乳腺癌療法，如以HER2為靶點(diǎn)赫賽汀療法給增加了許多女性的開支,；然而近一半的乳腺癌從一開始治療就對赫賽汀產(chǎn)生了耐藥,。如今來自密歇根大學(xué)癌癥研究中心的科學(xué)家發(fā)現(xiàn)了癌癥細(xì)胞為何如此耐藥的原因，研究者表示,，癌細(xì)胞完全是通過另外一種路徑來作用的,，其中一種涉及炎癥，這就為癌細(xì)胞不依賴HER2為靶點(diǎn)提供了基礎(chǔ),。
這種途徑涉及一種蛋白質(zhì)名為白介素-6（IL-6）,，研究人員在小鼠中進(jìn)行實(shí)驗(yàn)，解釋了一種藥物可以阻塞IL-6,，進(jìn)而克服赫賽汀耐藥,。進(jìn)一步研究表明，結(jié)合赫賽汀的IL-6抑制劑或許可以治療HER2陽性的乳腺癌患者,。
相關(guān)研究成果將刊登在8月24日的國際雜志Molecular Cell上,。并不是所有的癌細(xì)胞都對赫賽汀耐藥,，關(guān)鍵是癌細(xì)胞產(chǎn)生了癌癥干細(xì)胞，腫瘤組織中的癌干細(xì)胞可以促使腫瘤加速生長并且擴(kuò)散,。這就使得腫瘤變得非常惡性而且很容易散布全身,。研究者揭示，IL-6抑制劑可以抑制癌干細(xì)胞的增加,。
研究者發(fā)現(xiàn)在很多赫賽汀耐藥的乳腺癌患者中,，IL-6的炎癥循環(huán)引導(dǎo)著癌干細(xì)胞的活動。同似乎研究者表示,，通過阻塞IL-6回路可以完全抑制癌癥和癌干細(xì)胞的生長,。在小鼠中使用IL-6結(jié)合赫賽汀的抑制劑可以改變癌癥發(fā)展，并且不會對赫賽汀產(chǎn)生耐藥,。
IL-6在諸如風(fēng)濕性關(guān)節(jié)炎等炎癥疾病中扮演著重要的角色,，塔西單抗是以IL-6為靶點(diǎn)的藥物，并且已經(jīng)得到FDA批準(zhǔn)用于類風(fēng)濕性關(guān)節(jié)炎,。目前研究者正在進(jìn)行臨床試驗(yàn),，研究者表示，他們的研究發(fā)現(xiàn)為乳腺癌患者的治療可以帶來很大希望,。
（生物谷Bioon.com）
編譯自：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.
