Insulin-like Growth Factor-1, IGF-binding Protein-3, C-peptide and Colorectal Cancer: a Case-control Study

Context: Insulin-like growth factor peptides play important roles in regulating cell growth, cell differentiation,and apoptosis, and have been demonstrated to promote the development of colorectal cancer (CRC). Objective: Toexamine the association of insulin-related biomarkers including insulin-like growth factor-1 (IGF-1), insulin-likegrowth factor binding protein-3 (IGFBP-3) and C-peptide with CRC risk and assess their relevance in predictivemodels. Materials and Methods: The odds ratios of colorectal cancer for serum levels of IGF-1, IGFBP-3 andC-peptide were estimated using unconditional logistic regression models in 100 colorectal cancer cases and 100control subjects. Areas under the receiving curve (AUC) and integrated discrimination improvement (IDI)statistics were used to assess the discriminatory potential of the models. Results: Serum levels of IGF-1 andIGFBP-3 were negatively associated with colorectal cancer risk (OR=0.07, 95%CI: 0.03-0.16, P for trend <.01,OR=0.06, 95%CI: 0.03-0.15, P for trend <.01 respectively) and serum C-peptide was positively associated withrisk of colorectal cancer (OR=4.38, 95%CI: 2.13-9.06, P for trend <.01). Compared to the risk model, predictionfor the risk of colorectal cancer had substantially improved when all selected biomarkers IGF-1, IGFBP-3 andinverse value of C-peptide were simultaneously included inthe reference model [P for AUC improvement was 0.02and the combined IDI reached 0.166% (95 % CI; 0.114-0.219)]. Conclusions: The results provide evidence foran association of insulin-related biomarkers with colorectal cancer risk and point to consideration as candidatepredictor markers.     

Insulin-like growth factor (IGF)-I, IGF-binding protein-3 and colorectal adenomas in Japanese men.

Several epidemiological studies have found that high levels of plasma insulin-like growth factor (IGF)-I and low levels of IGF-binding protein (IGFBP)-3 are related to an increased risk of colorectal cancer or late-stage adenomas. We examined the relation of body mass index, fasting and 2-h postload plasma glucose levels and plasma concentrations of IGF-I and IGFBP-3 to colorectal adenomas in middle-aged Japanese men. The study subjects comprised 157 cases of histologically diagnosed colorectal adenomas and 311 controls with normal colonoscopy or non-polyp benign lesions in a consecutive series of 803 men receiving a preretirement health examination at two hospitals of the Self Defense Forces (SDF). After adjustment for rank in the SDF, hospital, smoking and IGFBP-3, a statistically nonsignificant modest increase in the prevalence odds of colorectal adenomas was observed for the highest versus the lowest quartile level of IGF-I. The increase was slightly greater with further adjustment for 2-h glucose concentrations (adjusted odds ratio 1.8, 95% confidence interval 1.0-4.5, trend P=0.06). Men with high levels of IGFBP-3 showed only a minimal decrease in risk after adjustment for IGF-I. The association with IGF-I was less evident for advanced adenomas (>5 mm in size or tubulovillous/villous). Fasting and 2-h glucose and body mass index were more strongly positively associated with colorectal adenomas than IGF-I, especially with advanced adenomas, independently of IGF-I and IGFBP-3. The findings suggest that plasma IGF-I and IGFBP-3 may be involved in colorectal tumorigenesis regardless of the stage in growth of adenoma, but not as a mediator for the effects of being overweight or of hyperglycemia.     

Dietary Determinants of Circulating Insulin-like Growth Factor (IGF)-I and IGF Binding Proteins 1, -2 and -3 in Women in the Netherlands

