Impact of Insulin-Like Growth Factor Receptor-I Function on Angiogenesis, Growth, and Metastasis of Colon Cancer

Abstract

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 Ͻ 0.05) that was associated with decreased tumor cell proliferation, VEGF expression, and vessel count and with increased tumor cell apoptosis (p Ͻ 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 Ͻ 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.

A Comparison and Catalog of Intrinsic Tumor Growth Models

“…Unfortunately, very few data sets exist that allow tumors to grow large enough in order to get a proper estimate of the carrying capacity. We specifically sought out data sets that included data for large populations in order to properly compare the former two models with the latter three (Fujiwara et al, 1993;Takahashi et al, 1992;Murgo, 1985;Richmond et al, 1983;Kisfalvi et al, 2009;Reinmuth et al, 2002;Nakata et al, 1998;Caltagirone et al, 2000;Ricker et al, 2004).…”

ZD6126 inhibits orthotopic growth and peritoneal carcinomatosis in a mouse model of human gastric cancer

“…Tissue sections were sectioned and stained for H&E, CD31 (vessels), TUNEL (apoptotic cells), BrdU (proliferative cells) and PCNA (proliferative cells), as previously described (Reinmuth et al, 2002;Stoeltzing et al, 2003). All tumour tissues were counterstained either with Gill's 3 haematoxylin (Sigma; immunochistochemical analysis), or incubated with 300 mg/ml of Hoechst stain for 1 -2 min (Sigma, immunofluorescent analysis).…”

Potential crosstalk between insulin-like growth factor receptor type 1 and epidermal growth factor receptor in progression and metastasis of pancreatic cancer

“…[1][2][3][4][5][6] In addition, the ligand-binding activation of IGF1R through the PI3K signaling pathway is known to promote proliferation in some cancer cell lines, and to protect many different cell types from a variety of proapoptotic damage. 3,4,7,[8][9][10] Among the tyrosine kinase receptor families, the mechanism of action of the epidermal growth factor receptor (EGFR) family, especially EGFR and HER-2 (c-erbB2), is that which has been best characterized. 11,12 EGFR and HER-2 are also thought to be involved in the development of cancers.…”