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:

Modifying IGF1 activity: an approach to treat endocrine disorders, atherosclerosis and cancer

Nature Reviews Drug Discovery volume 6, pages 821–833 (2007)Cite this article

Key Points

  • Insulin-like growth factor 1 (IGF1) is a generalized growth stimulant. All tissues in the body contain IGF1 receptors and, therefore, increases in IGF1 result in a generalized increase in growth.

  • IGF1 concentrations are controlled primarily by nutrient intake and pituitary growth hormone secretion. Nutrient restriction can result in greatly diminished IGF1 action and catabolism, whereas administration of growth hormone results in increased IGF1 concentrations in tissues and an increased anabolic response.

  • The anabolic actions of IGF1 have been exploited for therapeutic purposes by using IGF1 administration to treat short children who are resistant to the growth promoting effects of growth hormone.

  • The use of IGF1 in catabolic states has had some success in small clinical trials. However, a better knowledge of the molecular events that result in increased catabolism in many of these conditions is likely to provide a foundation for making more rational decisions regarding the best way to use IGF1 and for selecting those diseases in which IGF1 would have the greatest likelihood of therapeutic success.

  • Both decreases in IGF1 concentration and peripheral actions worsen the response to insulin deficiency in diabetes. Optimal exploitation of IGF1's insulin-like properties has not been forthcoming. Future research is likely to focus on how this signalling pathway can be better manipulated to enhance insulin action in insulin sensitive tissues without inducing off-target effects.

  • IGF1 has a role in the development of atherosclerosis. As treatment of atherosclerosis is a chronic therapy, simply targeting the IGF1 receptor may result in unacceptable toxicity. A promising approach has been to target coreceptors, such as αVβ3, which indirectly alters vascular cell responses to IGF1. As this receptor is expressed on a limited number of cell types, this reduces the probability of off-target effects. The efficacy of this approach will be determined in future clinical trials.

  • The concept of blocking the IGF1 receptor in cancer is based on sound experimental animal data showing that targeting this receptor results in tumour cell apoptosis, the principle therapeutic hurdle in cancer. This approach is likely to be limited by side effects that are induced by a combination of cancer chemotherapy and blocking IGF1 receptors in normal tissues. By using antibodies to target specific cell types or by simultaneously inhibiting other growth factor receptors, it may be possible to overcome some of these potential toxicities.

Abstract

Insulin-like growth factor 1 (IGF1) is a polypeptide hormone that has a high degree of structural similarity to human proinsulin. Owing to its ubiquitous nature and its role in promoting cell growth, strategies to inhibit IGF1 actions are being pursued as potential adjunctive measures for treating diseases such as short stature, atherosclerosis and diabetes. In addition, most tumour cell types possess IGF1 receptors and conditions in the tumour microenvironment, such as hypoxia, can lead to enhanced responsiveness to IGF1. Therefore, inhibiting IGF1 action has been proposed as a specific mechanism for potentiating the effects of existing anticancer therapies or for directly inhibiting tumour cell growth.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1: Autocrine and paracrine actions of IGF1.
Figure 2: Growth hormone and IGF1 actions on glucose homeostasis.
Figure 3: IGF1 and atherosclerosis.
Figure 4: IGF1 actions and mechanisms of tumour development.

Similar content being viewed by others

References

  1. Clemmons D. R. Value of insulin-like growth factor system markers in the assessment of growth hormone status. Endocrinol. Metab. Clin. North Am. 36, 109–120 (2007).

    CAS  PubMed  Google Scholar 

  2. Riedemann, J. & Macaulay, V. M. IGF1R signalling and its inhibition. Endocr. Relat. Cancer 1, 533–543 (2006).

    Google Scholar 

  3. Jones, J. I. & Clemmons, D. R. Insulin-like growth factors and their binding proteins: biological actions. Endocr. Rev. 16, 3–34 (1995).

    CAS  PubMed  Google Scholar 

  4. Yakar, S. et al. Normal growth and development in the absence of hepatic insulin-like growth factor I. Proc. Natl Acad. Sci. USA 96, 7324–7329 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Edwall, D., Schalling, M., Jennische, E. & Norstedt, G. Induction of insulin-like growth factor I messenger ribonucleic acid during regeneration of rat skeletal muscle. Endocrinology 124, 820–825 (1989).

    CAS  PubMed  Google Scholar 

  6. Cercek, B., Fishbein, M. C., Forrester, J. S., Helfant, R. H. & Fagin, J. A. Induction of insulin-like growth factor I messenger RNA in rat aorta after balloon denudation. Circ. Res. 66, 1755–1760 (1990).

    CAS  PubMed  Google Scholar 

  7. Chu, C. R., Kaplan, L. D., Fu, F. H., Crossett, L. S. & Studer, R. K. Recovery of articular cartilage metabolism following thermal stress is facilitated by IGF-1 and JNK inhibitor. Am. J. Sports Med. 32, 191–196 (2004).

    PubMed  Google Scholar 

  8. O'Donnell, S. L., Frederick, T. J., Krady, J. K., Vannucci, S. J. & Wood, T. L. IGF1 and microglia/macrophage proliferation in the ischemic mouse brain. Glia 39, 85–97 (2002).

    PubMed  Google Scholar 

  9. Lassarre, C. & Ricort, J. M. Growth factor-specific regulation of insulin receptor substrate-1 expression in MCF-7 breast carcinoma cells: effects on the insulin-like growth factor signalling pathway. Endocrinol. 144, 4811–4819 (2003).

    CAS  Google Scholar 

  10. Swantek, J. L. & Baserga R. Prolonged activation of ERK2 by epidermal growth factor and other growth factors requires a functional insulin-like growth factor 1 receptor. Endocrinol. 140 3163–3169 (1999).

    CAS  Google Scholar 

  11. Arnqvist, H. J., Bornfeldt, K. E., Chen, Y. & Lindstrom, T. The insulin-like growth factor system in vascular smooth muscle: interaction with insulin and growth factors. Metabolism 44, 58–66 (1995).

    CAS  PubMed  Google Scholar 

  12. Yee, D. Targeting insulin-like growth factor pathways. Br. J. Cancer 94, 465–468 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. D'Ercole, A. J. Insulin-like growth factors and their receptors in growth. Endocrinol. Metab. Clin. North Am. 25, 573–590 (1996).

    CAS  PubMed  Google Scholar 

  14. Ye, P. et al. Astrocyte-specific overexpression of insulin-like growth factor-I promotes brain overgrowth and glial fibrillary acidic protein expression. J. Neurosci. Res. 78, 472–484 (2004).

