Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Growth hormone, the insulin-like growth factor axis, insulin and cancer risk

Abstract

Growth hormone (GH), insulin-like growth factor (IGF)-I and insulin have potent growth-promoting and anabolic actions. Their potential involvement in tumor promotion and progression has been of concern for several decades. The evidence that GH, IGF-I and insulin can promote and contribute to cancer progression comes from various sources, including transgenic and knockout mouse models and animal and human cell lines derived from cancers. Assessments of the GH–IGF axis in healthy individuals followed up to assess cancer incidence provide direct evidence of this risk; raised IGF-I levels in blood are associated with a slightly increased risk of some cancers. Studies of human diseases characterized by excess growth factor secretion or treated with growth factors have produced reassuring data, with no notable increases in de novo cancers in children treated with GH. Although follow-up for the vast majority of these children does not yet extend beyond young adulthood, a slight increase in cancers in those with long-standing excess GH secretion (as seen in patients with acromegaly) and no overall increase in cancer with insulin treatment, have been observed. Nevertheless, long-term surveillance for cancer incidence in all populations exposed to increased levels of GH is vitally important.

Key Points

  • Growth hormone (GH), insulin-like growth factor I (IGF-I) and insulin have the potential to promote tumor growth and progression

  • Cumulative evidence from epidemiological studies supports an association between raised circulating levels of IGF-I and a slightly increased risk of certain cancers

  • Acromegaly, a disorder characterized by long-standing excess GH secretion, is associated with a small increased risk of colorectal and thyroid cancers

  • In follow-up studies through childhood, cancer risk is not raised by therapeutic use of GH, with the exception of a small increase in second cancers in childhood cancer survivors

  • Conditions characterized by hyperinsulinemia, such as obesity and type 2 diabetes mellitus, are associated with increased risk of several cancer types

  • Overall, cancer risk is not increased by the therapeutic use of insulin and/or insulin analogs in patients with diabetes mellitus, but the evidence is complex

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Summary of meta-analyses linking circulating levels of IGF-I and IGFBP-3 with the incidence of prostate, breast, colorectal, and lung cancers.
Figure 2: Associations of acromegaly with colorectal and thyroid cancer in population-based studies.
Figure 3: Schematic diagram of insulin and IGF-I receptors, their main downstream pathways, and main biological end points.
Figure 4: Schematic representation of the inter-relationships between obesity, insulin resistance and pathways that might favor tumor development.
Figure 5: Summary of meta-analyses linking diabetes with cancer risk.
Figure 6: Illustration of the strength of evidence linking the GH–IGF axis to cancer.

Similar content being viewed by others

References

  1. Luft, R. & Olivecrona, H. Hypophysectomy in the treatment of malignant tumors. Cancer 10, 789–794 (1957).

    Article  CAS  PubMed  Google Scholar 

  2. Moon, H. D., Simpson, M. E., Li, C. H. & Evans, H. M. Neoplasms in rats treated with pituitary growth hormone. III. Reproductive organs. Cancer Res. 10, 549–556 (1950).

    CAS  PubMed  Google Scholar 

  3. Moon, H. D., Simpson, M. E., Li, C. H. & Evans, H. M. Neoplasms in rats treated with pituitary growth hormone; adrenal glands. Cancer Res. 10, 364–370 (1950).

    CAS  PubMed  Google Scholar 

  4. Moon, H. D., Simpson, M. E., Li, C. H. & Evans, H. M. Neoplasms in rats treated with pituitary growth hormone; pulmonary and lymphatic tissues. Cancer Res. 10, 297–308 (1950).

    CAS  PubMed  Google Scholar 

  5. Rose, D. P., Gottardis, M. & Noonan, J. J. Rat mammary carcinoma regressions during suppression of serum growth hormone and prolactin. Anticancer Res. 3, 323–325 (1983).

    CAS  PubMed  Google Scholar 

  6. Ramsey, M. M. et al. Growth hormone-deficient dwarf animals are resistant to dimethylbenzanthracine (DMBA)-induced mammary carcinogenesis. Endocrinology 143, 4139–4142 (2002).

    Article  CAS  PubMed  Google Scholar 

  7. Swanson, S. M. & Unterman, T. G. The growth hormone-deficient Spontaneous Dwarf rat is resistant to chemically induced mammary carcinogenesis. Carcinogenesis 23, 977–982 (2002).

    Article  CAS  PubMed  Google Scholar 

  8. Deitel, K. et al. Reduced growth of human sarcoma xenografts in hosts homozygous for the lit mutation. J. Surg. Oncol. 81, 75–79 (2002).

    Article  CAS  PubMed  Google Scholar 

  9. Yang, X. F., Beamer, W. G., Huynh, H. & Pollak, M. Reduced growth of human breast cancer xenografts in hosts homozygous for the lit mutation. Cancer Res. 56, 1509–1511 (1996).

    CAS  PubMed  Google Scholar 

  10. Zhang, X. et al. Inhibition of estrogen-independent mammary carcinogenesis by disruption of growth hormone signaling. Carcinogenesis 28, 143–150 (2007).

    Article  PubMed  Google Scholar 

  11. Törnell, J. et al. High frequency of mammary adenocarcinomas in metallothionein promoter-human growth hormone transgenic mice created from two different strains of mice. J. Steroid Biochem. Mol. Biol. 43, 237–242 (1992).

    Article  PubMed  Google Scholar 

  12. Törnell, J., Rymo, L. & Isaksson, O. G. Induction of mammary adenocarcinomas in metallothionein promoter-human growth hormone transgenic mice. Int. J. Cancer 49, 114–117 (1991).

    Article  PubMed  Google Scholar 

  13. Wennbo, H. et al. Activation of the prolactin receptor but not the growth hormone receptor is important for induction of mammary tumors in transgenic mice. J. Clin. Invest. 100, 2744–2751 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Baker, J., Liu, J. P., Robertson, E. J. & Efstratiadis, A. Role of insulin-like growth factors in embryonic and postnatal growth. Cell 75, 73–82 (1993).

