The “Naked Truth”

The naked mole-rat (NMR, Heterocephalus glaber) stands out from other rodent species for its long lifespan, which reaches approximately 30 years. ¹³ Even more noteworthy for this species is its apparent tumor resistance with a lack of reported neoplasia. ⁹ These features in NMRs have attracted the interest of many researchers to study it as a possible tool to finally unlock and understand mechanisms of aging and cancer resistance.

Conventionally, mice and rats are standard animal models for cancer research due in part to their short lifespan and high incidence of cancer. ¹ The relatively rapid onset of cancer in these models could suggest that anticancer mechanisms are less abundant in these species. ¹³ Using similar assumptions, scientists have hypothesized that NMRs must have either higher levels or more efficient anticancer mechanisms. Researchers have worked to detect which specific traits may confer cancer resistance to NMRs and several targets have been identified.

High molecular weight hyaluronan is secreted by NMR fibroblasts and overall is more abundant than in other species. Its accumulation is explained by a decreased activity of degrading enzymes as well as the unique sequence of hyaluronan synthase 2. ⁸ NMR cells have higher affinity for this extracellular matrix (ECM) component compared to mouse and humans. ⁸ This cellular interaction with the ECM leads to reduced growth because increased contact inhibition pathways activate the tumor suppressor locus inhibiting cyclin-dependent kinases 4a/b (Ink4a/b). ^13,14 The Ink4a/b locus encodes 3 tumor suppressor proteins (p15^INK4b, p16^INK4a, and alternate reading frame [ARF]), and this locus is one of the most commonly mutated sites in many human cancers. ¹⁴ In NMRs, the locus also produces a fourth protein (pALT^INK4a/b) that is unique to this species and has enhanced tumor suppressor activities compared to p15^INK4b or p16^INK4a. ¹⁴ To further validate this cancer inhibition pathway, hyaluronan was experimentally depleted and NMRs cells underwent neoplastic transformation. ¹³

Senescence is a physiologically nonreversible cellular state in which cells cease to divide. It can be induced by a variety of cellular stresses (eg, DNA damage), and by critical shortening of telomeres. ¹⁰ Senescent cells remain metabolically active and acquire a distinct secretory phenotype with production of a variety of growth factors, cytokines and enzymes with autocrine and paracrine effects. ¹⁰ While some secretions (eg, growth factors) can contribute to wound repair, other secretions (eg, metalloproteinases) could promote spread of cancer cells. As such, cellular senescence cannot be completely regarded as a tumor suppressor or resistance mechanism. A recent study showed that depletion of senescent cells in nonprogeroid mice extended their lifespan and partially reverted the age-related phenotype in certain organ systems. ² In support of this finding, NMRs have only nominal evidence of senescent cells. ⁴ A possible reason for this low level might be the experimental observation that a portion of NRM cells undergo apoptosis upon contact inhibition-induced senescence. ¹³

Several additional mechanisms may link the enhanced longevity and cancer resistance of NMRs including a higher rate of autophagy, higher telomerase activity and higher fidelity of mRNA translation into proteins compared to other species. ^9,11,16

The absence of overt cancer in this species, reported in several studies, has been an extraordinary backdrop and accelerant for NMR study in cancer research. ^5,6,9 However, in this issue of Veterinary Pathology, Delaney et al report 2 cases of cancer in zoo-raised NMRs. Thus, NMRs are in fact susceptible to cancer. ⁷ This unexpected and new observation raises several points of considerations for future investigational cancer studies using NMRs.

Cancer research could be significantly supplemented by studying the cause(s) of morbidity and mortality in this special population. In doing so, standard pathological phenotyping and cause-of-death analyses for each case should be performed following guidelines for laboratory rodent models to maintain uniform standards for species comparisons. ^3,12,15 Standardized pathological approaches will likely help identify additional cases of neoplasms, the presence of metastasis and define critical biological timelines for onset of tumorigenesis.

Traditional laboratory rodent models often lack spontaneous epithelial tumors (ie, carcinomas) that are the more common human cancers. This difference in tumor spectrum is recognized as a potential limitation for studying these rodent models of human cancers. ¹ Although small in number (n = 2), the initial report of cancer in NMRs is intriguing because both affected animals had tumors of epithelial or neuroepithelial origin. ⁷ Might the longevity of NMRs or other emergent factors predispose this species to a tumor spectrum more similar to humans for translational studies? Additional studies will likely expose and clarify the types of tumors in NMRs.

Lastly, could comparative analysis (eg, “triangulation”) between species further develop understanding of tumorigenesis by dissecting the molecular profiles of specific tumor types? For instance, do NMR tumors have somatic mutations affecting the INK4 locus as commonly seen in humans? Is the high molecular weight hyaluronan pathway affected? Are the molecular signatures comparable among mice, rats and/or humans? Do certain molecular signatures correlate to similarities or differences in prognosis or in diagnostic morphology? Further studies involving this type of comparative cancer research may help to answer these important questions and reveal the mechanisms of resistance to cancer.