Cancer‐associated fibroblasts educate normal fibroblasts to facilitate cancer cell spreading and T‐cell suppression

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 (ROS), which induced NF-B-mediated expression of inflammatory cytokines and the extracellular matrix protein asporin (ASPN), while expression of a common CAF marker gene, -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, ASPN high /IDO-1 high /KYNU high /-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.

Crosstalk of tumor stromal cells orchestrates invasion and spreading of gastric cancer

“…We found that CAF‐conditioned media (CM), as well as a mixture of NFs and CAFs in mice xenografts, activated NFs via ROS‐induced activation of nuclear factor NF‐κB signaling, resulting in the generation of CEFs, which secreted pro‐inflammatory cytokines, such as IL‐1β, IL‐6, CXCL‐1, and CXCL‐6, as well as ASPN 26 . ASPN further activated IGF‐I signaling and the tryptophan metabolic pathway, leading to T‐cell cytotoxicity.…”

“…ASPN further activated IGF‐I signaling and the tryptophan metabolic pathway, leading to T‐cell cytotoxicity. Inflammatory cytokines, ASPN, and downstream molecules were successively transmitted from fibroblast to fibroblast, ultimately resulting in cancer cell spreading and tumor dissemination 26 …”

“…Among the genes more highly expressed in CEFs than in NFs and CAFs from more than two patients were those encoding kynureninase (KYNU) and pregnancy‐associated plasma protein‐A (PAPP‐A), with these proteins being the most highly elevated in CEFs (Figure 3a,b). Because recombinant ASPN, which is rarely expressed in gastric cancer cells, also increased the expression of indoleamine 2,3‐dioxygenase 1 (IDO‐1), KYNU, and PAPP‐A, these CEFs could be divided into at least two separate groups, ASPN high /IDO‐1 high /KYNU high /αSMA low and ASPN high /PAPP‐A high /αSMA low CEFs 26 …”

“…(c) Simplified schematic of the kynurenine pathway. These figures were from the cited publication 26 . CAF, cancer‐associated fibroblast; CEF, CAF‐educated fibroblast; NF, normal fibroblast…”

“…By contrast, fibrosis has been observed in large tumor areas beyond the regions in which cancer cell nests reside, suggesting that pro‐tumor fibroblasts could be generated even in the absence of direct education by cancer cells. We mentioned a novel mechanism of fibroblast activation involves the education of normal fibroblasts (NFs) by CAFs, generating pro‐tumor fibroblasts, described as CAF‐educated fibroblasts (CEFs) 26 . ASPN may participate in this process.…”