    Article  CAS  PubMed  Google Scholar 

  15. Olivo-Marston, S. E. et al. Genetic reduction of circulating insulin-like growth factor-1 inhibits azoxymethane-induced colon tumorigenesis in mice. Mol. Carcinog. 48, 1071–1076 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Wu, Y. et al. Reduced circulating insulin-like growth factor I levels delay the onset of chemically and genetically induced mammary tumors. Cancer Res. 63, 4384–4388 (2003).

    CAS  PubMed  Google Scholar 

  17. Wu, Y., Yakar, S., Zhao, L., Hennighausen, L. & LeRoith, D. Circulating insulin-like growth factor-I levels regulate colon cancer growth and metastasis. Cancer Res. 62, 1030–1035 (2002).

    CAS  PubMed  Google Scholar 

  18. Dunn, S. E. et al. Dietary restriction reduces insulin-like growth factor I levels, which modulates apoptosis, cell proliferation, and tumor progression in p53-deficient mice. Cancer Res. 57, 4667–4672 (1997).

    CAS  PubMed  Google Scholar 

  19. Christofori, G., Naik, P. & Hanahan, D. Deregulation of both imprinted and expressed alleles of the insulin-like growth factor 2 gene during beta-cell tumorigenesis. Nat. Genet. 10, 196–201 (1995).

    Article  CAS  PubMed  Google Scholar 

  20. Bates, P. et al. Mammary cancer in transgenic mice expressing insulin-like growth factor II (IGF-II). Br. J. Cancer 72, 1189–1193 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Moorehead, R. A., Sanchez, O. H., Baldwin, R. M. & Khokha, R. Transgenic overexpression of IGF-II induces spontaneous lung tumors: a model for human lung adenocarcinoma. Oncogene 22, 853–857 (2003).

    Article  CAS  PubMed  Google Scholar 

  22. Rogler, C. E. et al. Altered body composition and increased frequency of diverse malignancies in insulin-like growth factor-II transgenic mice. J. Biol. Chem. 269, 13779–13784 (1994).

    CAS  PubMed  Google Scholar 

  23. van Buul-Offers, S. C. et al. Overexpression of human insulin-like growth factor-II in transgenic mice causes increased growth of the thymus. J. Endocrinol. 144, 491–502 (1995).

    Article  CAS  PubMed  Google Scholar 

  24. Ward, A., Bates, P., Fisher, R., Richardson, L. & Graham, C. F. Disproportionate growth in mice with Igf-2 transgenes. Proc. Natl Acad. Sci. USA 91, 10365–10369 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Wolf, E., Kramer, R., Blum, W. F., Föll, J. & Brem, G. Consequences of postnatally elevated insulin-like growth factor-II in transgenic mice: endocrine changes and effects on body and organ growth. Endocrinology 135, 1877–1886 (1994).

    Article  CAS  PubMed  Google Scholar 

  26. Carboni, J. M. et al. Tumor development by transgenic expression of a constitutively active insulin-like growth factor I receptor. Cancer Res. 65, 3781–3787 (2005).

    Article  CAS  PubMed  Google Scholar 

  27. Jones, R. A. et al. Transgenic overexpression of IGF-IR disrupts mammary ductal morphogenesis and induces tumor formation. Oncogene 26, 1636–1644 (2007).

    Article  CAS  PubMed  Google Scholar 

  28. Lopez, T. & Hanahan, D. Elevated levels of IGF-1 receptor convey invasive and metastatic capability in a mouse model of pancreatic islet tumorigenesis. Cancer Cell 1, 339–353 (2002).

    Article  CAS  PubMed  Google Scholar 

  29. DeAngelis, T., Ferber, A. & Baserga, R. Insulin-like growth factor I receptor is required for the mitogenic and transforming activities of the platelet-derived growth factor receptor. J. Cell Physiol. 164, 214–221 (1995).

    Article  CAS  PubMed  Google Scholar 

  30. Sell, C. et al. Effect of a null mutation of the insulin-like growth factor I receptor gene on growth and transformation of mouse embryo fibroblasts. Mol. Cell Biol. 14, 3604–3612 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Sell, C. et al. Simian virus 40 large tumor antigen is unable to transform mouse embryonic fibroblasts lacking type 1 insulin-like growth factor receptor. Proc. Natl Acad. Sci. USA 90, 11217–11221 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Chopin, L. K., Veveris-Lowe, T. L., Philipps, A. F. & Herington, A. C. Co-expression of GH and GHR isoforms in prostate cancer cell lines. Growth Horm. IGF Res. 12, 126–136 (2002).

    Article  CAS  PubMed  Google Scholar 

  33. Raccurt, M. et al. High stromal and epithelial human gh gene expression is associated with proliferative disorders of the mammary gland. J. Endocrinol. 175, 307–318 (2002).

    Article  CAS  PubMed  Google Scholar 

  34. Slater, M., Cooper, M. & Murphy, C. R. Human growth hormone and interleukin-6 are upregulated in endometriosis and endometrioid adenocarcinoma. Acta Histochem. 108, 13–18 (2006).

    Article  PubMed  Google Scholar 

  35. Yang, X. et al. Growth hormone receptor expression in human colorectal cancer. Dig. Dis. Sci. 49, 1493–1498 (2004).

    Article  CAS  PubMed  Google Scholar 

  36. Wu, X. et al. Growth hormone receptor overexpression predicts response of rectal cancers to pre-operative radiotherapy. Eur. J. Cancer. 42, 888–894 (2006).

    Article  CAS  PubMed  Google Scholar 

  37. Schally, A. V. & Varga, J. L. Antagonists of growth hormone-releasing hormone in oncology. Comb. Chem. High Throughput Screen. 9, 163–170 (2006).

    Article  CAS  PubMed  Google Scholar 

  38. Gil-Puig, C. et al. Pit-1 is expressed in normal and tumorous human breast and regulates GH secretion and cell proliferation. Eur. J. Endocrinol. 153, 335–344 (2005).

