SPARCs fly


SPARC (secreted protein acidic and rich in cysteine) is an extracellular matrix glycoprotein that has been implicated in multiple aspects of human cancer. In bladder cancer, it has been described as both a tumor suppressor and tumor promoter. To understand SPARC's functions in bladder cancer, Said et al. developed a chemical carcinogenesis model of bladder cancer in wild-type and Sparc-deficient mice. The panels above show photos (upper)  hematoxylin and eosin (H&E)-stained lung sections (lower, 100x magnification) from wild-type (SP+/+) and Sparc-deficient mice (SP-/-). Said and colleagues found that mice that lacked Sparc developed larger, more aggressive bladder cancer with larger tumors and a greater number of metastases. In human bladder tumors, SPARC expression was negatively correlated with disease survival, suggesting that SPARC is a tumor promoter.      

Published January 16, 2013, by Jillian Hurst

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Loss of SPARC in bladder cancer enhances carcinogenesis and progression
Neveen Said, … , Rolf A. Brekken, Dan Theodorescu
Neveen Said, … , Rolf A. Brekken, Dan Theodorescu
Published January 16, 2013
Citation Information: J Clin Invest. 2013;123(2):751-766. https://doi.org/10.1172/JCI64782.
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Research Article Oncology

Loss of SPARC in bladder cancer enhances carcinogenesis and progression

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.

Authors

Neveen Said, Henry F. Frierson, Marta Sanchez-Carbayo, Rolf A. Brekken, Dan Theodorescu

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