November 10, 2014

Thank you for a very well written and informative article, Emma. However, I also agree with Susanne and would like to learn a little more on how cancer causing viruses – and virally infected cells – can evade the immune system.

My curiosity arises from 2 directions in that for my immunology masters I once wrote an essay on immune surveillance and cancer – it was a contentious issue back then and the EBV story featured heavily in my argument in favour. Also the role of T-lymphocytes were far less well understood and their phenotyping was in its infancy.

Secondly, my very own squamous cell carcinoma of the neck turned out to have a HPV origin.

The good news is that I am 3 years clear, thanks to a wonderfully dedicated oncology team at Southend and the improvement in treatment options over the last 3 decades.

Susanne Johnson November 8, 2014

Great blog. Really nicely written. But the original question:
‘ if most people get infected with HPV at some point, why do just a few of them develop cancer?’
Was not really answered. Not much about how hpv evades the immune system and nothing about smoking and deactivated T lymphocytes. That’s a missed opportunity to remind people how smoking is associated with cervical cancer
The piece was more about how hpv causes cancer and about screening and vaccination.
Excellent though

Anne Hills November 7, 2014

Interesting historical over view. But I’m still puzzled why cervical screening stops at 65.

Karen November 7, 2014

I have had a number of vocal cord operations which were initially “singers nodes” to polyps and latterly papillomas does this mean that I will need to be screened?

Alexandra Rose September 16, 2014

Fascinating and informative. Thank you.

History of Modern Biomedicine Research Group September 16, 2014

Thanks for a great blog piece! Dr Anne Szarewski, who sadly passed away last year, and Professor Jack Cuzick were memorable participants in the Wellcome Witness Seminar on ‘History of Cervical Cancer and the Role of the Human Papillomavirus, 1960-2000′. As a complement to this blog, readers interested in the historical aspects of the research might like to download the transcript of the meeting. A .pdf is available for free from the History of Modern Biomedicine Research Group’s website, here:
http://www.histmodbiomed.org/witsem/vol38