Li Xuefei, Jolly Mohit Kumar, George Jason T, Pienta Kenneth J, Levine Herbert
Center for Theoretical Biological Physics, Rice University, Houston, TX, United States.
Department of Bioengineering, Rice University, Houston, TX, United States.
Front Oncol. 2019 Jan 23;9:10. doi: 10.3389/fonc.2019.00010. eCollection 2019.
Tumor microenvironments contain multiple cell types interacting among one another via different signaling pathways. Furthermore, both cancer cells and different immune cells can display phenotypic plasticity in response to these communicating signals, thereby leading to complex spatiotemporal patterns that can impact therapeutic response. Here, we investigate the crosstalk between cancer cells and macrophages in a tumor microenvironment through (computational) co-culture models. In particular, we investigate how macrophages of different polarization (M vs. M) can interact with epithelial-mesenchymal plasticity of cancer cells, and conversely, how cancer cells exhibiting different phenotypes (epithelial vs. mesenchymal) can influence the polarization of macrophages. Based on interactions documented in the literature, an interaction network of cancer cells and macrophages is constructed. The steady states of the network are then analyzed. Various interactions were removed or added into the constructed-network to test the functions of those interactions. Also, parameters in the mathematical models were varied to explore their effects on the steady states of the network. In general, the interactions between cancer cells and macrophages can give rise to multiple stable steady-states for a given set of parameters and each steady state is stable against perturbations. Importantly, we show that the system can often reach one type of stable steady states where cancer cells go extinct. Our results may help inform efficient therapeutic strategies.
肿瘤微环境包含多种细胞类型，它们通过不同的信号通路相互作用。此外，癌细胞和不同的免疫细胞都可以响应这些通信信号而表现出表型可塑性，从而导致可能影响治疗反应的复杂时空模式。在这里，我们通过（计算）共培养模型研究肿瘤微环境中癌细胞与巨噬细胞之间的相互作用。具体而言，我们研究不同极化的巨噬细胞（M1 与 M2）如何与癌细胞的上皮-间质可塑性相互作用，反之，表现出不同表型（上皮与间质）的癌细胞如何影响巨噬细胞的极化。基于文献中记载的相互作用，构建了癌细胞与巨噬细胞的相互作用网络。然后分析该网络的稳态。在构建的网络中去除或添加各种相互作用以测试这些相互作用的功能。此外，改变数学模型中的参数以探索它们对网络稳态的影响。一般来说，对于给定的一组参数，癌细胞与巨噬细胞之间的相互作用可以产生多个稳定的稳态，并且每个稳态对扰动都是稳定的。重要的是，我们表明该系统通常可以达到一种稳定的稳态，即癌细胞灭绝。我们的结果可能有助于为有效的治疗策略提供信息。
