title: STC1 expression by cancer-associated fibroblasts drives metastasis of colorectal cancer.
abstract: Platelet-derived growth factor (PDGF) receptor signaling is a major functional determinant of cancer-associated fibroblasts (CAF). Elevated expression of PDGF receptors on stromal CAFs is associated with metastasis and poor prognosis, but mechanism(s) that underlie these connections are not understood. Here, we report the identification of the secreted glycoprotein stanniocalcin-1 (STC1) as a mediator of metastasis by PDGF receptor function in the setting of colorectal cancer. PDGF-stimulated fibroblasts increased migration and invasion of cocultured colorectal cancer cells in an STC1-dependent manner. Analyses of human colorectal cancers revealed significant associations between stromal PDGF receptor and STC1 expression. In an orthotopic mouse model of colorectal cancer, tumors formed in the presence of STC1-deficient fibroblasts displayed reduced intravasation of tumor cells along with fewer and smaller distant metastases formed. Our results reveal a mechanistic basis for understanding the contribution of PDGF-activated CAFs to cancer metastasis.
authors.affiliation: Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Cristina
authors.initials: C
authors.lastname: Peña
authors.forename: María Virtudes
authors.initials: MV
authors.lastname: Céspedes
authors.forename: Maja Bradic
authors.initials: MB
authors.lastname: Lindh
authors.forename: Sara
authors.initials: S
authors.lastname: Kiflemariam
authors.forename: Artur
authors.initials: A
authors.lastname: Mezheyeuski
authors.forename: Per-Henrik
authors.initials: PH
authors.lastname: Edqvist
authors.forename: Christina
authors.initials: C
authors.lastname: Hägglöf
authors.forename: Helgi
authors.initials: H
authors.lastname: Birgisson
authors.forename: Linda
authors.initials: L
authors.lastname: Bojmar
authors.forename: Karin
authors.initials: K
authors.lastname: Jirström
authors.forename: Per
authors.initials: P
authors.lastname: Sandström
authors.forename: Eleonor
authors.initials: E
authors.lastname: Olsson
authors.forename: Srinivas
authors.initials: S
authors.lastname: Veerla
authors.forename: Alberto
authors.initials: A
authors.lastname: Gallardo
authors.forename: Tobias
authors.initials: T
authors.lastname: Sjöblom
authors.forename: Andy C-M
authors.initials: AC
authors.lastname: Chang
authors.forename: Roger R
authors.initials: RR
authors.lastname: Reddel
authors.forename: Ramón
authors.initials: R
authors.lastname: Mangues
authors.forename: Martin
authors.initials: M
authors.lastname: Augsten
authors.forename: Arne
authors.initials: A
authors.lastname: Ostman
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D018920:Coculture Techniques; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D020869:Gene Expression Profiling; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism*; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D051379:Mice; D018345:Mice, Knockout; D009361:Neoplasm Invasiveness; D009374:Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D034622:RNA Interference; D017479:Receptors, Platelet-Derived Growth Factor / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014183:Transplantation, Heterologous
chemical_list: D006023:Glycoproteins; D010982:Platelet-Derived Growth Factor; C051795:teleocalcin; D017479:Receptors, Platelet-Derived Growth Factor