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Abstract

Insulin is a major regulator of cell metabolism but, in addition, is also a growth factor. Insulin effects in target cells are mediated by the insulin receptor (IR), a transmembrane protein with enzymatic (tyrosine kinase) activity. The insulin receptor, however, is represented by a heterogeneous family of proteins, including two different IR isoforms and also hybrid receptors resulting from the IR hemireceptor combination with a hemireceptor of the cognate IGF-1 receptor. These different receptors may bind insulin and its analogs with different affinity and produce different biologic effects. Since many years, it is known that many cancer cells require insulin for optimal in vitro growth. Recent data indicate that: (1) insulin stimulates growth mainly via its own receptor and not the IGF-1 receptor; (2) in many cancer cells, the IR is overexpressed and the A isoform, which has a predominant mitogenic effect, is more represented than the B isoform. These characteristics provide a selective growth advantage to malignant cells when exposed to insulin. For this reason, all conditions of hyperinsulinemia, both endogenous (prediabetes, metabolic syndrome, obesity, type 2 diabetes before pancreas exhaustion and polycystic ovary syndrome) and exogenous (type 1 diabetes) will increase the risk of cancer. Cancer-related mortality is also increased in patients exposed to hyperinsulinemia but other factors, related to the different diseases, may also contribute. The complexity of the diseases associated with hyperinsulinemia and their therapies does not allow a precise evaluation of the cancer-promoting effect of hyperinsulinemia, but its detrimental effect on cancer incidence and mortality is well documented.

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References

  1. Taniguchi CM, Emanuelli B, Kahn CR (2006) Critical nodes in signalling pathways: insights into insulin action. Nat Rev Mol Cell Biol 7(2):85–96

    Article  CAS  PubMed  Google Scholar 

  2. Ebina Y et al (1985) The human insulin receptor cDNA: the structural basis for hormone-activated transmembrane signalling. Cell 40(4):747–758

    Article  CAS  PubMed  Google Scholar 

  3. Ward CW, Lawrence MC (2009) Ligand-induced activation of the insulin receptor: a multi-step process involving structural changes in both the ligand and the receptor. BioEssays 31(4):422–434

    Article  CAS  PubMed  Google Scholar 

  4. Brogiolo W et al (2001) An evolutionarily conserved function of the Drosophila insulin receptor and insulin-like peptides in growth control. Curr Biol 11(4):213–221

    Article  CAS  PubMed  Google Scholar 

  5. Frasca F et al (1999) Insulin receptor isoform A, a newly recognized, high-affinity insulin-like growth factor II receptor in fetal and cancer cells. Mol Cell Biol 19(5):3278–3288

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Giddings SJ, Carnaghi LR (1992) Insulin receptor gene expression during development: developmental regulation of insulin receptor mRNA abundance in embryonic rat liver and yolk sac, developmental regulation of insulin receptor gene splicing, and comparison to abundance of insulin-like growth factor 1 receptor mRNA. Mol Endocrinol 6(10):1665–1672

    CAS  PubMed  Google Scholar 

  7. Belfiore A (2007) The role of insulin receptor isoforms and hybrid insulin/IGF-I receptors in human cancer. Curr Pharm Des 13(7):671–686

    Article  CAS  PubMed  Google Scholar 

  8. Kasuya J et al (1993) Characterization of human placental insulin-like growth factor-I/insulin hybrid receptors by protein microsequencing and purification. Biochemistry 32(49):13531–13536

    Article  CAS  PubMed  Google Scholar 

  9. Benyoucef S et al (2007) Characterization of insulin/IGF hybrid receptors: contributions of the insulin receptor L2 and Fn1 domains and the alternatively spliced exon 11 sequence to ligand binding and receptor activation. Biochem J 403(3):603–613

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Siddle K et al (2001) Specificity in ligand binding and intracellular signalling by insulin and insulin-like growth factor receptors. Biochem Soc Trans 29(Pt 4):513–525

