Loss of SPARC in bladder cancer enhances carcinogenesis and progression

Article (PDF Available)inThe Journal of clinical investigation 123(2) · January 2013with11 Reads
DOI: 10.1172/JCI64782 · Source: PubMed
Abstract
Secreted protein acidic and rich in cysteine (SPARC) has been implicated in multiple aspects of human cancer. However, its role in bladder carcinogenesis and metastasis are unclear,with some studies suggesting it may be a promoter and others arguing the opposite. Using a chemical carcinogenesis model in Sparc-deficient mice and their wild-type littermates, we found that loss of SPARC accelerated the development of urothelial preneoplasia (atypia and dysplasia), neoplasia, and metastasis and was associated with decreased survival. SPARC reduced carcinogen-induced inflammation and accumulation of reactive oxygen species as well as urothelial cell proliferation. Loss of SPARC was associated with an inflammatory phenotype of tumor-associated macrophages and fibroblasts, with concomitant increased activation of urothelial and stromal NF-κB and AP1 in vivo and in vitro. Syngeneic spontaneous and experimental metastasis models revealed that tumor- and stroma-derived SPARC reduced tumor growth and metastasis through inhibition of cancer-associated inflammation and lung colonization. In human bladder tumor tissues, the frequency and intensity of SPARC expression were inversely correlated with disease-specific survival. These results indicate that SPARC is produced by benign and malignant compartments of bladder carcinomas where it functions to suppress bladder carcinogenesis, progression, and metastasis.
    • "The results of our study revealed that the clearance function of TAM in stabilin-1 ko mice was decreased and accompanied reduced tumor growth in vivo. We have proposed enhanced clearance of SPARC in wild type mice as a reason of increased tumor growth since tumorinhibiting effect of extracellular SPARC in several types of cancer including breast cancer was widely demonstrated in vitro and in vivo [8, 10, 12,[14][15][16][51][52][53]. Attenuating effect of SPARC on tumor growth was attributed to its direct cytostatic effect on tumor cells, as well as induction of tumor cell apoptosis and its regulatory effect on tumor ECM deposition. "
    [Show abstract] [Hide abstract] 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.
    Article · Apr 2016
    • "The results of our study revealed that the clearance function of TAM in stabilin-1 ko mice was decreased and accompanied reduced tumor growth in vivo. We have proposed enhanced clearance of SPARC in wild type mice as a reason of increased tumor growth since tumorinhibiting effect of extracellular SPARC in several types of cancer including breast cancer was widely demonstrated in vitro and in vivo [8, 10, 12,[14][15][16][51][52][53]. Attenuating effect of SPARC on tumor growth was attributed to its direct cytostatic effect on tumor cells, as well as induction of tumor cell apoptosis and its regulatory effect on tumor ECM deposition. "
    [Show abstract] [Hide abstract] 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.
    Full-text · Article · Apr 2016
    • "In some reports, it was shown that aberrations in chromosome 2 participate in alternative tumors of the bladder, such as lymphomas [22,23], with a particular role of CHOP (C/EBP homologous protein). Also, AP1 (activator protein 1) whose function with NFκB and positive regulation of tumor progression is linked to loss of SPAPC [24], was predicted by our analysis. Finally, MYC was uniquely annotated among metastatic TCCs, underlining its recent suggestions for therapeutic targeting in the disease [25,26]. "
    Full-text · Article · Jan 2016 · Oncotarget
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