    CAS  PubMed  Google Scholar 

  15. Isgaard, J. et al. Regulation of insulin-like growth factor messenger ribonucleic acid in rat growth plate by growth hormone. Endocrinol. 122, 1515–1520 (1988).

    CAS  Google Scholar 

  16. Liu, J. P., Baker, J., Perkins, A. S., Robertson, E. J. & Efstratiadis, A. Mice carrying null mutations of the genes encoding insulin-like growth factor I (Igf-1) and type 1 IGF receptor (Igf1r). Cell 75, 59–72 (1993). This paper establishes that IGF1 and IGF1 receptor are necessary for growth.

    CAS  PubMed  Google Scholar 

  17. Lissett, C. A., Gleeson, H. & Shalet, S.M. The insulin-like growth factor I generation test in adults. Horm. Res. 62, 44–49 (2004).

    CAS  PubMed  Google Scholar 

  18. Hartman, M. L. et al. A low dose euglycemic infusion of recombinant human insulin-like growth factor I rapidly suppresses fasting-enhanced pulsatile growth hormone secretion in humans. J. Clin. Invest. 91, 2453–2462 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Merimee, T. J., Zapf, J. & Froesch, E. R. Insulin-like growth factors in the fed and fasted states. J. Clin. Endocrinol. Metab. 55, 999–1002 (1982).

    CAS  PubMed  Google Scholar 

  20. Clemmons, D. R. & Van Wyk, J. J. Factors controlling blood concentration of somatomedin C. Clin. Endocrinol. Metab. 13, 113–143 (1984).

    CAS  PubMed  Google Scholar 

  21. Leung, K. C., Johannsson, G., Leong, G. M. & Ho, K. K. Estrogen regulation of growth hormone action. Endocr. Rev. 25, 693–721 (2004).

    CAS  PubMed  Google Scholar 

  22. Daughaday, W. H. & Rotwein, P. Insulin-like growth factors I and II. Peptide, messenger ribonucleic acid and gene structures, serum and tissue concentrations. Endocr. Rev. 10, 68–91 (1989).

    CAS  PubMed  Google Scholar 

  23. De Meyts, P. et al. Role of time factor in signalling specificity: application to mitogenic and metabolic signalling by the insulin and insulin-like growth factor-I receptor tyrosine kinases. Metabolism 44, 2–11 (1995).

    CAS  PubMed  Google Scholar 

  24. Lopaczynski, W. Differential regulation of signalling pathways for insulin and insulin-like growth factor I. Acta Biochim. Pol. 46, 51–60 (1999).

    CAS  PubMed  Google Scholar 

  25. Laviola, L., Natalicchio, A. & Giorgino, F. The IGF1 signalling pathway. Curr. Pharm. Des. 13, 663–669 (2007).

    CAS  PubMed  Google Scholar 

  26. Frystyk J. Free insulin-like growth factors — measurements and relationships to growth hormone secretion and glucose homeostasis. Growth Horm. IGF Res. 14, 337–375 (2004).

    CAS  PubMed  Google Scholar 

  27. Baxter, R. C. Circulating levels and molecular distribution of the acid-labile (α) subunit of the high molecular weight insulin-like growth factor-binding protein complex. J. Clin. Endocrinol. Metab. 70, 1347–1353 (1990).

    CAS  PubMed  Google Scholar 

  28. Bereket, A. et al. Insulin-like growth factor binding protein-3 proteolysis in children with insulin-dependent diabetes mellitus: a possible role for insulin in the regulation of IGFBP-3 protease activity. J. Clin. Endocrinol. Metab. 80, 2282–2288 (1995).

    CAS  PubMed  Google Scholar 

  29. Busby, W. H., Snyder, D. K. & Clemmons, D. R. Radioimmunoassay of a 26,000-dalton plasma insulin-like growth factor-binding protein: control by nutritional variables. J. Clin. Endocrinol. Metab. 67, 1225–1230 (1988).

    CAS  PubMed  Google Scholar 

  30. Jones, J. I. & Clemmons, D. R. Insulin-like growth factors and their binding proteins: biological actions. Endocr. Rev. 16, 3–34 (1995).

    CAS  PubMed  Google Scholar 

  31. Payne, A.M. et al. Motor neuron targeting of IGF-1 prevents specific force decline in aging mouse muscle. J. Physiol. 570, 283–294 (2006).

    CAS  PubMed  Google Scholar 

  32. Lee, H. K. et al. Insulin-like growth factor-1 induces migration and expression of laminin-5 in cultured human corneal epithelial cells. Invest. Ophthalmol. Vis. Sci. 47, 873–882 (2006).

    PubMed  Google Scholar 

  33. Song, Y. H. et al. Muscle-specific expression of IGF-1 blocks angiotensin II-induced skeletal muscle wasting. J. Clin. Invest. 115, 451–458 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Putz, T. et al. Epidermal growth factor (EGF) receptor blockade inhibits the action of EGF, insulin-like growth factor I and a protein kinase A activator on the mitogen-activated protein kinase pathway in prostate cancer cell lines. Cancer Res. 59, 227–233 (1999).

    CAS  PubMed  Google Scholar 

  35. Nahta, R., Yuan, L. X., Zhang, B., Kobayashi, R. & Esteva, F. J. Insulin-like growth factor-I receptor/human epidermal growth factor receptor 2 heterodimerization contributes to trastuzumab resistance of breast cancer cells. Cancer Res. 65 11118–11128 (2005).

    CAS  PubMed  Google Scholar 

  36. Ranke, M. D. Insulin-like growth factor-I treatment of growth disorders, diabetes mellitus and insulin resistance. Trends Endocrinol. Metab. 16 190–197 (2005).

    CAS  PubMed  Google Scholar 

  37. Backeljauw, P. F. & Underwood, L. E. GHIS, Collaborative Group. Therapy for 6.5–7.5 years with recombinant insulin-like growth factor I in children with growth hormone insensitivity syndrome: a clinical research center study. J. Clin. Endocrinol. Metab. 86, 1504–1510 (2001). This paper shows the results of long-term treatment with IGF1 on growth.

    CAS  PubMed  Google Scholar 

  38. Rosenfeld, R. G. Molecular mechanisms of IGF1 deficiency. Horm. Res. 65, 15–20 (2006).

    CAS  PubMed  Google Scholar 

  39. Lang, C. H., Hong-Brown, L. & Frost, R. A. Cytokine inhibition of JAK–STAT signalling: a new mechanism of growth hormone resistance. Pediatric Nephrol. 20, 306–312 (2005).

