Published on June 21st, 2013 | by Michael Ricciardi0
Simple Molecule Seems to Prevent Cancer in Naked Mole Rats – May Lead to Anti-Cancer Drug
They’re not the most impressive or attractive looking creatures in the world, with their poor eyesight and rubbery, wrinkled skin, but the naked mole rat (Heterocephalus glaber), has other impressive abilities; chief of which are its long lifespan and the fact that these subterranean creatures don’t get cancer.
For this reason, researchers like Andrei Seluanov at the University of Rochester, New York, have focused their clinical work on unraveling the mysteries of the naked mole rat’s (Heterocephalus glaber) innate resistance to tumorogenesis. Compared to mice, which rarely live longer than 4 years (and also get cancer), the mole rat’s long lifespan — often exceeding 30 years — may in fact be the result of this innate anti-cancer ability (that, and the fact that its underground life cycle seldom exposes it to solar radiation).
Seluanov’s current research builds upon his 2009 work in which he and his team, after culturing the mole rat’s fibroblasts (a connective tissue cell type), discovered that these cells were highly sensitive to the presence of other nearby cells and grew in less crowded colonies than mouse fibroblasts.
In what turned out to be a fortuitous but accidental discovery, the team found that the “broth” (the growth medium) in which they grew the cells soon turned into a very sticky substance that was so viscous that it clogged the drains in their lab.
Seluanov decided to find out just what this viscous fluid was made of — following an intuition that it might have something to do with the creature’s cancer resistance ability.
A ‘sticky wicket’ reveals it secrets
The team analyzed the drain-clogging goo and determined that it was mainly comprised of a sugary molecule called hyaluronic acid (HA). The mole rat’s fibroblasts secret this substance (along with collagen and other biomolecules) which then builds up what is called the extracellular matrix (ECM). The ECM is what give our tissues (organs) their shape and makes skin elastic.
As it turns out, naked mole rats — which are more closely related to porcupines than rats — produce long chains of HA and in larger amounts compared to other animals.
The team hypothesized that these long-chain HA molecules form a “tight cage” around cells, thus preventing any neoplastic (pre-cancerous) cells from proliferating unchecked. This caging function essentially stopped pre-cancerous cell growth in it tracks.
Using tissue-cultures to test this hypothesis, the team blocked expression of the gene that codes for HA, thus making the cells cancerous. They also found that they could induce cancer in the cells by increasing levels of a protein that breaks down the sugary molecule. These altered cells, when implanted under the skin of the mole rats, readily formed tumors.
Other experimental biologists applaud the work, citing its strong evidence supporting the role of HA in cancer prevention, but also note that other mechanisms are likely playing a role here. For example, a Harvard Medical School research team (Gladyshev et al) sequenced the creature’s genome and discovered numerous cancer-associated genes that differ from the sequences of similar genes found in other vertebrate animals.
Such gene sequence differences can be very slight (like a single nucleotide variation, or SNV) but a single substitution or change in a gene’s sequence of nucleotide “letters”can often make the difference between a cancer-causing molecule and one that prevents or blocks cancer.
Further, recent research has shown that the ECM is not a “static” cellular envelope, but is actively engaged in exchanging chemical signals with the cells it surrounds. This fact could also impact the role of the HA molecules.
At present, is is not clear how exactly HA confers cancer resistance. Seluanov and his team are planning genetic engineering experiments with lab mice in the hopes of translating their previous research; the engineered mice will be endowed with the same, long-chain HA molecule-producing ability as the naked mole rat. The ultimate goal is to develop a drug that stimulates this form of HA to prevent the spread (metastasis) of cancer in humans.
The research ‘Simple molecule prevents mole rats from getting cancer’ (Seluanov et al) was published in the June 19, 2013 on-line edition of Nature.
More About Mole Rats
Naked mole rats (Heterocephalus glaber), also known as ‘sand puppies’ or desert mole rats, are native to East Africa and spend their lives in subterranean groups tending to the needs of a single breeding queen. They are described as “eusocial” and are one of only two such mammal species known (the other being the Damaraland mole rat). Eusociality is considered to be the highest form of social organization in animals and is distinguished by cooperative brood care, overlapping adult generations and division of labor by reproductive and (partially) non-reproductive groups (in these respects it is somewhat similar to human caste societies).
The naked mole rat is unable to feel pain (like the corrosive sting of acids) and is the only mammal known to lack the ability to internally regulate its body temperature (called a thermoconformer).