IGFBP-2 - taking the lead in growth, metabolism and cancer

  • Steven W. Yau
  • Walid J. Azar
  • Matthew A. Sabin
  • George A. Werther
  • Vincenzo  C. Russo


The activity of the Insulin-like Growth Factors (IGFs) ligands elicited via their receptors and transduced by various intracellular signal pathways is modulated by the IGF Binding Proteins (IGFBPs). Among all the IGFBPs, IGFBP-2 has been implicated in the regulation of IGF activity in most tissue and organs. Besides binding to IGFs in the circulation these IGF-regulatory activities of IGFBP-2 involve interactions with components of the extracellular matrix, cell surface proteoglycans and integrin receptors. In addition to these local peri-cellular activities, IGFBP-2 exerts other key functions within the nucleus, where IGFBP-2 directly or indirectly promotes transcriptional activation of specific genes. All of these IGFBP-2 activities, intrinsic or dependent on IGFs, contribute to its functional roles in growth/development, metabolism and malignancy as evidenced by studies in IGFBP-2 animal models and also by many in vitro studies. Finally, preclinical studies have demonstrated that IGFBP-2 administration can be beneficial in improving metabolic responses (inhibition of adipogenesis and enhanced insulin sensitivity), while blockade of IGFBP-2 appears to be an effective approach to inhibiting tumour growth and metastasis.


IGF system IGFBP-2 Growth Metabolism Obesity Diabetes Leukaemia Lung cancer Colon cancer 



This work was supported by the National Health and Medical Research Council (NHMRC) of Australia (Project Grant, # 1008062) awarded to GAW and VCR. MAS is supported through a National Health and Medical Research Council Professional Training Fellowship (APP1012201). SWY is a recipient of an Australian Postgraduate Award scholarship. We also wish to acknowledge the generous support from the Murdoch Childrens Research Institute and the Royal Children’s Hospital Foundation to GAW, MAS and VCR. We also like to thank the Victorian Government Operational Infrastructure Support Program.

Disclosure statement

This work was supported by the National Health and Medical Research Council (NHMRC) of Australia (Project Grant, # 1008062) awarded to GAW, VCR, and by the Victorian Government Operational Infrastructure Support Program. SWY is a recipient of an Australian Postgraduate Award scholarship.


  1. Zapf J, Froesch ER (1986) Insulin-like growth factors/somatomedins: structure, secretion, biological actions and physiological role. Horm Res 24:121–130PubMedGoogle Scholar
  2. Daughaday WH, Rotwein P (1989) Insulin-like growth factors I and II. Peptide messenger ribonucleic acid and gene structures, serum, and tissue concentrations. Endocr Rev 10:68–91PubMedGoogle Scholar
  3. Han VK, D’Ercole AJ, Lund PK (1987) Cellular localization of somatomedin (insulin-like growth factor) messenger RNA in the human fetus. Science 236:193–197PubMedGoogle Scholar
  4. Murphy LJ, Bell GI, Friesen HG (1987) Tissue distribution of insulin-like growth factor I and II messenger ribonucleic acid in the adult rat. Endocrinology 120:1279–1282PubMedGoogle Scholar
  5. Sepp-Lorenzino L (1998) Structure and function of the insulin-like growth factor I receptor. Breast Cancer Res Treat 47:235–253PubMedGoogle Scholar
  6. Milazzo G, Yip CC, Maddux BA, Vigneri R, Goldfine ID (1992) High-affinity insulin binding to an atypical insulin-like growth factor-I receptor in human breast cancer cells. J Clin Investig 89:899–908PubMedCentralPubMedGoogle Scholar
