Tumor Acidity as Evolutionary Spite

Abstract

Most cancer cells shift their metabolic pathway from a metabolism reflecting the Pasteur-effect into one reflecting the Warburg-effect. This shift creates an acidic microenvironment around the tumor and becomes the driving force for a positive carcinogenesis feedback loop. As a consequence of tumor acidity, the tumor microenvironment encourages a selection of certain cell phenotypes that are able to survive in this caustic environment to the detriment of other cell types. This selection can be described by a process which can be modeled upon spite: the tumor cells reduce their own fitness by making an acidic environment, but this reduces the fitness of their competitors to an even greater extent. Moreover, the environment is an important dimension that further drives this spite process. Thus, diminishing the selective environment most probably interferes with the spite process. Such interference has been recently utilized in cancer treatment.

A general reaction–diffusion model of acidity in cancer invasion

“…Nevertheless, it is promising that we have attained such behaviours, in part because they may provide good targets for model validation. In this respect our model fits into a larger goal of assessing possible experiments that will test the acid-mediated invasion hypothesis, an important task in light of novel treatment strategies, such as buffering therapy (Robey et al 2009;Silva et al 2009;Martin et al 2010Martin et al , 2011Alfarouk et al 2011;Robey and Martin 2011), to which the hypothesis has given rise.…”

“…If true, this could lead to novel therapeutic strategies. One such treatment currently in developmentbuffering therapy-was motivated by the modelling conclusions in Gatenby and Gawlinski (1996) and aims to strip a developing tumour of its selective advantage by neutralising the pH of the microenvironment (Robey et al 2009;Silva et al 2009;Martin et al 2010Martin et al , 2011Alfarouk et al 2011;Robey and Martin 2011). In this paper we aim to further our understanding of acid-mediated invasion by generalising the GatenbyGawlinski model from the highly aggressive special cases considered in Gatenby and Gawlinski (1996) to capture a wider range of tumour behaviours which may be clinically relevant.…”

Tumor metabolism, cancer cell transporters, and microenvironmental resistance

“…Lactate is extruded continuously from transformed cells due to a switch from the Pasteur effect to the Warburg effect 1 . The presence of lactate extracellularly preserves a favorable habitat for malignant cells and an unfavorable environment for normal cells, so it offers and evolutionary advantage to tumor cells 50 . Tumor cells are highly adaptable, and it has been noted that individual tumors are composed of cells of different metabolic phenotypes.…”

“…In tumorigenesis, all of these components are working together in this unusual acidic medium 50 . Although some studies suggest that these ion channels mediate carcinogenesis by creating a hostile and sanctuary environment 29,39,118 , other suggests that these ion channels are an adaptation to the intolerable acidity created within cancer cells 119 .…”

“…Extrusion of protons into the extracellular milieu results in the generation of an acidic pH 1,50 . This extracellular acidity leads to protonation of weakly basic drugs as doxorubicin, decreasing their partitioning inside cells 42 ( Figure 4).…”