    Article  CAS  PubMed  Google Scholar 

  39. Kaulsay, K. K. et al. Autocrine stimulation of human mammary carcinoma cell proliferation by human growth hormone. Exp. Cell Res. 250, 35–50 (1999).

    Article  CAS  PubMed  Google Scholar 

  40. Mukhina, S. et al. Phenotypic conversion of human mammary carcinoma cells by autocrine human growth hormone. Proc. Natl Acad. Sci. USA 101, 15166–15171 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Zhu, T. et al. Oncogenic transformation of human mammary epithelial cells by autocrine human growth hormone. Cancer Res. 65, 317–324 (2005).

    CAS  PubMed  Google Scholar 

  42. Xu, X. Q. et al. Gene expression profiling to identify oncogenic determinants of autocrine human growth hormone in human mammary carcinoma. J. Biol. Chem. 280, 23987–24003 (2005).

    Article  CAS  PubMed  Google Scholar 

  43. Kim, K. W. et al. Insulin-like growth factor II induced by hypoxia may contribute to angiogenesis of human hepatocellular carcinoma. Cancer Res. 58, 348–351 (1998).

    CAS  PubMed  Google Scholar 

  44. Moromisato, D. Y., Moromisato, M. Y., Zanconato, S. & Roberts, C. T. Jr. Effect of hypoxia on lung, heart, and liver insulin-like growth factor-I gene and receptor expression in the newborn rat. Crit. Care Med. 24, 919–924 (1996).

    Article  CAS  PubMed  Google Scholar 

  45. Feldser, D. et al. Reciprocal positive regulation of hypoxia-inducible factor 1α and insulin-like growth factor 2. Cancer Res. 59, 3915–3918 (1999).

    CAS  PubMed  Google Scholar 

  46. Zelzer, E. et al. Insulin induces transcription of target genes through the hypoxia-inducible factor HIF-1α/ARNT. EMBO J. 17, 5085–5094 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Grulich-Henn, J. et al. Transport of insulin-like growth factor-I across endothelial cell monolayers and its binding to the subendothelial matrix. Exp. Clin. Endocrinol. Diabetes 110, 67–73 (2002).

    Article  CAS  PubMed  Google Scholar 

  48. Lee, O. H. et al. Identification of angiogenic properties of insulin-like growth factor II in in vitro angiogenesis models. Br. J. Cancer. 82, 385–391 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Shigematsu, S. et al. IGF-1 regulates migration and angiogenesis of human endothelial cells. Endocr. J. 46 (Suppl.), S59–S62 (1999).

    Article  CAS  PubMed  Google Scholar 

  50. Mira, E., Mañes, S., Lacalle, R. A., Márquez, G. & Martínez, A. C. Insulin-like growth factor I-triggered cell migration and invasion are mediated by matrix metalloproteinase-9. Endocrinology 140, 1657–1664 (1999).

    Article  CAS  PubMed  Google Scholar 

  51. Zhang, D., Bar-Eli, M., Meloche, S. & Brodt, P. 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, 19683–19690 (2004).

    Article  CAS  PubMed  Google Scholar 

  52. Sachdev, D. & Yee, D. Disrupting insulin-like growth factor signaling as a potential cancer therapy. Mol. Cancer Ther. 6, 1–12 (2007).

    Article  CAS  PubMed  Google Scholar 

  53. Sachdev, D., Zhang, X., Matise, I., Gaillard-Kelly, M. & Yee, D. The type I insulin-like growth factor receptor regulates cancer metastasis independently of primary tumor growth by promoting invasion and survival. Oncogene 29, 251–262 (2010).

    Article  CAS  PubMed  Google Scholar 

  54. Gualberto, A. & Pollak, M. Emerging role of insulin-like growth factor receptor inhibitors in oncology: early clinical trial results and future directions. Oncogene 28, 3009–3021 (2009).

    Article  CAS  PubMed  Google Scholar 

  55. Wu, J. D. et al. Combined in vivo effect of A12, a type 1 insulin-like growth factor receptor antibody, and docetaxel against prostate cancer tumors. Clin. Cancer Res. 12, 6153–6160 (2006).

    Article  CAS  PubMed  Google Scholar 

  56. Yuen, J. S. et al. Validation of the type 1 insulin-like growth factor receptor as a therapeutic target in renal cancer. Mol. Cancer Ther. 8, 1448–1459 (2009).

    Article  CAS  PubMed  Google Scholar 

  57. Dallas, N. A. et al. Chemoresistant colorectal cancer cells, the cancer stem cell phenotype, and increased sensitivity to insulin-like growth factor-I receptor inhibition. Cancer Res. 69, 1951–1957 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Tolcher, A. W. et al. Phase I, pharmacokinetic, and pharmacodynamic study of AMG 479, a fully human monoclonal antibody to insulin-like growth factor receptor 1. J. Clin. Oncol. 27, 5800–5807 (2009).

    Article  CAS  PubMed  Google Scholar 

  59. Olmos, D. et al. Safety, pharmacokinetics, and preliminary activity of the anti-IGF-1R antibody figitumumab (CP-751,871) in patients with sarcoma and Ewing's sarcoma: a phase 1 expansion cohort study. Lancet Oncol. 11, 129–135 (2010).

    Article  CAS  PubMed  Google Scholar 

  60. Kimura, T. et al. Targeting of bone-derived insulin-like growth factor-II by a human neutralizing antibody suppresses the growth of prostate cancer cells in a human bone environment. Clin. Cancer Res. 16, 121–129 (2010).

    Article  CAS  PubMed  Google Scholar 

  61. Chan, J. M. et al. Plasma insulin-like growth factor-I and prostate cancer risk: a prospective study. Science 279, 563–566 (1998).

    Article  CAS  PubMed  Google Scholar 

  62. Hankinson, S. E. et al. Circulating concentrations of insulin-like growth factor-I and risk of breast cancer. Lancet 351, 1393–1396 (1998).

