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.
Highlights
Multifunctional scavenger receptor stabilin-1 (STAB1, FEEL-1, CLEVER-1, KIAA0246) is expressed on resident tissue macrophages and sinusoidal endothelial cells in healthy organism, and its expression on both macrophages and different subtypes of endothelial cells is induced during chronic inflammation and tumor progression [1, 2].Analysis of the stabilin-1 function in in vitro model systems revealed its involvement in endocytic and phagocytic clearance of “unwanted-self” components, intracellular sorting of endogenously synthesized chitinase-like protein SI-CLP, and transcytosis of growth hormone family member placental lactogen
Using stabilin-1 knockout mice we demonstrated that the absence of stabilin-1 on tumor-associated macrophages (TAM) results in reduced growth of TS/A mammary adenocarcinoma which is accompanied by impaired endocytic clearance function of TAM and reduced uptake of SPARC capable of inducing TS/A tumor cell death
In the current study we demonstrate the expression of scavenger receptor stabilin-1 on TAM in human breast cancer and reveal its tumor-promoting role using stabilin-1 ko breast cancer mouse model
Summary
Multifunctional scavenger receptor stabilin-1 (STAB1, FEEL-1, CLEVER-1, KIAA0246) is expressed on resident tissue macrophages and sinusoidal endothelial cells in healthy organism, and its expression on both macrophages and different subtypes of endothelial cells is induced during chronic inflammation and tumor progression [1, 2].Analysis of the stabilin-1 function in in vitro model systems revealed its involvement in endocytic and phagocytic clearance of “unwanted-self” components, intracellular sorting of endogenously synthesized chitinase-like protein SI-CLP, and transcytosis of growth hormone family member placental lactogen. Endocytic ligands of stabilin-1 include modified lipoproteins, apoptotic cells, cytokine GDF15/MIC1 and soluble component of extracellular matrix SPARC [3,4,5,6]. Several studies reported that SPARC inhibits primary growth of lung carcinoma, neuroblastoma and metastasis of breast cancer in animal tumor models [8,9,10,11]. Forced expression of SPARC in 4T1 breast cancer cell line resulted in reduced tumor growth in vivo [13]. Stabilin-1 ligands such as SPARC are known to modulate tumor progression the role of endocytic clearance function of stabilin-1 in TAM and its relation to tumor growth was not studied before
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