© 1999 by Oxford University Press
Journal of the National Cancer Institute, Vol. 91, No. 2, 151-156,
January 20, 1999
© 1999 Oxford University Press
Plasma Levels of Insulin-Like Growth Factor-I and Lung Cancer Risk: a Case-Control Analysis
Affiliations of authors: H. Yu, Section of Cancer Prevention and Control, Feist-Weiller Cancer Center, Louisiana State University Medical Center, Shreveport; M. R. Spitz, J. Gu, X. Wu (Department of Epidemiology), W. K. Hong (Department of Thoracic/Head and Neck Medical Oncology), The University of Texas M. D. Anderson Cancer Center, Houston; J. Mistry, Diagnostic Systems Laboratory, Inc. Webster, TX.
Correspondence to: Xifeng Wu, M.D. Ph.D., Department of Epidemiology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030.
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ABSTRACT |
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BACKGROUND: Insulin-like growth factors (IGFs), in particular IGF-I and IGF-II, strongly stimulate the proliferation of a variety of cancer cells, including those from lung cancer. To examine the possible causal role of IGFs in lung cancer development, we compared plasma levels of IGF-I, IGF-II, and an IGF-binding protein (IGFBP-3) in patients with newly diagnosed lung cancer and in control subjects. METHODS: From an ongoing hospital-based, case-control study, we selected 204 consecutive patients with histologically confirmed, primary lung cancer and 218 control subjects who were matched to the case patients by age, sex, race, and smoking status. IGF-I, IGF-II, and IGFBP-3 plasma levels were measured by enzyme-linked immunosorbent assay and then divided into quartiles, based on their distribution in the control subjects. Associations between the IGF variables and lung cancer risk were estimated by use of odds ratios (ORs). Reported P values are two-sided. RESULTS: IGF and IGFBP-3 levels were positively correlated (all r>.27; all P<.001). High plasma levels of IGF-I were associated with an increased risk of lung cancer (OR = 2.06; 95% confidence interval [CI] = 1.19-3.56; P = .01), and this association was dose dependent in both univariate and multivariate analyses. Plasma IGFBP-3 showed no association with lung cancer risk unless adjusted for IGF-I level; when both of these variables were analyzed together, high plasma levels of IGFBP-3 were associated with reduced risk of lung cancer (OR = 0.48; 95% CI = 0.25-0.92; P = .03). IGF-II was not associated with lung cancer risk. CONCLUSIONS: Plasma levels of IGF-I are higher and plasma levels of IGFBP-3 are lower in patients with lung cancer than in control subjects. If these findings can be confirmed in prospective studies, measuring levels of IGF-I and IGFBP-3 in blood may prove useful in assessing lung cancer risk.
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INTRODUCTION |
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Cancer cells exhibit numerous abnormal cellular activities—involving cell differentiation, transformation, proliferation, and apoptosis—that are maintained and controlled by a large number of peptide growth factors. Among the growth factors, insulin-like growth factors (IGFs) play a crucial role in regulating cell proliferation and differentiation. IGFs including IGF-I and IGF-II are peptide hormones with strong mitogenic effects on both normal and cancerous cells, including lung cancer cells (1,2). In addition to stimulating cell proliferation, IGFs also suppress cellular apoptotic pathways to facilitate cell growth (3,4). The actions of IGFs on cell proliferation and apoptosis are mediated via a specific cell-membrane receptor, insulin-like growth factor-I receptor (IGF-IR), which has been shown to be involved in cell transformation (5) and which contains tyrosine kinase activity. Binding of IGFs to this receptor activates the tyrosine kinase and initiates ras- and PI3 kinase-related signal transduction pathways (6).
The interaction between IGFs and IGF-IR is regulated by the IGF-binding proteins (IGFBPs). Six IGFBPs (IGFBP-1 to IGFBP-6) with high affinity for IGFs have been identified and characterized (2). The binding proteins normally inhibit the action of IGFs by blocking the binding of IGFs to their receptor; however, under certain circumstances, they can enhance IGF action by protecting IGFs from degradation (7-9). The dual regulatory effects of the IGFBPs are further modulated by many factors including the IGFBP proteases, which include prostate-specific antigen (PSA) and cathepsin D (2,10,11). Cell culture studies indicate that the antiproliferative effects of retinoic acid (a metabolite of vitamin A) and of wild-type p53 protein are mediated through increased expression of IGFBP-3, which in turn inhibits the mitogenic effect of IGFs on cell proliferation (12-15).
Cell culture experiments (16-19) have demonstrated that most lung cancer cell lines (small-cell and non-small-cell) are able to express IGFs and their binding proteins. Although IGFs are known to be potent mitogens for lung cancer cells and are present in lung tissue, evidence that IGFs can influence the development of lung cancer remains unknown. To examine the hypothesis that IGFs and their major binding protein in plasma play a causal role in lung cancer, we compared plasma levels of IGF-I, IGF-II, and IGFBP-3 in patients with newly diagnosed lung cancers and in age-, sex-, race-, and smoking status-matched control subjects.
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MATERIALS AND METHODS |
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Study Population
The patients and control subjects were selected consecutively from an ongoing case-control study of lung cancer conducted in the Department of Epidemiology at The University of Texas M. D. Anderson Cancer Center. The study subjects were described in detail elsewhere (20). Briefly, the case subjects were consecutive patients with lung cancer registered in the Departments of Thoracic Surgery and Thoracic Medical Oncology at The University of Texas M. D. Anderson Cancer Center. These patients were newly diagnosed with histologically confirmed primary lung cancer. However, histologic rereview is not completed. They had been referred for diagnosis or definitive treatment and had received no previous radiotherapy or chemotherapy. After the patients were informed about the study and agreed to sign an informed consent form for participation, an in-person interview with the use of a structured questionnaire was scheduled.
