Insulin-like growth factor (IGF)-I is an important mitogen required by some cell types to progress from the G1 phase to the S phase of the cell cycle. IGF binding proteins (IGFBPs) can have opposing actions, in part by binding IGF-I, but also by direct inhibitory effects on target cells. As mitogens and anti-apoptotic agents, IGFs may be important in carcinogenesis, possibly by increasing the risk of cellular transformation by enhancing cell turnover. Indeed, many types of neoplastic cells express or overexpress IGF-I receptors, which stimulate mitogenesis when activated by IGF-I in vitro. In vivo, tissue IGF bioactivity is determined not only by circulating IGF-I and IGFBP levels, but also by local production of IGFs, IGFBPs, and possibly IGFBP proteases that enhance IGF-I availability by cleaving IGFBPs. Because determinants of tissue IGF bioactivity appear to be regulated in parallel with circulating IGF-I level, it is reasonable to hypothesize that the substantial intraindividual variability in circulating levels of IGF-I and IGFBP-3 may be important in determining risk of some cancers. In recent epidemiologic studies, relatively high plasma IGF-I and low IGFBP-3 levels have been independently associated with greater risk of prostate cancer in men, breast cancer among premenopausal women, and colorectal adenoma and cancer in men and women and possibly lung cancer. These include prospective data from the Physicians’ Health Study and the Nurses’ Health Study. In general, two- to fourfold elevated risks have been observed for prostate cancer in men in the top quartile of IGF-I relative to those in the bottom quartile, and low levels of IGFBP-3 were associated with an approximate doubling of risk. For breast cancer, an association with IGF-I for postmenopausal women was not apparent, but strong associations were observed for premenopausal cases in the Nurses’ Health Study. Further study is needed to confirm this subgroup finding in women. Recent data also indicate that high IGF-I and low IGFBP-3 increase risk of colorectal cancer and large or villous adenomas. Of note, for colorectal neoplasia, fourfold elevated risks were observed in men and women with low IGFBP-3, whereas high IGF-I was associated with a doubling of risk. These emerging epidemiologic data indicate that high levels of IGF-I and low levels of IGFBP-3 are associated with an increased risk of at least several types of carcinoma that are common in economically developed countries. Further study is required to determine the clinical relevance of these findings.

Keywords:
Insulin-like growth factor, Insulin-like growth factor binding protein-3, Cancer risk, Colorectal neoplasms, Breast neoplasms, Prostate neoplasms
1.
Aaronson S: Growth factors and cancer. Science 1991;254:1146–1153.
2.
Rechler M: Growth inhibition by insulin-like growth factor (IGF) binding protein-3 – what’s IGF got to do with it? Endocrinology 1997;138:2645–2647.
3.
Rajah R, Valentinis B, Cohen P: Insulin-like growth factor (IGF)-binding protein-3 induces apoptosis and mediates the effects of transforming growth factor-1 on programmed cell death through a p53 and IGF-independent mechanism. J Biol Chem 1997;272:12181–12188.
4.
Jones J, Clemmons D: Insulin-like growth factors and their binding proteins: biological actions. Endocr Rev 1995;16:3–34.
5.
Vogelstein B, Fearon ER, Hamilton SR, Kern SE, Preisinger AC, Leppert M, Nakamura Y, White R, Smits AMM, Bos JL: Genetic alterations during colorectal-tumor development. N Engl J Med 1988;319:525–532.
6.
Baserga R: The insulin-like growth factor I receptor: a key to tumor growth? Cancer Res 1995;55:249–252.
7.
Pollak M, Costantino J, Polychronakos C, Blauer SA, Guyda H, Redmond C, Fisher B, Margolese R: Effect of tamoxifen on serum insulinlike growth factor I levels in stage I breast cancer patients. J Natl Cancer Inst 1990;82:1693–1697.
8.
Huynh H, Yang X, Pollak M: Estradiol and antiestrogens regulate a growth inhibitory insulin-like growth factor binding protein 3 autocrine loop in human breast cancer cells. J Biol Chem 1996;271:1016–1021.
