The dynamics of tumor growth and associated events cover multiple time and spatial scales, generally including extracellular, cellular and intracellular modifications. The main goal of this study is ...to model the biological and physical behavior of tumor evolution in presence of normal healthy tissue, considering a variety of events involved in the process. These include hyper and hypoactivation of signaling pathways during tumor growth, vessels’ growth, intratumoral vascularization and competition of cancer cells with healthy host tissue. The work addresses two distinctive phases in tumor development—the avascular and vascular phases—and in each stage two cases are considered—with and without normal healthy cells. The tumor growth rate increases considerably as closed vessel loops (anastomoses) form around the tumor cells resulting from tumor induced vascularization. When taking into account the host tissue around the tumor, the results show that competition between normal cells and cancer cells leads to the formation of a hypoxic tumor core within a relatively short period of time. Moreover, a dense intratumoral vascular network is formed throughout the entire lesion as a sign of a high malignancy grade, which is consistent with reported experimental data for several types of solid carcinomas. In comparison with other mathematical models of tumor development, in this work we introduce a multiscale simulation that models the cellular interactions and cell behavior as a consequence of the activation of oncogenes and deactivation of gene signaling pathways within each cell. Simulating a therapy that blocks relevant signaling pathways results in the prevention of further tumor growth and leads to an expressive decrease in its size (82% in the simulation).
Objectives
Computational modeling of biological systems is a powerful tool to clarify diverse processes contributing to cancer. The aim is to clarify the complex biochemical and mechanical ...interactions between cells, the relevance of intracellular signaling pathways in tumor progression and related events to the cancer treatments, which are largely ignored in previous studies.
Materials and Methods
A three‐dimensional multiscale cell‐based model is developed, covering multiple time and spatial scales, including intracellular, cellular, and extracellular processes. The model generates a realistic representation of the processes involved from an implementation of the signaling transduction network.
Results
Considering a benign tumor development, results are in good agreement with the experimental ones, which identify three different phases in tumor growth. Simulating tumor vascular growth, results predict a highly vascularized tumor morphology in a lobulated form, a consequence of cells' motile behavior. A novel systematic study of chemotherapy intervention, in combination with targeted therapy, is presented to address the capability of the model to evaluate typical clinical protocols. The model also performs a dose comparison study in order to optimize treatment efficacy and surveys the effect of chemotherapy initiation delays and different regimens.
Conclusions
Results not only provide detailed insights into tumor progression, but also support suggestions for clinical implementation. This is a major step toward the goal of predicting the effects of not only traditional chemotherapy but also tumor‐targeted therapies.
The model simulates the tumor development processes at intracellular, cellular, and extracellular scales. A diagram of the different events at each scale is shown. The extracellular scale describes tumor growth associated with angiogenesis, by calculating the diffusion of VEGF, nutrients, and the therapeutic drugs. The environmental conditions activate receptors' prompting signaling cascades inside cells, and, consequently, the behavior of each cell is predicted at the intracellular scale. The interaction between cells of different phenotypes is described at the cellular level.
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