The control subjects were identified from a control-pool database established from registrants of a large, private, multispecialty health care provider, Kelsey-Seybold Clinic, which involves a health maintenance organization, managed care, and fee-for-service patients in the Houston metropolitan area. There are more than 40 000 individuals enrolled in our potential control database. Control subjects were frequency matched to the case patients by sex, age (within 5 years), and ethnicity (white, black, or Hispanic), with a 1 : 1 ratio. Each randomly selected control subject was contacted by telephone to confirm his or her willingness to participate, and an appointment was scheduled at a Kelsey-Seybold Clinic site convenient to the participant. If the person refused to participate or was deemed ineligible, another potential control subject was selected. Since the study is ongoing and control subject selection is not conducted concurrently with case patient accrual, perfect 1 : 1 matching has not yet been achieved. Furthermore, some subjects did not have sufficient plasma specimens available for the study. Therefore, there are some discrepancies among the matching variables between case patients and control subjects. We adjusted these differences in our data analysis. There are no differences in consent rates between case patients and control subjects. The study was approved by the Institutional Review Boards at The University of Texas M. D. Anderson Cancer Center and the Kelsey-Seybold Foundation.
Specimen Collection
After the interview, 10-mL blood specimens were drawn from each participant through venipuncture. The blood was collected in a heparinized tube and transported immediately to the laboratory, where the specimens were separated and processed. The plasma was collected after centrifugation of the blood at 1500 rpm for 10 minutes at room temperature and was stored at -80 °C. To assess the degradation of IGF-I and IGFBP-3 in stored plasma, a previous study compared levels of IGF-I and IGFBP-3 in stored heparinized plasma and in fresh specimens. No difference was found between the two types of specimen (21).
Measurements of IGFs and IGFBP-3
Three commercially available immunoassay kits (DSL, Webster, TX) were used in the study to determine the plasma levels of IGF-I, IGF-II, and IGFBP-3 through enzyme-linked immunosorbent assay. Cross-reaction of the antibodies with other members of the IGF family is not detected at physiologic concentrations, according to the manufacturer. The intra-assay and inter-assay precision is between 4.5%-8.6% and 3.3%-6.8% of the coefficient of variation, respectively, for the IGF-I assay; between 3.4%-6.7% and 5.9%-7.9% for the IGF-II assay; and between 7.3%-9.6% and 8.2%-11.4% for the IGFBP-3 assay.
The assays were performed following the instructions of the manufacturer (DSL) and without knowledge of case-control status. To separate IGFs from their binding proteins, we mixed plasma specimens with acid-ethanol extraction buffer before measurement. The extraction procedure has been evaluated, and the efficiency of the extraction was identical to that for acid-column chromatography. For IGFBP-3, the specimens were diluted 100-fold in an assay buffer before the test. To assess the impact of freeze-thaw cycles on the values of IGF-I, IGF-II, and IGFBP-3 in heparinized plasma, we measured each of 10 plasma specimens once per freeze-thaw cycle for five cycles. Levels of IGF-I, IGF-II, and IGFBP-3 in plasma remained constant over these freeze-thaw cycles.
Statistical Analysis
The correlations among the three growth factors were examined by use
of the Spearman correlation coefficient. The distributions of the
studied variables between the case patients and control subjects were
compared by use of the 
2 test for categorical data and
the two-sample Student's t test for numerical data. All
P values were two-sided. Associations were considered
statistically significant at P<.05. Since the distributions
of IGF-I and IGFBP-3 in the population were positively skewed, the
levels of IGFs and IGFBP-3 were analyzed categorically on the basis of
their quartile distribution in the control group (Table
1).
To assess the strength of the association
between lung cancer risk and the growth factors, we calculated the odds
ratio (OR) and its 95% confidence interval (CI) with the use of
unconditional logistic regression analysis (22). The logistic
regression model was developed as both univariate and multivariate
models. In the multivariate analysis, the following variables were
included in the model: sex, age, ethnicity (white, black, or Hispanic),
cigarette smoking status (never, former, or current), body mass
index (BMI = kg of body weight/m2 of height), and family
history of any cancer (yes or no in their first-degree relatives). The
interactions between IGF-I and IGF-II and between IGFs and IGFBP-3 were
also examined in the logistic regression model by use of the product of
the two given variables.
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RESULTS |
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As expected, plasma IGF-I and IGF-II levels were correlated (r = .27; P<.001), and both IGFs were even more closely correlated with IGFBP-3 (r = 0.51 and P<.001 for IGF-I; r = .63 and P<.001 for IGF-II). The mean and quartile values of IGF-I, IGF-II, and IGFBP-3 in the 204 patients and 218 control subjects are shown in Table 1
. The
mean and median levels of IGF-I were 16% and 11% higher,
respectively, in case patients than in control subjects; however, for
IGF-II and IGFBP-3, there was little difference in the means or medians
between the case patients and control subjects.
Table 2 summarizes the categorical distributions of
the three IGF variables together with other variables measured in the
two study populations. Because the control subjects were selected to
match the patients on sex, age, race, and cigarette smoking status, no
statistically significant differences were observed between the two groups for
these variables. The BMI was slightly higher in the control subjects than in
the patients, and the difference was statistically significant (P =
.03). Patients in the highest fourth quartile of IGF-I level made up 36.3%
of the total, compared with 24.8% of control subjects (P = .04).