9.
Huynh H, Yang XF, Pollak M: A role for insulin-like growth factor binding protein 5 in the antiproliferative action of the antiestrogen ICI 182780. Cell Growth Differ 1996;7:1501–1506.
10.
Peehl DM, Cohen P, Rosenfeld RG: The insulin-like growth factor system in the prostate. World J Urol 1995;13:306–311.
11.
Mantzoros CS, Tzonou A, Signorello LB, Stampfer M, Trichopoulos D, Adami H-O: Insulin-like growth factor 1 in relation to prostate cancer and benign prostatic hyperplasia. Br J Cancer 1997;76:1115–1118.
12.
Chan JM, Stampfer MJ, Giovannucci E, Gann PH, Ma J, Wilkinson P, Hennekens CH, Pollak M: Plasma insulin-like growth factor-I and prostate cancer risk: a prospective study. Science 1998;279:563–566.
13.
Wolk A, Mantzoros CS, Andersson S-O, Bergström R, Signorello LB, Lagiou P, Adami H-O, Trichopoulos D: Insulin-like growth factor 1 and prostate cancer risk: a population-based, case-control study. J Natl Cancer Inst 1998;90:911–915.
14.
Pollak MN, Perdue JF, Margolese RG, Baer K, Richard M: Presence of somatomedin receptors on primary human breast and colon carcinomas. Cancer Lett 1987;38:223–230.
15.
Guo YS, Narayan S, Yallampalli C, Singh P: Characterization of insulinlike growth factor I receptors in human colon cancer. Gastroenterology 1992;102:1101–1108.
16.
Watkins L, Lewis L, Levine A: Characterization of the synergistic effect of insulin and transferrin and the regulation of their receptors on a human colon carcinoma cell line. Int J Cancer 1990;45:372–375.
17.
Koenuma M, Yamori T, Tsuruo T: Insulin and insulin-like growth factor 1 stimulate proliferation of metastatic variants of colon carcinoma 26. Jpn J Cancer Res 1989;80:51-58.
18.
Bjork J, Nilsson J, Hultcrantz R, Johansson C: Growth-regulatory effects of sensory neuropeptides, epidermal growth factor, insulin, and somatostatin on the non-transformed intestinal epithelial cell line IEC-6 and the colon cancer cell line HT 29. Scand J Gastroenterol 1993;28:879–884.
19.
Cats A, Dullaart R, Kleibeuker J, Kuipers F, Sluiter W, Hardonk M, de Vries E: Increased epithelial cell proliferation in the colon of patients with acromegaly. Cancer Res 1996;56:523–526.
20.
Klein I, Parveen G, Gavaler J, Vanthiel D: Colonic polyps in patients with acromegaly. Ann Intern Med 1982;97:27–30.
21.
Ituarte E, Petrini J, Hershman J: Acromegaly and colon cancer. Ann Intern Med 1984;101:627–628.
22.
Pines A, Rozen P, Ron E, Gilat T: Gastrointestinal tumors in acromegalic patients. Am J Gastroenterol 1985;80:266–269.
23.
Ritter M, Richter W, Schwandt P: Acromegaly and colon cancer. Ann Intern Med 1987;106:636–637.
24.
Ziel F, Peters A: Acromegaly and gastrointestinal adenocarcinomas. Ann Intern Med 1988;109:514–515.
25.
Brunner J, Johnson C, Zafar S, Peterson E, Brunner J, Mellinger R: Colon cancer and polyps in acromegaly: increased risk associated with family history of colon cancer. Clin Endocrinol 1990;32:65–71.
26.
Terzolo M, Tappero G, Borretta G, Asnaghi G, Pia A, Reimondo G, Boccuzzi A, Cesario F, Rovero E, Paccotti P, Angeli A:High prevalence of colonic polyps in patients with acromegaly. Influence of sex and age. Arch Intern Med 1994;154:1272–1276.
