The Role of the IGF Axis in Human Malignancy: Evidence from Epidemiological Studies and Tissue Analysis

  • Julia V. Burnier
  • Shun Li
  • Pnina BrodtEmail author
Part of the Energy Balance and Cancer book series (EBAC, volume 1)


Clinical and experimental evidence obtained over the last three decades has collectively identified the insulin-like growth factor (IGF) axis as a major player in human cancer progression. This has led to a concerted effort to target the IGF axis, particularly the IGF-I receptor, for cancer therapy and has already resulted in the development of several inhibitors including insulin-like growth factor-I receptor (IGF-IR) antibodies and specific kinase inhibitors that have advanced into the clinic, with promising results. Detailed reviews on the role of the IGF-IR in malignancy based on animal studies and clinical evidence and on current therapeutic strategies for targeting the IGF axis are provided by other chapters in this collection. In this chapter, we review the epidemiological studies that have contributed to the identification of circulating IGF levels as a potential cancer risk factor and discuss possible reasons for, and the implications of, the disparity in the results obtained in different clinical studies. In addition, recent evidence, based on gene and protein arrays, that identifies IGF axis proteins as potential molecular regulators of tumor invasion is also reviewed highlighting the potential functional relevance of circulating and tumor-derived IGFs to cancer progression and metastasis.


Axis Protein Benign Prostatic Epithelium 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



