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 8

Mechanisms of IL-33–mediated crosstalk between CAFs and TAMs in cancer metastasis.

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Mechanisms of IL-33–mediated crosstalk between CAFs and TAMs in cancer m...
Mechanistic insights on IL-33–mediated crosstalk between pericytes (PCs)/cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs) in cancer metastasis. PDGFRβ+ PCs/CAFs produce high levels of IL-33, which recruits TAMs and induces M2 macrophage polarization through its ST2 receptor. IL-33–stimulated TAMs produce high levels of MMP9 through activation of NF-κB, which transcriptionally activates the MMP9 promoter. MMP9 in turn degrades laminin, one of the key components in the basement membrane (BM). Deterioration of BM around the tumor vasculature allows tumor cells (TCs) to intravasate into the circulation. Circulating tumor cells (CTCs) eventually recolonize in distal organs, such as lungs, for further growth to become the clinically detectable metastatic mass.