Implications of acidic tumor microenvironment for neoplastic growth and cancer treatment: a computer analysis

The acidic microenvironment found in most solid tumors appears to be a main regulator for the self-organized development of neoplastic growth and invasion. Induced by mitogenic stimulation and/or oncogenic alterations in their signal transduction network, tumor cells develop an improved capability for acid extrusion. This clamps intracellular pH to slightly alkaline values permissive for growth and proliferation and provides tumor cells with an enhanced resistance against acidic extracellular conditions. Since rapid tumor cell growth under hypoxic conditions is accompanied by glycolytic metabolism, and consequently, acid production, acid export is further enhanced. Local extracellular acidification is facilitated by microcirculatory inadequacy resulting in both reduced buffering capacity and functional heterogeneity inside the tumor. Significant microenvironmental pH gradients promote tumor cell invasion and inhibit the immune response. The scenario is checked by means of a dynamic computer model. The stochastic minimal model supports the hypothesis that acidification of the microenvironment by malignant cells cannot only be regarded as a supplementary side effect of tumor cell metabolism, but rather as a strategic principle to 'enslave' processes normally counteracting neoplastic growth and invasion. The results are discussed with respect to current concept for cancer treatment.