Fang Yanhua, Liang Shanshan, Gao Jianong, Wang Zhe, Li Cheng, Wang Ruoyu, Yu Weiting
The Key Laboratory of biomarker high throughput screening and target translation of breast and gastrointestinal tumor, Affiliated Zhongshan Hospital of Dalian University, No.6 Jiefang Street, Zhongshan District, Dalian, 116001, Liaoning, China.
Outpatient Department, General Hospital of Northern Theater Command, No.83 Culture Road, Shenhe District, Shengyang, 110015, Liaoning, China.
Cancer Cell Int. 2022 Nov 19;22(1):364. doi: 10.1186/s12935-022-02787-5.
Radiotherapy is one of the essential treatment modalities for nasopharyngeal carcinoma (NPC), however, radioresistance still poses challenges. Three-dimensional (3D) tumor culture models mimic the in vivo growth conditions of cells more accurately than 2D models. This study is to compare the tumor biological behaviors of NPC cells in 2D, On-Surface 3D and Embedded 3D systems, and to investigate the correlation between radioresistance and extracellular matrix (ECM) stiffness.
The morphology and radioresistance of the human NPC cell line CNE-1 were observed in 2D and 3D systems. The CCK-8 assay, wounding healing assays, flow cytometry, soft agar assays, and western blot analysis were used to evaluate differences in biological behaviors such as proliferation, migration, cell cycle distribution, and stem cell activity. Different ECM stiffness systems were established by co-blending collagen and alginate in varying proportions. ECM stiffness was evaluated by compressive elastic moduli measurement and colony formation assay was used to assess radioresistance of NPC cells in systems with different ECM stiffness after irradiation.
Compared to 2D models, the morphology of NPC cells in 3D culture microenvironments has more in common with in vivo tumor cells and 3D cultured NPC cells exhibit stronger radioresistance. Integrin β1 but not the epithelial-to-mesenchymal transition pathway in 3D models boost migration ability. Cell proliferation was enhanced, the proportion of tumor stem cells was increased, and G1/S phase arrest occurred in 3D models. NPC cells cultured in softer ECM systems (with low alginate proportions) exhibit striking resistance to ionizing radiation.
The tumor biological behaviors of NPC cells in 3D groups were obviously different from that of 2D. Radioresistance of NPC cells increased with the stiffness of ECM decreasing.
放射治疗是鼻咽癌（NPC）的重要治疗方式之一，但放射抗性仍然是一个挑战。三维（3D）肿瘤培养模型比二维模型更准确地模拟细胞的体内生长条件。本研究旨在比较NPC细胞在二维、表面3D和嵌入式3D系统中的肿瘤生物学行为，并探讨放射抗性与细胞外基质（ECM）硬度之间的相关性。
在二维和三维系统中观察人NPC细胞系CNE-1的形态和放射抗性。采用CCK-8法、伤口愈合试验、流式细胞术、软琼脂试验和蛋白质印迹分析来评估增殖、迁移、细胞周期分布和干细胞活性等生物学行为的差异。通过将胶原蛋白和海藻酸钠按不同比例共混建立不同的ECM硬度系统。通过压缩弹性模量测量评估ECM硬度，并使用集落形成试验评估照射后不同ECM硬度系统中NPC细胞的放射抗性。
与二维模型相比，三维培养微环境中NPC细胞的形态与体内肿瘤细胞更相似，三维培养的NPC细胞表现出更强的放射抗性。三维模型中整合素β1而非上皮-间质转化途径增强了迁移能力。三维模型中细胞增殖增强，肿瘤干细胞比例增加，并出现G1/S期阻滞。在较软的ECM系统（海藻酸钠比例低）中培养的NPC细胞对电离辐射表现出显著抗性。
三维组NPC细胞的肿瘤生物学行为与二维组明显不同。NPC细胞的放射抗性随着ECM硬度的降低而增加。
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