Abstract | BACKGROUND: METHODS: The impact of IGF signals on the expression of VEGF-A and VEGF-C in a human gastric cancer cell, MKN45, and vascular formation were assessed. The effects of IGF-IR/dn with or without bevacizumab on angiogenesis, lymphangiogenesis, and tumor suppression in mouse xenografts were assessed. RESULTS: IGFs induced the expression of VEGF ligands and up-regulated in vitro vascular vessel formation. IGF-IR/dn reduced VEGF expression, reduced the activation of both protein kinase B (Akt) and mitogen-activated protein kinase (MAPK), and reduced vascular formation, indicating that IGF-IR/dn inhibited tumor growth in mice by inhibiting both angiogenesis and lymphangiogenesis. However, IGF-IR/dn did not affect either blood sugar or body weight in these mice. The combination of IGF-IR/dn and bevacizumab was highly effective against these xenograft tumors, and only this combination resulted in the complete regression of 43% of tumors, reduced the expression of VEGF, and induced apoptosis. CONCLUSIONS: The current results indicated that IGF-IR is involved in angiogenesis and lymphangiogenesis through the modulation of VEGF ligand expression in the gastric cancer cell line MKN45. Targeting IGF-IR in combination with agents that block the VEGF pathway may have therapeutic utility for gastric cancer therapy.
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Authors | Hua Li, Yasushi Adachi, Hiroyuki Yamamoto, Yongfen Min, Hirokazu Ohashi, Masanori Ii, Yoshiaki Arimura, Takao Endo, Choon-Taek Lee, David P Carbone, Kohzoh Imai, Yasuhisa Shinomura |
Journal | Cancer
(Cancer)
Vol. 117
Issue 14
Pg. 3135-47
(Jul 15 2011)
ISSN: 1097-0142 [Electronic] United States |
PMID | 21264842
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2011 American Cancer Society. |
Chemical References |
- Antibodies, Monoclonal
- Antibodies, Monoclonal, Humanized
- Vascular Endothelial Growth Factor A
- Bevacizumab
- Receptor, IGF Type 1
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Topics |
- Animals
- Antibodies, Monoclonal
(therapeutic use)
- Antibodies, Monoclonal, Humanized
- Bevacizumab
- Cell Line, Tumor
- Female
- Humans
- Lymphangiogenesis
(drug effects)
- Mice
- Mice, Inbred BALB C
- Neovascularization, Pathologic
(drug therapy)
- Receptor, IGF Type 1
(antagonists & inhibitors, physiology)
- Signal Transduction
- Stomach Neoplasms
(blood supply, drug therapy, metabolism)
- Vascular Endothelial Growth Factor A
(metabolism)
- Xenograft Model Antitumor Assays
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