Abnormally high levels of P-cadherin – an adhesion molecule that enables cells to bind together – occur in about a third of all breast cancers and are associated with poor prognosis. Portuguese researchers , writing in the journal Oncogene1, found that the reason why these cancers are more aggressive is because excessive P-cadherin changes the cancer cells’ internal organization, making them mobile and invasive (invasiveness is the capacity to cross biological barriers such as membranes). Both these characteristics allow the formation of metastases - which is the spread of cancer cells from the original site of the tumour to other parts of the body - increasing the disease aggressiveness and explaining the poor prognoses associated with P-cadherin. But the research also found that an antibody that blocks P-cadherin can reverse these effects suggesting that treatments based on it can be developed.
Adhesion molecules keep cells together forming tissues and organs. Cancerous cells, on the other hand, are characterised by anomalous cellular division, immortality and most importantly, on the later stages of the illness, by an abnormal motility that allows the spreading of the cancer to other parts of the body (metastases formation).
So it made sense when abnormalities in adhesion molecules were linked to cancer, and many are now being used as markers for specific cancers and/or disease severity. Cadherins are one such family of adhesion molecules and abnormally high levels of P-cadherin - one of its members - have just recently been associated to particularly aggressive breast cancers. However, how over-expression of P-cadherin in the cell membrane can contribute to tumour aggressiveness was not clear and it was an attempt to answer this that led to the work now published by AS Ribeiro and J Paredes from IPATIMUP, University of Porto, Portugal.
For this the researchers developed two cell models of breast cancer: in the first, non-invasive (from cancer patients with no metastases) breast cancer cells were infected with a virus that abnormally increased their P-cadherin, while in the second model, invasive (so capable of forming metastases) breast cancer cells with high levels of P-cadherin were treated to reduce P-cadherin production. The idea was to observe what happened as these cancers cells gained and lost excessive P-cadherin to try to understand the link between P-cadherin over-expression and cancer aggressiveness.
Ribeiro and colleagues found that in the first model, previously non-invasive tumour cells had now became invasive after their P-cadherin levels were increased (antibodies blocking P-cadherin function stopped this effect), while in the second model the effect was the inverse - cancer cells passed from invasive to non-invasive as P-cadherin was reduced. These first results suggested that P-cadherin over-expression worked by triggering breast cancer invasive capacities.
Further analysis showed that P-cadherin over-expressing cells were also much more mobile than those with normal or reduced levels of this molecule, showing mobility patterns similar to invasive tumours and that, under the microscope, also looked very different. The cells with high levels of P-cadherin had now protrusions (tentacle like extensions) and changes in their actin cytoskeleton – the internal framework of the cell – typical of moving cells. Again, an antibody blocking P-cadherin function was able to reverse these changes, confirming that they were linked to over-expression of the molecule.
These results suggested that excessive P-cadherin reorganized cancer cells’ internal architecture making them mobile and invasive, and, by doing this, permitted the spread of the cancer what explained why these tumours are in general so aggressive.
But what are the exact molecular mechanisms involved? This is particularly important as their understanding allows scientists to develop more specific, and so not only less invasive, but also more powerful treatments against the disease.
It is known that for cancer progression the extracellular matrix - which is the outside part of the tissue that provides structural support to the cells within – needs to be destroyed (so the cells can pass through it and spread). Matrix metalloproteases (MMP) are a family of proteins known to do that, which have also been linked to a series of cancers including breast cancer. To investigate if MMPs could be behind the effects of P-cadherin, Ribeiro and Paredes looked at the medium where the cells were growing (as MMPs are released to the exterior of the cell) and, in fact, those cells over-producing P-cadherin were also releasing significant amounts of MMPs.
MMPs have also been linked to cancer cells invasion through the release of pro-invasive soluble fragments from membrane proteins – such as P-cadherin – and only very recently soluble P-cadherin (sP-cadherin) has been found in breast cancer fluids. This prompted Parede’s group to look for sP-cadherin, which they indeed found on the same cells that released MMPs. A MMP inhibitor stopped sP-cadherin production confirming the link between the two molecules.
Finally, Ribeiro investigated if sP-cadherin could directly trigger invasiveness in cancer cells by treating non-invasive cancer cells with medium from over-expressing P-cadherin cells. They found that not only the cells became invasive after the treatment, but also that when sP-cadherin was removed from the medium they remained non-invasive proving that this molecule was the key to the cancer cells transformation.
A capacity to migrate and invade forming metastases is crucial for cancer malignancy. Ribeiro and Parede’s work show that over-expression of P-cadherin - through the production of sP-cadherin - can trigger both processes in breast cancer cells explaining why high levels of this molecule seem to make breast cancers particularly aggressive.
But their work also reveals that antibodies that inhibit P-cadherin or MMPs can block sP-cadherin formation and, as such, might be used in therapy. And if cancer migration and invasiveness are under control then its eradication should be much easier.
At the moment the team of researchers is already studying P-cadherin over-expressing cells in live animals with cancer to confirm their role in the formation of metastases, since all the initial work was done in cells growing in the laboratory. They are also inactivating P-cadherin in these animals to try to control the disease.
"A human antibody has already been developed by the parmaceutical Pizer and is now being tested in several cancers but we still don't know if it works, but now that we understand better the molecular mechanim behind P-cadherin effect treatments can be developed ” says Joana Paredes the team leader
Although the number of deaths has been steadily declining, breast cancer is still the second leading cause of cancer deaths among women, with - according to the American Cancer Society - an average of 1.3 million women a year being diagnosed with the disease (data from 2008). And from these, about a third of the cases show alterations in their P-cadherin expression highlighting the importance of this new research.
1 Oncogene, advance online publication November 2009; doi: 10.1038/onc.2009.338
“Extracellular cleavage and shedding of P-cadherin: a mechanism underlying the invasive behaviour of breast cancer cells “
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