Acid-labile subunit


Colorectal carcinoma


Extracellular matrix


Enzyme-linked immunosorbent assay


Growth hormone




Hepatocellular carcinoma


Hepatocyte growth factor


Head and neck squamous cell carcinoma


Human papilloma virus


Insulin-like growth factor


Insulin-like growth factor binding protein


Insulin-like growth factor-I receptor




Insulin receptor


Immunoradiometric assay


Human breast adenocarcinoma cell line


Matrix metalloproteinase


Membrane type 1 matrix metalloproteinase


Non–small-cell lung cancer


Platelet-derived growth factor


Prostatic intraepithelial neoplasia


Prostate specific antigen




Small-cell lung cancer


Squamous intraepithelial lesion


Urokinase plasminogen activator


uPA receptor


  1. 1.
    Le Roith D, Bondy C, Yakar S, Liu J-L, Butler A (2001) The somatomedin hypothesis: 2001. Endocr Rev 22:53–74PubMedGoogle Scholar
  2. 2.
    Sell C (2003) Caloric restriction and insulin-like growth factors in aging and cancer. Horm Metab Res 35:705–711PubMedGoogle Scholar
  3. 3.
    Tannenbaum GS, Guyda HJ, Posner BI (1983) Insulin-like growth factors: a role in growth hormone negative feedback and body weight regulation via brain. Science 220:77–79PubMedGoogle Scholar
  4. 4.
    LeRoith D, Roberts CT (2003) The insulin-like growth factor system and cancer. Cancer Lett 195:127–137PubMedGoogle Scholar
  5. 5.
    Yakar S, LeRoith D, Brodt P (2005) The role of the growth hormone/insulin-like growth factor axis in tumor growth and progression: lessons from animal models. Cytokine Growth Factor Rev 16:407–420PubMedGoogle Scholar
  6. 6.
    Samani AA, Yakar S, LeRoith D, Brodt P (2007) The role of the IGF system in cancer growth and metastasis: overview and recent insights. Endocr Rev 28:20–47PubMedGoogle Scholar
  7. 7.
    Yu H, Rohan T (2000) Role of the insulin-like growth factor family in cancer development and progression. J Natl Cancer Inst 92:1472–1489PubMedGoogle Scholar
  8. 8.
    Thissen JP, Ketelslegers JM, Underwood LE (1994) Nutritional regulation of the insulin-like growth factors. Endocr Rev 15:80–101PubMedGoogle Scholar
  9. 9.
    Nam SY, Lee EJ, Kim KR et al (1997) Effect of obesity on total and free insulin-like growth factor (IGF)-1, and their relationship to IGF-binding protein (BP)-1, IGFBP-2, IGFBP-3, insulin, and growth hormone. Int J Obes Relat Metab Disord 21:355–359PubMedGoogle Scholar
  10. 10.
    Liu JP, Baker J, Perkins AS, Robertson EJ, Efstratiadis A (1993) Mice carrying null mutations of the genes encoding insulin-like growth factor I (Igf-1) and type 1 IGF receptor (Igf1r). Cell 75:59–72PubMedGoogle Scholar
  11. 11.
    Powell-Braxton L, Hollingshead P, Warburton C et al (1993) IGF-I is required for normal embryonic growth in mice. Genes Dev 7:2609–2617PubMedGoogle Scholar
  12. 12.
    Jones JI, Clemmons DR (1995) Insulin-like growth factors and their binding proteins: biological actions. Endocr Rev 16:3–34PubMedGoogle Scholar
  13. 13.
    Mohan S, Baylink DJ (2002) IGF-binding proteins are multifunctional and act via IGF-dependent and -independent mechanisms. J Endocrinol 175:19–31PubMedGoogle Scholar
  14. 14.
    Gunnell D (2001) Height, leg length, and cancer risk: a systematic review. Epidemiol Rev 23(2):313–342PubMedGoogle Scholar
  15. 15.
    Gunnell DJ, Smith GD, Holly JM, Frankel S (1998) Leg length and risk of cancer in the Boyd Orr cohort. BMJ 317:1350–1351PubMedPubMedCentralGoogle Scholar
  16. 16.
    Frankel S, Gunnell DJ, Peters TJ, Maynard M, Davey Smith G (1998) Childhood energy intake and adult mortality from cancer: the Boyd Orr Cohort Study. BMJ 316:499–504PubMedPubMedCentralGoogle Scholar
  17. 17.
    Loeper S, Ezzat S (2008) Acromegaly: re-thinking the cancer risk. Rev Endocr Metab Disord 9:41–58PubMedGoogle Scholar
  18. 18.
    Borofsky ND, Vogelman JH, Krajcik RA, Orentreich N (2002) Utility of insulin-like growth factor-1 as a biomarker in epidemiologic studies. Clin Chem 48:2248–2251PubMedGoogle Scholar
  19. 19.
    Ray BS (1967) Current cancer concepts. Hypophysectomy as palliative treatment. JAMA 200:974–975PubMedGoogle Scholar
  20. 20.
    Hankinson SE, Willett WC, Colditz GA et al (1998) Circulating concentrations of insulin-like growth factor-I and risk of breast cancer. Lancet 351:1393–1396PubMedGoogle Scholar
  21. 21.
    Yee D, Rosen N, Favoni RE, Cullen KJ (1991) The insulin-like growth factors, their receptors, and their binding proteins in human breast cancer. Cancer Treat Res 53:93–106PubMedGoogle Scholar
  22. 22.
    Bruning PF, Van Doorn J, Bonfrer JM et al (1995) Insulin-like growth-factor-binding protein 3 is decreased in early-stage operable pre-menopausal breast cancer. Int J Cancer 62:266–270PubMedGoogle Scholar
  23. 23.
    Schernhammer ES, Holly JM, Pollak MN, Hankinson SE (2005) Circulating levels of insulin-like growth factors, their binding proteins, and breast cancer risk. Cancer Epidemiol Biomarkers Prev 14:699–704PubMedGoogle Scholar
  24. 24.
    Vadgama JV, Wu Y, Datta G, Khan H, Chillar R (1999) Plasma insulin-like growth factor-I and serum IGF-binding protein 3 can be associated with the progression of breast cancer, and ­predict the risk of recurrence and the probability of survival in African-American and Hispanic women. Oncology 57:330–340PubMedGoogle Scholar
  25. 25.
    Renehan AG, Zwahlen M, Minder C, O’Dwyer ST, Shalet SM, Egger M (2004) Insulin-like growth factor (IGF)-I, IGF binding protein-3, and cancer risk: systematic review and meta-regression analysis. Lancet 363:1346–1353PubMedGoogle Scholar
