Stabilin-1 is expressed in human breast cancer and supports tumor growth in mammary adenocarcinoma mouse model
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Vladimir Riabov1,2,9, Shuiping Yin1, Bin Song1, Aida Avdic2, Kai Schledzewski2, Ilja Ovsiy2, Alexei Gratchev2, Maria Llopis Verdiell1, Carsten Sticht4, Christina Schmuttermaier1,2, Hiltrud Schönhaber2, Christel Weiss5, Alan P. Fields6, Katja Simon-Keller3, Frederick Pfister3, Sebastian Berlit7, Alexander Marx3, Bernd Arnold8, Sergij Goerdt2, Julia Kzhyshkowska1,9
1Institute for Transfusion Medicine and Immunology, Medical Faculty Mannheim, Ruprecht-Karls University of Heidelberg, Mannheim, Germany
2Department of Dermatology, Medical Faculty Mannheim, Ruprecht-Karls University of Heidelberg, Mannheim, Germany
3Institute of Pathology, Medical Faculty Mannheim, Ruprecht-Karls University of Heidelberg, Mannheim, Germany
4Center for Medical Research, Medical Faculty Mannheim, Ruprecht-Karls University of Heidelberg, Mannheim, Germany
5Department for Medical Statistics and Biomathematics, Medical Faculty Mannheim, Ruprecht-Karls University of Heidelberg, Mannheim, Germany
6Department of Cancer Biology, Mayo Clinic Comprehensive Cancer Center, Jacksonville, Florida, USA
7Department of Obstetrics and Gynaecology, University Medical Center Mannheim, Heidelberg University, Mannheim, Germany
8Department of Molecular Immunology, German Cancer Research Center, Heidelberg, Germany
9Laboratory for Translational Cellular and Molecular Biomedicine, Tomsk State University, Tomsk, Russia
Julia Kzhyshkowska, e-mail: [email protected]
Keywords: tumor-associated macrophages, scavenger receptor, SPARC, stabilin-1, breast cancer
Received: July 21, 2015 Accepted: April 02, 2016 Published: April 20, 2016
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.
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