Abstract
Hypoxia and the pH level of the tumor microenvironment have a great impact on the treatment of tumors. Here, the tumor growth is controlled by regulating the oxygen concentration and the acidity of the tumor microenvironment by introducing a two-dimensional multiscale cellular automata model of avascular tumor growth. The spatiotemporal evolution of tumor growth and metabolic variations is modeled based on biological assumptions, physical structure, states of cells, and transition rules. Each cell is allocated to one of the following states: proliferating cancer, nonproliferating cancer, necrotic, and normal cells. According to the response of the microenvironmental conditions, each cell consumes/produces metabolic factors and updates its state based on some stochastic rules. The input parameters are compatible with cancer biology using experimental data. The effect of neighborhoods during mitosis and simulating spatial heterogeneity is studied by considering multicellular layer structure of tumor. A simple Darwinist mutation is considered by introducing a critical parameter (Nmm) that affects division probability of the proliferative tumor cells based on the microenvironmental conditions and cancer hallmarks. The results show that Nmm regulation has a significant influence on the dynamics of tumor growth, the growth fraction, necrotic fraction, and the concentration levels of the metabolic factors. The model not only is able to simulate the in vivo tumor growth quantitatively and qualitatively but also can simulate the concentration of metabolic factors, oxygen, and acidity graphically. The results show the spatial heterogeneity effects on the proliferation of cancer cells and the rest of the system. By increasing Nmm, tumor shrinkage and significant increasing in the oxygen concentration and the pH value of the tumor microenvironment are observed. The results demonstrate the model's ability, providing an essential tool for simulating different tumor evolution scenarios of a patient and reliable prediction of spatiotemporal progression of tumors for utilizing in personalized therapy.
Highlights
The cellular metabolism within a solid tumor is considerably different from the metabolism of the corresponding normal tissue [1]
Since hypoxia and the pH level of the tumor microenvironment have a large impact on a treatment, here, we focused on regulating the oxygen concentration and the acidity of tumor microenvironment in order to control the tumor growth rate
Since cellular automata is capable of producing complex patterns by applying simple rules, it is appropriate for expressing many features of selforganizing complex systems like tumors
Summary
The cellular metabolism within a solid tumor is considerably different from the metabolism of the corresponding normal tissue [1]. Most nonproliferating tissues primarily metabolize glucose to pyruvate by glycolysis in the presence of oxygen. Clinical observations in cancer cells by fluorodeoxyglucose-positron emission tomography have led to a hypothesis known as the acid-mediated tumor invasion. This hypothesis proposes that tumor-derived acid facilitates tumor invasion by promoting normal neighborhood cell death and extracellular matrix degradation of the parenchyma surrounding growing tumors. In other words, it results in altered glucose metabolism and increased glucose uptake, which is critical for the development of the invasive phenotype [5]
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