    Google Scholar 

  40. Mauras, N. & Beaufrere, B. Recombinant human insulin-like growth factor-I enhances whole body protein anabolism and significantly diminishes the protein catabolic effects of prednisone in humans without a diabetogenic effect. J. Clin. Endocrinol. Metab. 80, 869–874 (1995).

    CAS  PubMed  Google Scholar 

  41. Debroy, M. A. et al. Anabolic effects of insulin-like growth factor in combination with insulin-like growth factor binding protein-3 in severely burned adults. J. Trauma 47, 904–910, (1999).

    CAS  PubMed  Google Scholar 

  42. Grinspoon, S. et al. Effects of short-term recombinant human insulin-like growth factor I administration on bone turnover in osteopenic women with anorexia nervosa. J. Clin. Endocrinol. Metab. 81, 3864–3870 (1996).

    CAS  PubMed  Google Scholar 

  43. Boonen, S. et al. Musculoskeletal effects of the recombinant human IGF1/IGF binding protein-3 complex in osteoporotic patients with proximal femoral fracture: a double-blind, placebo-controlled pilot study. J. Clin. Endocrinol. Metab. 87, 1593–1599 (2002). This study shows an effect of IGF1 on osteopaenia.

    CAS  PubMed  Google Scholar 

  44. Vlachopapadopoulou, E. et al. Metabolic and clinical response to recombinant human insulin-like growth factor I in myotonic dystrophy — a clinical research center study. J. Clin. Endocrinol. Metab. 80, 3715–3723 (1995).

    CAS  PubMed  Google Scholar 

  45. Borasio, G., et al. A placebo-controlled trial of insulin-like growth factor-I in amyotrophic lateral sclerosis. European ALS/IGF1 Study Group. Neurology 51, 583–586 (1998).

    CAS  PubMed  Google Scholar 

  46. Lai, E. et al. Effect of recombinant human insulin-like growth factor-I on progression of ALS. A placebo-controlled study. The North America ALS/IGF1 Study Group. Neurology 49, 1621–1630 (1997).

    CAS  PubMed  Google Scholar 

  47. Avruch, J. et al. Insulin and amino-acid regulation of mTOR signalling and kinase activity through the Rheb GTPase. Oncogene 25, 6361–6372 (2006).

    CAS  PubMed  Google Scholar 

  48. Kuzuya, H. et al. Trial of insulinlike growth factor I therapy for patients with extreme insulin resistance syndromes. Diabetes 42, 696–705 (1999).

    Google Scholar 

  49. Fernandez, A. M. et al. Functional inactivation of the IGF1 and insulin receptors in skeletal muscle causes type 2 diabetes. Genes Dev. 15, 1926–1934 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Pennisi, P. et al. Recombinant human insulin-like growth factor-I treatment inhibits gluconeogenesis in a transgenic mouse model of type 2 diabetes mellitus. Endocrinology 147, 2619–2630 (2006).

    CAS  PubMed  Google Scholar 

  51. Yakar, S. et al. Inhibition of growth hormone action improves insulin sensitivity in liver IGF-1-deficient mice. J. Clin. Invest. 113, 96–105 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Saukkonen, T. et al. Dose-dependent effects of recombinant human insulin-like growth factor (IGF)-I/IGF binding protein-3 complex on overnight growth hormone secretion and insulin sensitivity in type 1 diabetes. J. Clin. Endocrinol. Metab. 89, 4634–4641 (2004).

    CAS  PubMed  Google Scholar 

  53. Thrailkill, K. M. et al. Cotherapy with recombinant human insulin-like growth factor I and insulin improves glycemic control in type 1 diabetes. RhIGF1 in IDDM Study Group. Diabetes Care 22, 585–592 (1999). This study shows that IGF1 has efficacy in type 1 diabetes.

    CAS  PubMed  Google Scholar 

  54. Quattrin, T. et al. Improvement of HbA1c without increased hypoglycemia in adolescents and young adults with type 1 diabetes mellitus treated with recombinant human insulin-like growth factor-I and insulin. rhIGF1 in IDDM Study Group. J. Pediatr. Endocrinol. Metab. 14, 267–277 (2001).

    CAS  PubMed  Google Scholar 

  55. RH in NIDDM Study Group, Evidence from a dose ranging study that recombinant insulin-like growth factor-I (RhIGF1) effectively and safely improves glycemic control in the non-insulin dependent diabetes mellitus. Diabetes 45 (Suppl. 2) 27A (1996).

  56. Moses, A. C., Young, S. C., Morrow, L. A., O'Brien, M. & Clemmons, D. R. Recombinant human insulin-like growth factor I increases insulin sensitivity and improves glycemic control in type II diabetes. Diabetes 45, 91–100 (1996). This study demonstrates that IGF1 enhances insulin sensitivity in type 2 diabetes.

    CAS  PubMed  Google Scholar 

  57. Schwartz, S. L. RHIGF1 co-therapy with Insulin Subgroup. RHIGF1 improves glucose control in insulin requiring type 2 diabetes. Proc. 5th Annu. Meeting Am. Diabetes Assoc., San Antonio, Texas, USA. Abstr. 582 (1997).

  58. Clemmons, D. R. et al. Rh/IGF1/rhIGFBP-3 administration to patients with type 2 diabetes mellitus reduces insulin requirements while also lowering fasting glucose. Growth Horm. IGF Res. 15, 265–274 (2005).

    CAS  PubMed  Google Scholar 

  59. Hizuka, N., et al. Serum high molecular weight form of insulin-like growth factor II from patients with non-islet cell tumour hypoglycemia is O-glycosylated. J. Clin. Endocrinol. Metab. 83, 2875–2877 (1998).

    CAS  PubMed  Google Scholar 

  60. Bahr, M., Kolter, T., Seipke, G. & Eckel J. Growth promoting and metabolic activity of the human insulin analogue (GLYA21, ArgB31, ArgB32) insulin (HOE 901) in muscle cells. Eur. J. Pharmacol. 320, 259–265 (1997).

    CAS  PubMed  Google Scholar 

  61. Ish-Shalom, D. et al. Mitogenic properties of insulin and insulin analogues mediated by the insulin receptor. Diabetol. 40, S25–S31 (1997).

    CAS  Google Scholar 

  62. Hua, Q. X. et al. Mini-proinsulin and mini-IGF1: homologous protein sequences encoding non-homologous structures. J. Mol. Biol. 277, 103–118 (1998).

    CAS  PubMed  Google Scholar 

  63. Slieker, L. J. et al. Modifications in the B10 and B26–30 regions of the B chain of human insulin alter affinity for the human IGF1 receptor more than for the insulin receptor. Diabetol. 40, S54–S61 (1997).

