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Anastacia Iacono
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The naked mole-rat is the longest living rodent with a maximum lifespan exceeding 28 years. In addition to its longevity, naked mole-rats have an extraordinary resistance to cancer as tumors have never been observed in these rodents. Furthermore, we show that a combination of activated Ras and SV40 LT fails to induce robust anchorage-independent growth in naked mole-rat cells, while it readily transforms mouse fibroblasts. The mechanisms responsible for the cancer resistance of naked mole-rats were unknown. Here we show that naked mole-rat fibroblasts display hypersensitivity to contact inhibition, a phenomenon we termed "early contact inhibition." Contact inhibition is a key anticancer mechanism that arrests cell division when cells reach a high density. In cell culture, naked mole-rat fibroblasts arrest at a much lower density than those from a mouse. We demonstrate that early contact inhibition requires the activity of p53 and pRb tumor suppressor pathways. Inactivation of both p53 and pRb attenuates early contact inhibition. Contact inhibition in human and mouse is triggered by the induction of p27(Kip1). In contrast, early contact inhibition in naked mole-rat is associated with the induction of p16(Ink4a). Furthermore, we show that the roles of p16(Ink4a) and p27(Kip1) in the control of contact inhibition became temporally separated in this species: the early contact inhibition is controlled by p16(Ink4a), and regular contact inhibition is controlled by p27(Kip1). We propose that the additional layer of protection conferred by two-tiered contact inhibition contributes to the remarkable tumor resistance of the naked mole-rat.
Unlike humans and other mammals, which become less fertile with age, naked mole-rats can reproduce throughout their remarkably long lifespans. Photo: John Brighenti/Wikimedia Commons 2.0 Generic License
Unlike humans and other mammals, which become less fertile with age, naked mole-rats can reproduce throughout their remarkably long lifespans. A new study, published today in Nature Communications, sheds light on unique processes that bestow the rodents with what seems like eternal fertility, findings that could eventually point to new therapies for people.
The researchers compared ovaries from naked mole-rats and mice across different stages of development. Despite their similar sizes, mice live four years at most and start to show a drop in fertility by nine months, whereas naked mole-rats have a life expectancy of 30 years or more.
They found that naked mole-rat females have exceptionally large numbers of egg cells compared to mice and that death rates of these cells were lower than in mice. For example, at 8 days old, naked mole-rat females had 1.5 million egg cells per ovary, about 95 times more than mice of the same age.
Most remarkably, the study found that oogenesis happens postnatally in naked mole-rats. Egg precursor cells were actively dividing in 3-month-old animals, and these precursors were found in 10-year-old animals, suggesting that oogenesis could continue throughout their lives.
Naked mole-rats live in colonies of several dozen to hundreds of individuals. Like bees or ants, colony members divvy up tasks, including providing defense, digging tunnels, caring for young and collecting food. Only the single dominant female in a colony can breed, and she suppresses reproduction in other females to maintain her queenly status.
To learn more about this process, the researchers removed 3-year-old females from the colony to prompt reproductive activation and compared these new queens with subordinate females. They found that non-breeding subordinates had egg precursor cells in their ovaries, but the cells started dividing only after a transition to queen.
Other authors who contributed to the study were Mariela Faykoo-Martinez, Dr. Michael D. Wilson and Dr. Melissa M. Holmes, of the University of Toronto; Meagan Goben, Patrick T. Walsh and Dr. Samia H. Lopa, of the University of Pittsburgh; Dr. Jennifer K. Grenier, Ashley McGrath, Dr. Alexandra M. Prado, Jacob Sinopoli, Kate Wagner and Dr. Paula E. Cohen, of Cornell; and Dr. Diana J. Laird, of the University of California San Francisco.
Cellular senescence is an evolutionary adaptation that prevents damaged cells from dividing out of control and developing into full-blown cancer. However, senescence has a negative side too: by stopping cell division in order to prevent potential tumors, it also accelerates aging.
Previous studies indicated that when cells that had undergone senescence were removed from mice, the mice were less frail in advanced age as compared to mice that aged naturally with senescent cells intact.
Gorbunova and Seluanov have long researched cancer and its relation to aging and DNA repair. They have identified several mechanisms that contribute to longevity and cancer resistance in naked mole rats, including the chemical HMW-HA (high molecular weight hyaluronan). But they believe there are more pieces to the puzzle.
The researchers found that although naked mole rats exhibited cellular senescence similar to mice, their senescent cells also displayed unique features that may contribute to their cancer resistance and longevity.
The cellular senescence mechanism permanently arrests a cell to prevent it from dividing, but the cell still continues to metabolize. The researchers found that naked mole rats are able to more strongly inhibit the metabolic process of the senescent cells, resulting in higher resistance to the damaging effects of senescence.
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Naked mole-rats engage in behaviors that may seem rude by human standards. The animals sometimes walk over each other, or push each other if they meet head-on in a tunnel. However, all of those behaviors are normal for naked mole-rats.
Naked mole-rats are pink, nearly hairless subterranean rodents that live in burrows in eastern Africa. These surprisingly long-lived animals are one of the only true eusocial mammals; they live in large colonies in which only one female breeds and the majority of individuals spend their lives working for the colony.
Naked mole-rats can live for an incredibly long time and have an exceptional resistance to cancer thanks to unique conditions in their bodies that stop cancer cells multiplying, according to new research.
Understanding how these remarkable animals are almost completely immune to cancer could improve our understanding of the early stages of the disease in people and lead to new ways to prevent or better treat it.
Until now, it was thought that naked mole-rats almost never got cancer because their healthy cells were resistant to being converted into cancer cells. However, researchers at the University of Cambridge have shown for the first time that genes known to cause cancer in cells of other rodents can also lead naked mole-rat cells to become cancerous. The results are published today in the journal Nature.
This finding suggests that what sets naked mole-rats apart is the microenvironment - the complex system of cells and molecules surrounding a cell, including the immune system. The researchers believe interactions with this microenvironment are what stops the initial stages of cancer from developing into tumours, rather than a cancer resistance mechanism within healthy cells as previously thought.
Naked mole-rats (Heterocephalus glaber) are burrowing rodents native to East Africa. They can live for up to 37 years and are highly cancer resistant, with only a few cases ever observed in captive animals. Other unusual traits that have made them of interest to science include being the only cold-blooded mammal, lacking pain sensitivity to chemical stimuli in their skin and being able to withstand very low levels of oxygen (hypoxia).
In the study, the researchers analysed 79 different cell lines, grown from five different tissues (intestine, kidney, pancreas, lung and skin) of 11 individual naked mole-rats. They infected cells with modified viruses to introduce cancer causing genes. These genes are known to cause cancer in mice and rat cells, but were not expected to be able to transform naked mole-rat cells into cancer cells.
The scientists will now continue to investigate the mechanisms by which naked mole-rats stop cancer cells from developing into tumours. One avenue of particular interest is the unique immune system of naked mole-rats, as our immune systems play a critical role in protecting us from cancer and this power has already been effectively exploited in modern immunotherapy treatments.
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