Oncotarget

Research Papers:

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

Vladimir Riabov _, Shuiping Yin, Bin Song, Aida Avdic, Kai Schledzewski, Ilja Ovsiy, Alexei Gratchev, Maria Llopis Verdiell, Carsten Sticht, Christina Schmuttermaier, Hiltrud Schönhaber, Christel Weiss, Alan P. Fields, Katja Simon-Keller, Frederick Pfister, Sebastian Berlit, Alexander Marx, Bernd Arnold, Sergij Goerdt and Julia Kzhyshkowska

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Oncotarget. 2016; 7:31097-31110. https://doi.org/10.18632/oncotarget.8857

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Abstract

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

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.


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