Dissecting the role of basement membrane components in a xenograft model of cutaneous SCC

Contents:

• Project information
• Lay summary

Applicant: Professor Edel Ann O’Toole, Professor of Molecular Dermatology, Honorary Consultant Dermatologist

Institution: Centre for Cutaneous Research, Blizard Institute of Cell and Molecular Science Queen Mary University of London

Grant: £173,877 - (01/01/2011 – 01/05/2015)

Lay summary

Type VII collagen (ColVII) is a molecule which is responsible for adherence of the upper (epidermis) to the lower (dermis) part of the skin. Patients with recessive dystrophic epidermolysis bullosa (RDEB) have reduced or absent levels of ColVII due to a mistake in their DNA. As a result, patients have blistering and scarring of the skin as well as a greatly increased risk of a type of skin cancer, squamous cell carcinoma (SCC). Patients develop SCC in areas of scarring as early as the third decade of life, and many die within 5 years of having their first SCC removed.

In this study the researchers analysed the effect of reduced/absent levels of ColVII on cutaneous SCC behaviour using RNA interference (RNAi), a technique where SCC cells are manipulated in the laboratory to lose ColVII expression. They showed that SCC cells without ColVII had an increased migration and invasion potential suggesting they have a higher tendency to metastasise, i.e. spread to areas outside the skin.

Other aspects related to cancer formation were also seen such as disorganised differentiation (a physiological process where cells in the lower part of the epidermis commit to move towards the surface through progressive changes and is usually deregulated in skin cancer), and abnormal levels of molecules known to “help” cancer cells to invade. A molecule known as TGF-beta seems to be implicated in skin cancer in cells with loss of ColVII. They performed in vivo experiments and were able to demonstrate that cells that don’t express ColVII invade more and express higher levels of TGF-beta and other molecules relevant for cell invasion, confirming previous results.

They have also shown in the laboratory and in in vivo models that loss of ColVII increases angiogenesis, a process where new blood vessels form from pre-existing ones. Angiogenesis has a crucial role in tumour development as it “helps” tumour cells to survive by supplying oxygen and nutrients. The observed changes were confirmed in skin sections from RDEB SCC patients. More recently, they were able to inject human recombinant ColVII (known to be identical to native human ColVII) and revert formation of blood vessels further confirming the role of ColVII in angiogenesis.

They have studied further growth factors involved in angiogenesis and identified Vascular Endothelial Growth Factor as being another important small molecule expressed by skin cancer in RDEB patients.

The work in this study suggests that TGF-beta signalling and Vascular Endothelial Growth Factor may both be targets in RDEB SCC. There are existing drugs targeting both pathways and this group plans to perform further work to see if targeting these pathways will help patients with RDEB SCC. Prof O’Toole and her team published a scientific paper in the Journal of the National Cancer Institute in 2016 describing this work.

The funding from DEBRA UK has really moved forward our research in skin cancer and RDEB.  We are keen to perform further work to see if inhibiting angiogenesis inhibits tumour growth in RDEB. 

Edel O’Toole 

Investigator Biography Edel O’Toole is Professor of Molecular Dermatology and Centre Lead of the Centre for Cell Biology and Cutaneous Research at Barts and the London School of Medicine and Dentistry.  She first became interested in collagen and EB when working with David Woodley at Northwestern University in Chicago.  Her group has worked on RDEB and skin cancer for the last 10 years and continues to work to understand more about skin cancer in RDEB in order to find a better treatment for patients.