CANCER RESEARCH UK scientists have discovered the link between people with the skin blistering disease Epidermolysis Bullosa Simplex-Dowling-Meara, (EBS –DM) – and tumour growth, according to research published in Journal of Investigative Dermatology *today (Monday).
Recent research has shown that people with severe EBS have an increased risk of the skin cancer basal cell carcinoma compared with the general population, but scientists did not known why. EBS is caused by mutations in the skin structural protein keratin.
The researchers based at Cancer Research UK’s Cell Structure Research Group at The University of Dundee compared tissue cultures of cells carrying severe keratin mutations with normal cells.
The scientists investigated the molecular events which take place after both sets of cells were damaged mechanically in the lab – to mimic the action of rubbing a person’s skin, which is enough to cause blistering in people with EBS.
Damage to EBS-DM cells causes dramatic changes to cells’ internal scaffolding made of keratin and called the intermediate filaments (IFs). For a long time scientists thought that IFs may play a role in tumour development since alterations in the cells’ structural proteins have already been observed in tumours.
The investigations revealed for the first time that changes in IF structure activate an established cell signalling pathway responsible for cell growth and proliferation, called ERK.
Activated ERK switches on powerful survival signals to stop damaged cells entering programmed cell death – called apoptosis. This causes a greater incidence of tumours in people with EBS-DM because damaged cells continue to grow when normally they would die.
Dr David Russell, Cancer Research UK scientist and study lead author, said: “These fascinating findings show that even slight damage to the skin of people with EBS can kick-start a signalling pathway which prevents the skin from killing and clearing damaged cells.
“Keeping these cells alive may be the body’s way of preserving the protective ‘barrier’ function of skin but we have shown that it may also cause cells to turn cancerous which could explain the increased incidence of basal cell carcinoma in EBS individuals.
He added: “It may also be the case that altered keratin filaments may allow cells to escape more easily which help us better understand how cancers spread.”
Dr Lesley Walker, Cancer Research UK’s director of cancer information, said: “A better understanding of the cell’s structural proteins and the role that they may play in tumour development will provide us with new approaches for cancer therapy.”
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Russell, D., Ross, H., & Lane, E. (2009). ERK Involvement in Resistance to Apoptosis in Keratinocytes with Mutant Keratin Journal of Investigative Dermatology DOI: 10.1038/jid.2009.327
The exact way the mutated keratin molecules activate the ERK pathway is not yet clear. But the scientists confirmed the link between damage to cells carrying the DM-EBS mutation and tumour growth by showing that when the ERK pathway is blocked, or if the production of mutant keratin is blocked, then programmed cell death activity returns to that seen in normal cells.