The team of researchers, led by Professor Vera Gorbunova and Assistant Professor Andrei Seluanov, found that abnormally growing cells in blind mole rats secrete the interferon beta protein, which causes those cells to rapidly die. Seluanov and Gorbunova hope the discovery will eventually help lead to new cancer therapies in humans. Their findings are being published this week in the Proceedings of the National Academy of Sciences.
Blind mole rats and naked mole rats—both subterranean rodents with long life spans—are the only mammals never known to develop cancer. Three years ago, Seluanov and Gorbunova determined the anti-cancer mechanism in the naked mole rat. Their research found that a specific gene—p16—makes the cancerous cells in naked mole rats hypersensitive to overcrowding, stopping them from proliferating when too many crowd together.
“We expected blind mole rats to have a similar mechanism for stopping the spread of cancerous cells,” said Seluanov. “Instead, we discovered they’ve evolved their own mechanism.”
Gorbunova and Seluanov made their discovery by isolating cells from blind mole rats and forcing them to proliferate in culture beyond what occurs in the animal. After dividing approximately 15-20 times, all of the cells in the culture dish died rapidly. The researchers determined that this rapid death occurred because the cells recognized their pre-cancerous state and began secreting a suicidal protein called interferon beta. The precancerous cells died by a mechanism that kills both abnormal cells and their neighbors, resulting in a “clean sweep.”
“Not only were the cancerous cells killed off, but so were the adjacent cells, which may also be prone to tumorous behavior,” said 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 Gorbunova.
The research team also included Christopher Hine, Xiao Tian, and Julia Ablaeva from Rochester, Andrei Gudkov at Roswell Park Cancer Institute in Buffalo, NY, and Eviatar Nevo at the University of Haifa in Israel.
Gorbunova and Seluanov say they next want to find out exactly what triggers the secretion of interferon beta after cancerous cells begin proliferating in blind mole rats.
Gorbunova believes the anti-cancer mechanism is an adaptation to subterranean life: “Blind mole rats spend their lives in underground burrows protected from predators. Living in this environment, they could perhaps afford to evolve a long lifespan, which includes developing efficient anti-cancer defenses.”
Update: Here’s What We Know in 2024
The secretion of interferon beta (IFN-β) in blind mole rats is triggered primarily by hyperplasia, which occurs when there is rapid cell proliferation. As the cells begin to proliferate excessively, they recognize their pre-cancerous state and respond by releasing IFN-β, leading to a concerted cell death mechanism that eliminates both the abnormal cells and their neighboring cells. This process is characterized by a combination of necrotic and apoptotic pathways, effectively serving as a “clean sweep” to prevent potential tumor formation [1][2].
Research indicates that this response is part of an evolved strategy in blind mole rats to combat cancer, particularly in reaction to hyperplastic growths or carcinogenic exposure. The massive release of IFN-β acts as a signal for cell death, which is crucial in maintaining their cancer resistance [1][4]. Additionally, the blind mole rat’s genome exhibits duplications of genes involved in the IFN pathway, further supporting this unique mechanism [1].
In summary, the trigger for IFN-β secretion in blind mole rats is the acute sensitivity of their cells to hyperplasia, which initiates a robust immune response aimed at eliminating potentially malignant cells before they can develop into tumors.
What Causes the Acute Sensitivity to Hyperplasia?
The acute sensitivity of blind mole rat cells to hyperplasia, which triggers a robust immune response, is likely caused by several evolutionary adaptations and specific cellular mechanisms. While the exact triggers remain an area of ongoing research, several factors contribute to this phenomenon:
1. Genetic Adaptations: Blind mole rats have evolved unique genetic traits that enhance their ability to detect and respond to abnormal cell growth. This includes duplications of genes involved in immune responses, particularly those related to the interferon pathway, which plays a critical role in recognizing and responding to cellular stress and damage.
2. Cellular Recognition Mechanisms: The cells in blind mole rats possess heightened sensitivity to changes in their environment, particularly during hyperplastic growth. When cells begin to proliferate excessively, they can recognize their pre-cancerous state due to the activation of specific signaling pathways that lead to the secretion of interferon beta (IFN-β). This recognition is crucial for initiating programmed cell death (apoptosis) in both the abnormal cells and adjacent cells that may also be at risk for tumorigenesis.
3. Robust Innate Immune Response: The innate immune system of blind mole rats is highly effective at detecting and responding to malignant transformations. Components such as natural killer (NK) cells and macrophages are likely involved in this process, providing an immediate defense against abnormal cell proliferation. This contrasts with many other species, where cancerous cells can evade immune detection.
4. Environmental Adaptations: Living underground, blind mole rats face different evolutionary pressures compared to surface-dwelling mammals. Their subterranean lifestyle may have favored the development of efficient anti-cancer mechanisms as a means of survival in a relatively isolated environment where longevity and health are critical for reproductive success.
