Reduced SMAD2/3 activation independently predicts increased depth of human cutaneous squamous cell carcinoma
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Aidan M. Rose1,2, Lindsay C. Spender1, Christopher Stephen2, Alastair Mitchell3, William Rickaby4, Susan Bray5, Alan T. Evans6, Jasbani Dayal1, Karin J. Purdie7, Catherine A. Harwood7, Charlotte M. Proby1, Irene M. Leigh1,7, Philip J. Coates5,8 and Gareth J. Inman1
1Division of Cancer Research, School of Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee, Scotland, DD1 9SY, UK
2Department of Plastic and Reconstructive Surgery, Ninewells Hospital and Medical School, NHS Tayside, Dundee, Scotland, DD1 9SY, UK
3Department of Dermatology, Ninewells Hospital and Medical School, NHS Tayside, Dundee, Scotland, DD1 9SY, UK
4Dermatopathology Laboratory, St. John’s Institute of Dermatology, St.Thomas’ Hospital, London, SE1 7EH, UK
5Tayside Tissue Bank, Ninewells Hospital and Medical School, NHS Tayside, Dundee, Scotland, DD1 9SY, UK
6Department of Pathology, Ninewells Hospital and Medical School, NHS Tayside, Dundee, Scotland, DD1 9SY, UK
7Centre for Cell Biology and Cutaneous Research, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, E1 2AT, UK
8Regional Centre for Applied Molecular Oncology (RECAMO), Masaryk Memorial Cancer Institute, Brno, 656 53, Czech Republic
Gareth J. Inman, email: [email protected]
Keywords: TGF-β; IHC; SMAD; carcinoma; FFPE
Received: August 01, 2017 Accepted: February 10, 2018 Epub: February 22, 2018 Published: March 06, 2018
The incidence of cutaneous squamous cell carcinoma (cSCC) is rising. Whilst the majority are cured surgically, aggressive metastatic cSCC carry a poor prognosis. Inactivating mutations in transforming growth factor beta (TGF-β) receptors have been identified amongst genetic drivers of sporadic tumours and murine models of cSCC, suggesting a tumour suppressor function for TGF-β in normal skin. However, paradoxically, TGF-β acts as a tumour promoter in some murine model systems. Few studies have analysed the role of TGF-β/activin signalling in human normal skin, hyper-proliferative skin disorders and cSCC. Antibodies recognising phospho-SMAD proteins which are activated during canonical TGF-β/activin signalling were validated for use in immunohistochemistry. A tissue microarray comprising FFPE lesional and perilesional tissue from human primary invasive cSCC (n=238), cSCC in-situ (n=2) and keratocanthoma (n=9) were analysed in comparison with tissues from normal human scalp (n=10). Phosphorylated SMAD2 and SMAD3 were detected in normal interfollicular epidermal keratinocytes and were also highly localised to inner root sheath, matrix cells and Keratin 15 positive cells. Lesional cSCC tissue had significantly reduced activated SMAD2/3 compared to perilesional tissue, consistent with a tumour suppressor role for SMAD2/3 activators in cSCC. Increased cSCC tumour thickness inversely correlated with the presence of phospho-SMADs in tumour tissue suggesting that a reduction in canonical TGF-β/activin signalling may be associated with disease progression.
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