Role of Glypican-1 in Pancreatic Cancer

描述（由申请人提供）：胰腺导管腺癌（PDAC）过表达多种酪氨酸激酶受体，如I型FGF受体（FGFR-1）及其配体。这些配体中的许多是肝素结合生长因子（HBGF），其促有丝分裂作用通常依赖于与硫酸乙酰肝素蛋白聚糖（HSPG）的相互作用，所述硫酸乙酰肝素蛋白聚糖促进配体与高亲和力受体结合。我们已经确定PDAC过表达磷脂酰肌醇蛋白聚糖-1，但不表达高水平的磷脂酰肌醇蛋白聚糖家族的其他5个成员，提高了磷脂酰肌醇蛋白聚糖-1在PDAC中可能具有独特和重要作用的可能性。然而，Glypcian-1在PDAC中的确切作用及其作用机制尚不清楚。因此，我们将使用4种互补的方法来检验磷脂酰肌醇蛋白聚糖-1在PDAC中至关重要并且其通过促进有丝分裂、侵袭和/或转移起作用的假设。我们将首先检查磷脂酰肌醇蛋白聚糖-1表达是否与肿瘤分级和分期或患者生存相关。其次，我们将建立胰腺癌细胞系，过表达磷脂酰肌醇蛋白聚糖-1，以及细胞系的磷脂酰肌醇蛋白聚糖-1表达被抑制磷脂酰肌醇蛋白聚糖-1反义构建体，以评估磷脂酰肌醇蛋白聚糖-1在癌细胞生长，侵袭和转移中的作用，在适当的体外和体内模型系统。第三，我们将确定磷脂酰肌醇蛋白聚糖-1的任何致瘤作用是否通过I型成纤维细胞生长因子受体（FGFR-1）的存在而增强，因为该受体在PDAC中过表达并被多种HBGF激活。为此，我们将在存在或不存在两种主要FGFR-1同种型的情况下用编码磷脂酰肌醇蛋白聚糖-1的cDNA转染培养的人胰腺导管细胞。第四，我们将通过检查其聚糖化状态及其与FGFR复合物的相互作用，以及通过工程化各种磷脂酰肌醇蛋白聚糖-1嵌合蛋白并将其作用与野生型磷脂酰肌醇蛋白聚糖-1的作用进行比较，来探索磷脂酰肌醇蛋白聚糖-1赋予培养的胰腺癌细胞生长优势的机制。总之，这些研究将有助于阐明磷脂酰肌醇蛋白聚糖-1在PDAC中的作用。

DESCRIPTION (provided by applicant): Pancreatic ductal adenocarcinomas (PDACs) overexpress multiple tyrosine kinase receptors such as the type I FGF receptor (FGFR-1), and their ligands. Many of these ligands are heparin-binding growth factors (HBGFs), whose mitogenic actions are often dependent on interactions with heparan sulfate proteoglycans (HSPGs) that facilitate ligand binding to high affinity receptors. We have determined that PDACs overexpress glypican-1 but de not express high levels of other 5 members of the glypican family, raising the possibility that glypican-1 may have a unique and important role in PDAC. However, the exact role of glypcian-1 in PDAC and its mechanisms of action are not well understood. Therefore, we will use 4 complementary approaches to test the hypothesis that glypican-1 is of paramount importance in PDAC and that it acts by promoting mitogenesis, invasion and/or metastasis. We will first examine whether glypican-1 expression correlates with tumor grade and stage, or patient survival. Second, we will establish pancreatic cancer cell lines that overexpress glypican-1, as well as cell lines whose glypican-1 expression is suppressed by a glypican-1 antisense construct, in order to assess the role of glypican-1 in cancer cell growth, invasion, and metastasis in appropriate in vitro and in vivo model systems. Third, we will determine whether any tumorigenic effects of glypican-1 are enhanced by the presence of the type I fibroblast growth factor receptor (FGFR-1), since this receptor is overexpressed in PDAC and is activated by multiple HBGFs. To this end, we will transfect cultured human pancreatic ductal cells with cDNAs encoding glypican-1 in the absence or presence of the two major FGFR-1 isoforms. Fourth, we will explore the mechanisms whereby glypican-1 confers a growth advantage to cultured pancreatic cancer cells by examining its glycanation status and its interactions with FGFR complexes, and by engineering various glypican-1 chimeric proteins and comparing their actions with the actions of wild type glypican-1. Together, these studies will help to elucidate the role of glypican-1 in PDAC.