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.

Figure 1.

A comparison between the interaction spaces presented by the spite models proposed by Hamilton (left panel) and Wilson (right panel). Mutualism could be represented through the support of tumor growth by nonmalignant cells [30]. Moreover, some cancer cells become addicted to InterLeukin-3 to survive (primed cell for death) and so benefit from the immune system, and this is a kind of selfishness [31]. Yet, microenvironment acidity-induced cancer spite (MAICS) results in excessive cell death and eventually might prevent its spreadability and so it lies under the altruism umbrella because it results in an encapsulated tumor [32]. Cannibalism at the end results in death of both normal and malignant cells under the context of organismal selection so it is compatible with spite. Therefore, it would be very interesting if further studies carry on for determining how tumors handle the thresholds of the four quadrants.

Figure 2.

Here we propose a hypothetical model in which the environment where the player interactions are carried out (i.e., the acidic extracellular space; blue background) can play an important role in determining the choice and dynamics of spite. At this point, it is not possible to determine if there is a space-time quadrant where the environment has a greater or lesser effect and this will be an interesting point for future research. (a) Because microenvironment acidity-induced cancer spite (MAICS) blunts the immune system [33], interference with MAICS would probably create a shifting to Wilsonian spite. Thus, the third party reappears (Z-axis in (b) (Wilsonian spite) (b) This kind of shifting does not misconstrue to malignant and normal cells only but a spite process could happen also between secondary tumor cells (cannibal cells) and primary tumor cells.