  26. 26.
    Shi R, Yu H, McLarty J, Glass J (2004) IGF-I and breast cancer: a meta-analysis. Int J Cancer 111:418–423PubMedGoogle Scholar
  27. 27.
    Rinaldi S, Peeters PH, Berrino F et al (2006) IGF-I, IGFBP-3 and breast cancer risk in women: the European Prospective Investigation into Cancer and Nutrition (EPIC). Endocr Relat Cancer 13:593–605PubMedGoogle Scholar
  28. 28.
    Pasanisi P, Venturelli E, Morelli D, Fontana L, Secreto G, Berrino F (2008) Serum insulin-like growth factor-I and platelet-derived growth factor as biomarkers of breast cancer prognosis. Cancer Epidemiol Biomarkers Prev 17:1719–1722PubMedGoogle Scholar
  29. 29.
    Byrne C, Colditz GA, Willett WC, Speizer FE, Pollak M, Hankinson SE (2000) Plasma insulin-like growth factor (IGF) I, IGF-binding protein 3, and mammographic density. Cancer Res 60:3744–3748PubMedGoogle Scholar
  30. 30.
    Bremnes Y, Ursin G, Bjurstam N, Rinaldi S, Kaaks R, Gram IT (2007) Insulin-like growth factor and mammographic density in postmenopausal Norwegian women. Cancer Epidemiol Biomarkers Prev 16:57–62PubMedGoogle Scholar
  31. 31.
    Peyrat JP, Bonneterre J, Hecquet B et al (1993) Plasma insulin-like growth factor-1 (IGF-1) concentrations in human breast cancer. Eur J Cancer 29A:492–497PubMedGoogle Scholar
  32. 32.
    Barni S, Lissoni P, Brivio F et al (1994) Serum levels of insulin-like growth factor-I in operable breast cancer in relation to the main prognostic variables and their perioperative changes in relation to those of prolactin. Tumori 80:212–215PubMedGoogle Scholar
  33. 33.
    Ng EH, Ji CY, Tan PH, Lin V, Soo KC, Lee KO (1998) Altered serum levels of insulin-like growth-factor binding proteins in breast cancer patients. Ann Surg Oncol 5:194–201PubMedGoogle Scholar
  34. 34.
    Vatten LJ, Holly JM, Gunnell D, Tretli S (2008) Nested case-control study of the association of circulating levels of serum insulin-like growth factor I and insulin-like growth factor binding protein 3 with breast cancer in young women in Norway. Cancer Epidemiol Biomarkers Prev 17:2097–2100PubMedGoogle Scholar
  35. 35.
    Schernhammer ES, Holly JM, Hunter DJ, Pollak MN, Hankinson SE (2006) Insulin-like growth factor-I, its binding proteins (IGFBP-1 and IGFBP-3), and growth hormone and breast cancer risk in The Nurses Health Study II. Endocr Relat Cancer 13:583–592PubMedGoogle Scholar
  36. 36.
    Espelund U, Cold S, Frystyk J, Orskov H, Flyvbjerg A (2008) Elevated free IGF2 levels in localized, early-stage breast cancer in women. Eur J Endocrinol 159:595–601PubMedGoogle Scholar
  37. 37.
    Peyrat JP, Bonneterre J (1992) Type 1 IGF receptor in human breast diseases. Breast Cancer Res Treat 22:59–67PubMedGoogle Scholar
  38. 38.
    Pezzino V, Papa V, Milazzo G, Gliozzo B, Russo P, Scalia PL (1996) Insulin-like growth factor-I (IGF-I) receptors in breast cancer. Ann N Y Acad Sci 784:189–201PubMedGoogle Scholar
  39. 39.
    Ando S, Panno ML, Salerno M et al (1998) Role of IRS-1 signaling in insulin-induced modulation of estrogen receptors in breast cancer cells. Biochem Biophys Res Commun 253:315–319PubMedGoogle Scholar
  40. 40.
    Voskuil DW, Bosma A, Vrieling A, Rookus MA, van’t Veer LJ (2004) Insulin-like growth factor (IGF)-system mRNA quantities in normal and tumor breast tissue of women with sporadic and familial breast cancer risk. Breast Cancer Res Treat 84:225–233PubMedGoogle Scholar
  41. 41.
    Railo MJ, von Smitten K, Pekonen F (1994) The prognostic value of insulin-like growth factor-I in breast cancer patients. Results of a follow-up study on 126 patients. Eur J Cancer 30A:307–311PubMedGoogle Scholar
  42. 42.
    Turner BC, Haffty BG, Narayanan L et al (1997) Insulin-like growth factor-I receptor overexpression mediates cellular radioresistance and local breast cancer recurrence after lumpectomy and radiation. Cancer Res 57:3079–3083PubMedGoogle Scholar
  43. 43.
    Peiro G, Benlloch S, Sanchez-Tejada L et al (2009) Low activation of Insulin-like Growth Factor 1-Receptor (IGF1R) is associated with local recurrence in early breast carcinoma. Breast Cancer Res Treat 117(2):433–441PubMedGoogle Scholar
  44. 44.
    Creighton CJ, Casa A, Lazard Z et al (2008) Insulin-like growth factor-I activates gene transcription programs strongly associated with poor breast cancer prognosis. J Clin Oncol 26:4078–4085PubMedPubMedCentralGoogle Scholar
  45. 45.
    Yee D (2002) The insulin-like growth factor system as a treatment target in breast cancer. Semin Oncol 29:86–95PubMedGoogle Scholar
  46. 46.
    Sachdev D, Yee D (2006) Inhibitors of insulin-like growth factor signaling: a therapeutic approach for breast cancer. J Mammary Gland Biol Neoplasia 11:27–39PubMedGoogle Scholar
  47. 47.
    Yee D (2007) Targeting insulin-like growth factor pathways. Br J Cancer 96(Suppl):R7–R10PubMedGoogle Scholar
  48. 48.
    Wolk A, Mantzoros CS, Andersson SO et al (1998) Insulin-like growth factor 1 and prostate cancer risk: a population-based, case-control study. J Natl Cancer Inst 90:911–915PubMedGoogle Scholar
  49. 49.
    Mantzoros CS, Tzonou A, Signorello LB, Stampfer M, Trichopoulos D, Adami HO (1997) Insulin-like growth factor 1 in relation to prostate cancer and benign prostatic hyperplasia. Br J Cancer 76:1115–1118PubMedPubMedCentralGoogle Scholar
  50. 50.
