Stabilin-1 is expressed in human breast cancer and supports tumor growth in mammary adenocarcinoma mouse model

Abstract

// Vladimir Riabov 1, 2, 9 , Shuiping Yin 1 , Bin Song 1 , Aida Avdic 2 , Kai Schledzewski 2 , Ilja Ovsiy 2 , Alexei Gratchev 2 , Maria Llopis Verdiell 1 , Carsten Sticht 4 , Christina Schmuttermaier 1, 2 , Hiltrud Schönhaber 2 , Christel Weiss 5 , Alan P. Fields 6 , Katja Simon-Keller 3 , Frederick Pfister 3 , Sebastian Berlit 7 , Alexander Marx 3 , Bernd Arnold 8 , Sergij Goerdt 2 , Julia Kzhyshkowska 1, 9 1 Institute for Transfusion Medicine and Immunology, Medical Faculty Mannheim, Ruprecht-Karls University of Heidelberg, Mannheim, Germany 2 Department of Dermatology, Medical Faculty Mannheim, Ruprecht-Karls University of Heidelberg, Mannheim, Germany 3 Institute of Pathology, Medical Faculty Mannheim, Ruprecht-Karls University of Heidelberg, Mannheim, Germany 4 Center for Medical Research, Medical Faculty Mannheim, Ruprecht-Karls University of Heidelberg, Mannheim, Germany 5 Department for Medical Statistics and Biomathematics, Medical Faculty Mannheim, Ruprecht-Karls University of Heidelberg, Mannheim, Germany 6 Department of Cancer Biology, Mayo Clinic Comprehensive Cancer Center, Jacksonville, Florida, USA 7 Department of Obstetrics and Gynaecology, University Medical Center Mannheim, Heidelberg University, Mannheim, Germany 8 Department of Molecular Immunology, German Cancer Research Center, Heidelberg, Germany 9 Laboratory for Translational Cellular and Molecular Biomedicine, Tomsk State University, Tomsk, Russia Correspondence to: Julia Kzhyshkowska, e-mail: julia.kzhyshkowska@medma.uni-heidelberg.de Keywords: tumor-associated macrophages, scavenger receptor, SPARC, stabilin-1, breast cancer Received: July 21, 2015      Accepted: April 02, 2016      Published: April 20, 2016 ABSTRACT Stabilin-1 is a multifunctional scavenger receptor expressed on alternatively-activated macrophages. Stabilin-1 mediates phagocytosis of “unwanted-self” components, intracellular sorting, and endocytic clearance of extracellular ligands including SPARC that modulates breast cancer growth. The expression of stabilin-1 was found on tumor-associated macrophages (TAM) in mouse and human cancers including melanoma, lymphoma, glioblastoma, and pancreatic insulinoma. Despite its tumor-promoting role in mouse models of melanoma and lymphoma the expression and functional role of stabilin-1 in breast cancer was unknown. Here, we demonstrate that stabilin-1 is expressed on TAM in human breast cancer, and its expression is most pronounced on stage I disease. Using stabilin-1 knockout (ko) mice we show that stabilin-1 facilitates growth of mouse TS/A mammary adenocarcinoma. Endocytosis assay on stabilin-1 ko TAM demonstrated impaired clearance of stabilin-1 ligands including SPARC that was capable of inducing cell death in TS/A cells. Affymetrix microarray analysis on purified TAM and reporter assays in stabilin-1 expressing cell lines demonstrated no influence of stabilin-1 expression on intracellular signalling. Our results suggest stabilin-1 mediated silent clearance of extracellular tumor growth-inhibiting factors (e.g. SPARC) as a mechanism of stabilin-1 induced tumor growth. Silent clearance function of stabilin-1 makes it an attractive candidate for delivery of immunomodulatory anti-cancer therapeutic drugs to TAM.