Loss of SPARC in bladder cancer enhances carcinogenesis and progression
Neveen Said, Henry F. Frierson, Marta Sanchez-Carbayo, Rolf A. Brekken, Dan Theodorescu
Neveen Said, Henry F. Frierson, Marta Sanchez-Carbayo, Rolf A. Brekken, Dan Theodorescu
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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 2

Loss of SPARC accelerates bladder carcinogenesis and progression.

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Loss of SPARC accelerates bladder carcinogenesis and progression. (A) Re...
(A) Representative H&E-stained sections of bladder pathology. Original magnification, ×200. (B) Mice were assigned to 4 cohorts as a function of BBN exposure, and the distribution of the ensuing bladder pathology in each cohort is represented in bar graphs showing the percentage of animals (P < 0.05, χ2 test). (C) Kaplan-Meier curves showing significantly decreased survival in Sparc–/– mice as compared with Sparc+/+ counterparts. (D) The incidence of upper tract urothelial tumors in the 15- to 25-week and greater than 25-week cohorts. *P < 0.05; Fisher exact test. (E) The incidence of metastasis in Sparc+/+ and Sparc–/– mice in 15- to 25-week and greater than 25-week cohorts *P < 0.05; Fisher exact test. (F) Incidence and number of visible lung metastases in the 15- to 25-week and greater than 25-week cohorts. *P < 0.05; χ2 test; **P < 0.05, Student’s t test. (G) Representative H&E-stained lung sections showing larger size of lung metastases in Sparc–/– lungs. Original magnification, ×100. Only animals with invasive primary tumors were considered for analyses in D–G.