基于IB-LBM的肿瘤细胞粘附与血行转移的力学机制研究

The tumor cell adhesion to the micro-vessel wall is a critical step in the distant cancer metastasis. Our recent in vivo experimental studies have indicated that the tumor cell perfers to aggregate and firmly adhere to the bent of curved micro-vessels, and the complex mechanical microenvironment at the curvatures and branches appear to render these sites prone to adhesion and metastasis of tumor cell. However, the precise mechanism of this phenomenon is not yet clearly understood. In this research project, based on the immersed boundary-lattice Boltzmann method (IB-LBM), GPU parallel computing technology, and the stochastic Monte Carlo method, the blood flow in the curved and bifurcated micro-vessel is modeled as a suspension of multiple deformable red blood cells (RBCs), and the effect of flowing RBCs on the migration, deformation and adhesion of tumor cell are examined, and then the quantitative relationship between complex forces and tumor cell adhesion are also clearly established. After that, a novel receptor-ligand kinetic model will be proposed for the adhesion between tumor cell and endothelial cells, and then the mechanical mechanisms of tumor cell adhesion and transvascular metastasis in the curved and bifurcated microvessel will also be clarified. By implementing this research project, it not only will provide a novel idea and technique for studying the mechanical mechanisms of tumor cells adhesion and metastasis in microcirculation, but also will enlarge the application space of IB-LBM and GPU to the cancer research area. Meanwhile, it may eventually provide a rational basis for the development of novel therapeutic strategies to combat cancer.

肿瘤细胞粘附是癌症经血道实现远端转移的决定性环节。我们最新的实验研究表明：肿瘤细胞容易聚集并牢固粘附于弯曲微血管，且弯曲分叉微血管内的力学微环境和肿瘤粘附与转移的现象相关。然而，对于这一现象背后确切的力学机制目前尚不清楚。本项目拟基于IB-LBM模拟方法、GPU并行技术和随机Monte Carlo方法，将三维弯曲分叉微血管内的血液流动看作是变形红细胞群的悬浮液，研究肿瘤细胞在其中的迁移、变形与粘附规律，厘清各个力学因素与肿瘤细胞粘附的定量关系，构建完善的针对肿瘤细胞的受体－配体粘附动力学模型，揭示肿瘤细胞在弯曲分叉微血管内粘附与血行转移的力学机制。通过对本项目的研究，不仅为肿瘤细胞粘附与转移机制的研究提供了新的思路和方法，而且极大拓展了IB-LBM和GPU科学计算的应用空间，研究结果有助于为揭开肿瘤转移的奥秘和改进癌症治疗的策略提供合理的科学依据。

肿瘤细胞与内皮细胞的粘附是癌症通过血液循环实现远端转移的决定性环节。项目组通过开展大鼠体内实验，发现肿瘤细胞容易牢固粘附在弯曲微血管的拐点处，且微血管内的力学微环境和肿瘤细胞粘附及转移的现象密切相关，但对于这种现象背后确切的力学机制不明确。为了解释肿瘤细胞粘附与血行转移的力学机制，项目组完成了5方面研究工作：(1)成功发展了一套IB-LBM算法与随机Monte Carlo方法相结合的计算生物力学方法，并从数值模拟的准确性、稳定性以及计算效率等方面优化了该方法，为研究血液流动、细胞流变和细胞粘附等问题提供了高效的数值工具。(2)详细分析了红细胞受拉伸力和剪切力的变形和松弛及其在微血管内的运动和变形，将血液视为变形红细胞群的悬浮液，重点讨论了红细胞群的力学性能对血液流动特性的影响，阐明了肿瘤细胞发生迁移、变形、粘附及转移的血液环境。(3)成功开展了肿瘤细胞粘附的大鼠体内实验和数值模拟，证实了现有肿瘤细胞粘附模型的局限性，重点考虑了微血管内力学微环境对肿瘤细胞粘附的影响，提出了更完善的肿瘤细胞和内皮细胞的受体-配体粘附动力学模型，为研究癌症粘附与血行转移机制提供了模型支持。(4)详细讨论了微血管结构、血浆流动条件、红细胞力学性能以及肿瘤细胞力学性能对肿瘤细胞粘附与转移的影响，同时分析了肿瘤细胞穿越内皮细胞间隙的外渗行为，厘清了肿瘤细胞粘附、外渗及血行转移的力学机制，为揭开癌症转移的奥秘和改进癌症治疗的策略提供了科学依据。(5)扩展研究了基于微流控芯片技术的循环肿瘤细胞增强分选机制，找到了控制循环肿瘤细胞分选效果的关键因素；拓展分析了利用呼吸测试的人类肺癌快速无创检测技术，用分形理论简单快速判断肺癌的严重程度和病发位置，为发展人类肺癌疾病的快速无创医学检测技术提供了的理论依据。