    CAS  Google Scholar 

  64. Sakai, K., Lowman, H. B. & Clemmons, D. R. Increases in free, unbound insulin-like growth factor I enhance insulin responsiveness in human hepatoma G2 cells in culture. J. Biol. Chem. 277, 13620–13627 (2002).

    CAS  PubMed  Google Scholar 

  65. Chen, C. et al. Discovery of a series of nonpeptide small molecules that inhibit the binding of insulin-like growth factor (IGF) to IGF-binding proteins. J. Med. Chem. 44, 4001–4010 (2001).

    CAS  PubMed  Google Scholar 

  66. Liu, X. J., Xie, Q., Zhu, Y. F., Chen, C. & Ling, N. Identification of a nonpeptide ligand that releases bioactive insulin-like growth factor-I from its binding protein complex. J. Biol. Chem. 276, 32419–32422 (2001).

    CAS  PubMed  Google Scholar 

  67. Grundy, S. M. Metabolic syndrome: connecting and reconciling cardiovascular and diabetes worlds. J. Am. Coll. Cardiol. 47, 1093–1100 (2006).

    CAS  PubMed  Google Scholar 

  68. Juul, A., Scheike, T., Davidsen, M., Gyllenborg, J. & Jorgensen, T. Low serum insulin-like growth factor I is associated with increased risk of ischemic heart disease: a population-based case-control study. Circulation 106, 939–944 (2002).

    CAS  PubMed  Google Scholar 

  69. Vaessen, N. et al. A polymorphism in the gene for IGF1: functional properties and risk for type 2 diabetes and myocardial infarction. Diabetes 50, 637–642 (2001).

    CAS  PubMed  Google Scholar 

  70. Khorsandi, M., Fagin, J. A., Fishbein, M. C., Forrester, J. S. & Cercek, B. Effects of hypophysectomyon vascular insulin-like growth factor-I gene expression after balloon denudation in rats. Atherosclerosis 93 115–122 (1992).

    CAS  PubMed  Google Scholar 

  71. Zhu, B., Zhao, G., Witte, D. P., Hui, D. Y. & Fagin, J. A. Targeted overexpression of IGF1 in smooth muscle cells of transgenic mice enhances neointimal formation through increased proliferation and cell migration after intraarterial injury. Endocrinology 142, 3598–3606 (2001).

    CAS  PubMed  Google Scholar 

  72. Du, J., Peng, T., Scheidegger, K. J. & Delafontaine, P. Angiotensin II activation of insulin-like growth factor 1 receptor transcription is mediated by a tyrosine kinase-dependent redox-sensitive mechanism. Arterioscler. Thromb. Vasc. Biol. 19, 2119–2126 (1999).

    CAS  PubMed  Google Scholar 

  73. Kirstein, M., Aston, C., Hintz, R. & Vlassara, H. Receptor-specific induction of insulin-like growth factor I in human monocytes by advanced glycosylation end product-modified proteins. J. Clin. Invest. 90, 439–446 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Brink, M., Chrast, J., Price, S. R., Mitch, W. E. & Delafontaine, P. Angiontensin II stimulates gene expression of cardiac insulin-like growth factor I and its receptor through effects on blood pressure and food intake. Hypertension 34, 1053–1059 (1999).

    CAS  PubMed  Google Scholar 

  75. Wang, J. et al. Overexpression of insulin-like growth factor-binding protein-4 (IGFBP-4) in smooth muscle cells of transgenic mice through a smooth muscle α-actin–IGFBP-4 fusion gene induces smooth muscle hypoplasia. Endocrinology 139, 2605–2614 (1998).

    CAS  PubMed  Google Scholar 

  76. Grant, M. B. et al. Localization of insulin-like growth factor I and inhibition of coronary smooth muscle cell growth by somatostatin analogues in human coronary smooth muscle cells. A potential treatment for restenosis? Circulation 89, 1511–1517 (1994).

    CAS  PubMed  Google Scholar 

  77. Hayry, P. et al. Stabile D-peptide analog of insulin-like growth factor-1 inhibits smooth muscle cell proliferation after carotid ballooning injury in the rat. FASEB J. 9, 1336–1344 (1995).

    CAS  PubMed  Google Scholar 

  78. Ling, Y., Maile, L. A. & Clemmons, D. R. Tyrosine phosphorylation of the β3-subunit of the αVb3 integrin is required for membrane association of the tyrosine phosphatase SHP-2 and its further recruitment to the insulin-like growth factor I receptor. Mol. Endocrinol. 17, 1824–1833 (2003).

    CAS  PubMed  Google Scholar 

  79. Ling, Y., Maile, L. A., Lieskovska, J., Badley-Clarke, J. & Clemmons, D. R. Role of SHPS-1 in the regulation of insulin-like growth factor I-stimulated SHC and mitogen-activated protein kinase activation in vascular smooth muscle cells. Mol. Biol. Cell 16, 3353–3364 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Nichols, T. C. et al. Reduction in atherosclerotic lesion size in pigs by αVβ3 inhibitors is associated with inhibition of insulin-like growth factor-I-mediated signalling. Circ. Res. 85, 1040–1045 (1999).

    CAS  PubMed  Google Scholar 

  81. Sachdev, D. & Yee, D. The IGF system and breast cancer. Endocr. Relat. Cancer 8, 197–209 (2001).

    CAS  PubMed  Google Scholar 

  82. Kaleko, M., Rutter, W. J. & Miller, A. D. Overexpression of the human insulin-like growth factor I receptor promotes ligand-dependent neoplastic transformation. Mol. Cell Biol. 10, 464–473 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Miura, M., Surmacz, E., Burgaud, J. L. & Baserga, R. Different effects on mitogenesis and transformation of a mutation at tyrosine 1251 of the insulin-like growth factor I receptor. J. Biol. Chem. 270, 22639–22644 (1995).

    CAS  PubMed  Google Scholar 

  85. 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).

    CAS  PubMed  Google Scholar 

  86. Dupont, J., Pierre, A., Froment, P. & Moreau, C. The insulin-like growth factor axis in cell cycle progression. Horm. Metab. Res. 35, 740–750 (2003).

    CAS  PubMed  Google Scholar 

  87. Coats, S., Flanagan, W. M., Nourse, J. & Roberts, J. M. Requirement of p27Kip1 for restriction point control of the fibroblast cell cycle. Science 272, 877–880 (1996).

    CAS  PubMed  Google Scholar 

  88. O'Connor, R., Fennelly, C. & Krause, D. Regulation of survival signals from the insulin-like growth factor-I receptor. Biochem. Soc. Trans. 28 47–15 (2000).

