Journal of Molecular Cell Biology（《分子細胞生物學報》）2012年第3期“復雜疾病的系統(tǒng)生物學研究”專輯中發(fā)表了一篇美國佐治亞大學生物化學與分子生物學系徐鷹教授關于“Hypoxia and miscoupling between reduced energy efficiency and signaling to cell proliferation drive cancer to grow increasingly faster” 的論文,，報道了細胞內(nèi)低氧引起能量效率與控制細胞增殖的關系的失調(diào),，從而促進腫瘤的快速生長。這一假設與傳統(tǒng)認為的“基因突變導致腫瘤生長”觀點有著很大的區(qū)別,。此文在線出版后，立即受到包括ScienceDaily在內(nèi)的國際媒體廣泛關注,。
過去的研究將細胞內(nèi)低氧水平看作癌癥發(fā)展的促進因素之一,，但并不是腫瘤生長的驅(qū)動因素。徐教授說,，隨機的基因突變單獨無法解釋全球癌癥的高發(fā)病率,。他又說，將數(shù)學和計算機知識應用于生物學而形成的生物信息學使研究人員可以從一種新的角度看待癌癥,?；蛲蛔兛赡苁拱┘毎诟偁幹袃?yōu)于健康細胞，但這樣的話新生癌細胞生長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的不良變化,。“癌癥治療藥物力求達到根源——在分子水平上——一個特定的突變，但往往不能根治,，”徐教授說：“所以我們想基因突變可能并不是癌癥的主要驅(qū)動因素,。”的確，徐教授的分析發(fā)現(xiàn),，長期的細胞內(nèi)缺氧可能是癌生長的一個關鍵驅(qū)動因素,。
目前大多數(shù)的癌癥研究希望通過藥物對抗與某種特定癌癥相關的基因突變，進而達到治療癌癥的目的,。徐教授課題組從Stanford Microarray Database數(shù)據(jù)庫下載了7種癌癥（乳腺癌,、腎癌、肝癌,、肺癌,、卵巢癌、胰腺癌及胃癌）的相關數(shù)據(jù),，通過一款軟件程序分析這7種癌癥中異常的基因表達模式,。他們以基因HIF1A作為一個細胞氧含量的標記物，所有被實驗的7種癌細胞中,，HIF1A水平都有顯著的升高,，這表明這些癌細胞中氧含量顯著的降低,。
細胞內(nèi)氧含量降低，導致氧化磷酸化反應的中斷,，而氧化磷酸化反應是細胞將食物轉(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，所以為了存活癌細胞必須努力得到更多的食物,，尤其是葡萄糖,。當氧含量水平下降到極限時，血管新生——即生成新血管的過程——啟動了,。新生血管提供新鮮的氧氣,，提高細胞內(nèi)和腫瘤的氧含量水平，并延緩癌細胞的生長,，但這都是暫時的。
“得到更多的食物后,，癌細胞就會生長,；這就會導致整個腫瘤實體增長而更加缺氧。反過來,，能量轉(zhuǎn)換效率將更加低下,，從而使細胞更加饑餓，促使細胞從血液循環(huán)中獲得更多的食物,，形成一個惡性循環(huán),。這或許是腫瘤形成的一個關鍵驅(qū)動因素，”徐說,。這個全新的癌細胞生長模式可能用于解釋為什么很多腫瘤很快（3-6個月以內(nèi)）產(chǎn)生耐藥性,。他強調(diào)了未來非常有必要通過大量的癌癥實驗研究來論證這一新模式。如果這一模式得以成立,，研究人員的首要任務是探索防止細胞內(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 …
