Getting to the root of tumour blood vessels

reposted from: http://scienceblog.cancerresearchuk.org/2013/01/18/getting-to-the-root-of-tumour-blood-vessels/

crabsallover highlights, key points, comments / links.

Posted on January 18, 2013 by Marianne Baker

This entry is part 2 of 3 in the series Microenvironment

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, andpericytes, which support them around the outside.

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

Cancer - the tumour microenvironment

reposted from: http://scienceblog.cancerresearchuk.org/2013/01/11/getting-to-know-the-neighbours-the-tumour-microenvironment/

crabsallover highlights, key points, comments / links.

Getting to know the neighbours – the tumour microenvironment

Posted on January 11, 2013 by Marianne Baker

This entry is part 1 of 3 in the series Microenvironment

Tumour cells don’t live in isolation

Despite the huge progress that has been made over recent decades, more than 150,000 people lose their lives to cancer every year in the UK, usually because the disease has spread through their body.

Understanding why this happens – and how we can treat tumours once they have spread – is crucial if we are to beat cancer.

Cancer is not just one but hundreds of different diseases, depending on where in the body it started and the underlying molecular faults that drive it.

Over the years, many researchers have poured their efforts into understanding individual types of cancer -  such as the recent work from Cancer Research UK’s Professor Carlos Caldas showing that breast cancer can be divided into ten distinct types – as well as searching for the fundamental characteristics of cancer cells (for example, our very own Sir Paul Nurse and Sir Tim Hunt’s Nobel prize-winning work on understanding how all cells divide).

Much of the effort in developing new cancer treatments has focused on identifying and targeting specific molecules in cancer cells – good examples of this approach in action are revolutionary ‘targeted’ drugs like breast cancer drug trastuzumab (better known as Herceptin) and leukaemia drug imatinib (also called Glivec).

But as well as this focus on cancer cells themselves, it’s becoming increasingly clear that tumours are more than just collections of rogue cells. Blood vessels, immune cells and other healthy tissues are hijacked to support a tumour, helping it grow, spread and resist treatment.

Researchers are increasingly turning their attention to this ‘bad neighbourhood’ around a around a tumour, to understand how it can be brought back under control to treat cancer more effectively.

There’s more to cancer than cancer cells

Solid tumours (cancers excluding those affecting the blood) can be thought of as being a bit like a rogue organ in the body, rather than a growing cluster of identical cancer cells.

So modern-day cancer research often involves studying this whole system in order to further our understanding of cancer and tackle it effectively.

All the different types of cells within tumours, the proteins that surround them and the conditions they create together are referred to by scientists as the tumour microenvironment.

This ‘neighbourhood’ includes blood vessels and lymphatic vessels (which carry a fluid called lymph, containing many of the components of our immune system). There are also cells and molecules from the immune system itself, and wound-healing cells called fibroblasts, as well as a sticky protein ‘glue’ (known as the matrix) that supports all of the cells and stops them from drifting apart when they need to be held together.

Can we target the microenvironment to treat cancer?

All of the different parts of the microenvironment play their own roles in helping tumours to grow, and while their importance is still to be fully understood, research is going strong in this area. Through looking in greater detail at the tumour microenvironment, we’ll be able to understand more about how tumours grow and spread, and how we can stop them.

For a personal view from one of our researchers working in this area, check out this interview with Professor Fran Balkwill at the Barts Cancer Institute in London. Professor Balkwill gives us her views on why it’s important to think about treating cancer and its environment together, and why she’s excited about it.

But that’s not all. Because this is such a hot topic in research, we’ve got a series of postscoming up about the tumour microenvironment and its importance in cancer research today, covering blood vessels, cancer spread and inflammation.

Watch out for them over the coming weeks, to find out more about this fascinating and important area.

Marianne

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

Feeling the heat – the link between inflammation and cancer

reposted from: Cancer Research UK

crabsallover highlights, key points, comments / links.

Posted on February 1, 2013 by Safia Danovi

Inflammation is crucial for cancer development

.. the infrastructure supporting a tumour – its ‘microenvironment’ – is a hot topic in cancer research at the moment. In Cancer Research UK previous post in this series, we looked at how otherwise healthy cells collude to form the blood vessels nourishing the tumour. Today, we’ll tell a story that began in 1863, when a German pathologist called Rudolf Virchow peered down his microscope.

