Li Xinyang, Escoffier Hugues, Sauter Thomas, Tavassoli Mahvash
Head and Neck Oncology Group, Centre for Host Microbiome Interaction, King's College London, Hodgkin Building, London SE1 1UL, UK.
Department of Life Sciences and Medicine, University of Luxembourg, L-4370 Belvaux, Luxembourg.
Cancers (Basel). 2025 Jan 15;17(2):267. doi: 10.3390/cancers17020267.
Cancer-associated fibroblasts have been reported to play a central role in driving cancer progression, promoting metastasis, and conferring resistance to therapy in HNSCC.
Indirect and direct co-culture models of HPV-positive and HPV-negative HNSCC cells with fibroblasts were developed to study the effect of fibroblasts on cancer cells. ELISA was used to measure IL-6 secretion in these models. To dissect the underlying signalling mechanisms, the effects of IL-6, an IL-6 receptor (IL-6R) inhibitor, a MAPK/ERK inhibitor, and a JAK/STAT inhibitor were evaluated. Epithelial-to-mesenchymal transition (EMT) was assessed by measuring EMT markers and conducting scratch assays and spheroid assays. Radioresistance was evaluated using clonogenic assays. Additionally, radioresistant (RR) cell lines were established from parental cells to examine the correlation between radioresistance and EMT.
Fibroblasts were found to drive EMT-like changes and heightened radioresistance in HNSCC cells through IL-6 secretion. Remarkably, these Fb-driven effects were robustly reversed using IL-6R and MAPK/ERK inhibitors in both HPV-positive and HPV-negative cell lines, whereas JAK/STAT inhibitors proved effective only in HPV-negative cells. RR cell lines exhibit a more aggressive phenotype than their parental counterparts, marked by pronounced EMT features and heightened resistance to radiotherapy. Importantly, these aggressive characteristics were substantially attenuated by targeting IL-6R or MAPK/ERK pathways.
This study highlights the critical role of fibroblast-secreted IL-6 in driving and maintaining EMT and radioresistance in HNSCC, resulting in a more aggressive tumour phenotype. Targeting the IL-6/IL-6R/ERK pathway emerges as a promising therapeutic approach for combating CAF-driven tumour progression and improving clinical outcomes in patients with aggressive, therapy-resistant HNSCC.
据报道，癌症相关成纤维细胞在头颈部鳞状细胞癌（HNSCC）的癌症进展、促进转移以及赋予治疗抗性方面发挥核心作用。
建立HPV阳性和HPV阴性HNSCC细胞与成纤维细胞的间接和直接共培养模型，以研究成纤维细胞对癌细胞的影响。采用酶联免疫吸附测定（ELISA）法检测这些模型中白细胞介素-6（IL-6）的分泌情况。为剖析潜在的信号传导机制，评估了IL-6、IL-6受体（IL-6R）抑制剂、丝裂原活化蛋白激酶/细胞外信号调节激酶（MAPK/ERK）抑制剂和Janus激酶/信号转导和转录激活因子（JAK/STAT）抑制剂的作用。通过检测上皮-间质转化（EMT）标志物以及进行划痕试验和球体试验来评估EMT。使用克隆形成试验评估放射抗性。此外，从亲本细胞建立放射抗性（RR）细胞系，以研究放射抗性与EMT之间的相关性。
发现成纤维细胞通过分泌IL-6驱动HNSCC细胞发生类似EMT的变化并增强放射抗性。值得注意的是，在HPV阳性和HPV阴性细胞系中，使用IL-6R和MAPK/ERK抑制剂可有力逆转这些由成纤维细胞驱动的效应，而JAK/STAT抑制剂仅在HPV阴性细胞中有效。RR细胞系表现出比其亲本细胞更具侵袭性的表型，其特征为明显的EMT特征和对放疗的抗性增强。重要的是，通过靶向IL-6R或MAPK/ERK途径，这些侵袭性特征得到显著减弱。
本研究强调了成纤维细胞分泌的IL-6在驱动和维持HNSCC的EMT及放射抗性方面的关键作用，从而导致更具侵袭性的肿瘤表型。靶向IL-6/IL-6R/ERK途径成为一种有前景的治疗方法，可对抗癌症相关成纤维细胞驱动的肿瘤进展，并改善侵袭性、治疗抗性HNSCC患者的临床结局。
