Are there any comparatively simple ways in which natural cancer suppression mechanisms can be greatly enhanced? This is an interesting question to consider. The current repertoire of the cancer research and medical communities include what are arguably a few examples of an enhanced natural suppression mechanism, such as the various ways to drive more cancerous cells into a state of senescence than would normally make that transition. The study of the comparative biology of aging has uncovered a variety of suppression mechanisms in naked mole rats and elephants that might lead to human therapies, but I suspect that "simple" will not describe the programs needed to make any of those therapies a reality. More practical are means to enhance the immune system's capacity to attack cancer, spurring greater creation or greater replication of immune cells; examples include present IL-7 recombinant protein therapies, or potential future FOXN1 gene therapies.
The author of the open access paper below hypothesizes the existence of a cancer kill switch that has been overlooked largely because it exists in primates but not mice. If he is correct, then this would seem to offer an approach to therapy that falls squarely into the category of a potentially simple approach to enhance a natural mechanism. I feel that one should always treat single author papers with a certain polite skepticism until verified, however, even if, as seems to be the case here, it is reporting on work carried out by a team. The short version of the hypothesis is that (a) high levels of DHEAS can trigger the death of cells in which the primary tumor suppressor TP53 is disabled by mutation, (b) humans have unusually high levels of DHEAS in comparison to short-lived mammals such as mice, and (c) in humans, DHEAS levels fall with age, and thus the mechanism ceases to operate.
This has the look of a mechanism expensive enough to verify to discourage most teams from attempting to replicate findings in the absence of further supporting data. The only primate species in which the author believes the mechanism to exist are all endangered, protected, and cannot be easily studied in this context. The mechanism may exist in dogs, but that variant may or may not be close enough to the human variant to be useful. Further, the mechanism might almost be designed to be hard to work with in cell cultures and tissue models of cancer. There is also the very important question of the size of the effect: even if this is all as described, is it a significant effect in comparison to other issues that increase cancer risk in aging? Will it make enough of a difference if pursued and reactivated?
Cancer risk as a function of increasing age in elephants, wildebeest, moose and most other long-lived animals is linear, with little increase in slope with advancing age. This is in sharp contrast to cancer risk in humans, which increases in conformance with a logistic curve with a 30-year lag phase followed by steep exponential kinetics until very late in the life span. Taken together, these observations suggest that tumor suppression mechanisms in non-human species are generally of a type that does not substantially diminish over their lifespan, whereas those in humans do diminish with increasing age.
The p53 tumor suppressor is an ancient protein found in organisms ranging from Caenorhabditis elegans to Homo sapiens. Over the past four decades, a paradigm has evolved in which p53 is thought to function in a very similar manner across widely disparate species. More than half of all human tumors have been found to have mutations in TP53 (the human version of p53), and TP53 appears to be inactivated by other means in the remaining tumors where such mutations are absent. Findings have encouraged an exceptional degree of confidence among workers in the field that mouse models of tumor suppression offer reasonable approximations of mechanisms of tumor suppression in humans.
Thus, for the past several decades, the guiding paradigm with respect to the p53 tumor suppressor has been that it functions in a more or less similar manner across species at least as diverse as man and mouse, and probably across species even more diverse than that. It is our belief, however, that the establishment of this paradigm has come at the expense of ignoring more fundamental paradigms, and the prevailing p53 paradigm may have misled the endeavor of cancer research. The concept of species-specific mechanisms of tumor suppression is gaining increasing support. Recent evidence in the elephant, the blind mole rat, and canines, all support the concept that species-specific mechanisms of tumor suppression may in fact be relatively common.
Exposure to significant cellular stress is well known to activate the p53 tumor suppressor to induce apoptosis. We have recently reported our detection in canines of a rudimentary form of an otherwise primate-specific adrenal androgen-mediated 'kill switch' in which cell death is triggered by the inactivation of p53. It has been hiding in plain sight within the p53 repertoire and may have kept so well hidden because it depends on the unique, primate-specific evolution of extraordinarily high post-natal levels of circulating DHEAS. In humans, this begins at about age 6 years with the advent of adrenarche, the development of the adrenal zona reticularis, a tissue the only apparent function of which is to synthesize DHEAS. True adrenarche may only occur in the human, chimpanzee, and bonobo.
Nevertheless, dogs have a rudimentary zona reticularis and a homologue of adrenarche has been reported in them. Based upon this finding, we formulated the hypothesis that canines might also possess a homologue of the otherwise primate-specific adrenal androgen-mediated tumor suppressor system and that at least some canine tumors might retain sensitivity to triggering of this system.
Circulating DHEAS does not occur in common laboratory rats or mice, and the near exclusive use of such rodent models in cancer research over the past 40 years clearly contributed to the delay in the discovery of the primate-specific, adrenal androgen-mediated kill switch tumor suppression system. Additional research impediments have also contributed to the kill switch mechanism remaining occult throughout these decades of p53 research. Thus, it cannot be studied in transformed cells, because these have already escaped succumbing to it because of kill switch failure; following such failure, such transformed cells have also incurred an obfuscating patchwork of follow-on mutations and epigenetic variations. The kill switch tumor suppressor system is also a single cell phenomenon, and single cell analysis techniques have not yet reached the level of sophistication required to detect in real time a unique event occurring at a low rate in a vast excess of unaffected cells; let alone an event designed to extinguish that cell from existence. Our detection of this kill switch tumor suppression mechanism depended upon a rudimentary form of it occurring in dogs, and the fact that our laboratory works exclusively with dogs with spontaneous cancer.