近日，美國羅切斯特大學的研究人員發(fā)現(xiàn)了盲鼴鼠對抗癌癥的機制，這與三年前他們發(fā)現(xiàn)的裸鼴鼠對抗癌癥的機制不同，相關論文發(fā)表在國際期刊《PNAS》雜志上。盲鼴鼠是中東地區(qū)常見的生活于地下的小型嚙齒動物，其壽命可達21年。

　　盲鼴鼠和裸鼴鼠都是生活在地下的長壽嚙齒動物，也是僅有的兩種不會患癌癥的哺乳動物。三年前，這個研究團隊發(fā)現(xiàn)一個特殊的基因P16使得裸鼴鼠體內(nèi)的癌細胞對過度擁擠異常敏感，即當細胞過度增殖生存環(huán)境變得擁擠時便停止生長。

　　Seluanov說，原本認為盲鼴鼠阻止癌細胞生長的機制與裸鼴鼠相同，但是二者卻進化出各自的機制。盲鼴鼠體內(nèi)異常生長的細胞可通過分泌interferon beta蛋白將自己快速殺死，Vera Gorbunova和Andrei Seluanov教授領導了此項研究，他們希望借以找到治療癌癥的方法。

　　研究者首先從盲鼴鼠體內(nèi)分離出成纖維細胞，在體外進行培養(yǎng)，在分裂了大約15-20次之后，所有的細胞都迅速死亡了。這是因為細胞達到了癌癥前期狀態(tài)，分泌的自殺蛋白interferon beta不但殺死了癌細胞本身也殺死了其周圍可能發(fā)展為癌細胞的細胞。

　　Gorbunova說，雖然人類沒有像盲鼴鼠殺死癌細胞的機制，但是如果我們能夠刺激癌癥患者體內(nèi)的癌細胞也產(chǎn)生如盲鼴鼠將癌細胞一網(wǎng)打盡的反應，那么攻克癌癥將不是難題。他認為這種抗癌機制是盲鼴鼠對地下生活適應的結果，在進一步的研究中，研究者希望找到促進了interferon beta分泌的具體機制。

　　Cancer resistance in the blind mole rat is mediated by concerted necrotic cell death mechanism

　　Vera Gorbunovaa,1, Christopher Hinea,2, Xiao Tiana, Julia Ablaevaa, Andrei V. Gudkovb, Eviatar Nevoc,1, and Andrei Seluanova

　　Blind mole rats Spalax (BMR) are small subterranean rodents common in the Middle East. BMR is distinguished by its adaptations to life underground, remarkable longevity (with a maximum documented lifespan of 21 y), and resistance to cancer. Spontaneous tumors have never been observed in spalacids. To understand the mechanisms responsible for this resistance, we examined the growth of BMR fibroblasts in vitro of the species Spalax judaei and Spalax golani. BMR cells proliferated actively for 7–20 population doublings, after which the cells began secreting IFN-β, and the cultures underwent massive necrotic cell death within 3 d. The necrotic cell death phenomenon was independent of culture conditions or telomere shortening. Interestingly, this cell behavior was distinct from that observed in another long-lived and cancer-resistant African mole rat, Heterocephalus glaber, the naked mole rat in which cells display hypersensitivity to contact inhibition. Sequestration of p53 and Rb proteins using SV40 large T antigen completely rescued necrotic cell death. Our results suggest that cancer resistance of BMR is conferred by massive necrotic response to overproliferation mediated by p53 and Rb pathways, and triggered by the release of IFN-β. Thus, we have identified a unique mechanism that contributes to cancer resistance of this subterranean mammal extremely adapted to life underground.

　　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, and stops 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 the 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 which 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 in 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," said Gorbunova. "Living in this environment, they could perhaps afford to evolve a long lifespan, which includes developing efficient anti-cancer defenses."