    CAS  PubMed  Google Scholar 

  89. Samani, A. A. & Brodt, P. The receptor for the type I insulin-like growth factor and its ligands regulate multiple cellular functions that impact on metastasis. Surg. Oncol. Clin. N. Am. 10, 289–312 (2001).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  91. Chan, J. M. et al. Plasma insulin-like growth factor-I and prostate cancer risk: a prospective study. Science 279, 563–566 (1998). This study shows a correlation between IGF1 concentrations and cancer risk.

    CAS  PubMed  Google Scholar 

  92. 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).

    CAS  PubMed  Google Scholar 

  93. Probst-Hensch, N. M. et al. IGF-1, IGF-2 and IGFBP-3 in prediagnostic serum: association with colorectal cancer in a cohort of Chinese men in Shanghai. Br. J. Cancer 85, 1695–1699 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Petridou, E. et al. Endometrial cancer and the IGF system: a case-control study in Greece. Oncology 64, 341–345 (2003).

    PubMed  Google Scholar 

  95. Zhao, H. et al. Plasma levels of insulin-like growth factor-1 and binding protein-3, and their association with bladder cancer risk. J. Urol. 169, 714–717 (2003).

    CAS  PubMed  Google Scholar 

  96. Cui, H. et al. Loss of IGF2 imprinting: a potential marker of colorectal cancer risk. Science 299, 1753–1755 (2003).

    CAS  PubMed  Google Scholar 

  97. Prawitt, D. et al. Microdeletion and IGF2 loss of imprinting in a cascade causing Beckwith-Wiedemann syndrome with Wilms' tumour. Nature Genet. 37 785–786 (2005).

    CAS  PubMed  Google Scholar 

  98. Hakam, A. et al. Expression of insulin-like growth factor-1 receptor in human colorectal cancer. Hum. Pathol. 30, 1128–1133 (1999).

    CAS  PubMed  Google Scholar 

  99. Xie, Y., Skytting, B., Nilsson, G., Brodin, B. & Larsson, O. Expression of insulin-like growth factor-1 receptor in synovial sarcoma: association with an aggressive phenotype. Cancer Res. 59, 3588–3591 (1999).

    CAS  PubMed  Google Scholar 

  100. All-Ericsson, C. et al. Insulin-like growth factor-1 receptor in uveal melanoma: a predictor for metastatic disease and a potential therapeutic target. Invest. Ophthalmol. Vis. Sci. 43, 1–8 (2002).

    PubMed  Google Scholar 

  101. Gicquel, C. et al. Molecular markers and long-term recurrences in a large cohort of patients with sporadic adrenocortical tumours. Cancer Res. 61, 6762–6767 (2001).

    CAS  PubMed  Google Scholar 

  102. Catrina, S. B. et al. Insulin-like growth factor-I receptor activity is essential for Kaposi's sarcoma growth and survival. Br. J. Cancer 92, 1467–1474 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Catrina, S. B. et al. Hypoxia-inducible factor-1α and hypoxia-inducible factor-2α are expressed in Kaposi sarcoma and modulated by insulin-like growth factor-I. Clin. Cancer 12, 4506–4514 (2006).

    CAS  Google Scholar 

  104. Fukuda, R. et al. Insulin-like growth factor 1 induces hypoxia-inducible factor 1-mediated vascular endothelial growth factor expression, which is dependent on MAP kinase and phosphatidylinositol 3-kinase signalling in colon cancer cells. J. Biol. Chem. 277, 38205–38211 (2002).

    CAS  PubMed  Google Scholar 

  105. Treins, C., Giorgetti-Peraldi, S., Murdaca, J., Monthouel-Kartmann, M. N. & Van Obberghen, E. Regulation of hypoxia-inducible factor (HIF)-1 activity and expression of HIF hydroxylases in response to insulin-like growth factor I. Mol. Endocrinol. 19, 1304–1317 (2005).

    CAS  PubMed  Google Scholar 

  106. Stawowy, P. et al. Porprotein convertases regulate insulin-like growth factor 1-induced membrane-type 1 matrix metalloprotease in VSMCs via endoproteollytic activation of the insulin-like growth factor-1 receptor. Biochem. Biophys. Res. Commun. 321, 531–538 (2004).

    CAS  PubMed  Google Scholar 

  107. Zhang, D. & Brodt, P. Type 1 insulin-like growth factor results MT1-MMP synthesis and tumour invasion via PI-3 kinase/Akt signalling. Oncogene 22, 974–982 (2003).

    CAS  PubMed  Google Scholar 

  108. 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 

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

    CAS  PubMed  Google Scholar 

  110. Zhang, D., Bar-Eli, M., Meloche, S. & Brodt, P. Dual regulation of MMP-2 expression by the type 2 insulin-like growth factor receptor: the phosphatidylinositol 3-kinase/Akt and Raf/ERK pathways transmit opposing signals. J. Biol. Chem. 279, 19683–19690 (2004).

    CAS  PubMed  Google Scholar 

  111. DiGiovanni, J. et al. Deregulated expression of insulin-like growth factor 1 in prostate epithelium leads to neoplasia in transgenic mice. Proc. Natl Acad. Sci. USA 97, 3455–3460 (2000). This study suggests that IGF1 is involved in neoplastic transformation.

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  113. Cosaceanu, D. et al. Ionizing radiation activates IGF-1R triggering a cytoprotective signalling by interfering with Ku-DNA binding and by modulating Ku86 expression via a p38 kinase-dependent mechanism. Oncogene 26, 2423–2434 (2007).

    CAS  PubMed  Google Scholar 

  114. Shahrabani-Gargir, L., Pandita, T. K. & Werner, H. Ataxia-telangiectasia mutated gene controls insulin-like growth factor I receptor gene expression in a deosyribonucleic acid damage response pathway via mechanisms involving zinc-finger transcription factors Sp1 and WT1. Endocrinology 145, 5679–5687 (2004).

    CAS  PubMed  Google Scholar 

  115. Gooch, J. L., Van Den Berg, C. L. & Yee, D. Insulin-like grwoth factor (IGF)-I rescues breast cancer cells from chemotherapy-induced cell death-proliferative and anti-apoptotic effects. Breast Cancer Res. Treat. 56, 1–10 (1999).

    CAS  PubMed  Google Scholar 

  116. Beech, D. J., Perer, E., Helms, J., Gratzer, A. & Deng, N. Insulin-like growth factor-I receptor activation blocks doxorubicin cytotoxicity in sarcoma cells. Oncol. Rep. 10, 181–184 (2003).

