RESUMEN
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.
Asunto(s)
Adenocarcinoma/metabolismo , Neoplasias de la Mama/metabolismo , Moléculas de Adhesión Celular Neuronal/biosíntesis , Neoplasias Mamarias Experimentales/metabolismo , Receptores Mensajeros de Linfocitos/biosíntesis , Adenocarcinoma/genética , Adenocarcinoma/patología , Animales , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Moléculas de Adhesión Celular Neuronal/genética , Procesos de Crecimiento Celular/fisiología , Modelos Animales de Enfermedad , Femenino , Células HEK293 , Humanos , Macrófagos/metabolismo , Macrófagos/patología , Neoplasias Mamarias Experimentales/genética , Neoplasias Mamarias Experimentales/patología , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , Receptores Mensajeros de Linfocitos/genética , TransfecciónRESUMEN
BACKGROUND & AIMS: Gastrointestinal (GI) and liver diseases inflict a heavy economic burden. Although the burden is considerable, current and accessible information on the prevalence, morbidity, and cost is sparse. This study was undertaken to estimate the economic burden of GI and liver disease in the United States for use by policy makers, health care providers, and the public. METHODS: Data were extracted from a number of publicly available and proprietary national databases to determine the prevalence, direct costs, and indirect costs for 17 selected GI and liver diseases. Indirect cost calculations were purposefully very conservative. These costs were compared with National Institutes of Health (NIH) research expenditures for selected GI and liver diseases. RESULTS: The most prevalent diseases were non-food-borne gastroenteritis (135 million cases/year), food-borne illness (76 million), gastroesophageal reflux disease (GERD; 19 million), and irritable bowel syndrome (IBS; 15 million). The disease with the highest annual direct costs in the United States was GERD ($9.3 billion), followed by gallbladder disease ($5.8 billion), colorectal cancer ($4.8 billion), and peptic ulcer disease ($3.1 billion). The estimated direct costs for these 17 diseases in 1998 dollars were $36.0 billion, with estimated indirect costs of $22.8 billion. The estimated direct costs for all digestive diseases were $85.5 billion. Total NIH research expenditures were $676 million in 2000. CONCLUSIONS: GI and liver diseases exact heavy economic and social costs in the United States. Understanding the prevalence and costs of these diseases is important to help set priorities to reduce the burden of illness.