Stabilin-1 Supports Breast Cancer Growth by Silent Clearance of SPARC

Stabilin-1 is a multifunctional scavenger receptor expressed on alternatively-activated macrophages. Stabilin-1 mediates phagocytosis of “unwanted-self” components, transcytosis, intracellular sorting, and endocytic clearance of extracellular ligands including SPARC known to modulate breast cancer growth. Recently, the expression of stabilin-1 was found on tumor-associated macrophages (TAM) in several types of mouse and human cancers such as 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. In this study we demonstrated that stabilin-1 is expressed on TAM in human breast cancer biopsies, and its expression is most pronounced on stages I and II of disease. Uisng stabilin-1 knock-out mice we showed that stabilin-1 facilitates primary tumor growth in mouse TS/A mammary adenocarcinoma. Functional endocytosis assay on ex vivo TAM demonstrated that attenuated tumor growth in stabilin-1 knockout mice was associated with impaired SPARC clearance by TAM. Affymetrix microarray analysis of TAM purified from wild type and stabilin-1 knockout mice, and reporter assays in stabilin-1 expressing cell lines demonstrated that the absence of stabilin-1 did not have significant effect on TAM transcriptional programs or induction of intracellular signalling. We concluded that stabilin-1 affects tumor growth by silent clearance of extracellular tumor growth-regulating factors such as SPARC. Silent clearance function of stabilin-1 makes it an attractive candidate for delivery of immunomodulatory anti-cancer therapeutic drugs to TAM.