Tumor cell-derived TGF-ß at tumor center independently predicts recurrence and poor survival in oral squamous cell carcinoma.

ABSTRACT

BACKGROUND: Transforming growth factor-ß (TGF-ß) exerts its versatile function (oncogenic or tumor suppressive role) during the carcinogenesis in tumor microenvironment-dependent manner. Considering the tumor heterogeneity, spatial and temporal distribution of TGF-ß in oral squamous cell carcinoma (OSCC) remained to be elucidated. METHODS: Formalin-fixed, paraffin-embedded sections derived from 73 patients with OSCC were immunostained, revealing expression patterns of TGF-ß, both at the regions of tumor center (TC) and invasive tumor front (ITF). RESULTS: The TGF-ß levels on tumor cells, fibroblast-like cells (FLCs), and tumor-infiltrating lymphocytes (TILs) were comparable and showed to be cell-type-independent manner. Although TC regions harbored less positive staining of TGF-ß than ITF in tumor cells (TGF-ßTumor cell ) (89.0% vs 98.3%; P = 0.037), FLCs (TGF-ßFLC ) (86.3% vs 96.6%; P = 0.043), and TILs (TGF-ßTIL ) (83.6% vs 94.8%; P = 0.044), respectively, TGF-ß at TC regions, not at ITF, correlated to poor clinical outcomes. At TC regions, patients with high TGF-ßTumor cell had high recurrence rate, and patients with high TGF-ßTIL showed inferior worst pattern of invasion. Of note, high TGF-ßTumor cell at TC predicted shorter overall survival time, recurrence-free survival, and disease-free survival in patients with OSCC, whereas high TGF-ßTIL had no association with survival time. Cox regression analyses indicated that tumor cell-derived TGF-ß at TC was an independent risk factor for survival outcome in patients with OSCC. CONCLUSIONS: Tumor cell-derived TGF-ß at TC regions, but not at ITF, could be a promising predictor for disease recurrence and poor prognosis of patients with OSCC.