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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Available from: Waseem Jerjes, Jun 26, 2014
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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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    ABSTRACT: Crosstalk between cancer cells and carcinoma-associated fibroblasts (CAFs) has earned recognition as an interaction that plays a pivotal role in carcinogenesis. Thus, we attempted to clarify whether increase in the level of CAFs promotes cancer progression by proportionally enhancing the interaction between cancer cells and CAFs. We first analyzed clinical correlation between the levels of fibroblasts and cancer progression and found that the level of CAFs made a noticeable difference on the prognosis of patients with oral squamous cell carcinoma (OSCC). In vivo animal study also demonstrated that tumor volume depended on the dose of CAFs that was co-injected with OSCC cells. The same tendency was observed in an in vitro study. We also found that interleukin-1α (IL-1α) secreted from OSCC cells had dual effects on CAFs: IL-1α not only promoted the proliferation of CAFs but also upregulated the secretion of cytokines in CAFs such as CCL7, CXCL1, and IL-8. The induction activity of cytokine secretion by IL-1α surpassed that of proliferation in OSCC cells. In summary, we unraveled an important interactive mechanism of carcinogenesis: IL-1α released from carcinoma stimulates the proliferation of CAFs and the simultaneous increase in cytokine secretion from CAFs promotes cancer progression in human OSCC. On the basis of these findings, we propose that the level of CAFs is eligible for being selected as a prognostic factor that will be useful in routine diagnosis. We also propose that blockage of reciprocal interaction between cancer cells and CAFs will provide an insight for developing novel chemotherapeutic strategy.
    Neoplasia (New York, N.Y.) 11/2014; 16(11). DOI:10.1016/j.neo.2014.09.003 · 5.40 Impact Factor
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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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    ABSTRACT: Oral squamous cell carcinoma (OSCC) patients have a high mortality rate; thus, new clinical biomarkers and therapeutic options are needed. MicroRNAs (miRNAs) are short noncoding RNAs that regulate posttranscriptional gene expression and are commonly deregulated in OSCC and other cancers. MicroRNA-21 (miR-21) is the most consistently overexpressed miRNA in several types of cancer, and it might be a useful clinical biomarker and therapeutic target. To better understand the role of miR-21 in OSCC, paraffin-embedded tumor tissue samples from 86 patients with primary OSCC were analyzed by in situ hybridization. We found that miR-21 was primarily expressed in the tumor stroma and in some tumor-associated blood vessels with no expression in the adjacent normal epithelia or stroma. Using image analysis, we quantitatively estimated miR-21 expression levels specifically in the stroma of a cohort of OSCC samples. These miR-21 levels significantly correlated with disease free survival with the highest levels being located in the stroma. Stromal miR-21 expression was independently associated with a poorer prognosis, even after adjusting for clinical parameters (perineural invasion and N-stage) in a multivariate analysis. In summary, we have shown that miR-21 is located in the carcinoma cells, stroma and blood vessels of tumors, and its expression specifically in the stromal compartment has a negative prognostic value in OSCC.
    PLoS ONE 04/2014; 9(4):e95193. DOI:10.1371/journal.pone.0095193 · 3.23 Impact Factor
    • "Patients whose specimens were weakly positive for α-SMA had 5 year mean survival rate of 82%; whereas, patients with samples that were strongly positive with α-SMA had a mean survival rate of 38% indicating that the presence of more number of MFs in the stroma is associated with poor prognosis.[35] Thus, the presence of increased stromal MFs is an effective predictor of oral squamous cell carcinoma patient mortality.[46] "
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    ABSTRACT: Myofibroblasts (MFs) are modified fibroblasts that express features of smooth muscle differentiation and were first observed in granulation tissue during wound healing. These cells play a key role in physiologic and pathologic processes like wound healing and tumorigenesis. The presence of MFs has been reported in normal oral tissues and pathologic conditions like reactive lesions, benign tumors, locally aggressive tumors and malignancies affecting the oral cavity. This article briefly reviews the important hallmarks related to the discovery, characterization and tissue distribution of MFs in oral health and disease.
    Journal of Oral and Maxillofacial Pathology 03/2014; 18(1):52-7. DOI:10.4103/0973-029X.131905
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