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Molecular profiling of tumour budding implicates TGFβ-mediated epithelial-mesenchymal transition as a therapeutic target in oral squamous cell carcinoma

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@article{4395101cea374e09bd9dae20412fcca2,
title = "Molecular profiling of tumour budding implicates TGFβ-mediated epithelial-mesenchymal transition as a therapeutic target in oral squamous cell carcinoma",
abstract = "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 Kr{\"u}ppel-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.",
keywords = "Antineoplastic Agents, Biomarkers, Tumor, Carcinoma, Squamous Cell, Disease-Free Survival, Drug Design, Epithelial-Mesenchymal Transition, Female, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Genetic Predisposition to Disease, Head and Neck Neoplasms, Humans, Immunohistochemistry, In Situ Hybridization, Kaplan-Meier Estimate, Laser Capture Microdissection, Lymphatic Metastasis, Male, MicroRNAs, Middle Aged, Molecular Targeted Therapy, Mouth Neoplasms, Oligonucleotide Array Sequence Analysis, Phenotype, Polymerase Chain Reaction, Predictive Value of Tests, Reproducibility of Results, Retrospective Studies, Signal Transduction, Time Factors, Transforming Growth Factor beta",
author = "Jensen, {D H} and E Dabelsteen and L Specht and Kanstrup, {Anne-Marie Fiehn} and Therkildsen, {M H} and L J{\o}nson and J Vikesaa and Nielsen, {F C} and {von Buchwald}, C",
note = "Copyright {\textcopyright} 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.",
year = "2015",
month = aug,
doi = "10.1002/path.4550",
language = "English",
volume = "236",
pages = "505--16",
journal = "Journal of Pathology",
issn = "0022-3417",
publisher = "John/Wiley & Sons Ltd",
number = "4",

}

RIS

TY - JOUR

T1 - Molecular profiling of tumour budding implicates TGFβ-mediated epithelial-mesenchymal transition as a therapeutic target in oral squamous cell carcinoma

AU - Jensen, D H

AU - Dabelsteen, E

AU - Specht, L

AU - Kanstrup, Anne-Marie Fiehn

AU - Therkildsen, M H

AU - Jønson, L

AU - Vikesaa, J

AU - Nielsen, F C

AU - von Buchwald, C

N1 - Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

PY - 2015/8

Y1 - 2015/8

N2 - 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.

AB - 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.

KW - Antineoplastic Agents

KW - Biomarkers, Tumor

KW - Carcinoma, Squamous Cell

KW - Disease-Free Survival

KW - Drug Design

KW - Epithelial-Mesenchymal Transition

KW - Female

KW - Gene Expression Profiling

KW - Gene Expression Regulation, Neoplastic

KW - Genetic Predisposition to Disease

KW - Head and Neck Neoplasms

KW - Humans

KW - Immunohistochemistry

KW - In Situ Hybridization

KW - Kaplan-Meier Estimate

KW - Laser Capture Microdissection

KW - Lymphatic Metastasis

KW - Male

KW - MicroRNAs

KW - Middle Aged

KW - Molecular Targeted Therapy

KW - Mouth Neoplasms

KW - Oligonucleotide Array Sequence Analysis

KW - Phenotype

KW - Polymerase Chain Reaction

KW - Predictive Value of Tests

KW - Reproducibility of Results

KW - Retrospective Studies

KW - Signal Transduction

KW - Time Factors

KW - Transforming Growth Factor beta

U2 - 10.1002/path.4550

DO - 10.1002/path.4550

M3 - Journal article

C2 - 25925492

VL - 236

SP - 505

EP - 516

JO - Journal of Pathology

JF - Journal of Pathology

SN - 0022-3417

IS - 4

ER -

ID: 46000661