Wednesday, 30 April 2014

A two-pronged attack to stop cancer in its tracks

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Cancer results from an accumulation of mistakes or abnormalities in genes that normally control cell survival, growth and migration. Genes are the instruction manual for our cells, and when these instructions are altered cells may begin to multiply (proliferate) uncontrollably. The resulting mass of new cells forms the primary tumour, and when this tumour outgrows the site in which it developed it begins to migrate in search of other suitable tissues within the body to support its growth. This spread, also called metastasis, allows cancer to disperse throughout the body, making it harder to treat and worsening the prognosis for the patient.

Drug treatments for cancer aim to either kill the abnormal cells or to prevent their growth and spread so that they are easier to treat using physical methods such as surgery and radiotherapy. One way to do this is to interfere with the chains of molecular messengers, called pathways, within the cell that are responsible for directing these processes. MEK is one such molecular messenger that plays a central role in cell growth and proliferation. MEK can be blocked by a range of drugs, and several of these have been tested against cancer in clinical trials, however there was limited evidence of a beneficial effect when only this one messenger was targeted.

A recent study by a team at the University of Manchester investigated the possible reasons for these disappointing results using a lab-based experiment. They grew a ball of human malignant melanoma (skin cancer) cells and embedded it in a gel made from collagen. Collagen is one of several proteins that act as a scaffold in the body to support cells within their tissues. Using this experimental system they were able to study these human cancer cells in a 3-dimensional environment that is representative of a real-life tumour and its surroundings.

First of all they exposed this artificial tumour to a drug that blocks MEK (selumetinib) and found that, as in previous experiments, some cells died and the proliferation of the remaining cells was almost completely prevented. Unexpectedly, however, it encouraged these surviving cells to migrate away from the original mass and through the collagen. Therefore blocking MEK alone could promote the spread of cancer throughout the body, which is an undesirable outcome because it makes it more difficult to treat. To overcome this problem the researchers looked for a way to prevent this migration, and in order to find a suitable target they first needed to find out how the cells were moving.

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Their investigations revealed that the cells were using a method called ‘mesenchymal’ invasion to migrate through the collagen, which involves two processes. The first is the disruption of the surrounding collagen scaffold by the release of molecules that break bonds in the protein chain, facilitating movement of the cells through it. The second involves binding of the cell surface to the collagen via adaptor molecules at so-called focal adhesion sites. These sites act like anchors, allowing the cells to pull forwards against them in order to pass through.

Now they knew how the cells were moving the team set about trying to stop them. One important regulator of adhesion-based migration is a molecular messenger called SRC kinase, which is over-active in many cancers, including the cancer cells used in this experiment. Using the same 3D tumour model, the researchers found that by using a drug (saracatinib) to block SRC kinase they could prevent the migration of cells through the collagen in which they were suspended, although it did not slow down their proliferation. A stain that highlights the presence of focal adhesion sites revealed that this drug prevented migration by reducing the formation of these anchoring points between the cells and the collagen.

Finally, by combining the MEK-blocking selumetinib and the SRC kinase-blocking saracatinib the researchers were able to successfully prevent both the growth of the artificial tumour and the spread of the melanoma cells through the surrounding collagen.

This research has important implications for the development of new anti-cancer drugs. Research into these drugs is increasingly aimed at targeting specific messengers in pathways that are important for the survival, growth and spread of cancer cells. Finding out which particular genes or messaging pathways are affected in each individual cancer can build up a ‘fingerprint’ that makes it possible to target these treatments only at those tumours that are likely to respond. However this research highlights that it is vital that we understand the consequences of targeting each of these messengers on its own. Cancers are highly adaptive, therefore combination therapies that attack more than one aspect of the cancer’s survival mechanisms are more likely to be successful and less likely to cause unwanted side effects than therapies with only a single target.

This summary by Clare Finlay was shortlisted for Access to Understanding 2014 and was commended by the judges. It describes research published in the following article, selected for inclusion in the competition by Cancer Research UK:

PMCID: PMC3378628
J. Ferguson, I. Arozarena, M. Ehrhardt & C. Wellbrock.
Oncogene (2013) 32(1), 86-96.

Access to Understanding entrants are asked to write a plain English summary of a research article. For Access to Understanding 2014 there were 10 articles to choose from, selected by the Europe PMC fundersThe articles are all available from Europe PMC, are free to read and download, and were supported by one or more of the Europe PMC funders.

Look out here and on Twitter @EuropePMC_news for further competition news and other Europe PMC announcements.   

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