Abstract
Background
Prediagnosis obesity and diabetes are associated with survival from pancreatic cancer, but the underlying mechanisms have not been characterized. Because both are associated with dysregulation in circulating insulin-like growth factor (IGF) levels, we evaluated the associations of prediagnosis IGF levels (IGF-I, IGF-II) and IGF binding protein 3 (IGFBP-3) with pancreatic cancer survival.
Methods
Participants were subjects enrolled in the intervention arm of the PLCO Cancer Screening Trial who developed exocrine pancreatic cancer during follow-up (N = 178, 116 men and 67 women). Participants provided blood samples at enrollment, before cancer diagnosis. Cox proportional hazards regression model, adjusted for confounders was used to investigate associations of IGF biomarkers with pancreatic cancer survival. Because of the well-documented, gender-specific differences in circulating IGF biomarkers, and differential associations of IGF biomarkers with mortality, we evaluated associations separately among males and females.
Results
Median survival was 172 days. Higher IGF-II and IGFBP-3 levels were associated with pancreatic cancer survival among males but not among females. The hazard ratios (HR) of death among men in the highest tertiles of IGF-II and IGFBP-3 compared with men in the lowest tertiles were 0.40 (95% confidence interval (CI) 0.23–0.71, p < 0.01) and 0.59 (95% CI 0.35–0.97, p = 0.10), respectively. There were no statistically significant associations between IGF-I concentrations, IGF-I/IGFBP-3, and pancreatic cancer survival.
Conclusions
Higher prediagnosis circulating IGF-II and IGFBP-3 levels are associated with better pancreatic cancer survival among men but not women. A greater understanding of how IGF signaling is related to pancreatic cancer survival could have utility in improving pancreatic cancer prognosis.
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References
Wolfgang CL, Herman JM, Laheru DA, Klein AP, Erdek MA, Fishman EK, et al. Recent progress in pancreatic cancer. CA Cancer J Clin. 2013;63:318–48.
Klein AP, Lindstrom S, Mendelsohn JB, Steplowski E, Arslan AA, Bueno-de-Mesquita HB, et al. An absolute risk model to identify individuals at elevated risk for pancreatic cancer in the general population. PloS One. 2013;8:e72311.
Toriola AT, Stolzenberg-Solomon R, Dalidowitz L, Linehan D, Colditz G. Diabetes and pancreatic cancer survival: a prospective cohort-based study. Br J Cancer. 2014;111:181–85.
Pollak M. The insulin and insulin-like growth factor receptor family in neoplasia: an update. Nat Rev Cancer. 2012;12:159–69.
Kahn SE, Hull RL, Utzschneider KM. Mechanisms linking obesity to insulin resistance and type 2 diabetes. Nature. 2006;444:840–46.
Khandwala HM, McCutcheon IE, Flyvbjerg A, Friend KE. The effects of insulin-like growth factors on tumorigenesis and neoplastic growth. Endocrine Rev. 2000;21:215–44.
Baxter RC. IGF binding proteins in cancer: mechanistic and clinical insights. Nat Rev Cancer. 2014;14:329–41.
Lashinger LM, Malone LM, McArthur MJ, Goldberg JA, Daniels EA, Pavone A, et al. Genetic reduction of insulin-like growth factor-1 mimics the anticancer effects of calorie restriction on cyclooxygenase-2-driven pancreatic neoplasia. Cancer Prev Res. 2011;4:1030–40.
Douglas JB, Silverman DT, Pollak MN, Tao Y, Soliman AS, Stolzenberg-Solomon RZ. Serum IGF-I, IGF-II, IGFBP-3, and IGF-I/IGFBP-3 molar ratio and risk of pancreatic cancer in the prostate, lung, colorectal, and ovarian cancer screening trial. Cancer Epidemiol Biomarkers Prev. 2010;19:2298–306.
Rohrmann S, Grote VA, Becker S, Rinaldi S, Tjonneland A, Roswall N, et al. Concentrations of IGF-I and IGFBP-3 and pancreatic cancer risk in the European Prospective Investigation into Cancer and Nutrition. Br J Cancer. 2012;106:1004–10.
