Molecular mechanisms of IL-33–mediated stromal interactions in cancer metastasis
Patrik Andersson, Yunlong Yang, Kayoko Hosaka, Yin Zhang, Carina Fischer, Harald Braun, Shuzhen Liu, Guohua Yu, Shihai Liu, Rudi Beyaert, Mayland Chang, Qi Li, Yihai Cao
Patrik Andersson, Yunlong Yang, Kayoko Hosaka, Yin Zhang, Carina Fischer, Harald Braun, Shuzhen Liu, Guohua Yu, Shihai Liu, Rudi Beyaert, Mayland Chang, Qi Li, Yihai Cao
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Research Article Cell biology Oncology

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

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.

Authors

Patrik Andersson, Yunlong Yang, Kayoko Hosaka, Yin Zhang, Carina Fischer, Harald Braun, Shuzhen Liu, Guohua Yu, Shihai Liu, Rudi Beyaert, Mayland Chang, Qi Li, Yihai Cao

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Figure 7

IL-33–induced MMP9 in macrophages promotes metastasis in human PDAC.

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IL-33–induced MMP9 in macrophages promotes metastasis in human PDAC. (A)...
(A) IL-33 protein levels in human melanoma and pancreatic cancers (n = 3 samples per group). (B) Staining of MiaPaCa2 PDAC and UACC257 melanoma tumor tissues. Light blue indicates fibrotic components (Masson’s trichrome; scale bar: 50 μm). (C) qPCR quantification of Mmp9 mRNA expression in 3 human pancreatic tumors (n = 6 samples per group). (D) Immunohistochemical staining and quantification of Iba1+ (red) macrophages in vehicle- and a soluble ST2–treated MiaPaCa2 tumors (n = 8 random fields per group; scale bar: 100 μm). (E) Immunohistochemical staining and quantification of CD31+ (red) and laminin+ (green) structures in vehicle- and a soluble ST2–treated MiaPaCa2 tumors. Arrowheads indicate laminin/CD31 double-positive signals. Quantification of the percentage of laminin+/CD31+ signals per field (n = 8 random fields per group; scale bar: 100 μm). (F) Immunohistochemical staining and quantification of CD31+ (red) and laminin+ (green) structures in vehicle- and SB-3CT–treated MiaPaCa2 tumors. Arrowheads indicate laminin/CD31 double-positive signals. Quantification of the percentage of laminin+/CD31+ signals per field (n = 8 random fields per group; scale bar: 100 μm). (G) Lung histology of MiaPaCa2 tumor-bearing mice receiving vehicle or a soluble ST2 treatments. Dashed line marks the border between the metastatic nodule (T) and surrounding lung tissues (L) (scale bar: 250 μm). Quantification of percentage of animals with visible pulmonary metastasis (n = 6–10 mice per group). (H) Lung histology of MiaPaCa2 tumor-bearing mice receiving vehicle or SB-3CT treatments. Dashed line marks the border between the metastatic nodule and surrounding lung tissues (scale bar: 250 μm). Quantification of the percentage of animals with visible pulmonary metastasis (n = 6–10 mice per group). Mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001, Student’s t test.