  7. Moxham CP, Duronio V, Jacobs S (1989) Insulin-like growth factor I receptor beta-subunit heterogeneity. Evidence for hybrid tetramers composed of insulin- like growth factor I and insulin receptor heterodimers. J Biol Chem 264:13238–13244PubMedGoogle Scholar
  8. Siddle K, Soos MA, Field CE, Nave BT (1994) Hybrid and atypical insulin/insulin-like growth factor I receptors. Horm Res 41(Suppl 2):56–64PubMedGoogle Scholar
  9. Sakano K, Enjoh T, Numata F, Fujiwara H, Marumoto Y, Higashihashi N, Sato Y, Perdue JF, Fujita-Yamaguchi Y (1991) The design, expression, and characterization of human insulin- like growth factor II (IGF-II) mutants specific for either the IGF-II/cation-independent mannose 6-phosphate receptor or IGF-I receptor. J Biol Chem 266:20626–20635PubMedGoogle Scholar
  10. Braulke T (1999) Type-2 IGF receptor: a multi-ligand binding protein. Horm Metab Res 31:242–246PubMedGoogle Scholar
  11. Firth SM, Baxter RC (2002) Cellular actions of the insulin-like growth factor binding proteins. Endocr Rev 23:824–854PubMedGoogle Scholar
  12. Twigg SM, Kiefer MC, Zapf J, Baxter RC (2000) A central domain binding site in insulin-like growth factor binding protein-5 for the acid-labile subunit. Endocrinology 141:454–457PubMedGoogle Scholar
  13. Galea CA, Mobli M, McNeil KA, Mulhern TD, Wallace JC, King GF, Forbes BE, Norton RS (2012) Insulin-like growth factor binding protein-2: NMR analysis and structural characterization of the N-terminal domain. Biochimie 94:608–616PubMedGoogle Scholar
  14. Forbes BE, Turner D, Hodge SJ, McNeil KA, Forsberg G, Wallace JC (1998) Localization of an insulin-like growth factor (IGF) binding site of bovine IGF binding protein-2 using disulfide mapping and deletion mutation analysis of the C-terminal domain. J Biol Chem 273:4647–4652PubMedGoogle Scholar
  15. Ho PJ, Baxter RC (1997a) Insulin-like growth factor-binding protein-2 in patients with prostate carcinoma and benign prostatic hyperplasia. Clin Endocrinol 46:333–342Google Scholar
  16. Russo VC, Rekaris G, Baker NL, Bach LA, Werther GA (1999) Basic fibroblast growth factor induces proteolysis of secreted and cell membrane-associated insulin-like growth factor binding protein-2 in human neuroblastoma cells. Endocrinology 140:3082–3090PubMedGoogle Scholar
  17. Graham ME, Kilby DM, Firth SM, Robinson PJ, Baxter RC (2007) The in vivo phosphorylation and glycosylation of human insulin-like growth factor-binding protein-5. Mol Cell Proteomics 6:1392–1405PubMedGoogle Scholar
  18. Coverley JA, Baxter RC (1997) Phosphorylation of insulin-like growth factor binding proteins. Mol Cell Endocrinol 128:1–5PubMedGoogle Scholar
  19. Daza DO, Sundström G, Bergqvist CA, Duan C, Larhammar D (2011) Evolution of the insulin-like growth factor binding protein (IGFBP) family. Endocrinology 152:2278–2289PubMedGoogle Scholar
  20. Song SW, Fuller GN, Khan A, Kong S, Shen W, Taylor E, Ramdas L, Lang FF, Zhang W (2003) IIp45, an insulin-like growth factor binding protein 2 (IGFBP-2) binding protein, antagonizes IGFBP-2 stimulation of glioma cell invasion. Proc Natl Acad Sci U S A 100:13970–13975PubMedCentralPubMedGoogle Scholar
  21. Frommer KW, Reichenmiller K, Schutt BS, Hoeflich A, Ranke MB, Dodt G, Elmlinger MW (2006) IGF-independent effects of IGFBP-2 on the human breast cancer cell line Hs578T. J Mol Endocrinol 37:13–23PubMedGoogle Scholar
