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Molecular profiling of tumour budding implicates TGFβ-mediated epithelial-mesenchymal transition as a therapeutic target in oral squamous cell carcinoma
The Journal of pathology, 2015-08, Vol.236 (4), p.505-516
2015

Details

Autor(en) / Beteiligte
Titel
Molecular profiling of tumour budding implicates TGFβ-mediated epithelial-mesenchymal transition as a therapeutic target in oral squamous cell carcinoma
Ist Teil von
  • The Journal of pathology, 2015-08, Vol.236 (4), p.505-516
Ort / Verlag
Chichester, UK: John Wiley & Sons, Ltd
Erscheinungsjahr
2015
Link zum Volltext
Quelle
Wiley Online Library
Beschreibungen/Notizen
  • Although tumour budding is an adverse prognostic factor for many cancer types, the molecular mechanisms governing this phenomenon are incompletely understood. Therefore, understanding the molecular basis of tumour budding may provide new therapeutic and diagnostic options. We employ digital image analysis to demonstrate that the number of tumour buds in cytokeratin‐stained sections correlates with patients having lymph node metastases at diagnosis. The tumour bud count was also a predictor of overall survival, independent of TNM stage. Tumour buds and paired central tumour areas were subsequently collected from oral squamous cell carcinoma (OSCC) specimens, using laser capture microdissection, and examined with RNA sequencing and miRNA‐qPCR arrays. Compared with cells from the central parts of the tumours, budding cells exhibited a particular gene expression signature, comprising factors involved in epithelial–mesenchymal transition (EMT) and activated TGFβ signalling. Transcription factors ZEB1 and PRRX1 were up‐regulated concomitantly with the decreased expression of mesenchymal–epithelial (MET) transcription factors (eg OVOL1) in addition to Krüppel‐like factors and Grainyhead‐like factors. Moreover, miR‐200 family members were down‐regulated in budding tumour cells. We used immunohistochemistry to validate five markers of the EMT/MET process in 199 OSCC tumours, as well as in situ hybridization in 20 OSCC samples. Given the strong relationship between tumour budding and the development of lymph node metastases and an adverse prognosis, therapeutics based on inhibiting the activation of TGFβ signalling may prove useful in the treatment of OSCC. Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Sprache
Englisch
Identifikatoren
ISSN: 0022-3417
eISSN: 1096-9896
DOI: 10.1002/path.4550
Titel-ID: cdi_proquest_miscellaneous_1698035093
Format
–
Schlagworte
Antineoplastic Agents - therapeutic use, Biomarkers, Tumor - genetics, Biomarkers, Tumor - metabolism, Carcinoma, Squamous Cell - drug therapy, Carcinoma, Squamous Cell - genetics, Carcinoma, Squamous Cell - metabolism, Carcinoma, Squamous Cell - mortality, Carcinoma, Squamous Cell - pathology, Disease-Free Survival, Drug Design, epithelial-mesenchymal transition, Epithelial-Mesenchymal Transition - drug effects, Epithelial-Mesenchymal Transition - genetics, Female, Gene Expression Profiling - methods, Gene Expression Regulation, Neoplastic, Genetic Predisposition to Disease, Head and Neck Neoplasms - drug therapy, Head and Neck Neoplasms - genetics, Head and Neck Neoplasms - metabolism, Head and Neck Neoplasms - mortality, Head and Neck Neoplasms - pathology, Humans, Immunohistochemistry, In Situ Hybridization, Kaplan-Meier Estimate, Laser Capture Microdissection, lymph node metastasis, Lymphatic Metastasis, Male, MicroRNAs - genetics, MicroRNAs - metabolism, Middle Aged, Molecular Targeted Therapy, Mouth Neoplasms - drug therapy, Mouth Neoplasms - genetics, Mouth Neoplasms - metabolism, Mouth Neoplasms - mortality, Mouth Neoplasms - pathology, Oligonucleotide Array Sequence Analysis, oral squamous cell carcinoma, Phenotype, Polymerase Chain Reaction, Predictive Value of Tests, Reproducibility of Results, Retrospective Studies, Signal Transduction - drug effects, Signal Transduction - genetics, Squamous Cell Carcinoma of Head and Neck, TGFβ, Time Factors, Transforming Growth Factor beta - genetics, Transforming Growth Factor beta - metabolism, tumour budding

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