    CAS  PubMed  Google Scholar 

  117. Abe, S. et al. Increased expression of insulin-like growth factor I is associated with Ara-C resistance in leukaemia. Tohoku J. Exp. Med. 209, 217–228 (2006).

    CAS  PubMed  Google Scholar 

  118. Cardillo, M. R. et al. Insulin-like growth factor (IGF)-I, IGF-II, and IGF type I receptor (IGFR-I) expression in prostatic cancer. Anticancer Res. 23, 3825–3835 (2003).

    CAS  PubMed  Google Scholar 

  119. Weber, M. M. et al. Overexpression of the insulin-like growth factor I receptor in human colon carcinomas. Cancer 95, 2086–2095 (2002).

    CAS  PubMed  Google Scholar 

  120. Outban, A., Muraca, P., Yeatman, T. & Coppola, D. Expression and distribution of insulin-like growth factor-1 receptor in human carcinomas. Hum. Pathol. 34, 803–808 (2003).

    Google Scholar 

  121. Roy, R. N., Gerulath, A. H., Cecutti, A. & Bhavnani, B. R. Discordant expression of insulin-like growth factors and their receptor messenger ribonucleic acids in endometrial carcinomas relative to normal endometrium. Mol. Cell Endocrinol. 153, 19–27 (1999).

    CAS  PubMed  Google Scholar 

  122. Gammeltoft, S., Ballotti, R., Kowalski, A., Westermark, B. & Van Obberghen, E. Expression of two types of receptor for insulin-like growth factors in human malignant glioma. Cancer Res. 48, 1233–1237 (1988).

    CAS  PubMed  Google Scholar 

  123. Ota, A., Wilson, G. L. & Leroith, D. Insulin-like growth factor I receptors on mouse neuroblastoma cells. Two β subunits are derived from differences in glycosylation. Eur. J. Biochem. 174, 521–530 (1988).

    CAS  PubMed  Google Scholar 

  124. Kellerer, M. et al. An altered IGF1 receptor is present in human leukemic cells. J. Biol. Chem. 265, 9340–9345 (1990).

    CAS  PubMed  Google Scholar 

  125. Pandini, G. et al. IGF-II binding to insulin receptor isoform A induces a partially different gene expression profile from insulin binding. Ann. NY Acad. Sci. 1028, 450–456 (2004).

    CAS  PubMed  Google Scholar 

  126. Denley, A., Wallace, J. C., Cosgrove, L. J. & Forbes, B.E. The insulin receptor isoform exon 11-(IR-A) in cancer and other diseases: a review. Horm. Metab. Res. 1028, 450–456 (2003).

    Google Scholar 

  127. Zhang, D. & Brodt, P. Type 1 insulin-like growth factor results MT1-MMP synthesis and tumour invasion via PI-3 kinase/Akt signalling. Oncogene 22, 974–982 (2003).

    CAS  PubMed  Google Scholar 

  128. Chang, V.S. et al. Correlation between insulin-like growth factor-binding protein-3 promoter methylation and prognosis of patients with stage I non-small cell lung cancer. Clin. Cancer Res. 8, 3669–3675 (2002).

    CAS  PubMed  Google Scholar 

  129. Yi, H. K. et al. Impact of PTEN on the expression of insulin-like growth factors (IGFs) and IGF-binding proteins in human gastric adenocarcinoma cells. Biochim. Biophys. Res. Commun. 330, 760–767 (2005).

    CAS  Google Scholar 

  130. Brodt, P., Reich, R., Moroz, L. A. & Chambers, A. F. Differences in the repertoires of basement membrane degrading enzymes in two carcinoma sublines with distinct patterns of site-selective metastasis. Biochim. Biophys. Acta 1139, 77–83 (1992).

    CAS  PubMed  Google Scholar 

  131. Mitsui, Y. et al. ADAM28 is overexpressed in human breast carcinomas: implications for carcinoma cell proliferation through cleavage of insulin-like growth factor binding protein-3. Cancer Res. 66, 9913–9920 (2006).

    CAS  PubMed  Google Scholar 

  132. Nakamura, M. et al. Matrix metalloproteinase-7 degrades all insulin-like growth factor binding proteins and facilitates insulin-like growth factor bioavailability. Biochem. Biophys. Res. Commun. 333, 1011–1016 (2005).

    CAS  PubMed  Google Scholar 

  133. Miyamoto, S. et al. Matric metalloprotease-7 facilitates insulin-like growth factor bioavailability through its proteinase activity on insulin-like growth factor binding protein 3. Cancer Res. 64, 665–671 (2004).

    CAS  PubMed  Google Scholar 

  134. Girnita, L., Girnita, A. & Larsson, O. Mdm2-dependent ubiquitination and degradation of the insulin-like growth factor 1 receptor. Proc. Natl Acad. Sci. USA 100, 8247–8252 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Dong, G. et al. Decreased expression of Wilms' tumour gene WT-1 and elevated expression of insulin growth factor-II (IGF-II) and type 1 IGF receptor genes in prostatic stromal cells from patients with benign prostatic hyperplasia. J. Clin. Endocrinol. Metab. 82, 2198–2203 (1997).

    CAS  PubMed  Google Scholar 

  136. Arteaga, C. L. et al. Blockade of the type 1 somatomedin receptor inhibits growth of human breast cancer cells in athymic mice. J. Clin. Invest. 84, 1418–1423 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. Kalebi, T. et al. In vivo treatment with antibody against IGF1 receptor suppresses growth of human rhadomyosarcoma and down-regulates p24cdc2. Cancer Res. 54, 5531–5534 (1994).

    Google Scholar 

  138. Scotlandi, K. et al. Blockade of insulin-like growth factor-I receptor inhibits the growth of Ewing's sarcoma in athymic mice. Cancer Res. 58, 4127–4131 (1998).

    CAS  PubMed  Google Scholar 

  139. Zia, F. et al. Monoloncal antibody αIR-3 inhibits non-small cell lung cancer growth in vitro and in vivo. J. Cell Biochem. 24, 269–275 (1996).

    CAS  Google Scholar 

  140. Goetsch, L. et al. A recombinant humanized anti-insulin-like growth factor receptor type 1 antibody (h2C10) enhances the antitumour activity of vinorelbine and antiepidermal growth factor receptor therapy against human cancers. Int. J. Cancer 113, 316–326 (2005).

    CAS  PubMed  Google Scholar 

  141. Lu, D. et al. A fully human recombinant IgG-like bi-specific antibody to both the epidermal growth factor receptor and the insulin-like growth factor receptor for enhanced antitumour activity. J. Biol. Chem. 280, 19665–19672 (2005).

