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 tumorand 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.

Molecular biology of bladder cancer: new insights into pathogenesis and clinical diversity

“…Further work on the consequences of loss of RHOGDI2 expression implicated endothelin 1 (EDN1) and versican (VCAN) as promoters of an inflammatory environment involving macrophages and the chemokine (C-C motif) ligand 2 (CCL2)-chemokine (C-C motif) receptor 2 (CCR2) signalling axis that is permissive for metastasis 177 178 . A similar relationship of loss of secreted protein acidic and rich in cysteine (SPARC) with metastasis and regulation of inflammatory response in bladder cancer has been reported 179 . Reduced expression of activating transcription factor 3 (ATF3), also a regulator of inflammation, has been implicated in driving metastasis through transcriptional regulation of gelsolinmediated actin re-modelling.…”

Secreted Protein Acidic and Rich in Cysteine (SPARC) Mediates Metastatic Dormancy of Prostate Cancer in Bone

“…SPARC plays a significant role in tissue remodeling, maintaining cell matrix integrity and interaction and collagen fiber assembly (34). Stroma-as well as tumor-secreted SPARC is known to affect tumor growth in cell type-and context-dependent manners by regu- lating cell proliferation, adhesion, migration, invasion, and angiogenesis (25,(35)(36)(37)(38). In prostate cancer, apparent conflicting results regarding SPARC expression in both clinical and experimental studies suggest that the role of SPARC is even more complex.…”

Microenvironmental Influences on Metastasis Suppressor Expression and Function during a Metastatic Cell’s Journey

“…Src interacts with and phosphorylates RhoGDI2 to enhance the metastasis suppressive effects [109]. Recently, Said et al showed that RhoGDI2-deficient disseminated tumor cells secrete several soluble factors (i.e., ECM molecules, versican, CCL2 and IL6) that stimulate macrophage recruitment [110][111][112]. The resulting 'inflammation storm' induces formation of a pulmonary pre-metastatic niche.…”