期刊
JCI INSIGHT
卷 3, 期 20, 页码 -出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/jci.insight.122375
关键词
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资金
- European Research Council advanced grant ANGIOFAT [250021]
- Swedish Research Council
- Swedish Cancer Foundation
- Swedish Children's Cancer Foundation
- Karolinska Institutet Foundation
- Karolinska Institutet distinguished professor award
- Torsten Soderberg Foundation
- Maud and Birger Gustavsson Foundation
- Novo Nordisk Foundation
- Knut and Alice Wallenberg Foundation
- Natural Science Foundation of China [81773059]
- Shanghai Pujiang Program [18PJ1400600]
- European Research Council (ERC) [250021] Funding Source: European Research Council (ERC)
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.
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