High-molecular-mass hyaluronan mediates the cancer resistance of the naked mole rat

Abstract

The naked mole-rat displays exceptional longevity, with a maximum lifespan exceeding 30 years1–3. This is the longest reported lifespan for a rodent species and is especially striking considering the small body mass of the naked mole-rat. In comparison, a similarly sized house mouse has a maximum lifespan of 4 years4,5. In addition to their longevity, naked mole-rats show an unusual resistance to cancer. Multi-year observations of large naked mole-rat colonies did not detect a single incidence of cancer2,6. Here we identify a mechanism responsible for the naked mole-rat’s cancer resistance. We found that naked mole-rat fibroblasts secrete extremely high molecular weight hyaluronan (HA), which is over five times larger than human or mouse HA. This high molecular weight HA accumulates abundantly in naked mole rat tissues due to the decreased activity of HA-degrading enzymes and a unique sequence of hyaluronan synthase 2 (HAS2). Furthermore, the naked mole-rat cells are more sensitive to HA signaling, as the naked mole rat cells have a higher affinity to HA than the mouse or human cells. Perturbation of the signaling pathways sufficient for malignant transformation of mouse fibroblasts fails to transform naked mole-rat cells. However, once high molecular weight HA is removed by either knocking down HAS2 or overexpressing the HA-degrading enzyme, Hyal2, naked mole-rat cells become susceptible to malignant transformation and readily form tumors in mice. We speculate that naked mole-rats have evolved a higher concentration of HA in the skin to provide skin elasticity needed for life in underground tunnels. This trait may have then been co-opted to provide cancer resistance and longevity to this species.

Copy number variation associates with mortality in long‐lived individuals: a genome‐wide assessment

“…The STARD13 gene has moreover been associated ( P  ≤ 1 × 10 −5 ) with plasma levels of amyloid beta peptides that, among other things, play a role in Alzheimer's disease and hypertension (Chouraki et al ., 2014). In addition, also the CCDC3 and IRAK1BP1 genes could be speculated to play a role in human lifespan, as they have been reported to inhibit inflammation (Conner et al ., 2008, 2010; Azad et al ., 2014), and as revealed by the GO enrichment analysis, the majority of the other genes are involved in cell adhesion, which has previously been linked to longevity and age‐related diseases (Wolfson et al ., 2009; Tian et al ., 2013). …”

Molecular evolution of the hyaluronan synthase 2 gene in mammals: implications for adaptations to the subterranean niche and cancer resistance

“…There has been considerable interest in the ability of NMRs to resist cancer [1,2], and recently, a mechanism involving the production of a high molecular mass hyaluronan (HMM-HA) has been proposed [3]. Hyaluronan (HA) is a glycosaminoglycan and its presence in a variety of tissues and the extracellular matrix has been linked to many cellular processes, such as cell division, motility and morphogenesis [4], and also implicated in the development of some cancers [5].…”

Interdisciplinarity: Bring biologists into biomimetics

“…Naked mole rats, for instance, which can live up to about 30 years -an order of magnitude longer than related rodents -may have adaptations that are relevant to the treatment of age-related diseases such as cancer. Indeed, experiments have revealed that an extracellular substance makes the cells of naked mole rats remarkably tumour-resistant 5 .…”