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Originally published as JCO Early Release 10.1200/JCO.2008.19.8937 on December 8 2008 © 2009 American Society of Clinical Oncology.
Insulin–Insulin-Like Growth Factor Axis and Colon Cancer
Division of Hematology and Oncology, Princess Margaret Hospital, University of Toronto, Toronto, Ontario, Canada
Division of Hematology and Oncology, Princess Margaret Hospital; and Samuel Lunenfeld Research Institute at Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada There is now compelling evidence linking physical inactivity and obesity with an increased risk of developing colon cancer. Several studies suggest that this association between lifestyle factors and colon cancer is mediated by hyperinsulinemia and insulin resistance, via the insulin–insulin-like growth factor (IGF) axis. Lending further support to this hypothesis is the fact that elevated plasma glucose and type II diabetes are also recognized as risk factors for developing colon cancer.1 Activation of the insulin-IGF axis may not only be an important risk factor for developing colon cancer, but may also have important prognostic implications in patients diagnosed with the disease. This parallels what has been previously shown in breast cancer where elevated levels of plasma insulin or C-peptide, or the presence of the insulin resistance syndrome, can increase the risk of both breast cancer recurrence and death.2-4 Understanding the insulin-IGF pathway and its role in colon cancer is therefore of clinical importance. The insulin-IGF pathway consists of three ligands (insulin, IGF-1, and IGF-2), six receptors (insulin receptor [IR] alpha [fetal], IR beta [adult], IGF-1 receptor [IGF-1R], IGF-2R, hybrid IGF-1R/IR alpha, hybrid IGF-1R/IR beta), and up to seven binding proteins (IGFBP1-7; Fig 1). Until recently much of the research on this pathway focused on IGF-1, a peptide growth factor that is secreted primarily by the liver in response to pituitary growth hormone, or high caloric intake. In the circulation, IGF-1 is mostly bound to IGFBP3, which not only regulates IGF-1 bioavailability, but may also have independent effects on cell proliferation and apoptosis. IGF-1 binds and activates both insulin and IGF receptors that are expressed on a number of cells including colon cancer cells. IGF-1-mediated receptor activation leads to cell growth, proliferation, and inhibition of apoptosis.5 Initial interest in the role of IGF-1 in colon cancer stemmed from observations that there was an increased risk of colorectal cancer noted in patients with acromegaly, a condition characterized by elevated levels of both pituitary growth hormone and IGF-1. This potential link was further supported by several in vitro studies on human colon cancer cells, which showed that IGF-1 promoted cell proliferation, IGF-1 receptors were frequently overexpressed on colon cancer cells, and IGF-1 R blockade with a monoclonal antibody inhibited cell proliferation.6 Clinically, however, a link between IGF-1 and colon cancer is less clear. Two prospective epidemiologic studies have shown that higher plasma IGF-1 and lower plasma IGFBP3 are associated with an increased risk of developing colon cancer; however, these associations were only statistically significant after adjustment for each other. It is unclear whether IGF-1 and IGFBP3 are causal factors in colorectal cancer.7-9
Insulin, another member of this family, which is most widely known for its metabolic effects, may also play an important role in colorectal carcinogenesis and progression. Preclinical studies have shown that insulin not only promotes the growth and survival of colorectal cancer cells, but can also promote IGF-I biosynthesis, and enhance IGF-I bioavailability by inhibiting the production of IGFBPs 1, 2, and 3.10 Insulin also directly stimulates in vitro mitogenesis of cultured normal colorectal epithelial cells and tumor angiogenesis.11 Animals fed high-fat, high caloric diets have increased insulin levels, develop insulin resistance, and experience increased colon tumor growth when compared with those fed calorie-restricted diets.12 There is also evidence linking elevated plasma insulin and glucose with increased adenoma risk and decreased apoptosis of normal colonic mucosal cells.10 Taken together, these results indicate that both IGF-1 and insulin may play a key role in colon cancer carcinogenesis and that further exploration is needed. Wolpin et al,13 in their article in this issue of Journal of Clinical Oncology, have demonstrated that, among patients with curatively resected colorectal cancer, higher levels of prediagnosis C-peptide and lower levels of plasma IGFBP1 