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 6

Bladder carcinogenesis is associated with increased activation of NF-κB and p38-JNK–AP-1.

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Bladder carcinogenesis is associated with increased activation of NF-κB ...
(A) Western blot analysis of lysates from dissected bladder tissue from BBN-treated Sparc–/– and Sparc+/+ mice with preneoplasia (IAD and CIS; n = 3 each) showing increased phosphorylation of NF-κB p65 (Ser276 and Ser536), p38, SAPK/JNK (Thr183/Tyr185), and c-Jun (p63). Equal protein loading was confirmed by tubulin. (B and C) Immunostaining of bladder tissue sections shows the nuclear localization of phosphorylated c-Jun and cytoplasmic and nuclear localization and scoring of p65–NF-κB, respectively, in the normal, IAD, CIS, and invasive cancerous lesions. Original magnification, ×200.