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Insulin-like growth factors (IGF-I, IGF-II) and their binding proteins (IGFBP-1-6) play a key role in cell proliferation, differentiation and apoptosis, suggesting possible involvement in carcinogenesis. Several epidemiological studies show associations of IGFs with prostate cancer. We searched the published literature for all studies relating levels of IGFs or IGFBPs with prostate cancer. We performed random effects meta-analysis to calculate summary odds ratios. The number of studies (prostate cancer cases) included in each meta-analysis were 42 (7,481) IGF-I; 10 (923) IGF-II; 3 (485) IGFBP-1; 5 (577) IGFBP-2; 29 (6,541) IGFBP-3 and 11 (3,545) IGF-1:IGFBP-3 ratio. The pooled odds ratios (95% confidence intervals) per standard deviation increase in peptide were: IGF-I, OR 5 1.21 (1.07, 1.36); IGF-II, OR 5 1.17 (0.93, 1.47); IGFBP-1, OR 5 1.21 (0.62, 2.33); IGFBP-2, OR 5 1.18 (0.90, 1.54); IGFBP-3, OR 5 0.88 (0.79, 0.98); IGFI:IGFBP-3 ratio, OR 5 1.10 (0.97, 1.24). For all exposures, there was substantial heterogeneity (all I 2 > 75%), partly explained by study design: the magnitude of associations was smaller in prospective vs. retrospective studies, and for IGFBP-3, the inverse association with prostate cancer risk was seen in retrospective but not prospective studies. There was weak evidence that associations of IGF-I and IGFBP-3 with prostate cancer were stronger for advanced disease. Our meta-analysis confirms that raised circulating lGF-I is positively associated with prostate cancer risk. Associations between IGFBP-3 and prostate cancer were inconsistent, and there was little evidence for a role of IGF-II, IGFBP-1 or IGFBP-2 in prostate cancer risk. ' 2008 Wiley-Liss, Inc.Key words: prostate cancer; meta-analysis; insulin-like growth factor; insulin-like growth factor binding protein Insulin-like growth factors (IGF-I and IGF-II) and their binding proteins (IGFBP-1-6) play a key role in cell proliferation, differentiation and apoptosis, in many tissues including the prostate. These processes are all involved in malignant transformation, and components of the IGF system may therefore be involved in the aetiology and/or progression of prostate cancer. 1 Several epidemiological studies show positive associations of IGF levels with prostate cancer risk, but the results are inconsistent. A recently published analysis based on individual patient data from 12 prospective studies (n 5 3,700 prostate cancer cases) found an increased risk in the highest compared to the lowest quintiles of both IGF-I and IGFBP-3 (IGF-I odds ratio 5 1.38, 96% confidence interval: 1.19,1.60; IGFBP-3 OR 1.23, 95% CI: 1.06,1.43), although the risk associated with IGFBP-3 was abolished in models controlling for IGF-I. 2 The authors found no association with IGF-II or IGFBP-2. Another meta-analysis of 9 prospective studies, 3 which included 1,512 men with prostate cancer, found an increased risk associated with the highest compared to the lowest quartile of IGF-I (OR 5 1.31, 95% CI: 1.03,1.71), but no association of IGF-II or IGFBP-3. Th...

Insulin-like growth factor (IGF) -independent growth inhibition of human breast cancer cells, Hs578T, by IGFbinding protein-3 (IGFBP-3) has previously been demonstrated. Cell growth is a balance between proliferation and programmed cell death (apoptosis). We have investigated whether IGFBP-3 can affect apoptosis of Hs578T cells. As no induction of apoptosis was found, we also investigated its effect on the response to ceramide, an intracellular second messenger that mediates the signal for apoptosis. Using the cell permeable ceramide analogue, C2, induction of apoptosis was established by 3-(4,5-dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide) assay, trypan blue uptake, morphological criteria, and flow cytometry. Incubation of cells with non-glycosylated IGFBP-3 (ngIGFBP-3; 0.5-100 ng/ml) resulted in no growth inhibition or increase in apoptosis; whereas, C2 (1-30 M) resulted in a dose-dependent induction of apoptosis. Addition of IGFs to the cells, alone or with C2, elicited no response in terms of proliferation or survival, respectively. When the cells were preincubated with ngIGFBP-3 before addition of C2 (2-5 M), apoptosis was accentuated in a dose-dependent manner (at 100 ng/ml IGFBP-3, apoptosis increased from 11 to 88%). In conclusion, we found that IGFBP-3 had no direct inhibitory effect on Hs578T cells but could accentuate apoptosis induced by the physiological trigger ceramide in an IGF-independent manner.