Physicochemical microenvironment as key regulator for tumor microevolution, invasion, and immune response: Targets for endocytotechnological approaches in cancer treatment

Solid tumors exhibit a poorly organized vascularization and a deviant energy metabolism which result in an acidic pH and large hypoxic areas in the tumor microenvironment. Such physicochemical conditions have been shown to be promoters of the microevolution of malignant cells, inhibitors of the immune response, and co-factors for tumor cell invasion. To arrive at testable predictions, we developed a stochastic mathematical computer model for spatio-temporal tumor growth which integrates published experimental evidence on cellular pH regulation, cell proliferation, pH-induced apoptosis, and pH-dependent immune response. The computer simulations demonstrate that the imbalance between mitochondrial respiration and cytoplasmic glycolysis as well as the poorly organized vascularization result in an acidic microenvironment which locally confers competitive advantages on tumor cells at the expense of adjacent normal cells. Endocytotechnological treatment schemes which restore a tumor microenvironment reflecting that one found in normal tissues are proposed to improve the efficiency of immunotherapies and classical methods for cancer treatment.