Concomitant over-expression of vascular endothelial growth factor and its receptors in pancreatic cancer

Int J Cancer. 2000 Jan 1;85(1):27-34. doi: 10.1002/(sici)1097-0215(20000101)85:1<27::aid-ijc5>3.0.co;2-8.

Abstract

Vascular endothelial growth factor (VEGF) is a potent angiogenic polypeptide that activates 2 distinct high-affinity tyrosine kinase receptors, flk-1/KDR and flt-1. In the present study, we characterized the expression of VEGF and its receptors flk-1/KDR and flt-1 in the normal human pancreas and in human pancreatic cancer tissues and cell lines. VEGF, flk-1/KDR and flt-1 mRNA levels were elevated in cancer tissues compared with normal pancreas. By immuno-histochemistry, VEGF, flk-1/KDR and flt-1 immunoreactivity co-localized in many of the cancer cells within the tumor mass. Three (AsPC-1, Capan-1 and MIAPaCa-2) of 6 pancreatic cancer cell lines expressed flk-1/KDR mRNA and protein, and 4 cell lines (AsPC-1, Capan-1, T3M4 and PANC-1) expressed flt-1 mRNA transcripts. Binding studies with (125)I-labeled VEGF165 indicated that only Capan-1 cells exhibited high levels of specific binding. Furthermore, VEGF enhanced the growth of Capan-1 cells but was without effect in the other cell lines. VEGF also enhanced mitogen-activated protein kinase (MAPK) phosphorylation and c-fos induction in Capan-1 cells, whereas the MAPK kinase inhibitor PD98059 abolished the growth-stimulatory effect of VEGF. These data indicate that human pancreatic cancers have the capacity to over-express VEGF and its receptors and suggest that in some instances VEGF may directly promote pancreatic cancer growth via the MAPK pathway.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenocarcinoma / metabolism*
  • Adenocarcinoma / pathology
  • Adult
  • Aged
  • Blotting, Northern
  • Cell Division / drug effects
  • Dose-Response Relationship, Drug
  • Endothelial Growth Factors / biosynthesis*
  • Endothelial Growth Factors / pharmacology
  • Female
  • Humans
  • Immunohistochemistry
  • Lymphokines / biosynthesis*
  • Lymphokines / pharmacology
  • Male
  • Middle Aged
  • Pancreas / cytology
  • Pancreas / metabolism
  • Pancreatic Neoplasms / metabolism*
  • Pancreatic Neoplasms / pathology
  • Proto-Oncogene Proteins / biosynthesis*
  • Receptor Protein-Tyrosine Kinases / biosynthesis*
  • Receptors, Growth Factor / biosynthesis*
  • Receptors, Vascular Endothelial Growth Factor
  • Signal Transduction / drug effects
  • Tumor Cells, Cultured
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factor Receptor-1
  • Vascular Endothelial Growth Factors

Substances

  • Endothelial Growth Factors
  • Lymphokines
  • Proto-Oncogene Proteins
  • Receptors, Growth Factor
  • VEGFA protein, human
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors
  • Receptor Protein-Tyrosine Kinases
  • Receptors, Vascular Endothelial Growth Factor
  • Vascular Endothelial Growth Factor Receptor-1