    Article  CAS  PubMed  Google Scholar 

  63. Yu, H. et al. Plasma levels of insulin-like growth factor-I and lung cancer risk: a case–control analysis. J. Natl Cancer Inst. 91, 151–156 (1999).

    Article  CAS  PubMed  Google Scholar 

  64. Ma, J. 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).

    Article  CAS  PubMed  Google Scholar 

  65. Yu, H. & Rohan, T. Role of the insulin-like growth factor family in cancer development and progression. J. Natl Cancer Inst. 92, 1472–1489 (2000).

    Article  CAS  PubMed  Google Scholar 

  66. Morris, J. K., George, L. M., Wu, T. & Wald, N. J. 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, 112–117 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Renehan, A. G. et al. Insulin-like growth factor (IGF)-I, IGF binding protein-3, and cancer risk: systematic review and meta-regression analysis. Lancet 363, 1346–1353 (2004).

    Article  CAS  PubMed  Google Scholar 

  68. Endogenous Hormones and Breast Cancer Collaborative Group. Insulin-like growth factor 1 (IGF-I), IGF binding protein 3 (IGFBP3), and breast cancer risk: pooled individual data analysis of 17 prospective studies. Lancet Oncol. 11, 530–542 (2010).

  69. Chen, B. et al. IGF-I and IGFBP-3 and the risk of lung cancer: a meta-analysis based on nested case–control studies. J. Exp. Clin. Cancer Res. 28, 89 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Rinaldi, S. et al. Serum levels of IGF-I, IGFBP-3 and colorectal cancer risk: results from the EPIC cohort, plus a meta-analysis of prospective studies. Int. J. Cancer 126, 1702–1715 (2010).

    CAS  PubMed  Google Scholar 

  71. Roddam, A. W. et al. Insulin-like growth factors, their binding proteins, and prostate cancer risk: analysis of individual patient data from 12 prospective studies. Ann. Intern. Med. 149, 461–471 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  72. Renehan, A. G., Atkin, W. S., O'Dwyer, S. T. & Shalet, S. M. The effect of cigarette smoking use and cessation on serum insulin-like growth factors. Br. J. Cancer 91, 1525–1531 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Firth, S. M. & Baxter, R. C. Cellular actions of the insulin-like growth factor binding proteins. Endocr. Rev. 23, 824–854 (2002).

    Article  CAS  PubMed  Google Scholar 

  74. Khoury-Shakour, S. et al. Genetic variation in IGF-1 and breast cancer risk in Ashkenazi carriers and noncarriers of BRCA1/2 mutations. Eur. J. Cancer Prev. 18, 361–367 (2009).

    Article  CAS  PubMed  Google Scholar 

  75. Su, X. et al. Genetic variation and circulating levels of IGF-I and IGFBP-3 in relation to risk of proliferative benign breast disease. Int. J. Cancer 126, 180–190 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Ressler, S. et al. Insulin-like growth factor-binding protein-3 in osteosarcomas and normal bone tissues. Anticancer Res. 29, 2579–2587 (2009).

    CAS  PubMed  Google Scholar 

  77. Baris, D. et al. Acromegaly and cancer risk: a cohort study in Sweden and Denmark. Cancer Causes Control 13, 395–400 (2002).

    Article  CAS  PubMed  Google Scholar 

  78. Kauppinen-Mäkelin, R. et al. Increased cancer incidence in acromegaly—a nationwide survey. Clin. Endocrinol. 72, 278–279 (2009).

    Article  Google Scholar 

  79. Orme, S. M., McNally, R. J., Cartwright, R. A. & Belchetz, P. E. Mortality and cancer incidence in acromegaly: a retrospective cohort study. United Kingdom Acromegaly Study Group. J. Clin. Endocrinol. Metab. 83, 2730–2734 (1998).

    CAS  PubMed  Google Scholar 

  80. Ron, E. et al. Acromegaly and gastrointestinal cancer. Cancer 68, 1673–1677 (1991).

    Article  CAS  PubMed  Google Scholar 

  81. Renehan, A. G. & Brennan, B. M. Acromegaly, growth hormone and cancer risk. Best Pract. Res. Clin. Endocrinol. Metab. 22, 639–657 (2008).

    Article  CAS  PubMed  Google Scholar 

  82. Colao, A. et al. The association of fasting insulin concentrations and colonic neoplasms in acromegaly: a colonoscopy-based study in 210 patients. J. Clin. Endocrinol. Metab. 92, 3854–3860 (2007).

    Article  CAS  PubMed  Google Scholar 

  83. Renehan, A. G. et al. Acromegaly and colorectal cancer: a comprehensive review of epidemiology, biological mechanisms, and clinical implications. Horm. Metab. Res. 35, 712–725 (2003).

    Article  CAS  PubMed  Google Scholar 

  84. Watanabe, S. et al. Leukemia and other malignancies among GH users. J. Pediatr. Endocrinol. 6, 99–108 (1993).

    Article  CAS  PubMed  Google Scholar 

  85. Banerjee, I. & Clayton, P. E. Growth hormone treatment and cancer risk. Endocrinol. Metab. Clin. North Am. 36, 247–263 (2007).

    Article  CAS  PubMed  Google Scholar 

  86. Bell, J. et al. Long-term safety of recombinant human growth hormone in children. J. Clin. Endocrinol. Metab. 95, 167–177 (2010).

    Article  CAS  PubMed  Google Scholar 

  87. Sklar, C. A. et al. Risk of disease recurrence and second neoplasms in survivors of childhood cancer treated with growth hormone: a report from the Childhood Cancer Survivor Study. J. Clin. Endocrinol. Metab. 87, 3136–3141 (2002).

    Article  CAS  PubMed  Google Scholar 

  88. Ergun-Longmire, B. et al. Growth hormone treatment and risk of second neoplasms in the childhood cancer survivor. J. Clin. Endocrinol. Metab. 91, 3494–3498 (2006).

