Nat Med：发现一种癌症耐药性产生新机制

对于患诸如乳腺癌、前列腺癌、肺癌和结肠癌之类的实体瘤患者而言，对化疗药物产生耐药性是几乎不可避免的而且也是致命性的，因为癌症会转移或者说扩散至全身。来自美国弗雷德哈钦森癌症研究中心(Fred Hutchinson Cancer Research Center)的一个科学家小组发现一种关键性因子促进这种耐药性产生，这种信息可能最终被用来改善治疗方法的疗效，从而为晚期癌症患者赢取宝贵的时间。2012年8月5日，他们将他们的研究发现在线发表Nature Medicine期刊上。

在这项研究中，论文通信作者Peter S. Nelson博士和同事们发现一类正常的非癌变细胞---成纤维细胞---位于癌症的微环境中，当接触到化疗药物时，这些细胞遭受DNA损伤而促进一一系列刺激癌症生长的生长因子产生。在正常情况下，成纤维细胞有助于维持结缔组织的结构完整性，而且它们在伤口愈合和骨胶原产生中发挥着关键性作用。

特别地，研究人员发现损伤DNA的抗癌治疗诱导成纤维细胞在肿瘤微环境中快速产生一种被称作WNT16B的蛋白，高水平的WNT16B蛋白能够让癌细胞生长、侵袭周围组织和抵抗化疗药物。令他们吃惊的是，他们观察到产生的WNT水平增加了30倍。WNT基因家族和蛋白家族在正常发育中和一些癌症产生中发挥着重要作用，但是在此之前，科学家们并不知道它们也在耐药性上发挥着非常重要的作用。

这一发现提示着发现一种阻断肿瘤微环境中的这种治疗反应的方法可能会改善治疗方法的有效性。

本文编译自Scientists find new mechanism behind resistance to cancer treatment

doi: 10.1038/nm.2890
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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.