New Mole Rat Cancer Resistance Pathway Discovered

In a study of a species of mole rats, biologists have identified a cancer resistance mechanism different from another long-lived, cancer-resistant mole rat species discovered earlier.

The researchers, led by Professor Vera Gorbunova and Assistant Professor Andrei Seluanov of the University of Rochester (Rochester, NY, USA), found that abnormally growing cells from blind mole rats secrete interferon-beta (IFN-β) that triggers those and neighboring cells to rapidly die. Blind mole rats (BMR) from the Middle East and naked mole rats from Africa, both subterranean rodents with long life spans, are the only examined mammals never known to naturally develop cancer and in which spontaneous tumors have never been observed. Previously, a team led by Profs. Seluanov and Gorbunova identified an anticancer mechanism in the naked mole rat in which the p16 gene causes cancerous cells from these rats to become hypersensitive to overcrowding, preventing them from proliferating further. "We expected blind mole rats to have a similar mechanism [...]. Instead, we discovered they've evolved their own mechanism," said Prof. Seluanov.

In the current study, growth of BMR fibroblast cells in vitro, from the BMR species Spalax judaei and Spalax golani, were examined. The cells were made to actively proliferate for an abnormally large number of population doublings, after which the precancerous-like cells began secreting IFN-β and the cultures underwent massive, concerted necrotic cell death within 3 days. The necrotic cell death phenomenon was independent of culture conditions or telomere shortening. Sequestration of p53 and Rb proteins using SV40 large T antigen completely rescued necrotic cell death. The results suggest that cancer resistance in BMR is conferred by massive necrotic response to overproliferation mediated by p53 and Rb pathways, and triggered by the release of IFN-β.

"Not only were the cancerous cells killed off, but so were the adjacent cells, which may also be prone to tumorous behavior," said Prof. Seluanov. "While people don't use the same cancer-killing mechanism as blind mole rats, we may be able to combat some cancers and prolong life if we could stimulate the same clean sweep reaction in cancerous human cells," said Prof. Gorbunova. Profs. Gorbunova and Seluanov added that next they want to determine what initiates this suicidal secretion of IFN-β.

The study was published online ahead of print November 5, 2012, in the journal Proceedings of the National Academy of Sciences of the United States of America (PNAS).

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