  22. Pereira JJ, Meyer T, Docherty SE, Reid HH, Marshall J, Thompson EW, Rossjohn J, Price JT (2004) Bimolecular interaction of insulin-like growth factor (IGF) binding protein-2 with alphavbeta3 negatively modulates IGF-I-mediated migration and tumor growth. Cancer Res 64:977–984PubMedGoogle Scholar
  23. Perks CM, Vernon EG, Rosendahl AH, Tonge D, Holly JM (2007) IGF-II and IGFBP-2 differentially regulate PTEN in human breast cancer cells. Oncogene 26:5966–5972PubMedGoogle Scholar
  24. Foulstone EJ, Zeng L, Perks CM, Holly JM (2013) Insulin-like growth factor binding protein 2 (IGFBP-2) promotes growth and survival of breast epithelial cells: novel regulation of the estrogen receptor. EndocrinologyGoogle Scholar
  25. Russo VC, Schutt BS, Andaloro E, Ymer SI, Hoeflich A, Ranke MB, Bach LA, Werther GA (2005) Insulin-like growth factor binding protein-2 binding to extracellular matrix plays a critical role in neuroblastoma cell proliferation, migration, and invasion. Endocrinology 146:4445–4455PubMedGoogle Scholar
  26. Shen X, Xi G, Maile LA, Wai C, Rosen CJ, Clemmons DR (2012) Insulin-like growth factor binding protein-2 functions coordinately with receptor protein tyrosine phosphatase beta and the IGF-I receptor to regulate IGF-I-stimulated signaling. Mol Cell Biol 32:4116–4130PubMedCentralPubMedGoogle Scholar
  27. Kuang Z, Yao S, Keizer DW, Wang CC, Bach LA, Forbes BE, Wallace JC, Norton RS (2006) Structure, dynamics and heparin binding of the C-terminal domain of insulin-like growth factor-binding protein-2 (IGFBP-2). J Mol Biol 364:690–704PubMedGoogle Scholar
  28. Besnard V, Corroyer S, Trugnan G, Chadelat K, Nabeyrat E, Cazals V, Clement A (2001) Distinct patterns of insulin-like growth factor binding protein (IGFBP)-2 and IGFBP-3 expression in oxidant exposed lung epithelial cells. Biochim Biophys Acta (BBA) Mol Cell Res 1538:47–58Google Scholar
  29. Terrien X, Bonvin E, Corroyer S, Tabary O, Clement A, Henrion Caude A (2005) Intracellular colocalization and interaction of IGF-binding protein-2 with the cyclin-dependent kinase inhibitor p21CIP1/WAF1 during growth inhibition. Biochem J 392:457–465PubMedCentralPubMedGoogle Scholar
  30. Miyako K, Cobb LJ, Francis M, Huang A, Peng B, Pintar JE, Ariga H, Cohen P (2009) PAPA-1 Is a nuclear binding partner of IGFBP-2 and modulates its growth-promoting actions. Mol Endocrinol 23:169–175PubMedCentralPubMedGoogle Scholar
  31. Azar WJ, Azar SH, Higgins S, Hu JF, Hoffman AR, Newgreen DF, Werther GA, Russo VC (2011) IGFBP-2 enhances VEGF gene promoter activity and consequent promotion of angiogenesis by neuroblastoma cells. Endocrinology 152:3332–3342PubMedGoogle Scholar
  32. Azar WJ, Zivkovic S, Werther GA, Russo VC (2014) IGFBP-2 nuclear translocation is mediated by a functional NLS sequence and is essential for its pro-tumorigenic actions in cancer cells. Oncogene 33:578–588PubMedGoogle Scholar
  33. Schedlich LJ, Le Page SL, Firth SM, Briggs LJ, Jans DA, Baxter RC (2000) Nuclear import of insulin-like growth factor-binding protein-3 and -5 is mediated by the importin beta subunit. J Biol Chem 275:23462–23470PubMedGoogle Scholar
  34. Iosef C, Gkourasas T, Jia CY, Li SS, Han VK (2008) A functional nuclear localization signal in insulin-like growth factor binding protein-6 mediates its nuclear import. Endocrinology 149:1214–1226PubMedGoogle Scholar
