Fibroblast gene expression profile reflects the stage of tumour progression in oral squamous cell carcinoma

• Published in: The Journal of pathology 2011-03, Vol.223 (4), p.459-469
• Main Authors: Lim, Kue Peng, Cirillo, Nicola, Hassona, Yazan, Wei, Wenbin, Thurlow, Johanna K, Cheong, Sok Ching, Pitiyage, Gayani, Parkinson, E Ken, Prime, Stephen S
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Carcinoma, Squamous Cell - genetics; Carcinoma, Squamous Cell - metabolism; Carcinoma, Squamous Cell - pathology; Cell adhesion molecules; Collagen; copy number; Data processing; Developmental stages; Disease Progression; DNA microarrays; fibroblast gene signatures; Fibroblasts; Fibroblasts - metabolism; Gels; Gene expression; Gene Expression Profiling - methods; Gene Expression Regulation, Neoplastic; Head and neck cancer; Head and Neck Neoplasms - genetics; Head and Neck Neoplasms - metabolism; Humans; Investigative techniques, diagnostic techniques (general aspects); Keratinocytes; Malignancy; Medical sciences; Membrane proteins; Mouth Mucosa - cytology; Mouth Mucosa - metabolism; Mouth Neoplasms - genetics; Mouth Neoplasms - metabolism; Mouth Neoplasms - pathology; Mucosa; Neoplasm Invasiveness; Neoplasm Proteins - metabolism; oral cancer; oral squamous cell carcinoma; Otorhinolaryngology. Stomatology; p53 protein; Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques; Principal components analysis; Prognosis; Reverse Transcriptase Polymerase Chain Reaction - methods; Survival Analysis; Transcription; Tumor Cells, Cultured; Tumors; tumour progression; Upper respiratory tract, upper alimentary tract, paranasal sinuses, salivary glands: diseases, semeiology
• ISSN: 0022-3417; 1096-9896
• DOI: 10.1002/path.2841

Oral cancer is a highly aggressive malignancy with poor prognosis. This study examined the behaviour of fibroblast strains from normal oral mucosa, dysplastic epithelial tissue, and genetically stable (minimal copy number alterations—CNA; minimal loss of heterozygosity—LOH; wild‐type p53; wild‐type p16$^{{\rm INK4A}}$) and unstable (extensive CNA and LOH; inactivation of p53 and p16$^{{\rm INK4A}}$) oral squamous cell carcinoma (OSCC). Fibroblasts from genetically unstable OSCC relative to the other fibroblast subtypes grew more slowly and stimulated the invasion of a non‐tumourigenic keratinocyte cell line into fibroblast‐rich collagen gels. To understand these findings, genome‐wide transcriptional profiles were generated using the GeneChip® cDNA whole transcript microarray platform. Principal component analysis showed that the fibroblasts could be distinguished according to the stage of tumour development. Tumour progression was associated with down‐regulation of cell cycle‐ and cytokinesis‐related genes and up‐regulation of genes encoding transmembrane proteins including cell adhesion molecules. Gene expression was validated in independent fibroblast strains using qRT‐PCR. Gene connectivity and interactome‐transcriptome associations were determined using a systems biology approach to interrogate the gene expression data. Clusters of gene signatures were identified that characterized genetically unstable and stable OSCCs relative to each other and to fibroblasts from normal oral mucosa. The expression of highly connected genes associated with unstable OSCCs, including those that encode α‐SMA and the integrin α6, correlated with poor patient prognosis in an independent dataset of head and neck cancer. The results of this study demonstrate that fibroblasts from unstable OSCCs represent a phenotypically distinguishable subset that plays a major role in oral cancer biology. Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.