Insulin-like growth factor-I has recently been linked to prostate cancer risk in a series of studies. The initial observation was a relatively small case-control study noting increased IGF-I in men with prostate cancer but not benign prostate hyperplasia.30 A much larger nested case-control study using data derived from the Physicians' Health Study cohort has confirmed and extended this initial report.31 In the Chan et al.31 report, increasing plasma levels of IGF-I were directly linked to increasing prostate cancer risk. Importantly, this increased risk was detected in men with both normal and elevated PSA measurements, suggesting that these risk factors were independent of one another. When examining men with the highest quartile of IGF-I, the prospective risk of prostate cancer was increased 2.4-fold, relative to those with an IGF-I in the lowest quartile. In a multivariate analysis adjusting for PSA and the major circulating IGF-I binding protein (IGFBP-3), men with a PSA < 4 ng per mL and highest quartile PSA had a 4.3-fold prostate cancer risk. After a similar IGFBP-3 adjustment, men with a PSA >4 ng per mL in combination with the highest quartile of IGF-I had a 17.5-fold risk of prostate cancer. On the basis of the findings of this study, a combination of PSA and IGF-I determinations could be used to construct a prospective risk-factor profile considerably more powerful than race or family history. Another large case-control study performed in Sweden has confirmed the association between IGF-I and prostate cancer32 and found this association to be particularly strong in men < 70 years old. In the Swedish study, no association was found between IGF-I level and stage at presentation, and no association was found between IGF-binding protein-3 (IGFBP-3) concentration and prostate cancer risk.
The mechanism whereby IGF-I might contribute to prostate cancer risk may involve several potential pathways. Studies in prostatic tumor cell lines indicate that IGF-I can stimulate androgen-receptor-mediated gene transcription in the absence of exogenous androgen.33 Interestingly, this effect is blocked by antiandrogens. Experiments in animal models demonstrate that tumor growth can be inhibited by strategies designed to disrupt IGF-I signaling pathways. Overexpression of the inhibitory IGF-binding protein-4 (IGFBP-4) delays onset of prostate tumor formation.34 Furthermore, a dominant negative mutant of the IGF-I receptor inhibits prostate cancer growth in both soft-agar and animal models.35 Growth is stimulated by IGF-I in stromal as well as epithelial cells.36 These experiments indicate that disruption of IGF-I signaling pathways can inhibit prostatic tumor growth under a variety of modeled conditions. Interestingly, the secreted serine protease PSA can catalyze IGFBP-3 fragmentation.37 After PSA-induced cleavage, this binding protein has a markedly reduced IGF-I binding affinity. Thus, it is conceivable that PSA-secreting cells could increase "free" IGF-I concentrations in the local cellular microenvironment, thereby increasing the amount of IGF-I available to interact with its cell surface receptor. In the clinical setting, acromegalics have a marked increase in prostate volume that reverses with successful acromegalic treatment.38 Taken together, a variety of basic and clinical data support the concept that IGF-I can stimulate prostatic growth, and clinical studies clearly support the concept that increasing plasma IGF-I levels are associated with a substantially increased prostate cancer risk in men.
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