Lee Junho, Lee Donggu, Lawler Sean, Kim Yangjin
Department of Mathematics, Konkuk University, Seoul, Republic of Korea.
Department of neurosurgery, Brigham and Women's Hospital & Harvard Medical School, Boston, Massachusetts, United States of America.
PLoS Comput Biol. 2021 Feb 17;17(2):e1008257. doi: 10.1371/journal.pcbi.1008257. eCollection 2021 Feb.
Lung cancer is one of the leading causes of cancer-related deaths worldwide and is characterized by hijacking immune system for active growth and aggressive metastasis. Neutrophils, which in their original form should establish immune activities to the tumor as a first line of defense, are undermined by tumor cells to promote tumor invasion in several ways. In this study, we investigate the mutual interactions between the tumor cells and the neutrophils that facilitate tumor invasion by developing a mathematical model that involves taxis-reaction-diffusion equations for the critical components in the interaction. These include the densities of tumor and neutrophils, and the concentrations of signaling molecules and structure such as neutrophil extracellular traps (NETs). We apply the mathematical model to a Boyden invasion assay used in the experiments to demonstrate that the tumor-associated neutrophils can enhance tumor cell invasion by secreting the neutrophil elastase. We show that the model can both reproduce the major experimental observation on NET-mediated cancer invasion and make several important predictions to guide future experiments with the goal of the development of new anti-tumor strategies. Moreover, using this model, we investigate the fundamental mechanism of NET-mediated invasion of cancer cells and the impact of internal and external heterogeneity on the migration patterning of tumour cells and their response to different treatment schedules.
肺癌是全球癌症相关死亡的主要原因之一，其特征是劫持免疫系统以实现活跃生长和侵袭性转移。中性粒细胞原本应作为第一道防线对肿瘤建立免疫活动，但却被肿瘤细胞以多种方式破坏，从而促进肿瘤侵袭。在本研究中，我们通过建立一个涉及相互作用关键成分的趋化 - 反应 - 扩散方程的数学模型，来研究肿瘤细胞与中性粒细胞之间促进肿瘤侵袭的相互作用。这些关键成分包括肿瘤细胞和中性粒细胞的密度，以及信号分子和诸如中性粒细胞胞外陷阱（NETs）等结构的浓度。我们将该数学模型应用于实验中使用的博伊登侵袭实验，以证明肿瘤相关中性粒细胞可通过分泌中性粒细胞弹性蛋白酶增强肿瘤细胞侵袭。我们表明，该模型既能重现关于NET介导的癌症侵袭的主要实验观察结果，又能做出一些重要预测以指导未来实验，目标是开发新的抗肿瘤策略。此外，使用该模型，我们研究了NET介导的癌细胞侵袭的基本机制以及内部和外部异质性对肿瘤细胞迁移模式及其对不同治疗方案反应的影响。
