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. ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA101306-04
Application #
7034638
Study Section
Special Emphasis Panel (ZRG1-PTHB (01))
Program Officer
Jhappan, Chamelli
Project Start
2003-04-01
Project End
2008-03-31
Budget Start
2006-04-01
Budget End
2007-03-31
Support Year
4
Fiscal Year
2006
Total Cost
$330,445
Indirect Cost
Name
Dartmouth College
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
041027822
City
Hanover
State
NH
Country
United States
Zip Code
03755
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