2012年8月17日 訊 /生物谷BIOON/ --近日，刊登在國際著名雜志Cancer Research上的一篇研究報(bào)告中指出,，個(gè)體病人多個(gè)卵巢癌基因組的存在以及基因LRP1B下調(diào)作用的缺失和特定患者的化學(xué)耐藥性的發(fā)展相關(guān),，這些特定患者具有漿液性癌癥亞型特征，而且其在初次治療后,，病癥又會(huì)復(fù)發(fā),。
在研究過程中，研究者使用病人的腫瘤樣品來研究其對(duì)化學(xué)療法耐藥性的分子機(jī)制,。高度漿液性癌癥在上皮侵入性卵巢癌患者死亡中占到了2/3的比例,，患者首次進(jìn)行手術(shù)，然后化療,；進(jìn)而癌癥復(fù)發(fā)以至于最終癌細(xì)胞對(duì)化療產(chǎn)生耐藥,，研究者重點(diǎn)研究這個(gè)過程中在患者體內(nèi)發(fā)生的分子機(jī)制改變。
研究者分析了來自個(gè)體病人的癌癥轉(zhuǎn)移病灶以及22對(duì)預(yù)處理和治療后的腫瘤樣品,，以進(jìn)行空間和時(shí)效性的基因組改變分析,。空間變化是一種在初期手術(shù)后對(duì)不同腫瘤樣品進(jìn)行的基因組異質(zhì)性的測(cè)量方法,，腫瘤發(fā)生突變可以隨著時(shí)間慢慢進(jìn)行,，尤其是在面對(duì)化學(xué)療法的時(shí)候。而時(shí)效性的變化可以給我們以指示,，指示腫瘤改變了多少,，以及在經(jīng)過多次化療后腫瘤的改變程度。
研究者比較了化療敏感婦女和化療耐藥性婦女的基因組水平的改變,，在開始進(jìn)行化療的時(shí)候,，腫瘤細(xì)胞對(duì)其是敏感的，但是隨著化療的不斷使用,，腫瘤細(xì)胞慢慢開始產(chǎn)生耐藥性,。研究者Bowtell表示，同一個(gè)體中多個(gè)癌癥基因組的存在可以幫助我們來研究癌細(xì)胞如何逃避化療的分子機(jī)制,，并且解釋為何我們難以取得疾病的發(fā)展進(jìn)程,。研究者發(fā)現(xiàn)最為頻繁的基因組改變是基因LRP1B的突變或者下調(diào),，該基因編碼一類蛋白家族成員,，其主要負(fù)責(zé)運(yùn)輸脂質(zhì)進(jìn)入細(xì)胞。為了證實(shí)研究發(fā)現(xiàn),，研究者檢驗(yàn)了在卵巢癌細(xì)胞系在LRP1B存在或者缺失情況下的效應(yīng),。結(jié)果表明，LRP1B的缺失可以引發(fā)癌細(xì)胞對(duì)多柔比星脂質(zhì)體（一種化療方法）耐藥性的出現(xiàn),。
目前,，研究者幾乎不能預(yù)測(cè)癌癥復(fù)發(fā)對(duì)于化療的直接效應(yīng),，而LRP1B的出現(xiàn)增加了一些其它的分子機(jī)制，如果研究者可以繪制癌細(xì)胞產(chǎn)生耐藥性的機(jī)制圖譜,，那么研究者將會(huì)預(yù)測(cè)是否有些婦女會(huì)對(duì)某些藥物產(chǎn)生反應(yīng),，并且也可以找到逆轉(zhuǎn)癌細(xì)胞耐藥的方法。（生物谷Bioon.com）
編譯自：Mechanisms of Acquired Chemoresistance in Ovarian Cancer Identified
doi:10.1158/0008-5472.CAN-11-3873
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Primary Tumor Hypoxia Recruits CD11b+/Ly6Cmed/Ly6G+ Immune Suppressor Cells and Compromises NK Cell Cytotoxicity in the Premetastatic Niche
Jaclyn Sceneay1,4, Melvyn T. Chow2,4, Anna Chen1,4, Heloise M. Halse2, Christina S.F. Wong1, Daniel M. Andrews2, Erica K. Sloan7, Belinda S. Parker3,4,5, David D. Bowtell1,4,5,6, Mark J. Smyth2,4,5,6, and Andreas Möller1,4,5,6
Hypoxia within a tumor acts as a strong selective pressure that promotes angiogenesis, invasion, and metastatic spread. In this study, we used immune competent bone marrow chimeric mice and syngeneic orthotopic mammary cancer models to show that hypoxia in the primary tumor promotes premetastatic niche formation in secondary organs. Injection of mice with cell-free conditioned medium derived from hypoxic mammary tumor cells resulted in increased bone marrow–derived cell infiltration into the lung in the absence of a primary tumor and led to increased metastatic burden in mammary and melanoma experimental metastasis models. By characterizing the composition of infiltrating bone marrow–derived cells, we identified CD11b+/Ly6Cmed/Ly6G+ myeloid and CD3−/NK1.1+ immune cell lineages as key constituents of the premetastatic niche. Furthermore, the cytotoxicity of natural killer (NK) cells was significantly decreased, resulting in a reduced antitumor response that allowed metastasis formation in secondary organs to a similar extent as ablation of NK cells. In contrast, metastatic burden was decreased when active NK cells were present in premetastatic lungs. Together, our findings suggest that primary tumor hypoxia provides cytokines and growth factors capable of creating a premetastatic niche through recruitment of CD11b+/Ly6Cmed/Ly6G+ myeloid cells and a reduction in the cytotoxic effector functions of NK cell populations. Cancer Res; 72(16); 3906–11. ©2012 AACR.