Our body’s immune system forms a defensive shield that any fighting force would be proud of. One of its most powerful weapons is inflammation, a carefully orchestrated manoeuvre designed to eliminate enemies such as bacteria, injured cells and chemical irritants. Without it, we probably wouldn't survive beyond infancy.

But inflammation has a split personality – one that can wreak havoc for those unfortunate enough to experience it. And we now know that inflammation’s dark side is a powerful force in cancer development, where it aids and abets tumour growth and spread around the body.

Hell hath no fury

Let’s start with the way inflammation normally works. Our skin constitutes the first line of defence against microscopic invaders. But whenever this barrier is breached, the wrath of the immune system is unleashed – and things get ugly.

As bacteria and other microbes enter the body though an open wound, cells of the immune system (often referred to as ‘white blood cells’) rush to the site of injury, forming the welcoming committee from hell. This highly trained militia gets to work immediately, showering intruders with toxic chemicals, punching holes in their surface or swallowing them whole.

From the outside, this molecular thuggery manifests in swelling, heat, redness and pain – symptoms that anyone who’s ever scraped a knee will be familiar with.

It’s brutal, but it’s over quickly – it has to be, to minimise collateral damage to healthy tissue. As the enemy is eaten and beaten into surrender, signals urge victorious immune cells to return to base camp. Repair and recovery teams move in to direct the process of healing. Blood vessels sprout. A scab forms. Skin grows. And before long, calm returns and it’s back to business as usual.

The heat is on!

While we might not be able to live without it, too much inflammation can cause serious damage.  Chronic, persistent inflammation is behind a host of health problems such as rheumatoid arthritis and psoriasis. And after finding immune cells in tumour samples, Rudolf Virchow was the first to ask whether inflammation might also contribute to cancer.

Unfortunately, he was right – many chronic inflammatory diseases (such as pancreatitis and Crohn’s disease) can increase a person’s cancer risk. And cancers caused by infectious agents (like stomach cancer caused by infection with the bacteria Helicobacter pylori, or liver cancer caused by infection with the hepatitis B or C virus) are characterised by one thing: chronic inflammation.

In the case against inflammation, the evidence is damning.

Rudolf Virchow was the first to link inflammation and cancer

It’s getting hot in here

So how does inflammation lead to cancer? Here’s the current thinking.

When a tiny tumour starts growing from a few rogue cells, it can scavenge enough oxygen and nutrients from its surroundings. But as it grows bigger, demand starts to outstrip supply, and things start getting desperate.

As they struggle to survive, and as they accumulate more and more genetic faults, the cancer cells release chemical signals that lure immune cells called macrophages and granulocytes to infiltrate the tumour.

Once inside the tumour’s inner sanctum, these cells secrete molecules (called cytokines) that kick-start the growth of blood vessels (angiogenesis), which ferry in much-needed oxygen and nutrients.

Other cytokines encourage growth of a sort of cellular ‘pillow’ called the stroma against which the tumour rests. Meanwhile, other inflammatory cells spritz the tumour with molecules (free radicals) that further damage their DNA. Inflammation might also fire the starting gun for metastasis by producing chemicals that help tumour cells nibble through the molecules tethering them to their surroundings.

Taken together, it’s clear that fledgling tumours hijack inflammation and use it to accelerate the progression towards full-blown cancer. As one of our own experts once commented:

“If genetic damage is the match that lights the fire, inflammation may provide the fuel that feeds the flames.”

Stay cool, boy

So how do we turn down the heat? Scientists, including our own are working on how to dampen inflammation, making it much harder for cancers to flourish. They’re hacking into the molecular circuitry controlling inflammation, looking for ways to hotwire the system with next-generation drugs.

But what if we could manipulate inflammation to prevent cancer developing in the first place?Recent results suggest that the answer might be anything but next-generation. In fact, it’s been around since Hippocrates.

Better known to most of us by its brand name aspirin, acetylsalicyclic acid has been used for over a century to quell inflammation, and there’s now a body of evidence highlighting its potential in cancer prevention. While there’s still a way to go to work out who should take aspirin, how much, and for how long, it’s becoming clear that blocking inflammation will play a big role in cancer prevention and treatment in the future.