    Article  CAS  PubMed  Google Scholar 

  89. Stochholm, K. et al. Morbidity and GH deficiency: a nationwide study. Eur. J. Endocrinol. 158, 447–457 (2008).

    Article  CAS  PubMed  Google Scholar 

  90. Svensson, J. & Bengtsson, B. A. Safety aspects of GH replacement. Eur. J. Endocrinol. 161 (Suppl. 1), S65–S74 (2009).

    Article  CAS  PubMed  Google Scholar 

  91. Chung, T. T. et al. Safety of GH replacement in hypopituitary patients with nonirradiated pituitary and peripituitary tumours. Clin. Endocrinol. 68, 965–969 (2008).

    Article  CAS  Google Scholar 

  92. Ho, K. K. Consensus guidelines for the diagnosis and treatment of adults with GH deficiency II: a statement of the GH Research Society in association with the European Society for Pediatric Endocrinology, Lawson Wilkins Society, European Society of Endocrinology, Japan Endocrine Society, and Endocrine Society of Australia. Eur. J. Endocrinol. 157, 695–700 (2007).

    Article  CAS  PubMed  Google Scholar 

  93. Midyett, L. K., Rogol, A. D., Van Meter, Q. L., Frane, J. & Bright, G. M. Recombinant insulin-like growth factor (IGF)-I treatment in short children with low IGF-I levels: first-year results from a randomized clinical trial. J. Clin. Endocrinol. Metab. 95, 611–619 (2010).

    Article  CAS  PubMed  Google Scholar 

  94. Chernausek, S. D., Backeljauw, P. F., Frane, J., Kuntze, J. & Underwood, L. E. Long-term treatment with recombinant insulin-like growth factor (IGF)-I in children with severe IGF-I deficiency due to growth hormone insensitivity. J. Clin. Endocrinol. Metab. 92, 902–910 (2007).

    Article  CAS  PubMed  Google Scholar 

  95. European Medicines Agency European Medicines Agency [online], (2009).

  96. Tidyman, W. E. & Rauen, K. A. Noonan, Costello and cardio-facio-cutaneous syndromes: dysregulation of the Ras-MAPK pathway. Expert Rev. Mol. Med. 10, e37 (2008).

    Article  PubMed  Google Scholar 

  97. Tidyman, W. E. & Rauen, K. A. The RASopathies: developmental syndromes of Ras/MAPK pathway dysregulation. Curr. Opin. Genet. Dev. 19, 230–236 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Brems, H., Beert, E., de Ravel, T. & Legius, E. Mechanisms in the pathogenesis of malignant tumours in neurofibromatosis type 1. Lancet Oncol. 10, 508–515 (2009).

    Article  CAS  PubMed  Google Scholar 

  99. Jorge, A. A., Malaquias, A. C., Arnhold, I. J. & Mendonca, B. B. Noonan syndrome and related disorders: a review of clinical features and mutations in genes of the RAS/MAPK pathway. Horm. Res. 71, 185–193 (2009).

    CAS  PubMed  Google Scholar 

  100. Schubbert, S., Shannon, K. & Bollag, G. Hyperactive Ras in developmental disorders and cancer. Nat. Rev. Cancer 7, 295–308 (2007).

    Article  CAS  PubMed  Google Scholar 

  101. Bentires-Alj, M. et al. Activating mutations of the noonan syndrome-associated SHP2/PTPN11 gene in human solid tumors and adult acute myelogenous leukemia. Cancer Res. 64, 8816–8820 (2004).

    Article  CAS  PubMed  Google Scholar 

  102. Denayer, E. et al. Tumor spectrum in children with Noonan syndrome and SOS1 or RAF1 mutations. Genes Chromosomes Cancer 49, 242–252 (2010).

    CAS  PubMed  Google Scholar 

  103. Nava, C. et al. Cardio-facio-cutaneous and Noonan syndromes due to mutations in the RAS/MAPK signalling pathway: genotype-phenotype relationships and overlap with Costello syndrome. J. Med. Genet. 44, 763–771 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Howell, S. J., Wilton, P., Lindberg, A. & Shalet, S. M. Growth hormone and neurofibromatosis. Horm. Res. 53 (Suppl. 1), 70–76 (2000).

    CAS  PubMed  Google Scholar 

  105. Romano, A. A. et al. Growth response, near-adult height, and patterns of growth and puberty in patients with Noonan syndrome treated with growth hormone. J. Clin. Endocrinol. Metab. 94, 2338–2344 (2009).

    Article  CAS  PubMed  Google Scholar 

  106. Rosenberg, P. S., Alter, B. P. & Ebell, W. Cancer risks in Fanconi anemia: findings from the German Fanconi Anemia Registry. Haematologica 93, 511–517 (2008).

    Article  PubMed  Google Scholar 

  107. Stahnke, N. Leukemia in growth-hormone-treated patients: an update, 1992. Horm. Res. 38 (Suppl. 1), 56–62 (1992).

    Article  PubMed  Google Scholar 

  108. Deans, A. J. & West, S. C. FANCM connects the genome instability disorders Bloom's Syndrome and Fanconi Anemia. Mol. Cell. 36, 943–953 (2009).

    Article  CAS  PubMed  Google Scholar 

  109. Corpet, D. E., Jacquinet, C., Peiffer, G. & Taché, S. Insulin injections promote the growth of aberrant crypt foci in the colon of rats. Nutr. Cancer 27, 316–320 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Tran, T. T., Medline, A. & Bruce, W. R. Insulin promotion of colon tumors in rats. Cancer Epidemiol. Biomarkers Prev. 5, 1013–1015 (1996).

    CAS  PubMed  Google Scholar 

  111. Koohestani, N. et al. Aberrant crypt focus promotion and glucose intolerance: correlation in the rat across diets differing in fat, n-3 fatty acids and energy. Carcinogenesis 19, 1679–1684 (1998).

