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This entry is part 2 of 5 in the series Microenvironment

Plant roots

Blood vessels are the ‘roots’ of a tumour. Image source: Wikimedia Commons

In the first of this series we explained how the ‘neighbourhood’, or microenvironment, around a cancer affects how it grows and spreads.

In this next post we’re taking a look at how blood vessels grow into, and feed, a tumour.

Angiogenesis

As we’ve said before, a tumour can be thought of as a ‘rogue organ’ in the body – not one that is useful to us, but one that has the same requirements as any other. This includes a network of blood vessels (vasculature), supplying the cancer cells with oxygen and nutrients, and removing waste products. And, in the case of cancer, enabling it to survive, grow, and spread around the body.

But while the blood supply feeding our healthy tissues grows as we develop in the womb, a tumour has to ‘plumb in’ its own blood supply from nearby blood vessels – a process known as angiogenesis.

And because angiogenesis is so fundamental to how cancers grow and spread, it’s an exciting focus for cancer researchers all over the world.

Getting to the root of the problem

Cancers are a bit like weeds in the garden – they look like their neighbours but take up space and out-compete other plants, and have the potential to run riot over the entire garden if left uncontrolled.

As all good gardeners know, the best way to get rid of weeds for good is to destroy their roots. Fail to do this, and they’ll just start growing again.

In a similar way, blood vessels are the ‘roots’ of a tumour, feeding it and allowing it to grow bigger. Targeting these roots and cutting off the blood supply should therefore be a good approach for treating cancer.  And that’s exactly what many researchers in the field of tumour angiogenesis are trying to do.

Targeting tumour blood vessels

The idea of targeting blood vessels to treat cancer is based on the discovery that most blood vessels in adults are quiescent - in other words, they’ve done all the growing they need to and have then stopped.

But there are a couple of exceptions.  Every month, new blood vessels grow in a woman’s uterus during her menstrual cycle. And every time a cut heals, new vessels grow back during that process. But (in theory at least) treatments targeting new blood vessel growth should be relatively free of side-effects, because they’re designed to target the growing blood vessels in tumours and not the established quiescent vessels.

Also, the components of blood vessels within tumours aren’t actually cancerous themselves – they’re healthy cells that have been hijacked by a cancer to do things they usually wouldn’t. This means they should be less likely to develop resistance to treatments, because they’re less able to mutate and evolve in the same way as cancer cells. So – at least in theory – this seems like another plus point.

Some drugs that target tumour blood vessels have already been developed, including “first generation” therapies such as bevacizumab (Avastin), which blocks a molecule called VEGF that is produced in large amounts by tumours to provoke angiogenesis.

Unfortunately, bevacizumab didn’t show the impressive results in cancer patients that might have been expected from early lab studies (although it fared better in combination with other chemotherapy drugs). And these types of drugs haven’t had as few side effects as researchers had hoped.

In the 30 years since VEGF was discovered, many Cancer Research UK scientists have contributed to our growing understanding of how it – along with a multitude of other molecules – is important in angiogenesis. As a result, rather than focusing on VEGF alone, other molecular messengers can be targeted at the same time to try to avoid resistance and increase the drugs’ effectiveness. “Second/third generation” anti-angiogenic therapies such as sunitinib (Sutent) and sorafenib (Nexavar) have made it to the clinic, but researchers are still working out how best to use them.

So while the idea of blocking blood vessel growth once seemed straightforward, the reality turned out not to be quite so simple. But why?

What’s so special about tumour blood vessels?

Researchers now think that the key to targeting blood vessels in tumours lies in understanding what makes them different from healthy ones. While the cells that make up tumour blood vessels are themselves quite normal (in that their genetic information isn’t damaged like it is in cancer cells) the blood vessels as a whole are very messed up.

There are two main types of cells that make up the tiny blood vessels (called capillaries or microvessels) found in tumours: endothelial cells that line the walls of vessel tubes, and pericytes, which support them around the outside.

A Roman Phalanx

A Roman Phalanx – a little bit like blood vessels. Image source: Wikimedia Commons

In healthy capillaries, these cell types are quite well-organised. The endothelial cells fit together like the shields of a Roman phalanx and the pericytes support them at key points, helping to stabilise the structure.

But inside tumours, there are big gaps in the walls of the capillaries.  Endothelial cells come and go as they please, sometimes the pericytes don’t show up to help out, and sometimes even cancer cells get involved and pretend to be endothelial cells. The tubes have irregular sizes and are chaotically organised, twisting tortuously about instead of lining up neatly like healthy capillaries.