were associated with increased mortality. They performed a prospective observational study nested within two large US cohorts to evaluate the association between mortality and prediagnosis circulating C-peptide, IGFBP1, IGF-I and IGFBP3. The use of C-peptide as a surrogate marker for plasma insulin secretion is not ideal; though in the nonfasting state, it is probably a more accurate marker of insulin resistance than insulin. There is growing evidence that C-peptide can independently activate intracellular signaling pathways that could affect cell growth and proliferation, leading to the possibility that C-peptide has effects that are not insulin related. In Wolpin's study, it is interesting to note that C-peptide levels were associated with overall mortality but not colorectal cancer-specific mortality, whereas IGFBP1 was strongly associated with both overall and colorectal cancer–specific death. Since, hepatic expression of the IGFBP1 gene is strongly regulated by insulin, IGFBP1 may actually be a better marker of insulin activity than nonfasting C-peptide. However, like C-peptide, IGFBP1 may also exert direct effects on cellular function and may play an independent role in carcinogenesis and tumor progression. Unlike prior studies examining risk of developing colorectal cancer,8 this study did not report an association between IGF-1 or IGFBP3 levels and prognosis of colorectal cancer. This could indicate that IGF-I and IGFBP3 do not play a role in colon carcinogenesis; alternatively, plasma levels of IGF-I or IGFBP3 may not accurately reflect local concentrations, produced by autocrine or paracrine secretion. Wolpin et al13 reported that the influence of IGFBP1 levels on mortality appeared to be the greatest in patients with a prediagnosis body mass index (BMI) above the cohort median, supporting a link between obesity and colon cancer. The prognostic impact of BMI specifically on colon cancer recurrence has been evaluated recently with somewhat inconsistent results. In a prospective, observational study of 1,053 patients with stage III colon cancer on a randomized trial, Meyerhardt et al14 reported that neither BMI nor weight change was significantly associated with an increased risk of cancer recurrence and death. This result differs from that reported by Dignam et al15 where obese patients (BMI > 35 kg/m2) had a 27% statistically significant increase in colon cancer recurrence or death. The article by Wolpin et al13 adds to the body of literature suggesting a link between hyperinsulinemia and colon cancer. Insulin is currently the best established biochemical link between obesity and colon cancer; and controlling hyperinsulinemic states, such as insulin resistance syndrome and type 2 diabetes, may decrease the risk of developing colon cancer and improve prognosis in patients with colon cancer. From a therapeutic standpoint, studies are now underway or planned to examine whether lifestyle factors or drugs such as metformin, which reduce circulating insulin levels, may have a beneficial effect in the prevention and treatment of cancer. An ongoing phase II/III study,16 for example, is examining the effect of exercise on biomarkers of colon cancer risk, and similarly in breast cancer, an adjuvant lifestyle intervention study17 is also ongoing in which the primary end point is disease-free survival. Another key neoadjuvant study is opening imminently and will look at the potential benefit of metformin on proliferation rates and signaling pathways in nondiabetic breast cancer patients, and will hopefully answer an important question with respect to insulin levels and breast cancer using a relatively inexpensive drug intervention (Pamela Goodwin, personal communication, November 2008). Novel agents targeting the IGF-1 receptor have also entered clinical evaluation18—they may be particularly effective in breast cancers where an IGF gene signature which correlated highly with numerous poor prognostic factors has recently been identified.19 Given the common mitogenic signaling pathways for IGF-1 and insulin, it is likely that a similar signature exists for insulin—research to address this possibility in both breast cancer and colorectal cancer is urgently needed. As noted, lifestyle interventions, targeting diet, obesity, and physical inactivity that may modify insulin levels are also being evaluated in both breast and colon cancer. As we move forward in this field, an openness to potential contributions of all of these factors will be critical. Choosing appropriate markers for members of the insulin/IGF family will be important, and may also help to establish whether it is these individual factors, glucose metabolism and energy balance in general, or the interplay between them that is most important in colorectal cancer. Correlative studies and molecular evaluation of tumor biopsies will also be necessary to determine effects at the tissue level. Although further research is warranted to confirm and expand the findings of the article by Wolpin et al,13 it would appear at this point that targeting the insulin-IGF pathway in colon cancer, through pharmacologic or lifestyle interventions, holds significant therapeutic promise. