Peña C, Céspedes MV, Lindh MB, Kiflemariam S, Mezheyeuski A, Edqvist PH, Hägglöf C, Birgisson H, Bojmar L, Jirström K, Sandström P, Olsson E, Veerla S, Gallardo A, Sjöblom T, Chang AC, Reddel RR, Mangues R, Augsten M, Ostman A
Cancer Res. 73 (4) 1287-1297 [2013-02-15; online 2012-12-18]
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.
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