Browsing by Subject "Osteonectin"
Now showing 1 - 2 of 2
Results Per Page
Sort Options
Item Regulation of Pericyte Behavior by Secreted Protein Acidic and Rich in Cysteine(2011-02-01T19:36:55Z) Rivera, Lee Benjamin; Brekken, RolfPericytes migrate to newly formed vessels where they induce vessel quiescence and promote vessel stability. Secreted Protein Acidic and Rich in Cysteine (SPARC) is a multifunctional matricellular protein believed to be involved in the regulation of vascular cell migration and proliferation during angiogenesis. We previously found that SPARC-deficient mice exhibited abnormal vascular function and decreased pericyte-associated vessels in an orthotopic model of pancreatic ductal adenocarcinoma (PDAC), suggesting that SPARC regulates pericyte behavior during tumor angiogenesis. Pericyte expression of SPARC was detected in PDAC lesions of P48Cre: LSLKrasG12D: Ink4Alox/lox mice as well as in normal mouse pancreata by indirect immunofluorescence. Primary mouse pericytes were isolated and the following parameters were characterized: proliferation, migration, the ability to induce bEnd.3 cell cord formation, TGFbeta1-induced activity, and TGFbeta1 receptor expression. Here I report that SPARC regulates pericyte migration. I found that SPARC is expressed by pericytes in vivo and confirmed that SPARC-deficient mice have fewer pericyte-associated vessels using a transgenic model of PDAC. Primary pericytes isolated from SPARC-/- mice proliferate faster than their SPARC+/+ counterparts but are less able to induce bEnd.3 cord-formation in vitro. SPARC deficiency also results in defective filopodia and focal adhesion formation and impedes pericyte migration, an effect that is blocked by inhibiting TGFbeta. Furthermore, I demonstrate that SPARC interacts with the TGFbeta1 accessory receptor endoglin in pericytes. In SPARC-deficient pericytes, endoglin aberrantly associates with focal complexes. SPARC deficiency also induces endoglin-mediated, TGFbeta1-induced blockade of pericyte migration, and results in alphaV integrin-mediated activation of TGFbeta1. These results demonstrate that SPARC controls pericyte migration by regulating endoglin and alphaV integrin-mediated TGFbeta1 activity.Item SPARC: a Matricellular Regulator of the Tumor Microenvironment(2010-01-12T19:14:41Z) Arnold, Shanna Alexandria; Brekken, Rolf A.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]