by ecancer reporter Janet Fricker

Cancer resistance in naked mole rats may be mediated in part by the production of hyaluronan, a natural component found in the extracellular matrix, reports a study published online in Nature.

The naked mole rat (Heterocephalus glaber) is known for its exceptional longevity with a maximum lifespan exceeding 30 years, the longest reported life span for a rodent species

In addition the naked mole rat appears to be almost entirely protected from developing cancer, which makes them particularly interesting subjects for cancer and longevity studies.

When Vera Gorbunova and colleagues, from the University of New York, USA, cultured multiple lines of naked mole-rat fibroblasts they noticed that after a few days their culture media became particularly viscous.

The team went on to identify the viscous ‘substance’;  as high molecular mass HA (HMM-HA). HA is an un branched disaccharide glucuronic acid/N-acetylglucosamine polymer known to be one of the main components of the extra cellular matrix.

Undertaking pulse-field electrophoresis analysis of HA extracted from the tissue culture media, the team showed that HA secreted by naked mole-rat cells had a molecular mass of 6–12MDa; whereas mouse and guinea-pig HA had a molecular mass ranging from 0.5 to 3MDa  and human HA from 0.5 to2MDa.

Biological responses triggered by HA have been found to depend on the polymer length. HMM-HA represses mitogenic signalling and has anti-inflammatory properties, where as low molecular HA promotes proliferation and inflammation.

The authors believe that high molecular mass HA accumulates in the naked mole-rat tissue due to the decreased activity of the HA degrading enzymes and a unique sequence of hyaluronan synthase 2 (HAS2).

They were able to show that once high molecular mass HA had been removed by either ‘knocking down’ HAS2 or over expressing the HA-degrading enzyme, HYAL2, naked mole-rat cells became susceptible to malignant transformation and readily formed tumours in mice.

In previous studies the team had identified that early contact inhibition (ECI), a novel anticancer mechanism involving the process of arrested cell growth when cells come into contact with each other in the extracellular matrix, occurs at a much lower density in naked mole-rat cells than mouse cells.

Loss of ECI, they suggest, makes cells more susceptible to malignant transformation.

To demonstrate  that HA signalling triggers ECI via the CD44 receptor the team went on to culture naked mole rat cells in the presence of a CD44 blocking antibody.

They showed that that  naked mole-rat cells grown with CD44 antibodies achieved higher cell densities.

ECI signalling from HMM-HA, they believe, is in part transmitted via the CD44 receptor.

Naked mole rats, the author suggest, have evolved to produce high-molecular mass hyaluronan to generate the flexible skins that are needed to squeeze through underground tunnels.

Interestingly, they also found that cells from the blind mole rat, a different subterranean rodent phylogenetically closer to mice and rats than to the naked mole rat, also secreted HMM-HA.

“Using naked mole-rat HMM-HA in the clinic or targeting HYAL2, or the HA–CD44 signalling pathway, opens new avenues for cancer prevention and life extension,” conclude the authors.

Reference
X Tian, J Azpurua, C Hine, et al. High-molecular-mass hyaluronan mediates the cancer resistance of the naked mole rat. Nature. doi:10.1038/nature12234