This makes a tumour’s blood vessels very leaky and inefficient, causing them to release signals that drive even more blood vessel growth to feed the growing tumour in a vicious cycle.

Unexpected effects

To try and understand the disappointing results of anti-angiogenic drugs, scientists took a closer look at what was happening to blood vessels inside tumours in response to the treatment. What they found was unexpected (although our researchers Alan Le Serve and Kurt Hellmann had actually predicted this might happen back in the 1970s). Instead of destroying tumour blood vessels, anti-angiogenic drugs seem to make the strange and disordered capillaries become more normal.

At first, people thought this spelled disaster for the whole concept of anti-angiogenic therapy – surely if the treatment makes the tumour blood vessels better at their job, the cancer will just grow and spread faster. This is the opposite of what doctors and their patients want!

But on closer inspection, this ‘normalisation effect’ actually looks like it might be a positive thing – if we can catch it at just the right time. Here’s why:

  • Making tumour blood vessels better at delivering nutrients and oxygen to the tumour can have positive effects on some cancer treatments. For example, if chemotherapy is given together with anti-angiogenics, the more efficient blood flow means more of the chemo drug can get to more of the cancer cells to kill them. This explains why drugs like bevacizumab seem to work better when given alongside chemo.
  • Because of their disorganised blood supply, many tumours have relatively low oxygen levels – a phenomenon known as hypoxia – which seems to protect cancer cells from being destroyed by radiotherapy. Stabilising blood vessels means that more oxygen gets into the tumour, raising oxygen levels inside it. This could help to make radiotherapy more effective.
  • As tumour blood vessels become more normal, they seem to attract more supporting pericytes, which help to secure capillaries against wandering cells. Some researchers have shown that this could reduce the risk of cancer spreading (metastasis), which happens when cancer cells enter the bloodstream and travel to another site in the body. If entering blood vessels becomes more difficult for cancer cells, this could be a good way to protect against cancer spread.

Combining all these things together, it seems that while anti-angiogenics might not be useful in the way we originally thought (by killing blood vessels and starving tumours), they might instead make the other kinds of treatments even more effective.

Where next?

Researchers all over the world – including those funded by Cancer Research UK – are now applying these new insights in the hunt for life-saving cancer treatments. Here are just a few examples of our pioneering work in this area:

  • Professor Kairbaan Hodivala-Dilke at the Barts Cancer Institute in London is determined to bring cancer therapies based on angiogenesis to the clinic. Work in her lab looking a Down’s syndrome – a phenomenon apparently unrelated to cancer – has helped us understand more about tumours and blood vessel growth.
  • Professor Adrian Harris heads a team at Oxford University. Their cutting-edge research aims to uncover more about how tumours attract a blood supply and the characteristics of low-oxygen tumour environments, turning this knowledge into improved cancer therapies. Professor Harris’ work has contributed to our current understanding of the famous blood vessel growth-stimulator VEGF, and another molecular messenger called delta-like 4 (DLL4). Their research has also picked apart other key features of tumours such as hypoxia and prompted the development of new cancer treatments.
  • Professor David Tuveson, who until recently was based at the Cancer Research UK Cambridge Research Institute, made a big step forward in understanding the role of blood vessels in pancreatic cancer – a  deadly disease for which new treatments are urgently needed.

In pancreatic cancer, the tumour cell environment is very dense. The leakiness of blood vessels leads to a very high fluid pressure within the tumour that collapses capillaries and makes blood flow almost non-existent. This means that chemotherapy drugs (which are carried in the bloodstream) simply can’t get into the tumour.

Professor Tuveson’s team found that the solution to this problem may lie in using a combination of drugs, including one that breaks down the dense packing within the tumour. This helps to open up the tumour blood vessels, allowing chemotherapy drugs to get through.

Hope for the future

Researching anti-angiogenic therapy has been somewhat of a rollercoaster of hope, disappointment and renewed optimism.

At first it seemed like a hugely promising target for all solid tumours, then the results from the clinic didn’t live up to expectations. Now it appears they could be really effective after all, but maybe not in the ways we expected. Only further research can tell us exactly how these potentially powerful therapies can be put to work to beat cancer.

But blood vessel growth isn’t the only area we’re seeing interesting developments in: there’s also the immune system, and cancer spread, so watch this space for more posts on the tumour microenvironment.

Marianne

  • Marianne Baker did her PhD at Barts Cancer Institute, funded by Cancer Research UK

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