OBJECTIVE: Epidemiological studies suggest that individuals with elevated plasma concentrations of insulin-like growth factor (IGF-I) are at increased risk of developing cancer. We assessed whether dietary intake of total energy, protein, alcohol, phytoestrogens and related foods, and tomatoes and lycopene was associated with plasma levels of IGF-I and IGF binding proteins (IGFBPs) in Dutch women. METHODS: A cross-sectional study was conducted in 224 premenopausal and 162 postmenopausal women, aged 49-69, participating in the Prospect-EPIC study in the Netherlands. Diet was assessed using a food frequency questionnaire. RESULTS: In postmenopausal women, higher alcohol intake was associated with lower plasma IGFBP-1 concentrations (alcohol 1.4 to 20 g/day: 20% decrease in IGFBP-1; p = 0.04), and higher intake of plant lignans was associated with higher IGFBP-1 concentrations (plant lignans 0 to 1 mg/day: 59% increase in IGFBP-1; p =0.02). Higher soy intake was associated with higher plasma IGFBP-2 concentrations in premenopausal women (soy 0 to 2.5 g/day: 3% increase in IGFBP-2; p = 0.04). No independent associations of dietary factors with IGF-I or IGFBP-3 concentrations were observed. However, in premenopausal women alcohol intake was inversely associated with IGF-I and positively associated with IGFBP-3 after mutual adjustment. CONCLUSIONS: In this study population, with limited variation in dietary intake, total energy, protein, phytoestrogens and lycopene were not associated with IGF-I and IGFBP-3. Alcohol was inversely, and some measures of phytoestrogen intake were positively associated with plasma IGFBP-1 or -2 concentrations. The roles of IGFBP-1 and -2 in relation to IGF-I bioactivity and cancer deserve further investigation.     

Obesity, Weight Gain and Risk of Colon Adenomas in Japanese Men

Obesity has been related to increased risk of colon cancer or adenomas, but the epidemiologic findings are not entirely consistent. We examined the relation of not only body mass index (BMI) but also waist-to-hip ratio (WHR) and weight gain to colon adenoma risk in men who received a preretirement health examination at the Japan Self Defense Forces (SDF) Fukuoka and Kumamoto Hospitals during the period from 995 to 1996. In the series of 803 men at age 47–55 years, 189 cases of colon adenomas and 226 controls with normal total colonoscopy were identified. Weight at 10 years before was ascertained by referring to the recorded data. After allowance for hospital, rank in the SDF, smoking and alcohol use, weight gain over the past 10 years was significantly associated with increased risk of colon adenomas (odds ratio for ≥ 6 kg versus ≤−2 kg = 2.2; 95% confidence interval 1.0–4.8). High BMI and high WHR were each associated with increased risk, but only WHR was related to the risk independently of weight gain. In particular, weight gain accompanied with a high WHR was associated with a significant increase in the risk. Men with high physical activity tended to have lower risk. Associations with obesity-related variables and physical activity were not materially differential as regards the location and size of adenoma. The findings indicate that weight gain in middle age leading to abdominal obesity increases the risk of colon adenomas, and consequently of colon cancer.     

Glucose Intolerance, Plasma Insulin Levels, and Colon Adenomas in Japanese Men

Hyperinsulinemia may be related to colon carcinogenesis. Several studies have suggested that diabetes mellitus is related to increased risk of colon cancer. We examined cross-sectionally the relation of fasting plasma insulin levels and glucose tolerance status to colon adenomas. In a consecutive series of 951 men undergoing total colonoscopy for a health examination at the Japan Self Defense Forces Fukuoka Hospital from April 1998 to August 1999, we identified 233 cases of colon adenomas and 497 controls with normal colonoscopy. Glucose tolerance status was determined by a 75-g oral glucose tolerance test, and subjects were classified as normal, unpaired glucose tolerance (IGT) or non-insulin dependent diabetes mellitus (NIDDM). Plasma insulin levels were measured after subjects had fasted overnight. Logistic regression analysis and analysis of covariance was used to control for age and obesity. While plasma insulin levels were unrelated to colon adenomas, NIDDM was associated with a significantly increased risk of colon adenomas. There was no association between IGT and colon adenomas. NIDDM was more strongly associated with proximal colon adenomas. The findings suggest that long-term hyperinsulinemic status associated with NIDDM may increase the risk of colon adenomas, and subsequently of colon cancer.     

