SPARC: a Matricellular Regulator of the Tumor Microenvironment



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SPARC, secreted protein acidic and rich in cysteine, is a matricellular protein that governs extracellular matrix (ECM) deposition and maturation during times of tissue remodeling such as wound healing and tumorigenesis. The function of host-derived SPARC in an orthotopic model of pancreatic cancer was assessed. Pancreatic tumors grown in SPARC-null mice were more invasive than tumors grown in wild-type counterparts. Active TGFbeta1 was found to be increased significantly in tumors grown in SPARC-null mice. TGFbeta1 is known to contribute to many aspects of tumor development including metastasis, endothelial cell permeability, inflammation and fibrosis, all of which were altered in the absence of host SPARC. Given these results, we performed a survival study to assess the contribution of increased TGFbeta1 activity to tumor progression in SPARC-null mice using Losartan, an AT1 angiotensin II receptor antagonist that diminishes TGFbeta1 production in vivo. Tumors grown in SPARC-null mice progressed more quickly than those grown in wild-type littermates resulting in a median survival of 28.0 days and 35.5 days, respectively (p=0.018). Losartan therapy extended median survival of SPARC-null animals to 40.0 days, equivalent to losartan treated wild-type controls. Furthermore, SPARC-null mice treated with Losartan experienced a reduction in local invasion, metastatic incidence and metastatic burden. These results confirm that aberrant TGFbeta1 activation in the absence of host SPARC contributes significantly to tumor progression and suggests that SPARC, by controlling ECM deposition and maturation, can regulate cytokine availability and activation. [Keywords: SPARC; Osteonectin; pancreatic cancer; angiogenesis; extracellular matrix; microenvironment; transforming growth factor; collagen; permeability; tumor]