Differential Impacts of Insulin-Like Growth Factor-Binding Protein-3 (IGFBP-3) in Epithelial IGF-Induced Lung Cancer Development

Abstract

The IGF axis has been implicated in the risk of various cancers. We previously reported a potential role of tissue-derived IGF in lung tumor formation and progression. However, the role of IGFbinding protein (IGFBP)-3, a major IGFBP, on the activity of tissue-driven IGF in lung cancer development is largely unknown. Here, we show that IGF-I, but not IGF-II, protein levels in non-small-cell lung cancer (NSCLC) were significantly higher than those in normal and hyperplastic bronchial epithelium. We found that IGF-I and IGFBP-3 levels in NSCLC tissue specimens were significantly correlated with phosphorylated IGF-IR (pIGF-IR) expression. We investigated the impact of IGFBP-3 expression on the activity of tissue-driven IGF-I in lung cancer development using mice carrying lung-specific human IGF-I transgene (Tg), a germline-null mutation of IGFBP-3, or both. . These data show that IGF-I is overexpressed in NSCLC, leading to activation of IGF-IR, and that IGFBP-3, depending on its expression level, either inhibits or potentiates IGF-I actions in lung carcinogenesis.

Epidermal growth factor receptor and K‐Ras mutations and resistance of lung cancer to insulin‐like growth factor 1 receptor tyrosine kinase inhibitors

“…Demographic information for those patients was described previously. 16 Formalin-fixed, paraffin-embedded primary NSCLC sections (5 lm thick) were placed in a tissue microarray (TMA). Immunohistochemical (IHC) evaluation of the NSCLC TMA was performed as previously described.…”

“…Immunohistochemical (IHC) evaluation of the NSCLC TMA was performed as previously described. 16 Anti-pIGF-1R (Tyr 1135/1136)/IR (Tyr1162/1163) antibody (Biosource, Camarillo, Calif; diluted 1:200) or anti-pEGFR (Tyr1068) antibody (Zymed Laboratories, San Francisco, Calif; diluted 1:100) was used for staining. Immunostaining for IGF-1R, and pIGF-1R/IR (membrane) was quantified by a lung cancer pathologist who used a 4-value intensity score (0, 1þ, 2þ, and 3þ), and the extent of reactivity was expressed as a percentage.…”

IGFBP3 Modulates Lung Tumorigenesis and Cell Growth through IGF1 Signaling

“…No cases of IGFBP3 gene deletion in humans have been reported, but hypermethylation of the IGFBP3 promoter is involved in loss of IGFBP3 expression in NSCLC, and may be related to the development of acquired treatment resistance (16)(17)(18)(19). Although a prior report has shown that heterozygously deleted Igfbp3 transgenic mice with mutant IGF1 expression have higher lung tumorigenesis, there was no increased tumorigenesis in homozygously deleted Igfbp3 mice compared with wild-type Igfbp3 control, which was unexplained (20). Our previous data from lung cancer cell lines suggested that lung cancer cells express significantly lower levels of IGFBP3 when they develop resistance to cisplatin and radiation (21).…”

Prediction of Survival in Resected Non–Small Cell Lung Cancer Using a Protein Expression–Based Risk Model: Implications for Personalized Chemoprevention and Therapy

“…These markers have been investigated using in vitro and in vivo early carcinogenesis models, and were found to be key to the pathogenesis of NSCLC, both adenocarcinoma and squamous cell carcinoma. The markers chosen relate to cell adhesion and extracellular matrix interactions (CASK, CD51 (8), EpCAM (9), SPP1 (10)), inflammation (CXCR2 (11)), growth factors and effector pathways (IGF-1R(12), IGFBP3 (13), insulin receptor (14), pIGF-1R, pEGFR (15, 16)), growth and metabolism (pAkt (17, 18), pSrc (19), pmTor (18), pAMPK (20), pS6 (17), SFN (21), UBE2C), and DNA replication and repair (FEN1, MCM2, MCM6, TPX2 (21, 22)). We then aimed to investigate these biomarkers in early stage lung cancer and to gain a better understanding of the cellular and molecular processes that drive lung carcinogenesis.…”