  35. Chelsky D, Ralph R, Jonak G (1989) Sequence requirements for synthetic peptide-mediated translocation to the nucleus. Mol Cell Biol 9:2487–2492PubMedCentralPubMedGoogle Scholar
  36. Pintar JE, Cerro JA, Wood TL (1996) Genetic approaches to the function of insulin-like growth factor- binding proteins during rodent development. Horm Res 45:172–177PubMedGoogle Scholar
  37. Wood TL, Rogler LE, Czick ME, Schuller AG, Pintar JE (2000) Selective alterations in organ sizes in mice with a targeted disruption of the insulin-like growth factor binding protein-2 gene. Mol Endocrinol 14:1472–1482PubMedGoogle Scholar
  38. Chen TL, Chang LY, DiGregorio DA, Perlman AJ, Huang YF (1993) Growth factor modulation of insulin-like growth factor-binding proteins in rat osteoblast-like cells. Endocrinology 133:1382–1389PubMedGoogle Scholar
  39. Palermo C, Manduca P, Gazzerro E, Foppiani L, Segat D, Barreca A (2004) Potentiating role of IGFBP-2 on IGF-II-stimulated alkaline phosphatase activity in differentiating osteoblasts. Am J Physiol Endocrinol Metab 286:E648–E657PubMedGoogle Scholar
  40. Wang E, Wang J, Chin E, Zhou J, Bondy CA (1995) Cellular patterns of insulin-like growth factor system gene expression in murine chondrogenesis and osteogenesis. Endocrinology 136:2741–2751PubMedGoogle Scholar
  41. Conover CA, Johnstone EW, Turner RT, Evans GL, John Ballard F, Doran PM, Khosla S (2002) Subcutaneous administration of insulin-like growth factor (IGF)-II/IGF binding protein-2 complex stimulates bone formation and prevents loss of bone mineral density in a rat model of disuse osteoporosis. Growth Hormon IGF Res 12:178–183Google Scholar
  42. Fisher MC, Meyer C, Garber G, Dealy CN (2005) Role of IGFBP2, IGF-I and IGF-II in regulating long bone growth. Bone 37:741–750PubMedGoogle Scholar
  43. DeMambro VE, Clemmons DR, Horton LG, Bouxsein ML, Wood TL, Beamer WG, Canalis E, Rosen CJ (2008) Gender-specific changes in bone turnover and skeletal architecture in Igfbp-2-null mice. Endocrinology 149:2051–2061PubMedCentralPubMedGoogle Scholar
  44. Kawai M, Breggia AC, DeMambro VE, Shen X, Canalis E, Bouxsein ML, Beamer WG, Clemmons DR, Rosen CJ (2011) The heparin-binding domain of IGFBP-2 has IGF binding-independent biologic activity in the growing skeleton. J Biol Chem 286:14670–14680PubMedCentralPubMedGoogle Scholar
  45. DeMambro VE, Maile L, Wai C, Kawai M, Cascella T, Rosen CJ, Clemmons D (2012) Insulin-like growth factor-binding protein-2 is required for osteoclast differentiation. J Bone Miner Res 27:390–400PubMedCentralPubMedGoogle Scholar
  46. Xi G, Wai C, DeMambro V, Rosen CJ, Clemmons DR (2014) IGFBP-2 directly stimulates osteoblast differentiation. J Bone Miner Res 29:2427–2438PubMedGoogle Scholar
  47. Hoeflich A, Wu M, Mohan S, Foll J, Wanke R, Froehlich T, Arnold GJ, Lahm H, Kolb HJ, Wolf E (1999) Overexpression of insulin-like growth factor-binding protein-2 in transgenic mice reduces postnatal body weight gain. Endocrinology 140:5488–5496PubMedGoogle Scholar
  48. Hoeflich A, Nedbal S, Blum WF, Erhard M, Lahm H, Brem G, Kolb HJ, Wanke R, Wolf E (2001) Growth inhibition in giant growth hormone transgenic mice by overexpression of insulin-like growth factor-binding protein-2. Endocrinology 142:1889–1898PubMedGoogle Scholar
  49. Russo VC, Bach LA, Werther GA (1995) Cell membrane association of insulin-like growth factor binding protein-2 (IGFBP-2) in the rat brain olfactory bulb. Prog Growth Factor Res 6:329–336PubMedGoogle Scholar
