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Alterations of Transforming Growth Factor-β Signaling in Squamous Cell Carcinomas

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Signaling Pathways in Squamous Cancer

Abstract

Genetic mouse models have clearly demonstrated that either activation or attenuation of the transforming growth factor-(TGF-)β and the TGF-β signaling pathway can have a major impact on either the genesis and/or the progression of squamous cell carcinomas (SCC) in the epidermis as well as in the head-and-neck region. In general, inactivation of the TGF-β signaling pathway in stratified squamous epithelium promotes the de novo emergence of benign papillomas that have the potential to progress to invasive SCC. On the other hand, activation of TGF-β signaling in established SCC clearly favors their progression to highly invasive and metastatic SCC. Furthermore, a large number of reports of structural and functional alterations in TGF-β pathway components in human SCC cell lines as well as tumor specimens strongly support the idea that this pathway in general, and TGF-β receptors in particular, play an important role in human SCC as well. Attenuation of either Type I TGF-β receptor (TβR)-I or -II signaling promotes SCC development in mice, and mutation and/or loss of expression of TβR-I or -II receptors are commonly seen in human SCC. Thus, approximately 10–15% of head and neck squamous cell carcinoma (HNSCC) display evidence of functional inactivation of TβR receptor signaling, as defined by the absence of pSmad2 and -3 or the presence of an inactivating TGFBR gene mutation. Patients with this tumor type appear to have a particularly favorable clinical outcome. On the other hand, in approximately 40–60% of human SCC TβR expression is reduced but not eliminated. In this context, exposure of the tumor cells to bioactive TGF-β will activate a proinvasive and -metastatic gene expression program, thereby conferring a worse clinical outcome. Therefore, we would like to propose that a structural and functional analysis of the TβR receptors potentially represents a powerful prognostic tool for the management of patients with SCC.

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Abbreviations

DMBA:

7,12-Dimethylbenz(a)anthracene

ECM:

Extracellular matrix

EMT:

Epithelial-to-mesenchymal transition

HNSCC:

Human head-and-neck squamous cell carcinoma(s)

IHC:

Immunohistochemistry

MMP:

Matrix metalloproteinase

SCC:

Squamous cell carcinoma(s)

SSCP:

Single-strand conformation polymorphism

TGFBR1, Tgfbr-1 :

Type I TGF-β receptor gene

TGFBR2, Tgfbr-2 :

Type II TGF-β receptor gene

TGF-β:

Transforming growth factor-β

TPA:

12-tetradecanoyl-phorbol-13-acetate

TβR-I:

Type I TGF-β receptor

TβR-II:

Type II TGF-β receptor

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Authors and Affiliations

  1. Division of Medical Oncology, Department of Internal Medicine, The Cancer Institute of New Jersey, UMDNJ-Robert Wood Johnson Medical School, New Brunswick, NJ, 08901, USA

    Michael Reiss

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  1. Wen Xie
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  2. Michael Reiss
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Correspondence to Michael Reiss .

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Editors and Affiliations

  1. Center for Molecular Toxicology &, Carcinogenesis, Pennsylvania State University, University Park, 16801, Pennsylvania, USA

    Adam B. Glick

  2. National Institute on Deafness &, Other Communication Disorders, National Institute of Health, Bethesda, 20892, Maryland, USA

    Carter Van Waes

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Xie, W., Reiss, M. (2011). Alterations of Transforming Growth Factor-β Signaling in Squamous Cell Carcinomas. In: Glick, A., Waes, C. (eds) Signaling Pathways in Squamous Cancer. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-7203-3_3

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