For IGF-II and IGFBP-3, there were no differences between patients and control
subjects in the quartile distributions.
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In our logistic regression analysis, the risk of lung cancer was positively associated with the level of IGF-I in plasma, and the trend was statistically significant (P = .01) (Table 3).
The OR was 2.06 (95% CI = 1.19-3.56) for the
highest quartile of IGF-I compared with the lowest (P = .01)
(Table 3). This pattern persisted when other variables including age,
sex, race, cigarette smoking status, BMI, and family history of any
cancer were adjusted in the regression model (Table
4). Because IGFBP-3 regulates the action of IGF-I and
because plasma levels of IGFBP-3 and IGF-I are correlated, we also
evaluated the association between IGF-I and the disease risk while we
adjusted for IGFBP-3 levels. With inclusion of IGFBP-3 in the logistic
model, we observed a more substantial increase in the risk of lung
cancer associated with IGF-I. The ORs were 2.75 (95% CI =
1.37-5.53) for the fourth quartile and 1.96 (95% CI = 1.02-3.80)
for the third quartile compared with the first (lowest) quartile, and
both ORs were statistically significant (P = .004 and
P = .04, respectively). However, the interaction term between
IGF-I and IGFBP-3 was not significant in the logistic model (data not shown).
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Adjusting IGFBP-3 in the model not only enhanced the strength of the association between IGF-I and lung cancer but also demonstrated a potential protective effect of this binding protein. IGFBP-3 levels in plasma did not appear to be associated with risk of lung cancer when this variable was analyzed either in the contingency table (Table 2
) or
in the logistic regression with the univariate model (Table 3) or the
multivariate model without including IGF-I (Table 4). When IGF-I was
included in the logistic model, the results suggested that the risk of
lung cancer could be reduced by more than 50% for those individuals
with the highest quartile of IGFBP-3 levels as compared with those with
the lowest quartile (OR = 0.48; 95% CI = 0.25-0.92; P =
.03). However, there was no clear dose-response relationship for IGFBP-3.
The distribution of the case patients and control subjects within the
four categories of IGF-II did not differ (P = .75, Table 2).
In the logistic regression analysis, the risk of lung cancer was
modestly elevated in the highest quartile compared with the lowest
quartile of IGF-II, but the difference was not statistically
significant (OR = 1.33; 95% CI = 0.77-2.31; P = .31,
Table 3). When we adjusted for IGF-I and IGFBP-3 and their interactions
in the model, we found no significant association between IGF-II and
disease risk (data not shown).
There was no association between cigarette smoking status (never, former, or current smoker) and levels of IGFs and IGFBP-3 among the control subjects (data not shown). We also examined pack-years of smoking, duration of smoking, and the total number of cigarettes smoked in relation to plasma levels of IGF-I, IGF-II, and IGFBP-3. None of the correlations analyzed were shown to be significant (data not shown), suggesting that levels of IGFs and IGFBP-3 in plasma were not influenced by cigarette smoking.
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DISCUSSION |
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In this case-control study, we found that higher plasma levels of IGF-I were associated with an increased risk of lung cancer and that the association remained statistically significant when we adjusted for the variables of age, sex, race, cigarette smoking status, BMI, and family history of any cancer in the analysis. In addition, the study demonstrated a dose-response relationship between the risk of lung cancer and levels of IGF-I. The association became stronger when we adjusted for IGFBP-3 in the analysis. The study also indicated that IGFBP-3 was associated with a reduced risk of the disease, but this effect was seen only when we adjusted for IGF-I in the analysis. In the univariate analysis, IGFBP-3 did not show any statistically significant association with the risk of lung cancer. Despite its close correlation with IGF-I and IGFBP-3 in plasma, IGF-II was not associated with risk when analyzed individually or after adjustment was made for IGF-I, IGFBP-3, or other variables.
Recently, two prospective studies reported higher plasma levels of IGF-I in association with increased risks of prostate cancer in men (21) and of breast cancer in premenopausal women (23). We were impressed with the striking similarities between these studies and our own, although three different types of cancers were investigated and our study was a retrospective analysis. There was a substantial association between IGF-I levels in plasma and risks of all three cancers. All three studies consistently showed a strong, dose-response relationship between increased risks of these cancers and elevated levels of IGF-I. The effect of IGF-I tended to be more significant when adjustment was made for levels of IGFBP-3 in the analyses. For prostate and lung cancers, IGFBP-3 also showed some protective effects; however, by itself, IGFBP-3 did not demonstrate such an effect. Also, for both prostate and lung cancers, no association was found for IGF-II.
The consistency of the findings for IGF-I prompts us to speculate that IGF-I either may have a carcinogenic effect or may be a powerful growth promoter and that circulating IGF-I levels may serve as a biomarker for assessing lung cancer risk. It may also be possible that an increased plasma IGF-I level is part of the phenotype of certain types of cancer that require IGF-I to maintain their high rate of proliferation and growth. Results from cell culture studies and animal experiments have suggested that IGF-I is a potent mitogen for a variety of cancer cells, including breast, prostate, lung, colon, and liver cells (1,24-26). IGF-I increases DNA synthesis and up-regulates the expression of cyclin D1, thereby accelerating the cell cycle from G1 to S phase (27). While stimulating cell proliferation, IGF-I also shuts down the apoptotic pathway (3,4). Because the actions of IGF-I are mediated through the IGF-IR, removing the receptor from the cell membrane could abolish its mitogenic and apoptotic effects (2,28,29). In addition, IGF-IR is involved in cell transformation, and interruption of IGF-IR expression on the cell membrane blocks cell transformation induced by a tumor virus or an oncogene product (28).