    Stattin P, Bylund A, Rinaldi S et al (2000) Plasma insulin-like growth factor-I, insulin-like growth factor-binding proteins, and prostate cancer risk: a prospective study. J Natl Cancer Inst 92:1910–1917PubMedGoogle Scholar
  51. 51.
    Stattin P, Rinaldi S, Biessy C, Stenman UH, Hallmans G, Kaaks R (2004) High levels of circulating insulin-like growth factor-I increase prostate cancer risk: a prospective study in a population-based nonscreened cohort. J Clin Oncol 22:3104–3112PubMedGoogle Scholar
  52. 52.
    Harman SM, Metter EJ, Blackman MR, Landis PK, Carter HB (2000) Serum levels of insulin-like growth factor I (IGF-I), IGF-II, IGF-binding protein-3, and prostate-specific antigen as predictors of clinical prostate cancer. J Clin Endocrinol Metab 85:4258–4265PubMedGoogle Scholar
  53. 53.
    Shaneyfelt T, Husein R, Bubley G, Mantzoros CS (2000) Hormonal predictors of prostate cancer: a meta-analysis. J Clin Oncol 18:847–853PubMedGoogle Scholar
  54. 54.
    Djavan B, Bursa B, Seitz C et al (1999) Insulin-like growth factor 1 (IGF-1), IGF-1 density, and IGF-1/PSA ratio for prostate cancer detection. Urology 54:603–606PubMedGoogle Scholar
  55. 55.
    Cutting CW, Hunt C, Nisbet JA, Bland JM, Dalgleish AG, Kirby RS (1999) Serum insulin-like growth factor-1 is not a useful marker of prostate cancer. BJU Int 83:996–999PubMedGoogle Scholar
  56. 56.
    Finne P, Auvinen A, Koistinen H et al (2000) Insulin-like growth factor I is not a useful marker of prostate cancer in men with elevated levels of prostate-specific antigen. J Clin Endocrinol Metab 85:2744–2747PubMedGoogle Scholar
  57. 57.
    Allen NE, Key TJ, Appleby PN et al (2007) Serum insulin-like growth factor (IGF)-I and IGF-binding protein-3 concentrations and prostate cancer risk: results from the European Prospective Investigation into Cancer and Nutrition. Cancer Epidemiol Biomarkers Prev 16:1121–1127PubMedGoogle Scholar
  58. 58.
    Baffa R, Reiss K, El-Gabry EA et al (2000) Low serum insulin-like growth factor 1 (IGF-1): a significant association with prostate cancer. Tech Urol 6:236–239PubMedGoogle Scholar
  59. 59.
    Rowlands MA, Gunnell D, Harris R, Vatten LJ, Holly JM, Martin RM (2009) Circulating insulin-like growth factor peptides and prostate cancer risk: a systematic review and meta-analysis. Int J Cancer 124(10):2416–2429PubMedPubMedCentralGoogle Scholar
  60. 60.
    Roddam AW, Allen NE, Appleby P et al (2008) Insulin-like growth factors, their binding proteins, and prostate cancer risk: analysis of individual patient data from 12 prospective studies. Ann Intern Med 149(461–71):W83–W88Google Scholar
  61. 61.
    Tennant M, Thrasher J, Twomey P, Drivdahl R, Birnbaum R, Plymate S (1996) Protein and messenger ribonucleic acid (mRNA) for the type 1 insulin- like growth factor (IGF) receptor is decreased and IGF-II mRNA is increased in human prostate carcinoma compared to benign prostate epithelium. J Clin Endocrinol Metab 81:3774–3782PubMedGoogle Scholar
  62. 62.
    Chott A, Sun Z, Morganstern D et al (1999) Tyrosine kinases expressed in vivo by human prostate cancer bone marrow metastases and loss of the type 1 insulin-like growth factor receptor. Am J Pathol 155:1271–1279PubMedGoogle Scholar
  63. 63.
    Hellawell GO, Turner GD, Davies DR, Poulsom R, Brewster SF, Macaulay VM (2002) Expression of the type 1 insulin-like growth factor receptor is up-regulated in primary prostate cancer and commonly persists in metastatic disease. Cancer Res 62:2942–2950PubMedGoogle Scholar
  64. 64.
    Cox ME, Gleave ME, Zakikhani M et al (2009) Insulin receptor expression by human prostate cancers. Prostate 69:33–40PubMedGoogle Scholar
  65. 65.
    Orme SM, McNally RJ, Cartwright RA, Belchetz PE (1998) Mortality and cancer incidence in acromegaly: a retrospective cohort study. United Kingdom Acromegaly Study Group. J Clin Endocrinol Metab 83:2730–2734PubMedGoogle Scholar
  66. 66.
    Pines A, Rozen P, Ron E, Gilat T (1985) Gastrointestinal tumors in acromegalic patients. Am J Gastroenterol 80:266–269PubMedGoogle Scholar
  67. 67.
    Ron E, Gridley G, Hrubec Z, Page W, Arora S, Fraumeni JF Jr (1991) Acromegaly and gastrointestinal cancer. Cancer 68:1673–1677PubMedGoogle Scholar
  68. 68.
    Richter M, Jurek D, Wrba F et al (2002) Cells obtained from colorectal microadenomas mirror early premalignant growth patterns in vitro. Eur J Cancer 38:1937–1945PubMedGoogle Scholar
  69. 69.
    Singer CF, Hudelist G, Lamm W, Mueller R, Czerwenka K, Kubista E (2004) Expression of tyrosine kinases in human malignancies as potential targets for kinase-specific inhibitors. Endocr Relat Cancer 11:861–869PubMedGoogle Scholar
  70. 70.
    Nomura AM, Stemmermann GN, Lee J, Pollak MN (2003) Serum insulin-like growth factor I and subsequent risk of colorectal cancer among Japanese-American men. Am J Epidemiol 158:424–431PubMedGoogle Scholar
  71. 71.
    Gunter MJ, Hoover DR, Yu H et al (2008) Insulin, insulin-like growth factor-I, endogenous estradiol, and risk of colorectal cancer in postmenopausal women. Cancer Res 68:329–337PubMedGoogle Scholar
  72. 72.
    Giovannucci E, Pollak MN, Platz EA et al (2000) 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 9:345–349PubMedGoogle Scholar
  73. 73.
    Ma J, Pollak M, Giovannucci E et al (2000) A prospective study of plasma levels of insulin-like growth factor I (IGF-I) and IGF-binding protein-3, and colorectal cancer risk among men. Growth Horm IGF Res 10(Suppl A):S28–S29PubMedGoogle Scholar
