Stabilin-1 Is Expressed On Tumor-Associated Macrophages In Breast Cancer And Supports Tumor Growth In Animal Model Of Breast Adenocarcinoma By Clearance Of Sparc

Tumor-associated macrophages (TAM) are crucial participants in malignant progression. Acquisition of M2 (alternatively activated) phenotype by TAM during tumor progression enhances the immunosuppressive and tumor-supportive properties of TAM resulting in tumor invasion, metastasis and angiogenesis. Previously we have found that stabilin-1, a multifunctional scavenger/sorting receptor, is a marker of M2 macrophages that is expressed by TAM in several murine tumor models. However, its role in tumor progression was not defined. In order to identify the role of stabilin-1 in tumor progression, the model of mammary adenocarcinoma (TS/A) was established in BALB/c mice with stabilin-1 knockout. The growth of TS/A mammary adenocarcinoma in stabilin-1 knockout (ko) mice was suppressed by 36%. To identify the role of stabilin-1 in TAM biology and reveal functions of stabilin-1 that are important for tumor progression, isolation of high purity TAM from TS/A murine adenocarcinoma was established and optimized. Flow cytometry analysis revealed that adhesion/internalisation of extracellular SPARC was decreased in the isolated stabilin-1 ko TAM compared to wt TAM. Immunofluorescent/confocal microscopy showed that transport of SPARC into the endocytic pathway was significantly impaired in the stabilin-1 ko TAM. Since SPARC is known to inhibit the development of solid tumors including breast cancer we hypothesize that knockout of stabilin-1 in TAM induces accumulation of extracellular SPARC resulting in suppression of tumor growth. Analysis of two cohorts of female patients with breast carcinoma of different stages demonstrated that stabilin-1 is expressed on significant part of tumor associated macrophages. Three types of TAM were identified by co-staining with anti-stabilin-1 RS1 antibody and anti-CD68 antibody: CD68+stabilin-1-, CD68+stabilin-1+ and CD68-stabilin-1+. The highest levels of stabilin-1 expression and highest amount of stabilin-1+ TAM were found on stages I and IIa, suggesting that stabilin-1 is required for tumor growth at early stages of tumor progression. Our data indicate that stabilin-1 expression on TAM is necessary on the early stages of tumor growth in human cancer. Genetic knockout of stabilin-1 results in decrease in tumor growth in mouse adenocarcinoma model. In addition, tumor-associated macrophages deficient in stabilin-1 expression have significantly decreased ability for the endocytic clearance of SPARC. Citation Format: Vladimir Ryabov, Ilja Ovsij, Aida Avdic, Kai Schledzewski, Alexei Gratchev, Nan Wang, Bernd Arnold, Sergij Goerdt, Frederick Pfister, Alexander Marx, Limin Zheng, Julia Kzhyshkowska. Stabilin-1 is expressed on tumor-associated macrophages in breast cancer and supports tumor growth in animal model of breast adenocarcinoma by clearance of SPARC. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1668. doi:10.1158/1538-7445.AM2014-1668