EPIDERMAL GROWTH FACTOR AND PANCREATIC CANCER

Summary

Principal Investigator: M Korc
Affiliation: Dartmouth Medical School
Country: USA
Abstract: The molecular mechanisms that lead to malignant transformation of pancreatic exocrine cells and their subsequent growth advantage are not known. However, it is established that cultured human pancreatic cancer cells overexpress the epidermal growth factor receptor (EGFR). In contrast, the receptors for insulin, insulin-like growth factor 1 (IGF- 1), tumor necrosis factor (TNF), interferon-gamma (IFN), and acetylcholine are not overexpressed in these cells. In addition to having increased EGFR mRNA levels, these cells produce transforming growth factor-alpha (TFG-alpha) and avidly bind and internalize EGF and TFG-alpha. However, in human pancreatic cancer cells. EGF is recycled and is not readily processed into low molecular weight moieties while TGF-alpha is rapidly degraded. Although both ligands induce EGFR tyrosine phosphorylation and enhance phosphatidylinositol hydrolysis in these cells, their actions on these important biological processes exhibit quantitative and qualitative differences. Further, TGF-alpha is more potent that EGF at stimulating their anchorage-independent growth, and is less efficient than EGF at down regulating EGFR. These observations raise the possibility that EGF and TGF-alpha may exert complementary effects that together may combine to provide pancreatic cancer cells with a unique growth advantage. Indeed, we recently found that EGFR, EGF, and TGF-alpha are overexpressed in human pancreatic cancer tissues. Therefore, in the present proposal we will test the hypothesis that excessive activation of EGFR by EGF and TGF-alpha may be of fundamental importance for the growth of human pancreatic cancer cells. To test our hypothesis, we will elucidate the mechanisms that allow EGF and TGF-alpha to exhibit biological differences in pancreatic cancer cells, study the signal transduction pathways that are activated by EGF and TGF-alpha in these cells by comparison with normal rat and human pancreatic duct cells, use specific antisense expression constructs and/or antisense oligodeoxynucleotides to inhibit TGF-alpha expression in cultured human pancreatic cancer cells, use similar techniques as well as dominant EGFR mutations to inhibit EGFR expression and EGFR-mediated mitogenesis in these cells, and assess the regulation of TGF-alpha gene expression in relation to the pancreatic microenvironment. We will also determine the potential role of EGFR overactivation in a nude mouse model of pancreatic cancer, and determine whether TGF-alpha coupled to pseudomonas toxin can inhibit the growth of pancreatic cancers. Finally, we will use the knowledge gained from our studies to develop a non-invasive diagnostic test for pancreatic cancer.
Funding Period: 1989-04-01 - 1995-06-30
more information: NIH RePORT

Top Publications

  1. ncbi Suppression of ovarian cancer cell tumorigenicity and evasion of Cisplatin resistance using a truncated epidermal growth factor receptor in a rat model
    John K Chan
    Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Stanford Cancer Center, 300 Pasteur Drive HH333, Stanford, CA 94305 5317, USA
    Cancer Res 65:3243-8. 2005
  2. ncbi FXYD3 is overexpressed in pancreatic ductal adenocarcinoma and influences pancreatic cancer cell growth
    Hany Kayed
    Department of General Surgery, University of Heidelberg, Heidelberg, Germany
    Int J Cancer 118:43-54. 2006
  3. ncbi Expression and differential signaling of heregulins in pancreatic cancer cells
    Armin Kolb
    Department of General Surgery, University of Heidelberg, Heidelberg, Germany
    Int J Cancer 120:514-23. 2007
  4. ncbi Identification of a fibroblast growth factor receptor 1 splice variant that inhibits pancreatic cancer cell growth
    Zhanbing Liu
    Department of General, Visceral and Transplantation Surgery, University of Ulm, Ulm, Germany
    Cancer Res 67:2712-9. 2007

Scientific Experts

  • J K Chan
  • Murray Korc
  • Armin Kolb
  • Zhanbing Liu
  • Helmut Friess
  • Jorg Kleeff
  • Thomas Giese
  • Hany Kayed
  • Max Bachem
  • Nicola Neiss
  • Nichole Arnold
  • Doris Henne-Bruns
  • Shaoxia Zhou
  • Nathalia A Giese
  • Marko Kornmann
  • Markus W Buchler
  • Shereen Keleg
  • Klaus Felix
  • Roland Penzel
  • Hanswalter Zentgraf
  • Knut Ketterer

Detail Information

Publications4

  1. ncbi Suppression of ovarian cancer cell tumorigenicity and evasion of Cisplatin resistance using a truncated epidermal growth factor receptor in a rat model
    John K Chan
    Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Stanford Cancer Center, 300 Pasteur Drive HH333, Stanford, CA 94305 5317, USA
    Cancer Res 65:3243-8. 2005
    ..Thus, EGFR blockade may ultimately prove to be a useful therapeutic tool in the treatment of cisplatin-sensitive and cisplatin-resistant ovarian cancers...
  2. ncbi FXYD3 is overexpressed in pancreatic ductal adenocarcinoma and influences pancreatic cancer cell growth
    Hany Kayed
    Department of General Surgery, University of Heidelberg, Heidelberg, Germany
    Int J Cancer 118:43-54. 2006
    ..In conclusion, overexpression of FXYD3 in pancreatic cancer may contribute to the proliferative activity of this malignancy...
  3. ncbi Expression and differential signaling of heregulins in pancreatic cancer cells
    Armin Kolb
    Department of General Surgery, University of Heidelberg, Heidelberg, Germany
    Int J Cancer 120:514-23. 2007
    ..High HRG-beta levels but not HRG-alpha levels were associated with decreased patient survival. In conclusion, HRG is expressed by pancreatic cancer cells and influences pancreatic cancer cell growth and patient survival...
  4. ncbi Identification of a fibroblast growth factor receptor 1 splice variant that inhibits pancreatic cancer cell growth
    Zhanbing Liu
    Department of General, Visceral and Transplantation Surgery, University of Ulm, Ulm, Germany
    Cancer Res 67:2712-9. 2007
    ..Our results show that FGFR1-IIIb is a functional FGFR that inhibits the transformed phenotype of human pancreatic cancer cells...