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

Aidan M. Rose, Lindsay C. Spender, Christopher Stephen, Alastair Mitchell, William Rickaby, Susan Bray, Alan T. Evans, Jasbani Dayal, Karin J. Purdie, Catherine A. Harwood, Charlotte M. Proby, Irene M. Leigh, Philip J . Coates, Gareth J. Inman (Lead / Corresponding author)

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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.

Original languageEnglish
Pages (from-to)14552-14566
Number of pages15
JournalOncotarget
Volume9
Issue number18
Early online date22 Feb 2018
DOIs
Publication statusPublished - 6 Mar 2018

Fingerprint

Squamous Cell Carcinoma
Skin
Transforming Growth Factor beta
Inhibin-beta Subunits
Neoplasms
Keratin-15
Transforming Growth Factor beta Receptors
Carcinoma in Situ
Scalp
Keratinocytes
Carcinogens
Disease Progression
Immunohistochemistry
Mutation
Antibodies
Incidence

Keywords

  • Carcinoma
  • FFPE
  • IHC
  • SMAD
  • TGF-β

Cite this

Rose, Aidan M. ; Spender, Lindsay C. ; Stephen, Christopher ; Mitchell, Alastair ; Rickaby, William ; Bray, Susan ; Evans, Alan T. ; Dayal, Jasbani ; Purdie, Karin J. ; Harwood, Catherine A. ; Proby, Charlotte M. ; Leigh, Irene M. ; Coates, Philip J . ; Inman, Gareth J. / Reduced SMAD2/3 activation independently predicts increased depth of human cutaneous squamous cell carcinoma. In: Oncotarget. 2018 ; Vol. 9, No. 18. pp. 14552-14566.
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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.",
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Reduced SMAD2/3 activation independently predicts increased depth of human cutaneous squamous cell carcinoma. / Rose, Aidan M.; Spender, Lindsay C.; Stephen, Christopher ; Mitchell, Alastair ; Rickaby, William ; Bray, Susan; Evans, Alan T.; Dayal, Jasbani; Purdie, Karin J.; Harwood, Catherine A.; Proby, Charlotte M.; Leigh, Irene M.; Coates, Philip J .; Inman, Gareth J. (Lead / Corresponding author).

In: Oncotarget, Vol. 9, No. 18, 06.03.2018, p. 14552-14566.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Reduced SMAD2/3 activation independently predicts increased depth of human cutaneous squamous cell carcinoma

AU - Rose, Aidan M.

AU - Spender, Lindsay C.

AU - Stephen, Christopher

AU - Mitchell, Alastair

AU - Rickaby, William

AU - Bray, Susan

AU - Evans, Alan T.

AU - Dayal, Jasbani

AU - Purdie, Karin J.

AU - Harwood, Catherine A.

AU - Proby, Charlotte M.

AU - Leigh, Irene M.

AU - Coates, Philip J .

AU - Inman, Gareth J.

N1 - 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). 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)

PY - 2018/3/6

Y1 - 2018/3/6

N2 - 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.

AB - 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.

KW - Carcinoma

KW - FFPE

KW - IHC

KW - SMAD

KW - TGF-β

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VL - 9

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