Nonlinear relationship of insulin-like growth factor (IGF)-I and IGF-I/IGF-binding protein-3 ratio with indices of adiposity and plasma insulin concentrations (Sweden)

Objective: In this study we test the hypothesis of a nonlinear relationship of IGF-I with indices of body fat such as body mass index (BMI), insulin, and leptin. Methods: The controls used in three case–control cancer studies nested in the Northern Sweden Health and Disease Cohort, were combined for this analysis. Measurements of plasma IGF-I, IGFBP-3, insulin, and leptin were available for 445 men and 391 women. Results: In both men and women we found the highest mean IGF-I levels in subjects with BMI between 24 and 26. IGF-I concentrations decreased toward BMI 20 and BMI > 30 in men; however, the results for women did not reach statistical significance. The molar ratio of IGF-I/IGFBP-3 showed a similar profile to that of IGF-I, although much less pronounced. The observed peak mean IGF-I levels in the second quintiles of insulin and leptin in men supported these findings. No significant variation of mean IGF-I levels across quintiles of insulin and leptin were observed in women. Conclusions: The results of this study provide evidence that IGF-I plasma concentrations vary substantially over a wide range of body weight and that the relationship is nonlinear.     

Circulating Insulin-like Growth Factor (IGF)-I and IGF Binding Protein (IGFBP)-3 Levels and Postmenopausal Breast Cancer Risk in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) Cohort

Early prospective studies suggested circulating insulin-like growth factor (IGF)-I was positively associated with risk of premenopausal, but not postmenopausal, breast cancer; however, a recent, large analysis reported a statistically significant positive association with postmenopausal disease. Therefore, we conducted a large study nested within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial cohort to assess the association between circulating IGF-I and IGF binding protein (IGFBP)-3 levels and subsequent postmenopausal breast cancer risk. We included 389 breast cancer cases and 470 controls, aged 55-74, not using exogenous hormones at blood draw, and matched by age at and date of serum collection. Mean follow-up was 8.5 years; mean time between serum collection and diagnosis was 4.0 years. We used Cox proportional hazards regression models to obtain hazard ratios (HRs) and 95% confidence intervals (95% CIs). Multivariate HRs for IGF-I, IGFBP-3, and the molar ratio IGF-I/IGFBP-3, comparing the highest quintile to the lowest, were 1.28 (95% CI, 0.67-2.44), 1.12 (95% 0.55-2.27), and 1.25 (95% 0.72-2.15), respectively. Multivariate HRs per one quintile increase were 1.07 (95% 0.92-1.25) for IGF-I, 1.01 (95% 0.86-1.18) for IGFBP-3, and 1.10 (95% 0.98-1.24) for the molar ratio. These models included accepted breast cancer risk factors and height, along with baseline BMI and serum estradiol, both of which increased the risk associated with IGF-I and the molar ratio. IGF-I and the IGF-I/IGFBP-3 molar ratio were positively, although not statistically significantly, associated with postmenopausal breast cancer risk. Further research should emphasize larger studies, including pooled analyses, analyses by cancer subtype, improved exposure assessment, and possible mechanisms.     

Variation in Plasma Insulin-like Growth Factor-1 and Insulin-like Growth Factor Binding Protein-3: Personal and Lifestyle Factors (United States)

Insulin-like growth factors (IGFs) play an important role in cell proliferation and apoptosis, and recent epidemiologic studies have suggested that circulating IGF-1 and IGF binding protein-3 (IGFBP-3) may be related to colorectal, breast, and prostate cancer risk. The purpose of this analysis was to investigate the role of various personal and lifestyle factors in the inter-individual variation of circulating IGF-1 and IGFPB-3. We measured plasma levels of IGF-1 and IGFBP-3 in a sequential sample of 333 population-based control subjects enrolled in the Seattle Colorectal Cancer Family Registry from August 1999 through December 2001, who had provided a blood sample. Total IGF-1 and IGFBP-3 were measured from plasma samples using ELISA assays. Interviewer-administered questionnaires collected data on various personal and lifestyle factors. Multivariate-adjusted linear regression was used to assess the associations between specific personal and lifestyle factors with IGF-1 and IGFBP-3 levels. Age, body mass index, and postmenopausal hormone use were statistically significantly inversely related to IGF-1 concentrations, and milk consumption was significantly positively related to IGF-1 levels. Only age was significantly related to circulating IGFBP-3. Although the sources of inter-individual variation of IGF-1 and IGFB-3 are not yet fully understood, this analysis provides some insights into factors that may contribute.^★ Support: This research was supported in part by National Cancer Institute Grants U01CA74794, R01CA76366, and R03CA94785, and by National Institute of Health training grant 5-T32-CA09168.     