    Article  CAS  PubMed  Google Scholar 

  11. Lammers R et al (1989) Differential signalling potential of insulin- and IGF-1-receptor cytoplasmic domains. EMBO J 8(5):1369–1375

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Denley A et al (2004) Structural determinants for high-affinity binding of insulin-like growth factor II to insulin receptor (IR)-A, the exon 11 minus isoform of the IR. Mol Endocrinol 18(10):2502–2512

    Article  CAS  PubMed  Google Scholar 

  13. Belfiore A, Malaguarnera R (2011) Insulin receptor and cancer. Endocr Relat Cancer 18(4):R125–R147

    Article  CAS  PubMed  Google Scholar 

  14. Malaguarnera R et al (2012) Proinsulin binds with high affinity the insulin receptor isoform A and predominantly activates the mitogenic pathway. Endocrinology 153(5):2152–2163

    Article  CAS  PubMed  Google Scholar 

  15. Frasca F et al (2003) Insulin and hybrid insulin/IGF receptors are major regulators of breast cancer cells. Breast Dis 17:73–89

    Article  CAS  PubMed  Google Scholar 

  16. Kurtzhals P et al (2000) Correlations of receptor binding and metabolic and mitogenic potencies of insulin analogs designed for clinical use. Diabetes 49(6):999–1005

    Article  CAS  PubMed  Google Scholar 

  17. Sciacca L, Le Moli R, Vigneri R (2012) Insulin analogs and cancer. Front Endocrinol 3:21

    Article  CAS  Google Scholar 

  18. Vigneri P et al (2009) Diabetes and cancer. Endocr Relat Cancer 16(4):1103–1123

    Article  CAS  PubMed  Google Scholar 

  19. Rose DP, Vona-Davis L (2012) The cellular and molecular mechanisms by which insulin influences breast cancer risk and progression. Endocr Relat Cancer 19(6):R225–R241

    Article  CAS  PubMed  Google Scholar 

  20. Giovannucci E et al (2010) Diabetes and cancer: a consensus report. Diabetes Care 33(7):1674–1685

    Article  PubMed  PubMed Central  Google Scholar 

  21. Bailyes EM et al (1997) Insulin receptor/IGF-I receptor hybrids are widely distributed in mammalian tissues: quantification of individual receptor species by selective immunoprecipitation and immunoblotting. Biochem J 327(Pt 1):209–215

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. White MF (1998) The IRS-signalling system: a network of docking proteins that mediate insulin action. Mol Cell Biochem 182(1–2):3–11

    Article  CAS  PubMed  Google Scholar 

  23. Belfiore A et al (2009) Insulin receptor isoforms and insulin receptor/insulin-like growth factor receptor hybrids in physiology and disease. Endocr Rev 30(6):586–623

    Article  CAS  PubMed  Google Scholar 

  24. Milazzo G et al (1992) Insulin receptor expression and function in human breast cancer cell lines. Cancer Res 52(14):3924–3930

    CAS  PubMed  Google Scholar 

  25. Frittitta L et al (1997) The insulin receptor content is increased in breast cancers initiated by three different oncogenes in transgenic mice. Breast Cancer Res Treat 45(2):141–147

    Article  CAS  PubMed  Google Scholar 

  26. Osborne CK et al (1978) Correlation among insulin binding, degradation, and biological activity in human breast cancer cells in long-term tissue culture. Cancer Res 38(1):94–102

    CAS  PubMed  Google Scholar 

  27. Frittitta L et al (1993) Structural and functional studies of insulin receptors in human breast cancer. Breast Cancer Res Treat 25(1):73–82

    Article  CAS  PubMed  Google Scholar 

  28. Papa V et al (1990) Elevated insulin receptor content in human breast cancer. J Clin Invest 86(5):1503–1510

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Vella V et al (2001) The IGF system in thyroid cancer: new concepts. Mol Pathol 54(3):121–124

