Stabilin-1 is expressed in human breast cancer and supports tumor growth in mammary adenocarcinoma mouse model.
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.
Institute for Transfusion Medicine and Immunology, Medical Faculty Mannheim, Ruprecht-Karls University of Heidelberg, Mannheim, Germany.|Department of Dermatology, Medical Faculty Mannheim, Ruprecht-Karls University of Heidelberg, Mannheim, Germany.|Laboratory for Translational Cellular and Molecular Biomedicine, Tomsk State University, Tomsk, Russia.
Vladimir
V
Riabov
Institute for Transfusion Medicine and Immunology, Medical Faculty Mannheim, Ruprecht-Karls University of Heidelberg, Mannheim, Germany.
Shuiping
S
Yin
Institute for Transfusion Medicine and Immunology, Medical Faculty Mannheim, Ruprecht-Karls University of Heidelberg, Mannheim, Germany.
Bin
B
Song
Department of Dermatology, Medical Faculty Mannheim, Ruprecht-Karls University of Heidelberg, Mannheim, Germany.
Aida
A
Avdic
Department of Dermatology, Medical Faculty Mannheim, Ruprecht-Karls University of Heidelberg, Mannheim, Germany.
Kai
K
Schledzewski
Department of Dermatology, Medical Faculty Mannheim, Ruprecht-Karls University of Heidelberg, Mannheim, Germany.
Ilja
I
Ovsiy
Department of Dermatology, Medical Faculty Mannheim, Ruprecht-Karls University of Heidelberg, Mannheim, Germany.
Alexei
A
Gratchev
Institute for Transfusion Medicine and Immunology, Medical Faculty Mannheim, Ruprecht-Karls University of Heidelberg, Mannheim, Germany.
Maria
M
Llopis Verdiell
Center for Medical Research, Medical Faculty Mannheim, Ruprecht-Karls University of Heidelberg, Mannheim, Germany.
Carsten
C
Sticht
Institute for Transfusion Medicine and Immunology, Medical Faculty Mannheim, Ruprecht-Karls University of Heidelberg, Mannheim, Germany.|Department of Dermatology, Medical Faculty Mannheim, Ruprecht-Karls University of Heidelberg, Mannheim, Germany.
Christina
C
Schmuttermaier
Department of Dermatology, Medical Faculty Mannheim, Ruprecht-Karls University of Heidelberg, Mannheim, Germany.
Hiltrud
H
Schönhaber
Department for Medical Statistics and Biomathematics, Medical Faculty Mannheim, Ruprecht-Karls University of Heidelberg, Mannheim, Germany.
Christel
C
Weiss
Department of Cancer Biology, Mayo Clinic Comprehensive Cancer Center, Jacksonville, Florida, USA.
Alan P
AP
Fields
Institute of Pathology, Medical Faculty Mannheim, Ruprecht-Karls University of Heidelberg, Mannheim, Germany.
Katja
K
Simon-Keller
Institute of Pathology, Medical Faculty Mannheim, Ruprecht-Karls University of Heidelberg, Mannheim, Germany.
Frederick
F
Pfister
Department of Obstetrics and Gynaecology, University Medical Center Mannheim, Heidelberg University, Mannheim, Germany.
Sebastian
S
Berlit
Institute of Pathology, Medical Faculty Mannheim, Ruprecht-Karls University of Heidelberg, Mannheim, Germany.
Alexander
A
Marx
Department of Molecular Immunology, German Cancer Research Center, Heidelberg, Germany.
Bernd
B
Arnold
Department of Dermatology, Medical Faculty Mannheim, Ruprecht-Karls University of Heidelberg, Mannheim, Germany.
Sergij
S
Goerdt
Institute for Transfusion Medicine and Immunology, Medical Faculty Mannheim, Ruprecht-Karls University of Heidelberg, Mannheim, Germany.|Laboratory for Translational Cellular and Molecular Biomedicine, Tomsk State University, Tomsk, Russia.
Julia
J
Kzhyshkowska
D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015816:Cell Adhesion Molecules, Neuronal / Q000096:biosynthesis* / Q000235:genetics; D048708:Cell Growth Processes / Q000502:physiology; D004195:Disease Models, Animal; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D016201:Receptors, Lymphocyte Homing / Q000096:biosynthesis* / Q000235:genetics; D014162:Transfection
D015816:Cell Adhesion Molecules, Neuronal; D016201:Receptors, Lymphocyte Homing; C449926:STAB1 protein, human; C486732:Stab1 protein, mouse
SPARC; breast cancer; scavenger receptor; stabilin-1; tumor-associated macrophages