CORRESPONDENCE

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

Andrew G. Renehan, Sarah T. O'Dwyer, Stephen M. Shalet

Affiliations of authors: A. G. Renehan, S. T. O'Dwyer (Department of Surgery), S. M. Shalet (Department of Endocrinology), Christie Hospital NHS Trust, Manchester, U.K.

Correspondence to: Andrew G. Renehan, F.R.C.S., F.D.S., Christie Hospital NHS Trust, Wilmslow Rd., Withington, Manchester, M2Q 4BX, U.K.

We have followed with great interest the evolving evidence that circulating levels of insulin-like growth factor (IGF)-I and IGF-binding protein (IGFBP)-3 may be important predictors of risk for prostate, breast, and now colorectal cancers (1,2). Regarding colorectal cancer, most cancers are believed to develop from adenomatous polyps, known as the adenoma-carcinoma sequence (3). This sequence led us to investigate prospectively the relationship between serum IGF-I and IGFBP-3 and the presence of adenoma—as a surrogate marker of colorectal cancer risk—in an age-defined population (healthy 55- to 64-year-old males and females) undergoing flexible sigmoidoscopy screening. Three-hundred seventy-four individuals were enrolled, among whom adenomas were found in 56 (15%). Blood was taken at the time of endoscopy. Serum IGF-I was measured, after acid-alcohol extraction, by radioimmunoasay with the use of a polyclonal rabbit antihuman serum (4), and serum IGFBP-3 was determined with the use of an immunoradiometric assay with reagents from Diagnostic Systems Laboratory (Houston, TX). The statistical analysis was performed in a similar manner to that used in the report by Ma et al. (1).

IGF-I correlated positively with IGFBP-3 (Pearson correlation coefficient = .59; P<.001). Serum levels (mean ± standard deviation) for IGF-I were similar among case subjects (i.e., with adenomas) (193 ± 72 ng/mL) and control subjects (181 ± 59 ng/mL). Similarly, there were no differences in IGFBP-3 levels between case subjects (3246 ± 694 ng/mL) and control subjects (3105 ± 595 ng/mL). The lack of an association remained after adjustment (logistic regression) for sex, hormone replacement therapy status (current user or stopped use within the past month versus other) in women, and body mass index. We explored the joint effects of IGF-I and IGFBP-3 (categorized into tertiles based on the distribution among control subjects), but we found no excess of adenomas in any combination [Table 1,Go similar to Table 3 in (1)]. This lack of excess remained true when adenomas were categorized as either low or high risk (high risk was defined as >1 cm, severe dysplasia, tubulovillous or villous histology, or greater than two adenomas).


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Table 1. Odds ratio (OR)* of association between colorectal adenomas and tertiles of insulin-like growth factor (IGF)-I and insulin-like growth factor-binding protein (IGFBP)-3 in screened, healthy individuals aged 55-64 years

 
The lack of an association between IGF-I and IGFBP-3 and the presence of adenomas in our data does not, in itself, negate the findings of Ma et al. (1) but may provide an alternative hypothesis about the role of these circulating peptides in predicting tumor formation. One possible explanation for the apparent difference in results may be that IGF-I and IGFBP-3, while not predictive of neoplastic risk for all adenomas, may alternatively predict the transformation of late adenoma to adenocarcinoma. Our sample of individuals with high-risk adenomas (n = 20) may simply have been too small to detect such an effect.

If the findings of Ma et al. (1) are duplicated and evidence increases for an association between IGF-I and/or IGFBP-3 and the presence of adenomas, colorectal cancer could join the ranks of breast and prostate cancers as an "endocrine-dependent" cancer. This finding would represent a major new perspective in our understanding of the biology of this disease. In contrast to breast and prostate cancers, however, the local expression of IGFs and their binding proteins may theoretically be influenced by the intraluminal environment (i.e., dietary) as well as systemic factors. To date, the regulation of the intestinal IGF system remains poorly understood and clearly warrants further research.

REFERENCES

1 Ma J, Pollak MN, Giovannucci E, Chan JM, Tao Y, Hennekens CH, et al. Prospective study of colorectal cancer risk in men and plasma levels of insulin-like growth factor (IGF)-I and IGF-binding protein-3. J Natl Cancer Inst 1999;91:620-5.[Abstract/Free Full Text]

2 Burroughs KD, Dunn SE, Barrett JC, Taylor JA. Insulin-like growth factor-I: a key regulator of human cancer risk? J Natl Cancer Inst 1999;91: 579-81.[Free Full Text]

3 Winawer SJ, Fletcher RH, Miller L, Godlee F, Stoler MH, Mulrow CD, et al. Colorectal cancer screening: clinical guidelines and rationale. Gastroenterology 1997;112:594-642.[Medline]

4 Toogood AA, Jones J, O'Neill PA, Thorner MO, Shalet SM. The diagnosis of severe growth hormone deficiency in elderly patients with hypothamic-pituitary disease. Clin Endocrinol (Oxf) 1998;48:569-76.[Medline]


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