Image Source: Serial/Trash
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.
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.
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.
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.
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.
Image Source: Shutterstock Copyright: Lightspring
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.
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.
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.
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.
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 funders. The 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.
