Multiscale modeling of tumor growth and angiogenesis: Evaluation of tumor-targeted therapy

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).
Author summary Mathematical modeling and simulation of cancer across different biological scales is becoming increasingly important in the development of therapeutic strategies. In the current work, a multiscale model is presented to study the growth and progression of tumor and angiogenesis based on tumor-host interactions which allows investigating the effects of tumor-targeted therapy. Considering the signal-transduction networks involved in various types of cancers, we proposed a cascade that encompasses some significant signaling pathways. A Boolean network model is employed to describe the receptors cross-talk. As a result of the activation of oncogenes and deactivation of pertinent gene signaling pathways within each cell, the cellular interactions and cell behavior are modeled. By linking cells state with environmental cues, the tumor morphology is determined. Consistent with the experimental observations, the intratumoral vascularization density resulting from the simulation reports malignancy grade as a prognostic parameter. Moreover, our model permits to explore possible novel therapeutic procedures, including therapies targeting specific pathways. It captures cellular apoptosis by receptor inhibition in tumor development as a new area of mathematical modeling of targeted therapy.