REPORTS

Joint Effect of Insulin-Like Growth Factors and Mutagen Sensitivity in Lung Cancer Risk

Xifeng Wu, He Yu, Christopher I. Amos, Waun K. Hong, Margaret R. Spitz

Affiliations of authors: X. Wu, Department of Epidemiology, The University of Texas M. D. Anderson Cancer Center, and School of Public Health, The University of Texas Health Science Center, Houston; H. Yu, Section of Cancer Prevention and Control, Feist-Weiller Cancer Center, Louisiana State University Medical Center, Shreveport; C. I. Amos, M. R. Spitz (Department of Epidemiology), W. K. Hong (Department of Thoracic/Head and Neck Medical Oncology), The University of Texas M. D. Anderson Cancer Center.

Correspondence to: Xifeng Wu, M.D., Ph.D., Department of Epidemiology, Box 189, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030 (e-mail: xwu{at} notes.mdacc.tmc.edu).


    ABSTRACT
 Top
 Notes
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Background: We hypothesize that accumulation of genetic damage is dependent on an individual's intrinsic carcinogen sensitivity and on various humoral factors (e.g., insulin-like growth factors [IGFs]) that enhance proliferation, resistance to apoptotic cell death, and clonal outgrowth of genetically damaged cells. We tested this hypothesis by determining whether proliferation potential and genetic instability are associated with the risk of lung cancer. Methods: In a study of 183 lung cancer patients and 227 matched control subjects, we examined the joint effects of latent genetic instability (measured as mutagen sensitivity) and elevated proliferation potential (assessed by measuring IGFs) in lung cancer risk. Levels of IGF-I, IGF-II, and IGF-binding protein-3 (IGFBP-3) in plasma were measured by use of immunoassay kits. Mutagen sensitivity was assessed by quantitating bleomycin- and benzo[a]pyrene diol epoxide (BPDE)-induced chromatid breaks in peripheral blood lymphocyte cultures. Results: Although not statistically significant, the mean levels of IGF-I and the molar ratio of IGF-I/IGFBP-3 were higher in patients with advanced or poorly differentiated disease than in patients with early or well-differentiated disease. Variation in IGFs was not associated with any specific histologic type or tumor stage. High levels of IGF-I and enhanced mutagen sensitivity were individually associated with increased risk of lung cancer: odds ratio (OR) of 2.13 (95% confidence interval [CI] = 1.20–3.78) for IGF-I, 2.50 (95% CI = 1.49–4.20) for bleomycin sensitivity, and 2.95 (95% CI = 1.72–5.06) for BPDE sensitivity. The OR was statistically significantly elevated to 8.88 for both higher IGF-I and bleomycin sensitivity (95% CI = 3.67–21.50) and to 13.53 for higher IGF-I and BPDE sensitivity combined (95% CI = 4.48–40.89). With all three risk factors considered together, the OR was 17.09 (95% CI = 4.16–70.27). High levels of IGFBP-3 alone were associated with reduced lung cancer risk: OR = 0.59 (95% CI = 0.33–1.05). Conclusions: Our data suggest that individuals with genetic instability and higher proliferation potential are at enhanced risk for lung cancer.



