Lee Jih-Chin, Wu Alexander T H, Chen Jia-Hong, Huang Wen-Yen, Lawal Bashir, Mokgautsi Ntlotlang, Huang Hsu-Shan, Ho Ching-Liang
Department of Otolaryngology-Head and Neck Surgery, Tri-Service General Hospital, National Defense Medical Center, 325 Cheng-Kung Road Section 2, Taipei 114, Taiwan.
The Ph.D. Program of Translational Medicine, College of Science and Technology, Taipei Medical University, Taipei 11031, Taiwan.
Cancers (Basel). 2020 Dec 14;12(12):3759. doi: 10.3390/cancers12123759.
Despite advancements in diagnostic and standard treatment modalities, including surgery, radiotherapy, and chemotherapy, overall survival rates of advanced-stage head and neck squamous cell carcinoma (HNSCC) patients have remained stagnant for over three decades. Failure of these treatment modalities, coupled with post-therapy complications, underscores the need for alternative interventions and an in-depth understanding of the complex signaling networks involved in developing treatment resistance. Using bioinformatics tools, we identified an increased expression of c-Met, STAT3, and CD44 corresponding to a poor prognosis and malignant phenotype of HNSCC. Subsequently, we showed that tumorsphere-derived exosomes promoted cisplatin (CDDP) resistance and colony and tumorsphere formation in parental HNSCC cells, accompanied by an increased level of oncogenic/immune evasive markers, namely, c-Met, STAT3, CD44, and PD-L1. We then evaluated the therapeutic potential of a new small molecule, HNC0014. The molecular docking analysis suggested strong interactions between HNC0014 and oncogenic molecules; c-Met, STAT3, CD44, and PD-L1. Subsequently, we demonstrated that HNC0014 treatment suppressed HNSCC tumorigenic and expression of stemness markers; HNC0014 also reduced cancer-associated fibroblast (CAF) transformation by Exo- and CAF-induced tumorigenic properties. HNC0014 treatment alone suppressed tumor growth in a cisplatin-resistant (SAS tumorspheres) mouse xenograft model and with higher inhibitory efficacy when combined with CDDP. More importantly, HNC0014 treatment significantly delayed tumor growth in a syngeneic mouse HNSCC model, elicited an antitumor immune profile, and reduced the total c-Met, STAT3, and their phosphorylated forms, PD-L1 and CD44, contents in serum exosomes. Collectively, our findings provide supports for HNC0014 as a multi-targeted immunotherapeutic lead compound for further development.
尽管在诊断和标准治疗方式（包括手术、放疗和化疗）方面取得了进展，但晚期头颈部鳞状细胞癌（HNSCC）患者的总体生存率在过去三十多年里一直停滞不前。这些治疗方式的失败，再加上治疗后并发症，凸显了需要替代干预措施以及深入了解参与产生治疗抗性的复杂信号网络。使用生物信息学工具，我们发现c-Met、STAT3和CD44的表达增加与HNSCC的不良预后和恶性表型相对应。随后，我们表明肿瘤球衍生的外泌体促进了亲本HNSCC细胞中的顺铂（CDDP）抗性以及集落和肿瘤球形成，同时致癌/免疫逃避标志物c-Met、STAT3、CD44和PD-L1的水平升高。然后，我们评估了一种新的小分子HNC0014的治疗潜力。分子对接分析表明HNC0014与致癌分子c-Met、STAT3、CD44和PD-L1之间有强烈的相互作用。随后，我们证明HNC0014治疗可抑制HNSCC的致瘤性和干性标志物的表达；HNC0014还通过外泌体和CAF诱导的致瘤特性降低了癌症相关成纤维细胞（CAF）的转化。单独使用HNC0014治疗可抑制顺铂抗性（SAS肿瘤球）小鼠异种移植模型中的肿瘤生长，与CDDP联合使用时具有更高的抑制效果。更重要的是，HNC0014治疗在同基因小鼠HNSCC模型中显著延迟了肿瘤生长，引发了抗肿瘤免疫反应，并降低了血清外泌体中总c-Met、STAT3及其磷酸化形式、PD-L1和CD44的含量。总的来说，我们的研究结果为HNC0014作为一种多靶点免疫治疗先导化合物的进一步开发提供了支持。
