Department of Radiation Oncology, University of Virginia, Charlottesville, Virginia, USA.
J Clin Invest. 2013 Feb;123(2):751-66. doi: 10.1172/JCI64782. Epub 2013 Jan 16.
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.
富含半胱氨酸的酸性分泌蛋白（SPARC）与人类癌症的多个方面有关。然而，其在膀胱癌发生和转移中的作用尚不清楚，一些研究表明它可能是促进剂，而另一些则持相反观点。使用 Sparc 缺陷小鼠及其野生型同窝仔鼠的化学致癌模型，我们发现 SPARC 的缺失加速了尿路上皮的癌前病变（异型增生和发育不良）、肿瘤发生和转移的发展，并与生存率降低有关。SPARC 减少了致癌物引起的炎症和活性氧的积累以及尿路上皮细胞的增殖。SPARC 的缺失与肿瘤相关的巨噬细胞和成纤维细胞的炎症表型有关，伴有体内和体外尿路上皮和基质 NF-κB 和 AP1 的激活增加。同基因自发和实验性转移模型表明，肿瘤和基质来源的 SPARC 通过抑制癌症相关炎症和肺定植来减少肿瘤生长和转移。在人类膀胱癌组织中，SPARC 的表达频率和强度与疾病特异性存活率呈负相关。这些结果表明，SPARC 由膀胱癌的良性和恶性区室产生，其功能是抑制膀胱癌的发生、进展和转移。
