THE ROLE OF SPARC IN GLIOMA INVASION

SPARC 在神经胶质瘤侵袭中的作用

• 批准号: 7214102
• 负责人: SANDRA ANN REMPEL
• 金额: $ 24.58万
• 依托单位: HENRY FORD HEALTH SYSTEM
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7214102
• 关键词: Address; Adhesions; Astrocytes; Astrocytoma; Binding; Biological Process; Blocking Antibodies; Brain; CD29 Antigen; Cell Communication; Cell Cycle Progression; Cell Nucleus; Cell Proliferation; Cell model; Cells; Complex; Condition; Confocal Microscopy; Cyclin A; Cysteine; Cytoplasm; Data Analyses; Environment; Enzymes; Extracellular Matrix; Extracellular Matrix Degradation; Extracellular Matrix Proteins; Figs - dietary; Focal Adhesions; Gelatinase A; Gelatinase B; Gelatinases; Glioma; Growth; Human; Implant; In Vitro; Integrins; Invasive; Ki-67 Antigen; Knock-out; Knockout Mice; MMP14 gene; Matrix Metalloproteinases; Mediating; Methods; Modeling; Morphology; Mus; Nature; Pathway interactions; Patients; Phenotype; Plasminogen Activator Inhibitor 1; Play; Process; Proteins; Rate; Regulation; Reporting; Research Design; Research Personnel; Rodent; Role; S-Phase Fraction; Signal Transduction; Standards of Weights and Measures; Stress Fibers; TP53 gene; Testing; Tumor Cell Invasion; Tumor Volume; Vitronectin; base; cell motility; enzyme activity; extracellular; human MMP14 protein; in vivo; inhibitor/antagonist; migration; neoplastic cell; novel; outcome forecast; receptor; research study; therapeutic target; tumor; tumor growth

DESCRIPTION (provided by applicant): 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.

描述（申请人提供）：胶质瘤患者预后差很大程度上是由于这些肿瘤的高度侵袭性。分泌蛋白酸性和富含半胱氨酸（SPARC）在胶质瘤中高表达。我们已经证明SPARC在体外和体内具有不同的作用，促进胶质瘤侵袭，同时减缓胶质瘤增殖。改变这些表型的能力使其成为治疗神经胶质瘤的主要治疗靶点。然而，尚不清楚这两种机制是否可以独立靶向，从而允许抑制其在入侵中的作用，但允许其抑制生长作用。此外，侵袭性表型是复杂的，既需要改变肿瘤细胞的运动性，也需要细胞外基质（ECM）的降解，为浸润细胞提供空间。SPARC在这两种功能中的作用也可能需要分别针对。此外，尚不清楚SPARC是否在细胞内起作用，或者大脑内源性SPARC在这一过程中起什么作用（如果有的话）。我们提出SPARC通过不同的机制调节ECM降解、肿瘤细胞运动和肿瘤细胞增殖。以下具体目标是针对这些独立的途径的特征。在Specific Aim 1中，我们将描述SPARC在体外调节侵袭的细胞外机制。该目标将侧重于SPARC通过增加相邻ECM的降解来促进入侵的能力。特别是，我们将研究其与ECM蛋白玻璃体连接蛋白的相互作用，与sparc上调的调节ECM降解的酶（MMP-2, MT1-MMP, PAl-1）和α v整合素的相互作用。在特异性目标2中，我们将描述SPARC调节体内入侵的细胞外机制。我们将在体内进行平行实验，以确定内源性SPARC是否在SPARC诱导的入侵中发挥作用，以及是否可以通过干扰整合素和/或MMP活性来抑制诱导的入侵。在Specific Aim 3中，我们将确定肿瘤细胞中SPARC的缺失是否足以在体内抑制肿瘤侵袭并增加肿瘤的生长和增殖。我们将使用一种由p53-/- / Sparc +/+与p53-/- / Sparc -/-转化的星形胶质细胞组成的新型肿瘤模型来确定Sparc的缺失是否将高侵袭性p53-/- / Sparc +/+肿瘤转化为非侵袭性、高增殖的肿瘤。在Specific Aim 4中，我们将确定SPARC是否通过β a1整合素依赖或不依赖的细胞内信号传导介导运动性，而不是增殖。我们还将确定SPARC对表型的调节是否源于细胞与细胞外定位的差异。

项目成果

Controlling integrin specificity and stem cell differentiation in 2D and 3D environments through regulation of fibronectin domain stability.

• DOI: 10.1016/j.biomaterials.2008.10.047
• 发表时间: 2009-02
• 期刊: BIOMATERIALS
• 影响因子: 14
• 作者: Martino, Mikael M.;Mochizuki, Mayumi;Rothenfluh, Dominique A.;Rempel, Sandra A.;Hubbell, Jeffrey A.;Barker, Thomas H.
• 通讯作者: Barker, Thomas H.

SPARC affects glioma cell growth differently when grown on brain ECM proteins in vitro under standard versus reduced-serum stress conditions.

在标准和低血清应激条件下，SPARC 在体外脑 ECM 蛋白上生长时，对神经胶质瘤细胞生长的影响不同。

• DOI: 10.1093/neuonc/5.4.244
• 发表时间: 2003
• 期刊: Neuro-oncology
• 影响因子: 15.9
• 作者: Vadlamuri,SatyaV;Media,Joe;Sankey,SteadmanS;Nakeff,Alexander;Divine,George;Rempel,SandraA
• 通讯作者: Rempel,SandraA

Inhibition of HSP27 alone or in combination with pAKT inhibition as therapeutic approaches to target SPARC-induced glioma cell survival.

• DOI: 10.1186/1476-4598-11-20
• 发表时间: 2012-04-05
• 期刊: Molecular cancer
• 影响因子: 37.3
• 作者: Schultz CR;Golembieski WA;King DA;Brown SL;Brodie C;Rempel SA
• 通讯作者: Rempel SA

Loss of Sparc in p53-null Astrocytes Promotes Macrophage Activation and Phagocytosis Resulting in Decreased Tumor Size and Tumor Cell Survival.

p53 缺失星形胶质细胞中 Sparc 的缺失促进巨噬细胞激活和吞噬作用，导致肿瘤大小和肿瘤细胞存活率下降。

• DOI: 10.1111/bpa.12161
• 发表时间: 2015
• 期刊: Brain pathology (Zurich, Switzerland)
• 作者: Thomas,StaceyL;Schultz,ChadR;Mouzon,Ezekiell;Golembieski,WilliamA;ElNaili,Reima;Radakrishnan,Archanna;Lemke,Nancy;Poisson,LailaM;Gutiérrez,JorgeA;Cottingham,Sandra;Rempel,SandraA
• 通讯作者: Rempel,SandraA

Secreted protein acidic and rich in cysteine promotes glioma invasion and delays tumor growth in vivo.

富含半胱氨酸的酸性分泌蛋白可促进神经胶质瘤侵袭并延缓体内肿瘤生长。

• 发表时间: 2002
• 期刊: Cancer research
• 影响因子: 11.2
• 作者: Schultz,Chad;Lemke,Nancy;Ge,Shugang;Golembieski,WilliamA;Rempel,SandraA
• 通讯作者: Rempel,SandraA