Computer simulation of hypoxia regulates avascular tumor growth through p27 expression

摘要

The growth dynamics of tumors is controlled by nutrients, biomechanical forces and other factors at different stages and in different environments is still largely unknown. We present a computer simulation for avascular tumor growth aimed at investigating the interaction between tumor morphology and the local environment. At the cellular level, a Glazier-Graner-Hogeweg (GGH) model describes cellular dynamics including cell proliferation, viability and adhesion. At the subcellular level, the expression of protein p27 regulates the cell cycle. At the extracellular level, the diffusion of oxygen, glucose and hydrogen ions describe the chemical dynamics involved in metabolism. In avascular phase, tumor cell proliferation depends on consuming oxygen and glucose from the pre-existing surrounding tissue. When the oxygen level drops below a threshold, the tumor cells become hypoxic and start anaerobic metabolism (glycolysis). Experimental evidence suggests that cancer cells undergo hypoxia-induced quiescence (G0 phase in the cell cycle). We assume that this progression is affected by protein p27, whose expression is upregulated under hypoxia, inhibits the activation of the cyclin dependent kinases (CDKs), thus preventing DNA synthesis and regulating the cell-cycle. Our work demonstrates tumor cells can undergo quiescence by increasing their levels of p27, which increase their survival chances in hypoxia situation. It also demonstrates the value of combining of computer simulation with experiments to uncover the interaction between the local micro-environment and the growth dynamics of the tumor.