VEGF-RII influences the prognosis of pancreatic cancer.
OBJECTIVE
To evaluate whether the vascular endothelial growth factor (VEGF) pathway can be used as a target for effective treatment of pancreatic cancer.


BACKGROUND
VEGF and its receptors (VEGF-RI and -RII) are the predominant regulators of tumor neoangiogenesis, a key element for tumor growth and progression. However, VEGF receptor expression has been thought to be limited to endothelial cells, limiting the possibility of targeting it for therapy of pancreatic cancer.


METHODS
Protein localization and mRNA were studied in pancreatic cancer specimens, normal pancreas, human pancreatic cancer cell lines, and an endothelial cell line. Cell proliferation was determined by [ H] thymidine uptake. Both VEGF receptors were genetically eliminated by antisense technology. The same approach was used in a murine model of pancreatic cancer in a therapeutic approach.


RESULTS
VEGF-RI mRNA and VEGF-RII mRNA were expressed in 17 and 15 of 24 pancreatic cancer samples, respectively. VEGF receptors were found not only in blood vessels but also in pancreatic cancer cells. VEGF-RII expression correlated with poor tumor differentiation and was associated with poorer survival, while VEGF-RI expression did not correlate. VEGF treatment led to extensive growth stimulation in six of seven pancreatic cancer cell lines, which was completely inhibited by antisense treatment against VEGF-RII. Liposome-mediated gene transfer in nude mice with pancreatic tumors markedly reduced local tumor growth and decreased metastatic tumor spread.


CONCLUSIONS
The VEGF/VEGF-RII pathway regulates angiogenesis and local tumor growth and spread in pancreatic cancer. Genetic targeting of VEGF-RII blocks local growth and metastatic spread of pancreatic cancer cells in vivo and therefore offers a potential new therapeutic option for patients with this disease.
Büchler
Peter
P
Department of Surgery, UCLA School of Medicine, University of California, Los Angeles, California 90095-6904, USA.
Reber
Howard A
HA
Büchler
Markus W
MW
Friess
Helmut
H
Hines
Oscar J
OJ
D000230:Adenocarcinoma / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D000818:Animals; D014408:Biomarkers, Tumor / Q000032:analysis*; D046508:Culture Techniques; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000473:pathology; D010179:Pancreas / Q000098:blood supply*; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D011336:Probability; D011379:Prognosis; D040262:Receptors, Vascular Endothelial Growth Factor / Q000032:analysis*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012680:Sensitivity and Specificity; D013045:Species Specificity; D018709:Statistics, Nonparametric; D015996:Survival Rate; D014407:Tumor Cells, Cultured; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000032:analysis*; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000032:analysis*
D014408:Biomarkers, Tumor; D040262:Receptors, Vascular Endothelial Growth Factor; D040301:Vascular Endothelial Growth Factor Receptor-2; D040321:Vascular Endothelial Growth Factor Receptor-3