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Peto's paradox: Elephants, whales, Chihuahuas and cancer
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We have long been fascinated by the relationship between oncogenesis and ontogenesis, the factors that influence both, and the potential “reversibility” of cancer.
Decades ago, Leroy C. Stevens, PhD, and G. Barry Pierce, MD, conducted a series of studies in 129 strain mice that demonstrated the reversibility of certain types of malignant change and the role of the “steel” gene — the human homolog of c-KIT or stem cell factor — in the development of murine teratocarcinoma. What is so intriguing is their observation that the implantation of murine teratocarcinoma cells at different sites could lead to overt undifferentiated malignancy or to the evolution of well-differentiated tissues.
In humans, we can now cure advanced germ cell tumors by a combination of chemotherapy and surgery, often finding that resected residual masses after chemotherapy contain fully differentiated tissues without overt malignant elements. This was initially thought to portend permanent cure, but in recent times we have learned that unresected masses sometimes retain occult malignant potential and can de-differentiate decades later creating a new, life-threatening problem. What triggers this late process is not known.
Peto’s paradox
The triggers of cancers that are unrelated to specific expression or alteration of oncogenes or suppressor genes, and without obvious carcinogen exposure, have been the subjects of intense study for decades. In the past few months, we have had to review our fundamental concepts of tumor biology after reminders in the popular press of the impact of the so-called “Peto’s paradox,” the observation that, despite the dramatic size differential between whales and elephants compared with humans — with concomitantly vastly increased cell numbers, which would be subject to mutation — there is no concomitant increase in the proportion of these large mammals that develop spontaneous malignancy.
Of course, we are all sadly aware that the Beluga whales found in the St. Lawrence Estuary have a surprisingly high incidence of cancer, perhaps due to the toxic waste emanating from some the adjacent heavy industries upstream. However, beyond that, the prevalence of cancer in large epidemiological and pathological surveys of elephants and whales, respectively with a 100- to 500-fold greater body mass and number of cells than humans, have shown no increment in incidence or frequency of malignant tumors.
Theoretical explanations
Many theoretical explanations have been advanced, including lower somatic mutation rates, different tissue architecture, variation in immunological function, alterations of apoptotic process, varied telomere length or function, or redundancy of tumor suppressor genes.
Nagy and colleagues have proposed the fanciful concept that malignant tumors are disadvantaged in larger hosts because natural selection acts on competing phenotypes among the cancer cell population, favoring aggressive clones that then grow as a hypertumor arising from the initial “parent” tumor, leading to the destruction of both.
Abegglen and colleagues have postulated an interesting explanation with provocative supporting data. Although confirming that cancer mortality did not increase with body size and/or life span, they showed that elephants have at least 20 copies of the TP53 suppressor gene, and that their lymphocytes underwent p53-mediated apoptosis at a lower threshold and thus at higher rates than their human counterparts after exposure to radiation or doxorubicin. These processes could potentially offer an evolutionary de facto strategy for cancer avoidance in larger animals. However, it should be noted that there are some potential weaknesses to this body of work, including some assumptions related to the similarity of regulation and control of p53 function in elephants and humans, and lack of knowledge of the functionality of the proteins produced by TP53 retrogenes in elephants.
That said, this is interesting work that captured the imagination of the press, and consequently led to new conversations at cocktail parties — and perhaps a new line of research in the domain of the well-funded cancer prevention lobby.
When one thinks of size and cancer, those who own the courageous, somewhat yappy, breed of sad-eyed, five-pound Chihuahuas might become anxious. So, I checked my sources, and it appears that, for some reason, although they are prey to hypoglycemia, hydrocephalus, dental problems, tracheal collapse, arthritis and bladder stones, they do not have an increased incidence of cancer. However, I did find one report suggesting that overfeeding and obesity do lead to an increased risk for some cancers in these little dogs, a curious parallel to the human condition.
Lastly, although it has been proposed that shark cartilage may be useful for cancer therapy, based on the myth that sharks do not develop malignancy, the fact is that sharks actually do get cancer. Thus, this essay does not support that proposition, and further I wish to emphasize that the thought that the hunting of elephants and whales, to secure some unproven constituent for alternative medications, is a dreadful idea.
References:
Abegglen LM, et al. JAMA. 2015;doi:10.1001/jama.2015.13134.
Caulin AF and Maley CC. Trends Ecol Evol. 2011,doi:10.1016/j.tree.2011.01.002.
Martineau D, et al. Environ Health Perspect. 2002;110:285-292.
Nagy JD, et al. Integ Comp Biol. 2007;doi:10.1093/icb/icm062.
Peto R, et al. Brit J Cancer. 1975;32:411-426.
For more information:
Derek Raghavan, MD, PhD, FACP, FRACP, FASCO, is HemOnc Today’s Chief Medical Editor for Oncology. He also is president of Levine Cancer Institute at Carolinas HealthCare System. He can be reached at derek.raghavan@carolinashealthcare.org.
Disclosure: Raghavan reports no relevant financial disclosures.