Growth hormone, the insulin-like growth factor axis, insulin and cancer risk (original) (raw)

• Luft, R. & Olivecrona, H. Hypophysectomy in the treatment of malignant tumors. Cancer 10, 789–794 (1957).
  Article CAS PubMed Google Scholar
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• Yang, X. et al. Growth hormone receptor expression in human colorectal cancer. Dig. Dis. Sci. 49, 1493–1498 (2004).
  Article CAS PubMed Google Scholar
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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).
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• Kauppinen-Mäkelin, R. et al. Increased cancer incidence in acromegaly—a nationwide survey. Clin. Endocrinol. 72, 278–279 (2009).
  Article Google Scholar
• 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
• Ron, E. et al. Acromegaly and gastrointestinal cancer. Cancer 68, 1673–1677 (1991).
  Article CAS PubMed Google Scholar
• 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
• 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
• 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
• Watanabe, S. et al. Leukemia and other malignancies among GH users. J. Pediatr. Endocrinol. 6, 99–108 (1993).
  Article CAS PubMed Google Scholar
• 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
• 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
• 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
• 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
• Stochholm, K. et al. Morbidity and GH deficiency: a nationwide study. Eur. J. Endocrinol. 158, 447–457 (2008).
  Article CAS PubMed Google Scholar
• Svensson, J. & Bengtsson, B. A. Safety aspects of GH replacement. Eur. J. Endocrinol. 161 (Suppl. 1), S65–S74 (2009).
  Article CAS PubMed Google Scholar
• 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
• 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
• 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
• 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
• European Medicines Agency European Medicines Agency [online], (2009).
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• Stahnke, N. Leukemia in growth-hormone-treated patients: an update, 1992. Horm. Res. 38 (Suppl. 1), 56–62 (1992).
  Article PubMed Google Scholar
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• World Cancer Research Fund. Food, Nutrition, Physical Activity, and the Prevention of Cancer: a Global Perspective (American Institute for Cancer Research, Washington, 2007).
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• Giovannucci, E. Insulin and colon cancer. Cancer Causes Control 6, 164–179 (1995).
  Article CAS PubMed Google Scholar
• 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
• 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
• 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
• 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
• Pisani, P. Hyper-insulinaemia and cancer, meta-analyses of epidemiological studies. Arch. Physiol. Biochem. 114, 63–70 (2008).
  Article CAS PubMed Google Scholar
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• Pocock, S. J. & Smeeth, L. Insulin glargine and malignancy: an unwarranted alarm. Lancet 374, 511–513 (2009).
  Article PubMed Google Scholar
• Smith, U. & Gale, E. A. Does diabetes therapy influence the risk of cancer? Diabetologia 52, 1699–1708 (2009).
  Article CAS PubMed Google Scholar
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• Wyatt, D. Lessons from the national cooperative growth study. Eur. J. Endocrinol. 151 (Suppl. 1), S55–S59 (2004).
  Article CAS PubMed Google Scholar
• Safety and Appropriateness of Growth Hormone Treatments in Europe [online], (2010).