Zika病毒可以被用来对抗癌症吗?

The 2014 outbreak of Zika virus in Brazil was heralded by a dramatic increase in cases of babies born with microcephaly, a condition characterised by an undersized head and brain, caused by infection during pregnancy. But why the virus targets the nervous system wasn't known. Now scientists at Cambridge University have uncovered the answer and may have serendipitously discovered a means to make safer Zika vaccines as well as a treatment for brain cancer. Taking up the story with Chris Smith was virologist Ian Goodfellow...

Ian - Zika infection during pregnancy can lead to this increased occurrence of microcephaly - children with small heads essentially. We got involved in a collaborative project with some researchers here at the Cancer Research Institute to try to understand why Zika virus causes microcephaly, and essentially, what we found was that Zika virus likes to grow in cells that express a protein known as MSI1. This protein is a regulator of genes involved in neural development. Zika virus likes to infect these neuronal progenitor cells because they have high levels of this protein and, by doing so, it kills those cells.

In fact, if we take normal laboratory cells that don’t express this protein and we try to infect them with Zika, it doesn’t really replicate very well. But if we introduce this protein and then infect them with Zika virus, the virus will replicate very well and will also kill the cells.

Chris - What put you onto the fact that Zika is hungry for this protein in the first place?

Ian - Our collaborators at the C.R.I. identified a family where there were two children born with microcephaly and it turned out these two children had a mutation in this gene (MSI1). This put us onto the idea that maybe MSI1 might be involved in the development of microcephaly. MSI1 is a key regulator for other genes in neuronal development, so when the virus infects those cells it also inhibits the ability of that protein to function so the expression of genes involved in normal brain development is altered by the virus. But, at the same time, it’s also trying to kill those cells it infects.

Chris - The Zika virus comes in, it soaks up this factor in the cells that would normally be necessary for those cells to develop normally as nerve cells. Uses them to encourage the virus to grow and, therefore, pushes the cells off target, they turn into turn into the wrong thing and die, but you end up with Zika virus at the end of it?

Ian - Absolutely, that’s exactly what happens. The one point I’d make as well is that at this point we still don’t know what that protein is doing in the virus life cycle. We know it’s important, but we don’t know exactly what it’s doing. But it is possible potentially in the future if we were able to make a mutated virus that didn’t bind to this MSI1 protein and, therefore, didn’t replicate in the neuronal progenitor cells but does generate a good immune response, we could use that as a potential vaccine and this is something we would like to explore in the future.

Tim - Ian Goodfellow, who wants to prevent Zika infections. But surprisingly, Zika actually might also be useful. Some researchers who are interested in exploiting Zika's tendency to kill brain cells by using it as a weapon to treat certain cancers in the nervous system...

Harry - My name is Harry Bulstrode; I’m a clinical lecturer in the Neurosurgery Department here at Addenbrooke’s Hospital, Cambridge.

The project that I’m working on is based on brain tumours, particularly nasty brain tumours called a glioblastoma. Glioblastomas grow and invade into brain and we operate on these tumours, and remove the tumours, but they invariably recur. So they come back and typically these patients only survive a few months or maybe a year or two, so it’s really a devastating diagnosis.

Part of the reason that these tumours are so nasty, we think, is that they include a population of stem cells - what we call glioma stem cells. When we look at these cells we find that they behave really very similarly to the stem cells in a baby’s brain that cause rapid growth of the brain in the womb. So, as a baby, you need your stem cells to divide and grow very, very quickly and it seems like the cancer is using the same programme that those baby stem cells are using to grow in the adult when it should be switched off.

It seems that the Zika virus is attacking the stem cells in the baby’s brain and that’s why it’s causing small brains and failure of brain development in the baby. It seems that the Zika virus doesn’t attack normal adult brain very much because adults can get Zika virus without becoming severely ill. What that makes us wonder is that whether we might have here a virus that will specifically attack the stem cell population that shouldn’t be present in the adult but is present in adults with brain tumours.

Chris - If you kill off those stem cells using Zika virus, which you might not be able to get at using surgery because you might end up doing devastating damage to the person’s brain to get all of them out, the virus will, effectively, ferret them out for you and where it hits healthy brain tissue again, it will just switch off?

Harry - Yeah. That’s the hope that after any operation for these tumours, there are always a few cells left behind because they’ve invaded so widely in the brain. In fact, in the 1930s when these operations were first being done, people used to cut out half the brain to try and cure these patients, the tumour would still come back in the other half of the brain. So these patients were left disabled and the tumours still come back. What’s clear is that we need to find a new way to get at these stem cells that are hiding in normal brain, and it seems like Zika might offer us some ideas about how to do that.

Chris - How do you envisage actually starting?

Harry - We can grow the stem cells we’re interested in - both the baby stem cells and also the tumour stem cells. We can grow those in dishes and then we can infect them and see what happens. What we can then do is think about developing a mouse model where mice with brain tumours are then treated with the Zika virus to see if the Zika virus can attack the brain tumours in the mouse, and we can begin to see the effect on tumour versus the effect on normal brain.