Prospective Study of Colorectal Cancer Risk in Men and Plasma Levels of Insulin-Like Growth Factor (IGF)-I and IGF-Binding Protein-3

Background: Insulin-like growth factor-I (IGF-I) is a potent mitogen for normal and neoplastic cells, whereas IGF-binding protein-3 (IGFBP-3) inhibits cell growth in many experimental systems. Acromegalics, who have abnormally high levels of growth hormone and IGF-I, have higher rates of colorectal cancer. We therefore examined associations of plasma levels of IGF-I and IGFBP-3 with the risk of colorectal cancer in a prospective case– control study nested in the Physicians’ Health Study. Methods: Plasma samples were collected at baseline from 14 916 men without diagnosed cancer. IGF-I, IGF-II, and IGFBP-3 were assayed among 193 men later diagnosed with colorectal cancer during 14 years of follow-up and among 318 ageand smoking-matched control subjects. All P values are two-sided. Results: IGFBP-3 levels correlated with IGF-I levels (r = .64) and with IGF-II levels (r = .90). After controlling for IGFBP-3, age, smoking, body mass index (weight in kg/[height in m]), and alcohol intake, men in the highest quintile for IGF-I had an increased risk of colorectal cancer compared with men in the lowest quintile (relative risk [RR] = 2.51; 95% confidence interval [CI] = 1.15–5.46; P for trend = .02). After controlling for IGF-I and other covariates, men with higher IGFBP-3 had a lower risk (RR = 0.28; 95% CI = 0.12– 0.66; P for trend = .005, comparing extreme quintiles). The associations were consistent during the first and the second 7-year follow-up intervals and among younger and older men. IGF-II was not associated with risk. Conclusions: Our findings suggest that circulating IGF-I and IGFBP-3 are related to future risk of colorectal cancer. [J Natl Cancer Inst 1999;91:620–5] Insulin-like growth factors (IGFs)-I and -II are mitogenic in normal and neoplastic cells and act by binding to cellsurface IGF receptors (1–5). Several studies suggest that IGF-I and IGF-II are important in the pathophysiology of colorectal carcinoma. IGF receptors are found in human colon cancers (5), and fulllength messenger RNAs for IGFs have been detected in human tumor cells (6–8). Exogenous IGF-I and -II stimulate proliferation of human colorectal cancer cells (9,10), whereas blockade of the IGF-I receptor inhibits tumor cell growth (11). Individuals with acromegaly, a disease of somatic growth caused by increased growth hormone and IGF-I, have an increased incidence of colonic cancer (12–14). IGF-binding protein-3 (IGFBP-3) binds more than 95% of the IGF in serum and influences cell proliferation by modulating access of IGFs to the IGF receptors (15–17). IGFBP-3 also apparently inhibits growth and induces apoptosis through IGF-independent mechanisms (18,19). Most circulating IGF-I and IGFBP-3 are synthesized in the liver, where expression of each is increased by growth hormone. There is considerable between-person variability in blood levels of IGF-I, IGFII, and IGFBP-3 (1,20). Tissue IGF bioactivity is influenced by circulating IGF levels and by local expression of IGFs, IGFBPs, and IGFBP proteases (21). Some factors that regulate determinants of local IGF bioactivity may regulate circulating IGF-I levels in a parallel fashion (22,23). Although colonic tumors secrete IGF-II, which may stimulate neoplastic growth (6,7,24,25), the role of circulating IGF-II is poorly understood (15). We previously reported a strong positive association between baseline plasma IGF-I levels and subsequent risk of prostate cancer (26) or premenopausal breast cancer (27). We therefore hypothesized that men with high plasma levels of IGF-I would have increased risk of colorectal cancer, men with high levels of IGFBP-3 would have lower risk, and men with high IGF-I and low IGFBP-3 would have the highest risk.