Abstract

Well-differentiated head and neck squamous cell carcinoma (HNSCC), accounts for approximately 10% of all HNSCCs and, while these cases are associated with good prognosis after surgery, these are resistant to chemotherapy. Here we designed a retrospective study to evaluate the effects of histological differentiation on tongue squamous cell carcinoma (TSCC) patients undergoing surgery or metronomic neoadjuvant chemotherapy. The metronomic neoadjuvant chemotherapy significantly improved overall survival of patients with poorly or moderately differentiated tumour, but not those with well-differentiated tumour. Analysis of the Cancer Genome Atlas (TCGA) showed that FAT1 mutations were significantly enriched in more differentiated HNSCC while ASPM mutations were significantly enriched among the poorly differentiated HNSCC. Interestingly, Wnt/β-catenin pathway was activated in well-differentiated HNSCC. Active β-catenin is translocated to the nucleus in the well-differentiated oral squamous cell carcinoma cell lines. Wnt inhibitor, Wnt974, were synergistic with methotrexate in killing well-differentiated oral squamous cell carcinoma (OSCC) cell lines. TCGA data analyses reveal a signature in patients with well-differentiated HNSCC who have no benefits from metronomic neoadjuvant chemotherapy, suggesting that there might be novel nosology and therapeutic candidates for improving HNSCC patient survival. Well-differentiated OSCC is synergistically killed by combination chemotherapy with Wnt inhibitor, making it promising therapeutic candidates.

摘要

高分化头颈部鳞状细胞癌 (HNSCC) 约占所有 HNSCC 的 10%，虽然这些病例与手术后的良好预后相关，但它们对化疗有抵抗力。在这里，我们设计了一项回顾性研究，以评估组织学分化对接受手术或节拍新辅助化疗的舌鳞状细胞癌 (TSCC) 患者的影响。节拍式新辅助化疗显着改善了低分化或中分化肿瘤患者的总生存期，但对高分化肿瘤患者却没有。癌症基因组图谱 (TCGA) 的分析表明，FAT1突变在分化程度更高的 HNSCC 中显着富集，而ASPM低分化 HNSCC 的突变显着富集。有趣的是，Wnt/β-catenin 通路在分化良好的 HNSCC 中被激活。在分化良好的口腔鳞状细胞癌细胞系中，活性 β-连环蛋白易位至细胞核。Wnt 抑制剂 Wnt974 与甲氨蝶呤协同杀死高分化口腔鳞状细胞癌 (OSCC) 细胞系。TCGA 数据分析揭示了高分化 HNSCC 患者的特征，这些患者没有从节拍新辅助化疗中获益，这表明可能有新的疾病学和治疗候选者可以提高 HNSCC 患者的生存率。分化良好的 OSCC 通过联合化疗与 Wnt 抑制剂协同杀死，使其成为有希望的治疗候选者。