  50. Rehfeldt C, Renne U, Sawitzky M, Binder G, Hoeflich A (2010) Increased fat mass, decreased myofiber size, and a shift to glycolytic muscle metabolism in adolescent male transgenic mice overexpressing IGFBP-2. Am J Physiol Endocrinol Metab 299:E287–E298PubMedGoogle Scholar
  51. Eckstein F, Pavicic T, Nedbal S, Schmidt C, Wehr U, Rambeck W, Wolf E, Hoeflich A (2002) Insulin-like growth factor-binding protein-2 (IGFBP-2) overexpression negatively regulates bone size and mass, but not density, in the absence and presence of growth hormone/IGF-I excess in transgenic mice. Anat Embryol (Berlin) 206:139–148Google Scholar
  52. Hoeflich A, Schmidt P, Foll J, Rottmann O, Weber MM, Kolb HJ, Pirchner F, Wolf E (1998) Altered growth of mice divergently selected for body weight is associated with complex changes in the growth hormone/insulin-like growth factor system. Growth Hormon IGF Res 8:113–123Google Scholar
  53. Barrios V, Buno M, Pozo J, Munoz MT, Argente J (2000) Insulin-like growth factor-binding protein-2 levels in pediatric patients with growth hormone deficiency, eating disorders and acute lymphoblastic leukemia. Horm Res 53:221–227PubMedGoogle Scholar
  54. Hall K, Lundin G, Povoa G (1988) Serum levels of the low molecular weight form of insulin-like growth factor binding protein in healthy subjects and patients with growth hormone deficiency, acromegaly and anorexia nervosa. Acta Endocrinol (Copenh) 118:321–326Google Scholar
  55. Hotta M, Fukuda I, Sato K, Hizuka N, Shibasaki T, Takano K (2000) The relationship between bone turnover and body weight, serum insulin-like growth factor (IGF) I, and serum IGF-binding protein levels in patients with anorexia nervosa. J Clin Endocrinol Metab 85:200–206PubMedGoogle Scholar
  56. Wheatcroft SB, Kearney MT, Shah AM, Ezzat VA, Miell JR, Modo M, Williams SCR, Cawthorn WP, Medina-Gomez G, Vidal-Puig A, Sethi JK, Crossey PA (2007a) IGF-binding protein-2 protects against the development of obesity and insulin resistance. Diabetes 56:285–294PubMedCentralPubMedGoogle Scholar
  57. Hedbacker K, Birsoy K, Wysocki RW, Asilmaz E, Ahima RS, Farooqi IS, Friedman JM (2010) Antidiabetic effects of IGFBP2, a leptin-regulated gene. Cell Metab 11:11–22PubMedGoogle Scholar
  58. Claudio M, Benjamim F, Riccardo B, Massimiliano C, Francesco B, Luciano C (2010a) Adipocytes IGFBP-2 expression in prepubertal obese children. Obesity (Silver Spring) 18:2055–2057Google Scholar
  59. Ballerini MG, Ropelato MG, Domene HM, Pennisi P, Heinrich JJ, Jasper HG (2004) Differential impact of simple childhood obesity on the components of the growth hormone-insulin-like growth factor (IGF)-IGF binding proteins axis. J Pediatr Endocrinol Metab 17:749–757PubMedGoogle Scholar
  60. Frystyk J, Skjaerbaek C, Vestbo E, Fisker S, Orskov H (1999) Circulating levels of free insulin-like growth factors in obese subjects: the impact of type 2 diabetes. Diabetes Metab Res Rev 15:314–322PubMedGoogle Scholar
  61. Levitt RJ, Georgescu M-M, Pollak M (2005) PTEN-induction in U251 glioma cells decreases the expression of insulin-like growth factor binding protein-2. Biochem Biophys Res Commun 336:1056–1061PubMedGoogle Scholar
  62. Mehrian-Shai R, Chen CD, Shi T, Horvath S, Nelson SF, Reichardt JK, Sawyers CL (2007) Insulin growth factor-binding protein 2 is a candidate biomarker for PTEN status and PI3K/Akt pathway activation in glioblastoma and prostate cancer. Proc Natl Acad Sci U S A 104:5563–5568PubMedCentralPubMedGoogle Scholar