The interaction between IGF-I and IGF-IR is regulated by the IGFBPs. In the univariate analysis, of two of the studies cited above, this protein failed to show any association with the risk of prostate or lung cancer. However, when analyzed together with IGF-I, IGFBP-3 appeared to be associated with a reduced risk of both prostate and lung cancers, but the binding protein also appeared to enhance the associations between risk of these cancers and plasma IGF-I level. These observations in epidemiologic studies are compatible with the results from in vitro and in vivo studies, demonstrating that IGFBP-3 suppresses the mitogenic and apoptotic effects of IGF-I on cancer cells. This suppression is explained by the fact that IGFBP-3 prevents the interaction between IGF-I and IGF-IR because of IGF-I's higher binding affinity for the binding protein than for the receptor. Recent experiments (30) also suggest that IGFBP-3 may inhibit cell growth independently of IGF-I.
The relationship between IGF-I and IGFBP-3 in lung cancer may shed light on the action of two antiproliferative molecules whose effects have been studied in lung cancer, retinoic acid and p53. Mutation of the p53 tumor suppressor gene (also known as TP53) has been linked to the development of many cancers, including lung cancer (31). One of the main functions of the p53 protein is to slow down cell division—which allows cells to repair DNA damage or to initiate apoptosis if the damage is irreversible. The suppression of cell division by p53 is speculated to be mediated through IGFBP-3, because wild-type p53 protein is shown to increase IGFBP-3 expression. IGFBP-3 subsequently suppresses the mitogenic effect of IGF-I, which results in the inhibition of cell proliferation (13). The possible link between IGF-I and p53 is further supported by an observation that the function of p53 protein is suppressed by IGF-I. As a transcription factor, p53 protein must be intranuclear to exert its action. When cells undergo division induced by IGF-I, p53 protein is expelled from the nucleus (32). In addition, p53 protein down-regulates the expression of IGF-IR (15). The growth of bladder tumors induced by p-cresidine in p53-deficient transgenic mice was suppressed by decreasing serum levels of IGF-I through diet restriction, and restoring IGF-I levels in serum resulted in resumption of tumor growth and progression (33). This study also indicated that tumor growth control by IGF-I was related to IGF-I's mitogenic and anti-apoptotic effects.
Cell culture studies (12,14,34) have found that retinoic acid stimulated the production of IGFBP-3, which in turn inhibited the action of IGF-I. Findings from our study support such a relationship between IGF-I and IGFBP-3 and, furthermore, indicate that monitoring changes in IGFBP-3 and IGF-I levels in the blood may help to evaluate the effectiveness of vitamin supplements as chemopreventive agents.
In our study, the BMI was lower in the case subjects than in the control subjects, and the difference was statistically significant (P = .03). However, this difference should not have any impact on the association between IGF-I and lung cancer risk, because the ORs did not show substantial changes when we adjusted for BMI in the analysis. Furthermore, no correlation between IGF-I and BMI has been observed in previous studies (19,35,36). Because this is a case-control study, findings from our study need to be further confirmed by prospective cohort studies. Nevertheless, similarities between our study and two cohort studies on different cancer sites lend support to our speculation that IGF-I may be involved in the disease's development. If our observations can be confirmed in prospective studies, the measurement of plasma levels of IGF-I and IGFBP-3 will have potential utility in assessing lung cancer risk and/or in monitoring the effectiveness of chemoprevention interventions.
Supported by Public Health Service grants U19CA68437 (to W. K. Hong), R01CA55769 (to M. R. Spitz), and 1R03CA70191 (to X. Wu) from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services. Dr. Hong is an American Cancer Society Clinical Research Professor.
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Manuscript received May 29, 1998; revised November 4, 1998; accepted November 17, 1998.
