Reduced SMAD2/3 activation independently predicts increased depth of human cutaneous squamous cell carcinoma

Rose, A. M. et al. (2018) Reduced SMAD2/3 activation independently predicts increased depth of human cutaneous squamous cell carcinoma. Oncotarget, 9(18), pp. 14552-14566. (doi: 10.18632/oncotarget.24545) (PMID:29581863) (PMCID:PMC5865689)

Abstract

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.

• Item Type: Articles
• Additional Information: A.M.R. was supported by Cancer Research UK [Clinical PhD Fellowship/Centre grant (A12976) and Postdoctoral Research Bursary for Clinical Trainees (A22912)] and the Academy of Medical Sciences [Starter Grant for Clinical Lecturers (SGL015\1022)]. G.J.I., K.J.P, C.A.H, I.M.L. and C.M.P. were supported by a Cancer Research UK programme grant (A13044) and a European Research Council grant (250170). L.C.S. was supported by Worldwide Cancer Research grant (11-0788).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Inman, Professor Gareth and Spender, Dr Lindsay
• Authors: Rose, A. M., Spender, L. C., Stephen, C., Mitchell, A., Rickaby, W., Bray, S., Evans, A. T., Dayal, J., Purdie, K. J., Harwood, C. A., Proby, C. M., Leigh, I. M., Coates, P. J., and Inman, G. j.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Oncotarget
• Publisher: Impact Journals
• ISSN: 1949-2553
• ISSN (Online): 1949-2553
• Published Online: 22 February 2018
• Copyright Holders: Copyright © 2018 Rose et al
• First Published: First published in Oncotarget 9(18):14552-14566
• Publisher Policy: Reproduced under a Creative Commons License