Abstract
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.
Highlights
Lung cancer is still the leading cause of cancer-associated deaths worldwide, with 1.8 million deaths in 2018 [1, 2]
When cancer patients are diagnosed with tumours at a primary site, the cancer cells are often found in the blood or already metastasized to the secondary sites in other organs
Neutrophils have been considered as merely a bystander in the tumor microenvironment (TME) and metastasis [5,6,7] but they are emerging as an important player due to consistent and continuous evidences of their tumorpromoting roles [3]
Summary
Lung cancer is still the leading cause of cancer-associated deaths worldwide, with 1.8 million deaths in 2018 [1, 2]. Various cell types such as immune cells, fibroblasts, and endothelial cells in a tumor microenvironment (TME) interact with tumor cells via the cytokines and growth factors. While the classical form of neutrophils, called N1 TANs, can effectively eliminate tumor cells via lysis [11,12,13], TNF-α [14], or inducing tumor cell apoptosis [15], another form, called N2 TANs, can support tumor growth, invasion, metastasis [16,17,18,19,20] and poor clinical outcomes in many cancers [21]. Metastatic cancer cells were able to induce neutrophils to form metastasispromoting NETs without involving infection processes [22]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
