2012年8月17日 讯 /生物谷BIOON/ --近日,刊登在国际著名杂志Cancer Research上的一篇研究报告中指出,个体病人多个卵巢癌基因组的存在以及基因LRP1B下调作用的缺失和特定患者的化学耐药性的发展相关,这些特定患者具有浆液性癌症亚型特征,而且其在初次治疗后,病症又会复发。
在研究过程中,研究者使用病人的肿瘤样品来研究其对化学疗法耐药性的分子机制。高度浆液性癌症在上皮侵入性卵巢癌患者死亡中占到了2/3的比例,患者首次进行手术,然后化疗;进而癌症复发以至于最终癌细胞对化疗产生耐药,研究者重点研究这个过程中在患者体内发生的分子机制改变。
研究者分析了来自个体病人的癌症转移病灶以及22对预处理和治疗后的肿瘤样品,以进行空间和时效性的基因组改变分析。空间变化是一种在初期手术后对不同肿瘤样品进行的基因组异质性的测量方法,肿瘤发生突变可以随着时间慢慢进行,尤其是在面对化学疗法的时候。而时效性的变化可以给我们以指示,指示肿瘤改变了多少,以及在经过多次化疗后肿瘤的改变程度。
研究者比较了化疗敏感妇女和化疗耐药性妇女的基因组水平的改变,在开始进行化疗的时候,肿瘤细胞对其是敏感的,但是随着化疗的不断使用,肿瘤细胞慢慢开始产生耐药性。研究者Bowtell表示,同一个体中多个癌症基因组的存在可以帮助我们来研究癌细胞如何逃避化疗的分子机制,并且解释为何我们难以取得疾病的发展进程。研究者发现最为频繁的基因组改变是基因LRP1B的突变或者下调,该基因编码一类蛋白家族成员,其主要负责运输脂质进入细胞。为了证实研究发现,研究者检验了在卵巢癌细胞系在LRP1B存在或者缺失情况下的效应。结果表明,LRP1B的缺失可以引发癌细胞对多柔比星脂质体(一种化疗方法)耐药性的出现。
目前,研究者几乎不能预测癌症复发对于化疗的直接效应,而LRP1B的出现增加了一些其它的分子机制,如果研究者可以绘制癌细胞产生耐药性的机制图谱,那么研究者将会预测是否有些妇女会对某些药物产生反应,并且也可以找到逆转癌细胞耐药的方法。(生物谷Bioon.com)
编译自: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.