Insulin-like growth factor I, IGF-binding protein 3, and lung cancer risk in a prospective study of men in China

Epidemiology Branch and Laboratory of Pulmonary Pathobiology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA.
JNCI Journal of the National Cancer Institute (Impact Factor: 12.58). 06/2002; 94(10):749-54.
Source: PubMed


Insulin-like growth factor I (IGF-I) stimulates cell proliferation and inhibits apoptosis in the lung and other tissues by interacting with the IGF-I receptor. The major binding protein for IGF-I, insulin-like growth factor-binding protein 3 (IGFBP-3), modulates the effects of IGF-I but also inhibits cell growth and induces apoptosis independent of IGF-I and its receptor. In a prospective study of men in Shanghai, China, we examined the association between serum levels of IGF-I and IGFBP-3 and the subsequent risk of lung cancer.
From 1986 to 1989, serum was collected from 18,244 men aged 45-64 years living in Shanghai without a history of cancer. We analyzed IGF-I and IGFBP-3 levels in serum from 230 case patients who developed incident lung cancer during follow-up and from 740 control subjects.
Among 230 case patients and 659 matched control subjects, increased IGF-I levels were not associated with increased risk of lung cancer. However, for subjects in the highest quartile relative to the lowest quartile of IGFBP-3, the odds ratio (OR) for lung cancer, adjusted for smoking and IGF-I, was 0.50 (95% confidence interval [CI] = 0.25 to 1.02). When the analysis was restricted to ever smokers (184 case patients and 344 matched control subjects), the OR for lung cancer in men in the highest quartile of IGFBP-3 relative to those in the lowest quartile, adjusted for smoking and IGF-I, was 0.41 (95% CI = 0.18 to 0.92).
In this prospective study of Chinese men, higher serum levels of IGF-I did not increase the risk of lung cancer. However, subjects with higher serum levels of IGFBP-3 were at reduced risk of lung cancer. This finding is consistent with experimental data that indicate that IGFBP-3 can inhibit cellular proliferation and induce apoptosis independent of IGF-I and the IGF-I receptor.