Rudolf Virchow will never know that his work sparked an entire field of cancer research but thanks to him, the fight against cancer is hotting up.

More on the evidence for use of aspirin to prevent cancer on this Crabsallover blog.

In this series

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<< Getting to the root of tumour blood vessels

More articles like this:

• More on inflammation and bowel cancer
  Just a quick one. We’ve written before about the links between inflammation and cancer, and couched a lot of what we’ve written in all sorts of caveats like ‘may’ and...
• Inflammation and cancer: Sharpin at the sharp end
  It’s taken six years, the development of a new experimental technique and a move from Germany to London, but an international team of scientists, including some funded by Cancer Research...
• Turning up the heat on cancer
  PARP inhibitors have made an appearance many times on this blog. Designed to exploit a genetic “Achilles’ heel” in tumours, they’re currently showing promise in clinical trials for breast, ovarian...

Aspirin Foundation: Aspirin for the elderly to reduce cancer risk - Sarah Lyness - Cancer Research UK

Aspirin Foundation: Aspirin for the elderly to reduce cancer risk - Sarah Lyness - Cancer Research UK

reposted from:

crabsallover highlights, key points, comments / links.

Cancer Research UK seem to be gearing up to recommend a daily dose of aspirin with patients getting advice from GPs and NICE (and CMO?) giving guidance to GPs.


Sarah Lyness, Director of Information at the charity Cancer Research UK, talks to ecancer at the Aspirin Foundation's 'Aspirin for the older person' meeting at the Royal Society of Medicine, London, 3rd November 2011. Given the recent research reported in news about aspirin and cancer prevention, CRUK are looking at the potential for daily doses of aspirin for ages 50-65, patient uptake of preventative aspirin, and ensuring patients are as informed as possible.

Cancer Research UK comment on Peter Rothwell Aspirin & Cancer papers

reposted from: http://scienceblog.cancerresearchuk.org/2012/03/21/aspirin-and-cancer-the-picture-becomes-clearer/ with edits by crabsallover.

crabsallover highlights, key points, comments / links.


Aspirin and cancer – the picture becomes clearer Posted on March 21, 2012 by Jess Harris

Aspirin has been around for over a century. “Should I be taking aspirin to reduce the risk of dying from cancer?”

This is likely to be the question on many people’s minds today, which sees the publication of three reports on the effects of aspirin on cancer risk, and cancer spread – No 1 and No 2 in the Lancet, and No 3 in sister journal Lancet Oncology.

But before we look at today’s studies, we need to set the scene. Over the last few years, the evidence has been building that regularly taking the simple, cheap drug aspirin could reduce the risk of dying from cancer.

For example, a large study by Peter Rothwell from December 2010 showed that people who took 75 milligrams of aspirin (the same dose as in a ‘junior’ aspirin) every day had a reduced risk of dying from cancer.

But these results didn’t answer all the questions, and we felt it was too early to start recommending that people take low-dose aspirin every day. This is because aspirin’s not a harmless drug. In some people it can cause serious side effects, like internal bleeding.

On top of this, it wasn’t clear what the best dose is, or at what age it’s best to start taking aspirin.

Today’s studies clarify the picture a little, but because of the uncertainties we’re still recommending that people discuss things with their doctor before taking aspirin.

What do the latest studies add? The three studies published today were all led by Professor Peter Rothwell at Oxford University, who’s one of the world’s top aspirin researchers.

The studies looked at data from several large trials of taking daily, low-dose aspirin that aimed to find out aspirin’s effect on heart disease, and also measured how many people were diagnosed with cancer.

Preventing cancer Taken together, the studies provided more information about how aspirin affects the risk of cancer developing in the first place.

Earlier studies had shown that aspirin probably reduces the risk of developing bowel cancer, and some other cancers in the digestive system. But this study showed that, after three years of daily low-dose aspirin, the risk of developing cancer at all dropped significantly in both men and women.

In fact, there were nine cases of cancer in every 1,000 people taking aspirin, compared with twelve cases per 1,000 people not taking it – an absolute reduction of three cases per 1,000 people.