  74. 74.
    Ma J, Pollak MN, Giovannucci E et al (1999) 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 91:620–625PubMedGoogle Scholar
  75. 75.
    Tripkovic I, Tripkovic A, Strnad M, Capkun V, Zekan L (2007) Role of insulin-like growth factor-1 in colon cancerogenesis: a case-control study. Arch Med Res 38:519–525PubMedGoogle Scholar
  76. 76.
    Renehan AG, Painter JE, Atkin WS, Potten CS, Shalet SM, O’Dwyer ST (2001) High-risk colorectal adenomas and serum insulin-like growth factors. Br J Surg 88:107–113PubMedGoogle Scholar
  77. 77.
    Keku TO, Sandler RS, Simmons JG et al (2008) Local IGFBP-3 mRNA expression, apoptosis and risk of colorectal adenomas. BMC Cancer 8:143PubMedGoogle Scholar
  78. 78.
    Donovan EA, Kummar S (2008) Role of insulin-like growth factor-1R system in colorectal carcinogenesis. Crit Rev Oncol Hematol 66:91–98PubMedGoogle Scholar
  79. 79.
    Otani T, Iwasaki M, Sasazuki S, Inoue M, Tsugane S (2007) Plasma C-peptide, insulin-like growth factor-I, insulin-like growth factor binding proteins and risk of colorectal cancer in a nested case-control study: the Japan public health center-based prospective study. Int J Cancer 120:2007–2012PubMedGoogle Scholar
  80. 80.
    Hakam A, Yeatman TJ, Lu L et al (1999) Expression of insulin-like growth factor-1 receptor in human colorectal cancer. Hum Pathol 30:1128–1133PubMedGoogle Scholar
  81. 81.
    Weber MM, Fottner C, Liu SB, Jung MC, Engelhardt D, Baretton GB (2002) Overexpression of the insulin-like growth factor I receptor in human colon carcinomas. Cancer 95:2086–2095PubMedGoogle Scholar
  82. 82.
    Fuchs CS, Goldberg RM, Sargent DJ et al (2008) Plasma insulin-like growth factors, insulin-like binding protein-3, and outcome in metastatic colorectal cancer: results from intergroup trial N9741. Clin Cancer Res 14:8263–8269PubMedGoogle Scholar
  83. 83.
    Renehan AG, Jones J, Potten CS, Shalet SM, O’Dwyer ST (2000) Elevated serum insulin-like growth factor (IGF)-II and IGF binding protein-2 in patients with colorectal cancer. Br J Cancer 83:1344–1350PubMedGoogle Scholar
  84. 84.
    All-Ericsson C, Girnita L, Seregard S, Bartolazzi A, Jager MJ, Larsson O (2002) Insulin-like growth factor-1 receptor in uveal melanoma: a predictor for metastatic disease and a potential therapeutic target. Invest Ophthalmol Vis Sci 43:1–8PubMedGoogle Scholar
  85. 85.
    Mallikarjuna K, Pushparaj V, Biswas J, Krishnakumar S (2006) Expression of insulin-like growth factor receptor (IGF-1R), c-Fos, and c-Jun in uveal melanoma: an immunohistochemical study. Curr Eye Res 31:875–883PubMedGoogle Scholar
  86. 86.
    Brokaw J, Katsaros D, Wiley A et al (2007) IGF-I in epithelial ovarian cancer and its role in disease progression. Growth Factors 25:346–354PubMedGoogle Scholar
  87. 87.
    Lukanova A, Lundin E, Toniolo P et al (2002) Circulating levels of insulin-like growth factor-I and risk of ovarian cancer. Int J Cancer 101:549–554PubMedGoogle Scholar
  88. 88.
    Peeters PH, Lukanova A, Allen N et al (2007) Serum IGF-I, its major binding protein (IGFBP-3) and epithelial ovarian cancer risk: the European Prospective Investigation into Cancer and Nutrition (EPIC). Endocr Relat Cancer 14:81–90PubMedGoogle Scholar
  89. 89.
    Dal Maso L, Augustin LS, Franceschi S et al (2004) Association between components of the insulin-like growth factor system and epithelial ovarian cancer risk. Oncology 67:225–230PubMedGoogle Scholar
  90. 90.
    Lu L, Katsaros D, Wiley A et al (2006) The relationship of insulin-like growth factor-II, insulin-like growth factor binding protein-3, and estrogen receptor-alpha expression to disease progression in epithelial ovarian cancer. Clin Cancer Res 12:1208–1214PubMedGoogle Scholar
  91. 91.
    Mathur SP, Landen CP, Datta SM, Hoffman MC, Mathur RS, Young RC (2003) Insulin-like growth factor II in gynecological cancers: a preliminary study. Am J Reprod Immunol 49:113–119PubMedGoogle Scholar
  92. 92.
    Wu X, Tortolero-Luna G, Zhao H, Phatak D, Spitz MR, Follen M (2003) Serum levels of insulin-like growth factor I and risk of squamous intraepithelial lesions of the cervix. Clin Cancer Res 9:3356–3361PubMedGoogle Scholar
  93. 93.
    Schaffer A, Koushik A, Trottier H et al (2007) Insulin-like growth factor-I and risk of high-grade cervical intraepithelial neoplasia. Cancer Epidemiol Biomarkers Prev 16:716–722PubMedGoogle Scholar
  94. 94.
    Izycki T, Chyczewska E, Naumnik W, Talalaj J, Panek B, Ossolinska M (2004) Serum levels of IGF-I and IGF-II in patients with lung cancer during chemotherapy. Exp Oncol 26:316–319PubMedGoogle Scholar
  95. 95.
    Yu H, Spitz MR, Mistry J, Gu J, Hong WK, Wu X (1999) Plasma levels of insulin-like growth factor-I and lung cancer risk: a case-control analysis. J Natl Cancer Inst 91:151–156PubMedGoogle Scholar
  96. 96.
    Spitz MR, Barnett MJ, Goodman GE, Thornquist MD, Wu X, Pollak M (2002) Serum insulin-like growth factor (IGF) and IGF-binding protein levels and risk of lung cancer: a case-control study nested in the beta-Carotene and Retinol Efficacy Trial Cohort. Cancer Epidemiol Biomarkers Prev 11:1413–1418PubMedGoogle Scholar
  97. 97.
    Ahn J, Weinstein SJ, Snyder K, Pollak MN, Virtamo J, Albanes D (2006) No association between serum insulin-like growth factor (IGF)-I, IGF-binding protein-3, and lung cancer risk. Cancer Epidemiol Biomarkers Prev 15:2010–2012PubMedGoogle Scholar
  98. 98.
