da Silva Sabrina Daniela, Marchi Fabio Albuquerque, Su Jie, Yang Long, Valverde Ludmila, Hier Jessica, Bijian Krikor, Hier Michael, Mlynarek Alex, Kowalski Luiz Paulo, Alaoui-Jamali Moulay A
Department of Otolaryngology Head and Neck Surgery, Sir Mortimer B. Davis-Jewish General Hospital, Montreal, QC H3T 1E2, Canada.
Segal Cancer Centre and Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, Departments of Medicine, Oncology, and Pharmacology and Therapeutics, Faculty of Medicine, McGill University, Montreal, QC H3T 1E2, Canada.
Cancers (Basel). 2021 Jan 5;13(1):153. doi: 10.3390/cancers13010153.
Invasive oral squamous cell carcinoma (OSCC) is often ulcerated and heavily infiltrated by pro-inflammatory cells. We conducted a genome-wide profiling of tissues from OSCC patients (early versus advanced stages) with 10 years follow-up. Co-amplification and co-overexpression of , a transcriptional activator of epithelial-mesenchymal-transition (EMT), and colony-stimulating factor-1 (), a major chemotactic agent for tumor-associated macrophages (TAMs), were observed in metastatic OSCC cases. The overexpression of these markers strongly predicted poor patient survival (log-rank test, = 0.0035 and = 0.0219). Protein analysis confirmed the enhanced expression of TWIST1 and CSF1 in metastatic tissues. In preclinical models using OSCC cell lines, macrophages, and an in vivo matrigel plug assay, we demonstrated that gene overexpression induces the activation of while gene silencing down-regulates preventing OSCC invasion. Furthermore, excessive macrophage activation and polarization was observed in co-culture system involving OSCC cells overexpressing . In summary, this study provides insight into the cooperation between transcription factor and to promote OSCC invasiveness and opens up the potential therapeutic utility of currently developed antibodies and small molecules targeting cancer-associated macrophages.
侵袭性口腔鳞状细胞癌（OSCC）通常会发生溃疡，并被促炎细胞大量浸润。我们对有10年随访的OSCC患者（早期与晚期）组织进行了全基因组分析。在转移性OSCC病例中，观察到上皮-间质转化（EMT）的转录激活因子TWIST1和肿瘤相关巨噬细胞（TAM）的主要趋化因子集落刺激因子-1（CSF1）的共扩增和共过表达。这些标志物的过表达强烈预示患者生存不良（对数秩检验，P = 0.0035和P = 0.0219）。蛋白质分析证实了TWIST1和CSF1在转移组织中的表达增强。在使用OSCC细胞系、巨噬细胞的临床前模型以及体内基质胶栓试验中，我们证明TWIST1基因过表达诱导CSF1激活，而TWIST1基因沉默下调CSF1，阻止OSCC侵袭。此外，在涉及过表达TWIST1的OSCC细胞的共培养系统中观察到巨噬细胞过度激活和极化。总之，本研究深入了解了TWIST1转录因子与CSF1之间的协同作用以促进OSCC侵袭，并揭示了目前开发的靶向癌症相关巨噬细胞的抗体和小分子的潜在治疗效用。