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 L. J. Vatten, J. M. Holly, D. Gunnell, and S. Tretli Nested Case-Control Study of the Association of Circulating Levels of Serum Insulin-like Growth Factor I and Insulin-like Growth Factor Binding Protein 3 with Breast Cancer in Young Women in Norway Cancer Epidemiol. Biomarkers Prev., August 1, 2008; 17(8): 2097 - 2100. [Abstract] [Full Text] [PDF]
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A. Schaffer, A. Koushik, H. Trottier, E. Duarte-Franco, N. Mansour, J. Arseneau, D. Provencher, L. Gilbert, W. Gotlieb, A. Ferenczy, et al. Insulin-like Growth Factor-I and Risk of High-Grade Cervical Intraepithelial Neoplasia Cancer Epidemiol. Biomarkers Prev., April 1, 2007; 16(4): 716 - 722. [Abstract] [Full Text] [PDF]
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S. Lonn, P. D. Inskip, M. N. Pollak, S. J. Weinstein, J. Virtamo, and D. Albanes Glioma Risk in Relation to Serum Levels of Insulin-Like Growth Factors Cancer Epidemiol. Biomarkers Prev., April 1, 2007; 16(4): 844 - 846. [Abstract] [Full Text] [PDF]
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A. A. Samani, S. Yakar, D. LeRoith, and P. Brodt The Role of the IGF System in Cancer Growth and Metastasis: Overview and Recent Insights Endocr. Rev., February 1, 2007; 28(1): 20 - 47. [Abstract] [Full Text] [PDF]
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S. M. Park, M. K. Lim, S. A. Shin, and Y. H. Yun Impact of Prediagnosis Smoking, Alcohol, Obesity, and Insulin Resistance on Survival in Male Cancer Patients: National Health Insurance Corporation Study J. Clin. Oncol., November 1, 2006; 24(31): 5017 - 5024. [Abstract] [Full Text] [PDF]
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S.-H. Oh, O.-H. Lee, C. P. Schroeder, Y. W. Oh, S. Ke, H.-J. Cha, R.-W. Park, A. Onn, R. S. Herbst, C. Li, et al. Antimetastatic activity of insulin-like growth factor binding protein-3 in lung cancer is mediated by insulin-like growth factor-independent urokinase-type plasminogen activator inhibition. Mol. Cancer Ther., November 1, 2006; 5(11): 2685 - 2695. [Abstract] [Full Text] [PDF]
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J. Ahn, S. J. Weinstein, K. Snyder, M. N. Pollak, J. Virtamo, and D. Albanes No Association between Serum Insulin-Like Growth Factor (IGF)-I, IGF-Binding Protein-3, and Lung Cancer Risk. Cancer Epidemiol. Biomarkers Prev., October 1, 2006; 15(10): 2010 - 2012. [Full Text] [PDF]
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 L. Liao, R. K. Dearth, S. Zhou, O. L. Britton, A. V. Lee, and J. Xu Liver-Specific Overexpression of the Insulin-like Growth Factor-I Enhances Somatic Growth and Partially Prevents the Effects of Growth Hormone Deficiency Endocrinology, August 1, 2006; 147(8): 3877 - 3888. [Abstract] [Full Text] [PDF]
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 M. F. Rudd, E. L. Webb, A. Matakidou, G. S. Sellick, R. D. Williams, H. Bridle, T. Eisen, R. S. Houlston, and the GELCAPS Consortium Variants in the GH-IGF axis confer susceptibilityto lung cancer. Genome Res., June 1, 2006; 16(6): 693 - 701. [Abstract] [Full Text] [PDF]
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 P. M. Mah, J. Webster, P. Jonsson, U. Feldt-Rasmussen, M. Koltowska-Haggstrom, and R. J. M. Ross Estrogen Replacement in Women of Fertile Years with Hypopituitarism J. Clin. Endocrinol. Metab., November 1, 2005; 90(11): 5964 - 5969. [Abstract] [Full Text] [PDF]
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H.-Y. Lee, Y. S. Chang, J.-Y. Han, D. D. Liu, J. J. Lee, R. Lotan, M. R. Spitz, and W. K. Hong Effects of 9-cis-Retinoic Acid on the Insulin-Like Growth Factor Axis in Former Smokers J. Clin. Oncol., July 1, 2005; 23(19): 4439 - 4449. [Abstract] [Full Text] [PDF]
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L. M. Morimoto, P. A. Newcomb, E. White, J. Bigler, and J. D. Potter Variation in Plasma Insulin-Like Growth Factor-1 and Insulin-Like Growth Factor Binding Protein-3: Genetic Factors Cancer Epidemiol. Biomarkers Prev., June 1, 2005; 14(6): 1394 - 1401. [Abstract] [Full Text] [PDF]
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 K.-W. Lee, L. Ma, X. Yan, B. Liu, X.-k. Zhang, and P. Cohen Rapid Apoptosis Induction by IGFBP-3 Involves an Insulin-like Growth Factor-independent Nucleomitochondrial Translocation of RXR{alpha}/Nur77 J. Biol. Chem., April 29, 2005; 280(17): 16942 - 16948. [Abstract] [Full Text] [PDF]
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G. S. Warshamana-Greene, J. Litz, E. Buchdunger, C. Garcia-Echeverria, F. Hofmann, and G. W. Krystal The Insulin-Like Growth Factor-I Receptor Kinase Inhibitor, NVP-ADW742, Sensitizes Small Cell Lung Cancer Cell Lines to the Effects of Chemotherapy Clin. Cancer Res., February 15, 2005; 11(4): 1563 - 1571. [Abstract] [Full Text] [PDF]
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M. Ishikawa, J. Kitayama, S. Kazama, T. Hiramatsu, K. Hatano, and H. Nagawa Plasma Adiponectin and Gastric Cancer Clin. Cancer Res., January 15, 2005; 11(2): 466 - 472. [Abstract] [Full Text] [PDF]
