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Link between 'butterfly skin' and squamous cell carcinoma identified

Cells of a cutaneous squamous cell carcinoma (green) that invade the skin. Photo by: Dr. Venugopal Rao Mittapalli, courtesy of the University of Freiburg

Researchers from the University of Freiburg in Germany have identified the connection between the genetic skin condition recessive dystrophic epidermolysis bullosa (RDEB) – often called butterfly skin – and the rapidly progressing cutaneous squamous cell carcinomas (SCCs) that 90 per cent of RDEB patients develop, as well as the molecular mechanisms behind the link

RDEB is caused by a mutation of the gene COL7A1 which normally directs the production of collagen VII. In patients with RDEB, collagen VII, which normally works to bind the dermis to the epidermis, is absent so the patient’s skin become very fragile. Yet, according to a press release from the university (March 10, 2016), not much is known about the molecular mechanisms that connect RDEB to the later development of SCCs.

According to the study, published in Cancer Research (Feb. 15, 2016; 76(4):940-951), the authors analyzed skin samples from RDEB patients, and found evidence that suggested premalignant changes to the dermal microenvironment drive tumor progression in these patients. In particular, the repeated mechanical injury the fragile skin is prone to alters the dermis. The amount of proteins called pro-fibrotic growth factors increases, thereby increasing stiffness of the dermis. This environment permits the tumour cells to spread.

Additionally, the researchers subjected a murine model of RDEB to chemical carcinogenesis. They found that carcinogen-treated RDEB mice developed invasive tumours similar to human RDEB-associated cutaneous SCC, but wild-type mice formed papillomas, which the authors say indicated the aggressiveness of the RDEB-associated cutaneous SCCs is mutation-independent.

The authors found that the dermal instability in RDEB patients and consequent repeat injury increased the bioavailability of tumour growth factor-β(TGF-β), promoting extracellular matrix production, cross-linking, dermal fibril thickening, and stiffening of tissue. All of this contributed to myofibroblast activity and β1/pFAK/pAKT mechanosignalling in tumour cells.

These findings suggest new targets for drug therapy, according to the release. Molecules that inhibit TGF would reduce the stiffness and the spread of the RDEB cancer cells. “The new knowledge we have gained facilitates the design of prophylactic and therapeutic measures for delaying tumour progression and extending cancer-free periods in RDEB,” lead author Venugopal Rao Mittapalli PhD, a research investigator at the university’s medical centre, said.

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