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Aiello A et al (2010) HMGA1 protein is a positive regulator of the insulin-like growth factor-I receptor gene. Eur J Cancer 46(10):1919–1926

    Article  CAS  PubMed  Google Scholar 

  31. Chiefari E et al (2013) A polymorphism of HMGA1 is associated with increased risk of metabolic syndrome and related components. Sci Rep 3:1491

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Fusco A, Fedele M (2007) Roles of HMGA proteins in cancer. Nat Rev Cancer 7(12):899–910

    Article  CAS  PubMed  Google Scholar 

  33. Sciacca L et al (2002) In IGF-I receptor-deficient leiomyosarcoma cells autocrine IGF-II induces cell invasion and protection from apoptosis via the insulin receptor isoform A. Oncogene 21(54):8240–8250

    Article  CAS  PubMed  Google Scholar 

  34. Vella V et al (2002) A novel autocrine loop involving IGF-II and the insulin receptor isoform-A stimulates growth of thyroid cancer. J Clin Endocrinol Metab 87(1):245–254

    Article  CAS  PubMed  Google Scholar 

  35. Kalli KR et al (2002) Functional insulin receptors on human epithelial ovarian carcinoma cells: implications for IGF-II mitogenic signaling. Endocrinology 143(9):3259–3267

    Article  CAS  PubMed  Google Scholar 

  36. Soos MA et al (1990) Receptors for insulin and insulin-like growth factor-I can form hybrid dimers. Characterisation of hybrid receptors in transfected cells. Biochem J 270(2):383–390

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Spampinato D et al (2000) Insulin/insulin-like growth factor I hybrid receptors overexpression is not an early defect in insulin-resistant subjects. J Clin Endocrinol Metab 85(11):4219–4223

    Article  CAS  PubMed  Google Scholar 

  38. Pandini G et al (1999) Insulin and insulin-like growth factor-I (IGF-I) receptor overexpression in breast cancers leads to insulin/IGF-I hybrid receptor overexpression: evidence for a second mechanism of IGF-I signaling. Clin Cancer Res 5(7):1935–1944

    CAS  PubMed  Google Scholar 

  39. Pandini G et al (2007) Functional responses and in vivo anti-tumour activity of h7C10: a humanised monoclonal antibody with neutralising activity against the insulin-like growth factor-1 (IGF-1) receptor and insulin/IGF-1 hybrid receptors. Eur J Cancer 43(8):1318–1327

    Article  CAS  PubMed  Google Scholar 

  40. Pandini G et al (2002) Insulin/insulin-like growth factor I hybrid receptors have different biological characteristics depending on the insulin receptor isoform involved. J Biol Chem 277(42):39684–39695

    Article  CAS  PubMed  Google Scholar 

  41. Lukanova A et al (2004) Body mass index, circulating levels of sex-steroid hormones, IGF-I and IGF-binding protein-3: a cross-sectional study in healthy women. Eur J Endocrinol 150(2):161–171

    Article  CAS  PubMed  Google Scholar 

  42. Jenab M 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(2):368–376

    Article  CAS  PubMed  Google Scholar 

  43. Inzucchi SE (2002) Oral antihyperglycemic therapy for type 2 diabetes: scientific review. JAMA 287(3):360–372

    Article  CAS  PubMed  Google Scholar 

  44. Bo S et al (2012) Does use of metformin protect against cancer in Type 2 diabetes mellitus? J Endocrinol Invest 35(2):231–235

    Article  CAS  PubMed  Google Scholar 

  45. Coperchini F et al (2015) Expanding the therapeutic spectrum of metformin: from diabetes to cancer. J Endocrinol Invest 38(10):1047–1055

    Article  CAS  PubMed  Google Scholar 

  46. Giorgino F et al (1991) Overexpression of insulin receptors in fibroblast and ovary cells induces a ligand-mediated transformed phenotype. Mol Endocrinol 5(3):452–459