    Lukanova A, Toniolo P, Akhmedkhanov A et al (2001) A prospective study of insulin-like growth factor-I, IGF-binding proteins-1, -2 and -3 and lung cancer risk in women. Int J Cancer 92:888–892PubMedGoogle Scholar
  99. 99.
    Lee CY, Jeon JH, Kim HJ et al (2008) Clinical significance of insulin-like growth factor-1 receptor expression in stage I non-small-cell lung cancer: immunohistochemical analysis. Korean J Intern Med 23:116–120PubMedPubMedCentralGoogle Scholar
  100. 100.
    Brabant G, Wallaschofski H (2007) Normal levels of serum IGF-I: determinants and validity of current reference ranges. Pituitary 10:129–133PubMedGoogle Scholar
  101. 101.
    Ho KK, Gibney J, Johannsson G, Wolthers T (2006) Regulating of growth hormone sensitivity by sex steroids: implications for therapy. Front Horm Res 35:115–128PubMedGoogle Scholar
  102. 102.
    Caufriez A, Frankenne F, Hennen G, Copinschi G (1993) Regulation of maternal IGF-I by placental GH in normal and abnormal human pregnancies. Am J Physiol 265:E572–E577PubMedGoogle Scholar
  103. 103.
    Monaghan JM, Godber IM, Lawson N et al (2004) Longitudinal changes of insulin-like growth factors and their binding proteins throughout normal pregnancy. Ann Clin Biochem 41:220–226PubMedGoogle Scholar
  104. 104.
    Hong Y, Brismar K, Hall K, Pedersen NL, de Faire U (1997) Associations between insulin-like growth factor-I (IGF-I), IGF-binding protein-1, insulin and other metabolic measures after controlling for genetic influences: results from middle-aged and elderly monozygotic twins. J Endocrinol 153:251–257PubMedGoogle Scholar
  105. 105.
    Vaessen N, Heutink P, Janssen JA et al (2001) A polymorphism in the gene for IGF-I: functional properties and risk for type 2 diabetes and myocardial infarction. Diabetes 50:637–642PubMedGoogle Scholar
  106. 106.
    Jernstrom H, Deal C, Wilkin F et al (2001) Genetic and nongenetic factors associated with variation of plasma levels of insulin-like growth factor-I and insulin-like growth factor-binding protein-3 in healthy premenopausal women. Cancer Epidemiol Biomarkers Prev 10:377–384PubMedGoogle Scholar
  107. 107.
    Fletcher O, Gibson L, Johnson N et al (2005) Polymorphisms and circulating levels in the insulin-like growth factor system and risk of breast cancer: a systematic review. Cancer Epidemiol Biomarkers Prev 14:2–19PubMedGoogle Scholar
  108. 108.
    Milani D, Carmichael JD, Welkowitz J et al (2004) Variability and reliability of single serum IGF-I measurements: impact on determining predictability of risk ratios in disease development. J Clin Endocrinol Metab 89:2271–2274PubMedPubMedCentralGoogle Scholar
  109. 109.
    Shalet SM, Toogood A, Rahim A, Brennan BM (1998) The diagnosis of growth hormone deficiency in children and adults. Endocr Rev 19:203–223PubMedGoogle Scholar
  110. 110.
    Renehan AG, Jones J, O’Dwyer ST, Shalet SM (2003) Determination of IGF-I, IGF-II, IGFBP-2, and IGFBP-3 levels in serum and plasma: comparisons using the Bland-Altman method. Growth Horm IGF Res 13:341–346PubMedGoogle Scholar
  111. 111.
    Krebs A, Wallaschofski H, Spilcke-Liss E et al (2008) Five commercially available insulin-like growth factor I (IGF-I) assays in comparison to the former Nichols advantage IGF-I in a growth hormone treated population. Clin Chem Lab Med 46:1776–1783PubMedGoogle Scholar
  112. 112.
    Zhang D, Bar-Eli M, Meloche S, Brodt P (2004) Dual regulation of MMP-2 expression by the type 1 insulin-like growth factor receptor: the phosphatidylinositol 3-kinase/Akt and Raf/ERK pathways transmit opposing signals. J Biol Chem 279:19683–19690PubMedGoogle Scholar
  113. 113.
    Zhang D, Brodt P (2003) Type 1 insulin-like growth factor regulates MT1-MMP synthesis and tumor invasion via PI 3-kinase/Akt signaling. Oncogene 22:974–982PubMedGoogle Scholar
  114. 114.
    Zhang D, Samani AA, Brodt P (2003) The role of the IGF-I receptor in the regulation of matrix metalloproteinases, tumor invasion and metastasis. Horm Metab Res 35:802–808PubMedGoogle Scholar
  115. 115.
    Weber A, Hengge UR, Stricker I et al (2007) Protein microarrays for the detection of biomarkers in head and neck squamous cell carcinomas. Hum Pathol 38:228–238PubMedGoogle Scholar
  116. 116.
    Davidson B, Zhang Z, Kleinberg L et al (2006) Gene expression signatures differentiate ovarian/peritoneal serous carcinoma from diffuse malignant peritoneal mesothelioma. Clin Cancer Res 12:5944–5950PubMedGoogle Scholar
  117. 117.
    Ajisaka H, Fushida S, Yonemura Y, Miwa K (2001) Expression of insulin-like growth factor-2, c-MET, matrix metalloproteinase-7 and MUC-1 in primary lesions and lymph node metastatic lesions of gastric cancer. Hepatogastroenterology 48:1788–1792PubMedGoogle Scholar
  118. 118.
    Tannapfel A, Anhalt K, Hausermann P et al (2003) Identification of novel proteins associated with hepatocellular carcinomas using protein microarrays. J Pathol 201:238–249PubMedGoogle Scholar
  119. 119.
    Nakamura M, Miyamoto S, Maeda H et al (2005) Matrix metalloproteinase-7 degrades all insulin-like growth factor binding proteins and facilitates insulin-like growth factor bioavailability. Biochem Biophys Res Commun 333:1011–1016PubMedGoogle Scholar
  120. 120.
    Miyamoto S, Yano K, Sugimoto S et al (2004) Matrix metalloproteinase-7 facilitates insulin-like growth factor bioavailability through its proteinase activity on insulin-like growth factor binding protein 3. Cancer Res 64:665–671PubMedGoogle Scholar
