Cancer-associated fibroblasts regulate keratinocyte cell-cell adhesion via TGF-β-dependent pathways in genotype-specific oral cancer.
The interrelationship between malignant epithelium and the underlying stroma is of fundamental importance in tumour development and progression. In the present study, we used cancer-associated fibroblasts (CAFs) derived from genetically unstable oral squamous cell carcinomas (GU-OSCC), tumours that are characterized by the loss of genes such as TP53 and p16INK4Aand with extensive loss of heterozygosity, together with CAFs from their more genetically stable (GS) counterparts that have wild-type TP53 and p16INK4Aand minimal loss of heterozygosity (GS-OSCC). Using a systems biology approach to interpret the genome-wide transcriptional profile of the CAFs, we show that transforming growth factor-β (TGF-β) family members not only had biological relevance in silico but also distinguished GU-OSCC-derived CAFs from GS-OSCC CAFs and fibroblasts from normal oral mucosa. In view of the close association between TGF-β family members, we examined the expression of TGF-β1 and TGF-β2 in the different fibroblast subtypes and showed increased levels of active TGF-β1 and TGF-β2 in CAFs from GU-OSCC. CAFs from GU-OSCC, but not GS-OSCC or normal fibroblasts, induced epithelial-mesenchymal transition and down-regulated a broad spectrum of cell adhesion molecules resulting in epithelial dis-cohesion and invasion of target keratinocytes in vitro in a TGF-β-dependent manner. The results demonstrate that the TGF-β family of cytokines secreted by CAFs derived from genotype-specific oral cancer (GU-OSCC) promote, at least in part, the malignant phenotype by weakening intercellular epithelial adhesion.
Melbourne Dental School and Oral Health CRC, University of Melbourne, 3053 Carlton, Victoria, Australia, nicola.cirillo@unimelb.edu.au.
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Cirillo
Department of Dentistry, University of Jordan, Amman, Jordan.
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Hassona
Melbourne Dental School and Oral Health CRC, University of Melbourne, 3053 Carlton, Victoria, Australia.|Department of Neurosciences, Reproductive and Odontostomatological Sciences, Federico II University of Naples, Italy.
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Celentano
Cancer Research Initiatives Foundation, Sime Darby, Subang Jaya Medical Centre, 47500 Subang Jaya, Selangor, Malaysia.
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Lim
Melbourne Dental School and Oral Health CRC, University of Melbourne, 3053 Carlton, Victoria, Australia.
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Manchella
Centre for Clinical and Diagnostic Oral Sciences, Institute of Dentistry, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
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Parkinson
Centre for Clinical and Diagnostic Oral Sciences, Institute of Dentistry, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
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Prime
D000072645:Cancer-Associated Fibroblasts / Q000378:metabolism / Q000473:pathology*; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002448:Cell Adhesion; D002478:Cells, Cultured; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D005838:Genotype; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism / Q000473:pathology*; D019656:Loss of Heterozygosity; D009061:Mouth Mucosa / Q000378:metabolism / Q000473:pathology; D009062:Mouth Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D009361:Neoplasm Invasiveness; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism*; D053781:Transforming Growth Factor beta2 / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
C000614131:CDKN2A protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; C495901:TP53 protein, human; D053773:Transforming Growth Factor beta1; D053781:Transforming Growth Factor beta2; D016159:Tumor Suppressor Protein p53