Anti-flt1 peptide, a vascular endothelial growth factor receptor 1-specific hexapeptide, inhibits tumor growth and metastasis.
OBJECTIVE
The purpose of this study was to develop antagonists specific for the vascular endothelial growth factor receptor 1 (VEGFR1) and to investigate the effects of the antagonists on the VEGF-induced endothelial cell functions and tumor progression.


METHODS
Hexapeptides that inhibit binding of VEGFR1 and VEGF were identified through screening of synthetic peptide library. A selected peptide, anti-Flt1, was investigated for binding specificity with various receptors and ligand peptides. Effects of the peptide on proliferation, cell migration, and fibrin gel-based angiogenesis of endothelial cells were also investigated. The activity of anti-Flt1, in vivo, was evaluated for inhibition of tumor growth and metastasis in VEGF-secreting cancer cell-implanted mice by s.c. injections of the peptide.


RESULTS
Here, we report on a short peptide that binds to VEGFR1 and prevents binding of VEGF. A hexapeptide, anti-Flt1 (Gly-Asn-Gln-Trp-Phe-Ile or GNQWFI), was identified from peptide libraries. The anti-Flt1 peptide shows specificity toward binding to VEGFR1 and it inhibits binding of VEGF, placental growth factor (PlGF), and VEGF/PlGF heterodimer to VEGFR1. This peptide does not inhibit the proliferation of endothelial cells induced by VEGF and VEGF/PlGF heterodimer but it effectively blocks VEGF-induced migration of endothelial cells and their capacity to form capillary-like structures on fibrin gel-based in vitro angiogenesis system. Furthermore, growth and metastasis of VEGF-secreting tumor cells were also significantly inhibited by s.c. injections of anti-Flt1 peptide in nude mice. Accordingly, VEGF-induced migration and capillary formation are mediated through VEGFR1, and these processes may play an important role in the growth and metastasis of VEGF-secreting tumors.


CONCLUSIONS
We show that a peptide (anti-Flt1) specific for VEGFR1 inhibits growth and metastasis of tumor that secretes VEGF. The effects on endothelial cell functions, in vitro, indicate that the anticancer activity of anti-Flt1 peptide with reduced blood vessel density could also be due to the blocking of VEGFR1-mediated endothelial cell migration and tube formation. Although the effects of anti-Flt1 peptide still remain to be further characterized, the receptor 1-specific peptide antagonist, anti-Flt1, has potential as a therapeutic agent for various angiogenesis-related diseases, especially cancer.
Bae
Dong-Goo
DG
Department of Life Science, Division of Molecular and Life Sciences, Postech Biotech Center, Pohang University of Science and Technology, Pohang, Korea.
Kim
Tae-Dong
TD
Li
Ge
G
Yoon
Wan-Hee
WH
Chae
Chi-Bom
CB
D000595:Amino Acid Sequence; D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009362:Neoplasm Metastasis / Q000517:prevention & control*; D009842:Oligopeptides / Q000378:metabolism / Q000494:pharmacology*; D019151:Peptide Library; D011485:Protein Binding / Q000187:drug effects; D011994:Recombinant Proteins / Q000302:isolation & purification / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000037:antagonists & inhibitors* / Q000302:isolation & purification / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D020533:Angiogenesis Inhibitors; D009842:Oligopeptides; D019151:Peptide Library; D011994:Recombinant Proteins; D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1