Luft, R. & Olivecrona, H. Hypophysectomy in the treatment of malignant tumors. Cancer 10, 789–794 (1957).
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).
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).
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).
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).
Ramsey, M. M. et al. Growth hormone-deficient dwarf animals are resistant to dimethylbenzanthracine (DMBA)-induced mammary carcinogenesis. Endocrinology 143, 4139–4142 (2002).
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).
Deitel, K. et al. Reduced growth of human sarcoma xenografts in hosts homozygous for the lit mutation. J. Surg. Oncol. 81, 75–79 (2002).
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).
Zhang, X. et al. Inhibition of estrogen-independent mammary carcinogenesis by disruption of growth hormone signaling. Carcinogenesis 28, 143–150 (2007).
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).
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).
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).
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).
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).
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).
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).
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).
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).
Bates, P. et al. Mammary cancer in transgenic mice expressing insulin-like growth factor II (IGF-II). Br. J. Cancer 72, 1189–1193 (1995).
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).
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).
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).
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).
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).
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).
Jones, R. A. et al. Transgenic overexpression of IGF-IR disrupts mammary ductal morphogenesis and induces tumor formation. Oncogene 26, 1636–1644 (2007).
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).
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).
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).
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).
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).
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).
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).
Yang, X. et al. Growth hormone receptor expression in human colorectal cancer. Dig. Dis. Sci. 49, 1493–1498 (2004).
Wu, X. et al. Growth hormone receptor overexpression predicts response of rectal cancers to pre-operative radiotherapy. Eur. J. Cancer. 42, 888–894 (2006).
Schally, A. V. & Varga, J. L. Antagonists of growth hormone-releasing hormone in oncology. Comb. Chem. High Throughput Screen. 9, 163–170 (2006).
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).
Kaulsay, K. K. et al. Autocrine stimulation of human mammary carcinoma cell proliferation by human growth hormone. Exp. Cell Res. 250, 35–50 (1999).
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).
Zhu, T. et al. Oncogenic transformation of human mammary epithelial cells by autocrine human growth hormone. Cancer Res. 65, 317–324 (2005).
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).
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).
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).
Feldser, D. et al. Reciprocal positive regulation of hypoxia-inducible factor 1α and insulin-like growth factor 2. Cancer Res. 59, 3915–3918 (1999).
Zelzer, E. et al. Insulin induces transcription of target genes through the hypoxia-inducible factor HIF-1α/ARNT. EMBO J. 17, 5085–5094 (1998).
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).
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).
Shigematsu, S. et al. IGF-1 regulates migration and angiogenesis of human endothelial cells. Endocr. J. 46 (Suppl.), S59–S62 (1999).
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).
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).
Sachdev, D. & Yee, D. Disrupting insulin-like growth factor signaling as a potential cancer therapy. Mol. Cancer Ther. 6, 1–12 (2007).
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).
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).
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).
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).
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).
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).
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).
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).
Chan, J. M. et al. Plasma insulin-like growth factor-I and prostate cancer risk: a prospective study. Science 279, 563–566 (1998).
Hankinson, S. E. et al. Circulating concentrations of insulin-like growth factor-I and risk of breast cancer. Lancet 351, 1393–1396 (1998).
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).
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).
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).
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).
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).
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).
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).
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).
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).
Firth, S. M. & Baxter, R. C. Cellular actions of the insulin-like growth factor binding proteins. Endocr. Rev. 23, 824–854 (2002).
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).
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).
Ressler, S. et al. Insulin-like growth factor-binding protein-3 in osteosarcomas and normal bone tissues. Anticancer Res. 29, 2579–2587 (2009).
Baris, D. et al. Acromegaly and cancer risk: a cohort study in Sweden and Denmark. Cancer Causes Control 13, 395–400 (2002).
Kauppinen-Mäkelin, R. et al. Increased cancer incidence in acromegaly—a nationwide survey. Clin. Endocrinol. 72, 278–279 (2009).
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).
Ron, E. et al. Acromegaly and gastrointestinal cancer. Cancer 68, 1673–1677 (1991).
Renehan, A. G. & Brennan, B. M. Acromegaly, growth hormone and cancer risk. Best Pract. Res. Clin. Endocrinol. Metab. 22, 639–657 (2008).
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).
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).
Watanabe, S. et al. Leukemia and other malignancies among GH users. J. Pediatr. Endocrinol. 6, 99–108 (1993).
Banerjee, I. & Clayton, P. E. Growth hormone treatment and cancer risk. Endocrinol. Metab. Clin. North Am. 36, 247–263 (2007).
Bell, J. et al. Long-term safety of recombinant human growth hormone in children. J. Clin. Endocrinol. Metab. 95, 167–177 (2010).
