Abstract
BackgroundCarcinogenesis affects not only humans but almost all metazoan species. Understanding the rules driving the occurrence of cancers in the wild is currently expected to provide crucial insights into identifying how some species may have evolved efficient cancer resistance mechanisms. Recently the absence of correlation across species between cancer prevalence and body size (coined as Peto’s paradox) has attracted a lot of attention. Indeed, the disparity between this null hypothesis, where every cell is assumed to have an identical probability to undergo malignant transformation, and empirical observations is particularly important to understand, due to the fact that it could facilitate the identification of animal species that are more resistant to carcinogenesis than expected. Moreover it would open up ways to identify the selective pressures that may be involved in cancer resistance. However, Peto’s paradox relies on several questionable assumptions, complicating the interpretation of the divergence between expected and observed cancer incidences.DiscussionsHere we review and challenge the different hypotheses on which this paradox relies on with the aim of identifying how this null hypothesis could be better estimated in order to provide a standard protocol to study the deviation between theoretical/theoretically predicted and observed cancer incidence. We show that due to the disproportion and restricted nature of available data on animal cancers, applying Peto’s hypotheses at species level could result in erroneous conclusions, and actually assume the existence of a paradox. Instead of using species level comparisons, we propose an organ level approach to be a more accurate test of Peto’s assumptions.SummaryThe accuracy of Peto’s paradox assumptions are rarely valid and/or quantifiable, suggesting the need to reconsider the use of Peto’s paradox as a null hypothesis in identifying the influence of natural selection on cancer resistance mechanisms.
Highlights
Carcinogenesis affects humans but almost all metazoan species
While almost all metazoan species are affected by cancer [11,12,13,14] (Fig. 1), some animal species or individuals are more at cancer risk than others [4, 9, 15, 16], suggesting that resistance mechanisms have independently evolved in distant lineages [3, 4, 17]
We have shown that the hypotheses behind Peto’s paradox are rarely supported by evidence, and we question the relevance of using this paradox as a null hypothesis to identify selective pressures shaping cancer resistance mechanisms
Summary
In the constant search for novel therapeutic strategies against cancer, identifying and understanding natural tumor suppressor mechanisms could provide promising alternative avenues; this area of research still remains in its infancy [1,2,3,4,5]. Supporting evidence for Peto’s hypotheses is relatively scarce, mainly due to limited data on cancer prevalence in the wild [26], as well as owing to the fact that the existing evidence disproportionately focuses on certain organs and/or animal species. The simplicity of these hypotheses cast doubts on how accurate/relevant/correct is Peto’s paradox in explaining cancer resistance, when there is clear deviation from theoretical expectations to empirical data when considering cancer prevalence in human and animal populations. We discuss in details the potential ways to robustly assess the paradox, and argue that apart from body size, additional ecological, environmental and behavioral factors, together with the number of stem cells at the tissue/organismal levels should be considered when assessing cancer prevalence, and attempting to identify species with resistance to cancer
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