The Role of glypican-1 in Pancreatic Cancer Development and Progression

磷脂酰肌醇蛋白聚糖-1 (glypican-1) 在胰腺癌发生和进展中的作用

• 批准号: 7807715
• 负责人: Chery Angel Whipple
• 金额: $ 5.76万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-12-01 至 2013-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7807715
• 关键词: Adhesions; Attenuated; Autocrine Communication; CDKN2A gene; Cancer cell line; Cell Line; Cell surface; Cessation of life; Data; Development; Engineering; Exhibits; Fibroblast Growth Factor; Fibroblast Growth Factor 1; Fibroblasts; Frequencies; Glypican; Heparan Sulfate Proteoglycan; Heparin Binding Growth Factor; Heregulin; Human; In Vitro; KRAS2 gene; Length; Lesion; Maintenance; Malignant Neoplasms; Malignant neoplasm of pancreas; Modification; Molecular; Mouse Cell Line; Mutate; Mutation; Neoplasm Metastasis; Oncogenic; Pancreas; Pancreatic Adenocarcinoma; Pancreatic Ductal Adenocarcinoma; Paper; Pathway interactions; Play; Primary Neoplasm; Research; Retroviral Vector; Role; Series; Severities; Signal Pathway; Signal Transduction; Survival Rate; Testing; Transgenic Animals; Transgenic Mice; Tumor Suppressor Genes; United States; angiogenesis; cancer cell; cell growth; design; heparin-binding EGF-like growth factor; in vitro Assay; in vivo; migration; mouse model; novel; overexpression; paracrine; receptor; research study; response; therapeutic target; tumor; tumor growth

DESCRIPTION (provided by applicant): Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic and biologically aggressive malignancy that causes approximately 34,000 deaths in the United States each year. PDAC harbors several molecular alterations including activating KRAS mutations, homozygous deletion of the tumor suppressor gene p16INK4A/p14ARF, and overexpression of heparin binding growth factors and their receptors. In addition, glypican-1 (GPC1), a cell-surface heparan sulfate proteoglycan (HSPG) is released by cancer cells, expressed by fibroblasts, and is over-expressed in PDAC. GPC1 enhances the signaling pathways activated by several heparin binding growth factors (HBGFs), especially fibroblast growth factors (FGFs), heparin binding EGF like growth factor (HB-EGF), and heregulins. These HBGFs play critical roles in cell growth, differentiation, adhesion, transformation and metastasis. Additionally, suppression of GPC1 abrogates mitogenic signaling in response to HBGFs in vitro and attenuates tumor growth and metastasis in vivo. These data indicate that GPC1 is not only overexpressed in PDAC but also that host-derived and cancer cell-derived GPC1 contribute to enhanced tumor growth, angiogenesis, and metastasis. Therefore, three specific aims are proposed to test the hypothesis that GPC1 plays a pivotal role in PDAC progression and metastasis by enhancing oncogenic signaling pathways both in the tumor and within the tumor associated stroma. First, tumors and primary cancer cell lines isolated from the novel transgenic mouse model: Pdx-1-Cre; LSL-KrasG12D; INK4ALox/Lox; GPC1+/+ orGPCI -/-will be fully characterized through a series of mechanistic in-vitro assays desined to assess the impact of GPC1 on proliferation, migration, and invasion. Next, in order to delineate the structural components critical for GPC1 signaling functions, primary cancer cell lines that overexpress modified versions of GPC1 will be studied both in vitro and in an orthotopic syngeneic mouse model. Lastly, two transgenic mouse models will be created, one that overexpresses GPC1 alone and another that overexpresses GPC1 in conjunction with activated KrasG12D. These mouse models will be used to determine GPC1 contribution to the initiation and/or progression of pancreatic adenocarcinomas. This research will not only significantly enhance our understanding of how GPC1 functions, especially what regions are critical for its activity, but it will also assess the importance of GPC1 in tumor development and progression in pancreatic cancer. These data may provide support for the efficacy of targeting GPC1 either alone or in combination with other therapeutic targets.

描述（由申请人提供）：胰腺导管腺癌（PDAC）是一种高度转移和生物侵袭性的恶性肿瘤，在美国每年导致约34,000人死亡。PDAC包含几个分子改变，包括激活KRAS突变，肿瘤抑制基因p16INK4A/p14ARF的纯合缺失，以及肝素结合生长因子及其受体的过表达。此外，glypican-1 （GPC1）是一种细胞表面硫酸肝素蛋白聚糖（HSPG），由癌细胞释放，由成纤维细胞表达，并在PDAC中过表达。GPC1增强了几种肝素结合生长因子（HBGFs）激活的信号通路，特别是成纤维细胞生长因子（FGFs）、肝素结合EGF样生长因子（HB-EGF）和肝素调节因子。这些HBGFs在细胞生长、分化、粘附、转化和转移中起着关键作用。此外，抑制GPC1在体外抑制HBGFs的有丝分裂信号，并在体内减弱肿瘤的生长和转移。这些数据表明，GPC1不仅在PDAC中过表达，而且宿主来源和癌细胞来源的GPC1有助于促进肿瘤生长、血管生成和转移。因此，我们提出了三个特定的目的来验证GPC1通过增强肿瘤和肿瘤相关基质内的致癌信号通路在PDAC进展和转移中起关键作用的假设。首先，从新型转基因小鼠模型Pdx-1-Cre中分离出肿瘤和原发癌细胞系；LSL-KrasG12D;INK4ALox /液态氧;GPC1+/+ orGPCI -/-将通过一系列旨在评估GPC1对增殖、迁移和侵袭的影响的体外机制试验来充分表征。接下来，为了描述对GPC1信号功能至关重要的结构成分，将在体外和原位同基因小鼠模型中研究过表达GPC1修饰版本的原发性癌细胞系。最后，将建立两种转基因小鼠模型，一种是单独过表达GPC1，另一种是与活化的KrasG12D一起过表达GPC1。这些小鼠模型将用于确定GPC1在胰腺腺癌的发生和/或进展中的作用。这项研究不仅将显著增强我们对GPC1功能的理解，特别是对其活性至关重要的区域，而且还将评估GPC1在胰腺癌肿瘤发生和进展中的重要性。这些数据可能支持单独靶向GPC1或与其他治疗靶点联合靶向GPC1的有效性。