title: Insulin-like growth factor binding protein-3 suppresses vascular endothelial growth factor expression and tumor angiogenesis in head and neck squamous cell carcinoma.
abstract: Angiogenesis, the process by which new blood vessels are recruited to existing ones, is essential for tumor development. Insulin-like growth factor (IGF) binding protein-3 (IGFBP-3), which modulates bioavailability of IGF, has been studied for its potential role in angiogenesis during tissue regeneration and cancer development. In this study, we assessed the role of IGFBP-3 in tumor angiogenesis in head and neck squamous cell carcinoma (HNSCC) and human umbilical vein endothelial cells (HUVECs) using adenoviral (Ad-BP3) and recombinant (rBP3) IGFBP-3. Using an in vivo orthotopic tongue tumor model, we confirmed that both Ad-BP3 and rBP3 suppress the growth of UMSCC38 HNSCC cells in vivo. Ad-BP3 inhibited vascularization in tongue tumors and chorio-allantoic membrane, and suppressed angiogenesis-stimulating activities in UMSCC38 cells. In HUVECs, Ad-BP3 decreased migration, invasion, and tube formation. rBP3 also suppressed production of vascular endothelial growth factor (VEGF) in HUVECs and UMSCC38 cells. IGFBP-3-GGG, a mutant IGFBP-3 with loss of IGF binding capacity, suppressed VEGF production. In addition, we found that IGFBP-3 suppressed VEGF expression, even in mouse embryonic fibroblasts from an IGF-1R-null mouse. Finally, we demonstrated that IGFBP-3-GGG inhibits tumor angiogenesis and growth to the same degree as wild-type IGFBP-3. Taken together, these results support the hypothesis that IGFBP-3 has anti-angiogenic activity in HNSCC, at least in part due to IGF-independent suppression of VEGF production from vascular endothelial cells and cancer cells.
authors.affiliation: College of Pharmacy, Gachon University, Incheon.
authors.forename: Seung-Hyun
authors.initials: SH
authors.lastname: Oh
authors.forename: Woo-Young
authors.initials: WY
authors.lastname: Kim
authors.forename: Ok-Hee
authors.initials: OH
authors.lastname: Lee
authors.forename: Ju-Hee
authors.initials: JH
authors.lastname: Kang
authors.forename: Jong-Kyu
authors.initials: JK
authors.lastname: Woo
authors.forename: Jai-Hyun
authors.initials: JH
authors.lastname: Kim
authors.forename: Bonnie
authors.initials: B
authors.lastname: Glisson
authors.forename: Ho-Young
authors.initials: HY
authors.lastname: Lee
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000098:blood supply* / Q000473:pathology / Q000628:therapy; D045744:Cell Line, Tumor; D002465:Cell Movement; D002478:Cells, Cultured; D002642:Chick Embryo; D005260:Female; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods; D006258:Head and Neck Neoplasms / Q000098:blood supply* / Q000473:pathology* / Q000628:therapy; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism / Q000502:physiology; D006801:Humans; D007150:Immunohistochemistry; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D009154:Mutation; D009389:Neovascularization, Pathologic / Q000235:genetics* / Q000628:therapy; D018919:Neovascularization, Physiologic / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D047368:Tumor Burden; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D018972:Insulin-Like Growth Factor Binding Protein 3; D042461:Vascular Endothelial Growth Factor A