    Article  CAS  PubMed  Google Scholar 

  112. Yakar, S. et al. Increased tumor growth in mice with diet-induced obesity: impact of ovarian hormones. Endocrinology 147, 5826–5834 (2006).

    Article  CAS  PubMed  Google Scholar 

  113. Nunez, N. P. et al. Accelerated tumor formation in a fatless mouse with type 2 diabetes and inflammation. Cancer Res. 66, 5469–5476 (2006).

    Article  CAS  PubMed  Google Scholar 

  114. Karna, E. et al. Serum and tissue level of insulin-like growth factor-I (IGF-I) and IGF-I binding proteins as an index of pancreatitis and pancreatic cancer. Int. J. Exp. Pathol. 83, 239–245 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Pandini, G. et al. 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, 1935–1944 (1999).

    CAS  PubMed  Google Scholar 

  116. Heuson, J. C. & Legros, N. Influence of insulin deprivation on growth of the 7,12-dimethylbenz(a)anthracene-induced mammary carcinoma in rats subjected to alloxan diabetes and food restriction. Cancer Res. 32, 226–232 (1972).

    CAS  PubMed  Google Scholar 

  117. Heuson, J. C., Waelbroeck- van Gaver, C. & Legros, N. Growth inhibition of rat mammary carcinoma and endocrine changes produced by 2-Br-alpha-ergocryptine, a suppressor of lactation and nidation. Eur. J. Cancer 6, 353–356 (1970).

    Article  CAS  PubMed  Google Scholar 

  118. Nair, P. N., De Armond, D. T., Adamo, M. L., Strodel, W. E. & Freeman, J. W. Aberrant expression and activation of insulin-like growth factor-1 receptor (IGF-1R) are mediated by an induction of IGF-1R promoter activity and stabilization of IGF-1R mRNA and contributes to growth factor independence and increased survival of the pancreatic cancer cell line MIA PaCa-2. Oncogene 20, 8203–8214 (2001).

    Article  CAS  PubMed  Google Scholar 

  119. Lawlor, M. A. & Alessi, D. R. PKB/Akt: a key mediator of cell proliferation, survival and insulin responses? J. Cell Sci. 114, 2903–2910 (2001).

    CAS  PubMed  Google Scholar 

  120. Weijzen, S., Velders, M. P. & Kast, W. M. Modulation of the immune response and tumor growth by activated Ras. Leukemia 13, 502–513 (1999).

    Article  CAS  PubMed  Google Scholar 

  121. World Cancer Research Fund. Food, Nutrition, Physical Activity, and the Prevention of Cancer: a Global Perspective (American Institute for Cancer Research, Washington, 2007).

  122. Renehan, A., Tyson, M., Egger, M., Heller, R. F. & Zwahlen, M. Body mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies. Lancet 371, 569–578 (2008).

    Article  PubMed  Google Scholar 

  123. Renehan, A. G., Egger, M. & Zwahlen, M. Body mass index and cancer risk: the evidence for causal association. The Open Obesity Journal 2, 12–22 (2010).

    Google Scholar 

  124. Harvie, M., Hooper, L. & Howell, A. H. Central obesity and breast cancer risk: a systematic review. Obes. Rev. 4, 157–173 (2003).

    Article  CAS  PubMed  Google Scholar 

  125. Dai, Z., Xu, Y. C. & Niu, L. Obesity and colorectal cancer risk: a meta-analysis of cohort studies. World J. Gastroenterol. 13, 4199–4206 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  126. Roberts, D. L., Dive, C. & Renehan, A. G. Biological mechanisms linking obesity and cancer risk: new perspectives. Annu. Rev. Med. 61, 301–316 (2010).

    Article  CAS  PubMed  Google Scholar 

  127. Suikkari, A. M. et al. Insulin regulates the serum levels of low molecular weight insulin-like growth factor-binding protein. J. Clin. Endocrinol. Metab. 66, 266–272 (1988).

    Article  CAS  PubMed  Google Scholar 

  128. Böni-Schnetzler, M. et al. Insulin regulates the expression of the insulin-like growth factor binding protein 2 mRNA in rat hepatocytes. Mol. Endocrinol. 4, 1320–1326 (1990).

    Article  PubMed  Google Scholar 

  129. Giovannucci, E. Insulin and colon cancer. Cancer Causes Control 6, 164–179 (1995).

    Article  CAS  PubMed  Google Scholar 

  130. Kaaks, R. et al. Prospective study of IGF-I, IGF-binding proteins, and breast cancer risk, in northern and southern Sweden. Cancer Causes Control 13, 307–316 (2002).

    Article  PubMed  Google Scholar 

  131. Keinan-Boker, L. et al. Circulating levels of insulin-like growth factor I, its binding proteins -1, -2, -3, C-peptide and risk of postmenopausal breast cancer. Int. J. Cancer 106, 90–95 (2003).

    Article  CAS  PubMed  Google Scholar 

  132. Krajcik, R. A., Borofsky, N. D., Massardo, S. & Orentreich, N. Insulin-like growth factor I (IGF-I), IGF-binding proteins, and breast cancer. Cancer Epidemiol. Biomarkers Prev. 11, 1566–1573 (2002).

    CAS  PubMed  Google Scholar 

  133. Renehan, A. G., Frystyk, J. & Flyvbjerg, A. Obesity and cancer risk: the role of the insulin-IGF axis. Trends Endocrinol. Metab. 17, 328–336 (2006).

    Article  CAS  PubMed  Google Scholar 

  134. Pisani, P. Hyper-insulinaemia and cancer, meta-analyses of epidemiological studies. Arch. Physiol. Biochem. 114, 63–70 (2008).

    Article  CAS  PubMed  Google Scholar 

  135. Renehan, A. G. In Adipose Tissue in Health and Disease Ch. 19 (eds Leff, T. & Granneman, J. G.) 369–381 (Wiley-VCH, Weinheim, 2009).