The cancers most strongly prevented were oesophageal, stomach, bowel and lung cancers.

Preventing cancer spreading But a new – and somewhat unexpected – finding from this research is that cancer patients taking aspirin every day appeared to have a reduced risk of their cancers spreading.

In fact, not only were regular aspirin-takers less likely to be diagnosed with a cancer that’d already spread, but (compared to non-aspirin takers) patients on aspirin diagnosed with early localised cancers had a lower chance that their cancer would spread later on.

This is important, because when a cancer spreads it is much more difficult to treat, and nine out of ten cancer deaths are due to the disease spreading.

And it also hints that aspirin could be useful for people who’ve already been diagnosed with cancer – though, importantly, this will depend on the individual case.

This is because some cancer patients will also have a higher than normal risk of bleeding, because of their cancer or treatment. So it’s important that people with cancer talk to their doctors rather than deciding to take aspirin by themselves.

Because of these two effects (the reduced risk of getting cancer, and the prevention of it spreading) , the research also suggested that regularly taking aspirin reduced the risk of dying from cancer by nearly 40 per cent after people had been taking it for 5 years.

Balance of risks and benefits 
Finally, and importantly, the studies looked into the balance of benefits and harms of taking aspirin in a healthy population. This is critical, because if people are considering taking aspirin for preventing cancer, we’ve got to be very sure about whether it does good or harm overall.

As the graph below shows, over time, the benefit – lowering cancer risk – increased, while the risk of serious side effects, like internal bleeding, got smaller. Crucially, in the first three years of taking aspirin, the risk of serious internal bleeding was much higher in aspirin-takers than those who weren’t on the drug:

This risk went down over time, and after 5 years of taking the drug, the risk of internal bleeding was back at the same level as people who weren’t on the drug.



Overall, the risk of all the outcomes combined – cancer, serious internal bleeding and major heart and circulatory problems – was lower in the aspirin group. That seems to show the balance could be tipping to the benefit side. Here are the raw numbers:



But that’s not the only consideration – if people stop taking aspirin daily, their risk of a stroke goes up.

And certain people definitely shouldn’t take aspirin, because they’re at higher risk of serious complications. That includes people with asthma, stomach ulcers, haemophilia, or anyone taking other drugs that might interact badly with aspirin.

So what should I do? The first and most important thing is that if you’re considering starting to take aspirin daily, discuss it with your GP first, or your cancer specialist if you’ve been diagnosed with cancer.

In particular, there might be a reason why taking aspirin every day would be a bad idea for you personally – despite what the overall evidence says. And it’s worth discussing the benefits and harms, taking into account your own and your family’s medical history.

And if you do get the go ahead from your own doctor, you should make sure you don’t take aspirin on an empty stomach.

Today’s results are encouraging, and add to our understanding of the effects of taking aspirin daily. But there are still questions to answer. For example:

What is the optimal period of time to be taking aspirin for? At what age does the biggest benefit and smallest risk occur? Who is most likely to benefit, and who is most likely to get side effects? And how can we minimise the risk of a stroke when people stop taking the drug? Cancer Research UK scientists are running trials at the moment that aim to answer some of these questions.

And we’d also like to see some analysis and advice from the Governement about whether aspirin should be recommended more widely.

Until this is the case, taking aspirin should still be a decision you take in consultation with your doctor.

Jess



Cancer Research UK Chief Medical Officer, Professor Peter Johnson:

Search for 'Peter Rothwell' on this blog for more trials results linking aspirin to cancer reduction.

Diet and cancer- the EPIC study

reposted from: http://info.cancerresearchuk.org/healthyliving/dietandhealthyeating/theepicstudy/

crabsallover highlights, key points, comments / links.

Experts think that about a quarter of all cancer deaths are caused by unhealthy diets and obesity.

Our diet influences our risk of many cancers, including cancers of the bowel, stomach, mouth, foodpipe and breast.

You can reduce your cancer risk by eating a healthy, balanced diet that is:

• high in fibre, fruit and vegetables
• low in red and processed meat, saturated fat and salt.

source: http://info.cancerresearchuk.org/healthyliving/dietandhealthyeating/