27.
Jenkins P, Fairclough P, Richards T, Lowe D, Monson J, Grossman A, Wass J, Besser M: Acromegaly, colonic polyps and carcinoma. Clin Endocrinol 1997;47:17–22.
28.
Ron E, Gridley G, Hrubec Z, Page W, Arora S, Fraumeni J Jr: Acromegaly and gastrointestinal cancer. Cancer 1991;68:1673–1677.
29.
Barzilay J, Heatley G, Cushing G: Benign and malignant tumors in patients with acromegaly. Arch Intern Med 1991;151:1629–1632.
30.
Giovannucci E, Pollak MN, Platz EA, Willett WC, Stampfer MJ, Majeed N, Colditz GA, Speizer FE, Hankinson SE: Plasma insulin-like growth factor-1 and binding protein-3 and risk of colorectal cancer and adenoma in women (abstract 1399); in Proceedings of the 90th Annual Meeting of the American Association for Cancer Research, 1999, Philadelphia, Pa.
31.
Markowitz AJ, Winawer SJ: Management of colorectal polyps. CA Cancer J Clin 1997;47:93–112.
32.
Ma J, Pollak MN, Giovannucci E, Chan JM, Tao T, Hennekens CH, Stampfer MJ: Prospective study of colorectal cancer risk in men and plasma levels of insulin-like growth factor (IGF)-1 and IGF-binding protein-3. J Natl Cancer Inst 1999;91:620–625.
33.
Glass A, Kikendall J, Sobin L, Bowen P: Serum concentrations of insulin-like growth factor 1 in colonic neoplasia (letter). Acta Oncol 1994;33:70–71.
34.
Hankinson SE, Willett WC, Colditz GA, Hunter DJ, Michaud DS, Deroo B, Rosner B, Speizer FE, Pollak M: Circulating concentrations of insulin-like growth factor-I and risk of breast cancer. Lancet 1998;351:1393–1396.
35.
Bohlke K, Cramer DW, Trichopoulos D, Mantzoros CS: Insulin-like growth factor-I in relation to premenopausal ductal carcinoma in situ of the breast. Epidemiology 1998;9:570–573.
36.
Yu H, Spitz MR, Mistry J, Gu J, Hong WK, Wu X: Plasma levels of insulin-like growth factor-I and lung cancer risk: a case-control analysis. J Natl Cancer Inst 1999;91:151–156.
37.
Juul A, Bang P, Hertel NT, Main K, Dalgaard P, Jorgensen K, Muller J, Hall K, Skakkebæk NE: Serum insulin-like growth factor-I in 1030 healthy children, adolescents, and adults: relation to age, sex, stage of puberty, testicular size, and body mass index. J Clin Endocrinol Metab 1994;78:744–752.
38.
Juul A, Dalgaard P, Blum WF, Bang P, Hall K, Michaelsen KF, Muller J, Skakkebæk NE: Serum levels of insulin-like growth factor (IGF)-binding protein-3 (IGFBP-3) in healthy infants, children, and adolescents: the relation to IGF-I, IGF-II, IGFBP-1, IGFBP-2, age, sex, body mass index, and pubertal maturation. J Clin Endocrinol Metab 1995;80:2534–2542.
39.
Goodman-Gruen D, Barrett-Connor E: Epidemiology of insulin-like growth factor-I in elderly men and women: the Rancho Bernardo Study. Am J Epidemiol 1997;145:970–976.
40.
Juul A, Main K, Blum WF, Lindholm J, Ranke MB, Skakkebæk NE: The ratio between serum levels of insulin-like growth factor (IGF)-I and the IGF binding proteins (IGFBP-1, 2 and 3) decreases with age in healthy adults and is increased in acromegalic patients. Clin Endocrinol 1994;41:85–93.
41.
Giovannucci E, Ascherio A, Rimm EB, Colditz GA, Stampfer MJ, Willett WC: Physical activity, obesity, and risk for colon cancer and adenoma in men. Ann Intern Med 1995;122:327–334.
