Growth as the Root of all Evil in Carcinomas: Synergy between pH Buffering and Anti-Angiogenesis Prevents Emergence of Hallmarks of Cancer

Abstract

The term “cancef’ is applied to a wide variety of illnesses that stem from uncontrolled growth of cells originating within the host. Cancer leads to death when the tumor burden is sufficiently large to interfere with the normal physiological functions. Each tumor is itself, a heterogeneous collection of habitats, predominantly due to variability in blood flow and cellular populations that exploit multiple different survival mechanisms and adaptive strategies. The resulting spatial and temporal heterogeneity typically foils cancer treatment, so that complete eradication of the cancer cells is only rarely observed and, indeed, may simply be impossible. All cancers, however, retain several conserved traits, or hallmarks, which represent convergent evolution of cellular strategies that are indispensible for malignancy. In this article we study the evolution of different strategies during solid tumor growth and invasion of the stroma. Using spatial computational models, we simulated the growth of phe- notypically heterogeneous tumor populations within multiple microenvironmental habitats formed by variations inblood flow. The simulations demonstrate the dynamics by which hypoxia, pH and nutrient gradients formed during tumor growth, affect the choice among different cellular adaptive strategies: invasion/migration, proliferation, quiescence, and angiogenesis. We propose that the canonical hallmarks of cancer stem from the natural environmental pressures imposed by the tumor-host microenvironment during tumor growth, and that the use of treatments that remove or relieve these selective pressures, as opposed to exacerbating them or killing as many cancer cells as possible, may induce tumor dormancy, and lead to more benefits than aggressive therapy in cases of currently incurable cancers.