Science Magazine, in reviewing 2013, declared cancer immunotherapy to be the breakthrough of the year. With a little less fanfare, the same issue nominated an unusual African mammal, Heterocephalus glaber, vertebrate of 2013. Otherwise known as naked mole rats (NMRs) these mouse-sized, walrus-look-alikes did not win their award for cuteness. Rather, an impressive collection of biological oddities makes them objects of intensifying scientific focus. Crowning their eccentricity is an exceptionally long lifespan and total imperviousness to cancer: not a single spontaneous tumour has ever been documented either in wild, or captive NMRs. The following discussion will highlight recent scientific advances into understanding the biology behind this cancer resistance, with an emphasis on the benefits of using NMRs as a model of cancer resistance, over mouse models of cancer susceptibility.
Distant cousins of mice, naked mole rats have been living as subterranean desert burrowers for at least 24 million years. Predictably, this lifestyle has driven a host of adaptations beyond their unappealing appearance. Behaviourally, colony living has pushed NMRs to the extreme, making them one of the few mammals to have adopted eusociality – think of a beehive with a single breeding queen. Eusocial behavior and large group living is strongly associated with an increased lifespan. Indeed NMRs typically live to see 30, which based on their body mass is 5 times longer than expected. This long lifespan appears to result from reduced susceptibility to infectious disease and cancer, in combination with a delayed onset of aging.
Many explanations for this marked attenuation of senescence have been reported. For example, in contrast to mice, NMRs have a very efficient mechanism for bone remodeling allowing prolonged skeletal integrity and they also exhibit elevated cellular protection mechanisms including less protein denaturation and higher levels of oxidation-resistant lipids. Yet, contrary to popular theories on the biology of aging, NMRs do not have especially long telomeres, nor do they have abnormal antioxidant, or ROS activity. Resistance to tumorigenesis, however, is perhaps most immediately interesting for direct application to human health and as recent research demonstrates, is mediated by multiple layers of defense mechanisms.
Two papers published this year have helped pinpoint systems preventing NMR tumorigenesis. Earlier work had demonstrated that in contrast to cells from other rodents, NMR fibroblasts grown in vitro arrest their cell cycle at a low cell density; a process termed early contact inhibition (ECI). Further, these fibroblasts could not be transformed by disruption of p53 in the presence of oncogenic Ras signaling and as long as ECI remained functional, the cells did not undergo uncontrolled growth. It was found that the ECI of naked mole rat fibroblasts was mediated by secretion of extremely high-molecular-mass hyaluronan, a substance abundantly found in NMR tissues, which perhaps evolved to increase skin elasticity. Knockdown of NMR hyaluronan was sufficient to inhibit ECI, allow for malignant transformation, and produce tumour growth in vivo. In addition to abnormal cell density, NMR 28s ribosomal RNA, involved in protein translation, contains a unique 263 nucleotide-long fragment. The presence of this fragment coincided with increased translational accuracy despite a maintained translational rate. Thus the results demonstrate that NMRs produce fewer dysfunctional proteins and maintain an unusually stable proteome.
Their long life, resistance to disease, and eusocial behavior make naked mole rats an example of intriguing biology. However, the citation from Science rather reflects the potential utility in elucidating natural mechanisms of cancer resistance. Mice are the go-to animal model of cancer (and of course immunology). Indeed, a short generation time, low cost, and exquisitely developed tools for genetic manipulation make the mouse an incredible vehicle for conducting biomedical research. Unfortunately, some of these very strengths may become misleading, particularly in the case of cancer biology. Try as we might fool ourselves, mice are not people. In fact, in many key areas the two species are at opposite ends of a biological phenotype. When estimating a species’ longevity based on body mass (a remarkably accurate calculation) humans and NMRs are clear outliers, both living 5 times longer than predicted. Mice are outliers, as well, only their longevity dips in the other direction. With regards to tumorigenesis, it is telling that over 70% of all laboratory mice left to age will die from cancer while human cancer incidence and mortality is under 25%. Exclusively, studying cancer in such an animal risks overlooking pathways already fine-tuned for the prevention of malignancy.
Understanding the naked mole rat’s unique protective strategies provides foundation and inspiration for harnessing our own natural defenses. The researchers who characterized the hyaluronan of NMRs believe that human hyaluronan signaling pathways provide a promising target for therapeutic intervention. For the immunologist, this is a lesson worth remembering. Experimental strategy often revolves around understanding disease state physiology; all too often we miss the unceremonious processes of steady-state toiling to ward off malfunction. Although, the naked mole rat immune system has thus far remained only superficially characterized, its biological robustness hints at interesting adaptations. This African super-rodent may prove a complementary cage-mate to the classic mouse, in cancer biology, aging, immunology, and beyond.
- Edrey, Y., et al. Successful Aging and Sustained Good Health in the Naked Mole Rat:A Long-Lived Mammalian Model for Biogerontology and Biomedical Research .ILAR 52, 41-53 (2011).
- Azpurua, J. & Seluanov, A. Long-lived cancer-resistant rodents as new model species for cancer research. Front. Genet. 3, 319 (2012).
- Tian, X. et al. High-molecular-mass hyaluronan mediates the cancer resistance of the naked mole rat. Nature 499, 346–9 (2013).
- Azpurua, J. et al. Naked mole-rat has increased translational fi delity compared with the mouse , as well as a unique 28S ribosomal RNA cleavage. PNAS 110, 17350–17355 (2013).
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