Insulin, IGFs, and energy balance: Relevance to cancer risk.

CS23-01

In the late 1990's, we and other groups observed in prospective population studies that individuals with circulating insulin-like growth factor I (IGF-I) levels at the higher end of the broad normal range had increased risk of a subsequent diagnosis of common epithelial cancers, such as those of the prostate, breast, or colon. These observations have been reproduced by many, but not all, subsequent follow-up studies (1,2,3). More recent work (for example (4)) has provided evidence that specific germ line polymorphisms in certain genes encoding proteins involved in the IGF signaling pathway, including IGF-I itself, are associated with variation in cancer risk. In addition, a considerable body of circumstantial evidence relating IGF physiology to cancer risk has accumulated. For example, high mammographic breast density and high birth weight, both known to predict increased breast cancer risk, have been associated with higher levels of circulating IGF-I (5) or umbilical cord IGF-I levels (reviewed in 6), respectively. Also, the weak but detectable positive correlation between height and risk of certain cancers may exist because height acts as a crude surrogate for adolescent levels of circulating IGF-I. Laboratory experiments have yielded data consistent with some of the population findings. For example, crossing prostate cancer-predisposed TRAMP mice with mice that are growth hormone and IGF-I deficient due to the lit mutation results in attenuated carcinogenesis and neoplastic progression (7). Similarly, DMBA-induced chemical carcinogenesis in the mammary gland is attenuated in mice genetically manipulated to lower IGF-I levels (8). Population studies examining relationships between fasting insulin levels (or c-peptide levels) and cancer risk and prognosis are ongoing. Results reported to date that involve analysis of samples obtained near the time of cancer diagnosis (for example (9)) suggest that higher levels are associated with worse prognosis of common epithelial cancers, while prospective studies of healthy subjects suggest that those with higher levels of these analytes are at increased risk of aggressive cancer or cancer with fatal outcome (10). These results suggest a possible mechanism underlying the association between obesity and adverse outcome in prostate cancer, as obesity is often associated with hyperinsulinemia. While experimental data suggest that the well known inhibition of rodent carcinogenesis associated with dietary restriction is related to the suppressive effect of diet restriction on IGF-I levels (11), there is emerging evidence that in models where accelerated carcinogenesis is associated with excess caloric intake, elevations in insulin levels may be involved (12). The molecular and cellular biology underlying the observations reviewed above are the subject of ongoing research. The pathways downstream of the insulin and IGF-I receptors are well characterized. In general, pathway activation is associated with increased cell proliferation and increased cell survival. A hypothesis for increased cancer risk associated with increased IGF-I level postulates that even a small increase in pathway activation in epithelial cells at risk for transformation would increase probability of survival of cells accumulating genetic damage during the process of stepwise carcinogenesis - an effect which would increase the likelihood of accumulating sufficient damage for for full transformation. It is also possible, particularly with respect to observations relating insulin levels to poor outcome, that the neoplastic behavior of transformed cells is directly stimulated by insulin. Implications for Clinical Cancer Prevention: Pharmacologic targeting of insulin and/or IGF signaling by the use of anti-receptor antibodies or small molecule tyrosine kinase inhibitors is is receiving considerable attention in the context of cancer treatment, but these strategies are too early in development to be considered for prevention.The possibility that IGF-related germ line polymorphisms or levels of serum analytes related to IGF/insulin physiology may be clinically relevant in assessing absolute level of risk and/or the probability of successful risk reduction by specific lifestyle (eg dietary, exercise) or pharmacologic (eg tamoxifen or finasteride) interventions is under study. It is of interest that certain chemopreventive agents under study, such as retinoids (reviewed in (13)) or silibinin (14) may act in part through mechanisms that involve reduction of IGF bioactivity. Emerging evidence that hyperinsulinemia may be involved in the relationship between obesity and cancer mortality suggests that lifestyle and possibly pharmacologic strategies to lower insulin levels in at-risk subjects and/or newly diagnosed cancer patients