Does Cancer Biology Rely on Parrondo’s Principles?

Abstract

Many aspects of cancer biology remain puzzling, including the proliferative and survival success of malignant cells in spite of their high genetic and epigenetic instability as well as their ability to express migrating phenotypes and/or enter dormancy despite possible fitness loss. Understanding the potential adaptive value of these phenotypic traits is confounded by the fact that, when considered separately, they seem to be rather detrimental at the cell level, at least in the short term. Here, we argue that cancer’s biology and success could frequently be governed by processes underlying Parrondo’s paradox, whereby combinations of intrinsically losing strategies may result in winning outcomes. Oncogenic selection would favor Parrondo’s dynamics because, given the environmental adversity in which malignant cells emerge and evolve, alternating between various less optimal strategies would represent the sole viable option to counteract the changing and deleterious environments cells are exposed to during tumorigenesis. We suggest that malignant processes could be viewed through this lens, and we discuss how Parrondo’s principles are also important when designing therapies against cancer.

Bridging Tumorigenesis and Therapy Resistance With a Non-Darwinian and Non-Lamarckian Mechanism of Adaptive Evolution

“…Ubiquitous purifying selection is expected to most often purge these cells alongside possible beneficial mutations that frequently confer only a minimal selective advantage (49). Even when purifying selection is relaxed, the mere interaction of accruing deleterious mutations may facilitate adaptation (50,51). Finally, random genetic drift can lead to the fixation of deleterious mutations by sheer chance (52)(53)(54)(55)(56), and this drift also limits the ability of selection to refine a phenotype (57).…”

From developmental to atavistic bet‐hedging: How cancer cells pervert the exploitation of random single‐cell phenotypic fluctuations

“…Interestingly, cancer cells seem to harbor similar trends to exploit cellular stochasticity through bet-hedging processes. [34,35] Even though the strategies of retaining high variability at the phenotypic level, and of being more phenotypically stable may both appear to be losing strategies in the cancerous environment, the combination and fluctuation between them could constitute a Parrondo's paradox by being a winning strategy resulting from two losing strategies. [35] In other words, transitions between a state with strongly fluctuating expressions and lack of differentiated phenotypes that can be called cancer stem cell (CSC) in analogy with the properties of the "normal" stem cells, [36] and more differentiated states, would be advantageous in an evolutionary perspective.…”

Ecology and games in cancer: new insights into the disease

“…Parrondo’s paradox 14 is an anti-intuitive algorithm initially developed in physics and engineering which states that two losing strategies may win when combined. This paradox, it has been applied to evolutionary biology 15 and cancer 16 with interesting results. Applied to cancer therapy, for example, the strategy consists of two games played by a tumor cell after successively tossing a coin (head/tail) to make decisions.…”