Development and application of an agent‐based model for the simulation of the extravasation process of circulating tumor cells

Abstract

The primary cause for cancer-related death is metastasis, and although this phenomenon is the hallmark of cancer, it remains poorly understood. Since studies on the underlying mechanisms are still demanding by experimental means prognostic tools based on computer models can be of great value, not only for elucidating metastasis formation but also for assessing the prospective benefits as well as risks of a therapy for patients with advanced cancer. Here, we present an agent-based model (ABM), describing the complete process of platelet-assisted extravasation of circulating tumor cells (CTCs) from the chemoattraction of blood platelets by the CTCs up to the embedding of the CTCs in the epithelial tissue by computational means. From the simulation results, we conclude that the ABM produces results in consistency with experimental observations, which opens new perspectives for the development of computer models for predicting the efficacity of drug-based tumor therapies and assisting precision medicine approaches.agent-based model, circulating tumor cells, computer simulation of platelet-assisted extravasation, metastasis | INTRODUCTIONCancer is far from being a disease of the modern era. From an evolutionary point of view, it is a quite old disease. One of the oldest proven appearances of cancer was found in an Edmontosaurus. 1 However, cancer has developed to one of the diseases with a significant impact on the life expectancy of humans by causing nearly 10 million deaths per year worldwide. 2,3 Nowadays, the success of a cancer treatment is still highly dependent on the tumor stage of a carcinoma. 4 If the tumor is detected early and has not metastasized, the treatment has a higher chance to be successful, since it is still localized. By contrast, a carcinoma in an advanced stage has spread across multiple tissues/organs in the human body, decreasing the likelihood for a successful treatment. 4,5 To combat metastatic spreading, prognostic tools for the prediction of metastasis in combination with personalized strategies would be useful, but are still in an early stage of development. [6][7][8] The process of metastases formation comprises several steps. 9 First, the metastatic cells have to detach from the primary tumor, followed by the intravasation into the vascular system. 10 After the intravasation step, the cells, known