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.
Highlights
Cutaneous squamous cell carcinoma is the second most common skin cancer and one of the most common human cancers worldwide [1]
Increased cutaneous squamous cell carcinoma (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
formalin-fixed paraffin embedded (FFPE) SB-431542 treated SCCIC4 cells were negative for nuclear PO4-SMAD2 and PO4-SMAD3 staining
Summary
Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer and one of the most common human cancers worldwide [1]. Discrepant are the few studies to examine mediators of TGF-β signalling in normal human skin and cSCC tissue, which report contradictory findings related to the relevance and level of expression of TGF-β ligands, TGF-β receptors and SMAD transcription factors [9,10,11] It remains unclear, when TGF-β signalling might act to prevent or promote tumourigenesis in this disease. Further statistical analysis of PO4SMAD2/3 levels and their association with pathological features of cSCC demonstrate that increasing tumour depth (a known risk factor for nodal metastasis and poor prognosis) independently predicts a reduction in canonical TGF-β signalling activity. These findings suggest that a detectable reduction in PO4-SMAD2/3 levels within a primary tumour may be biologically associated with disease progression
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