    Article  CAS  PubMed  Google Scholar 

  47. Sciacca L et al (2013) Clinical and molecular mechanisms favoring cancer initiation and progression in diabetic patients. Nutr Metab Cardiovasc Dis 23(9):808–815

    Article  CAS  PubMed  Google Scholar 

  48. Frittitta L et al (1995) Insulin receptor overexpression in 184B5 human mammary epithelial cells induces a ligand-dependent transformed phenotype. J Cell Biochem 57(4):666–669

    Article  CAS  PubMed  Google Scholar 

  49. Shafie SM, Grantham FH (1981) Role of hormones in the growth and regression of human breast cancer cells (MCF-7) transplanted into athymic nude mice. J Natl Cancer Inst 67(1):51–56

    CAS  PubMed  Google Scholar 

  50. Wang YH, Scadden DT (2015) Targeting the Warburg effect for leukemia therapy: magnitude matters. Mol Cell Oncol 2(3):e981988

    PubMed  PubMed Central  Google Scholar 

  51. Srinivasan S, Guha M, Avadhani NG (2016) Mitochondrial respiratory defects promote the Warburg effect and cancer progression. Mol Cell Oncol 3(2):e1085120

    Article  CAS  PubMed  Google Scholar 

  52. Muti P et al (2002) Fasting glucose is a risk factor for breast cancer: a prospective study. Cancer Epidemiol Biomark Prev 11(11):1361–1368

    CAS  Google Scholar 

  53. Krone CA, Ely JT (2005) Controlling hyperglycemia as an adjunct to cancer therapy. Integr Cancer Ther 4(1):25–31

    Article  PubMed  Google Scholar 

  54. Boyle P et al (2013) Blood glucose concentrations and breast cancer risk in women without diabetes: a meta-analysis. Eur J Nutr 52(5):1533–1540

    Article  CAS  PubMed  Google Scholar 

  55. Carstensen B et al (2016) Cancer incidence in persons with type 1 diabetes: a five-country study of 9,000 cancers in type 1 diabetic individuals. Diabetologia 59(5):980–988

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Huang Y et al (2014) Prediabetes and the risk of cancer: a meta-analysis. Diabetologia 57(11):2261–2269

    Article  CAS  PubMed  Google Scholar 

  57. Shin HY et al (2014) Association between fasting serum glucose levels and incidence of colorectal cancer in Korean men: the Korean Cancer Prevention Study-II. Metabolism 63(10):1250–1256

    Article  CAS  PubMed  Google Scholar 

  58. Parekh N et al (2013) Metabolic dysregulation of the insulin-glucose axis and risk of obesity-related cancers in the Framingham heart study-offspring cohort (1971-2008). Cancer Epidemiol Biomark Prev 22(10):1825–1836

    Article  Google Scholar 

  59. Buysschaert M et al (2015) Prediabetes and associated disorders. Endocrine 48(2):371–393

    Article  CAS  PubMed  Google Scholar 

  60. Ahn HK et al (2015) Metabolic components and recurrence in early-stage cervical cancer. Tumour Biol 36(3):2201–2207

    Article  CAS  PubMed  Google Scholar 

  61. Cowey S, Hardy RW (2006) The metabolic syndrome: a high-risk state for cancer? Am J Pathol 169(5):1505–1522

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Trabert B et al (2015) Metabolic syndrome and risk of endometrial cancer in the united states: a study in the SEER-medicare linked database. Cancer Epidemiol Biomark Prev 24(1):261–267

    Article  Google Scholar 

  63. Bhindi B et al (2015) Dissecting the association between metabolic syndrome and prostate cancer risk: analysis of a large clinical cohort. Eur Urol 67(1):64–70

