Abstract
We recently reported our detection of an anthropoid primate-specific, ‘kill switch’ tumor suppression system that reached its greatest expression in humans, but that is fully functional only during the first twenty-five years of life, corresponding to the primitive human lifespan that has characterized the majority of our species' existence. This tumor suppression system is based upon the kill switch being triggered in cells in which p53 has been inactivated; such kill switch consisting of a rapid, catastrophic increase in ROS caused by the induction of irreversible uncompetitive inhibition of glucose-6- phosphate dehydrogenase (G6PD), which requires high concentrations of both inhibitor (DHEA) and G6P substrate. While high concentrations of intracellular DHEA are readily available in primates from the importation and subsequent de-sulfation of circulating DHEAS into p53-affected cells, both an anthropoid primate-specific sequence motif (GAAT) in the glucose-6-phosphatase (G6PC) promoter, and primate-specific inactivation of de novo synthesis of vitamin C by deletion of gulonolactone oxidase (GLO) were required to enable accumulation of G6P to levels sufficient to enable irreversible uncompetitive inhibition of G6PD. Malignant transformation acts as a counterforce opposing vertebrate speciation, particularly increases in body size and lifespan that enable optimized exploitation of particular niches. Unique mechanisms of tumor suppression that evolved to enable niche exploitation distinguish vertebrate species, and prevent one vertebrate species from serving as a valid model system for another. This here-to-fore unrecognized element of speciation undermines decades of cancer research data, using murine species, which presumed universal mechanisms of tumor suppression, independent of species. Despite this setback, the potential for pharmacological reconstitution of the kill switch tumor suppression system that distinguishes our species suggests that ‘normalization’ of human cancer risk, from its current 40% to the 4% of virtually all other large, long-lived species, represents a realistic near-term goal.
Highlights
Ever since Darwin, biologists have been unsuccessful at achieving a consensus regarding a description of species, and the process of speciation (Mayden 1997, Hey 2006)
Proper descriptions of species and speciation may not have been possible until the recent discoveries of species-specific mechanisms of tumor suppression, which we recently described in our Review paper ‘Detection of a primate-specific ‘kill switch’ tumor suppression mechanism that may fundamentally control cancer risk in humans’ (Nyce 2018), published in the November 2018 issue of Endocrine-Related Cancer
An apparent lex naturalis of vertebrate speciation. Because of their small size and short lifespan, mice evolved an economical, minimalist approach to tumor suppression in which the canonical p53 repertoire is sufficient to deal with cells that have suffered potentially transforming mutations
Summary
Ever since Darwin, biologists have been unsuccessful at achieving a consensus regarding a description of species, and the process of speciation (Mayden 1997, Hey 2006). Species-specific mechanisms of tumor suppression are fundamental elements of vertebrate speciation, and every vertebrate species has evolved its own, unique tumor suppression strategy to achieve the body plan that enables it to optimize resource assimilation. These unique tumor suppression strategies fundamentally distinguish vertebrate species. There is not a single drug in use in cancer today that did not fundamentally depend upon the use of murine species in its discovery and development, and the use of such model species is predicated upon there being a universal mechanism of action of p53, the ancient tumor suppression nexus from which cellular responses to potentially transforming DNA damage are distributed. This is exemplified by the fact that whereas p53 has long been called ‘the guardian of the genome,’ it is increasingly referred to as ‘the guardian of immune integrity,’ with its mutationstatus having the ability to modulate the immune state of both its micro- (for example, Fig. 3 in Munoz-Fontela et al 2016) and macro-environments (Pedersen et al 2013)
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