Journal of Molecular Cell Biology（《分子細(xì)胞生物學(xué)報(bào)》）2012年第3期“復(fù)雜疾病的系統(tǒng)生物學(xué)研究”專(zhuān)輯中發(fā)表了一篇美國(guó)佐治亞大學(xué)生物化學(xué)與分子生物學(xué)系徐鷹教授關(guān)于“Hypoxia and miscoupling between reduced energy efficiency and signaling to cell proliferation drive cancer to grow increasingly faster” 的論文,，報(bào)道了細(xì)胞內(nèi)低氧引起能量效率與控制細(xì)胞增殖的關(guān)系的失調(diào)，從而促進(jìn)腫瘤的快速生長(zhǎng),。這一假設(shè)與傳統(tǒng)認(rèn)為的“基因突變導(dǎo)致腫瘤生長(zhǎng)”觀(guān)點(diǎn)有著很大的區(qū)別,。此文在線(xiàn)出版后，立即受到包括ScienceDaily在內(nèi)的國(guó)際媒體廣泛關(guān)注,。
過(guò)去的研究將細(xì)胞內(nèi)低氧水平看作癌癥發(fā)展的促進(jìn)因素之一,，但并不是腫瘤生長(zhǎng)的驅(qū)動(dòng)因素。徐教授說(shuō),，隨機(jī)的基因突變單獨(dú)無(wú)法解釋全球癌癥的高發(fā)病率,。他又說(shuō)，將數(shù)學(xué)和計(jì)算機(jī)知識(shí)應(yīng)用于生物學(xué)而形成的生物信息學(xué)使研究人員可以從一種新的角度看待癌癥,?；蛲蛔兛赡苁拱┘?xì)胞在競(jìng)爭(zhēng)中優(yōu)于健康細(xì)胞，但這樣的話(huà)新生癌細(xì)胞生長(zhǎng)的模式就不需要癌變前兆的出現(xiàn),，如原癌基因突增等常見(jiàn)的不良變化,。“癌癥治療藥物力求達(dá)到根源——在分子水平上——一個(gè)特定的突變，但往往不能根治,，”徐教授說(shuō)：“所以我們想基因突變可能并不是癌癥的主要驅(qū)動(dòng)因素,。”的確，徐教授的分析發(fā)現(xiàn),，長(zhǎng)期的細(xì)胞內(nèi)缺氧可能是癌生長(zhǎng)的一個(gè)關(guān)鍵驅(qū)動(dòng)因素,。
目前大多數(shù)的癌癥研究希望通過(guò)藥物對(duì)抗與某種特定癌癥相關(guān)的基因突變，進(jìn)而達(dá)到治療癌癥的目的,。徐教授課題組從Stanford Microarray Database數(shù)據(jù)庫(kù)下載了7種癌癥（乳腺癌,、腎癌、肝癌,、肺癌,、卵巢癌、胰腺癌及胃癌）的相關(guān)數(shù)據(jù),，通過(guò)一款軟件程序分析這7種癌癥中異常的基因表達(dá)模式,。他們以基因HIF1A作為一個(gè)細(xì)胞氧含量的標(biāo)記物,，所有被實(shí)驗(yàn)的7種癌細(xì)胞中，HIF1A水平都有顯著的升高,，這表明這些癌細(xì)胞中氧含量顯著的降低,。
細(xì)胞內(nèi)氧含量降低，導(dǎo)致氧化磷酸化反應(yīng)的中斷,，而氧化磷酸化反應(yīng)是細(xì)胞將食物轉(zhuǎn)化為能量的一種高效途徑,。隨著氧含量的降低，細(xì)胞切換到糖酵解途徑生產(chǎn)能量單位,，即ATP,，這是一種效率非常低的能量獲取方式，所以為了存活癌細(xì)胞必須努力得到更多的食物,，尤其是葡萄糖,。當(dāng)氧含量水平下降到極限時(shí)，血管新生——即生成新血管的過(guò)程——啟動(dòng)了,。新生血管提供新鮮的氧氣,，提高細(xì)胞內(nèi)和腫瘤的氧含量水平，并延緩癌細(xì)胞的生長(zhǎng),，但這都是暫時(shí)的,。
“得到更多的食物后，癌細(xì)胞就會(huì)生長(zhǎng),；這就會(huì)導(dǎo)致整個(gè)腫瘤實(shí)體增長(zhǎng)而更加缺氧,。反過(guò)來(lái)，能量轉(zhuǎn)換效率將更加低下,，從而使細(xì)胞更加饑餓,，促使細(xì)胞從血液循環(huán)中獲得更多的食物，形成一個(gè)惡性循環(huán),。這或許是腫瘤形成的一個(gè)關(guān)鍵驅(qū)動(dòng)因素，”徐說(shuō),。這個(gè)全新的癌細(xì)胞生長(zhǎng)模式可能用于解釋為什么很多腫瘤很快（3-6個(gè)月以?xún)?nèi)）產(chǎn)生耐藥性,。他強(qiáng)調(diào)了未來(lái)非常有必要通過(guò)大量的癌癥實(shí)驗(yàn)研究來(lái)論證這一新模式。如果這一模式得以成立,，研究人員的首要任務(wù)是探索防止細(xì)胞內(nèi)低氧的辦法,，從而使腫瘤治療的手段發(fā)生巨大改變。（生物谷Bioon.com）
doi:10.1093/jmcb/mjs017
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Hypoxia and miscoupling between reduced energy efficiency and signaling to cell proliferation drive cancer to grow increasingly faster
Juan Cui1,†, Xizeng Mao1,†, Victor Olman1, P. J. Hastings2 and Ying Xu1,3,*
The question we address here is what drives cancer to grow in an accelerated fashion as it evolves. Various proposals have been made regarding the possible drivers of cancer growth such as driver mutations and autonomous growth signaling. While these are clearly relevant, they rely too much on specific types of genomic mutations or molecular abnormalities by chance across different cancer types, which makes the probability for cancer to occur/progress significantly lower than what we have witnessed about the current cancer occurrence rates worldwide, hence making them less probable to be the ultimate drivers of cancer growth (Loeb, 1998). We present here a model for the (accelerated) growth of a cancer based on the discovered gene-expression patterns derived from genome-scale transcriptomic data of seven solid carcinoma types, namely breast, kidney, liver, lung, ovary, pancreatic, and stomach cancers. Our data analysis clearly indicates that as a cancer advances, (i) its percentage of cells in the G0 phase of the cell cycle tends to become increasingly lower, indicating accelerated cell proliferation; (ii) when the hypoxia level goes up, the activity level of oxidative phosphorylation as the main energy (ATP) producer goes down and that of glycolysis goes up, which triggers cancer cells to accelerate the uptake of glucose from the blood circulation to make up for the lost efficiency in energy production, needed for them to stay viable; (iii) this switch in energy metabolisms leads to accelerated cell proliferation and further increased hypoxia, forming a vicious cycle of (accelerated) growth of cancer; (iv) this cycle breaks down when the new angiogenesis takes place triggered by the high hypoxia level, which decreases the hypoxia level and switches back to oxidative phosphorylation as the main energy producer and continues until the cells become too hypoxic again; and (v) the cellular hypoxia …
