【作者】 李昂；

【导师】 孙仁；

【作者基本信息】 上海交通大学 ， 力学， 2020， 博士

【摘要】 癌症在人体发生转移的过程主要经历两种微环境,其一是静脉血管内的血流环境,其二是细胞外基质环境。循环肿瘤细胞在血管内完成黏附和外渗后,进而侵入周边组织形成转移。了解肿瘤细胞转移的机制,对癌症诊断和治疗具有重要意义。依据已有的实验数据,论文建立了生物力学模型来研究肿瘤细胞黏附和转移的两个实例:1)血管中循环肿瘤细胞与白细胞的相互作用;2)间质液流作用下肿瘤细胞在三维细胞外基质中的转移。先前的研究表明,血液循环肿瘤细胞在多形核白细胞提供中间介导后,黏附率会提高约2倍。由于该过程发生在血管内的剪切流动中,因此其水动力学环境会对其黏附造成重要影响。本文用水动力学方法建立了近壁面肿瘤细胞运动模型,借助计算流体力学软件准定常地模拟肿瘤细胞整个近壁运动过程,并利用生物力学判据对白细胞和肿瘤细胞黏附与否进行判定。研究发现,当来流剪切率为50 s^-1时,循环肿瘤细胞接触到附着的白细胞后会始终沿其表面运动,最终形成黏附。在生化键的影响下,肿瘤细胞与白细胞的接触时间增加了近1倍;当来流剪切率提高至200 s^-1时,肿瘤细胞会在白细胞表面某一位置脱离,没有形成黏附,但形成的生化键可以将其接触时间延长58.6%。研究结果表明,当血液流动剪切率较低,或者细胞表面配体数量较高时,肿瘤细胞会与血管壁面上的白细胞形成黏附,当血液流动剪切率较高,或者细胞表面配体数量较低时,肿瘤细胞受到的迁移水动力大于生化键施加的黏附力,因而会在血液流中继续循环。论文得出了基于流动剪切率和细胞配体数量两个参数的癌细胞黏附判据。细胞外基质是人体结缔组织的主要构成物质,其主要成分是胶原蛋白纤维和间质液。恶性肿瘤在组织中的转移与外基质本身的特性有直接关联,如间质液流动、趋化物浓度分布、胶原纤维排列、胶原纤维刚度等因素。论文从力学角度分析了胶原蛋白纤维在流动冲刷下发生的重构现象,并根据Cox提出的低雷诺数流动下细长体水动力学问题的理论解,获得了细长圆柱形纤维的受力公式,推导出纤维排列方向与间质液流速的关系。在此基础上把肿瘤细胞的运动速度、胶原纤维群排列和刚度统一起来,提出了胶原纤维群对肿瘤细胞迁移的空间阻力模型。结合生化键模型、趋化模型和力平衡方程,最终建立起肿瘤细胞在细胞外基质中转移的综合模型。依据此模型,论文分别以流动与纤维群重构、流动与纤维群排列方向、流动与纤维刚度等关系为考察对象,利用自编程序和计算软件模拟了癌细胞在外基质中的转移过程。通过与已有的实验数据比较后得出如下结论:1)间质液流动造成的纤维群重新排列可以提高肿瘤细胞的方向性转移;2)间质液流动和平行于流场方向排列的纤维群对肿瘤细胞的方向性转移具有叠加效果,并且肿瘤细胞的位移与间质液流速符合异速生长型函数关系;3)间质液流动和纤维群刚度梯度方向对肿瘤细胞的方向性转移具有叠加效果;4)流动剪切力可提高肿瘤细胞表面局部黏附键强度,当肿瘤细胞上下游表面剪切力非对称分布时,细胞逆流动方向转移。更多还原

【Abstract】 The microenvironment of tumor metastasis can be divided into two different types:One is situated in such blood flows within venules and the other is in extracellular matrix（ECM）.After finishing adhesion and extravasation to the blood vessel,tumor cells invade to surrounding tissue and metastasis to distant organs.Better understanding of mechanism of the tumor migration is important to cancer diagnosis and treatment.According to the published experimental data,we establish a biomechanical model to study the two issues of tumor metastasis:1)Interaction between a circulating tumor cell and a leukocyte in blood vessel.2)Migration of a cancer cell through 3D ECM.Previous study shows the adhesion efficiency of circulating tumor cells can be double promoted since leukocytes exist.The hydrodynamic environment has an important influence on the tumor adhesion in blood shear flow.In this dissertation,a computational software coupled with a quasi-steady description is exploited to investigate the micro environment of a tumor cell approaching the wall.The final adhesion is determined by biomechanical cues during the cell migration progress.On the condition of shear rate 50 s^-1,the tumor cell rolls along the surface of the leukocyte during entire progress.The contact time of the tumor cell and leukocyte is doubled influenced by the biochemical bond.On the condition of shear rate 200 s^-1,the tumor cell detaches from the leukocyte at a moment.The contact time is prolonged by 58.6%influenced by the biochemical bond,which facilitates tumor cell adhesion to the leukocyte.When the shear rate is high and the number of receptors on cell surface is small,tumor cell adheres to the leukocyte.On the contrary,tumor cell cannot be adhered when the shear rate is low as well as the number of receptors on cell surface is large.Criterion of tumor cell adhesion is obtained with regard to shear rate and the number of receptors.ECM is the primary component of human tissues and the main fraction of ECM is collagen fiber and interstitial flow.Tumor metastasizes through surrounding tissues is directly related to the properties of ECM,such as interstitial flow,distribution of chemokines,collagen fiber alignment and stiffness of ECM.In this paper,the realignment of collagen fiber is studied from the perspective of mechanics.According to the analysis of a slender body in low-Reynolds-number flow proposed by Cox,we deduce the hydrodynamic force on the cylindrical fiber as well as the flow speed effect on the fiber alignment.Factors such as cell migration speed,ECM alignment and stiffness are integrated into the ECM resistance model.Ultimately,the tumor migration model is established based on the binding force,chemotaxis and balancing equation.Based on this model,we investigate the flow versus fiber reconstitution,flow versus fiber alignment and flow versus ECM stiffness.Matlab program and computational software are utilized to simulate cancer cell migration.Comparing the simulation and experiment,we claim 1)ECM realignment caused by interstitial flow facilitates tumor directional migration.2)Interstitial flow and parallel aligned ECM have synergistical effect on cell migration.Allometric function is found between the displacement and flow speed.3)Interstitial flow and ECM stiffness have synergistical effect on cell migration.4)Shear stress enhances the binding strength.The asymmetric shear stress at upstream and downstream of cell leads to cell migrating against flow.更多还原