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D. W. Voskuil, A. Vrieling, L. J. van't Veer, E. Kampman, and M. A. Rookus The Insulin-like Growth Factor System in Cancer Prevention: Potential of Dietary Intervention Strategies Cancer Epidemiol. Biomarkers Prev., January 1, 2005; 14(1): 195 - 203. [Abstract] [Full Text] [PDF]
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S. M. Gapstur, P. Kopp, B. C-H. Chiu, P. H. Gann, L. A. Colangelo, and K. Liu Longitudinal Associations of Age, Anthropometric and Lifestyle Factors with Serum Total Insulin-Like Growth Factor-I and IGF Binding Protein-3 Levels in Black and White Men: the CARDIA Male Hormone Study Cancer Epidemiol. Biomarkers Prev., December 1, 2004; 13(12): 2208 - 2216. [Abstract] [Full Text] [PDF]
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 H.-Y. Lee, H. Moon, K.-H. Chun, Y.-S. Chang, K. Hassan, L. Ji, R. Lotan, F. R. Khuri, and W. K. Hong Effects of Insulin-like Growth Factor Binding Protein-3 and Farnesyltransferase Inhibitor SCH66336 on Akt Expression and Apoptosis in Non-Small-Cell Lung Cancer Cells J Natl Cancer Inst, October 20, 2004; 96(20): 1536 - 1548. [Abstract] [Full Text] [PDF]
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 M. Pold, K. Krysan, A. Pold, M. Dohadwala, N. Heuze-Vourc'h, J. T. Mao, K. L. Riedl, S. Sharma, and S. M. Dubinett Cyclooxygenase-2 Modulates the Insulin-Like Growth Factor Axis in Non-Small-Cell Lung Cancer Cancer Res., September 15, 2004; 64(18): 6549 - 6555. [Abstract] [Full Text] [PDF]
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 S. D. Hursting, J. A. Lavigne, D. Berrigan, L. A. Donehower, B. J. Davis, J. M. Phang, J. C. Barrett, and S. N. Perkins Diet-Gene Interactions in p53-Deficient Mice: Insulin-like Growth Factor-1 as a Mechanistic Target J. Nutr., September 1, 2004; 134(9): 2482S - 2486S. [Abstract] [Full Text] [PDF]
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 A. C. Baege, G. L. Disbrow, and R. Schlegel IGFBP-3, a Marker of Cellular Senescence, Is Overexpressed in Human Papillomavirus-Immortalized Cervical Cells and Enhances IGF-1-Induced Mitogenesis J. Virol., June 1, 2004; 78(11): 5720 - 5727. [Abstract] [Full Text] [PDF]
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J. C. Oh, W. Wu, G. Tortolero-Luna, R. Broaddus, D. M. Gershenson, T. W. Burke, R. Schmandt, and K. H. Lu Increased Plasma Levels of Insulin-Like Growth Factor 2 and Insulin-Like Growth Factor Binding Protein 3 Are Associated with Endometrial Cancer Risk Cancer Epidemiol. Biomarkers Prev., May 1, 2004; 13(5): 748 - 752. [Abstract] [Full Text] [PDF]
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G. S. Warshamana-Greene, J. Litz, E. Buchdunger, F. Hofmann, C. Garcia-Echeverria, and G. W. Krystal The insulin-like growth factor-I (IGF-I) receptor kinase inhibitor NVP-ADW742, in combination with STI571, delineates a spectrum of dependence of small cell lung cancer on IGF-I and stem cell factor signaling Mol. Cancer Ther., May 1, 2004; 3(5): 527 - 536. [Abstract] [Full Text] [PDF]
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A. Colao, D. Ferone, P. Marzullo, and G. Lombardi Systemic Complications of Acromegaly: Epidemiology, Pathogenesis, and Management Endocr. Rev., February 1, 2004; 25(1): 102 - 152. [Abstract] [Full Text] [PDF]
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S.'i. Miyamoto, K. Yano, S. Sugimoto, G. Ishii, T. Hasebe, Y. Endoh, K. Kodama, M. Goya, T. Chiba, and A. Ochiai Matrix Metalloproteinase-7 Facilitates Insulin-Like Growth Factor Bioavailability through Its Proteinase Activity on Insulin-Like Growth Factor Binding Protein 3 Cancer Res., January 15, 2004; 64(2): 665 - 671. [Abstract] [Full Text] [PDF]
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Z. Szereday, A. V. Schally, J. L. Varga, C. A. Kanashiro, F. Hebert, P. Armatis, K. Groot, K. Szepeshazi, G. Halmos, and R. Busto Antagonists of Growth Hormone-Releasing Hormone Inhibit the Proliferation of Experimental Non-Small Cell Lung Carcinoma Cancer Res., November 15, 2003; 63(22): 7913 - 7919. [Abstract] [Full Text] [PDF]
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A. Skalkidou, E. Petridou, E. Papathoma, H. Salvanos, S. Kedikoglou, G. Chrousos, and D. Trichopoulos Determinants and Consequences of Major Insulin-like Growth Factor Components among Full-Term Healthy Neonates Cancer Epidemiol. Biomarkers Prev., September 1, 2003; 12(9): 860 - 865. [Abstract] [Full Text] [PDF]
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E. K. Maloney, J. L. McLaughlin, N. E. Dagdigian, L. M. Garrett, K. M. Connors, X.-M. Zhou, W. A. Blattler, T. Chittenden, and R. Singh An Anti-Insulin-like Growth Factor I Receptor Antibody That Is a Potent Inhibitor of Cancer Cell Proliferation Cancer Res., August 15, 2003; 63(16): 5073 - 5083. [Abstract] [Full Text] [PDF]
