In 2012 528,000 cases of cervical cancer were diagnosed worldwide. In the same year, more than half this number were estimated to have died as a result of this condition. The cause? A virus of the Papillomaviridae family, specifically one of the High Risk Human Papillomaviruses (HR-HPVs). Although mainly associated with cervical cancer in women, HR-HPVs cause an ever increasing number of head and neck, throat and genital tumours in both sexes.
Human Papillomaviruses lack an envelope, a coat made from the membrane of the host cell, possessing only an icosahedral capsid – a sturdy protein bubble that protects the viral DNA within. Viral DNA hijacks the host’s cellular machinery to produce new viral proteins which both continue virus assembly and cause cancer. It is still uncertain exactly how these proteins interact with our cells to cause cancer but some major players and pathways have been identified. Specifically, scientists believe that two particular proteins (the E6 and E7 proteins) may play an important role in this process.
These two E6/7 macromolecules can be referred as “oncoproteins”. Although quite scary, this term simply defines proteins which are involved in mechanisms that could cause a cell to behave abnormally, increasing the chances of them becoming cancerous. Specifically, these two proteins interfere with a wide variety of mechanisms that will trigger conversion to malignancy. Respectively, they either boost or block the activity of p53, Rb and E2F, three molecules that control a cell’s life cycle.
Considering the huge impact such cancers have on human life, it may seem unusual that we are still in the dark about so many aspects of HPV associated pathophysiology. Our limited knowledge is in part due to constraints implicit in this type of research. Specifically, for obvious ethical reasons, researchers are not able to study HPV associated cancers in living human subjects or deliberately induce cancers in subjects. Therefore, they must rely on model systems when studying these disorders. In the past, researches have used artificial keratinocytes (skin’s cells) and mouse models, to understand how processes work in living tissues. However, this work raises a few questions, such as: How do you compare findings in tissue alone to what you would find in a dynamic and complex living system and how well can we compare mouse models to human conditions?
We now have an answer to these questions, or at least something that marks the start of a deeper understanding. Researchers at the University of Missouri have been able to successfully develop and use living, fruit fly models. Mojgan Padash’s research team injected fruit flies with the E6 protein along with a human-derived one needed by the E6 to function. The first results show that, although abnormalities in the fruit flies’ skin were noticed, another molecule was needed in order to fully trigger cancer. Following the hypothesis that mutations in a human molecule called Ras, a family of “switch” proteins which activate cell growth-specific genes, the team introduced the latter into the fruit flies. Those “simple” abnormalities turned into malignant cancers, just as they would do in humans.
The results, published in the open access journal PLoS Pathogens, allow scientists to monitor biochemical pathways similar, if not identical, to those found in human sufferers. But why flies and not mice? Although further away from humans, sharing only 60% of the human genome against the 97.5% of mice, flies are easier to use than their murine counterpart. Fruit flies are easier to breed (so to quickly obtain new generations) and their genes can be mutated quicker than mice. Moreover, little to no ethical approval is needed to use them (they can be ordered online, with just one click!) and their easier to monitor development allows researcher to effectively model disease development. These fruit fly models, which are continuously refined and developed, have the potential to help in discovering new molecules involved in such processes.
It comes to no surprise that such information could impact heavily on future treatment, and even the prevention of pathologies caused by this increasingly dangerous family of viruses. So, next time you think about killing a fruit fly in your kitchen … maybe think twice.
Post by: Paolo Arru – @viraleclair
Paolo is currently a final year student in Microbiology at the University of Manchester, UK. Science communicator wannabe, he has a keen interest on everything related to HPV, viral oncology and parasitic infections to just say a few. Every bit of his free time is used for planning and getting involved in new projects, baking and getting lost in museums. You can follow him talking about science festivals, geeky stuff and bake off on