一個(gè)典型的癌細(xì)胞基因組中分散著成千上萬(wàn)的突變,有著數(shù)以百計(jì)的突變基因.然而,這些突變基因中只有一小部分被認(rèn)為是癌癥的驅(qū)動(dòng)子,負(fù)責(zé)癌癥特征的表現(xiàn),例如不受控制的細(xì)胞生長(zhǎng).癌癥生物學(xué)家們很大程度上忽略了其他突變,因?yàn)樗麄兿嘈拍切┩蛔儗?duì)癌癥的進(jìn)展發(fā)揮著微小的作用,甚至乎沒有作用.
但是由麻省理工學(xué)院（MIT）,、哈佛大學(xué),、Broad研究所和布萊根婦女醫(yī)院的一項(xiàng)聯(lián)合研究首次表明,這些偶然突變（passenger mutations）不只是湊熱鬧而已.當(dāng)它們積累到一定程度,就能減緩甚至停止癌癥的發(fā)展.
這一發(fā)現(xiàn)發(fā)表在本周的PNAS上,MIT物理和健康科學(xué)技術(shù)學(xué)院的Leonid Mirny副教授是這篇文章的資深作者.他說(shuō)：我們的結(jié)果暗示,癌癥應(yīng)該被視為一個(gè)漸進(jìn)的過(guò)程,它的進(jìn)程由驅(qū)動(dòng)子推動(dòng)細(xì)胞生長(zhǎng)與偶然突變逐漸累積破壞癌癥之間的微妙平衡決定.
另外,研究者們認(rèn)為,能夠使局面有利于偶然突變的藥物或許能為癌癥治療提供一種新的方法,即用癌癥本身的武器“突變”來(lái)?yè)魯∷约?盡管單個(gè)偶然突變的影響是微不足道的,“但是從總體上看,它們可以產(chǎn)生深遠(yuǎn)的影響,”Mirny說(shuō),“如果一種藥物可以讓它們更有害點(diǎn),每一個(gè)偶然突變的影響雖然很微小,但是集體的效應(yīng)卻可以建立.”
權(quán)力斗爭(zhēng)
癌癥的發(fā)展可以持續(xù)數(shù)年甚至數(shù)十年,在這一過(guò)程中,細(xì)胞會(huì)逐漸積累必要的驅(qū)動(dòng)突變.這些突變通常激活促進(jìn)細(xì)胞生長(zhǎng)的致癌基因,如Ras,或關(guān)閉通常抑制細(xì)胞增長(zhǎng)的腫瘤抑制基因,如p53.
偶然突變是伴隨驅(qū)動(dòng)子的突變而隨機(jī)產(chǎn)生的,它們通常被認(rèn)為是良性的:在自然群體中,自然選擇清除了有害的突變.然而,Mirny和他的同事們懷疑,癌癥的進(jìn)化過(guò)程可能是不同的,它們?cè)试S帶有極小有害效應(yīng)的突變不斷積累.
為了驗(yàn)證這一理論,研究人員創(chuàng)建了一個(gè)模擬癌癥增長(zhǎng)的計(jì)算機(jī)模型,隨著癌癥的發(fā)展過(guò)程,細(xì)胞獲得了隨機(jī)突變.這些模擬跟蹤了數(shù)以百萬(wàn)計(jì)的細(xì)胞,調(diào)查了每個(gè)細(xì)胞的分裂、突變和細(xì)胞死亡.
他們發(fā)現(xiàn),在獲得驅(qū)動(dòng)突變的較長(zhǎng)周期內(nèi)會(huì)出現(xiàn)許多偶然突變.當(dāng)一個(gè)癌細(xì)胞獲得一個(gè)新的驅(qū)動(dòng)突變時(shí),這個(gè)細(xì)胞及其后代在接收整個(gè)基因組時(shí),也會(huì)帶上那些初始細(xì)胞中的偶然突變.“否則這些突變不會(huì)蔓延到整個(gè)細(xì)胞群,”Mirny說(shuō),“他們基本上搭了驅(qū)動(dòng)突變的便車.”
