Insulin-like growth factor-I receptor blockade reduces tumor angiogenesis and enhances the effects of bevacizumab for a human gastric cancer cell line, MKN45.
BACKGROUND
Insulin-like growth factor (IGF)-I receptor (IGF-IR) signaling is required for tumorigenicity and tumor progression of gastrointestinal cancers. The authors previously reported the success of therapy for gastrointestinal cancers using adenoviruses that expressed dominant-negative IGF-IR (IGF-IR/dn). In addition, it has been demonstrated that IGF-IR signaling affects vascular endothelial growth factor (VEGF) expression in some other types of tumors. The objective of the current study was to evaluate this interaction by studying the roles of IGF-IR in tumor angiogenesis and lymphangiogenesis and their implications for targeted therapy in gastric cancer.


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.
First Department of Internal Medicine, Sapporo Medical University, Sapporo, Japan.
Hua
H
Li
Yasushi
Y
Adachi
Hiroyuki
H
Yamamoto
Yongfen
Y
Min
Hirokazu
H
Ohashi
Masanori
M
Ii
Yoshiaki
Y
Arimura
Takao
T
Endo
Choon-Taek
CT
Lee
David P
DP
Carbone
Kohzoh
K
Imai
Yasuhisa
Y
Shinomura
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D042583:Lymphangiogenesis / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors* / Q000502:physiology; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab; D017526:Receptor, IGF Type 1