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Stopping the spreading of tumours, a possible new therapy? (05/2007)

Scientists in Portugal and Germany report of research that suggest a new therapy to control the spread of tumour cells to new tissues, a process known as metastasis and that is associated with high risk of a fatal outcome. The research, to appear in Human Molecular Genetics, describe how the chaotic, increased motility of some tumour cells, known to be crucial for metastases, can be linked to the aberrant activation of a molecule called epidermal growth factor receptor (EGFR). It also shows how inhibition of this activation reverts high motile cells into a normal benign pattern of motility. The research suggests that EGFR inhibitors, which are readily available in the market, could be a potential new therapy in the control of metastases in some type tumours.

Cell survival depends on a constant string of signals from the environment, including those from adhesion molecules that assure that the cells are bound together within tissues and organs. Disappearance of these signals leads to death, preventing the cells of migrating and growth in places where they have no physiological role and could even do harm. But tumour cells can detach themselves and move to other tissues- a process known as metastasis -  and it has been shown that mutations in adhesion molecules can facilitate this process.

E-cadherin is one such example; an adhesion molecule present on epithelial cells that when mutated is linked to many cancers and the major determinant of tumour progression and invasion in epithelial ones. It also has been shown that cells that loose E-cadherin show chaotic, high mobility , which is associated with metastases and disease spreading in cancer. Studies of E-cadherin mutations are particularly relevant because of their contribution to metastases, which are associated with as much as 90% of all fatal cancer cases, but also because 80-90% of tumours originate from epithelial cells, even if most result from accumulation of several mutations in many different genes. 

But if the exact molecular mechanisms behind cancer progression upon E-cadherin mutations were not clear its interaction with several proteins involved in cell signalling – whereby cells detect and respond to external stimuli - including EGFR was well known. EGFR, like the name indicates, is involved in the regulation of cell growth, division and differentiation - making it particularly interesting since cancer is defined as an abnormal and uncontrolled cell division - and is also known to affect cell migration, which we know is altered in some E-cadherin mutated cells. All this led Ana Rita Mateus, Gianpaolo Suriano, Raquel Seruca and colleagues at Porto University, Portugal and at Technical University of Munique, Germany to ask if the abnormal motility of E-cadherin mutated cancer cells could be associated with EGFR.

In order to study this, the team of researchers analysed cells with mutated or normal E-cadherin looking at their interaction with EGFR. Because it has been previously suggested that EGFR interacts with the extracellular part of E-cadherin (E-cadherin is found across the cell membrane with part inside and part outside of the cell) it was decided to test 4 different mutations: 2 affecting the extracellular (out of the cell) part of molecule and 2 affecting the intracellular (inside the cell) region. All mutations were known to cause hereditary diffuse gastric cancer and reduce E-cadherin adhesion abilities but only those cells with extracellular mutations showed abnormal motility with random increased movement . As suspected, it was found that only the mutations in the extracellular part of E-cadherin affected the interaction with EGFR confirming that this as the area where contact occurred.

When the interactions between the different E-cadherins and EGFR were analysed, researchers found that in those cells with extracellular mutations (and aberrant motility) EGFR was very activated, but this did not occur in cells with normal or extracellular E-cadherin mutations. It is known that EGFR, which is found on the cell membrane, is activated by binding epidermal growth factor (EGF) leading to the stimulation of a series of molecules and pathways linked to DNA synthesis and cell proliferation that affect processes as diverse as cell migration, adhesion and also cell proliferation.

Mateus and colleagues’ results - where extracellular E-cadherin mutations disrupt the binding of this molecule with EGFR and result in an abnormal activation of EGFR - suggest that the intact molecules of E-cadherin control EGFR activation by binding to it and making it unavailable to EGF. It also suggests that is EGFR abnormal activation that is behind the dramatic mobility changes in extracellular mutated cells.

And in fact, it was then found that if EGFR activation was inhibited, cells with extracellular E-cadherin and the abnormal movements associated with metastases reverted into a normal pattern with restricted linear movements, very different from those found on high motile cells.

In result of their experiments, Mateus and colleagues suggest that while E-cadherin normally binds to EGFR blocking its availability to EGF and consequently its activation, in cells with extracellular mutations this interaction is disrupted and EGFR becomes (abnormally) high activated stimulating a series of pathways that result in the aberrant chaotic movements. In patients carrying such E-cadherin extracellular mutations this mechanism is likely to contribute to a worse prognosis..

Remarkably, Mateus and colleagues’ study also shows that by preventing EGFR activation the normal motility of these cells can be restored, suggesting a possible new therapy against tumour spreading in patients with this type of mutations.

Metastases are associated with high-risk cases as they are behind tumour spreading and to understand and reverse the molecular mechanisms behind their formation is a major step to increase patients’ chances. By specifically targeting metastases development (after removal of the first cancer site) we can avoid the limitations and serious side effects of more aggressive and less-specific treatment approaches such as chemotherapy and surgery, giving patients not only a better survival chance but also a better quality of life.

It is interesting to note also that the researchers show that not all E-cadherin mutations (extracellular versus intracellular mutations for example) facilitate the cancerous process in the same way, what means that patients with different mutations, even if in the same molecule, might need different therapies.

 1 Human Molecular Genetics 2007advance online publication (14 May 2007)

EGFR regulates RhoA-GTP dependent cell motility in E-cadherin mutant cells


Authors of the original paper

Ana Rita Mateus - amateus@ipatimup.pt

Gianpaolo Suriano - gsuriano@ipatimup.pt

Raquel Seruca - rseruca@ipatimup.pt

Link to the original article–  http://hmg.oxfordjournals.org/cgi/content/abstract/ddm113


In collaboration with the Observatório da Ciência e do Ensino Superior (OCES)
Financed by the Fundação para a Ciência e Tecnologia (FCT)