    CAS  PubMed  Google Scholar 

  142. Allen, G. W. et al. Insulin-like growth factor-I receptor signalling blockade combined with radiation. Cancer Res. 67, 1155–1162 (2007).

    CAS  PubMed  Google Scholar 

  143. Ye, J. J. et al. Combined effects of tamoxifen and a chimeric humanized single chain antibody against the type 1 IGF receptor on breast tumour growth in vivo. Horm. Metab. Res. 35, 836–842 (2003).

    CAS  PubMed  Google Scholar 

  144. Wu, J. D. et al. In vivo effects of the human type I insulin-like growth factor receptor antibody A12 on androgen-dependent and androgen-independent xenograft human prostate tumours. Clin. Cancer Res. 11, 3065–3074 (2005).

    CAS  PubMed  Google Scholar 

  145. Samani, A. A. et al. The role of IGF system in cancer growth and metastasis: overview and recent insights. Endo. Rev. 28, 20–47 (2007).

    CAS  Google Scholar 

  146. Lu, D. et al. Simultaneous blockade of both the epidermal growth factor receptor and the insulin-like growth factor receptor signalling pathways in cancer cells with a fully human recombinant bi-specific antibody. J. Biol. Chem. 279, 2856–2865 (2004). This study shows that inhibition of both the IGF1 and IGF1 receptors has a deleterious effect on tumour progression.

    CAS  PubMed  Google Scholar 

  147. Scotlandi, K. et al. Antitumour activity of the insulin-like growth factor-I receptor kinase inhibitor NVP-AEW541 in musculoskeletal tumours. Cancer Res. 65, 3868–3876 (2005). This study shows that inhibition of IGF1receptor kinase activity inhibits tumour progression.

    CAS  PubMed  Google Scholar 

  148. Warshamana-Greene, G. S. et al. The insulin-like growth factor-I receptor kinase inhibitor, NVP-ADW742, sensitizes small cell lung cancer cell lines to the effects of chemotherapy. Clin. Cancer Res. 11, 1563–1571 (2005).

    CAS  PubMed  Google Scholar 

  149. Martins, A. S. et al. Insulin-like growth factor I receptor pathway inhibition by ADW742, alone or in combination with imatinib, doxorubicin or vincristine, is a novel therapeutic approach in Ewing tumour. Clin. Cancer Res. 12, 3532–3540 (2006).

    CAS  PubMed  Google Scholar 

  150. Gotlieb, W. H. et al. Insulin-like growth factor receptor I targeting in epithelial ovarian cancer. Gynecol. Oncol. 100, 389–396 (2006).

    CAS  PubMed  Google Scholar 

  151. Girnita, A. et al. The insulin-like growth factor-I receptor inhibitor picropodophyllin causes tumour regression and attenuates mechanisms involved in invasion of uveal melanoma cells. Clin. Cancer Res. 12, 1383–1391 (2006).

    CAS  PubMed  Google Scholar 

  152. Menu, E. et al. Inhibiting the IGF-1 receptor tyrosine kinase with the cyclolignan PPP: an in vitro and in vivo study in the 5T33MM mouse model. Blood 107, 655–660 (2006).

    CAS  PubMed  Google Scholar 

  153. Min, Y. et al. Genetic blockade of the insulin-like growth factor-I receptor: a promising strategy for human pancreatic cancer. Cancer Res. 63, 6432–6441 (2003).

    CAS  PubMed  Google Scholar 

  154. Surmacz, E. Growth factor receptors as therapeutic targets: strategies to inhibit the insulin-like growth factor I receptor. Oncogene 22, 6589–6597 (2003).

    CAS  PubMed  Google Scholar 

  155. Andrews, D. W. et al. Results of a pilot study involving the use of an antisense oligodeoxynucleotide directed against the insulin-like growth factor type I receptor in malignant astrocytomas. J. Clin. Oncol. 19, 2189–2200 (2001).

    CAS  PubMed  Google Scholar 

  156. Dann, S. G., Selvaraj, A. & Thomas, G. mTOR complex1–S6K1 signalling: at the crossroads of obesity, diabetes and cancer. Trends Mol. Med. 13, 252–259 (2007).

    CAS  PubMed  Google Scholar 

  157. Sisci, D. & Surmacz, E. Crosstalk between IGF signalling and steroid hormone receptors in breast cancer. Curr. Pharm. Des. 13, 705–717 (2007).

    CAS  PubMed  Google Scholar 

  158. Fan, W. et al. Insulin-like growth factor 1/insulin signalling activates androgen signalling through direct interactions of Foxo1 with androgen receptor. J. Biol. Chem. 282, 7329–7338 (2007).

    CAS  PubMed  Google Scholar 

  159. Elliot, S. J. et al. Smoking induces glomerulosclerosis in aging oestrogen-deficient mice through crosstalk between TGF-β1 and IGF1 signalling pathways. J. Am. Soc. Nephrol. 17, 3315–3324 (2006).

    CAS  PubMed  Google Scholar 

  160. Kemp, S. F. Mecasermin rinfabate. Drugs Today 43, 149–155 (2007).

    CAS  Google Scholar 

  161. Varela-Nieto, I., Harti, M., Gorospe, I. & Leon, Y. Anti-apoptotic actions of insulin-like growth factors: lessons from development and implications in neoplastic cell transformation. Curr. Pharm. Des. 13, 687–703 (2007).

    CAS  PubMed  Google Scholar 

  162. Laviola, L., Natalicchio, A. & Giorgino, F. The IGF1 signalling pathway. Curr. Pharm. Des. 13, 663–669 (2007).

    CAS  PubMed  Google Scholar 

  163. Wu, K. D., Zhou, L., Burtrum, D., Ludwig, D. L. & Moore, M. A. Antibody targeting of the insulin-like growth factor I receptor enhances the anti-tumour response of multiple myeloma to chemotherapy through inhibition of tumour proliferation and angiogenesis. Cancer Immunol. Immunother. 56, 343–357 (2007).

    CAS  PubMed  Google Scholar 

  164. Li, S. L., Liang, S. J., Guo, N., Wu, A. M. & Fujita-Yamaguchi, Y. Single-chain antibodies against human insulin-like growth factor I receptor: expression, purification, and effect on tumour growth. Cancer Immuno. Immunother. 49, 253–252 (2000).

    Google Scholar 

  165. Sachdev, D. et al. A chimeric humanized single-chain antibody against the type I insulin-like growth factor (IGF) receptor renders breast cancer cells refractory to the mitogenic effects of IGF-I. Cancer Res. 63, 627–635 (2003).