    INTRODUCTION
 Top
 Notes
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Insulin-like growth factors (IGFs) are mitogenic peptide hormones involved in the regulation of cell proliferation and differentiation (1,2). Blocking the interaction between IGFs and their receptors can abolish IGF-stimulated proliferation of lung cancer cells (3,4). Most members of the IGF family, including IGF-I, IGF-II, IGF-I receptor, and six IGF-binding proteins (IGFBPs), are expressed in lung cancer cell lines (58). IGF-mediated activation of the IGF-I receptor stimulates the signal transduction pathway involving mitogen-activated protein (MAP) kinase and increases the expression of cyclin D1, which accelerates cell cycle progression from G1 to S phase (2,9). IGFs also suppress programmed cell death by increasing the synthesis of Bcl proteins and inhibiting that of Bax proteins (10,11). Furthermore, IGFs counter the actions of many antiproliferative molecules, such as retinoic acid. IGFBPs normally inhibit the mitogenic action of IGFs by blocking the binding of IGFs to their receptor (12). IGFBP-3 is the principal IGFBP in circulation. Two prospective studies (13,14) have shown that increased levels of IGF-I were associated with higher risks of prostate and breast cancers but that IGFBP-3 had a protective effect. We (15) recently reported that high IGF-I levels were coupled with an increased risk of lung cancer. Similarly, we (15) noted that, when IGF-I and IGFBP-3 were analyzed together, IGFBP-3 was associated with a reduced risk of lung cancer.

It has been hypothesized that the capacity to repair DNA varies within the general population (16). Mutagen sensitivity assays have been used as an indirect measure of DNA repair to estimate an individual's susceptibility to cancer (17,18). In vitro mutagens tested that reflect different DNA repair pathways are bleomycin (a radiomimetic agent) and benzo[a]pyrene diol epoxide (BPDE) (a tobacco mutagen) (19,20). We have shown that the mutagen-sensitive phenotype is associated with impaired DNA repair capacity and that individuals who are mutagen sensitive are at heightened risk for cancer (17,1929).

We hypothesize that accumulation of genetic damage is dependent on an individual's intrinsic sensitivity to carcinogens and on humoral factors, such as IGFs that enhance proliferation, resistance of damaged cells to apoptosis, and clonal outgrowth of genetically damaged populations. We propose further that there might be a synergistic effect of latent genetic instability and higher proliferation potential in lung cancer risk. To test these hypotheses, we assessed the joint effects of mutagen sensitivity and IGF levels on the risk of lung cancer in a case–control study.


    MATERIALS AND METHODS
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 Notes
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Study population. The study population was the same as in our previously published paper (15). Case patients, 183 previously untreated patients with histologically confirmed primary lung cancer, were recruited from The University of Texas M. D. Anderson Cancer Center, Houston. No age, sex, or stage restrictions were implemented in this study. Two hundred twenty-seven healthy control subjects, with no prior diagnosis of cancer, were recruited from a database composed of registrants of a multispecialty health maintenance organization in the Houston metropolitan area. The control subjects were matched to the case patients by age (within 5 years), sex, ethnicity, and smoking status. Many of the control subjects visit the clinic for their annual checkups; fewer than 5% have chronic diseases, such as diabetes.

Data collection. The study was approved by the Institutional Review Board at The University of Texas M. D. Anderson Cancer Center, and written informed consent was obtained for each participant. The epidemiologic data were assembled from personal interviews. After the interview was completed, blood was drawn into heparinized tubes to be used in cytogenetic and molecular genetic analyses.

Measurement of IGFs. Blood was centrifuged at 3000g for 10 minutes at room temperature to separate the plasma. Collected plasma was stored at -80°C. In a previous study (13) in which IGF-I and IGFBP-3 levels in stored plasma and fresh samples were compared, no difference was seen. The levels of IGF-I, IGF-II, and IGFBP-3 were determined by an enzyme-linked immunosorbent assay (DSL, Webster, TX). For the IGF-I assay, the ranges for the intra-assay and interassay precision for the coefficient of variation were 4.5%–8.6% and 3.3%–6.8%, respectively. For IGF-II, the ranges were 3.4%–6.7% and 5.9%–7.9%, respectively. For IGFBP-3, the ranges were 7.3%–9.6% and 8.2%–11.4%, respectively. The impact of freeze–thaw cycles on the levels of IGF-I, IGF-II, and IGFBP-3 was determined in 10 individual heparinized plasma specimens. We measured these compounds once per cycle through five freeze–thaw cycles and found that all of the compounds remained constant.

