Gastrin-releasing peptide (GRP) induces angiogenesis and the specific GRP blocker 77427 inhibits tumor growth in vitro and in vivo.
Angiogenesis is becoming a major target for antitumor therapies, and identifying new angiogenic factors and their specific inhibitors may provide new avenues for tumor management. Here we identify gastrin-releasing peptide (GRP) as a new angiogenic molecule that is secreted by tumors and acts directly upon GRP receptors in the endothelial cells. Addition of GRP increases endothelial cell migration and cord formation in vitro, and induces angiogenesis in an in vivo assay. We have recently identified a small molecule GRP blocker, compound 77427. This inhibitor significantly reduced endothelial cell cord formation in vitro and angiogenesis in vivo. Conversely, when applied to VEGF-induced angiogenesis, the small molecule did not have any effect, demonstrating its specificity. Furthermore, this GRP blocker was able to reduce lung tumor cell growth in vitro as demonstrated by MTT and clonogenic assays. When applied to a xenograft model with lung cancer cells, compound 77427 reduced tumor volume to undetectable sizes, although when the treatment was suspended, tumors began to grow again at normal rates. Our collective observations indicate that GRP is a new angiogenic peptide and that its inhibition offers an attractive tool to reduce tumor burden.
Martínez
Alfredo
A
Cell and Cancer Biology Branch and Vascular Biology Faculty, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. amartinez@cajal.csic.es
Zudaire
Enrique
E
Julián
Miguel
M
Moody
Terry W
TW
Cuttitta
Frank
F
D001483:Base Sequence; D017931:DNA Primers; D004730:Endothelium, Vascular / Q000502:physiology; D019886:Gastrin-Releasing Peptide / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000494:pharmacology*; D005786:Gene Expression Regulation; D006801:Humans; D008833:Microcirculation / Q000502:physiology; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D011743:Pyrimidines / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology
D017931:DNA Primers; D011743:Pyrimidines; D011994:Recombinant Proteins; D042461:Vascular Endothelial Growth Factor A; C502484:compound 77427; D019886:Gastrin-Releasing Peptide