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

Abstract

<p class="first" id="d2705878e274">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 &gt;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. </p><p class="first" id="d2705878e277"> <div class="figure-container so-text-align-c"> <img alt="" class="figure" src="/document_file/06ca8098-a04a-401b-aa2a-0aa02bd2a45e/PubMedCentral/image/jciinsight-3-122375-g160.jpg"/> </div> </p><p class="first" id="d2705878e282">IL-33 produced by cancer associated fibroblast and pericytes promotes polarization of tumor-associated macrophages, interaction with tumor microvessels, and cancer metastasis. </p>