5. Interferon Pathway Activation: The secretion of IFN-β acts as a signal for surrounding cells, promoting a “clean sweep” mechanism that eliminates not just the cancerous cells but also those nearby that might become cancerous. This mechanism is thought to be an evolutionary strategy to maintain tissue integrity and prevent cancer development.
In summary, the acute sensitivity of blind mole rat cells to hyperplasia results from a combination of genetic adaptations, enhanced cellular recognition capabilities, a robust innate immune response, and environmental factors that promote the evolution of effective cancer resistance mechanisms. Ongoing research aims to further elucidate these triggers and their implications for understanding cancer biology in other species, including humans.
What Might Help Humans?
The study of blind mole rats offers several promising opportunities for developing strategies to prevent human cancer. Here are some key avenues based on the research findings:
1. Understanding Interferon Beta (IFN-β) Mechanism: The blind mole rat’s ability to secrete IFN-β in response to hyperplastic growth presents a unique opportunity. By investigating how IFN-β induces concerted cell death (CCD) in pre-cancerous cells, researchers could explore ways to stimulate similar responses in human cells. This could lead to therapies that promote the elimination of abnormal cells before they develop into tumors [1][3].
2. Exploiting Unique Cellular Traits: Blind mole rat fibroblasts exhibit tumor-suppressive properties when cultured with human cancer cells. Identifying the specific compounds secreted by these fibroblasts could reveal new anti-cancer agents that inhibit tumor growth or induce apoptosis in malignant cells. This research is already underway, with scientists narrowing down potential proteins responsible for these effects [2][4].
3. Model Organism for Cancer Research: Blind mole rats serve as an excellent model for studying cancer resistance due to their unique biological traits, such as longevity and hypoxia tolerance. Utilizing them in research can provide insights into cancer prevention mechanisms that differ from traditional laboratory mice, which may not accurately predict human responses [4][5].
4. Targeting Reactive Oxygen Species (ROS): The presence of high molecular mass hyaluronan (HMM-HA) in blind mole rats helps protect against ROS-induced damage, which is a significant factor in cancer development. Understanding how HMM-HA contributes to cellular protection could inform the development of therapies aimed at enhancing ROS resistance in human tissues [1].
5. Investigating Genetic Adaptations: The genetic adaptations found in blind mole rats, such as alterations in the p53 gene and duplications of genes involved in the IFN pathway, could provide targets for genetic or pharmacological interventions in humans. By mimicking these adaptations, it may be possible to enhance the cancer resistance of human cells [1][3].
6. Developing Novel Therapeutics: The insights gained from blind mole rat biology could lead to the creation of new therapeutic agents that leverage their unique cancer-fighting mechanisms. Pharmaceutical companies are already interested in translating these findings into potential treatments for human cancers [2].
In summary, the unique biological features of blind mole rats present significant opportunities for advancing cancer prevention strategies in humans through targeted research and therapeutic development.
Read More on Adapting Mole Rat Anti-Cancer Strategies
[1] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6015544/
[2] https://www.templeton.org/grant/the-subterranean-blind-mole-rat-spalax-natural-experimental-animal-for-cancer-treatment-and-prevention-in-humans
[3] https://www.rochester.edu/newscenter/how-do-blind-mole-rats-ward-off-cancer/
[4] https://bmcbiol.biomedcentral.com/articles/10.1186/1741-7007-11-91
[5] https://bmcgenomics.biomedcentral.com/articles/10.1186/s12864-018-5417-z
[6] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8488014/
[7] https://www.nature.com/articles/nature.2012.11741
[8] https://pubmed.ncbi.nlm.nih.gov/23129611/
Read More on Mole Rate Acute Sensitivity to Hyperplasia
[1] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3721350/
[2] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9171538/
[3] https://www.nature.com/articles/s41568-021-00347-z
[4] https://www.nature.com/articles/s41577-020-0306-5
[5] https://www.cancer.gov/news-events/cancer-currents-blog/2019/oncolytic-virus-improves-immune-cell-metabolism
[6] https://www.sciencedirect.com/science/article/pii/S1044579X1500019X
[7] https://www.cancerresearchuk.org/about-cancer/what-is-cancer/body-systems-and-cancer/the-immune-system-and-cancer
[8] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6015544/
Read More about Mole Rate Cancer Resistence
[1] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6015544/
[2] https://pubmed.ncbi.nlm.nih.gov/23129611/
[3] https://www.rochester.edu/newscenter/how-do-blind-mole-rats-ward-off-cancer/
[4] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8488014/
[5] https://bmcbiol.biomedcentral.com/articles/10.1186/1741-7007-11-91
[6] https://www.nature.com/articles/nature.2012.11741
[7] https://bmcgenomics.biomedcentral.com/articles/10.1186/s12864-018-5417-z
[8] https://www.the-scientist.com/blind-mole-rats-use-junk-dna-to-combat-cancer-69262
