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Mol Cell:癌症细胞对赫赛汀产生耐药的原因

2012-07-23 T.Shen 生物谷

乳腺癌疗法,如以HER2为靶点赫赛汀疗法给增加了许多女性的开支;然而近一半的乳腺癌从一开始治疗就对赫赛汀产生了耐药。如今来自密歇根大学癌症研究中心的科学家发现了癌症细胞为何如此耐药的原因,研究者表示,癌细胞完全是通过另外一种路径来作用的,其中一种涉及炎症,这就为癌细胞不依赖HER2为靶点提供了基础。 这种途径涉及一种蛋白质名为白介素-6(IL-6),研究人员在小鼠中进行实验,解释了一种药物可以阻

乳腺癌疗法,如以HER2为靶点赫赛汀疗法给增加了许多女性的开支;然而近一半的乳腺癌从一开始治疗就对赫赛汀产生了耐药。如今来自密歇根大学癌症研究中心的科学家发现了癌症细胞为何如此耐药的原因,研究者表示,癌细胞完全是通过另外一种路径来作用的,其中一种涉及炎症,这就为癌细胞不依赖HER2为靶点提供了基础。

这种途径涉及一种蛋白质名为白介素-6(IL-6),研究人员在小鼠中进行实验,解释了一种药物可以阻塞IL-6,进而克服赫赛汀耐药。进一步研究表明,结合赫赛汀的IL-6抑制剂或许可以治疗HER2阳性的乳腺癌患者。

相关研究成果将刊登在8月24日的国际杂志Molecular Cell上。并不是所有的癌细胞都对赫赛汀耐药,关键是癌细胞产生了癌症干细胞,肿瘤组织中的癌干细胞可以促使肿瘤加速生长并且扩散。这就使得肿瘤变得非常恶性而且很容易散布全身。研究者揭示,IL-6抑制剂可以抑制癌干细胞的增加。

研究者发现在很多赫赛汀耐药的乳腺癌患者中,IL-6的炎症循环引导着癌干细胞的活动。同似乎研究者表示,通过阻塞IL-6回路可以完全抑制癌症和癌干细胞的生长。在小鼠中使用IL-6结合赫赛汀的抑制剂可以改变癌症发展,并且不会对赫赛汀产生耐药。

IL-6在诸如风湿性关节炎等炎症疾病中扮演着重要的角色,塔西单抗是以IL-6为靶点的药物,并且已经得到FDA批准用于类风湿性关节炎。目前研究者正在进行临床试验,研究者表示,他们的研究发现为乳腺癌患者的治疗可以带来很大希望。

编译自:Inflammatory Pathway Spurs Cancer Stem Cells to Resist HER2-Targeted Breast Cancer Treatment

doi:10.1016/j.molcel.2012.06.014
PMC:
PMID:

Activation of an IL6 Inflammatory Loop Mediates Trastuzumab Resistance in HER2+ Breast Cancer by Expanding the Cancer Stem Cell Population

Hasan Korkaya1, , , Gwang-il Kim1, 2, April Davis1, Fayaz Malik1, 3, N. Lynn Henry1, Suthinee Ithimakin1, Ahmed A. Quraishi1, Nader Tawakkol1, Rosemarie D'Angelo1, Amanda K. Paulson1, Susan Chung1, Tahra Luther1, Hayley J. Paholak1, Suling Liu1, Khaled A. Hassan1, Qin Zen1, Shawn G. Clouthier1, Max S. Wicha1, ,

Although inactivation of the PTEN gene has been implicated in the development of resistance to the HER2 targeting antibody trastuzumab, the mechanisms mediating this resistance remain elusive. We generated trastuzumab resistant cells by knocking down PTEN expression in HER2 overexpressing breast cancer cell lines and demonstrate that development of trastuzumab resistance in these cells is mediated by activation of an IL6 inflammatory feedback loop leading to expansion of the cancer stem cell (CSC) population. Long term trastuzumab treatment generates highly enriched CSCs which display an EMT phenotype secreting over 100-fold more IL6 than parental cells. An IL6 receptor antibody interrupted this inflammatory feedback loop reducing the cancer stem cell population resulting in decreased tumor growth and metastasis in mouse xenographs. These studies demonstrate that trastuzumab resistance may be mediated by an IL6 inflammatory loop and suggest that blocking this loop may provide alternative strategy to overcome trastuzumab resistance.

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    2013-04-02 维他命
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    2012-12-05 zhwj
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    2012-07-25 wrj0122
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