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2012年9月16日 訊 /生物谷BIOON/ --當缺氧時，腫瘤似乎應(yīng)當縮小。然而，大量研究已證實腫瘤缺氧，即腫瘤部分區(qū)域含有極低濃度的氧氣，的確與更加侵襲性的腫瘤行為和更差的預(yù)后相關(guān)聯(lián)。這似乎表明腫瘤不會屈服于缺氧，相反腫瘤過量增加血液供應(yīng)，因而經(jīng)常會導致缺氧，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。 在一項刊登在Cancer Research期刊上的最新研究中，美國科羅拉多大學癌癥中心研究人員在詳細地描述了這些缺氧條件導致侵襲性癌癥產(chǎn)生的機制。 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。我們也已經(jīng)知道癌干細胞標記物CD24在很多腫瘤中過量表達。這項研究證實這兩者之間存在關(guān)聯(lián)：缺氧性腫瘤中的HIF-1a導致CD24過量表達。也正是CD24讓腫瘤表現(xiàn)出侵襲性的生長和轉(zhuǎn)移特征?！?/p> 過量增加血液供應(yīng)會導致腫瘤缺氧，而腫瘤缺氧導致HIF-1a過量表達。HIF-1a過量表達會促進CD24產(chǎn)生，從而導致腫瘤生長和轉(zhuǎn)移。除了讓腫瘤變得更具侵襲性之外，研究人員還證實CD24讓腫瘤對化療產(chǎn)生耐藥性，從而當化療結(jié)束時，允許一小部分細胞---即前面提到的癌干細胞---再生腫瘤，而這又會導致腫瘤復(fù)發(fā)和惡化。 Theodorescu說，“如今想象一下我們靶向CD24。不論是通過移除細胞表達CD24的能力，還是殺死以這種蛋白為標記物的細胞，我們可能都能夠破壞這些最為危險性的細胞群體?！?/p> Theodorescu和同事們通過調(diào)整癌細胞樣品和模式動物中的HIF-1a和CD24水平而證實了這一點：讓HIF-1a保持較低水平，但人為讓CD24保持較高水平，癌細胞保持再生和轉(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，處于缺氧之中的細胞過量表達CD24，這會促進癌癥生長和轉(zhuǎn)移。如今，我們?yōu)檫@些缺氧性腫瘤找到一個合理的靶標，即CD24?！?生物谷Bioon.com) 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 transcription 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 transcriptional target and biological effector, strengthening the rationale to target CD24 for cancer therapy. |
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