Gastric cancer: the role of insulin‐like growth factor 2 (IGF 2) and its receptors (IGF 1R and M6‐P/IGF 2R)

Abstract

Insulin-like growth factor 2 (IGF 2) appears to be involved in the progression of many tumours. It binds to at least two different types of receptor: IGF type 1 (IGF 1R) and mannose 6-phosphate/IGF type 2 (M6-P/IGF 2R). Ligand binding to IGF 1R provokes mitogenic and anti-apoptotic effects. M6-P/IGF 2R has a tumour suppressor function--it mediates IGF 2 degradation. Mutation of M6-P/IGF 2R causes both diminished growth suppression and augmented growth stimulation. The aim of this study was to investigate the role of IGF 2 and its receptors (IGF 1R and IGF 2R) in human gastric cancer. The expression of IGF 2 and its receptors was measured in order to analyse the possible correlation between the activity of these genes and cell proliferation in two different gastric tumour types: diffuse and intestinal. The effect of IGF 1 receptor blockage on cell proliferation and anchorage-independent cell growth was also examined. Increased expression of IGF 2 and IGF 1R genes (at the mRNA and protein level) was found in gastric cancer when compared with non-tumour tissue. Furthermore, there was a significant difference between IGF 2 expression in the more aggressive diffuse type and that in the intestinal type of gastric cancer. Moreover, the IGF 2 peptide level in the culture media obtained from the diffuse type of cancer cells was significantly higher when compared with the intestinal type. The level of IGF 2 peptide in the conditioned media strongly correlated with [3H]thymidine incorporation and cell proliferation. On the contrary, IGF 2R mRNA expression was much higher in the intestinal type of cancer than in the diffuse type. In addition, IGF 2R protein expression was substantially lower with progression of the diffuse cancer type to a higher stage. The alphaIR3 monoclonal antibody strongly inhibited [3H]thymidine incorporation and decreased the number of colonies in soft agar of cells overexpressing IGF 2. These findings suggest that members of the IGF family are involved in the pathogenesis of gastric cancer, probably by autocrine/paracrine stimulation of cell growth. Such tumours might be excellent candidates for therapeutic strategies aimed at interference with this pathway.

Insulin-like growth factor 2 and its receptors (IGF 1R and IGF 2R/mannose 6-phosphate) in endometrial adenocarcinoma

“…All together, ours, as well as other experiments have unequivocally shown that a decrease in the level of IGF 2 and number of IGF IR causes a reversal of the transformed phenotype [7,8,10,12,30].…”

“…Together with the fact that almost all such samples had a decreased apoptosis rate, the increased proliferation index, as well as increased telomerase activity, indicate the important role of proteins of the IGF family in the pathogenesis of endometrial adenocarcinoma. Similar finding were also shown for colon [3], lung [8], gastric [10] and gynecological cancers [19], as well as hemangiopericytomas [20]. Furthermore, all these data [26] showed that in HEC-1A endometrial adenocarcinoma cells responsive to IGF 1, the IGF BP3 is the main binding protein expressed, and both soluble and cell-associated forms act as inhibitors of IGF 1-induced cellular proliferation.…”

Value of expression of insulin-like growth factor-1 receptor in gastric adenocarcinomas and normal gastric tissues

“…Antisense approaches inhibit IGF-1R synthesis. When IGF-1R-specific antibodies are used, the relationship between IGF-1R and its ligands is impaired, and thus, IGF-I-and IGF-II-mediated signaling is blocked (22).…”

Expression of insulin-like growth factor receptor type 1 correlate with lymphatic metastases in human gastric cancer

“…IGF-1R plays a role in cell transformation and maintenance of the phenotype in modified cells [7]. Moreover, IGF-1R influences the processes of adhesion, migration, invasion and metastasis of tumor cells [8,9]. It has been shown that IGF-1R activates the mitotic divisions and inhibit apoptosis of cancer cells through the activation of signaling MAP/ERK and PI3K/Akt-1 pathways [6,10].…”