Can Peto\u27s paradox be used as the null hypothesis to identify the role of evolution in natural resistance to cancer? A critical review

BACKGROUND: Carcinogenesis 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\u27s 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\u27s paradox relies on several questionable assumptions, complicating the interpretation of the divergence between expected and observed cancer incidences. DISCUSSIONS: Here 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\u27s 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\u27s assumptions. SUMMARY: The accuracy of Peto\u27s paradox assumptions are rarely valid and/or quantifiable, suggesting the need to reconsider the use of Peto\u27s paradox as a null hypothesis in identifying the influence of natural selection on cancer resistance mechanisms

Two steps to suicide in crickets harbouring hairworms

Sanchez MI, Ponton F, Schmidt-Rhaesa A, Hughes DP, Misse D, Thomas F. Two steps to suicide in crickets harbouring hairworms. Animal Behaviour. 2008;76(5):1621-1624

Weight curves of mice bitten by RVFV-exposed <i>Aedes aegypti</i>.

<p>Ten C57Bl/6 mice were anesthetized and exposed to bites of mosquitoes collected at D19 after virus exposure. The blue and violet curves correspond to mice bitten by 6 mosquitoes (6 of 6 and 4 of 6 mosquitoes were infected respectively). The yellow curve represents a mouse bitten by 8 mosquitoes (3 of 8 mosquitoes were infected). The red curve corresponds to a mouse bitten by 3 (3 of 3 mosquitoes were infected). The black curve corresponds to 7 mosquito bites (4 of 7 mosquitoes were infected) and the green curve corresponds to 9 mosquito bites (3 of 9 mosquitoes were infected). The red arrow indicates the death of the mouse. Two other mice were bitten by 6 mosquitoes (6 of 6 and 4 of 6 mosquitoes were infected respectively) and did not die after 11 days of observation (dark red and light blue curves). Mosquitoes did not feed on 2 mice (brown and turquoise curves).</p

Comparison of RVFV dissemination at D6 in various organs for the two routes of injection.

<p>Six C57Bl/6 mice were infected ID or IP with 10³ pfu, sacrificed at D6 post-infection and the viral titers were determined by plaque assay. The white bars correspond to the IP route and black bars to the ID route. Data are from 3 independent experiments. * indicates significant differences in viral titers between the two sets of data as determined by Mann-Withney test (** p<0.01); *** p<0.001).</p

Distribution of different cells in the blood of infected mice at 5 DPI.

a,b,c<p>The statistical significance of different comparisons (p<0.05) are represented by letters: a) uninfected mice vs. ZH-infected mice; b) RVFV-infected mice vs. RVFV+SGE infected mice; and c) healthy mice vs. RVFV+SGE infected mice. Ten mice were tested in each group.</p

Histological sections of liver at D5 post-infection.

<p>Five C57Bl/6 mice were injected with RVFV at 10³ pfu/mouse. Images A and C correspond to the livers of mice infected in the presence of 1 SGP and viewed at 4X and 10X magnification, respectively (inset in C is 40X). The arrow head in A and C identify inflammatory foci. The arrow in the inset of C identifies a necrotic hepatocyte, and the asterisk identifies neutrophil infiltration. Panel B and D correspond to the livers of mice infected in the absence of SGE at 4X and 10X magnification, respectively. The arrows in the inset in D show a necrotic hepatocyte foci.</p

Rare and unique adaptations to cancer in domesticated species : an untapped resource?

Strong and ongoing artificial selection in domestic animals has resulted in amazing phenotypic responses that benefit humans, but often at a cost to an animal's health, and problems related to inbreeding depression, including a higher incidence of cancer. Despite high rates of cancer in domesticated species, little attention has been devoted to exploring the hypothesis that persistent artificial selection may also favour the evolution of compensatory anticancer defences. Indeed, there is evidence for effective anti-cancer defences found in several domesticated species associated with different cancer types. We also suggest that artificial selection can favour the “domestication” of inherited oncogenic mutations in rare instances, retaining those associated to late and/or less aggressive cancers, and that by studying these seemingly rare anticancer adaptations, novel cancer treatments may be found

Weight curves of mice infected by ID and bitten by non-infected mosquitoes.

<p>Three lots (A, B and C) of 5 C57Bl/6 anesthetized mice were used for each experiment. They were injected ID with 50 pfu of RVFV before being exposed to the bites of 20 mosquitoes contained in cardboard boxes. After 15 minutes, blood-fed mosquitoes were collected and counted. After exposure, the weight of each mouse was recorded every day. Each curve corresponds to one mouse and the number of non-infected bites is indicated in the legend on the figure. Death occurred at the end of each curve.</p

Viral titers of major target organs at D5 post-infection.

<p>Three lots of <b>5 C57Bl/6 mice</b> were infected by ID injection of 10³ pfu RVFV with or without 1 SGP. RVFV titer was determined by plaque assay on E6 cells at D5 post-infection. Results are presented as box-and-whisker, indicating inside the box the median titer value and the bottom and top of the box being the 25th and 75th percentile. Whiskers correspond to the lowest and largest values of the titers. Mann-Withney test was employed to analyze the difference between sets of data for each organ. * p<0.05; ** p<0.01.</p

Survival curves of mice.

<p>Ten C57Bl/6 mice per group were injected with several doses of RVFV ranging from 10 to 10⁴ pfu/mouse (respectively A to D), in the absence (yellow curve) or presence of 1 SGP (red curve).</p