  121. 121.
    Miyamoto S, Nakamura M, Yano K et al (2007) Matrix metalloproteinase-7 triggers the matricrine action of insulin-like growth factor-II via proteinase activity on insulin-like growth factor binding protein 2 in the extracellular matrix. Cancer Sci 98:685–691PubMedGoogle Scholar
  122. 122.
    Oshima T, Akaike M, Yoshihara K et al (2008) Clinicopathological significance of the gene expression of matrix metalloproteinase-7, insulin-like growth factor-1, insulin-like growth factor-2 and insulin-like growth factor-1 receptor in patients with colorectal cancer: insulin-like growth factor-1 receptor gene expression is a useful predictor of liver metastasis from colorectal cancer. Oncol Rep 20:359–364PubMedGoogle Scholar
  123. 123.
    Gallego R, Codony-Servat J, Garcia-Albeniz X et al (2009) Serum IGF-I, IGFBP-3, and matrix metalloproteinase-7 levels and acquired chemo-resistance in advanced colorectal cancer. Endocr Relat Cancer 16:311–317PubMedGoogle Scholar
  124. 124.
    Sroka IC, McDaniel K, Nagle RB, Bowden GT (2008) Differential localization of MT1-MMP in human prostate cancer tissue: role of IGF-1R in MT1-MMP expression. Prostate 68:463–476PubMedGoogle Scholar
  125. 125.
    Bauer TW, Liu W, Fan F et al (2005) Targeting of urokinase plasminogen activator receptor in human pancreatic carcinoma cells inhibits c-Met- and insulin-like growth factor-I receptor-mediated migration and invasion and orthotopic tumor growth in mice. Cancer Res 65:7775–7781PubMedGoogle Scholar
  126. 126.
    Bauer TW, Fan F, Liu W et al (2005) Insulinlike growth factor-I-mediated migration and invasion of human colon carcinoma cells requires activation of c-Met and urokinase plasminogen activator receptor. Ann Surg 241:748–756; discussion 56–58PubMedGoogle Scholar
  127. 127.
    Nielsen TO, Andrews HN, Cheang M et al (2004) Expression of the insulin-like growth factor I receptor and urokinase plasminogen activator in breast cancer is associated with poor survival: potential for intervention with 17-allylamino geldanamycin. Cancer Res 64:286–291PubMedGoogle Scholar
  128. 128.
    Kornprat P, Rehak P, Ruschoff J, Langner C (2006) Expression of IGF-I, IGF-II, and IGF-IR in gallbladder carcinoma. A systematic analysis including primary and corresponding metastatic tumours. J Clin Pathol 59:202–206PubMedPubMedCentralGoogle Scholar
  129. 129.
    Schips L, Zigeuner R, Ratschek M, Rehak P, Ruschoff J, Langner C (2004) Analysis of insulin-like growth factors and insulin-like growth factor I receptor expression in renal cell carcinoma. Am J Clin Pathol 122:931–937PubMedGoogle Scholar
  130. 130.
    Varghese S, Burness M, Xu H, Beresnev T, Pingpank J, Alexander HR (2007) Site-specific gene expression profiles and novel molecular prognostic factors in patients with lower gastrointestinal adenocarcinoma diffusely metastatic to liver or peritoneum. Ann Surg Oncol 14:3460–3471PubMedGoogle Scholar
  131. 131.
    Savli H, Szendroi A, Romics I, Nagy B (2008) Gene network and canonical pathway analysis in prostate cancer: a microarray study. Exp Mol Med 40:176–185PubMedPubMedCentralGoogle Scholar
  132. 132.
    Wrobel G, Roerig P, Kokocinski F et al (2005) Microarray-based gene expression profiling of benign, atypical and anaplastic meningiomas identifies novel genes associated with meningioma progression. Int J Cancer 114:249–256PubMedGoogle Scholar
  133. 133.
    Sayer RA, Lancaster JM, Pittman J et al (2005) High insulin-like growth factor-2 (IGF-2) gene expression is an independent predictor of poor survival for patients with advanced stage serous epithelial ovarian cancer. Gynecol Oncol 96:355–361PubMedGoogle Scholar
  134. 134.
    So AI, Levitt RJ, Eigl B et al (2008) Insulin-like growth factor binding protein-2 is a novel therapeutic target associated with breast cancer. Clin Cancer Res 14:6944–6954PubMedGoogle Scholar
  135. 135.
    de Bont JM, van Doorn J, Reddingius RE et al (2008) Various components of the insulin-like growth factor system in tumor tissue, cerebrospinal fluid and peripheral blood of pediatric medulloblastoma and ependymoma patients. Int J Cancer 123:594–600PubMedGoogle Scholar
  136. 136.
    Gunter MJ, Hoover DR, Yu H et al (2009) Insulin, insulin-like growth factor-I, and risk of breast cancer in postmenopausal women. J Natl Cancer Inst 101:48–60PubMedPubMedCentralGoogle Scholar
  137. 137.
    Mu L, Katsaros D, Wiley A et al (2008) Peptide concentrations and mRNA expression of IGF-I, IGF-II and IGFBP-3 in breast cancer and their associations with disease characteristics. Breast Cancer Res Treat 115(1):151–162PubMedGoogle Scholar
  138. 138.
    Diorio C, Brisson J, Berube S, Pollak M (2008) Intact and total insulin-like growth factor-binding protein-3 (IGFBP-3) levels in relation to breast cancer risk factors: a cross-sectional study. Breast Cancer Res 10:R42PubMedPubMedCentralGoogle Scholar
  139. 139.
    Shin A, Ren Z, Shu XO, Cai Q, Gao YT, Zheng W (2007) Expression patterns of insulin-like growth factor 1 (IGF-I) and its receptor in mammary tissues and their associations with breast cancer survival. Breast Cancer Res Treat 105:55–61PubMedGoogle Scholar
  140. 140.
    Rollison DE, Newschaffer CJ, Tao Y, Pollak M, Helzlsouer KJ (2006) Premenopausal levels of circulating insulin-like growth factor I and the risk of postmenopausal breast cancer. Int J Cancer 118:1279–1284PubMedGoogle Scholar