    Google Scholar 

  136. Mitri, J., Castillo, J. & Pittas, A. G. Diabetes and risk of non-Hodgkin's lymphoma: a meta-analysis of observational studies. Diabetes Care 31, 2391–2397 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  137. Larsson, S. C., Mantzoros, C. S. & Wolk, A. Diabetes mellitus and risk of breast cancer: a meta-analysis. Int. J. Cancer 121, 856–862 (2007).

    Article  CAS  PubMed  Google Scholar 

  138. Larsson, S. C., Orsini, N. & Wolk, A. Diabetes mellitus and risk of colorectal cancer: a meta-analysis. J. Natl Cancer Inst. 97, 1679–1687 (2005).

    Article  PubMed  Google Scholar 

  139. Friberg, E., Orsini, N., Mantzoros, C. S. & Wolk, A. Diabetes mellitus and risk of endometrial cancer: a meta-analysis. Diabetologia 50, 1365–1374 (2007).

    Article  CAS  PubMed  Google Scholar 

  140. El-Serag, H. B., Hampel, H. & Javadi, F. The association between diabetes and hepatocellular carcinoma: a systematic review of epidemiologic evidence. Clin. Gastroenterol. Hepatol. 4, 369–380 (2006).

    Article  PubMed  Google Scholar 

  141. Huxley, R., Ansary-Moghaddam, A., Berrington de González, A., Barzi, F. & Woodward, M. Type-II diabetes and pancreatic cancer: a meta-analysis of 36 studies. Br. J. Cancer 92, 2076–2083 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Larsson, S. C., Andersson, S. O., Johansson, J. E. & Wolk, A. Diabetes mellitus, body size and bladder cancer risk in a prospective study of Swedish men. Eur. J. Cancer 44, 2655–2660 (2008).

    Article  PubMed  Google Scholar 

  143. Kasper, J. S. & Giovannucci, E. A meta-analysis of diabetes mellitus and the risk of prostate cancer. Cancer Epidemiol. Biomarkers Prev. 15, 2056–2062 (2006).

    Article  PubMed  Google Scholar 

  144. Yang, Y. X., Hennessy, S. & Lewis, J. D. Insulin therapy and colorectal cancer risk among type 2 diabetes mellitus patients. Gastroenterology 127, 1044–1050 (2004).

    Article  CAS  PubMed  Google Scholar 

  145. Bowker, S. L., Majumdar, S. R., Veugelers, P. & Johnson, J. A. Increased cancer-related mortality for patients with type 2 diabetes who use sulfonylureas or insulin. Diabetes Care 29, 254–258 (2006).

    Article  PubMed  Google Scholar 

  146. Novosyadlyy, R. et al. Insulin-mediated acceleration of breast cancer development and progression in a nonobese model of type 2 diabetes. Cancer Res. 70, 741–751 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Evans, J. M., Donnelly, L. A., Emslie-Smith, A. M., Alessi, D. R. & Morris, A. D. Metformin and reduced risk of cancer in diabetic patients. BMJ 330, 1304–1305 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  149. Currie, C. J., Poole, C. D. & Gale, E. A. The influence of glucose-lowering therapies on cancer risk in type 2 diabetes. Diabetologia 52, 1766–1777 (2009).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Jonasson, J. M. et al. Insulin glargine use and short-term incidence of malignancies—a population-based follow-up study in Sweden. Diabetologia 52, 1745–1754 (2009).

    Article  CAS  PubMed  Google Scholar 

  152. Pocock, S. J. & Smeeth, L. Insulin glargine and malignancy: an unwarranted alarm. Lancet 374, 511–513 (2009).

    Article  PubMed  Google Scholar 

  153. Smith, U. & Gale, E. A. Does diabetes therapy influence the risk of cancer? Diabetologia 52, 1699–1708 (2009).

    Article  CAS  PubMed  Google Scholar 

  154. Rosenstock, J. et al. Similar risk of malignancy with insulin glargine and neutral protamine Hagedorn (NPH) insulin in patients with type 2 diabetes: findings from a 5 year randomised, open-label study. Diabetologia 52, 1971–1973 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Dejgaard, A., Lynggaard, H., Råstam, J. & Krogsgaard Thomsen, M. No evidence of increased risk of malignancies in patients with diabetes treated with insulin detemir: a meta-analysis. Diabetologia 52, 2507–2512 (2009).

    Article  CAS  PubMed  Google Scholar 

  156. Home, P. D. & Lagarenne, P. Combined randomised controlled trial experience of malignancies in studies using insulin glargine. Diabetologia 52, 2499–2506 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Pollak, M., Blouin, M. J., Zhang, J. C. & Kopchick, J. J. Reduced mammary gland carcinogenesis in transgenic mice expressing a growth hormone antagonist. Br. J. Cancer 85, 428–430 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Wang, Z. et al. Disruption of growth hormone signaling retards early stages of prostate carcinogenesis in the C3(1)/T antigen mouse. Endocrinology 146, 5188–5196 (2005).

    Article  CAS  PubMed  Google Scholar 

  159. Anzo, M. et al. Targeted deletion of hepatic Igf1 in TRAMP mice leads to dramatic alterations in the circulating insulin-like growth factor axis but does not reduce tumor progression. Cancer Res. 68, 3342–3349 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Hong, S. H. et al. Murine osteosarcoma primary tumour growth and metastatic progression is maintained after marked suppression of serum insulin-like growth factor I. Int. J. Cancer 124, 2042–2049 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Wilker, E. et al. Enhancement of susceptibility to diverse skin tumor promoters by activation of the insulin-like growth factor-1 receptor in the epidermis of transgenic mice. Mol. Carcinog. 25, 122–131 (1999).

    Article  CAS  PubMed  Google Scholar 

  162. Wilker, E. et al. Role of PI3K/Akt signaling in insulin-like growth factor-1 (IGF-1) skin tumor promotion. Mol. Carcinog. 44, 137–145 (2005).

