Article

Stromal features are predictive of disease mortality in oral cancer patients. J Pathol

Centre for Tumour Biology, Bart's and The London School of Medicine and Dentistry, London, UK.
The Journal of Pathology (Impact Factor: 7.43). 03/2011; 223(4):470-81. DOI: 10.1002/path.2830
Source: PubMed

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.

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    • "Conflict of interest: The authors declare that they have no conflict of interest. Received 9 July 2014; Revised 3 September 2014; Accepted 4 September 2014 deeply related to poor prognosis in several human cancers have been reported [14] [15] [16]. "
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    • "Different cancer-associated fibroblasts have been described, but the one that is most consistently shown to have an adverse effect on prognosis are myofibroblasts [17]–[19]. Myofibroblasts express α-smooth muscle actin and are frequently found in the stroma of oral carcinomas with poor prognosis and in oral wounds [17]–[21]. Based on the findings described above, it is tempting to suggest that the increased expression of miR-21 that we [22] and others [11] have demonstrated in tissue from oral carcinomas is found in myofibroblasts and not in the carcinoma cells [23]. "
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