對于患諸如乳腺癌、前列腺癌,、肺癌和結(jié)腸癌之類的實體瘤患者而言,，對化療藥物產(chǎn)生耐藥性是幾乎不可避免的而且也是致命性的，因為癌癥會轉(zhuǎn)移或者說擴(kuò)散至全身,。來自美國弗雷德哈欽森癌癥研究中心(Fred Hutchinson Cancer Research Center)的一個科學(xué)家小組發(fā)現(xiàn)一種關(guān)鍵性因子促進(jìn)這種耐藥性產(chǎn)生,，這種信息可能最終被用來改善治療方法的療效，從而為晚期癌癥患者贏取寶貴的時間,。2012年8月5日,，他們將他們的研究發(fā)現(xiàn)在線發(fā)表Nature Medicine期刊上。
在這項研究中,，論文通信作者Peter S. Nelson博士和同事們發(fā)現(xiàn)一類正常的非癌變細(xì)胞---成纖維細(xì)胞---位于癌癥的微環(huán)境中,，當(dāng)接觸到化療藥物時，這些細(xì)胞遭受DNA損傷而促進(jìn)一一系列刺激癌癥生長的生長因子產(chǎn)生,。在正常情況下,，成纖維細(xì)胞有助于維持結(jié)締組織的結(jié)構(gòu)完整性，而且它們在傷口愈合和骨膠原產(chǎn)生中發(fā)揮著關(guān)鍵性作用,。
特別地,，研究人員發(fā)現(xiàn)損傷DNA的抗癌治療誘導(dǎo)成纖維細(xì)胞在腫瘤微環(huán)境中快速產(chǎn)生一種被稱作WNT16B的蛋白，高水平的WNT16B蛋白能夠讓癌細(xì)胞生長,、侵襲周圍組織和抵抗化療藥物,。令他們吃驚的是，他們觀察到產(chǎn)生的WNT水平增加了30倍,。WNT基因家族和蛋白家族在正常發(fā)育中和一些癌癥產(chǎn)生中發(fā)揮著重要作用,，但是在此之前，科學(xué)家們并不知道它們也在耐藥性上發(fā)揮著非常重要的作用,。
這一發(fā)現(xiàn)提示著發(fā)現(xiàn)一種阻斷腫瘤微環(huán)境中的這種治療反應(yīng)的方法可能會改善治療方法的有效性,。(生物谷：Bioon.com)
本文編譯自Scientists find new mechanism behind resistance to cancer treatment
doi: 10.1038/nm.2890
PMC:
PMID:
Treatment-induced damage to the tumor microenvironment promotes prostate cancer therapy resistance through WNT16B
Yu Sun,1 Judith Campisi,2, 3 Celestia Higano,4, 5 Tomasz M Beer,6, 7 Peggy Porter,1 Ilsa Coleman,1 Lawrence True8 & Peter S. Nelson1, 4, 5, 8
Acquired resistance to anticancer treatments is a substantial barrier to reducing the morbidity and mortality that is attributable to malignant tumors. Components of tissue microenvironments are recognized to profoundly influence cellular phenotypes, including susceptibilities to toxic insults. Using a genome-wide analysis of transcriptional responses to genotoxic stress induced by cancer therapeutics, we identified a spectrum of secreted proteins derived from the tumor microenvironment that includes the Wnt family member wingless-type MMTV integration site family member 16B (WNT16B). We determined that WNT16B expression is regulated by nuclear factor of κ light polypeptide gene enhancer in B cells 1 (NF-κB) after DNA damage and subsequently signals in a paracrine manner to activate the canonical Wnt program in tumor cells. The expression of WNT16B in the prostate tumor microenvironment attenuated the effects of cytotoxic chemotherapy in vivo, promoting tumor cell survival and disease progression. These results delineate a mechanism by which genotoxic therapies given in a cyclical manner can enhance subsequent treatment resistance through cell nonautonomous effects that are contributed by the tumor microenvironment.
