當(dāng)缺氧時(shí)，腫瘤似乎應(yīng)當(dāng)縮減少，然而，大量研究已證實(shí)腫瘤缺氧的情況下，腫瘤部分區(qū)域含有極低濃度的氧氣，反而會增加腫瘤的侵襲性行為和顯示出更差的預(yù)后。這似乎表明腫瘤不會屈服于缺氧，相反腫瘤的過量增加血液供應(yīng)，因而經(jīng)常會導(dǎo)致缺氧，從而給腫瘤發(fā)送生長和轉(zhuǎn)移的信號以便尋找新的氧氣源。比如，缺氧性膀胱癌可能轉(zhuǎn)移到肺部，而這經(jīng)常是致命性的。

　　在一項(xiàng)刊登在《Cancer Research》期刊上的最新研究中，美國科羅拉多大學(xué)癌癥中心研究人員在詳細(xì)地描述了這些缺氧條件導(dǎo)致侵襲性癌癥產(chǎn)生的機(jī)制。

　　論文通信作者Dan Theodorescu博士說，“我們已經(jīng)知道蛋白HIF-1a在缺氧性腫瘤中過量表達(dá)。我們也已經(jīng)知道癌干細(xì)胞標(biāo)記物CD24在很多腫瘤中過量表達(dá)。這項(xiàng)研究證實(shí)這兩者之間存在關(guān)聯(lián)：缺氧性腫瘤中的HIF-1a導(dǎo)致CD24過量表達(dá)。也正是CD24讓腫瘤表現(xiàn)出侵襲性的生長和轉(zhuǎn)移特征。”

　　過量增加血液供應(yīng)會導(dǎo)致腫瘤缺氧，而腫瘤缺氧導(dǎo)致HIF-1a過量表達(dá)。HIF-1a過量表達(dá)會促進(jìn)CD24產(chǎn)生，從而導(dǎo)致腫瘤生長和轉(zhuǎn)移。除了讓腫瘤變得更具侵襲性之外，研究人員還證實(shí)CD24讓腫瘤對化療產(chǎn)生耐藥性，從而當(dāng)化療結(jié)束時(shí)，允許一小部分細(xì)胞---即前面提到的癌干細(xì)胞---再生腫瘤，而這又會導(dǎo)致腫瘤復(fù)發(fā)和惡化。

　　Theodorescu說，“如今想象一下我們靶向CD24。不論是通過移除細(xì)胞表達(dá)CD24的能力，還是殺死以這種蛋白為標(biāo)記物的細(xì)胞，我們可能都能夠破壞這些最為危險(xiǎn)性的細(xì)胞群體。”

　　Theodorescu和同事們通過調(diào)整癌細(xì)胞樣品和模式動物中的HIF-1a和CD24水平而證實(shí)了這一點(diǎn)：讓HIF-1a保持較低水平，但人為讓CD24保持較高水平，癌細(xì)胞保持再生和轉(zhuǎn)移的能力；相反，讓CD24保持較低水平，但人為讓HIF-1a保持較高水平，癌細(xì)胞存活和增殖能力下降。

　　Theodorescu說，“這似乎表明在缺氧性腫瘤中，處于缺氧之中的細(xì)胞過量表達(dá)CD24，這會促進(jìn)癌癥生長和轉(zhuǎn)移。如今，我們?yōu)檫@些缺氧性腫瘤找到一個(gè)合理的靶標(biāo)，即CD24。”

　　CD24 is an effector of HIF-1 driven primary tumor growth and metastasis

　　Shibu Thomas1, Michael Harding1, Steven C Smith2, Jonathan B Overdevest3, Matthew D. Nitz3, Henry F Frierson Jr4, Scott A Tomlins5, Glen Kristiansen6, and Dan Theodorescu

　　Hypoxia drives malignant progression in part by promoting accumulation of the oncogenic transc**tion factor HIF-1α in tumor cells. Tumor aggressiveness also relates to elevation of the cancer stem cell-associated membrane protein CD24, which has been causally implicated in tumor formation and metastasis in experimental models. Here we link these two elements by showing that hypoxia induces CD24 expression through a functional hypoxia responsive element (HRE) in the CD24 promoter. HIF-1α overexpression induced CD24 mRNA and protein under normoxic conditions, with this effect traced to a recruitment of endogenous HIF-1α to the CD24 promoter. shRNA mediated-attenuation of HIF-1α or CD24 expression reduced cancer cell survival in vitro and in vivo at the levels of primary and metastatic tumor growth. CD24 overexpression in HIF-1α-depleted cancer cells rescued this decrease while HIF-1α overexpression in CD24-depleted cells did not. Analysis of clinical tumor specimens revealed a correlation between HIF-1α and CD24 levels and an association of their co-expression to decreased patient survival. Our results establish a mechanistic linkage between two critically important molecules in cancer, identifying CD24 as a critical HIF-1α transc**tional target and biological effector, strengthening the rationale to target CD24 for cancer therapy.