Wang Kangtao, Ning Siyi, Zhang Shuai, Jiang Mingming, Huang Yan, Pei Haiping, Li Ming, Tan Fengbo
Department of General Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
Department of General, Visceral & Transplant Surgery, Molecular OncoSurgery, Section Surgical Research, University of Heidelberg, Heidelberg, Baden-Württemberg, 69117, Germany.
J Exp Clin Cancer Res. 2025 Jan 30;44(1):30. doi: 10.1186/s13046-025-03297-8.
Colorectal cancer (CRC) has high incidence and mortality rates, with severe prognoses during invasion and metastasis stages. Despite advancements in diagnostic and therapeutic technologies, the impact of the tumour microenvironment, particularly extracellular matrix (ECM) stiffness, on CRC progression and metastasis is not fully understood.
This study included 107 CRC patients. Tumour stiffness was assessed using magnetic resonance elastography (MRE), and collagen ratio was analysed with Masson staining. CRC cell lines were cultured on matrices of varying stiffness, followed by transcriptome sequencing to identify stiffness-related genes. An HSF4 knockout CRC cell model was cultured in different ECM stiffness to evaluate the effects of HSF4 on cell proliferation, migration, and invasion in vitro and in vivo.
CRC tumour stiffness was significantly higher than normal tissue and positively correlated with collagen content and TNM staging. High-stiffness matrices significantly regulated cell functions and signalling pathways. High HSF4 (heat shock transcriptional factor 4) expression was strongly associated with tumour stiffness and poor prognosis. HSF4 expression increased with higher TNM stages, and its knockout significantly inhibited cell proliferation, migration, and invasion, especially on high-stiffness matrices. In vivo experiments confirmed that HSF4 promoted tumour growth and metastasis, independent of collagen protein increase.
This study reveals that tumour stiffness promotes the proliferation and metastasis of CRC by regulating EMT-related signalling pathways through HSF4. Tumour stiffness and HSF4 could be valuable targets for prognostic assessment and therapeutic intervention in CRC.
结直肠癌（CRC）的发病率和死亡率较高，在侵袭和转移阶段预后严重。尽管诊断和治疗技术取得了进展，但肿瘤微环境，特别是细胞外基质（ECM）硬度对CRC进展和转移的影响尚未完全了解。
本研究纳入了107例CRC患者。使用磁共振弹性成像（MRE）评估肿瘤硬度，并用Masson染色分析胶原比例。将CRC细胞系培养在不同硬度的基质上，然后进行转录组测序以鉴定与硬度相关的基因。在不同的ECM硬度条件下培养HSF4基因敲除的CRC细胞模型，以评估HSF4对细胞在体外和体内增殖、迁移及侵袭的影响。
CRC肿瘤硬度显著高于正常组织，且与胶原含量和TNM分期呈正相关。高硬度基质显著调节细胞功能和信号通路。高HSF4（热休克转录因子4）表达与肿瘤硬度和不良预后密切相关。HSF4表达随TNM分期升高而增加，其基因敲除显著抑制细胞增殖、迁移和侵袭，尤其是在高硬度基质上。体内实验证实，HSF4促进肿瘤生长和转移，且与胶原蛋白增加无关。
本研究表明，肿瘤硬度通过HSF4调节与上皮-间质转化（EMT）相关的信号通路，促进CRC的增殖和转移。肿瘤硬度和HSF4可能是CRC预后评估和治疗干预的有价值靶点。