Mutagen sensitivity assays. Mutagen sensitivity was measured in vitro in lymphocytes by counting chromatid breaks induced by bleomycin and BPDE as previously described (17). Briefly, blood cultures were incubated for 3 days and then exposed to bleomycin (0.03 U/mL) for 5 hours. Cells were harvested, and chromatid breaks were counted in 50 metaphases per sample and recorded as the mean number of breaks per cell. We modified the procedure for the BPDE assay by substituting BPDE at 2 µM for 24 hours (19,20). Laboratory personnel read the slides without knowledge of the individual's cancer status.

Statistical analysis. Plasma levels of IGF-I, IGF-II, and IGFBP-3 as well as bleomycin sensitivity and BPDE sensitivity were analyzed as continuous and categorical variables. We report results from two-sided tests. As continuous variables, the differences between case patients and control subjects were calculated with a two-sample Student's t test for demographic variables and mutagen sensitivity and a Wilcoxon rank sum test for IGFs (which are not normally distributed). As categorical variables, high levels of IGFs and mutagen sensitivity have been associated with increased lung cancer risk. Consequently, the 75th percentile values in the control subjects of IGF-I level (>=178 ng/mL), IGF-II level (>=682 ng/mL), bleomycin sensitivity (>=0.70 breaks per cell), and BPDE sensitivity (>=0.60 breaks per cell) were used as cutoff points for risk assessment. Because low levels of IGFBP-3 were associated with increased lung cancer risk, for control subjects, the 25th percentile value of IGFBP-3 levels (<=3133 ng/mL) was selected as the cutoff point. Individuals with levels less than or equal to the control subjects' 25th percentile were coded as at risk. All cutoff points were selected before we began the stratified and logistic regression analyses. Unconditional logistic regression analysis was used to evaluate the association between lung cancer risk and the risk factors by calculating the odds ratio (OR) and its corresponding 95% confidence interval (CI). Both univariate and multivariate regression analyses were performed, including sex, age, ethnicity, smoking status, body mass index (i.e., weight in g/[height in m]2), and family history of cancer (either "yes" or "no" in first-degree relatives). Joint effects were estimated by stratified analysis in which we formed joint strata of IGFs and mutagen sensitivity risk factors (see Tables 2–4GoGoGo). The joint relationships between IGFs and mutagen sensitivity were also modeled in the logistic regression model by including an interaction term between the variables that tests a multiplicative model. The interaction terms were coded as 1 if the individuals had high levels of IGF-I and exhibited the sensitive phenotype. The interaction terms were coded as 0 for all other individuals. Because IGFBP-3 regulates the action of IGF-I and IGF-II and because plasma levels of IGFBP-3 are associated with IGF-I and IGF-II (15), we evaluated the association of IGF-I, IGF-II, and disease risk, with adjustment for IGFBP-3 levels. We also investigated the effect of the IGF-I/IGFBP-3 molar ratio.


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Table 1. Levels of insulin-like growth factors (IGFs) among control subjects and case patients with lung cancer, by stage, grade, and histology*
 

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Table 2. Joint effects of bleomycin sensitivity and insulin-like growth factor (IGF)-I, IGF-II, or IGF-binding protein-3 (IGFBP-3)
 

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Table 3. Joint effects of benzo[a]pyrene diol epoxide (BPDE) sensitivity and insulin-like growth factor (IGF)-I, IGF-II, or IGF-binding protein-3 (IGFBP-3)
 

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Table 4. Three-way joint effects of mutagen sensitivity and insulin-like growth factor (IGF)-I, IGF-II, or IGF-binding protein-3 (IGFBP-3)
 

