Loss of SPARC in bladder cancer enhances carcinogenesis and progression

The Journal of clinical investigation (Impact Factor: 13.22). 01/2013; 123(2). DOI: 10.1172/JCI64782
Source: PubMed


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.

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    • "High levels of SPARC expression have been reported in breast [7, 8], prostate [9], colon rectal [10], and brain cancers [11, 12]. On the contrary, low levels of SPARC expression have been reported in other types of malignancies, as pancreas [13, 14], bladder cancer [15], and acute leukemia [16]. "
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    ABSTRACT: Oral squamous cell carcinoma (OSCC) remains a significant cause of morbidity and mortality, with approximately 540,000 new cases annually worldwide. The molecular mechanisms related to the pathogenesis of this disease are still poorly understood. The discovery of a molecular marker that allows the early detection of this cancer, which can be easily identified in biological samples, such as saliva, without intervening in advanced stages, is a challenge. Numerous studies have identified a panel of molecular markers differently expressed in OSCC and normal oral mucosa. In particular, it was found an aberrant expression of matricellular glycoprotein SPARC. SPARC is involved in normal tissue remodeling, regulating the deposition of extracellular matrix, but also in neoplastic transformation. In fact, aberrant SPARC expression was detected both in stromal cells associated with cancer and in tumor cells. The aim of our study was the evaluation of SPARC on a retrospective series of 119 OSCC cases and the validation of the obtained data on a prospective series of 27 patients with OSCC, of whom we have previously collected saliva, and smeared material. The obtained results were correlated with each other and with clinical pathological parameters at our disposal. The study demonstrated a prognostic value of SPARC, especially with regard to its expression in the stroma surrounding OSCC ( P < 0.05).
    12/2013; 2013(8):736438. DOI:10.1155/2013/736438
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    • "High levels of SPARC expression have been reported in breast [7] [8], prostate [9], colon rectal [10], and brain cancers [11] [12]. On the contrary, low levels of SPARC expression have been reported in other types of malignancies, as pancreas [13] [14], bladder cancer [15], and acute leukemia [16]. "
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    ABSTRACT: Outcome in multiple myeloma is highly variable and a better understanding of the factors that influence disease biology is essential to understand and predict behaviour in individual patients. In the present study we analysed combined genome wide DNA methylation and gene expression data of patients treated in the MRC Myeloma IX trial. We used this data to identify epigenetically repressed tumour suppressor genes with prognostic relevance in myeloma. We identified 195 genes with changes in methylation status that were significantly associated with prognosis. Combining DNA methylation and gene expression data led to the identification of the epigenetically regulated tumour modulating genes GPX3, RBP1, SPARC and TGFBI. Hypermethylation of these genes was associated with significantly shorter overall survival, independent of age, ISS score and adverse cytogenetics. The four differentially methylated and expressed genes are known to mediate important tumour suppressive functions including response to chemotherapy (TGFBI), interaction with the microenvironment (SPARC), retinoic acid signalling (RBP1) and the response to oxidative stress (GPX3), which could explain the prognostic impact of their differential methylation. Assessment of the DNA methylation status of the identified genes could contribute to the molecular characterisation of myeloma, which is prerequisite for an individualised treatment approach.
    Blood 05/2013; 122(2). DOI:10.1182/blood-2013-03-487884 · 10.45 Impact Factor
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