Targeting vascular endothelial growth factor receptor-1 and -3 with cediranib (AZD2171): effects on migration and invasion of gastrointestinal cancer cell lines.
The effect of vascular endothelial growth factor (VEGF) ligands and cediranib on tumor cell proliferation, migration, and invasion was determined. It has recently been suggested that autocrine signaling through the VEGF receptor (VEGFR) pathway may play a role in tumor cell survival, invasion, and migration. The purpose of the present study was to determine the expression of VEGFRs and VEGFR ligands in a panel of gastrointestinal carcinoma cells. Additionally, we evaluated the effects of VEGF autocrine signaling on tumor cell proliferation, migration, and invasion utilizing cediranib (AZD2171), a pan-VEGFR inhibitor. Five colorectal, three pancreatic, and two hepatocellular carcinoma cell lines were screened for VEGFR and VEGF expression by several methods. Expression of VEGFR-1 and VEGFR-3 was cell line-dependent, whereas VEGFR-2 was not detected. Secretion of VEGF-A was detected in the supernatants of all cell lines whereas VEGF-C secretion was detected in the Panc-1, MiaPaca2, and Hep1 cells only. Tumor cells showed increased migratory activity, but not proliferation, when stimulated with VEGFs. The pan-VEGFR inhibitor cediranib (100 nmol/L) inhibited tumor cell migration and invasion, with no effects on proliferation. Cediranib decreased VEGFR-1 and VEGFR-3 phosphorylation as well as activation of downstream effectors. VEGFR-1 and VEGFR-3 expression was detected in all the gastrointestinal carcinoma cells evaluated. Although activation of the VEGF pathway did not affect cell proliferation, our data indicate that this pathway seems to play a role in tumor cell migration and invasion in these cell lines. Therefore, inhibition of VEGFR by cediranib may represent a clinically relevant treatment option for gastrointestinal tumors.
Morelli
M Pia
MP
Division of Medical Oncology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO 80010, USA.
Brown
Amy M
AM
Pitts
Todd M
TM
Tentler
John J
JJ
Ciardiello
Fortunato
F
Ryan
Anderson
A
Jürgensmeier
Juliane M
JM
Eckhardt
S Gail
SG
D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005770:Gastrointestinal Neoplasms / Q000235:genetics / Q000473:pathology*; D020869:Gene Expression Profiling; D006801:Humans; D009361:Neoplasm Invasiveness; D011799:Quinazolines / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000187:drug effects*; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000187:drug effects*; D007211:Indoles
D000970:Antineoplastic Agents; D011799:Quinazolines; D040281:Vascular Endothelial Growth Factor Receptor-1; D040321:Vascular Endothelial Growth Factor Receptor-3; C500926:cediranib; D007211:Indoles