    Article  CAS  PubMed  Google Scholar 

  64. Vigneri P et al (2006) Obesity and cancer. Nutr Metab Cardiovasc Dis 16(1):1–7

    Article  CAS  PubMed  Google Scholar 

  65. von Hafe P et al (2004) Visceral fat accumulation as a risk factor for prostate cancer. Obes Res 12(12):1930–1935

    Article  Google Scholar 

  66. Stoll BA (2002) Upper abdominal obesity, insulin resistance and breast cancer risk. Int J Obes Relat Metab Disord 26(6):747–753

    Article  CAS  PubMed  Google Scholar 

  67. Weichhaus M et al (2012) A novel role for insulin resistance in the connection between obesity and postmenopausal breast cancer. Int J Oncol 41(2):745–752

    CAS  PubMed  Google Scholar 

  68. Calle EE et al (2003) Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med 348(17):1625–1638

    Article  PubMed  Google Scholar 

  69. Parekh N et al (2015) Insulin receptor variants and obesity-related cancers in the Framingham Heart Study. Cancer Causes Control 26(8):1189–1195

    Article  PubMed  Google Scholar 

  70. Emerging Risk Factors Collaboration et al (2011) Diabetes mellitus, fasting glucose, and risk of cause-specific death. N Engl J Med 364(9):829–841

    Article  Google Scholar 

  71. Mayer SB, Evans WS, Nestler JE (2015) Polycystic ovary syndrome and insulin: our understanding in the past, present and future. Womens Health 11(2):137–149

    CAS  Google Scholar 

  72. Mortada R, Williams T (2015) Metabolic syndrome: polycystic ovary syndrome. FP Essent 435:30–42

    PubMed  Google Scholar 

  73. Tokmak A et al (2014) Polycystic ovary syndrome and risk of endometrial cancer: a mini-review. Asian Pac J Cancer Prev 15(17):7011–7014

    Article  PubMed  Google Scholar 

  74. Palomba S et al (2015) Complications and challenges associated with polycystic ovary syndrome: current perspectives. Int J Womens Health 7:745–763

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Barry JA, Azizia MM, Hardiman PJ (2014) Risk of endometrial, ovarian and breast cancer in women with polycystic ovary syndrome: a systematic review and meta-analysis. Hum Reprod Update 20(5):748–758

    Article  PubMed  PubMed Central  Google Scholar 

  76. Zendehdel K et al (2003) Cancer incidence in patients with type 1 diabetes mellitus: a population-based cohort study in Sweden. J Natl Cancer Inst 95(23):1797–1800

    Article  PubMed  Google Scholar 

  77. Ebeling P, Tuominen JA, Koivisto VA (1996) Insulin analogues and carcinoma of the breast. Diabetologia 39(1):124–125

    CAS  PubMed  Google Scholar 

  78. ter Braak B et al (2015) Mammary gland tumor promotion by chronic administration of IGF1 and the insulin analogue AspB10 in the p53R270H/(+)WAPCre mouse model. Breast Cancer Res 17:14

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Milazzo G et al (1997) ASPB10 insulin induction of increased mitogenic responses and phenotypic changes in human breast epithelial cells: evidence for enhanced interactions with the insulin-like growth factor-I receptor. Mol Carcinog 18(1):19–25

    Article  CAS  PubMed  Google Scholar 

  80. Sciacca L et al (2010) Insulin analogues differently activate insulin receptor isoforms and post-receptor signalling. Diabetologia 53(8):1743–1753

    Article  CAS  PubMed  Google Scholar 

  81. Hemkens LG et al (2009) Risk of malignancies in patients with diabetes treated with human insulin or insulin analogues: a cohort study. Diabetologia 52(9):1732–1744

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Colhoun, H.M. and S.E. Group (2009) Use of insulin glargine and cancer incidence in Scotland: a study from the Scottish Diabetes Research Network Epidemiology Group. Diabetologia 52(9):1755–1765

    Article  Google Scholar 

  83. Currie CJ, Poole CD, Gale EA (2009) The influence of glucose-lowering therapies on cancer risk in type 2 diabetes. Diabetologia 52(9):1766–1777

