Lysyl oxidase promotes liver metastasis of gastric cancer via facilitating the reciprocal interactions between tumor cells and cancer associated fibroblasts
Lysyl oxidase promotes liver metastasis of gastric cancer via facilitating the reciprocal interactions between tumor cells and cancer associated fibroblasts
复制标题
赖氨酰氧化酶通过促进肿瘤细胞与癌症相关成纤维细胞之间的相互作用促进胃癌肝转移
DOI：
10.1016/j.ebiom.2019.10.037
复制
发表时间：
2019-11-01
期刊：
影响因子：
11.1
通讯作者：
Zhang, Zhi-Gang
中科院分区：
文献类型：
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作者：
Li, Qing;Zhu, Chun-Chao;Zhang, Zhi-Gang
背景：肝脏是胃癌远处转移的首选靶点之一。由于有效治疗手段仍然有限，发生肝转移的胃癌患者预后较差。我们筛选出赖氨酰氧化酶(LOX)，以研究其在肿瘤微环境(TME)中的作用，寻找潜在的治疗靶点。方法：对6例胃癌肝转移患者的原发灶和邻近正常肝组织进行转录分析。使用5个数据集对LOX进行过滤。对69例胃癌肝转移组织进行免疫组织化学(IHC)检测和预后分析。应用计算机断层扫描(CT)结合器官三维重建的生物发光成像技术，准确评价脾内注射小鼠肝脏转移瘤负荷。分离培养人和小鼠肝转移癌相关成纤维细胞(CAF)，研究LOX与转化生长因子-β1(TGF-β1)的相互作用。利用患者肝转移建立患者源性异种移植(PDX)模型，以评价LOX抑制剂β-氨基丙腈(BAPN)的治疗价值。结果：CAFS来源的LOX在GC的肝转移灶促进了生态位的形成和生长，从而预测了预后不良。与此同时，小生境中的肿瘤细胞分泌转化生长因子-β1，以滋养CAF，并刺激它们依次产生更多的LOX。LOX促进细胞增殖的机制是增强Warburg效应。LOX的抑制剂BPAN在体内和体外都能抑制LOX的作用。解释：我们的研究揭示了CAF与GC肝转移灶中的肿瘤细胞之间的正反馈回路。核心分子是促进Warburg效应的LOX。基金：国家自然科学基金项目中国(31872740)、上海市卫生计生委百人计划(2017BR043)、上海市科委项目(17ZR1416800)、仁济医院培训基金(PYMDT-003、PYIII-17-015)、国家自然科学基金中国(81672358)、上海市教委-高凤临床医学基金资助(20181708)、上海市学术技术带头人计划(19XD1403400)、上海市科委(18410721000)、上海市卫生局(2018BR32)、中国博士后科学基金(2018M640403)、中国国家自然科学基金(81701945)和上海市卫生健康委员会青年项目(20164Y0045)。(C)2019年提交人。爱思唯尔出版公司(Elsevier B.V.)
Background: Liver is one of the most preferred destinations of distant metastasis in gastric cancer (GC). As effective treatment is still limited, the prognosis of GC patients bearing liver metastasis is poor. We filter out lysyl oxidase (LOX) to study its function in the tumor microenvironment (TME) and seek for potential therapeutic targets.Methods: Transcription analysis on 6 cases of liver metastasis of GC patients with respective paired primary tumors and adjacent normal livers was performed. The filtration out of LOX was done using 5 datasets. 69 GC liver metastasis tissues were utilized to perform immunohistochemistry (IHC) and analyze prognosis. Computed Tomography (CT) combined 3D organ reconstruction bioluminescence imaging was performed to precisely evaluate the metastatic tumor burden on liver of intrasplenic injection mouse model. Human and mouse cancer associated fibroblasts (CAFs) in liver metastasis were separated to culture to study the interaction of LOX and TGF-beta 1. Patients-derived xenograft (PDX) model was established using liver metastasis of patients to evaluate the therapeutic value of LOX inhibitor beta-aminopropionitrile (BAPN).Results: CAFs-derived LOX at liver metastatic niche of GC promotes niche formation and outgrowth thus predicts poor prognosis. Meanwhile tumor cells in niche secrete TGF-beta 1 to nourish CAFs and stimulate them to produce more LOX in turn. The mechanism involved in LOX-mediated proliferation facilitation is enhancement of Warburg effect. The inhibitor of LOX, BPAN could hamper the effect brought by LOX in vivo and in vitro.Interpretation: Our study has unveiled a positive feedback loop between CAFs and tumor cells in liver metastasis niche of GC. The core molecule is LOX which facilitates Warburg effect. Targeting LOX with its inhibitor BAPN might serve as a potential therapeutic strategy.Fund: This research was supported by the National Natural Science Foundation of China (31872740), the 100-member plan of the Shanghai Municipal Commission of Health and Family Planning (2017BR043), Shanghai Science and Technology Commission Project(17ZR1416800), Renji Hospital Training Fund (PYMDT-003, PYIII-17-015), National Natural Science Foundation of China (81672358), the Shanghai Municipal Education Commission-Gao feng Clinical MedicineGrant Support (20181708), Program of Shanghai Academic/Technology Research Leader(19XD1403400), Science and Technology Commission of Shanghai Municipality (18410721000), Shanghai Municipal Health Bureau ( 2018BR32), China Postdoctoral Science Foundation (2018M640403), National Natural Science Foundation of China (81701945) and Youth project of Shanghai Municipal Health Commission(20164Y0045). (c) 2019 The Authors. Published by Elsevier B.V.