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Y. Wu, K. Cui, K. Miyoshi, L. Hennighausen, J. E. Green, J. Setser, D. LeRoith, and S. Yakar Reduced Circulating Insulin-like Growth Factor I Levels Delay the Onset of Chemically and Genetically Induced Mammary Tumors Cancer Res., August 1, 2003; 63(15): 4384 - 4388. [Abstract] [Full Text] [PDF]
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X. Wu, G. Tortolero-Luna, H. Zhao, D. Phatak, M. R. Spitz, and M. Follen Serum Levels of Insulin-like Growth Factor I and Risk of Squamous Intraepithelial Lesions of the Cervix Clin. Cancer Res., August 1, 2003; 9(9): 3356 - 3361. [Abstract] [Full Text] [PDF]
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L. A. Wetterau, M. J. Francis, L. Ma, and P. Cohen Insulin-Like Growth Factor I Stimulates Telomerase Activity in Prostate Cancer Cells J. Clin. Endocrinol. Metab., July 1, 2003; 88(7): 3354 - 3359. [Abstract] [Full Text] [PDF]
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C. Liu, F. Lian, D. E. Smith, R. M. Russell, and X.-D. Wang Lycopene Supplementation Inhibits Lung Squamous Metaplasia and Induces Apoptosis via Up-Regulating Insulin-like Growth Factor-binding Protein 3 in Cigarette Smoke-exposed Ferrets Cancer Res., June 15, 2003; 63(12): 3138 - 3144. [Abstract] [Full Text] [PDF]
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H. G. Skinner, D. S. Michaud, G. A. Colditz, E. L. Giovannucci, M. J. Stampfer, W. C. Willett, and C. S. Fuchs Parity, Reproductive Factors, and the Risk of Pancreatic Cancer in Women Cancer Epidemiol. Biomarkers Prev., May 1, 2003; 12(5): 433 - 438. [Abstract] [Full Text] [PDF]
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 K. D. Burroughs, J. Oh, J. C. Barrett, and R. P. DiAugustine Phosphatidylinositol 3-Kinase and Mek1/2 Are Necessary for Insulin-Like Growth Factor-I-Induced Vascular Endothelial Growth Factor Synthesis in Prostate Epithelial Cells: A Role for Hypoxia-Inducible Factor-1? Mol. Cancer Res., February 1, 2003; 1(4): 312 - 322. [Abstract] [Full Text] [PDF]
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S. M. Firth and R. C. Baxter Cellular Actions of the Insulin-Like Growth Factor Binding Proteins Endocr. Rev., December 1, 2002; 23(6): 824 - 854. [Abstract] [Full Text] [PDF]
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Y. S. Chang, L. Wang, D. Liu, L. Mao, W. K. Hong, F. R. Khuri, and H.-Y. Lee Correlation between Insulin-like Growth Factor-binding Protein-3 Promoter Methylation and Prognosis of Patients with Stage I Non-Small Cell Lung Cancer Clin. Cancer Res., December 1, 2002; 8(12): 3669 - 3675. [Abstract] [Full Text] [PDF]
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Y. S. Chang, K. Gong, S. Sun, D. Liu, A. K. El-Naggar, F. R. Khuri, W. K. Hong, and H.-Y. Lee Clinical Significance of Insulin-like Growth Factor-binding Protein-3 Expression in Stage I Non-Small Cell Lung Cancer Clin. Cancer Res., December 1, 2002; 8(12): 3796 - 3802. [Abstract] [Full Text] [PDF]
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M. R. Spitz, M. J. Barnett, G. E. Goodman, M. D. Thornquist, X. Wu, and M. Pollak Serum Insulin-like Growth Factor (IGF) and IGF-binding Protein Levels and Risk of Lung Cancer: A Case-Control Study Nested in the {beta}-Carotene and Retinol Efficacy Trial Cohort Cancer Epidemiol. Biomarkers Prev., November 1, 2002; 11(11): 1413 - 1418. [Abstract] [Full Text] [PDF]
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C. M. Friedenreich and M. R. Orenstein Physical Activity and Cancer Prevention: Etiologic Evidence and Biological Mechanisms J. Nutr., November 1, 2002; 132(11): 3456S - 3464. [Abstract] [Full Text] [PDF]
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M. D. Holmes, M. N. Pollak, W. C. Willett, and S. E. Hankinson Dietary Correlates of Plasma Insulin-like Growth Factor I and Insulin-like Growth Factor Binding Protein 3 Concentrations Cancer Epidemiol. Biomarkers Prev., September 1, 2002; 11(9): 852 - 861. [Abstract] [Full Text] [PDF]
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M. D. Holmes, M. N. Pollak, and S. E. Hankinson Lifestyle Correlates of Plasma Insulin-like Growth Factor I and Insulin-like Growth Factor Binding Protein 3 Concentrations Cancer Epidemiol. Biomarkers Prev., September 1, 2002; 11(9): 862 - 867. [Abstract] [Full Text] [PDF]
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S. Teramukai, T. Rohan, H. Eguchi, T. Oda, K. Shinchi, and S. Kono Anthropometric and Behavioral Correlates of Insulin-like Growth Factor I and Insulin-like Growth Factor Binding Protein 3 in Middle-aged Japanese Men Am. J. Epidemiol., August 15, 2002; 156(4): 344 - 348. [Abstract] [Full Text] [PDF]
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H.-Y. Lee, K.-H. Chun, B. Liu, S. A. Wiehle, R. J. Cristiano, W. K. Hong, P. Cohen, and J. M. Kurie Insulin-like Growth Factor Binding Protein-3 Inhibits the Growth of Non-Small Cell Lung Cancer Cancer Res., June 1, 2002; 62(12): 3530 - 3537. [Abstract] [Full Text] [PDF]
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S. J. London, J.-M. Yuan, G. S. Travlos, Y.-T. Gao, R. E. Wilson, R. K. Ross, and M. C. Yu Insulin-Like Growth Factor I, IGF-Binding Protein 3, and Lung Cancer Risk in a Prospective Study of Men in China J Natl Cancer Inst, May 15, 2002; 94(10): 749 - 754. [Abstract] [Full Text] [PDF]
