Recent Investigation of Naked Mole Rat Cancer Immunity

In addition to being very long lived for their size and showing few signs of degenerative aging over their life span, naked mole-rats are essentially immune to cancer. Arguably there is more research interest in this latter point than in the life span question. So far scientists have focused on contact inhibition of cellular replication, which seems to be much more aggressive in naked mole-rat cells: when cells begin to crowd, as in a potential cancer, their ability to divide is rapidly shut down. This better contact inhibition is probably partially due to a different form of the protein hyaluronan, involved in the processes by which the p16 gene acts as a cancer suppressor.

Here researchers find another new angle to add to these discoveries. Naked mole rats generate a novel protein from the same area of the genome as p16, one not produced in other mammals, and it seems to be a better tumor suppressor than the other proteins produced from that region. Since it can be produced via genetic engineering in the cells of other mammals, the logical next step might be to create a lineage of mice that have it and see what happens:

The naked mole rat (Heterocephalus glaber) is a long-lived and tumor-resistant rodent. Tumor resistance in the naked mole rat is mediated by the extracellular matrix component hyaluronan of very high molecular weight (HMW-HA). HMW-HA triggers hypersensitivity of naked mole rat cells to contact inhibition, which is associated with induction of the INK4 (inhibitors of cyclin dependent kinase 4) locus leading to cell-cycle arrest. The INK4a/b locus is among the most frequently mutated in human cancer. This locus encodes three distinct tumor suppressors: p15INK4b, ARF (alternate reading frame).

p16INK4a and ARF share common second and third exons with alternative reading frames. Here, we show that, in the naked mole rat, the INK4a/b locus encodes an additional product that consists of p15INK4b exon 1 joined to p16INK4a exons 2 and 3. We have named this isoform pALTINK4a/b (for alternative splicing). We show that pALTINK4a/b is present in both cultured cells and naked mole rat tissues but is absent in human and mouse cells. Additionally, we demonstrate that pALTINK4a/b expression is induced during early contact inhibition and upon a variety of stresses. When overexpressed in naked mole rat or human cells, pALTINK4a/b has stronger ability to induce cell-cycle arrest than either p15INK4b or p16INK4a. We hypothesize that the presence of the fourth product, pALTINK4a/b of the INK4a/b locus in the naked mole rat, contributes to the increased resistance to tumorigenesis of this species.

Link: http://dx.doi.org/10.1073/pnas.1418203112

Comments

Several papers now propose that the naked mole rat's longevity and cancer resistance is due to the nmr's intercellular glue (high molecular weight hyaluronan) that mediates cellular communication, and, perhaps, protects the extracellular matrix from non-enzymatic glycation and crosslinks.

This suggests experiments on short-lived related species to confirm this.
Possibly, the following paper provides a method:
"Absorption, Uptake and Tissue Affinity of High-Molecular-Weight Hyaluronan after Oral Administration in Rats and Dogs"
http://pubs.acs.org/doi/pdf/10.1021/jf8017029

Posted by: Lou Pagnucco at January 2nd, 2015 12:22 PM

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