A prospective study of serum insulin-like growth factor-I (IGF-I), IGF-II, IGF-binding protein-3 and breast cancer risk

The associations between serum concentrations of insulin-like growth factor-I (IGF-I), IGF-II and IGF-binding proteins (IGFBP)-3 and risk of breast cancer were investigated in a nested case-control study involving 117 cases (70 premenopausal and 47 postmenopausal at blood collection) and 350 matched controls within a cohort of women from the island of Guernsey, UK. Women using exogenous hormones at the time of blood collection were excluded. Premenopausal women in the top vs bottom third of serum IGF-I concentration had a nonsignificantly increased risk for breast cancer after adjustment for IGFBP-3 (odds ratio (OR) 1.71; 95% confidence interval (CI): 0.74-3.95; test for linear trend, P=0.21). Serum IGFBP-3 was associated with a reduction in risk in premenopausal women after adjustment for IGF-I (top third vs the bottom third: OR 0.49; 95% CI: 0.21-1.12, P for trend=0.07). Neither IGF-I nor IGFBP-3 was associated with risk in postmenopausal women and serum IGF-II concentration was not associated with risk in pre- or postmenopausal women. These data are compatible with the hypothesis that premenopausal women with a relatively high circulating concentration of IGF-I and low IGFBP-3 are at an increased risk of developing breast cancer.     

Prospective study of IGF-I,IGF-binding proteins,and breast cancer risk,in northern and southern Sweden

Objective: To examine the possible relationships of breast cancer risk to prediagnostic plasma levels of insulin; insulin-like growth factor-I (IGF-I); and IGF-binding proteins -1, -2, and -3. Methods: Within two prospective cohorts in Umeå and Malmö we measured plasma concentrations of insulin, IGF-I, and IGFBPs for a total of 513 incident breast cancer cases and 987 matched controls. Results: Globally, risk was unassociated with levels of IGF-I, IGFBP-3, or IGF-I adjusted for IGFBP-3. When breaking down the analysis by subgroups of age at blood donation, an increase in risk was observed for increasing levels of IGF-I in women aged 55 or older, in the Umeå cohort only (odds ratios of 1.00, 1.73, 1.76, 1.90; p _trend = 0.05). This effect weakened, however, when the analysis was restricted to subjects who did not use exogenous hormones for the treatment of menopausal symptoms. Levels of IGF-I and IGFBP-3 were not related to risk in younger women, recruited before age 50, contrary to observations from previous studies. In a subcohort where blood samples had been collected after at least four hours of fasting, breast cancer risk showed no clear associations with levels of insulin, IGFBP-1, or IGFBP-2. Conclusions: Our results do not confirm earlier findings of an association of plasma IGF-I levels with breast cancer risk especially in young women, but suggest a possible association with postmenopausal breast cancer risk, possibly among ERT/HRT users only. Our results do not support the hypothesis that elevated plasma insulin levels, and reduced levels of IGFBP-1 and IGFBP-2, are associated with increased breast cancer risk.     

Insulin-like growth factor (IGF)-I and IGF-binding protein 3 and the risk of premenopausal breast cancer: a meta-analysis of literature

Biologic evidence suggests substantial effect of insulin-like growth factor (IGF)-I in mammary cell carcinogenesis. However, controversy remains regarding the association between circulating IGF-I levels and the risk of premenopausal breast cancer in epidemiologic studies. In addition, the association of IGF-binding protein (IGFBP)-3, which binds with and modifies the effect of IGF-I, is unclear. To clarify these associations, we performed a meta-analysis of all the published studies. A systematic review of literature was conducted. Eligible study designs were nested case-control and population-based case-control studies that give estimates for menopausal women. The studies published between January 1990 and March 2003 were obtained from Medline. We obtained 7 studies, consisting of 688 premenopausal incident breast cancer cases and 1,366 controls, for our final evaluation. Summary statistics were odds ratios (ORs) comparing the highest and the lowest levels of IGF-I and IGFBP-3 adjusted for confounders other than IGF-I or IGFBP-3. There was neither evidence of heterogeneity between studies nor evidence of publication bias. The confounders considered and the contrast used for the ORs were the major source of variation. The subjects with higher circulating levels of IGF-I had marginally significant increased risk of breast cancer with an OR of 1.74 (95% CI = 0.97-3.13; p = 0.06). No significant difference was observed for IGFBP-3 group (OR = 1.60; 95% CI = 0.84-3.02; p = 0.15). In conclusion, we found a marginally significant association between circulating IGF-I levels and the risk of premenopausal breast cancer.     

