Impact of insulin-like growth factor receptor-I function on angiogenesis, growth, and metastasis of colon cancer.
Insulin-like growth factors and their principal receptor, IGF-I receptor (IGF-IR), are frequently expressed in human colon cancers and play a role in preventing apoptosis, enhancing cell proliferation, and inducing expression of vascular endothelial growth factor (VEGF). The role of IGF-IR in regulating angiogenesis and metastases of human colon cancer has not been elucidated. To determine the in vitro and in vivo effects of IGF-IR in human colon cancer growth and angiogenesis, human KM12L4 colon cancer cells were transfected with a truncated dominant-negative form of IGF-IR (IGF-IR dom-neg). IGF-IR dom-neg-transfected cells demonstrated markedly decreased constitutive expression of VEGF mRNA and protein. Subcutaneous injections of IGF-IR dom-neg-transfected cells in nude mice led to significantly decreased tumor growth (p < 0.05) that was associated with decreased tumor cell proliferation, VEGF expression, and vessel count and with increased tumor cell apoptosis (p < 0.05 for all parameters compared with controls). In addition, pericyte coverage of endothelial cells was significantly decreased in tumors from IGF-IR dom-neg-transfected cells. Following this observation, we demonstrated in vitro that vascular smooth muscle cells migrated significantly less in conditioned medium derived from IGF-IR dom-neg-transfected cells compared with medium from control cells. After splenic injections, IGF-IR dom-neg transfectants failed to produce liver metastases, in contrast to parental cells and mock transfectants (p < 0.05). In addition, IGF-IR dom-neg-transfected cells failed to form liver tumors after direct injection into the liver. These studies demonstrate that the IGF-IR plays an important role in multiple mechanisms that mediate the growth, angiogenesis, and metastasis of human colon cancer. IGF-IR is a valid target for the therapy of human colon cancer.
Reinmuth
Niels
N
Department of Cancer Biology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Fan
Fan
F
Liu
Wenbiao
W
Parikh
Alexander A
AA
Stoeltzing
Oliver
O
Jung
Young D
YD
Bucana
Corazon D
CD
Radinsky
Robert
R
Gallick
Gary E
GE
Ellis
Lee M
LM
D002455:Cell Division / Q000235:genetics; D002465:Cell Movement / Q000187:drug effects; D003110:Colonic Neoplasms / Q000098:blood supply* / Q000473:pathology* / Q000503:physiopathology; D016228:Endothelial Growth Factors / Q000235:genetics / Q000494:pharmacology; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000494:pharmacology; D008222:Lymphokines / Q000235:genetics / Q000494:pharmacology; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000502:physiology*; D011994:Recombinant Proteins / Q000378:metabolism / Q000494:pharmacology; D014158:Transcription, Genetic; D014162:Transfection; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D012333:RNA, Messenger; D011994:Recombinant Proteins; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1