    RESULTS
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 Notes
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 
By design, case patients and control subjects were well matched by sex, age, ethnicity, and smoking status. Both sexes were equally represented in case and control groups in this study (P = .74). Considerably more Caucasians (136 case patients and 189 control subjects) were included in the sample population compared with African-Americans (22 case patients and 18 control subjects) and Hispanic Americans (25 case patients and 20 control subjects) (P = .09). Table 1Go gives plasma levels of IGF-I, IGF-II, and IGFBP-3 in control subjects and in case patients by disease stage, grade, and histologic types. The level of IGF-I was statistically significantly higher in case patients than in control subjects. However, for IGF-II and IGFBP-3 levels, little difference was found between the case patients and control subjects (Table 1Go). Although these differences were not statistically significant, the level of IGF-I (mean [95% CI]) was higher in patients with advanced disease (185 ng/mL [95% CI = 166–204]) than in patients with early (165 ng/mL [95% CI = 141–189]) or regional (163 ng/mL [95% CI = 145–180]) disease. Similarly, patients with poorly differentiated disease (165 ng/mL [95% CI = 151–180]) exhibited higher IGF-I levels than patients with moderately (154 ng/mL [95% CI = 130–178]) or well-differentiated (136 ng/mL [95% CI = 103–169]) disease. No statistically significant differences were noted for levels of IGF-I by histologic subtype. The IGF-I/IGFBP-3 molar ratio was 0.14 (95% CI = 0.13–0.15) and 0.17 (95% CI = 0.16–0.18) for control subjects and case patients, respectively (P<.001). The IGF-I/IGFBP-3 molar ratio increased with disease stage: 0.16 (95% CI = 0.14–0.18) for early disease, 0.17 (95% CI = 0.15–0.19) for regional disease, and 0.18 (95% CI = 0.16–0.20) for distant disease. A similar trend was also observed for histologic grade.

We next calculated the ORs with logistic regression analysis (Table 1Go). Higher levels of plasma IGF-I carried a statistically significantly elevated risk for lung cancer (adjusted OR = 2.13; 95% CI = 1.20–3.78); higher IGFBP-3 plasma levels were associated with a reduced risk (adjusted OR = 0.59; 95% CI = 0.33–1.05). A higher IGF-I/IGFBP-3 molar ratio was also statistically significantly associated with increased lung cancer risk (OR = 1.79; 95% CI = 1.05–3.06).

The number of mutagen-induced breaks per cell was statistically significantly higher in case patients than in control subjects for both assays used—bleomycin sensitivity (adjusted OR = 2.50; 95% CI = 1.49–4.20) and BPDE sensitivity (adjusted OR = 2.95; 95% CI = 1.72–5.06) (data not shown).

The joint effects of bleomycin sensitivity and IGF-I, IGF-II, IGFBP-3, or IGF-I/IGFBP-3 molar ratio on the risk of lung cancer were next assessed in stratified analyses (Table 2Go). Using nonsensitive individuals with lower levels of IGF-I as the referent category, we found that a higher level of IGF-I alone was associated with an adjusted OR of 1.96 (95% CI = 1.07–3.60). The risk was also increased in individuals who were only bleomycin sensitive (adjusted OR = 2.86; 95% CI = 1.67–4.88). There was an 8.88-fold (adjusted OR = 8.88; 95% CI = 3.67–21.50) increased risk for those who were both bleomycin sensitive and had higher levels of IGF-I. We observed similar effects for bleomycin-sensitive individuals with higher levels of IGF-II (adjusted OR = 5.88; 95% CI = 2.45–14.13).

We performed similar analyses for the IGF-I/IGFBP-3 molar ratio and noted an 11.08-fold (95% CI = 4.56–26.92) increased risk for those who were both bleomycin sensitive and had a higher molar ratio. The joint effects of bleomycin sensitivity and IGF-I, IGF-II, or IGF-I/IGFBP-3 molar ratio on lung cancer risk appeared to be greater than multiplicative.

We then determined the relationships between the IGFs and mutagen sensitivity in the logistic regression model with the multiplicative model interaction term of the variables. The interaction term between the molar ratio and bleomycin sensitivity was associated with an OR of 3.10 (95% CI = 1.12–8.57), but other interaction terms were not statistically significant.

