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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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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Figure 7

Transcriptional activity of AP-1 and NF-κB in Sparc–/– and Sparc+/+ macrophages.

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Transcriptional activity of AP-1 and NF-κB in Sparc–/– and Sparc+/+ macr...
(A and B) Activation of AP-1 and NF-κB promoters in Sparc+/+ and Sparc–/– macrophages (Mac) cocultured with UC cells for 24 hours. Bars represent mean ± SEM of 2 independent experiments performed in triplicate. *P < 0.05, comparing Sparc+/+ UCs cultured with Sparc+/+ and Sparc–/– Macs; **P < 0.05, comparing Sparc–/– UCs cultured with Sparc+/+ and Sparc–/– Macs; ***P < 0.05, comparing Sparc–/– and Sparc+/+ UCs cultured with Sparc+/+ and Sparc–/– Macs. (C) Migration of primary Macs toward CGM, CM of Sparc+/+ and Sparc–/– UC cells. Bars represent mean ± SEM of 2 independent experiments performed in quadruplicate. *P < 0.05 between migration of Sparc–/– and Sparc+/+ Macs toward each attractant; **P < 0.05 between Sparc–/– and Sparc+/+ Macs migrating toward Sparc+/+ and Sparc–/– CM. (D) CM from Sparc–/– and Sparc+/+ Macs to stimulated Sparc–/– and Sparc+/+ UC cells Matrigel-invasiveness in Transwell assays. Bars represent mean ± SEM (n = 4). *P < 0.05 between Sparc–/– and Sparc+/+ UC cells migration toward CM; **P < 0.05 between the effect of CM of Sparc–/– and Sparc+/+ Macs on UCs invasiveness. All comparisons were performed with unpaired 2-tailed Student’s t test.