RRC ID 71964
著者 Itoh G, Takagane K, Fukushi Y, Kuriyama S, Umakoshi M, Goto A, Yanagihara K, Yashiro M, Tanaka M.
タイトル Cancer-associated fibroblasts educate normal fibroblasts to facilitate cancer cell spreading and T-cell suppression.
ジャーナル Mol Oncol
Abstract In some tumors, a small number of cancer cells are scattered in a large fibrotic stroma. Here, we demonstrate a novel mechanism for expansion of pro-tumor fibroblasts via cancer-associated fibroblast (CAF)-mediated education of normal fibroblasts (NFs). When NFs were incubated with conditioned medium from CAFs, the resulting CAF-educated fibroblasts (CEFs) generated reactive oxygen species, which induced NF-κB-mediated expression of inflammatory cytokines and the extracellular matrix protein asporin (ASPN), while expression of a common CAF marker gene, α-SMA, was not increased. ASPN further increased CEF expression of downstream molecules, including indoleamine 2,3-dioxygenase 1 (IDO-1), kynureninase (KYNU), and pregnancy-associated plasma protein-A (PAPP-A). These CEFs induce cytocidal effects against CD8+ T cells and IGF-I activation in cancer cells. CEFs were generated without cancer cells by the direct mixture of NFs and CAFs in mouse xenografts, and once CEFs were generated, they sequentially educated NFs, leading to continuous generation of CEFs. In diffuse-type gastric cancers, ASPNhigh /IDO-1high /KYNUhigh /α-SMA- CEFs were located at the distal invading front. These CEFs expanded in the fibrotic stroma and caused dissemination of cancer cells. ASPN may therefore be a key molecule in facilitating tumor spreading and T-cell suppression.
巻・号 16(1)
ページ 166-187
公開日 2022-1-1
DOI 10.1002/1878-0261.13077
PMID 34379869
PMC PMC8732346
MeSH Animals CD8-Positive T-Lymphocytes / metabolism Cancer-Associated Fibroblasts* / metabolism Extracellular Matrix Proteins / metabolism Fibroblasts / metabolism Humans Mice Stomach Neoplasms* / pathology
IF 6.574
リソース情報
ヒト・動物細胞 Li-7(RCB1941)