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Oncogene:上海交通大学孙宇研究组揭示临床肿瘤微环境因素导致获得性耐药机制

作者:孙宇 发布时间:2016-01-18

 2016年1月11日,国际学术权威刊物自然出版集团旗下子刊、国际肿瘤学重要学术期刊《Oncogene》中科院上海生命科学研究院、上海交通大学医学院健康科学研究所孙宇研究组的最新研究成果,研究题为“SFRP2 augments WNT16B signaling to promote therapeutic resistance in the damaged tumor microenvironment”,研究揭示Wnt信号通路在肿瘤耐药性形成过程中的核心地位和分子机制,并颠覆了过往人们对于SFRP2这一分子在很多癌型中对于Wnt通路拮抗作用的传统认识。博士生朱德祥和陈斐为论文共同第一作者,孙宇研究员为论文通信作者。

尽管当今人类已经拥有了医学史上最高明的诊疗手段,但在复杂疾病面前依旧显得力不从心。多年来困扰医生和患者的肿瘤耐药性,逐渐成为精准医学时代必须正视和积极解决的问题。多种“新型”临床技术不论怎样走马灯般变换出现,却往往忽视了在癌细胞自身基因组水平变化和表观遗传水平修饰之外的第三者-癌细胞周边的微环境。越来越多的证据表明,微环境对于肿瘤复发和转移率的持续走高起到举足轻重的作用。

研究人员以全基因组表达谱分析发现一种与Wnt信号通路调控有关的可溶因子SFRP2在经过基因毒试剂(如bleomycin)处理过的前列腺基质细胞PSC27中被高度上调。良性前列腺上皮细胞,癌变前列腺上皮细胞和前列腺基质组织内细胞之间SFRP2表达呈现明显的差异,基质细胞群在DNA损伤后更易发生SFRP2高度上调,即存在细胞类型特异性。DNA损伤条件下SFRP2的诱导性表达受到NF-κB复合体的调控。基质细胞生成的另一重要外泌分子WNT16B所影响的癌细胞canonical Wnt信号通路被SFRP2在微环境中进一步激活,该过程却可被DKK1废除。值得注意的是,癌细胞的增殖率、迁移率、侵袭性和异质性,均在广谱PSC27-RAD胞外液作用下大幅提高;而一旦SFRP2被清除,以上活性则显著减弱。WNT16B上调前列腺癌细胞对化疗试剂的耐受性,而SFRP2的存在却使其更加明显,暗示前者是该过程的中心分子、后者为辅助因素。利用促使前列腺癌组织内细胞凋亡程度显著上升的WNT16B特异性抗体,模拟临床治疗条件下的生理现实,针对负荷移植瘤的免疫缺陷型小鼠进行化疗和抗体给药,发现化疗本身使得肿瘤减小近40%,而协同使用免疫疗法可以进一步缩小肿块。

治疗过程中的癌症趋于向恶性发展并迅速获得耐药性,是目前临床医学面临的巨大难题。该研究发现微环境中的SFRP2实际是Wnt通路兴奋剂,而特异性抑制WNT16B可促进体内条件下肿瘤细胞凋亡,剥夺肿瘤从损伤性激活的微环境获得耐药性的途径,降低肿瘤对化疗药物的耐药性,为将来转化医学提供了重要借鉴和实验依据。

原文链接:

SFRP2 augments WNT16B signaling to promote therapeutic resistance in the damaged tumor microenvironment

原文摘要:

Most tumors initially respond to cytotoxic treatments, but acquired resistance often follows. The tumor microenvironment (TME) is a major barrier to clinical success by compromising therapeutic efficacy, and pathological relevance of multiple soluble factors released by a therapeutically remodeled TME remains largely unexplored. Here we show that the secreted frizzled-related protein 2 (SFRP2), a Wnt pathway modulator, is produced by human primary fibroblasts after genotoxic treatments. SFRP2 induction is remarkable in tumor stroma, with transcription mainly modulated by the nuclear factor-κB (NF-κB) complex, a property shared by several effectors of the DNA damage secretory program. Instead of directly altering canonical Wnt signaling, SFRP2 augments β-catenin activities initiated by WNT16B, another soluble factor from DNA-damaged stroma. WNT16B recognizes cancer cell surface receptors including frizzled (FZD) 3/4/6, a process enhanced by SFRP2, coordinated by the co-receptor LRP6 but subject to abrogation by DKK1. importantly, we found WNT16B plays a central role in promoting advanced malignancies particularly acquired resistance by counteracting cell death, an effect that can be minimized by a neutralizing antibody co-administered with classical chemotherapy. Furthermore, DNA damage-triggered expression of WNT16B is systemic, imaged by significant induction among diverse solid organs and circulation in peripheral blood, thereby holding promise as not only a TME-derived anticancer target but also a novel biomarker for clinical evaluation of treatment efficacy. Overall, our study substantiates the biological complexity and pathological implication of a therapy-activated TME, and provides the proof of principle of co-targeting tumor and the TME to prevent acquired resistance, with the aim of improving intervention outcome in an era of precision medicine

文章来源:生物帮