Pancreatic cancer cell-derived vascular endothelial growth factor is biologically active in vitro and enhances tumorigenicity in vivo.
Vascular endothelial growth factor (VEGF) is a potent angiogenic stimulator that acts by binding to high-affinity transmembrane receptors. Although both VEGF and its receptors are overexpressed in human pancreatic ductal adenocarcinoma (PDAC), this malignancy is not generally considered to be highly vascular. It is not known, therefore, whether the abundance of VEGF in PDAC is biologically relevant. To address this issue, we measured the angiogenic effects of pancreatic cancer cell-derived VEGF in an in vitro endothelial cell proliferation assay and characterized the consequences of suppressing VEGF expression on pancreatic tumor growth in an athymic nude mouse model. We found that human pancreatic cancer cell lines secrete large quantities of biologically active VEGF into conditioned medium (CM). Stable transfection of an anti-sense VEGF(189) (AS-VEGF(189)) expression construct into PANC-1 pancreatic cancer cells resulted in decreased VEGF expression and secretion, a decreased capacity of the resultant CM to enhance endothelial cell proliferation and a significant attenuation of tumor cell proliferation in vitro. Furthermore, when injected into athymic nude mice, AS-VEGF(189)-expressing cells exhibited an 80% decrease in tumor growth compared with control cells. These results support the hypothesis that VEGF promotes pancreatic cancer growth in vivo and suggest that anti-VEGF therapy may be useful in the treatment of this disease.
Luo
J
J
Division of Endocrinology, Diabetes and Metabolism, Departments of Medicine, Biological Chemistry and Pharmacology, University of Irvine, Irvine, CA, USA.
Guo
P
P
Matsuda
K
K
Truong
N
N
Lee
A
A
Chun
C
C
Cheng
S Y
SY
Korc
M
M
D000818:Animals; D015197:Carcinogenicity Tests; D002455:Cell Division / Q000187:drug effects; D004195:Disease Models, Animal; D016228:Endothelial Growth Factors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000473:pathology; D015870:Gene Expression / Q000187:drug effects; D005822:Genetic Vectors; D006801:Humans; D008222:Lymphokines / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D016376:Oligonucleotides, Antisense / Q000235:genetics / Q000494:pharmacology* / Q000627:therapeutic use; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D012313:RNA / Q000096:biosynthesis / Q000187:drug effects; D013997:Time Factors; D014162:Transfection; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D023041:Xenograft Model Antitumor Assays
D016228:Endothelial Growth Factors; D008222:Lymphokines; D016376:Oligonucleotides, Antisense; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D012313:RNA