STC1 Expression By Cancer-Associated Fibroblasts Drives Metastasis of Colorectal Cancer

Cristina Peña,Karin Jirström,Ramón Mangues,Helgi Birgisson,Maja Bradic Lindh,Srinivas Veerla,Per Sandström,Linda Bojmar,Arne Östman,Christina Hägglöf,Sara Kiflemariam,María Virtudes Céspedes,Artur Mezheyeuski,Alberto Gallardo,Martin Augsten,Roger R Reddel,Tobias Sjöblom,Elin Olsson ,Per-Henrík Edqvist ,Andy Chang

doi:10.1158/0008-5472.can-12-1875

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.

Highlights

Studies on metastasis have traditionally focused on properties of the malignant cells
Platelet-derived growth factor (PDGF) activation of fibroblasts increases their ability of paracrine stimulation of colon cancer cell migration and invasion
This study shows that PDGF receptor stimulation of fibroblasts significantly increases migration and invasion of cocultured colorectal cancer cells in an STC1dependent manner

Summary

Introduction

Studies on metastasis have traditionally focused on properties of the malignant cells. Recent studies in tumor biology have shown that the tumor microenvironment exerts major influence on tumor behavior, including the metastatic process [1,2,3]. Several inflammatory cell types of the tumor microenvironment have been shown to affect the metastatic capacity of the malignant cells [4]. Authors' Affiliations: 1Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden; 2Grupo de Oncogenesis y Antitumorales, Institute of Biomedical Research (IIB Sant Pau) and Network Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Barcelona, Spain; 3Department of Immunology, Genetics and Pathology and 4Department of Surgical Sciences, Colorectal Surgery, Uppsala University, Uppsala; 5Division of Surgery, Department of Clinical and Experimental Medicine, Faculty of Health Science, Linko€ping University, Linko€ping; Departments of 6Clinical Sciences and 7Clinical Genetics, Lund University, Lund, Sweden; and 8Children's Medical Research Institute and Sydney Medical School, University of Sydney, Sydney, Australia.

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