Carcinoma of the pancreas is a devasting disease that is characterized by poor survival rates and unresponsiveness to chemotherapy. The molecular mechanisms that lead to malignant transformation of pancreatic exocrine cells and subsequent growth advantage are not known. However, cultured human pancreatic cancer cells overexpress the epidermal growth factor (EGF) receptor (EGFR), produce transforming growth factor-alpha (TGF-alpha), and commonly exhibit mutations in the K-ras oncogene and p53 tumor suppressor gene that may lead to aberrant transduction of EGFR-mediated signaling pathways. In contrast to EGFR, the receptors for insulin, insulin-like growth factor 1 (EGF-1), tumor necrosis factor (TNF), interferon-gamma (IFN), and acetylcholine are not overexpressed in these cells. In vivo, human pancreatic tumors overexpressed EGFR and four growth factors that activate EGFR: EGF, TGF-alpha, amphiregulin (AR) and heparin-binding EGF-like growth factor (HB- EGF). Therefore, in the present proposal they will test the hypothesis that excessive activation of EGFR may be of fundamental importance for the growth advantage of human pancreatic cancer cells. To test the hypothesis, they will use specific antisense oligodeoxynucleotides and/or antisense expression constructs to inhibit the expression of EGFR-activating growth factors in human pancreatic cancer cells, examine the effects of a dominant-negative EGFR construct and of a specific and potent inhibitor of EGFR kinase activity on the growth of these cells, study the growth characteristics and signal transduction pathways that are activated by EGF, TGF-alpha HB-EGF, and AR in these cells, conduct similar studies with Chinese Hamster Ovary (CHO) cells expressing various levels of wild-type EGFR and a novel variant EGFR in the absence and presence of mutated p53, and determine whether the fifth member of the EGF family, betacellulin, is also overexpressed in human pancreatic tumors. Because chronic pancreatitis (CP) has been associated with an increased incidence of pancreatic cancer, they will also study the expression of the EGF family of peptides in the pancreas of CP patients. CP may be associated with episodes of acute injury termed acute pancreatitis (AP). Therefore, they will also study the expression of EGFR and EGF-like peptides in the pancreas of acute pancreatitis (AP) patients and in a rat model of acute pancreatic injury. Because both cancer and CP are associated with altered acinar cell differentiation, they will delineate the role of EGFR in pancreatic differentiation by studying the effects of EGFR and TGF- alpha in AR42J cells, a well-differentiated cell with acinar characteristics. To this end, they will express wild type and variant EGFR and precursor and authentic TGF-alpha in AR42J cells, and characterize the growth of these cells in vitro and following injection into nude mice in vivo.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
3R01CA040162-14S2
Application #
6348702
Study Section
Pathology B Study Section (PTHB)
Program Officer
Freeman, Colette S
Project Start
1989-04-01
Project End
2001-02-28
Budget Start
1998-06-01
Budget End
2001-02-28
Support Year
14
Fiscal Year
2000
Total Cost
$63,514
Indirect Cost
Name
University of California Irvine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
161202122
City
Irvine
State
CA
Country
United States
Zip Code
92697
Kolb, Armin; Kleeff, Jorg; Arnold, Nichole et al. (2007) Expression and differential signaling of heregulins in pancreatic cancer cells. Int J Cancer 120:514-23
Liu, Zhanbing; Neiss, Nicola; Zhou, Shaoxia et al. (2007) Identification of a fibroblast growth factor receptor 1 splice variant that inhibits pancreatic cancer cell growth. Cancer Res 67:2712-9
Kayed, Hany; Kleeff, Jorg; Kolb, Armin et al. (2006) FXYD3 is overexpressed in pancreatic ductal adenocarcinoma and influences pancreatic cancer cell growth. Int J Cancer 118:43-54
Chan, John K; Pham, Huyen; You, Xue Juan et al. (2005) Suppression of ovarian cancer cell tumorigenicity and evasion of Cisplatin resistance using a truncated epidermal growth factor receptor in a rat model. Cancer Res 65:3243-8
Kleeff, Jorg; Kothari, Nayantara H; Friess, Helmut et al. (2004) Adenovirus-mediated transfer of a truncated fibroblast growth factor (FGF) type I receptor blocks FGF-2 signaling in multiple pancreatic cancer cell lines. Pancreas 28:25-30
Guo, Junchao; Kleeff, Jorg; Li, Junsheng et al. (2004) Expression and functional significance of CDC25B in human pancreatic ductal adenocarcinoma. Oncogene 23:71-81
Liao, Quan; Guo, Junchao; Kleeff, Jorg et al. (2003) Down-regulation of the dual-specificity phosphatase MKP-1 suppresses tumorigenicity of pancreatic cancer cells. Gastroenterology 124:1830-45
Friess, H; Ding, J; Kleeff, J et al. (2003) Microarray-based identification of differentially expressed growth- and metastasis-associated genes in pancreatic cancer. Cell Mol Life Sci 60:1180-99
Ketterer, Knut; Rao, Shyam; Friess, Helmut et al. (2003) Reverse transcription-PCR analysis of laser-captured cells points to potential paracrine and autocrine actions of neurotrophins in pancreatic cancer. Clin Cancer Res 9:5127-36
Kleeff, Jorg; Fukahi, Kimi; Lopez, Martha E et al. (2002) Targeting of suicide gene delivery in pancreatic cancer cells via FGF receptors. Cancer Gene Ther 9:522-32

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