Stolzenberg-Solomon RZ, Limburg P, Pollak M, Taylor PR, Virtamo J, Albanes D. Insulin-like growth factor (IGF)-1, IGF-binding protein-3, and pancreatic cancer in male smokers. Cancer Epidemiol Biomark Prev. 2004;13:438–44.
Wolpin BM, Michaud DS, Giovannucci EL, Schernhammer ES, Stampfer MJ, Manson JE, et al. Circulating insulin-like growth factor axis and the risk of pancreatic cancer in four prospective cohorts. Br J Cancer. 2007;97:98–104.
Pollak MN, Schernhammer ES, Hankinson SE. Insulin-like growth factors and neoplasia. Nat Rev Cancer. 2004;4:505–18.
Ma J, Sawai H, Matsuo Y, Ochi N, Yasuda A, Takahashi H, et al. IGF-1 mediates PTEN suppression and enhances cell invasion and proliferation via activation of the IGF-1/PI3 K/Akt signaling pathway in pancreatic cancer cells. J Surg Res. 2010;160:90–101.
Brabant G, von Zur Muhlen A, Wuster C, Ranke MB, Kratzsch J, Kiess W, et al. (2003) Serum insulin-like growth factor I reference values for an automated chemiluminescence immunoassay system: results from a multicenter study. Horm Res 60:53–60.
Brabant G, Wallaschofski H. Normal levels of serum IGF-I: determinants and validity of current reference ranges. Pituitary. 2007;10:129–33.
Hietaniemi M, Pöykkö SM, Ukkola O, Päivänsalo M, Antero Kesäniemi Y. IGF‐I concentrations are positively associated with carotid artery atherosclerosis in women. Ann Med. 2005;37:373–82.
Undén A-L, Elofsson S, Brismar K. Gender differences in the relation of insulin-like growth factor binding protein-1 to cardiovascular risk factors: a population-based study. Clin Endocrinol. 2005;63:94–102.
Friedrich N, Haring R, Nauck M, Ludemann J, Rosskopf D, Spilcke-Liss E, et al. Mortality and serum insulin-like growth factor (IGF)-I and IGF binding protein 3 concentrations. J Clin Endocrinol Metab. 2009;94:1732–39.
Friedrich N, Schneider H, Dorr M, Nauck M, Volzke H, Klotsche J, et al. All-cause mortality and serum insulin-like growth factor I in primary care patients. Growth Horm IGF Res. 2011;21:102–06.
Zhu CS, Pinsky PF, Kramer BS, Prorok PC, Purdue MP, Berg CD, et al. (2013) The Prostate, lung, colorectal, and ovarian cancer screening Trial and its associated research resource. J Natl Cancer Inst 105(22):1684–93.
Oaks BM, Dodd KW, Meinhold CL, Jiao L, Church TR, Stolzenberg-Solomon RZ. Folate intake, post-folic acid grain fortification, and pancreatic cancer risk in the prostate, lung, colorectal, and ovarian cancer screening trial. Am J Clin Nutr. 2010;91:449–55.
Liou JM, Shun CT, Liang JT, Chiu HM, Chen MJ, Chen CC, et al. Plasma insulin-like growth factor-binding protein-2 levels as diagnostic and prognostic biomarker of colorectal cancer. J Clin Endocrinol Metab. 2010;95:1717–25.
Fuchs CS, Goldberg RM, Sargent DJ, Meyerhardt JA, Wolpin BM, Green EM, et al. Plasma insulin-like growth factors, insulin-like binding protein-3, and outcome in metastatic colorectal cancer: results from intergroup trial N9741. Clin Cancer Res. 2008;14:8263–69.
Harris LK, Westwood M. Biology and significance of signalling pathways activated by IGF-II. Growth Factors. 2012;30:1–12.
O’Gorman DB, Weiss J, Hettiaratchi A, Firth SM, Scott CD. Insulin-like growth factor-II/mannose 6-phosphate receptor overexpression reduces growth of choriocarcinoma cells in vitro and in vivo. Endocrinology. 2002;143:4287–94.
Chang S, Wu X, Yu H, Spitz MR. Plasma concentrations of insulin-like growth factors among healthy adult men and postmenopausal women: associations with body composition, lifestyle, and reproductive factors. Cancer Epidemiol Biomark Prev. 2002;11:758–66.
