The poor prognosis of glioma patients is largely due to the highly invasive nature of these tumors. Secreted protein acidic and rich in cysteine (SPARC) is highly expressed in gliomas. We have demonstrated that SPARC has disparate effects in vitro and in vivo, promoting glioma invasion while slowing glioma proliferation. The ability to alter these phenotypes makes it a prime therapeutic target for the treatment of gliornas. However, it is not known whether these two mechanisms can be targeted independently, thereby allowing the inhibition of its role in invasion but permitting its growth-suppressive effect. In addition the invasive phenotype is complex, requiring both changes in tumor cell motility as well as degradation of the extracellular matrix (ECM) to provide space for infiltrating cells. SPARC's role in both of these functions may also need to be targeted separately. Furthermore, it is not known if SPARC functions within the cell, or what contribution, if any, brain endogenous SPARC may contribute to the process. We propose that SPARC modulates ECM degradation, tumor cell motility, and tumor cell proliferation via separate mechanisms. The following Specific Aims are directed at characterizing these independent pathways.
In Specific Aim 1, we will characterize the extracellular mechanisms by which SPARC modulates invasion in vitro.
This aim will focus on SPARC's ability to promote invasion by increasing the degradation of the adjacent ECM. In particular, we will examine its interactions with the ECM protein vitronectin, with the SPARC-upregulated enzymes that modulate ECM degradation (MMP-2, MT1-MMP, PAl-1), and the alpha v integrins.
In Specific Aim 2, we will characterize the extracellular mechanisms by which SPARC modulates invasion in vivo. We will perform parallel experiments in vivo to determine whether endogenous SPARC plays a role in SPARC-induced invasion and whether the induced invasion can be inhibited by interfering with integrin and/or MMP activity.
In Specific Aim 3, we will determine whether the loss of SPARC in tumor cells is sufficient to inhibit tumor invasion and increase tumor growth and proliferation in vivo. We will use a novel tumor model consisting of p53-/- / Sparc +/+ versus p53-/- / Sparc -/-transformed astrocytes to determine whether the loss of SPARC converts the highly invasive p53-/- / Sparc +/+ tumors into noninvasive, highly proliferative tumors.
In Specific Aim 4, we will determine whether SPARC mediates motility, but not proliferation, via beta1 integrin-dependent or -independent intracellular signaling. We will also determine whether SPARC's regulation of the phenotypes results from differences in cellular versus extracellular localization.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA086997-07
Application #
7214102
Study Section
Special Emphasis Panel (ZRG1-CDP (02))
Program Officer
Snyderwine, Elizabeth G
Project Start
2000-07-01
Project End
2009-03-31
Budget Start
2007-04-01
Budget End
2009-03-31
Support Year
7
Fiscal Year
2007
Total Cost
$245,769
Indirect Cost
Name
Henry Ford Health System
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
073134603
City
Detroit
State
MI
Country
United States
Zip Code
48202
Thomas, Stacey L; Schultz, Chad R; Mouzon, Ezekiell et al. (2015) Loss of Sparc in p53-null Astrocytes Promotes Macrophage Activation and Phagocytosis Resulting in Decreased Tumor Size and Tumor Cell Survival. Brain Pathol 25:391-400
Alam, Ridwan; Schultz, Chad R; Golembieski, William A et al. (2013) PTEN suppresses SPARC-induced pMAPKAPK2 and inhibits SPARC-induced Ser78 HSP27 phosphorylation in glioma. Neuro Oncol 15:451-61
Schultz, Chad R; Golembieski, William A; King, Daniel A et al. (2012) Inhibition of HSP27 alone or in combination with pAKT inhibition as therapeutic approaches to target SPARC-induced glioma cell survival. Mol Cancer 11:20
McClung, Heather M; Golembieski, William A; Schultz, Chad R et al. (2012) Deletion of the SPARC acidic domain or EGF-like module reduces SPARC-induced migration and signaling through p38 MAPK/HSP27 in glioma. Carcinogenesis 33:275-84
Weaver, Matt; Workman, Gail; Schultz, Chad R et al. (2011) Proteolysis of the matricellular protein hevin by matrix metalloproteinase-3 produces a SPARC-like fragment (SLF) associated with neovasculature in a murine glioma model. J Cell Biochem 112:3093-102
Thomas, Stacey L; Alam, Ridwan; Lemke, Nancy et al. (2010) PTEN augments SPARC suppression of proliferation and inhibits SPARC-induced migration by suppressing SHC-RAF-ERK and AKT signaling. Neuro Oncol 12:941-55
Martino, Mikaƫl M; Mochizuki, Mayumi; Rothenfluh, Dominique A et al. (2009) Controlling integrin specificity and stem cell differentiation in 2D and 3D environments through regulation of fibronectin domain stability. Biomaterials 30:1089-97
Golembieski, William A; Thomas, Stacey L; Schultz, Chad R et al. (2008) HSP27 mediates SPARC-induced changes in glioma morphology, migration, and invasion. Glia 56:1061-75
Yunker, Christopher K; Golembieski, William; Lemke, Nancy et al. (2008) SPARC-induced increase in glioma matrix and decrease in vascularity are associated with reduced VEGF expression and secretion. Int J Cancer 122:2735-43
Lee, Hae Kyung; Xiang, Cunli; Cazacu, Simona et al. (2008) GRP78 is overexpressed in glioblastomas and regulates glioma cell growth and apoptosis. Neuro Oncol 10:236-43

Showing the most recent 10 out of 14 publications