  141. 141.
    Zhigang Z, Jieming L, Su L, Wenlu S (2007) Serum insulin-like growth factor I/free prostate specific antigen (IGF-I/fPSA) ratio enhances prostate cancer detection in men with total PSA 4.0–10.0 ng/ml. J Surg Oncol 96:54–61PubMedGoogle Scholar
  142. 142.
    Weiss JM, Huang WY, Rinaldi S et al (2007) IGF-1 and IGFBP-3: risk of prostate cancer among men in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. Int J Cancer 121:2267–2273PubMedGoogle Scholar
  143. 143.
    Severi G, Morris HA, MacInnis RJ et al (2006) Circulating insulin-like growth factor-I and binding protein-3 and risk of prostate cancer. Cancer Epidemiol Biomarkers Prev 15:1137–1141PubMedGoogle Scholar
  144. 144.
    Platz EA, Pollak MN, Leitzmann MF, Stampfer MJ, Willett WC, Giovannucci E (2005) Plasma insulin-like growth factor-1 and binding protein-3 and subsequent risk of prostate cancer in the PSA era. Cancer Causes Control 16:255–262PubMedGoogle Scholar
  145. 145.
    Meyer F, Galan P, Douville P et al (2005) A prospective study of the insulin-like growth factor axis in relation with prostate cancer in the SU.VI.MAX trial. Cancer Epidemiol Biomarkers Prev 14:2269–2272PubMedGoogle Scholar
  146. 146.
    Chen C, Lewis SK, Voigt L, Fitzpatrick A, Plymate SR, Weiss NS (2005) Prostate carcinoma incidence in relation to prediagnostic circulating levels of insulin-like growth factor I, insulin-like growth factor binding protein 3, and insulin. Cancer 103:76–84PubMedGoogle Scholar
  147. 147.
    Li L, Yu H, Schumacher F, Casey G, Witte JS (2003) Relation of serum insulin-like growth factor-I (IGF-I) and IGF binding protein-3 to risk of prostate cancer (United States). Cancer Causes Control 14:721–726PubMedGoogle Scholar
  148. 148.
    Woodson K, Tangrea JA, Pollak M et al (2003) Serum insulin-like growth factor I: tumor marker or etiologic factor? A prospective study of prostate cancer among Finnish men. Cancer Res 63:3991–3994PubMedGoogle Scholar
  149. 149.
    Shariat SF, Lamb DJ, Kattan MW et al (2002) Association of preoperative plasma levels of insulin-like growth factor I and insulin-like growth factor binding proteins-2 and -3 with prostate cancer invasion, progression, and metastasis. J Clin Oncol 20:833–841PubMedGoogle Scholar
  150. 150.
    Chokkalingam AP, Pollak M, Fillmore CM et al (2001) Insulin-like growth factors and prostate cancer: a population-based case-control study in China. Cancer Epidemiol Biomarkers Prev 10:421–427PubMedGoogle Scholar
  151. 151.
    Kurek R, Tunn UW, Eckart O, Aumuller G, Wong J, Renneberg H (2000) The significance of serum levels of insulin-like growth factor-1 in patients with prostate cancer. BJU Int 85:125–129PubMedGoogle Scholar
  152. 152.
    Jenab M, Riboli E, Cleveland RJ et al (2007) Serum C-peptide, IGFBP-1 and IGFBP-2 and risk of colon and rectal cancers in the European Prospective Investigation into Cancer and Nutrition. Int J Cancer 121:368–376PubMedGoogle Scholar
  153. 153.
    Haydon AM, Macinnis RJ, English DR, Morris H, Giles GG (2006) Physical activity, insulin-like growth factor 1, insulin-like growth factor binding protein 3, and survival from colorectal cancer. Gut 55:689–694PubMedPubMedCentralGoogle Scholar
  154. 154.
    Palmqvist R, Stattin P, Rinaldi S et al (2003) Plasma insulin, IGF-binding proteins-1 and -2 and risk of colorectal cancer: a prospective study in northern Sweden. Int J Cancer 107:89–93PubMedGoogle Scholar
  155. 155.
    Hunt KJ, Toniolo P, Akhmedkhanov A et al (2002) Insulin-like growth factor II and colorectal cancer risk in women. Cancer Epidemiol Biomarkers Prev 11:901–905PubMedGoogle Scholar
  156. 156.
    Probst-Hensch NM, Yuan JM, Stanczyk FZ, Gao YT, Ross RK, Yu MC (2001) IGF-1, IGF-2 and IGFBP-3 in prediagnostic serum: association with colorectal cancer in a cohort of Chinese men in Shanghai. Br J Cancer 85:1695–1699PubMedPubMedCentralGoogle Scholar
  157. 157.
    Kaaks R, Toniolo P, Akhmedkhanov A et al (2000) Serum C-peptide, insulin-like growth factor (IGF)-I, IGF-binding proteins, and colorectal cancer risk in women. J Natl Cancer Inst 92:1592–1600PubMedGoogle Scholar
  158. 158.
    Jenkins PJ, Frajese V, Jones AM et al (2000) Insulin-like growth factor I and the development of colorectal neoplasia in acromegaly. J Clin Endocrinol Metab 85:3218–3221PubMedGoogle Scholar
  159. 159.
    Renehan AG, Painter JE, O’Halloran D et al (2000) Circulating insulin-like growth factor II and colorectal adenomas. J Clin Endocrinol Metab 85:3402–3408PubMedGoogle Scholar
  160. 160.
    Manousos O, Souglakos J, Bosetti C et al (1999) IGF-I and IGF-II in relation to colorectal cancer. Int J Cancer 83:15–17PubMedGoogle Scholar
  161. 161.
    Morris JK, George LM, Wu T, Wald NJ (2006) Insulin-like growth factors and cancer: no role in screening. Evidence from the BUPA study and meta-analysis of prospective epidemiological studies. Br J Cancer 95:112–117PubMedPubMedCentralGoogle Scholar
  162. 162.
    Durai R, Yang W, Gupta S, Seifalian AM, Winslet MC (2005) The role of the insulin-like growth factor system in colorectal cancer: review of current knowledge. Int J Colorectal Dis 20:203–220PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Department of MedicineMcGill UniversityMontrealCanada
  2. 2.Department of OncologyMcGill UniversityMontrealCanada
  3. 3.Department of Surgery, Surgical Labs, Royal Victoria HospitalMcGill UniversityMontrealCanada

Personalised recommendations