24.11.2011 -

By Monica Rio

 

Every year more than 3,500 women in Italy are diagnosed with cervical cancer, and unfortunately, around 1000 of them will die because the treatments currently available are unable to cure the disease. In the world, 250,000 women die from this form of cancer, caused by the Human Papilloma Virus (HPV), every year. The scientific community has been studying this virus for a number of years and five years ago two vaccines were developed to prevent infection. While prevention is, of course, incredibly important, it is not a cure. Research must develop more effective treatments and new medicines if cervical cancer is to be beaten.

 

On the front line in the fight against the disease is a laboratory at the International Centre for Genetic Engineering and Biotechnology in Trieste. For years, the Tumour Virology Laboratory, led by Lawrence Banks, has been conducting cutting-edge research into the Papilloma Virus and the mechanisms which cause tumours to develop.

 

The laboratory has recently been awarded a research grant of €400,000 by the Wellcome Trust Foundation, a prestigious British institution which, over the last 75 years, has funded some of the most brilliant minds in biomedical research. Surrounded by test tubes, centrifuges and microscopes, we meet Banks in his laboratory and ask him to tell us more about the disease and about his research.

 

 

«The Papilloma Virus is sexually transmitted and affects around 50% of young women in the 20 to 24 age range, and 25% of 14 to 19 year olds. It is the most common sexually transmitted infection in the world, and 291million women are carriers. However, not all of them will become ill- only a small percentage will go on to develop cervical cancer in 10 or so years' time.»

 

Could the mass vaccination of all young women prevent HPV transmission and, in turn, tumours?

Yes. But let's look at a real example. Italy was one of the first European countries to implement a public vaccination campaign. The campaign began in 2008, and by the year 2012, 95% of all girls born in 1997 will have been vaccinated. However, all other women are still at risk of contracting the virus and the vaccine does not protect women who have already been infected. Vaccination can't be seen as the full and final solution, especially for developing nations where the distribution of the vaccine encounters enormous economic and logistical problems.

 

So, is the aim of your research to find new treatments?

I've been working on the Papilloma Virus since I first joined the ICGEB in 1990. Since then, I and my team have studied the molecular biology of HPV and the mechanism of action of the virus' two main cancer causing proteins, E6 and E7. This is a three-year, international project funded by Wellcome Trust, and we'll be working with Dr Sally Roberts from the Department of Cancer Studies at the University of Birmingham. The aim of our research is to understand the role of the oncogenic interactions of HPV E6-Pdz in the viral life cycle and in the malignant tumours caused by HPV.

 

During our previous studies, we noticed that one of these viral proteins, E6, is involved not just in primary tumour development but also in the development of metastases and their spread throughout the body. It seems that E6 works on healthy host cells inhibiting the production of oncosuppressors - substances which stop a tumour spreading between cells. To be more specific, in the cytoskeleton of the host cells we find Dlg and Scrib proteins which normally work as oncosuppressors.

 

E6 binds itself to these proteins, it stops them working, destroys the cell's defences and causes the growth of a tumour. Sometimes, though, instead of working as oncosuppressors we've actually seen Dlg and Scrib becoming oncogenes, and when they bind to E6, it seems to become even more powerful and they become accomplices in the growth of a tumour.

 

So, is it like the cell defences become deserters? Do they go over to the enemy side?

Yes, in a way they do. That's why we want to find out more about why these proteins sometimes behave like this and why, when they do, they cause more aggressive forms of cancer.

 

So are you going to study the interaction between E6 and the host cell's Dlg and Scrib proteins for the next three years?

We need to understand what causes these proteins to turn from oncosuppressors into oncogenes and whether there is a correlation between this and the stage of development of the tumour: maybe in the initial stages Dlg and Scrib are defenders and only become accomplices at a more advanced stage. We know that E6 uses a specific area to bind itself to the proteins in the host cell, a short strip of amino acids known as Pdz. On animal models in the lab we've seen that when we introduce a mutation in this region (E6-Pdz), E6 is much less efficient and so less able to cause a tumour to develop.

 

A mutation in this region also compromises the virus's ability to replicate itself within the cells of the uterus and spread the infection. So it's essential for us to investigate further the roles played by Dlg and Scrib and the E6-Pdz region, both during the normal life cycle of HPV and in the onset and development of cervical cancer, so that we can identify a specific molecular target for new gene therapy techniques and to develop new, more effective medicines.

 

The Papilloma virus is responsible not just for cervical cancers, but also for the development a number of other malignant tumours: bowel, throat, oesophagus, brain and skin cancers … will the results of this Wellcome Trust funded research project also have implications for these other HPV-caused cancers?

Absolutely. As we said before, both the survival and spread of HPV are controlled by its E6 and E7 proteins. Understanding the molecular mechanisms at the heart of E6's actions means understanding the secrets of the virus's pathogenesis, and that in turn means being in a position to deactivate HPV's 'weapons' and stop the development of cancer, in whatever organ has been infected.