The joint effects of IGF-I and BPDE sensitivity were similar to those seen with bleomycin sensitivity (Table 3Go). The risk for individuals with the sensitive phenotype and elevated IGF-I levels (adjusted OR = 13.53; 95% CI = 4.48–40.89) was substantially higher than the risk for individuals with either a higher level of IGF-I (OR = 2.04; 95% CI = 1.04–4.01) or BPDE sensitivity (OR = 2.89; 95% CI = 1.59–5.25). Similarly, the joint effects of IGF-II and BPDE sensitivity or the IGF-I/IGFBP-3 molar ratio and BPDE sensitivity were also greater than single factors alone.

When all three variables were considered together, the joint effects of IGFs, bleomycin sensitivity, and BPDE sensitivity are clearly observed (Table 4Go). With the use of individuals who had lower levels of IGF-I and were not sensitive to either bleomycin or BPDE as a referent group, one risk factor alone (high IGF-I levels, bleomycin sensitivity, or BPDE sensitivity) increased the risk of lung cancer by 1.6-fold to 2.5-fold. Two risk factors (high IGF-I levels plus bleomycin sensitivity, high IGF-I levels plus BPDE sensitivity, or bleomycin sensitivity plus BPDE sensitivity) elevated the risk 5.3-fold to 13-fold above the reference. When all three risk factors (IGF-I, bleomycin sensitive, and BPDE sensitive) were present, the risk was 17 times higher than that of the reference group (OR = 17.09; 95% CI = 4.16–70.27). In contrast, levels of IGF-II did not change lung cancer risk. The IGF-I/IGFBP-3 molar ratio was associated with the highest risk estimates. In the presence of all three risk phenotypes, the OR was 21.10 (95% CI = 5.23–85.24).


    DISCUSSION
 Top
 Notes
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 
This study found statistically significant differences in levels of IGF-I between case patients and control subjects. Although not statistically significant, the mean levels of IGF-I were higher in patients with advanced disease or poorly differentiated disease than in patients with early or well-differentiated disease. The IGF-I/IGFBP-3 molar ratio also seemed to be a relevant indicator of the severity of the disease. Therefore, IGFs may be both a tumor marker and a susceptibility factor.

This study also demonstrated joint effects between elevated IGF-I levels (higher proliferative potential) and the mutagen sensitivity phenotype (genetic instability) in the risk of lung cancer. If all three of the risk factors (higher levels of IGF-I, bleomycin sensitivity, and BPDE sensitivity) were considered together, the estimated relative risk reached as high as 17.09-fold. On the other hand, as reported previously (15), high levels of IGFBP-3 were associated with reduced lung cancer risk (OR = 0.59; 95% CI = 0.33–1.05). Furthermore, in the regression model for lung cancer risk, there was a statistically significant multiplicative interaction between the IGF-I/IGFBP-3 molar ratio and bleomycin sensitivity.

Biologically, IGF-I and mutagen sensitivity reflect two distinct cellular activities (i.e., cell proliferation and DNA repair). Cells with uncontrolled proliferation and with impaired or inactive DNA repair will contribute to a substantial increase in the population of damaged cells. As indicated in this study, accumulation of these abnormalities seems to have a profound impact on the risk of lung cancer.

Many in vitro studies have shown that IGF-I is a potent mitogen for a variety of normal and cancerous cells and that high levels of IGF-I in circulation appear to enhance cell proliferation (30). We would expect to find an association between a systemic increase in mitogens and an elevated risk for cancer. Indeed, several epidemiologic studies found that high levels of IGF-I in circulation were associated with increased risks for lung cancer (15), breast cancer (14), prostate cancer (13), and colorectal cancer (31). However, Lee et al. (32) have recently reported serum levels of IGF-I to be lower in lung cancer patients than in control subjects. A weakness of that study is that only 40 case subjects were included and the source of the control subjects was not defined.

