Department of Radiation Oncology, National Taiwan University Cancer Center, Taipei, Taiwan.
Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan.
Radiat Oncol. 2024 Sep 27;19(1):128. doi: 10.1186/s13014-024-02513-7.
The stiffness of the tumor microenvironment (TME) directly influences cellular behaviors. Radiotherapy (RT) is a common treatment for solid tumors, but the TME can impact its efficacy. In the case of liver cancer, clinical observations have shown that tumors within a cirrhotic, stiffer background respond less to RT, suggesting that the extracellular matrix (ECM) stiffness plays a critical role in the development of radioresistance.
This study explored the effects of ECM stiffness and the inhibition of lysyl oxidase (LOX) isoenzymes on the radiation response of liver cancer in a millimeter-sized three-dimensional (3D) culture. We constructed a cube-shaped ECM-based millimeter-sized hydrogel containing Huh7 human liver cancer cells. By modulating the collagen concentration, we produced two groups of samples with different ECM stiffnesses to mimic the clinical scenarios of normal and cirrhotic livers. We used a single-transducer system for shear-wave-based elasticity measurement, to derive Young's modulus of the 3D cell culture to investigate how the ECM stiffness affects radiosensitivity. This is the first demonstration of a workflow for assessing radiation-induced response in a millimeter-sized 3D culture.
Increased ECM stiffness was associated with a decreased radiation response. Moreover, sonoporation-assisted LOX inhibition with BAPN (β-aminopropionitrile monofumarate) significantly decreased the initial ECM stiffness and increased RT-induced cell death. Inhibition of LOX was particularly effective in reducing ECM stiffness in stiffer matrices. Combining LOX inhibition with RT markedly increased radiation-induced DNA damage in cirrhotic liver cancer cells, enhancing their response to radiation. Furthermore, LOX inhibition can be combined with sonoporation to overcome stiffness-related radioresistance, potentially leading to better treatment outcomes for patients with liver cancer.
The findings underscore the significant influence of ECM stiffness on liver cancer's response to radiation. Sonoporation-aided LOX inhibition emerges as a promising strategy to mitigate stiffness-related resistance, offering potential improvements in liver cancer treatment outcomes.
肿瘤微环境（TME）的硬度直接影响细胞行为。放射治疗（RT）是治疗实体瘤的常用方法，但 TME 会影响其疗效。在肝癌的情况下，临床观察表明，在肝硬化、硬度较大的背景下的肿瘤对 RT 的反应较差，这表明细胞外基质（ECM）硬度在产生放射抗性方面起着关键作用。
本研究探讨了 ECM 硬度和赖氨酰氧化酶（LOX）同工酶抑制对毫米级三维（3D）培养中肝癌放射反应的影响。我们构建了一个基于 ECM 的立方毫米级水凝胶，其中包含 Huh7 人肝癌细胞。通过调节胶原浓度，我们产生了两组具有不同 ECM 硬度的样本，以模拟正常和肝硬化肝脏的临床情况。我们使用单换能器系统进行基于剪切波的弹性测量，以得出 3D 细胞培养的杨氏模量，从而研究 ECM 硬度如何影响放射敏感性。这是首次展示用于评估毫米级 3D 培养中辐射诱导反应的工作流程。
增加 ECM 硬度与辐射反应降低有关。此外，BAPN（β-氨基丙腈单富马酸盐）的声孔辅助 LOX 抑制显著降低了初始 ECM 硬度并增加了 RT 诱导的细胞死亡。LOX 抑制在更硬的基质中特别有效地降低 ECM 硬度。将 LOX 抑制与 RT 结合使用可显著增加肝硬化肝癌细胞中辐射诱导的 DNA 损伤，增强其对辐射的反应。此外，LOX 抑制可与声孔作用结合使用以克服与硬度相关的放射抗性，从而为肝癌患者带来更好的治疗效果。
研究结果强调了 ECM 硬度对肝癌对辐射反应的重要影响。声孔辅助 LOX 抑制作为减轻与硬度相关的抗性的有前途的策略出现，为改善肝癌治疗结果提供了潜力。
