TGF-β1-mediated transition of resident fibroblasts to cancer-associated fibroblasts promotes cancer metastasis in gastrointestinal stromal tumor
release_vlm3bokt5je47fs66qjsnrjdlu
by
Hyunho Yoon, Chih-Min Tang, Sudeep Banerjee, Antonio L. Delgado, Mayra Yebra, Jacob Davis, Jason Sicklick
Abstract
<jats:title>Abstract</jats:title>Cancer-associated fibroblasts (CAFs) are the most abundant cells in the tumor microenvironment. Crosstalk between tumor cells and CAFs contributes to tumor survival in most epithelial cancers. Recently, utilizing gastrointestinal stromal tumor (GIST) as a model for sarcomas, we identified paracrine networks by which CAFs promote tumor progression and metastasis. However, the mechanisms by which CAFs arise in sarcomas remain unclear. Here, RNA sequencing analysis revealed that transforming growth factor-β1 (TGF-β1) is highly expressed in both tumor cells and CAFs. To determine the functional role of TGF-β1, we treated normal gastric fibroblasts (GFs) with recombinant TGF-β1, which caused the GFs to adopt a more stellate morphology, as well as increased the mRNA expression of CAF-mediated genes (<jats:italic>CCL2, RAB3B</jats:italic>, and <jats:italic>TNC</jats:italic>) and genes encoding fibroblast growth factors (<jats:italic>FGF</jats:italic>s). Moreover, while either GIST or CAF conditioned media enhanced the transition from GFs to CAFs, a TGF-β1-blocking antibody attenuated this effect. Transwell migration assays revealed that the TGF-β1-mediated transition from GFs to CAFs enhanced tumor cell migration. This migratory effect was abrogated by an anti-TGF-β1 antibody, suggesting that TGF-β1 secreted from GIST cells or CAFs is associated with GIST migration via GF-to-CAF transition. In addition, the murine spleen-to-liver metastasis model showed that GF pre-treated with TGF-β1 promoted GIST metastasis. Collectively, these findings reveal unappreciated crosstalk among tumor cells, CAFs, and normal resident fibroblasts in the stroma of sarcomas, which enhances a GF-to-CAF transition associated with tumor migration and metastasis.
In application/xml+jats
format
Archived Files and Locations
application/pdf 5.6 MB
file_elwtneqtjza7hnvhy5if2v5hhu
|
www.nature.com (publisher) web.archive.org (webarchive) |
Open Access Publication
In DOAJ
In ISSN ROAD
In Keepers Registry
ISSN-L:
2157-9024
access all versions, variants, and formats of this works (eg, pre-prints)
Crossref Metadata (via API)
Worldcat
SHERPA/RoMEO (journal policies)
wikidata.org
CORE.ac.uk
Semantic Scholar
Google Scholar