We have shown that IGFBP-3 has an inverse impact on the risk of lung cancer. Physiologically, IGFBP-3 binds IGFs with an affinity that is stronger than that of the specific IGF-I receptor on the cell membrane. IGF-I that is bound to IGFBP-3 cannot interact with its receptor; thus, the mitogenic and antiapoptotic actions of IGF-I are blocked. In this study, the effects of IGF-I and IGFBP-3 on lung cancer risk were consistent with their biologic functions described in cell culture and animal experiments. Experimental findings suggest that IGF-II has similar mitogenic activity on various cancer cells, but no relationship with cancer risk has been demonstrated in epidemiologic studies.

Hsu (16) hypothesized that the general population has a variety of DNA repair capacities (3338) and that latent genetic instability could be unmasked by in vitro mutagen challenge. Environmentally induced genetic damage would accumulate more quickly in people with DNA repair defects than in similarly exposed people without such defects; therefore, those with DNA repair defects might be at higher risk for cancer. A series of studies (17,2129) has indicated that mutagen sensitivity holds promise as a predictor of cancer risk. Bleomycin causes oxidative damage along with single- and double-stranded DNA breaks that require base-excision repair and recombinational DNA repair (39,40). Thus, the bleomycin assay is relevant to tobacco carcinogenesis because there are numerous compounds in cigarettes that can cause oxidative damage. BPDE is the metabolic product of benzo[a]pyrene, a tobacco carcinogen. BPDEs form covalent DNA adducts that can be repaired through the nucleotide excision pathway (41,42). We (19,20) have reported previously that there are synergistic interactions between bleomycin sensitivity and BPDE sensitivity for cancer risk.

To analyze the combined effect of IGF and mutagen sensitivity, we chose dichotomous variables for all three markers. Values at the 75th percentile distribution in the control group were used as a cutoff. Because the cutoff values were objective and a dose–response relationship with lung cancer risk was seen for all three markers in our previous studies (15,19), the selection of the cutoff should not affect the results of our study. The case patients and control subjects in the study were matched on age, sex, race, and smoking habits. The results of the analysis were not altered after these variables were adjusted. Despite lower values for the body mass index in case patients than in control subjects, the ORs did not show substantial changes when we adjusted the analysis for the body mass index. There was no statistically significant association between IGF-I levels and the body mass index. As stated previously, we also found that, although not statistically significant, the mean levels of IGF-I and the molar ratio of IGF-I/IGFBP-3 were higher in patients with advanced or poorly differentiated disease than in patients with early or well-differentiated disease. However, Mazzocolli et al. (43) observed a steady decrease in IGF-I serum levels in lung cancer patients in relation to advancing stage. Therefore, the relationship between serum levels of IGF-I and the disease progression needs further study.

Because our findings were derived from a case–control study, we cannot rule out the impact of disease status. However, findings of the cohort studies resembled those of case–control studies (31,44,45). Because the associations of IGF-I and IGFBP-3 with these cancers and lung cancer were similar, it would be reasonable to assume that IGF-I also may be elevated before the development of lung cancer.

In summary, the combination of high levels of IGF-I and mutagen sensitivity was associated with a higher risk for lung cancer than any one of the markers alone. Because IGF-I stimulates cell proliferation and mutagen sensitivity indicates impaired DNA repair, the finding that these markers have a joint impact on lung cancer risk advances our capacity to identify individuals who are at greater risk for lung cancer.


    NOTES
 
Supported by Public Health Service grants U19CA68437 (to W. K. Hong), R01CA55769 (to M. R. Spitz), and 1R01CA74880-01A2 (to X. Wu) from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services. W. K. Hong is an American Cancer Society Clinical Research Professor.


    REFERENCES
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 Notes
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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Manuscript received July 19, 1999; revised January 21, 2000; accepted February 15, 2000.


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