The Bionic Cancer-Resistant Extracellular Matrix of the Naked Mole-Rat

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Science Translational Medicine  31 Jul 2013:
Vol. 5, Issue 196, pp. 196ec125
DOI: 10.1126/scitranslmed.3007045

In the year 2050, children will be well versed in the exemplars of scientific folklore: Gravity was discovered when an apple fell on Newton’s head; penicillin was invented when Fleming’s petri dish acquired mold after he mistakenly left it open; cancer was cured when a group of scientists cultured the cells of a naked mole-rat.

Nature has performed a multibillion-year worldwide experiment of evolution and natural selection, providing a scientific petri dish containing adaptations and innovations often beyond the most creative ideas of the most innovative scientists. The naked mole-rat (NMR) is subjected to particularly intense evolutionary pressure to innovate because of its rugged lifestyle burrowing through self-created underground tunnels in East Africa. As one consequence of its adaptation, the NMR may be among nature’s ugliest creatures. As another, it is remarkably resistant to cancer. Tian et al. discovered that the cancer resistance of NMR cells is due to secretion of a high-molecular-mass version of hyaluronan (HMM-HA) and suggest potential therapeutic strategies for increasing HMM-HA production in humans.

The researchers observed that NMR fibroblasts increased the viscosity of their culture media by secreting HMM-HA. What’s more, these HMM-HA–excreting NMR cells displayed a p16INK4a-dependent early contact inhibition phenotype, in which cell growth was arrested at low cell densities. HAS2, a highly conserved enzyme responsible for HA synthesis, was overexpressed in NMR fibroblasts. When the authors looked more closely, they found that the NMR HAS2 protein contains two active-site amino acid substitutions not observed in other mammals, and molecular cloning experiments demonstrated that these substitutions lead to HMM-HA production. Indeed, NMR cells produce HMM-HA in vivo but also have decreased activity of HA-degrading enzymes, HAases. Adding back these HAases reversed the early contact inhibition phenotype, as did inhibition of the HA receptor, CD44. Moreover, NMR fibroblasts that are normally resistant to malignant transformation by H-Ras V12 and SV40 large T antigen lose this resistance by HAase-mediated degradation of HA, by CD44-mediated inhibition of HA, or by short hairpin RNA (shRNA)–mediated repression of HA. Mouse xenograft experiments confirmed that NMR cells are resistant to transformation, and resistance was overcome by HA knockdown by means of shRNA or overexpression of the HA-degrading enzyme HYAL2.

The authors suggest that NMR HMM-HA itself may be used clinically or that therapeutic strategies may be explored to increase production of HMM-HA, such as targeting HYAL2 or the CD44 signaling pathway. Of note, HMM-HA has been validated as a mechanism of cancer prevention, whereas pharmacologic cancer prevention strategies in healthy individuals is a tenuous proposition. However, induction of the early contact inhibition phenotype could promote tumor growth arrest, and this study suggests that promoting such a phenotype may be achieved through use of HMM-HA, or modulation of the CD44 or p16INK4a pathways.

X. Tian et al., High-molecular-mass hyaluronan mediates the cancer resistance of the naked mole rat. Nature 499, 346–349 (2013). [Abstract]

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