    Article  CAS  PubMed  Google Scholar 

  163. Sharon, R. et al. Insulin dependence of murine T-cell lymphoma. II. Insulin-deficient diabetic mice and mice fed low-energy diet develop resistance to lymphoma growth. Int. J. Cancer 53, 843–849 (1993).

    Article  CAS  PubMed  Google Scholar 

  164. Sakatani, T. et al. Loss of imprinting of Igf2 alters intestinal maturation and tumorigenesis in mice. Science 307, 1976–1978 (2005).

    Article  CAS  PubMed  Google Scholar 

  165. Lu, S. & Archer, M. C. Insulin-like growth factor binding protein-1 over-expression in transgenic mice inhibits hepatic preneoplasia. Mol. Carcinog. 36, 142–146 (2003).

    Article  CAS  PubMed  Google Scholar 

  166. Diehl, D. et al. IGFBP-2 overexpression reduces the appearance of dysplastic aberrant crypt foci and inhibits growth of adenomas in chemically induced colorectal carcinogenesis. Int. J. Cancer 124, 2220–2225 (2009).

    Article  CAS  PubMed  Google Scholar 

  167. Shukla, S. et al. Up-regulation of insulin-like growth factor binding protein-3 by apigenin leads to growth inhibition and apoptosis of 22Rv1 xenograft in athymic nude mice. FASEB J. 19, 2042–2044 (2005).

    Article  CAS  PubMed  Google Scholar 

  168. Silha, J. V. et al. Insulin-like growth factor (IGF) binding protein-3 attenuates prostate tumor growth by IGF-dependent and IGF-independent mechanisms. Endocrinology 147, 2112–2121 (2006).

    Article  CAS  PubMed  Google Scholar 

  169. Durai, R. et al. Increased apoptosis and decreased proliferation of colorectal cancer cells using insulin-like growth factor binding protein-4 gene delivered locally by gene transfer. Colorectal Dis. 9, 625–631 (2007).

    Article  CAS  PubMed  Google Scholar 

  170. Rho, S. B. et al. Insulin-like growth factor-binding protein-5 (IGFBP-5) acts as a tumor suppressor by inhibiting angiogenesis. Carcinogenesis 29, 2106–2111 (2008).

    Article  CAS  PubMed  Google Scholar 

  171. Yakar, S., Leroith, D. & Brodt, P. 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, 407–420 (2005).

    Article  CAS  PubMed  Google Scholar 

  172. Swerdlow, A. J., Higgins, C. D., Adlard, P. & Preece, M. A. Risk of cancer in patients treated with human pituitary growth hormone in the UK, 1959–85: a cohort study. Lancet 360, 273–277 (2002).

    Article  CAS  PubMed  Google Scholar 

  173. Mehls, O. et al. Does growth hormone treatment affect the risk of post-transplant renal cancer? Pediatr. Nephrol. 17, 984–989 (2002).

    Article  PubMed  Google Scholar 

  174. Tuffli, G. A., Johanson, A., Rundle, A. C. & Allen, D. B. Lack of increased risk for extracranial, nonleukemic neoplasms in recipients of recombinant deoxyribonucleic acid growth hormone. J. Clin. Endocrinol. Metab. 80, 1416–1422 (1995).

    CAS  PubMed  Google Scholar 

  175. Allen, D. B., Rundle, A. C., Graves, D. A. & Blethen, S. L. Risk of leukemia in children treated with human growth hormone: review and reanalysis. J. Pediatr. 131, S32–S36 (1997).

    Article  CAS  PubMed  Google Scholar 

  176. Nishi, Y. et al. Recent status in the occurrence of leukemia in growth hormone-treated patients in Japan. GH Treatment Study Committee of the Foundation for Growth Science, Japan. J. Clin. Endocrinol. Metab. 84, 1961–1965 (1999).

    Article  CAS  PubMed  Google Scholar 

  177. Swerdlow, A. J. et al. Growth hormone treatment of children with brain tumors and risk of tumor recurrence. J. Clin. Endocrinol. Metab. 85, 4444–4449 (2000).

    CAS  PubMed  Google Scholar 

  178. Blethen, S. L. et al. Safety of recombinant deoxyribonucleic acid-derived growth hormone: The National Cooperative Growth Study experience. J. Clin. Endocrinol. Metab. 81, 1704–1710 (1996).

    CAS  PubMed  Google Scholar 

  179. Maneatis, T., Baptista, J., Connelly, K. & Blethen, S. Growth hormone safety update from the National Cooperative Growth Study. J. Pediatr. Endocrinol. Metab. 13 (Suppl. 2), 1035–1044 (2000).

    PubMed  Google Scholar 

  180. Wyatt, D. Lessons from the national cooperative growth study. Eur. J. Endocrinol. 151 (Suppl. 1), S55–S59 (2004).

    Article  CAS  PubMed  Google Scholar 

  181. Safety and Appropriateness of Growth Hormone Treatments in Europe [online], (2010).

Download references

Acknowledgements

The authors are supported by the National Institute for Health Research Manchester Biomedical Research Center, UK. A. G. Renehan holds a senior lectureship award supported by the UK Clinical Research Collaboration.

Author information

Authors and Affiliations

Authors

Contributions

All authors contributed equally to all aspects of this review.

Corresponding author

Correspondence to Peter E. Clayton.

Ethics declarations

Competing interests

P. E. Clayton is a consultant and speaker for Ipsen and Merck Serono. He is a consultant for Pfizer. He is a speaker for, and has received grant/research support from, Novo Nordisk. A. G. Renehan is a consultant and speaker for, and has received grant/research support from, Novo Nordisk. The other authors declare no competing interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Clayton, P., Banerjee, I., Murray, P. et al. Growth hormone, the insulin-like growth factor axis, insulin and cancer risk. Nat Rev Endocrinol 7, 11–24 (2011). https://doi.org/10.1038/nrendo.2010.171

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrendo.2010.171

This article is cited by

Search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer