Uppal Abhineet, Wightman Sean C, Ganai Sabha, Weichselbaum Ralph R, An Gary
Department of Surgery, The University of Chicago Medicine, 5841 S, Maryland Avenue, MC 5094 S-032, Chicago, IL 60637, USA.
Theor Biol Med Model. 2014 Apr 12;11:17. doi: 10.1186/1742-4682-11-17.
Metastatic tumors are a major source of morbidity and mortality for most cancers. Interaction of circulating tumor cells with endothelium, platelets and neutrophils play an important role in the early stages of metastasis formation. These complex dynamics have proven difficult to study in experimental models. Prior computational models of metastases have focused on tumor cell growth in a host environment, or prediction of metastasis formation from clinical data. We used agent-based modeling (ABM) to dynamically represent hypotheses of essential steps involved in circulating tumor cell adhesion and interaction with other circulating cells, examine their functional constraints, and predict effects of inhibiting specific mechanisms.
We developed an ABM of Early Metastasis (ABMEM), a descriptive semi-mechanistic model that replicates experimentally observed behaviors of populations of circulating tumor cells, neutrophils, platelets and endothelial cells while incorporating representations of known surface receptor, autocrine and paracrine interactions. Essential downstream cellular processes were incorporated to simulate activation in response to stimuli, and calibrated with experimental data. The ABMEM was used to identify potential points of interdiction through examination of dynamic outcomes such as rate of tumor cell binding after inhibition of specific platelet or tumor receptors.
The ABMEM reproduced experimental data concerning neutrophil rolling over endothelial cells, inflammation-induced binding between neutrophils and platelets, and tumor cell interactions with these cells. Simulated platelet inhibition with anti-platelet drugs produced unstable aggregates with frequent detachment and re-binding. The ABMEM replicates findings from experimental models of circulating tumor cell adhesion, and suggests platelets play a critical role in this pre-requisite for metastasis formation. Similar effects were observed with inhibition of tumor integrin αV/β3. These findings suggest that anti-platelet or anti-integrin therapies may decrease metastasis by preventing stable circulating tumor cell adhesion.
Circulating tumor cell adhesion is a complex, dynamic process involving multiple cell-cell interactions. The ABMEM successfully captures the essential interactions necessary for this process, and allows for in-silico iterative characterization and invalidation of proposed hypotheses regarding this process in conjunction with in-vitro and in-vivo models. Our results suggest that anti-platelet therapies and anti-integrin therapies may play a promising role in inhibiting metastasis formation.
转移性肿瘤是大多数癌症发病和死亡的主要原因。循环肿瘤细胞与内皮细胞、血小板和中性粒细胞的相互作用在转移形成的早期阶段起着重要作用。这些复杂的动态过程在实验模型中已被证明难以研究。先前的转移计算模型主要集中在宿主环境中肿瘤细胞的生长，或根据临床数据预测转移的形成。我们使用基于主体的建模（ABM）来动态呈现循环肿瘤细胞与其他循环细胞粘附和相互作用所涉及的关键步骤的假设，研究其功能限制，并预测抑制特定机制的效果。
我们开发了早期转移的ABM（ABMEM），这是一个描述性的半机制模型，它复制了循环肿瘤细胞、中性粒细胞、血小板和内皮细胞群体的实验观察行为，同时纳入了已知表面受体、自分泌和旁分泌相互作用的表征。纳入了重要的下游细胞过程以模拟对刺激的反应激活，并根据实验数据进行校准。ABMEM通过检查动态结果（如抑制特定血小板或肿瘤受体后肿瘤细胞结合率）来确定潜在的阻断点。
ABMEM再现了关于中性粒细胞在内皮细胞上滚动、炎症诱导的中性粒细胞与血小板之间的结合以及肿瘤细胞与这些细胞相互作用的实验数据。用抗血小板药物模拟血小板抑制产生了不稳定的聚集体，频繁分离和重新结合。ABMEM复制了循环肿瘤细胞粘附实验模型的结果，并表明血小板在转移形成的这一先决条件中起关键作用。抑制肿瘤整合素αV/β3也观察到类似效果。这些发现表明，抗血小板或抗整合素疗法可能通过防止循环肿瘤细胞稳定粘附来减少转移。
循环肿瘤细胞粘附是一个复杂的动态过程，涉及多种细胞间相互作用。ABMEM成功捕捉了这一过程所需的关键相互作用，并允许结合体外和体内模型对关于这一过程的提出假设进行计算机模拟迭代表征和验证。我们的结果表明，抗血小板疗法和抗整合素疗法可能在抑制转移形成方面发挥有前景的作用。
