Expression and function of the insulin‐like growth factor I system in human non‐small‐cell lung cancer and normal lung cell lines

Abstract

In order to analyze the presence and the function of the "insulin-like growth factor I (IGF-I) system" in human non-small-cell lung cancer (N-SCLC) we tested 5 cell lines of different histological sub-types: A549, Ca-Lu-6, SK-Lu-1 (adenocarcinoma); Ca-Lu-1, SK-Mes-1 (squamous carcinoma) and one normal fibroblast-like fetal lung cell line (IMR-90) for expression of the IGF-I peptide and its RNA transcribed from the IGF-I gene; IGF-binding proteins (IGF-BP); IGF-I receptor (IGF-I-R) and its mRNA. In addition, we examined the capacity of exogenous human recombinant IGF-I to enhance the in vitro cell proliferation. In medium conditioned from cell cultures, we detected immunoreactive IGF-I material by radioimmunoassay. Western ligand blot and affinity labelling demonstrated the presence of several molecular species of IGF-BPs (IGF-BP-4, -1, -2, -3) as well. Northern blot analysis of polyA+ RNA from all cell lines examined revealed the presence of IGF-I and IGF-I-R mRNA. Moreover, binding studies on cultured cell lines showed one class of high-affinity, operative type-I IGF cell-surface binding sites. Finally, by thymidine uptake and colorimetric metabolic MTT assays, we found that most neoplastic cell lines react mitogenically to IGF-I and that its physiological effect is abolished by an anti-IGF-I-receptor antibody. These data indicate the importance of the IGF-I system in N-SCLC growth. Furthermore, they suggest that this mitogenic complex should be appraised as a possible target for anti-neoplastic drugs, antibodies or growth-factor analogues offering potential new approaches to therapy.

Serum Insulin‐like Growth Factors, Insulin‐like Growth Factor‐binding Protein‐3, and Risk of Lung Cancer Death: A Case‐control Study Nested in the Japan Collaborative Cohort (JACC) Study

“…This reduction in risk may partly be explained by latent lung cancer at baseline since the tumor itself produces IGF-I and may elevate blood levels. 2,3) Another explanation may be that the intraindividual variation of circulating IGF-I, though relatively small, 20,21) attenuated the association during the long follow-up. Possible residual confounding should also be considered because the analysis involving only the individually matched controls did not detect the increased risk.…”

“…1) IGF-I and IGF-II may promote the development of lung cancer by stimulating cell proliferation. In vitro studies have shown that IGF-I 2,3) and IGF-II 4) are potent mitogens for lung cancer cells. IGFBP-3, the principal blood IGFBP, binds more than 90% of the IGFs in circulation, thereby restricting the biological activity of IGFs.…”

Activation of Stat3 by receptor tyrosine kinases and cytokines regulates survival in human non-small cell carcinoma cells

“…We also studied the effect of IGF-1 on STAT activity in lung carcinoma cells given previous findings demonstrating the ability of IGF-1 to stimulate the growth of serum-deprived lung cancer cells and targeting the IGF-1 receptor can lead to tumor suppression (Ankrapp and Bevan, 1993;Favoni et al, 1994;Jiang et al, 1999). Despite the reported presence of IGF-1 receptors on the surface of A549 lung carcinoma cells, we were unable to convincingly demonstrate that addition of IGF-1 to these cells stimulated the DNA-binding activity of Stat3.…”

Modulation of the insulin-like growth factor-I system by N-(4-hydroxyphenyl)-retinamide in human breast cancer cell lines

“…Estimation of DNA synthesis after 24 h continuous exposure to 4-HPR, alone or in combination with 10 nM IGF-I, was performed following the procedures described in a previous report (Favoni et al, 1994). In brief, cells were plated in triplicate (7.5 x 104 ml-') in 35-mm-diameter Petri dishes.…”

“…Appropriate volumes of concentrated CM were resolved by sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) and blotted on nitrocellulose to quali-quantitatively characterize IGF-BPs, using the procedures previously described (Favoni et al, 1994). Binding proteins were visualized by autoradiography and their molecular weight estimated by comparison to defined low-range (18 000-106 000 Mr) prestained molecular weight markers (Bio-Rad Laboratories, Richmond, CA, USA).…”