基于LBM的肿瘤细胞黏附行为的力学调控机制研究

The most deadly aspect of cancer is its ability to metastasize to another location from where it starts. The adhesion of tumor cells to the micro-vessel wall in microcirculation is a critical step in cancer metastasis. The previous experimental studies have indicated that the tumor cells perfer to adhere and aggregate near the bent of curved and bifurcated micro-vessels. Our previous work has also revealed that the complex forces at the micro-vascular curvatures and branches appear to render these sites prone to metastasis of tumor cells. However, the precise mechanism of this phenomenon is not yet clearly understood. In this research proposal, the computerized-tomography technology and the lattice Boltzmann method together with the stochastic monte carlo method are adopted to investigate the mechanical mechanisms of tumor cells adhesion, and to find the quantitative relationship between complex forces and tumor cells adhesion in the curved and bifurcated micro-vessels. Moreover, a novel receptor-ligand kinetic model will be proposed for the adhesion between tumor cells and endothelial cells, which could be helpful for quantifying the adhesion behavior of tumor cells with the supports of simulation parameters and mathematical models. By implementing this research proposal, it not only will provide a novel technique for studying the mechanical mechanisms of tumor cells adhesion in microcirculation, but also will enlarge the application space of lattice Boltzmann simulations in cancer research area. Meanwihle, this research project may eventually provide a rational basis for the development of novel therapeutic strategies to combat cancer.

肿瘤细胞的"转移性"是癌症致死的主要原因。"肿瘤细胞黏附"是癌症经血道实现远处转移的关键。实验研究表明：肿瘤细胞容易黏附并聚集在微脉管的弯曲分叉部位。我们的前期工作证明：微脉管弯曲分叉部位的复杂力学因素与这些部位易于黏附与转移肿瘤的现象有关。对于这两者之间的定量关系目前仍不清楚。本项目拟采用C-T数字成像技术、晶格Boltzmann方法（LBM）和随机Monte Carlo方法，系统研究肿瘤细胞在弯曲分叉微脉管内发生黏附行为的力学调控机制，建立各力学因素与肿瘤细胞黏附之间的定量关系，构造合理的针对肿瘤细胞与内皮细胞间黏附的受体－配体结合动力学模型，为定量研究肿瘤细胞的黏附特性提供参数支持和模型支持。通过对本项目的研究，不仅为肿瘤黏附机制的研究提供了新方法，而且拓展了LBM科学计算的应用空间，同时也为揭开肿瘤转移的奥秘和改进癌症治疗的策略提供一个合理的科学依据。

癌症之所以难治，主要原因在于恶性肿瘤能从原发部位转移到新部位，约90%的癌症患者最终死于转移。转移是一个连续、复杂的病理过程，就由血道转移而言，至少需要经过3个步骤：①侵袭：肿瘤细胞穿越基底膜进入血液循环；②黏附：肿瘤细胞牢牢黏附于血管壁；③浸润：肿瘤细胞穿过血管壁进入靶器官，并在靶器官中继续增殖生长。进入循环系统的肿瘤细胞绝大多数被机体的免疫细胞迅速清除，只有不足0.01%的肿瘤细胞最终存活。只有牢牢黏附于血管壁的肿瘤细胞，才有机会穿过血管壁和进入靶器官，从而躲过血流的剪切力和靶器官的防御屏障而最终转移成功。因此，只要明确肿瘤细胞与内皮细胞之间的黏附机制，并阻碍这种牢固细胞黏附的发生，便可有效切断肿瘤经血道转移的必经步骤，减少恶性肿瘤的转移率，提高癌症患者的生存率。.肿瘤细胞黏附是肿瘤经由血道实现远端转移的决定性环节。实验研究表明：肿瘤细胞容易黏附并聚集在微脉管的弯曲部位。数值研究证明：微脉管弯曲部位的复杂力学因素与这些部位易于黏附与转移肿瘤的现象有关，但对于这两者之间的定量关系并不清楚。鉴于此，本项目通过采用格子Boltzmann方法和随机Monte Carlo方法相结合的计算方法，系统研究了肿瘤细胞在弯曲微脉管内发生黏附行为的力学调控机制。基于研究结果，我们完成了几点关键性的研究工作：(1)发展了一套基于格子Boltzmann方法和随机Monte Carlo方法相结合的的计算方法，为研究肿瘤细胞在微脉管系统内的黏附规律提供了新方法；(2)建立了管壁血流剪切力及其梯度与肿瘤细胞黏附之间的关系，为今后研究血管内各力学因素与肿瘤细胞黏附规律之间的定量关系提供数据支持；(3)构造了针对肿瘤细胞与内皮细胞之间黏附的受体－配体结合动力学模型，为定量研究肿瘤细胞的随机黏附行为奠定理论基础。通过对本项目的研究，不仅为肿瘤细胞黏附机制的研究提供了新方法，而且拓展了格子Boltzmann方法科学计算的应用空间，同时也为揭开肿瘤细胞转移的奥秘和改进癌症治疗的策略提供了合理的科学依据。