UM
Lysyl oxidase promotes liver metastasis of gastric cancer via facilitating the reciprocal interactions between tumor cells and cancer associated fibroblasts
Li,Qing1,2; Zhu,Chun Chao3; Ni,Bo3; Zhang,Zi Zhen3; Jiang,Shu Heng2; Hu,Li Peng2; Wang,Xu2; Zhang,Xiao Xin2; Huang,Pei Qi2; Yang,Qin2; Li,Jun2; Gu,Jian Ren1,2; Xu,Jia3; Luo,Kathy Qian4; Zhao,Gang2; Zhang,Zhi Gang2
2019-11-01
Source PublicationEBioMedicine
Volume49Pages:157-171
AbstractBackground: 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-β1. Patients-derived xenograft (PDX) model was established using liver metastasis of patients to evaluate the therapeutic value of LOX inhibitor β‐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-β1 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 Medicine Grant 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).
KeywordCAFs Gastric cancer Liver metastasis LOX Warburg effect
DOI10.1016/j.ebiom.2019.10.037
URLView the original
Language英语
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Cited Times [WOS]:13   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionUniversity of Macau
Affiliation1.Shanghai Medical College of Fudan University,Shanghai,200032,China
2.State Key Laboratory of Oncogenes and Related Genes,Shanghai Cancer Institute,Ren Ji Hospital,School of Medicine,Shanghai Jiao Tong University,Shanghai,200240,China
3.Department of Gastrointestinal Surgery,Ren Ji Hospital,School of Medicine,Shanghai Jiao Tong University,Shang HaiPu Dong,No. 1630, Dong Fang Road, Pu Dong New District,200127,China
4.Faculty of Health Sciences,University of Macau,Taipa,China
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GB/T 7714
Li,Qing,Zhu,Chun Chao,Ni,Bo,et al. Lysyl oxidase promotes liver metastasis of gastric cancer via facilitating the reciprocal interactions between tumor cells and cancer associated fibroblasts[J]. EBioMedicine,2019,49:157-171.
APA Li,Qing,Zhu,Chun Chao,Ni,Bo,Zhang,Zi Zhen,Jiang,Shu Heng,Hu,Li Peng,Wang,Xu,Zhang,Xiao Xin,Huang,Pei Qi,Yang,Qin,Li,Jun,Gu,Jian Ren,Xu,Jia,Luo,Kathy Qian,Zhao,Gang,&Zhang,Zhi Gang.(2019).Lysyl oxidase promotes liver metastasis of gastric cancer via facilitating the reciprocal interactions between tumor cells and cancer associated fibroblasts.EBioMedicine,49,157-171.
MLA Li,Qing,et al."Lysyl oxidase promotes liver metastasis of gastric cancer via facilitating the reciprocal interactions between tumor cells and cancer associated fibroblasts".EBioMedicine 49(2019):157-171.
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