模擬研究發(fā)現(xiàn)：在癌癥發(fā)展中,這個(gè)過(guò)程會(huì)重復(fù)五到十次;每一次都有新一波的破壞性偶然突變積累.如果有足夠多的有害偶然突變,他們的累積效應(yīng)就能減緩腫瘤的生長(zhǎng).腫瘤可能變成休眠狀態(tài),甚至退化,但是如果獲得了新的驅(qū)動(dòng)突變,細(xì)胞的增長(zhǎng)又會(huì)再次啟動(dòng).這種增長(zhǎng)模式與人類癌癥患者中常見的情況相吻合.
“癌癥可能并不是由一系列不可避免的事件的積累造成,而很可能是由驅(qū)動(dòng)突變與偶然突變之間的微妙平衡形成的.”Mirny說(shuō)：“藥物帶來(lái)的自然康復(fù)或病征緩解實(shí)際上可能由有害偶然突變的負(fù)載介導(dǎo).”
當(dāng)他們分析癌癥患者基因組中的偶然突變時(shí),發(fā)現(xiàn)了與模型預(yù)測(cè)相同的結(jié)果——微小有害突變的大量積累.
扭轉(zhuǎn)局勢(shì)
利用計(jì)算機(jī)模擬,研究人員測(cè)試了增加有害突變來(lái)治療腫瘤的可能性.在他們最初的模擬中,每一個(gè)有害的偶然突變會(huì)使細(xì)胞的健康下降約0.1%,當(dāng)這一比例增加到0.3%時(shí),腫瘤就會(huì)因負(fù)載了這些自身突變而縮小.
Mirny說(shuō),當(dāng)用藥物干擾已知的分子伴侶蛋白時(shí),同樣的效果也可以在真實(shí)的腫瘤中被發(fā)現(xiàn).蛋白質(zhì)合成后需要被折疊成正確的形狀,而分子伴侶能夠幫助蛋白實(shí)現(xiàn)這一過(guò)程.在癌細(xì)胞中,分子伴侶幫助蛋白質(zhì)折疊成正確的形狀,甚至當(dāng)它們突變時(shí)也是如此,這有助于抑制有害突變的影響.
一些能夠抑制分子伴侶蛋白的潛在藥物現(xiàn)在已經(jīng)被用于臨床上對(duì)癌癥的治療,盡管研究人員只是相信,它們的主要功能是抑制驅(qū)動(dòng)突變,而不是增強(qiáng)偶然突變的影響.
在這一研究中,研究人員比較了負(fù)載相同驅(qū)動(dòng)突變和不同偶然突變的相同癌細(xì)胞系,看誰(shuí)長(zhǎng)得更快.他們還將癌細(xì)胞系注射到了小鼠的體內(nèi),看看哪個(gè)是最有可能轉(zhuǎn)移.(生物谷Bioon.com)
A scanning electron micrograph of a squamous cell carcinoma, a type of skin cancer. The cell has been frozen and split open to reveal its nucleus.
A typical cancer cell has thousands of mutations scattered throughout its genome and hundreds of mutated genes. However, only a handful of those genes, known as drivers, are responsible for cancerous traits such as uncontrolled growth. Cancer biologists have largely ignored the other mutations, believing they had little or no impact on cancer progression. But a new study from MIT, Harvard University, the Broad Institute and Brigham and Women's Hospital reveals, for the first time, that these so-called passenger mutations are not just along for the ride. When enough of them accumulate, they can slow or even halt tumor growth. The findings, reported in this week's Proceedings of the National Academy of Sciences, suggest that cancer should be viewed as an evolutionary process whose course is determined by a delicate balance between driver-propelled growth and the gradual buildup of passenger mutations that are damaging to cancer, says Leonid Mirny, an associate professor of physics and health sciences and technology at MIT and senior author of the paper. Furthermore, drugs that tip the balance in favor of the passenger mutations could offer a new way to treat cancer, the researchers say, beating it with its own weapon—mutations. Although the influence of a single passenger mutation is minuscule, "collectively they can have a profound effect," Mirny says. "If a drug can make them a little bit more deleterious, it's still a tiny effect for each passenger, but collectively this can build up." Lead author of the paper is Christopher McFarland, a graduate student at Harvard. Other authors are Kirill Korolev, a Pappalardo postdoctoral fellow at MIT, Gregory Kryukov, a senior computational biologist at the Broad Institute, and Shamil Sunyaev, an associate professor at Brigham and Women's.