42.
Chute CG, Willett WC, Colditz GA, Stampfer MJ, Baron JA, Rosner B, Speizer FE: A prospective study of body mass, height, and smoking on the risk of colorectal cancer in women. Cancer Causes Control 1991;2:117–124.
43.
Albanes D, Jones DY, Schatzkin A, Micozzi MS, Taylor PR: Adult stature and risk of cancer. Cancer Res 1988;48:1658–1662.
44.
Hebert PR, Ajani U, Cook NR, Lee I-M, Chan KS, Hennekens CH: Adult height and incidence of cancer in male physicians (United States). Cancer Causes Control 1997;8:591–597.
45.
Harrela M, Koistinen H, Kaprio J, Lehtovirta M, Tuomilehto J, Eriksson J, Toivanen L, Koskenvuo M, Leinonen P, Koistinen R, Seppälä M: Genetic and environmental components of interindividual variation in circulating levels of IGF-I, IGF-II, IGFBP-1, and IGFBP-3. J Clin Invest 1996;98:2612–2615.
46.
Isley WL, Underwood LE, Clemmons DR: Dietary components that regulate serum somatomedin-C concentrations in humans. J Clin Invest 1983;71:175–182.
47.
Clemmons DR, Underwood LE, Dickerson RN, Brown RO, Hak LJ, MacPhee RD, Heizer WD: Use of plasma somatomedin-C/insulin-like growth factor I measurements to monitor the response to nutritional repletion in malnourished patients. Am J Clin Nutr 1985;41:191–198.
48.
Unterman TG, Vazquez RM, Slas AJ, Martyn PA, Phillips LS: Nutrition and somatomedin. XIII. Usefulness of somatomedin-C in nutritional assessment. Am J Med 1985;78:228–234.
49.
Ruggeri BA, Klurfeld DM, Kritchevsky D, Furlanetto RW: Caloric restriction and 7,12-dimethylbenz(a)anthracene-induced mammary tumor growth in rats: alterations in circulating insulin, insulin-like growth factors I and II, and epidermal growth factor. Cancer Res 1989;49:4130–4134.
50.
Klurfeld DM, Lloyd LM, Welch CB, Davis MJ, Tulp OL, Kritchevsky D: Reduction of enhanced mammary carcinogenesis in LA/N-cp (corpulent) rats by energy restriction. Proc Soc Exp Biol Med 1991;196:381–384.
51.
Pollak MN, Polychronakos C, Guyda H: Somatostatin analogue SMS 201-995 reduces serum IGF-I levels in patients with neoplasms potentially dependent on IGF-I. Anticancer Res 1989;9:889–891.
52.
Zarandi M, Horvath JE, Halmos G, Pinski J, Nagy A, Groot K, Rekasi Z, Schally AV: Synthesis and biological activities of highly potent antagonists of growth hormone-releasing hormone. Proc Natl Acad Sci USA 1994;91:12298–12302.
53.
Rudman D, Feller AG, Nagraj HS, Gergans GA, Lalitha PY, Goldberg AF, Schlenker RA, Cohn L, Rudman IW, Mattson DE: Effects of human growth hormone in men over 60 years old. N Engl J Med 1990;323:1–6.
54.
Cascinu S, Del Ferro E, Grianti C, Ligi M, Ghiselli R, Foglietti G, Saba V, Lungarotti F, Catalano G: Inhibition of tumor cell kinetics and serum insulin growth factor I levels by octreotide in colorectal cancer patients. Gastroenterology 1997;113:767–772.
55.
Dy D, Whitehead R, Morris D: SMS 201.995 inhibits in vitro and in vivo growth of human colon cancer. Cancer Res 1992;52:917–923.
56.
Cascinu S, Del Ferro E, Catalano G: A randomised trial of octreotide vs best supportive care only in advanced gastrointestinal cancer patients refractory to chemotherapy. Br J Cancer 1995;71:97–101.
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1999
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