    CAS  PubMed  Google Scholar 

  166. Maloney, E. K. et al. An anti-insulin-like growth factor I receptor antibody that is a potent inhibitor of cancer cell proliferation. Cancer Res. 63, 5073–5083 (2003).

    CAS  PubMed  Google Scholar 

  167. Burtrum, D. et al. A fully human monoclonal antibody to the insulin-like growth factor I receptor blocks ligand-dependent signalling and inhibits human tumour growth in vivo. Cancer Res. 63, 8912–8921 (2003).

    CAS  PubMed  Google Scholar 

  168. Wu, J. D. et al. In vivo effects of the human type I insulin-like growth factor receptor antibody A12 on androgen-dependent and androgen-independent human prostate tumours. Clin. Cancer Res. 11, 3065–3074 (2005).

    CAS  PubMed  Google Scholar 

  169. Wang, Y. et al. Inhibition of insulin-like growth factor-I receptor (IGF1R) signalling and tumour cell growth by a fully human neutralizing anti-IGF1R antibody. Mol. Cancer Ther. 4, 1214–1221 (2005). This study shows that inhibition of ligand binding to the IGF1 receptor inhibits tumour progression.

    CAS  PubMed  Google Scholar 

  170. Cohen, B. D. et al. Combination therapy enhances the inhibition of tumour growth with the fully human antitype I insulin-like growth factor receptor monoclonal antibody CP-751, 871. Clin. Cancer Res. 11, 2063–2073 (2005).

    CAS  PubMed  Google Scholar 

  171. Miyamoto, S. et al. Blockade of paracrine supply of insulin-like growth factors using neutralizing antibodies suppresses the liver metastasis of human colorectal cancers. Clin. Cancer Res. 11, 3494–3502 (2005).

    CAS  PubMed  Google Scholar 

  172. Sachdev, D., Singh, R., Fujita-Yamaguchi, Y. & Yee, D. Down-regulation of insulin receptor by antibodies against the type I insulin-like growth factor receptor: implications for anti-insulin-like growth factor therapy in breast cancer. Cancer Res. 66, 2391–2402 (2006).

    CAS  PubMed  Google Scholar 

  173. Garcia-Echeverria, C. et al. In vivo antitumour activity of NVP-AEW541- A novel, potent and selective inhibitor of the IGF1R kinase. Cancer Cell 5, 231–239 (2004).

    CAS  PubMed  Google Scholar 

  174. Wittman, M. et al. The discover of 4-I[(S)-2-(3-Chloro-phenyl)-2-hydroxy-ethlamino]-3-(4-methyl-6-morpholin-4-yl-1H-benzoimidazol-2-yl)-1H-pyridin-2-one (BMS-536924): an inhibitor of IGF-1R kinase with in vivo antitumour activity. J. Med. Chem. 48, 5639–5643 (2005).

    CAS  PubMed  Google Scholar 

  175. Haluska, P. et al. In vitro and in vivo antitumour effects of the dual insulin-like growth factor-I/insulin receptor inhibitor, BMS-554417. Cancer Res. 66, 362–371 (2006).

    CAS  PubMed  Google Scholar 

  176. Liu, T. J. et al. Inhibition of both focal adhesion kinase and insulin-like growth factor-I receptor kinase suppresses glioma proliferation in vitro and in vivo. Mol. Cancer Ther. 6, 1357–1367 (2007).

    CAS  PubMed  Google Scholar 

  177. Tanno, B. et al. Down-regulation of insulin-like growth factor I receptor activity by NVP-AEW541 has an antitumour effect on neuroblastoma cells in vitro and in vivo. Clin. Cancer Res. 12, 6772–6780 (2006).

    CAS  PubMed  Google Scholar 

  178. Mitsiades, C. S. et al. Inhibition of the insulin-like growth factor receptor-1 tyrosine kinase activity as a therapeutic strategy for multiple myeloma, other hematologic malignancies, and solid tumours. Cancer Cell 5, 221–230 (2004).

    CAS  PubMed  Google Scholar 

  179. Manara, M. C. et al. Preclinical in vivo study of new insulin-like growth factor-I receptor-specific inhibitor in Ewing's sarcoma. Clin. Cancer Res. 13, 1322–1330 (2007).

    CAS  PubMed  Google Scholar 

  180. Gable, K. L. et al. Diarylureas are small-molecule inhibitors of insulin-like growth factor I receptor signalling and breast cancer cell growth. Mol. Cancer Ther. 5, 1079–1086 (2006).

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Endocrinology, Department of Medicine, University of North Carolina, Chapel Hill, 27599-7170, North Carolina, USA

    David R. Clemmons

Authors
  1. David R. Clemmons
    View author publications

    You can also search for this author in PubMed Google Scholar

Ethics declarations

Competing interests

The author declares no competing financial interests.

Related links

Related links

DATABASES

OMIM

Amyotrophic lateral sclerosis

anorexia nervosa

Bell's palsy

coeliac disease

cystic fibrosis

myotonic dystrophy

FURTHER INFORMATION

Clemmons' laboratory homepage

Glossary

Stromal cells

Connective tissue cells, primarily fibroblasts, that are present in nearly every organ.

SOCS3

SOCS proteins bind to signalling elements in cytokine signalling pathways and inhibit their function.

Pseudotumour cerebri

A condition in which there is increased intracranial pressure but no tumour.

STAT5B

A signalling protein that following activation of a growth hormone receptor is phosphorylated and translocated to the nucleus where it induces gene transcription.

HIV wasting

A syndrome in which patients with HIV become severely catabolic despite a normal calorific intake.

Haemoglobin A1C

A form of haemoglobin that is sensitive to non-enzymatic glycosylation, which therefore reflects long-term changes in blood glucose.

Arthralgias

Joint pains.

CA repeats

Cytosine–adenine repeats that occur as polymorphisms in genes.

Cyclin dependent kinase-4

Following cyclin C1 binding, CDK4 phosphorylates critical substrates for cell progression through the cell cycle.

Cyclin E

A member of the cyclin family that binds to CDK1 and that is required for G1 to S phase transition.

Wilms' tumour

Also termed nephroblastoma. A tumour of kidney origin usually occurring in young children.

Hypoxia inducible factor 1

(HIF1). A transcription factor that is expressed in response to low oxygen.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Clemmons, D. Modifying IGF1 activity: an approach to treat endocrine disorders, atherosclerosis and cancer. Nat Rev Drug Discov 6, 821–833 (2007). https://doi.org/10.1038/nrd2359

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrd2359

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing