Concomitant over-expression of vascular endothelial growth factor and its receptors in pancreatic cancer.
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.
Itakura
J
J
Division of Endocrinology, Diabetes and Metabolism, Departments of Medicine, Biological Chemistry and Pharmacology, University of California, Irvine, CA, USA.
Ishiwata
T
T
Shen
B
B
Kornmann
M
M
Korc
M
M
D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology; D000328:Adult; D000368:Aged; D015152:Blotting, Northern; D002455:Cell Division / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D016228:Endothelial Growth Factors / Q000096:biosynthesis* / Q000494:pharmacology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008222:Lymphokines / Q000096:biosynthesis* / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D010179:Pancreas / Q000166:cytology / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis*; D020794:Receptor Protein-Tyrosine Kinases / Q000096:biosynthesis*; D017978:Receptors, Growth Factor / Q000096:biosynthesis*; D040262:Receptors, Vascular Endothelial Growth Factor; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D008222:Lymphokines; D011518:Proto-Oncogene Proteins; D017978:Receptors, Growth Factor; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor; D040281:Vascular Endothelial Growth Factor Receptor-1