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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Figure 3

IHC expression of SPARC in bladders of Sparc+/+ mice during multistep carcinogenesis.

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IHC expression of SPARC in bladders of Sparc+/+ mice during multistep ca...
(A) Immunostaining of sections of dissected bladder lesions showing the differential expression of SPARC in the urothelium and lamina propria. Original magnification, ×200. (B) The 2 arbitrary scores for intensity and frequency of SPARC immunostaining in the indicated groups of urothelium (left) and stromal (right) compartments were transformed into CESs as described in Methods. Boxes represent the mean ± SEM, with whiskers minimum and maximum scores for each group (n = 15 animals/group). *Correlation of composite scores in association with tumor grades by Kruskal-Wallis 1-way ANOVA followed by Dunn’s multiple comparison post-hoc test. **Correlation of composite scores between indicated groups by 1-way ANOVA with Bonferroni’s multiple comparison post-hoc test. (C) Immunostaining of SPARC protein in representative lung nodules from Figure 2G. Original magnification, ×200.