Young NJ, Metcalfe C, Gunnell D, Rowlands MA, Lane JA, Gilbert R, et al. A cross-sectional analysis of the association between diet and insulin-like growth factor (IGF)-I, IGF-II, IGF-binding protein (IGFBP)-2, and IGFBP-3 in men in the United Kingdom. Cancer Causes Control. 2012;23:907–17.
Florini JR, Magri KA, Ewton DZ, James PL, Grindstaff K, Rotwein PS. “Spontaneous” differentiation of skeletal myoblasts is dependent upon autocrine secretion of insulin-like growth factor-II. J Biol Chem. 1991;266:15917–23.
Fogelman DR, Holmes H, Mohammed K, Katz MH, Prado CM, Lieffers J, et al. Does IGFR1 inhibition result in increased muscle mass loss in patients undergoing treatment for pancreatic cancer? J Cachexia Sarcopenia Muscle. 2014;5:307–13.
Mayers JR, Wu C, Clish CB, Kraft P, Torrence ME, Fiske BP, et al. Elevation of circulating branched-chain amino acids is an early event in human pancreatic adenocarcinoma development. Nat Med. 2014;20:1193–98.
Clemmons DR. Insulin-like growth factor binding protein control secretion and mechanisms of action. Adv Exp Med Biol. 1991;293:113–23.
Ho KK, Gibney J, Johannsson G, Wolthers T. Regulating of growth hormone sensitivity by sex steroids: implications for therapy. Fron Horm Res. 2006;35:115–28.
Lin Y, Tamakoshi A, Kikuchi S, Yagyu K, Obata Y, Ishibashi T, et al. Serum insulin-like growth factor-I, insulin-like growth factor binding protein-3, and the risk of pancreatic cancer death. Int J Cancer. 2004;110:584–88.
Wolpin BM, Meyerhardt JA, Chan AT, Ng K, Chan JA, Wu K, et al. Insulin, the insulin-like growth factor axis, and mortality in patients with nonmetastatic colorectal cancer. J Clin Oncol. 2009;27:176–85.
Haydon AM, Macinnis RJ, English DR, Morris H, Giles GG. Physical activity, insulin-like growth factor 1, insulin-like growth factor binding protein 3, and survival from colorectal cancer. Int J Gastroenterol Hepatol. 2006;55:689–94.
Svensson J, Carlzon D, Petzold M, Karlsson MK, Ljunggren Ö, Tivesten Å, et al. Both low and high serum IGF-I levels associate with cancer mortality in older men. J Clin Endocrinol Metab. 2012;97:4623–30.
Major JM, Laughlin GA, Kritz-Silverstein D, Wingard DL, Barrett-Connor E. Insulin-like growth factor-I and cancer mortality in older men. J Clin Endocrinol Metab. 2010;95:1054–59.
Saydah S, Graubard B, Ballard-Barbash R, Berrigan D. Insulin-like growth factors and subsequent risk of mortality in the United States. Am J Epidemiol. 2007;166:518-26.
Van Bunderen CC, Van Nieuwpoort IC, Van Schoor NM, Deeg DJH, Lips P, Drent ML (2010) The association of serum insulin-like growth factor-I with mortality, cardiovascular disease, and cancer in the elderly: a population-based study. J Clin Endocrinol Metab 95:4616–24.
Acknowledgement
Adetunji T. Toriola is supported by the Siteman Cancer Center, Barnes-Jewish Hospital Foundation and Washington University School of Medicine Faculty Diversity Award. The funding sources have no roles in the study design, collection, analysis, and interpretation of data, in the writing of the manuscript, or in the decision to submit the manuscript for publication.
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The authors declare no potential conflicts of interest.
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Toriola, A.T., Ziegler, M., Li, Y. et al. Prediagnosis Circulating Insulin-Like Growth Factors and Pancreatic Cancer Survival. Ann Surg Oncol 24, 3212–3219 (2017). https://doi.org/10.1245/s10434-017-5988-y
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DOI: https://doi.org/10.1245/s10434-017-5988-y