Learning from Exotic Species

Research of unique features in exotic animal species often reveals unexpected biology and may even shed light on disease treatment. A recent paper by Tian et al. studies a long-lived, cancer-free rodent named the naked mole rat (Heterocephalus glaber) to understand the mechanism of cancer resistance. Previous work by the same group has suggested early contact inhibition (ECI) in the naked mole rat cells to be a novel anticancer mechanism. In the present study, the authors provide further mechanistic insights into ECI. They find that cells in naked mole rats secrete more high-molecular-mass hyaluronan (HMM-HA) compared to cells from other species such as human and mouse. The naked mole rat cells express hyaluronan synthase 2 (HAS2) with a unique sequence in a much higher level but produce less HA-degrading enzymes (HAases), therefore leading to more robust synthesis and slower degradation of HMM-HA. Accumulated HMM-HA then signals through the CD44-NF2/merlin pathway to initiate ECI. More importantly, the removal of HMM-HA either by overexpression of a HAase HYAL2 or by suppression of HAS2 renders the naked mole rat fibroblast cells more susceptible to malignant transformation. The naked mole rat has presumably evolved to secrete more HMM-HA to provide more flexible skin needed to squeeze through underground tunnels as an adaptation to a subterranean lifestyle. However, this unique trait may have been co-opted to offer cancer resistance and longevity. These remarkable findings implicate that the administration of HMM-HA, inhibition of HYAL2, and manipulation of HA-CD44-NF2/merlin-signaling pathway can be used as novel strategies for cancer therapy. Tian, X., et al. (2013). Nature. Published online June 19, 2013. http://dx.doi.org/10.1038/nature12234.