Vascular endothelial growth factor partially inhibits the trastuzumab-mediated antibody-dependent cellular cytotoxicity of human monocytes.
BACKGROUND
Vascular endothelial growth factor (VEGF) is produced by almost all cancer cells and VEGF receptor 1 (R1) (Flt-1) is abundantly expressed on human monocytes. In the present study, we investigated whether VEGF affects the antibody-dependent cell-mediated cytotoxicity (ADCC) of human monocytes mediated by trastuzumab.


METHODS
HER-2-expressing tumor cell lines (MKN-7, TE-4 and SKOV-3) were evaluated for trastuzumab-mediated ADCC of human monocytes in the presence of VEGF(165). The trastuzumab-mediated, monocyte-derived ADCC were treated with the anti-human blocking VEGF R1 or VEGF R2 mAb. VEGF-induced intracellular signaling on monocytes was quantified with ELISA kits.


RESULTS
VEGF partially inhibited the ADCC of human monocytes mediated by trastuzumab. The VEGF-induced deficiency of human monocytes for ADCC was completely recovered by the anti-human blocking VEGF R1 mAb, while the anti-VEGF R2 blocking mAb did not have any effect. Furthermore, VEGF treatment enhanced the phospho-Erk 1/2 in human monocytes.


CONCLUSIONS
VEGF partially inhibited the ADCC of human monocytes mediated by trastuzumab, and this inhibition was mainly mediated by VEGF R1 (Flt-1).
Mimura
Kousaku
K
First Department of Surgery, University of Yamanashi, Yamanashi, Japan.
Kono
Koji
K
Takahashi
Akihiro
A
Kawaguchi
Yoshihiko
Y
Mizukami
Yoshiki
Y
Fujii
Hideki
H
D043925:Angiogenesis Inducing Agents / Q000494:pharmacology*; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D018734:Genes, erbB-2; D006801:Humans; D009000:Monocytes / Q000187:drug effects* / Q000276:immunology; D000068878:Trastuzumab; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology*
D043925:Angiogenesis Inducing Agents; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D042461:Vascular Endothelial Growth Factor A; D000068878:Trastuzumab