The remarkable and still mysterious cancer resistance of blind mole rats

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Blind mole rats (Spalax spp) are extraordinary rodents that spend most of their lives underground, digging in poorly ventilated tunnels.  Their ability to conduct intensive aerobic work under low oxygen pressures is remarkable, as is their lifespan of 20 years or more, which despite its length is not associated with spontaneously arising tumors.  A paper published in BMC Biology now shows that their resistance to cancer extends to chemically-induced tumors, and that normal fibroblasts from these animals have the ability to suppress cancer cell viability and growth.

The BMC Biology paper by Manov et al reports that while laboratory mice and rats develop multiple skin cancers in response to applied carcinogens, the skin lesions produced by this treatment in blind mole rats heal without tumors being formed. In a second set of experiments subcutaneous injection with a carcinogen induced malignant fibrosarcomas in all mice and rats tested, but just one malignancy in a single old blind mole rat (of 12 animals tested). Exactly how the blind mole rats avoid forming these chemically-induced cancers requires further investigation but both carcinogenic protocols induce oxidative stress and the authors reasonably speculate that one or more of their many genetic adaptations to hypoxia may be involved.

Readers of the current wikipedia entry for Spalax might have the impression that the mechanism by which blind mole rats resist cancer has already been solved, and that it is due to “concerted” necrotic cell death triggered by interferon-beta in response to excessive cell proliferation.  This account stems from a study published last year in PNAS on blind mole rat fibroblasts grown in culture, however, and it is not yet clear that such a mechanism operates in vivo. Moreover the new study from Manov and colleagues also examines the growth of Spalax fibroblasts in culture and fails to replicate the observation of concerted necrotic cell death. In the PNAS study, culture supernatant from the dying Spalax fibroblasts (which from indirect assays on human cell lines was concluded to contain interferon-beta) triggered cell death in cultures of normal mouse fibroblasts but did not affect normal human fibroblasts. By contrast, Manov et al report that co-culture with Spalax fibroblasts, or medium conditioned by their growth does not adversely affect normal fibroblasts from a variety of rodents or humans, but does inhibit the growth and viability of human cancer cell lines and the Spalax fibrosarcoma cells. These latter experiments suggest that factors which act selectively against cancer cells are being produced by the Spalax fibroblasts and could be identified by further experimental work.

Might such a factor have been already found? Blind mole rats do not have a monopoly on cancer resistance and experiments on an even longer lived subterranean rodent, the naked mole rat (Heterocephalus glaber), recently hit the headlines when a paper in Nature identified high molecular weight hyaluronic acid (HMW-HA) as having a key role in their resistance to cancer. This study found that HMW-HA is present at high levels in these animals and that it is responsible for the  early contact inhibition their fibroblasts display when cultured, and for their resistance to oncogene-induced transformation into cells able to grow as transplanted tumors in immunodeficient mice. The paper includes supplementary data  showing that HMW-HA is also made by blind mole rat fibroblasts, but the latter do not show early contact inhibition when grown in culture and it is not obvious whether and how HMW-HA might contribute to their ability to avoid cancer. Blind and naked mole rats are not closely related evolutionarily, and have distinctive genetic adaptations and metabolic features. Both these subterranean rodents may have more to teach us about how to resist cancer, and the story of how blind mole rats do it is not yet completely told.


 

  • Lili

    The paper by Gorbunova on blind moles in PNAS is perforated like Swiss cheese.
    First it says that the death of blind moles normal cells results from the serum in the medium that encourage high proliferation of cells that are conceived as sort of oncogenic transformation and in order to avoid it, the cells go into programmed death. Then it says that the same manifestation occurs also in serum-free medium. Strange, isn’t it?

    Then Gorbunova claims that human fibroblasts do not enter cell death when growing with blind moles conditioned media because the interferon of human is different than that of rodents. But the level of interferon in blind moles medium is measured with assays that measure death versus survival of human cells. So, is interferon from blind moles cells kills human cells or not?
    Why did Gorbunova chose interferon? Just out of the blue? A shot in the dark? She could have chosen a dozen of other factors that have something to do with inflammation, wounds and cancer? Even if the interferon is indeed the magic factor, which seems it is not, the 1st thing to check is viral contaminations in her cell cultures from blind moles. This is well known to anybody who worked with cell cultures.

    About the story of the HMW-HA: any average M.Sc student that found that it exists in the cells of both naked and blind moles would be curious to compare between this two long-lived cancer-resistant animals. My guess is that Gorbunova didn’t do the comparison and didn’t check what happens between HMW-HA and “p” proteins in blind moles cells, because she had already decided that it is interferon that is responsible for cancer resistance of blind moles. Whatever she could have found, apart from the improbable connection between interferon and HMW-HA, would have revealed the non accidental pitfalls in her PNAS paper on the blind moles. She knows the truth. She was the PI on the paper. She is not so stupid. Maybe her desire to win the race on cracking down the mystery of cancer resistance of these two interesting animals shaded her credibility. With respect to this, an interesting thing is that the PNAS paper on the blind moles was coauthored and communicated by a member of the USA academy of science from the same institute as the research group that published the BMC paper. Anyone can draw his own assumptions J

    Anyhow the paper of Manov at al in BMC is tremendously interesting. Maybe after many long years of cancer research that made so little for the benefit and survival of cancer patients, which are not mice, these guys are really on a promising path.

    Proper disclosure: I know author(s) from the BMC Biology paper and we had a long discussions about the blind moles between the publication of the PNAS paper and BMC biology one

  • Lili

    I was intrigued and tremendously impressed by your studies, in this very provocative paper on the cancer resistance of the Spalax. Very well thought through and executed. Loved it. Notably their resistance to chemical carcinogens and killing human cancer cells. The last five decades of cancer research have yielded very little in terms of patient benefit, quality of life, overall survival, etc. You seem to be on to something.
    No comparison to the former paper in PNAS. The comments of Dr. Austin’s on the former results, are an understatement phrased in a very polite way. It is hard to grasp that all the authors and reviewers of that 1sr paper overlooked or didn’t observe the internal contradictions.