Determinants of circulating insulin-like growth factor (IGF)-I and IGF binding proteins 1–3 in premenopausal women: physical activity and anthropometry (Netherlands)

Objective: Epidemiologic studies suggest that subjects with elevated plasma concentrations of IGF-I are at increased risk of developing cancer. The objective of our study was to assess whether cancer risk factors such as lack of physical activity, obesity, and central body fat distribution are associated with plasma levels of IGF-I and related proteins (i.e. IGF binding proteins 1–3 and C-peptide). Methods: A cross-sectional study was conducted in a population of 225 premenopausal women, aged 49–57, participating in the Prospect–EPIC study in the Netherlands. Plasma concentrations of IGF-I, IGFBP-1, IGFBP-2, IGFBP-3, and C-peptide were determined. On the day of blood collection height, weight, and waist and hip circumference were measured. Habitual physical activity was assessed using a validated self-administered questionnaire. Results: Mean concentrations of plasma IGF-I, IGFBP-1, IGFBP-2, IGFBP-3, and C-peptide were 156.1, 14.3, 434.4, 3062, and 2.86 ng/ml, respectively. Women in the highest tertile for physical activity had lower plasma concentrations of IGF-I, IGFBP-3, and C-peptide, and higher concentrations of IGFBP-1 and IGFBP-2, as compared to women in the lowest tertile. However, these differences were not statistically significant. BMI and related measures were significantly inversely associated with IGFBP-1 and IGFBP-2, and positively with IGFBP-3 and C-peptide. Linear regression analyses showed that the non-significant association of physical activity with components of the plasma IGF system was further attenuated by adjusting for obesity and central body fat distribution. Conclusions: Our data suggest that an active lifestyle is not independently associated with the plasma IGF system. We did confirm that a lean body shape is associated with higher concentrations of IGFBP-1 and IGFBP-2, and possibly also with lower concentrations of IGF-I and IGFBP-3.     

Insulin-like growth factor (IGF)-1, IGF-binding protein-3, and pancreatic cancer in male smokers.

To investigate whether insulin-like growth factor (IGF)-1 and IGF-binding protein-3 (IGFBP-3) are prospectively associated with exocrine pancreatic cancer, we conducted a nested case-control study within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study cohort of 29,133 male Finnish smokers, aged 50-69 years. To avoid the potential influence of subclinical cancer on IGF-1 and IGFBP-3, all subjects in this study were alive without clinical evidence of cancer during their 5th year of the cohort follow-up. Four hundred randomly selected cohort controls and 93 incident pancreatic adenocarcinoma cases that occurred between their 5th follow-up year through 1997 (i.e., up to 12.7 years of follow-up) were included in this study. Concentrations of IGF-1 and IGFBP-3 were measured in serum samples obtained at baseline using ELISA. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using logistic regression models, adjusted for confounders. Neither IGF-1, IGFBP-3, nor the IGF-1:IGFBP-3 molar ratio was significantly associated with pancreatic cancer: highest compared to lowest tertile, OR = 0.67, 95% CI 0.37-1.21, P trend = 0.17; OR = 0.70, 95% CI 0.38-1.27, P trend = 0.12; and OR = 0.85, 95% CI 0.50-1.46, P trend = 0.54, respectively. Our results do not support the hypothesis that serum IGF-1 and IGFBP-3 concentrations are associated with pancreatic cancer risk among male smokers. Further studies are necessary to evaluate these associations in other populations.     

