title: 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: Department of Radiation Oncology, University of Virginia, Charlottesville, Virginia, USA.
authors: Neveen
authors: N
authors: Said
authors: Henry F
authors: HF
authors: Frierson
authors: Marta
authors: M
authors: Sanchez-Carbayo
authors: Rolf A
authors: RA
authors: Brekken
authors: Dan
authors: D
authors: Theodorescu
mesh_terms: D000818:Animals; D001483:Base Sequence; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D006023:Glycoproteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008819:Mice, Nude; D009602:Nitrosamines / Q000633:toxicity; D015676:Osteonectin; D011230:Precancerous Conditions / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D001749:Urinary Bladder Neoplasms / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000556:secondary; D019459:Urothelium / Q000378:metabolism / Q000473:pathology
chemical_list: D018797:Cell Cycle Proteins; D006023:Glycoproteins; D018836:Inflammation Mediators; D009602:Nitrosamines; D015676:Osteonectin; D034741:RNA, Small Interfering; C577241:SPARC protein, human; C578250:SPARC protein, mouse; D025521:Tumor Suppressor Proteins; C012279:dibutylnitrosamine