    Article  CAS  PubMed  Google Scholar 

  84. Jonasson JM et al (2009) Insulin glargine use and short-term incidence of malignancies-a population-based follow-up study in Sweden. Diabetologia 52(9):1745–1754

    Article  CAS  PubMed  Google Scholar 

  85. Mannucci E et al (2010) Doses of insulin and its analogues and cancer occurrence in insulin-treated type 2 diabetic patients. Diabetes Care 33(9):1997–2003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Pocock SJ, Smeeth L (2009) Insulin glargine and malignancy: an unwarranted alarm. Lancet 374(9689):511–513

    Article  PubMed  Google Scholar 

  87. Garg SK, Hirsch IB, Skyler JS (2009) Insulin glargine and cancer—an unsubstantiated allegation. Diabetes Technol Ther 11(8):473–476

    Article  CAS  PubMed  Google Scholar 

  88. Suissa S et al (2011) Long-term effects of insulin glargine on the risk of breast cancer. Diabetologia 54(9):2254–2262

    Article  CAS  PubMed  Google Scholar 

  89. Ruiter R et al (2012) Risk of cancer in patients on insulin glargine and other insulin analogues in comparison with those on human insulin: results from a large population-based follow-up study. Diabetologia 55(1):51–62

    Article  CAS  PubMed  Google Scholar 

  90. Investigators OT et al (2012) Basal insulin and cardiovascular and other outcomes in dysglycemia. N Engl J Med 367(4):319–328

    Article  CAS  Google Scholar 

  91. Vigneri R, Vigneri P, Frittitta L (2012) Basal insulin and cardiovascular and other outcomes. N Engl J Med 367(18):1761–1762 (author reply 1763-4)

    Article  PubMed  Google Scholar 

  92. Mathieu MC et al (1997) Insulin receptor expression and clinical outcome in node-negative breast cancer. Proc Assoc Am Physicians 109(6):565–571

    CAS  PubMed  Google Scholar 

  93. Law JH et al (2008) Phosphorylated insulin-like growth factor-i/insulin receptor is present in all breast cancer subtypes and is related to poor survival. Cancer Res 68(24):10238–10246

    Article  CAS  PubMed  Google Scholar 

  94. Kim JS et al (2012) Prognostic impact of insulin receptor expression on survival of patients with nonsmall cell lung cancer. Cancer 118(9):2454–2465

    Article  CAS  PubMed  Google Scholar 

  95. Helle SI (2004) The insulin-like growth factor system in advanced breast cancer. Best Pract Res Clin Endocrinol Metab 18(1):67–79

    Article  CAS  PubMed  Google Scholar 

  96. Janssen JA, Varewijck AJ (2014) IGF-IR Targeted Therapy: past, present and future. Front Endocrinol 5:224

    Google Scholar 

  97. Rostoker R et al (2015) Highly specific role of the insulin receptor in breast cancer progression. Endocr Relat Cancer 22(2):145–157

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Sciacca L et al (2014) Biological effects of insulin and its analogs on cancer cells with different insulin family receptor expression. J Cell Physiol 229(11):1817–1821

    Article  CAS  PubMed  Google Scholar 

  99. Parekh N et al (2010) Longitudinal associations of blood markers of insulin and glucose metabolism and cancer mortality in the third National Health and Nutrition Examination Survey. Cancer Causes Control 21(4):631–642

    Article  PubMed  Google Scholar 

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Acknowledgments

The researches in this review were supported, in part, by grants to RV from the AIRC (Associazione Italiana Ricerca Cancro, Milan, Italy).

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Vigneri, R., Goldfine, I.D. & Frittitta, L. Insulin, insulin receptors, and cancer. J Endocrinol Invest 39, 1365–1376 (2016). https://doi.org/10.1007/s40618-016-0508-7

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