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-kappa B-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-kappa B 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-kappa B-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.
[1]Karolinska Inst, Dept Microbiol Tumor & Cell Biol, S-17177 Stockholm, Sweden.
[2]Univ Ghent, Dept Biomed Mol Biol, Ghent, Belgium.
[3]VIB Ghent, Ctr Inflammat Res, Unit Mol Signal Transduct Inflammat, Ghent, Belgium.
[4]Weifang Peoples Hosp, Clin Oncol Dept, Weifang, Shandong, Peoples R China.
[5]Qingdao Univ, Affiliated Hosp, Cent Res Lab, Qingdao, Peoples R China.
[6]Univ Notre Dame, Dept Chem & Biochem, Notre Dame, IN 46556 USA.
[7]Shanghai Univ Tradit Chinese Med, Shuguang Hosp, Dept Med Oncol, Shanghai, Peoples R China.
[8]Shanghai Univ Tradit Chinese Med, Shuguang Hosp, Canc Inst, Shanghai, Peoples R China.
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