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).
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).
Stochholm, K. et al. Morbidity and GH deficiency: a nationwide study. Eur. J. Endocrinol. 158, 447–457 (2008).
Svensson, J. & Bengtsson, B. A. Safety aspects of GH replacement. Eur. J. Endocrinol. 161 (Suppl. 1), S65–S74 (2009).
Chung, T. T. et al. Safety of GH replacement in hypopituitary patients with nonirradiated pituitary and peripituitary tumours. Clin. Endocrinol. 68, 965–969 (2008).
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).
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).
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).
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).
Tidyman, W. E. & Rauen, K. A. The RASopathies: developmental syndromes of Ras/MAPK pathway dysregulation. Curr. Opin. Genet. Dev. 19, 230–236 (2009).
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).
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).
Schubbert, S., Shannon, K. & Bollag, G. Hyperactive Ras in developmental disorders and cancer. Nat. Rev. Cancer 7, 295–308 (2007).
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).
Denayer, E. et al. Tumor spectrum in children with Noonan syndrome and SOS1 or RAF1 mutations. Genes Chromosomes Cancer 49, 242–252 (2010).
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).
Howell, S. J., Wilton, P., Lindberg, A. & Shalet, S. M. Growth hormone and neurofibromatosis. Horm. Res. 53 (Suppl. 1), 70–76 (2000).
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).
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).
Stahnke, N. Leukemia in growth-hormone-treated patients: an update, 1992. Horm. Res. 38 (Suppl. 1), 56–62 (1992).
Deans, A. J. & West, S. C. FANCM connects the genome instability disorders Bloom's Syndrome and Fanconi Anemia. Mol. Cell. 36, 943–953 (2009).
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).
Tran, T. T., Medline, A. & Bruce, W. R. Insulin promotion of colon tumors in rats. Cancer Epidemiol. Biomarkers Prev. 5, 1013–1015 (1996).
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).
Yakar, S. et al. Increased tumor growth in mice with diet-induced obesity: impact of ovarian hormones. Endocrinology 147, 5826–5834 (2006).
Nunez, N. P. et al. Accelerated tumor formation in a fatless mouse with type 2 diabetes and inflammation. Cancer Res. 66, 5469–5476 (2006).
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).
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).
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).
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).
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).
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).
Weijzen, S., Velders, M. P. & Kast, W. M. Modulation of the immune response and tumor growth by activated Ras. Leukemia 13, 502–513 (1999).
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).
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).
Harvie, M., Hooper, L. & Howell, A. H. Central obesity and breast cancer risk: a systematic review. Obes. Rev. 4, 157–173 (2003).
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).
Roberts, D. L., Dive, C. & Renehan, A. G. Biological mechanisms linking obesity and cancer risk: new perspectives. Annu. Rev. Med. 61, 301–316 (2010).
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).
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).
Giovannucci, E. Insulin and colon cancer. Cancer Causes Control 6, 164–179 (1995).
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).
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).
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).
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).
Pisani, P. Hyper-insulinaemia and cancer, meta-analyses of epidemiological studies. Arch. Physiol. Biochem. 114, 63–70 (2008).
Renehan, A. G. In Adipose Tissue in Health and Disease Ch. 19 (eds Leff, T. & Granneman, J. G.) 369–381 (Wiley-VCH, Weinheim, 2009).
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).
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).
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).
Friberg, E., Orsini, N., Mantzoros, C. S. & Wolk, A. Diabetes mellitus and risk of endometrial cancer: a meta-analysis. Diabetologia 50, 1365–1374 (2007).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
Pocock, S. J. & Smeeth, L. Insulin glargine and malignancy: an unwarranted alarm. Lancet 374, 511–513 (2009).
Smith, U. & Gale, E. A. Does diabetes therapy influence the risk of cancer? Diabetologia 52, 1699–1708 (2009).
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).
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).
Home, P. D. & Lagarenne, P. Combined randomised controlled trial experience of malignancies in studies using insulin glargine. Diabetologia 52, 2499–2506 (2009).
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).
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).
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).
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).
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).
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).
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).
Sakatani, T. et al. Loss of imprinting of Igf2 alters intestinal maturation and tumorigenesis in mice. Science 307, 1976–1978 (2005).
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).
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).
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).
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).
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).
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).
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).
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).
Mehls, O. et al. Does growth hormone treatment affect the risk of post-transplant renal cancer? Pediatr. Nephrol. 17, 984–989 (2002).
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).
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).
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).
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).
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).
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).
Wyatt, D. Lessons from the national cooperative growth study. Eur. J. Endocrinol. 151 (Suppl. 1), S55–S59 (2004).
Safety and Appropriateness of Growth Hormone Treatments in Europe [online], (2010).