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Published on: May 1, 2015
Insulin-like growth factor binding protein-3 suppresses vascular endothelial growth factor expression and tumor
Seung-Hyun Oh1, Woo-Young Kim, Ok-Hee Lee
1College of Pharmacy, Gachon University, Incheon.
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.
Insights
Insulin-like growth factor binding protein-3 (IGFBP-3) inhibits tumor growth and blood vessel formation in head and neck squamous cell carcinoma (HNSCC). This anti-angiogenic effect is partly due to IGFBP-3
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Angiogenesis is crucial for tumor development.
- Insulin-like growth factor (IGF) binding protein-3 (IGFBP-3) influences IGF bioavailability and has been implicated in cancer.
- The role of IGFBP-3 in head and neck squamous cell carcinoma (HNSCC) angiogenesis requires further investigation.
Purpose of the Study:
- To investigate the role of IGFBP-3 in tumor angiogenesis within HNSCC.
- To determine the effects of IGFBP-3 on endothelial cell function and vascular endothelial growth factor (VEGF) production.
Main Methods:
- Utilized in vivo orthotopic tongue tumor models with UMSCC38 HNSCC cells.
- Administered adenoviral (Ad-BP3) and recombinant (rBP3) IGFBP-3.
- Assessed effects on tumor growth, vascularization, cell migration, invasion, and tube formation in HUVECs and UMSCC38 cells.
- Investigated VEGF production and IGF-independent mechanisms using a mutant IGFBP-3 (IGFBP-3-GGG) and cells from IGF-1R-null mice.
Main Results:
- Both Ad-BP3 and rBP3 significantly suppressed UMSCC38 HNSCC cell growth in vivo.
- IGFBP-3 inhibited vascularization in tongue tumors and the chorio-allantoic membrane.
- IGFBP-3 reduced HUVEC migration, invasion, and tube formation, and suppressed VEGF production in both HUVECs and UMSCC38 cells.
- IGFBP-3 suppressed VEGF production independently of IGF-1 receptor signaling.
Conclusions:
- IGFBP-3 exhibits anti-angiogenic activity in HNSCC.
- This anti-angiogenic effect is mediated, in part, by the IGF-independent suppression of VEGF production from both endothelial and cancer cells.
- IGFBP-3 represents a potential therapeutic target for HNSCC.
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