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Molecular mechanisms of IL-33-mediated stromal interactions in cancer metastasis

(2018) JCI INSIGHT. 3(20).
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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-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.
Keywords
TUMOR-CELL MIGRATION, PANCREATIC-CANCER, ZEBRAFISH MODEL, MACROPHAGES, BIOLOGY, IL-33, CHEMOTHERAPY, PROGRESSION, INVASION, THERAPY

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Citation

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Chicago
Andersson, Patrik, Yunlong Yang, Kayoko Hosaka, Yin Zhang, Carina Fischer, Harald Braun, Shuzhen Liu, et al. 2018. “Molecular Mechanisms of IL-33-mediated Stromal Interactions in Cancer Metastasis.” Jci Insight 3 (20).
APA
Andersson, P., Yang, Y., Hosaka, K., Zhang, Y., Fischer, C., Braun, H., Liu, S., et al. (2018). Molecular mechanisms of IL-33-mediated stromal interactions in cancer metastasis. JCI INSIGHT, 3(20).
Vancouver
1.
Andersson P, Yang Y, Hosaka K, Zhang Y, Fischer C, Braun H, et al. Molecular mechanisms of IL-33-mediated stromal interactions in cancer metastasis. JCI INSIGHT. 2018;3(20).
MLA
Andersson, Patrik et al. “Molecular Mechanisms of IL-33-mediated Stromal Interactions in Cancer Metastasis.” JCI INSIGHT 3.20 (2018): n. pag. Print.
@article{8586545,
  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 {\textrangle}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.},
  articleno    = {e122375},
  author       = {Andersson, Patrik and Yang, Yunlong and Hosaka, Kayoko and Zhang, Yin and Fischer, Carina and Braun, Harald and Liu, Shuzhen and Yu, Guohua and Liu, Shihai and Beyaert, Rudi and Chang, Mayland and Li, Qi and Cao, Yihai},
  issn         = {2379-3708},
  journal      = {JCI INSIGHT},
  language     = {eng},
  number       = {20},
  pages        = {18},
  title        = {Molecular mechanisms of IL-33-mediated stromal interactions in cancer metastasis},
  url          = {http://dx.doi.org/10.1172/jci.insight.122375},
  volume       = {3},
  year         = {2018},
}

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