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J. Hong, G. Zhang, F. Dong, and M. M. Rechler Insulin-like Growth Factor (IGF)-binding Protein-3 Mutants That Do Not Bind IGF-I or IGF-II Stimulate Apoptosis in Human Prostate Cancer Cells J. Biol. Chem., March 15, 2002; 277(12): 10489 - 10497. [Abstract] [Full Text] [PDF]
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S. F. Shariat, D. J. Lamb, M. W. Kattan, C. Nguyen, J. Kim, J. Beck, T. M. Wheeler, and K. M. Slawin Association of Preoperative Plasma Levels of Insulin-Like Growth Factor I and Insulin-Like Growth Factor Binding Proteins-2 and -3 With Prostate Cancer Invasion, Progression, and Metastasis J. Clin. Oncol., February 1, 2002; 20(3): 833 - 841. [Abstract] [Full Text] [PDF]
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Y. Wu, S. Yakar, L. Zhao, L. Hennighausen, and D. LeRoith Circulating Insulin-like Growth Factor-I Levels Regulate Colon Cancer Growth and Metastasis Cancer Res., February 1, 2002; 62(4): 1030 - 1035. [Abstract] [Full Text] [PDF]
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P. Cohen, G. M. Bright, A. D. Rogol, A.-M. Kappelgaard, and R. G. Rosenfeld Effects of Dose and Gender on the Growth and Growth Factor Response to GH in GH-Deficient Children: Implications for Efficacy and Safety J. Clin. Endocrinol. Metab., January 1, 2002; 87(1): 90 - 98. [Abstract] [Full Text] [PDF]
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E. Giovannucci Insulin, Insulin-Like Growth Factors and Colon Cancer: A Review of the Evidence J. Nutr., November 1, 2001; 131(11): 3109S - 3120. [Abstract] [Full Text] [PDF]
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S. M. Lippman and M. R. Spitz Lung Cancer Chemoprevention: An Integrated Approach J. Clin. Oncol., September 15, 2001; 19(90001): 74s - 82. [Abstract] [Full Text] [PDF]
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C. M. Friedenreich Physical Activity and Cancer Prevention: From Observational to Intervention Research Cancer Epidemiol. Biomarkers Prev., April 1, 2001; 10(4): 287 - 301. [Abstract] [Full Text]
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C. Deal, J. Ma, F. Wilkin, J. Paquette, F. Rozen, B. Ge, T. Hudson, M. Stampfer, and M. Pollak Novel Promoter Polymorphism in Insulin-Like Growth Factor-Binding Protein-3: Correlation with Serum Levels and Interaction with Known Regulators J. Clin. Endocrinol. Metab., March 1, 2001; 86(3): 1274 - 1280. [Abstract] [Full Text]
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E. M. Erfurth, B. Bülow, Z. Mikoczy, and L. Hagmar Incidence of a Second Tumor in Hypopituitary Patients Operated for Pituitary Tumors J. Clin. Endocrinol. Metab., February 1, 2001; 86(2): 659 - 662. [Abstract] [Full Text]
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J. Khosravi, A. Diamandi, J. Mistry, and A. Scorilas Insulin-Like Growth Factor I (IGF-I) and IGF-Binding Protein-3 in Benign Prostatic Hyperplasia and Prostate Cancer J. Clin. Endocrinol. Metab., February 1, 2001; 86(2): 694 - 699. [Abstract] [Full Text]
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H. Yu and T. Rohan Role of the Insulin-Like Growth Factor Family in Cancer Development and Progression J Natl Cancer Inst, September 20, 2000; 92(18): 1472 - 1489. [Abstract] [Full Text] [PDF]
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X. Wu, H. Yu, C. I. Amos, W. K. Hong, and M. R. Spitz Joint Effect of Insulin-Like Growth Factors and Mutagen Sensitivity in Lung Cancer Risk J Natl Cancer Inst, May 3, 2000; 92(9): 737 - 743. [Abstract] [Full Text] [PDF]
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E. Giovannucci, M. N. Pollak, E. A. Platz, W. C. Willett, M. J. Stampfer, N. Majeed, G. A. Colditz, F. E. Speizer, and S. E. Hankinson A Prospective Study of Plasma Insulin-like Growth Factor-1 and Binding Protein-3 and Risk of Colorectal Neoplasia in Women Cancer Epidemiol. Biomarkers Prev., April 1, 2000; 9(4): 345 - 349. [Abstract] [Full Text]
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E. A. Platz, M. N. Pollak, E. B. Rimm, N. Majeed, Y. Tao, W. C. Willett, and E. Giovannucci Racial Variation in Insulin-Like Growth Factor-1 and Binding Protein-3 Concentrations in Middle-Aged Men Cancer Epidemiol. Biomarkers Prev., December 1, 1999; 8(12): 1107 - 1110. [Abstract] [Full Text]
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H. Yu Re: Cyclin D1 Proteolysis: a Retinoid Chemoprevention Signal in Normal, Immortalized, and Transformed Human Bronchial Epithelial Cells J Natl Cancer Inst, October 6, 1999; 91(19): 1685 - 1685. [Full Text] [PDF]
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K. D. Burroughs, S. E. Dunn, J. C. Barrett, and J. A. Taylor Insulin-Like Growth Factor-I: a Key Regulator of Human Cancer Risk? J Natl Cancer Inst, April 7, 1999; 91(7): 579 - 581. [Full Text] [PDF]
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