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Between a ROCK and a hard place: how changing the surrounding tissue helps tumours to grow

Posted Jun 14 2011 12:00am

For many people, the first sign that they have cancer is the appearance of an unusual lump or bump .  But this isn’t just due to a growing collection of cancer cells. In fact, cancer cells cause changes in the tissue around a tumour, making it stiffer and firmer, eventually forming a hard lump.

In a paper published in the journal Cancer Cell this week, Cancer Research UK scientists have made an important step forward in understanding how this happens. And their discovery could potentially lead to new approaches for treating cancer by targeting the stuff around it, rather than the cancer cells themselves.

Here’s Professor Michael Olson from our Beatson Institute for Cancer Research in Glasgow, explaining more about his team’s new findings:

Link to transcript

The collagen connection

The stiffness that can be felt around tumours is due to increased levels of a protein called collagen, produced as the tissue around the cancer cells responds to their presence.

More often in the news for its role in cosmetic enhancement (such as the infamous ‘ trout pout ‘), collagen gives structure to our skin by creating a mesh of tiny interlocking strands. In the case of tumours, extra collagen creates a scaffold for the growing tumour cells, providing a stable structure on which they can grow and spread.

But despite the fact that the lumpy nature of cancer is one of the most obvious symptoms of the disease, relatively little is known about how the molecular scaffold that supports it is created and controlled.  So Professor Olson and his team set about finding out.

Molecular Meccano

The researchers focused their attention on a protein called ROCK , which was already known to play an important role in shifting the shape of the internal skeleton inside cells, known as the cytoskeleton.  Like a set of Meccano , the cytoskeleton is made up of sturdy struts that can be rearranged and bolted together in different conformations when a cell needs to grow, change shape or move.

Scientists have previously discovered that cells make more ROCK when they’re put under stress – for example, when they’re squeezed or stretched. This often happens as tumours grow or when cancer cells break away and start moving through the body, so ROCK is thought to be pretty important in the growth and spread of the disease.

To find out whether ROCK was playing a part in changes in structure outside a tumour – as well as inside the cells – the researchers used mice that produced ROCK in the skin when they were given a harmless drug.

The team discovered that patches of skin where ROCK had been turned on were much thicker and stiffer than unaffected areas and contained much more collagen than expected, even though there were no tumours present. This was an intriguing result – how could proteins that control the molecular Meccano inside cells be having an effect on their surroundings?

Finding the link

To find an answer, the team turned their attention to another protein – beta-catenin , which helps cells to respond to mechanical stress such as squashing or stretching by turning on particular genes.

When they looked at samples of skin tissue where ROCK had been switched on, the researchers discovered evidence that beta-catenin was highly active, switching on genes that make skin cells grow and multiply, causing the thickening and stiffening that the team had seen.

When the scientists checked samples from mice lacking beta-catenin, they didn’t see any of these genes switched on, strongly suggesting that beta-catenin was playing a vital role in making the skin cells multiply. But a lack of beta-catenin didn’t stop the build-up of extra collagen in the skin, suggesting that the two processes are separate

Finally, the scientists tested whether switching on ROCK was involved in the development of cancer. They discovered that switching on ROCK in the skin greatly increased the chances that non-cancerous skin lumps, known as papillomas , would turn into tumours. But when ROCK’s actions were blocked with an experimental chemical, fewer cancers developed and the amount of collagen in the surrounding skin was reduced.

Based on these results, it looks like the stretching and squeezing that happens when a tumour grows is switching on ROCK in the cancer cells (and probably the cells around them), leading to thickening and stiffening of the surrounding tissue and excessive production of collagen. This provides a scaffold for the cancer which, in turn, encourages more tumour growth.

Where next?

At the moment, this research has only been done in the lab, so it’s not yet clear exactly how the findings will translate into human cancers.

However, the researchers did study samples of skin tumours taken from 40 patients and found unusually high levels of ROCK. But it’s important to point out that’s no solid guarantee that ROCK is causing the same skin thickening in human cancers as in mice.  So the next step will be to study samples taken from cancer patients in greater detail, to find out whether the same processes are at work.

Finally, Professor Olson and his team found that switching off ROCK could prevent the development of tumours. This raises and intriguing possibility – that it might be possible to treat or prevent cancer by targeting the biological processes that remodel the tissue around a tumour as it grows, rather than going for the cancer cells directly.  Right now this is still speculation, but it’s an exciting avenue for future research.

Kat

Reference:

Samuel MS et al (2011). Actomyosin-Mediated Cellular Tension Drives Increased Tissue Stiffness and β-Catenin Activation to Induce Epidermal Hyperplasia and Tumor Growth. Cancer cell, 19 (6), 776-91 PMID: 21665151

 

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