Advertisement

Annals of Surgical Oncology

, Volume 24, Issue 11, pp 3212–3219 | Cite as

Prediagnosis Circulating Insulin-Like Growth Factors and Pancreatic Cancer Survival

  • Adetunji T. ToriolaEmail author
  • Mark Ziegler
  • Yize Li
  • Michael Pollak
  • Rachael Stolzenberg-Solomon
Pancreatic Tumors

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.

Notes

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.

Disclosure

The authors declare no potential conflicts of interest.

References

  1. 1.
    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.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    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.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    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.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Pollak M. The insulin and insulin-like growth factor receptor family in neoplasia: an update. Nat Rev Cancer. 2012;12:159–69.PubMedGoogle Scholar
  5. 5.
    Kahn SE, Hull RL, Utzschneider KM. Mechanisms linking obesity to insulin resistance and type 2 diabetes. Nature. 2006;444:840–46.CrossRefPubMedGoogle Scholar
  6. 6.
    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.CrossRefGoogle Scholar
  7. 7.
    Baxter RC. IGF binding proteins in cancer: mechanistic and clinical insights. Nat Rev Cancer. 2014;14:329–41.CrossRefPubMedGoogle Scholar
  8. 8.
    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.CrossRefGoogle Scholar
  9. 9.
    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.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    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.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    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.PubMedGoogle Scholar
  12. 12.
    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.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Pollak MN, Schernhammer ES, Hankinson SE. Insulin-like growth factors and neoplasia. Nat Rev Cancer. 2004;4:505–18.CrossRefPubMedGoogle Scholar
  14. 14.
    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.CrossRefPubMedGoogle Scholar
  15. 15.
    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.PubMedGoogle Scholar
  16. 16.
    Brabant G, Wallaschofski H. Normal levels of serum IGF-I: determinants and validity of current reference ranges. Pituitary. 2007;10:129–33.CrossRefPubMedGoogle Scholar
  17. 17.
    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.CrossRefPubMedGoogle Scholar
  18. 18.
    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.CrossRefGoogle Scholar
  19. 19.
    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.CrossRefPubMedGoogle Scholar
  20. 20.
    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.CrossRefGoogle Scholar
  21. 21.
    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.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    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.CrossRefPubMedGoogle Scholar
  23. 23.
    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.CrossRefPubMedGoogle Scholar
  24. 24.
    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.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Harris LK, Westwood M. Biology and significance of signalling pathways activated by IGF-II. Growth Factors. 2012;30:1–12.CrossRefPubMedGoogle Scholar
  26. 26.
    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.CrossRefPubMedGoogle Scholar
  27. 27.
    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.Google Scholar
  28. 28.
    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.CrossRefPubMedGoogle Scholar
  29. 29.
    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.PubMedGoogle Scholar
  30. 30.
    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.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    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.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Clemmons DR. Insulin-like growth factor binding protein control secretion and mechanisms of action. Adv Exp Med Biol. 1991;293:113–23.CrossRefPubMedGoogle Scholar
  33. 33.
    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.Google Scholar
  34. 34.
    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.CrossRefPubMedGoogle Scholar
  35. 35.
    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.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    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.Google Scholar
  37. 37.
    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.CrossRefPubMedGoogle Scholar
  38. 38.
    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.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    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.CrossRefPubMedGoogle Scholar
  40. 40.
    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.CrossRefPubMedGoogle Scholar

Copyright information

© Society of Surgical Oncology 2017

Authors and Affiliations

  • Adetunji T. Toriola
    • 1
    Email author
  • Mark Ziegler
    • 1
  • Yize Li
    • 1
  • Michael Pollak
    • 2
  • Rachael Stolzenberg-Solomon
    • 3
  1. 1.Department of Surgery, Division of Public Health Sciences, and Siteman Cancer CenterWashington University School of MedicineSt. LouisUSA
  2. 2.Department of OncologyMcGill UniversityMontrealCanada
  3. 3.Branch of Nutritional Epidemiology, Division of Cancer Epidemiology and Genetics, Department of Health and Human ServicesNational Cancer Institute, National Institutes of HealthRockvilleUSA

Personalised recommendations