Insulin,Insulin-like Growth Factor-I and Breast Cancer Risk in Japanese Women

To evaluate the effects of glucose metabolism related factors, such as insulin and insulin-like growth-factors ‍(IGFs), on breast cancer development among Japanese women, we conducted a case-referent study comparing 187 ‍women presenting with operable breast cancer and 190 women of the same age having no breast cancer. Odds ratios ‍(OR) and 95% confidence intervals (95%CI) were determined by multiple logistic regression analysis. ‍ In the present study, no association in risk was observed with increasing levels of IGF-I or IGF binding protein- ‍3 (IGFBP-3), before or after adjustment these factors. However, a suggestion of a positive association of an increased ‍breast cancer risk was evident in postmenopausal women with elevated plasma insulin levels, particularly those with ‍BMI>23.07. The OR for plasma insulin in the top tertile was 4.48 (95%CI:1.07-18.7) compared to the bottom tertile. ‍For C-peptide, there was a similar positive association, with a corresponding OR of 2.28. In addition, we observed ‍strong links between plasma insulin, C-peptide levels and estrogen receptor (ER) negative breast cancer, with ORs ‍of 2.79(95%CI:1.09-7.16), and 2.52 (95%CI:0.91-6.97) respectively, for the top versus bottom tertiles. In conclusion, ‍the present study suggested that plasma insulin level is a predictor of postmenopausal breast cancer in obese women ‍and ER negative breast cancer. Additional studies are needed to clarify the role of glucose metabolism pathways in ‍breast cancer development and interaction of IGF systems.     

A novel antitumor activity of deguelin targeting the insulin-like growth factor (IGF) receptor pathway via up-regulation of IGF-binding protein-3 expression in breast cancer

In this study, we investigated the antitumor effects of deguelin in several human breast cancer cells in vitro and in vivo. Deguelin inhibited cell viability and the anchorage-dependent and anchorage-independent colony formation of triple-negative (MDA-MB-231 and MDA-MB-468) and triple-positive (MCF-7) breast cancer cells, and it significantly reduced the growth of MCF-7 cell xenograft tumors. The induction of apoptosis, inhibition of insulin-like growth factor-1 receptor (IGF-1R) signaling activation, and up-regulation of IGF-binding protein-3 (IGFBP-3) expression may be associated with deguelin-mediated antitumor effects. Our findings suggest a potential therapeutic use for deguelin in patients with triple-negative breast cancer and for those with breast cancers who are sensitive to endocrine- and HER2-targeted therapies.     

Insulin-like growth factor (IGF)-I and IGF-II protein expression in pulmonary adenocarcinoma

Insulin-like growth factor (IGF)-I and IGF-II expression was studied immunologically in tissue specimens from 120 patients with pulmonary adenocarcinoma and was correlated with patient prognosis. Multivariate analysis showed that IGF-II expression had a significant influence on prognosis. Our findings suggest that IGF-I and IGF-II play an important role in tumor progression and that IGF-II is a useful prognostic marker for pulmonary adenocarcinomas.     

Serum levels of insulin-like growth factor-I, IGF-binding protein 1 and 3, and insulin and endometrial cancer risk

Insulin-like growth factor-I (IGF-I) and IGF-binding protein-1 and 3 (IGFPB-1, IGFPB-3) are expressed in normal and neoplastic endometrium. Their role and the role of insulin in the aetiology of endometrial cancer, is unclear. We performed a population-based case-control study in Sweden, including 288 endometrial cancer patients and 392 control women and analysed total serum IGF-I, IGFBP-1, IGFBP-3, insulin and BMI levels stratified by disease and hormone replacement therapy status (HRT). Non-parametric statistical tests and logistic regression analyses were performed to assess associations with endometrial cancer. There were no substantial differences between the mean serum levels of IGF-I between cases (115.5, s.d. 61.3) and controls (110.6; s.d. 50.4; Wilcoxon P=0.84), or between subgroups of women classified according to other risk factors for endometrial cancer. There were no trends of increasing risk according to quartiles of IGF-I, IGFBP-1, IGFBP-3 and insulin serum levels. There was an increasing risk of endometrial cancer according to the serum levels of IGFBP-1, which was observed only among women who had ever used HRT. Serum IGF-I, IGFBP-1, IGFBP-3 and insulin levels seem unrelated to endometrial cancer risk. Among users of HRT, increasing IGFBP-1 levels seem to increase endometrial cancer risk.