Abstract
Molecular mechanisms underlying the cancer stroma in metastasis need further exploration. Here, we discovered that cancer-associated fibroblasts (CAFs) produced high levels of IL-33 that acted on tumor-associated macrophages (TAMs), causing them to undergo the M1 to M2 transition. Genomic profiling of metastasis-related genes in the IL-33-stimulated TAMs showed a >200-fold increase of MMP9. Signaling analysis demonstrated the IL-33-ST2-NF-κB-MMP9-laminin pathway that governed tumor stroma-mediated metastasis. In mouse and human fibroblast-rich pancreatic cancers, genetic deletion of IL-33, ST2, or MMP9 markedly blocked metastasis. Pharmacological inhibition of NF-κB and MMP9 also blocked cancer metastasis. Deletion of IL-33, ST2, or MMP9 restored laminin, a key basement membrane component associated with tumor microvessels. Together, our data provide mechanistic insights on the IL-33-NF-κB-MMP9-laminin axis that mediates the CAF-TAM-committed cancer metastasis. Thus, targeting the CAF-TAM-vessel axis provides an outstanding therapeutic opportunity for cancer treatment.
Keywords:
Cancer; Cell Biology; Macrophages; Oncology.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cancer-Associated Fibroblasts / immunology
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Cancer-Associated Fibroblasts / metabolism
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Cell Communication / immunology
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Cell Line, Tumor
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Female
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Gene Expression Profiling
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Humans
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Interleukin-1 Receptor-Like 1 Protein / genetics
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Interleukin-1 Receptor-Like 1 Protein / metabolism
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Interleukin-33 / genetics
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Interleukin-33 / immunology
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Interleukin-33 / metabolism*
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Macrophages / immunology
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Macrophages / metabolism
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Male
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Matrix Metalloproteinase 9 / genetics
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Matrix Metalloproteinase 9 / metabolism
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Matrix Metalloproteinase Inhibitors / pharmacology
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Mice
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Mice, Knockout
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NF-kappa B / antagonists & inhibitors
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NF-kappa B / metabolism
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Neoplasms / immunology*
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Neoplasms / pathology
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Signal Transduction / immunology
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Tumor Microenvironment / drug effects
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Tumor Microenvironment / immunology*
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Xenograft Model Antitumor Assays
Substances
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IL1RL1 protein, human
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IL33 protein, human
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Il1rl1 protein, mouse
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Il33 protein, mouse
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Interleukin-1 Receptor-Like 1 Protein
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Interleukin-33
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Matrix Metalloproteinase Inhibitors
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NF-kappa B
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MMP9 protein, human
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Matrix Metalloproteinase 9
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Mmp9 protein, mouse
Grants and funding
Dr.Yunlong Yang