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The reciprocal interaction between tumor cells and activated fibroblasts mediated by TNF-?/IL-33/ST2L signaling promotes gastric cancer metastasis.

ABSTRACT: Gastric cancer (GC) is characterized by extensive local invasion, distant metastasis and poor prognosis. In most cases, GC progression is associated with aberrant expression of cytokines or activation of signaling cascades mediated by tumor-stroma interactions. However, the mechanisms by which these interactions contribute to GC progression are poorly understood. In this study, we find that IL-33 and its receptor ST2L are upregulated in the human GC and served as prognostic markers for poor survival of GC patients. In a co-culture model with GC cells and cancer-associated fibroblasts (CAFs), we further demonstrate that CAFs-derived IL-33 enhances the migration and invasion of GC cells by inducing the epithelial-mesenchymal transition (EMT) through activation of the ERK1/2-SP1-ZEB2 pathway in a ST2L-dependent manner. Furthermore, the secretion of IL-33 by CAFs can be induced by the proinflammatory cytokines TNF-? that is released by GC cells via TNFR2-NF-?B-IRF-1 pathway. Additionally, silencing of IL-33 expression in CAFs or ST2L expression in GC cells inhibits the peritoneal dissemination and metastatic potential of GC cells in nude mice. Taken together, these results characterize a critical role of the interaction between epithelial-stroma mediated by the TNF-?/IL-33/ST2L signaling in GC progression, and provide a rationale for targeting this pathway to treat GC metastasis.

SUBMITTER: Zhou Q

PROVIDER: S-EPMC7018661 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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The reciprocal interaction between tumor cells and activated fibroblasts mediated by TNF-α/IL-33/ST2L signaling promotes gastric cancer metastasis.

Zhou Quan Q Wu Xiongyan X Wang Xiaofeng X Yu Zhenjia Z Pan Tao T Li Zhen Z Chang Xinyu X Jin Zhijian Z Li Jianfang J Zhu Zhenggang Z Liu Bingya B Su Liping L

Oncogene 20191028 7

Gastric cancer (GC) is characterized by extensive local invasion, distant metastasis and poor prognosis. In most cases, GC progression is associated with aberrant expression of cytokines or activation of signaling cascades mediated by tumor-stroma interactions. However, the mechanisms by which these interactions contribute to GC progression are poorly understood. In this study, we find that IL-33 and its receptor ST2L are upregulated in the human GC and served as prognostic markers for poor surv ...[more]

PMID: 31659258

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Project description:BackgroundLiver 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.MethodsTranscription 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).ResultsCAFs-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.InterpretationOur 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).

Dataset Information

The reciprocal interaction between tumor cells and activated fibroblasts mediated by TNF-?/IL-33/ST2L signaling promotes gastric cancer metastasis.

Publications

The reciprocal interaction between tumor cells and activated fibroblasts mediated by TNF-α/IL-33/ST2L signaling promotes gastric cancer metastasis.

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