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Available from: Stephanie London, Jul 15, 2015
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    • "A total of 1 798 articles were retrieved after the first search in PubMed, MedLine, Embase and ISI Web of Knowledge. As shown in Fig. 1, six nested case-control studies [15], [16], [17], [18], [19], [20](Table 1)and eight case-control studies [21], [22], [23], [24], [25], [26] (two articles contained two studies that matched our needs respectively) (Table 2) met the criteria described in the previous section. The following data were collected from each study: name of the first author, year of publication, years of follow-up, region of the studies, mean age, gender of the cases, pathological type, assey methods of IGF-1 and IGFBP-3, number of the case and control groups, mean and standard deviation (SD) of IGF-1 and IGFBP-3, odds ratio (OR) for highest vs. lowest levels and its corresponding 95% confidence interval (CI), adjusting factors as well as other details described in the articles. "
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    ABSTRACT: The insulin-like growth factor (IGF) system was documented to play a predominant role in neoplasia. As lung cancer is one of the most malignant cancers, we conducted a meta-analysis in order to investigate the strength of association between circulating IGF-1 and IGFBP-3 levels and lung cancer. A systematic literature search was conducted to identify all prospective case-control studies and case-control studies on circulating IGFs and IGFBPs levels. Six nested case-control studies (1 043 case subjects and 11 472 control participants) and eight case-control studies (401 case subjects and 343 control participants) were included in this meta-analysis. Pooled measure was calculated as the inverse variance-weighted mean of the natural logarithm of multivariate adjusted OR with 95% CIs for highest vs. lowest levels to assess the association of circulating IGF-1 and IGFBP-3 concentrations and lung cancer. Standard mean difference (SMD) was also calculated to indicate the difference of the circulating IGF-1 and IGFBP-3 concentrations between the lung cancer case group and the control group. Of the nested case-control studies, ORs for the highest vs. lowest levels of IGF-1 and IGFBP-3 were 1.047 (95% CI: [0.802,1.367], P = 0.736) and 0.960 (95%CI: [0.591,1.559], P = 0.868) respectively; and SMDs were -0.079 (95%CI:[ -0.169, 0.011], P = 0.086) and -0.097 (95%CI:[ -0.264,0.071], P = 0.258) for IGF-1 and IGFBP-3 respectively. As to the case-control studies, SMDs were 0.568 (95%CI:[ -0.035, 1.171], P = 0.065) and -0.780 (95%CI:[ -1.358, -0.201], P = 0.008) for IGF-1 and IGFBP-3 respectively. Inverse association was shown between IGFBP-3 and lung cancer in the case-control studies,and the circulating level of IGFBP-3 underwent a decline during tumorogenesis and development of lung cancer, which suggested IGFBP-3 a promising candidate for the biomarker of lung cancer.
    PLoS ONE 11/2012; 7(11):e49884. DOI:10.1371/journal.pone.0049884 · 3.23 Impact Factor
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    • "Correspondingly , overexpression of IGFBP-3 has been shown to reduce the growth of a subset of nonsmall cell lung cancer (NSCLC) cells (Lee et al., 2002). In addition, recent studies (Yu et al., 1999; London et al., 2002) have identified a negative correlation between serum IGFBP-3 levels and the risk of lung cancer (Lee et al., 2002; London et al., 2002), indicating that IGFBP-3 may have a protective role against lung cancer. "
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    ABSTRACT: Recent studies have identified a negative correlation between serum levels of insulin-like growth factor binding protein-3 (IGFBP-3) and the risk of lung cancer. In this study, polymorphisms present at the -1590 site of the IGFBP-3 promoter were evaluated in relation to lung cancer risk in a Chinese Han population. A total of 248 nonsmall cell lung cancer (NSCLC) cases and 29 small cell lung cancer cases were compared with 252 matched, healthy controls. Polymerase chain reaction-based restriction fragment length polymorphism assays were used to detect polymorphisms present. The A/A genotype and an A allele were both associated with an increased risk of NSCLC after being adjusted for age and gender (adjusted odds ratio = 2.296, 95% confidence interval = 1.133-4.655; and adjusted odds ratio = 1.390, 95% confidence interval = 1.042-1.854, respectively). In conclusion, the A/A genotype and A allele of the IGFBP-3 promoter -1590 site may represent a genetic risk factor for NSCLC, with the A/A genotype being associated with a higher risk for squamous cell carcinoma than adenocarcinoma.
    Genetic Testing and Molecular Biomarkers 05/2011; 15(5):301-6. DOI:10.1089/gtmb.2010.0176 · 1.46 Impact Factor
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    • "In lung cancer, elevated plasma levels of IGF-1 have been associated with an increased risk of the disease [9]. Conversely, high plasma levels of IGFBP3 have been associated with reduced risk [10]. High IGF-1R expression is associated with poor survival in surgically treated NSCLC patients [11]. "
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    ABSTRACT: The IGF receptor type 1 (IGF-1R) pathway is frequently deregulated in human tumors and has become a target of interest for anti-cancer therapy. We used a panel of 22 non-small cell lung cancer (NSCLC) cell lines to investigate predictive biomarkers of response to R1507, a fully-humanized anti-IGF-1R monoclonal antibody (Ab; Roche). 5 lines were moderately sensitive (25-50% growth inhibition) to R1507 alone. While levels of phospho-IGF-1R did not correlate with drug sensitivity, 4 out of 5 sensitive lines displayed high levels of total IGF-1R versus 1 out of 17 resistant lines (p = 0.003, Fisher's Exact). Sensitive lines also harbored higher copy numbers of IGF-1R as assessed by independent SNP array analysis. Addition of erlotinib or paclitaxel to R1507 led to further growth inhibition in sensitive but not resistant lines. In one EGFR mutant lung adenocarcinoma cell line (11-18), R1507 and erlotinib co-treatment induced apoptosis, whereas treatment with either drug alone induced only cell cycle arrest. Apoptosis was mediated, in part, by the survival-related AKT pathway. Additionally, immunohistochemical (IHC) staining of total IGF-1R with an anti-total IGF-1R Ab (G11;Ventana) was performed on tissue microarrays (TMAs) containing 270 independent NSCLC tumor samples. Staining intensity was scored on a scale of 0 to 3+. 39.3% of tumors showed medium to high IGF-1R IHC staining (scores of 2+ or 3+, respectively), while 16.7% had scores of 3+. In NSCLC cell lines, high levels of total IGF-1R are associated with moderate sensitivity to R1507. These results suggest a possible enrichment strategy for clinical trials with anti-IGF-1R therapy.
    PLoS ONE 10/2009; 4(10):e7273. DOI:10.1371/journal.pone.0007273 · 3.23 Impact Factor
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