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: None Stock Ownership: None Honoraria: None Research Funding: Srikala S. Sridhar, Amgen Expert Testimony: None Other Remuneration: None AUTHOR CONTRIBUTIONS Conception and design: Srikala S. Sridhar, Pamela J. Goodwin Administrative support: Pamela J. Goodwin Collection and assembly of data: Srikala S. Sridhar, Pamela J. Goodwin Data analysis and interpretation: Srikala S. Sridhar, Pamela J. Goodwin Manuscript writing: Srikala S. Sridhar, Pamela J. Goodwin Final approval of manuscript: Srikala S. Sridhar, Pamela J. Goodwin
NOTES published online ahead of print at www.jco.org on December 8, 2008 REFERENCES 1. McKeown-Eyssen G: Epidemiology of colorectal cancer revisited: Are serum triglycerides and/or plasma glucose associated with risk? Cancer Epidemiol Biomarkers Prev 3:687-695, 1994[Abstract] 2. Goodwin PJ, Ennis M, Pritchard KI, et al: Fasting insulin and outcome in early-stage breast cancer: Results of a prospective cohort study. J Clin Oncol 20:42-51, 2002 3. Berrino F, Villarini A, De Petris M, et al: Adjuvant diet to improve hormonal and metabolic factors affecting breast cancer prognosis. Ann N Y Acad Sci 1089:110-118, 2006[CrossRef][Medline] 4. Pollak M: Insulin-like growth factor-related signaling and cancer development. Recent Results Cancer Res 174:49-53, 2007[CrossRef][Medline] 5. Goodwin PJ: Insulin in the adjuvant breast cancer setting: A novel therapeutic target for lifestyle and pharmacologic interventions? J Clin Oncol 26:833-834, 2008 6. Lahm H, Amstad P, Wyniger J, et al: Blockade of the insulin-like growth factor 1 receptor inhibits growth of human colorectal cancer cells: Evidence of a functional IGF-2–mediated autocrine loop. Int J Cancer 58:452-459, 1994[Medline] 7. Giovannucci E, Pollak MN, Platz EA, et al: A prospective study of plasma insulin-like growth factor-1 and binding protein-3 and risk of colorectal neoplasia in women. Cancer Epidemiol Biomarkers Prev 9:345-349, 2000 8. Ma J, Pollak MN, Giovannucci E, 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 91:620-625, 1999 9. Sandhu MS, Dunger DB, Giovannucci EL: Insulin, insulin-like growth factor-I (IGF-I), IGF binding proteins, their biologic interactions, and colorectal cancer. J Natl Cancer Inst 94:972-980, 2002 10. Keku TO, Lund PK, Galanko J, et al: Insulin resistance, apoptosis, and colorectal adenoma risk. Cancer Epidemiol Biomarkers Prev 14:2076-2081, 2005 11. Bruce WR, Giacca A, Medline A: Possible mechanisms relating diet and risk of colon cancer. Cancer Epidemiol Biomarkers Prev 9:1271-1279, 2000 12. Lasko CM, Bird RP: Modulation of aberrant crypt foci by dietary fat and caloric restriction: The effects of delayed intervention. Cancer Epidemiol Biomarkers Prev 4:49-55, 1995[Abstract] 13. Wolpin BM, Meyerhardt JA, Chan AT, et al: Insulin, the insulin-like growth factor axis, and mortality in patients with nonmetastatic colorectal cancer. J Clin Oncol [epub ahead of print on December 8, 2008] 14. Meyerhardt JA, Niedzwiecki D, Hollis D, et al: Impact of body mass index and weight change after treatment on cancer recurrence and survival in patients with stage III colon cancer: Findings from Cancer and Leukemia Group B 89803. J Clin Oncol 26:4109-4115, 2008 15. Dignam JJ, Polite BN, Yothers G, et al: Body mass index and outcomes in patients who receive adjuvant chemotherapy for colon cancer. J Natl Cancer Inst 98:1647-1654, 2006 16. Fred Hutchinson Cancer Research Center: Effect of exercise on biomarkers of colon cancer risk (APPEAL). http://clinicaltrials.gov/show/NCT00668161 17. Ontario Clinical Oncology Group, Novartis: Lifestyle intervention study in adjuvant treatment of early breast cancer (LISA). http://clinicaltrials.gov/show/NCT00463489 18. National Library of Medicine. http://clinicaltrials.gov 19. Creighton CJ, Casa A, Lazard Z, et al: Insulin-like growth factor-I activates gene transcription programs strongly associated with poor breast cancer prognosis. J Clin Oncol 26:4078-4085, 2008
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Copyright © 2009 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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