title: Stromal features are predictive of disease mortality in oral cancer patients.
abstract: Worldwide, approximately 405 000 cases of oral cancer (OSCC) are diagnosed each year, with a rising incidence in many countries. Despite advances in surgery and radiotherapy, which remain the standard treatment options, the mortality rate has remained largely unchanged for decades, with a 5-year survival rate of around 50%. OSCC is a heterogeneous disease, staged currently using the TNM classification, supplemented with pathological information from the primary tumour and loco-regional lymph nodes. Although patients with advanced disease show reduced survival, there is no single pathological or molecular feature that identifies aggressive, early-stage tumours. We retrospectively analysed 282 OSCC patients for disease mortality, related to clinical, pathological, and molecular features based on our previous functional studies [EGFR, αvβ6 integrin, smooth muscle actin (SMA), p53, p16, EP4]. We found that the strongest independent risk factor of early OSCC death was a feature of stroma rather than tumour cells. After adjusting for all factors, high stromal SMA expression, indicating myofibroblast transdifferentiation, produced the highest hazard ratio (3.06, 95% CI 1.65-5.66) and likelihood ratio (3.6; detection rate: false positive rate) of any feature examined, and was strongly associated with mortality, regardless of disease stage. Functional assays showed that OSCC cells can modulate myofibroblast transdifferentiation through αvβ6-dependent TGF-β1 activation and that myofibroblasts promote OSCC invasion. Finally, we developed a prognostic model using Cox regression with backward elimination; only SMA expression, metastasis, cohesion, and age were significant. This model was independently validated on a patient subset (detection rate 70%; false positive rate 20%; ROC analysis 77%, p < 0.001). Our study highlights the limited prognostic value of TNM staging and suggests that an SMA-positive, myofibroblastic stroma is the strongest predictor of OSCC mortality. Whether used independently or as part of a prognostic model, SMA identifies a significant group of patients with aggressive tumours, regardless of disease stage.
authors.affiliation: Centre for Tumour Biology, Bart's and The London School of Medicine and Dentistry, London, UK.
authors.forename: Daniel
authors.initials: D
authors.lastname: Marsh
authors.forename: Krishna
authors.initials: K
authors.lastname: Suchak
authors.forename: Karwan A
authors.initials: KA
authors.lastname: Moutasim
authors.forename: Sabarinath
authors.initials: S
authors.lastname: Vallath
authors.forename: Colin
authors.initials: C
authors.lastname: Hopper
authors.forename: Waseem
authors.initials: W
authors.lastname: Jerjes
authors.forename: Tahwinder
authors.initials: T
authors.lastname: Upile
authors.forename: Nicholas
authors.initials: N
authors.lastname: Kalavrezos
authors.forename: Shelia M
authors.initials: SM
authors.lastname: Violette
authors.forename: Paul H
authors.initials: PH
authors.lastname: Weinreb
authors.forename: Kerry A
authors.initials: KA
authors.lastname: Chester
authors.forename: Jagdeep S
authors.initials: JS
authors.lastname: Chana
authors.forename: John F
authors.initials: JF
authors.lastname: Marshall
authors.forename: Ian R
authors.initials: IR
authors.lastname: Hart
authors.forename: Allan K
authors.initials: AK
authors.lastname: Hackshaw
authors.forename: Kim
authors.initials: K
authors.lastname: Piper
authors.forename: Gareth J
authors.initials: GJ
authors.lastname: Thomas
mesh_terms: D000199:Actins / Q000378:metabolism; D000368:Aged; D014408:Biomarkers, Tumor / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000175:diagnosis / Q000473:pathology* / Q000556:secondary / Q000628:therapy; D004812:Epidemiologic Methods; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009062:Mouth Neoplasms / Q000175:diagnosis / Q000473:pathology* / Q000628:therapy; D058628:Myofibroblasts / Q000502:physiology; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000378:metabolism; D009367:Neoplasm Staging; D011379:Prognosis; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology*
chemical_list: D000199:Actins; D014408:Biomarkers, Tumor; D009363:Neoplasm Proteins