耶路撒冷希伯萊大學(xué)的研究人員在癌癥研究中取得了一項突破性進(jìn)展,，他們分析了低氧條件對一種熱門抗癌療法的影響，闡明了這一療法不能達(dá)到預(yù)期療效的原因,，為打破這一僵局提供了新的線索,。文章發(fā)表在本期的美國國家科學(xué)院院刊PNAS雜志上。
蛋白mTOR是雷帕霉素在哺乳動物中的作用目標(biāo),，能夠調(diào)節(jié)細(xì)胞對環(huán)境信號的應(yīng)答,。人們發(fā)現(xiàn)，mTOR在許多實(shí)體瘤中被強(qiáng)力激活,，因此將其作為癌癥治療中的重要靶標(biāo),。不過此前的研究顯示，雖然通過藥物抑制mTOR能夠成功殺死腫瘤外層的癌細(xì)胞,，但這類藥物在臨床試驗中,，對腫瘤中心的細(xì)胞效果并不理想,。
低氧是幾乎所有實(shí)體瘤都具備的普遍特性，能夠促進(jìn)癌細(xì)胞的糖酵解,、細(xì)胞增殖和血管生成,。低氧條件能夠影響腫瘤對藥物治療的應(yīng)答。此前科學(xué)家們已經(jīng)知道,，mTOR信號傳導(dǎo)會受到低氧條件的影響和改變,，但并不清楚這一過程中的具體機(jī)制。
耶路撒冷希伯萊大學(xué)的Raphael D. Levine教授及其同事,，在腦癌模型中對低氧條件進(jìn)行了分析,，希望明確低氧條件影響mTOR信號的機(jī)制，找到mTOR藥物療效不佳的原因,。
為此,，他們采用新型微芯片技術(shù)，來檢測單個癌細(xì)胞中的mTOR信號網(wǎng)絡(luò),，并在物理學(xué)理論的基礎(chǔ)上對數(shù)據(jù)進(jìn)行解讀,，使復(fù)雜的生物學(xué)系統(tǒng)簡單化。
研究人員對實(shí)體瘤中的常見低氧水平進(jìn)行了研究,，發(fā)現(xiàn)在這一條件下,，mTOR相關(guān)的信號網(wǎng)絡(luò)會發(fā)生轉(zhuǎn)變，使這一通路無法正常應(yīng)答mTOR藥物的治療,。研究人員將上述轉(zhuǎn)變解讀為一種相變,，并通過實(shí)驗進(jìn)行了驗證。
研究顯示,，在1.5% pO2（oxygen partial pressure）下,，mTOR信號通路無法應(yīng)答mTOR激酶抑制劑。而在1.5% pO2以上,，抑制劑能夠發(fā)揮正常作用,。研究人員指出，這種相變是信號網(wǎng)絡(luò)中的轉(zhuǎn)換點(diǎn),，發(fā)生得非常突然,。一旦信號傳導(dǎo)發(fā)生轉(zhuǎn)變，細(xì)胞就不會再以之前的方式進(jìn)行響應(yīng),。也就是說，此時mTOR藥物對腫瘤無法繼續(xù)起到抑制作用,。
這項研究明確了mTOR抑制劑臨床效果不佳的原因,，為人們展現(xiàn)了生物學(xué)過程的復(fù)雜性，而這種復(fù)雜性正是人們在尋找疾病治療方法時遇到的主要障礙之一,。(生物谷Bioon.com)
生物谷推薦英文摘要：
PNAS doi: 10.1073/pnas.1303060110
Hypoxia induces a phase transition within a kinase signaling network in cancer cells
Wei Weia,b,1, Qihui Shia,1,2, Francoise Remaclec,1, Lidong Qina,3, David B. Shackelfordd, Young Shik Shina, Paul S. Mischeld,4, R. D. Levinee,f,5, and James R. Heatha,5
Hypoxia is a near-universal feature of cancer, promoting glycolysis, cellular proliferation, and angiogenesis. The molecular mechanisms of hypoxic signaling have been intensively studied, but the impact of changes in oxygen partial pressure (pO2) on the state of signaling networks is less clear. In a glioblastoma multiforme (GBM) cancer cell model, we examined the response of signaling networks to targeted pathway inhibition between 21% and 1% pO2. We used a microchip technology that facilitates quantification of a panel of functional proteins from statistical numbers of single cells. We find that near 1.5% pO2, the signaling network associated with mammalian target of rapamycin (mTOR) complex 1 (mTORC1)—a critical component of hypoxic signaling and a compelling cancer drug target—is deregulated in a manner such that it will be unresponsive to mTOR kinase inhibitors near 1.5% pO2, but will respond at higher or lower pO2 values. These predictions were validated through experiments on bulk GBM cell line cultures and on neurosphere cultures of a human-origin GBM xenograft tumor. We attempt to understand this behavior through the use of a quantitative version of Le Chatelier’s principle, as well as through a steady-state kinetic model of protein interactions, both of which indicate that hypoxia can influence mTORC1 signaling as a switch. The Le Chatelier approach also indicates that this switch may be thought of as a type of phase transition. Our analysis indicates that certain biologically complex cell behaviors may be understood using fundamental, thermodynamics-motivated principles.
