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 6

Degradation of the basement membrane by the IL-33-ST2-NF-κB-MMP9 axis.

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Degradation of the basement membrane by the IL-33-ST2-NF-κB-MMP9 axis. (...
(A) Immunohistochemical staining and quantification of CD31+ (red) and laminin+ (green) structures in Panc02 tumors grown in WT, Il33–/–, or St2–/– mice. 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). (B) Immunohistochemical staining and quantification of CD31+ (red) and laminin+ (green) structures in vehicle- or soluble ST2–treated Panc02 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). (C) Immunohistochemical staining and quantification of CD31+ (red) and laminin+ (green) structures in PBS- or clodronate-treated Panc02 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). (D) Immunohistochemical staining and quantification of CD31+ (red) and laminin+ (green) structures in Panc02 tumors treated with vehicle or DHMEQ (a NF-κB inhibitor). 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). (E) Immunohistochemical staining and quantification of CD31+ (red) and laminin+ (green) structures in Panc02 tumors treated with vehicle or SB-3CT (a MMP9 inhibitor). 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 Panc02 tumors grown in WT or Mmp9–/– mice. 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). Mean ± SEM. **P < 0.01; ***P < 0.001, Student’s t test.