deserves investigation. This is important from a public health point of view, given the worrisome population trends with respect to obesity. Drugs such as metformin are known to have systemic insulin-lowering actions, and also to activate AMP kinase, which may in turn activate pathways that restrain proliferation (15). Metformin also is known to have a relatively favorable toxicity profile, and is in wide clinical use in the management of type II diabetes, which is associated with hyperinsulinemia and insulin resistance. Hypothesis-generating population studies (16,17) suggest unexpectedly low cancer burden in diabetics on metformin compared to diabetics on other therapies, and justify further research. Insulin-lowering approaches using currently available lifestyle and pharmacologic approaches may have potential in cancer prevention, particularly if targeted specifically to subpopulations with hyperinsulinemia. References 1. Chan, J. M., Stampfer, M. J., Giovannucci, E., Gann, P. H., Ma, J., Wilkinson, P., Hennekens, C. H., and Pollak, M. Plasma insulin-like growth factor-I and prostate cancer risk: a prospective study. Science, 279: 563-566, 1998. 2. Pollak, M., Schernhammer, E. S., Hankinson, S. E. Insulin-like growth factors and neoplasia. Nat.Rev.Cancer, 4: 505-518, 2004. 3. Renehan, A. G., Zwahlen, M., Minder, C., O'Dwyer, S. T., Shalet, S. M., and Egger, M. Insulin-like growth factor (IGF)-I, IGF binding protein-3, and cancer risk: systematic review and meta-regression analysis. Lancet, 363: 1346-1353, 2004. 4. Cheng I, Stram DO, Penney KL, Pike M, Le Marchand L, Kolonel LN, Hirschhorn J, Altshuler D, Henderson BE, Freedman ML. Common genetic variation in IGF1 and prostate cancer risk in the Multiethnic Cohort. J Natl Cancer Inst. 2006 Jan 18;98(2):123-34 5. Diorio, C., Pollak, M., Byrne, C., Masse, B., Hebert-Croteau, N., Yaffe, M., Cote, G., Berube, S., Morin, C., Brisson, J. Insulin-like growth factor-I, IGF-binding protein-3, and mammographic breast density. Cancer Epidemiology, Biomarkers & Prevention 14: 1065-1073, 2005. 6. Michels KB, Xue F. Role of birthweight in the etiology of breast cancer. Int J Cancer. 2006 Nov 1;119(9):2007-25 7. Majeed, N., Blouin, M-J., Kaplan-Lefko, P.J., Barry-Shaw, J., Greenberg, N.M., Gaudreau, P., Bismar, T.A., Pollak, M. A germ line mutation that delays prostate cancer progression and prolongs survival in a murine prostate cancer model. Oncogene 24: 4736-4740, 2005. 8. Pollak, M., Blouin, M-J., Jian-Chun, Z., Kopchick, J.J. Reduced mammary gland carcinogenesis in transgenic mice expressing a growth hormone antagonist. British Journal of Cancer, 85: 428-430, 2001 9. M. N. Pollak, J. W. Chapman, L. Shepherd, D. Meng, P. Richardson, C. Wilson, B. Orme, K. I. Pritchard. Insulin resistance, estimated by serum C-peptide level, is associated with reduced event-free survival for postmenopausal women in NCIC CTG MA.14 adjuvant breast cancer trial. Journal of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings. Vol 24, No. 18S (June 20 Supplement), 2006: 524 10. Jing Ma, Haojie Li, Michael Pollak, Tobias Kurth, Ed Giovannucci, Meir Stampfer. Prediagnostic plasma C-peptide levels and prostate cancer incidence and survival. submittted to AACR 5th Annual 'Frontiers in Cancer Preventon Research' meeting, Boston, 2006 11. Dunn SE, Kari FW, French J, Leininger JR, Travlos G, Wilson R, Barrett JC. Dietary restriction reduces insulin-like growth factor I levels, which modulates apoptosis, cell proliferation, and tumor progression in p53-deficient mice. Cancer Res. 1997: 57(21):4667-72. 12. Yakar S, Nunez NP, Pennisi P, Brodt P, Sun H, Fallavollita L, Zhao H, Scavo L, Novosyadlyy R, Kurshan N, Stannard B, East-Palmer J, Smith NC, Perkins SN, Fuchs-Young R, Barrett JC, Hursting SD, Leroith D. Increased tumor growth in mice with diet-induced obesity: impact of ovarian hormones. Endocrinology. 2006 Sep 7; [Epub ahead of print] 13. Zanardi S, Serrano D, Argusti A, Barile M, Puntoni M, Decensi A. Clinical trials with retinoids for breast cancer chemoprevention. Endocr Relat Cancer. 2006 Mar;13(1):51-68. 14. Zi, X., Zhang, J., Agarwal, R., Pollak M. Silibinin up-regulates insulin-like growth binding protein 3 expression and inhibits proliferation of androgen-independent prostate cancer cells. Cancer Research 60: 5617-5620, 2000. 15 Zakikhani M, Dowling R, Fantus G, Sonenberg N, Pollak M. Metformin is an AMP kinase dependent growth inhibitor for breast cancer cells. Cancer Research, in press, 2006. 16. Evans, J. M., Donnelly, L. A., Emslie-Smith, A. M., Alessi, D. R., and Morris, A. D. Metformin and reduced risk of cancer in diabetic patients. BMJ, 330: 1304-1305, 2005. 17. Bowker, S. L., Majumdar, S. R., Veugelers, P., and Johnson, J. A. Increased cancer-related mortality for patients with type 2 diabetes who use sulfonylureas or insulin. Diabetes Care, 29: 254-258, 2006.