  63. Martin JL, Baxter RC (2007) Expression of insulin-like growth factor binding protein-2 by MCF-7 breast cancer cells is regulated through the phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin pathway. Endocrinology 148:2532–2541PubMedGoogle Scholar
  64. Dean SJR, Perks CM, Holly JMP, Bhoo-Pathy N, Looi L-M, Mohammed NAT, Mun K-S, Teo S-H, Koobotse MO, Yip C-H, Rhodes A (2014) Loss of PTEN expression is associated with IGFBP2 expression, younger age, and late stage in triple-negative breast cancer. Am J Clin Pathol 141:323–333PubMedGoogle Scholar
  65. Grimberg A, Coleman CM, Shi Z, Burns TF, MacLachlan TK, Wang W, El-Deiry WS (2006) Insulin-like growth factor factor binding protein-2 is a novel mediator of p53 inhibition of insulin-like growth factor signaling. Cancer Biol Ther 5:1408–1414PubMedCentralPubMedGoogle Scholar
  66. Villani RM, Adolphe C, Palmer J, Waters MJ, Wainwright BJ (2010) Patched1 inhibits epidermal progenitor cell expansion and basal cell carcinoma formation by limiting Igfbp2 activity. Cancer Prev Res 3:1222–1234Google Scholar
  67. Rao G, Pedone CA, Valle LD, Reiss K, Holland EC, Fults DW (2004) Sonic hedgehog and insulin-like growth factor signaling synergize to induce medulloblastoma formation from nestin-expressing neural progenitors in mice. Oncogene 23:6156–6162PubMedGoogle Scholar
  68. Feldser D, Agani F, Iyer NV, Pak B, Ferreira G, Semenza GL (1999) Reciprocal positive regulation of hypoxia-inducible factor 1alpha and insulin-like growth factor 2. Cancer Res 59:3915–3918PubMedGoogle Scholar
  69. Harris AL (2002) Hypoxia–a key regulatory factor in tumour growth. Nat Rev Cancer 2:38–47PubMedGoogle Scholar
  70. Semenza GL (1999) Regulation of mammalian O2 homeostasis by hypoxia-inducible factor 1. Annu Rev Cell Dev Biol 15:551–578PubMedGoogle Scholar
  71. Semenza GL (2003) Targeting HIF-1 for cancer therapy. Nat Rev Cancer 3:721–732PubMedGoogle Scholar
  72. Poomthavorn P, Wong SHX, Higgins S, Werther GA, Russo VC (2009) Activation of a prometastatic gene expression program in hypoxic neuroblastoma cells. Endocr Relat Cancer 16:991–1004PubMedGoogle Scholar
  73. Matsumoto T, Gargosky SE, Iwasaki K, Rosenfeld RG (1996) Identification and characterization of insulin-like growth factors (IGFs), IGF-binding proteins (IGFBPs), and IGFBP proteases in human synovial fluid. J Clin Endocrinol Metab 81:150–155PubMedGoogle Scholar
  74. Ishikawa K, Ohe Y, Tatemoto K (1995) Synthesis and secretion of insulin-like growth factor (IGF)-II and IGF binding protein-2 by cultivated brain meningeal cells. Brain Res 697:122–129PubMedGoogle Scholar
  75. Mark S, Kübler B, Höning S, Oesterreicher S, John H, Braulke T, Forssmann W-G, Ständker L (2005) Diversity of human insulin-like growth factor (IGF) binding protein-2 fragments in plasma: primary structure, IGF-binding properties, and disulfide bonding pattern†. Biochemistry 44:3644–3652PubMedGoogle Scholar
  76. Ho PJ, Baxter RC (1997b) Characterization of truncated insulin-like growth factor-binding protein-2 in human milk. Endocrinology 138:3811–3818PubMedGoogle Scholar
  77. Giudice LC, Farrell EM, Pham H, Lamson G, Rosenfeld RG (1990) Insulin-like growth factor binding proteins in maternal serum throughout gestation and in the puerperium: effects of a pregnancy-associated serum protease activity. J Clin Endocrinol Metab 71:806–816PubMedGoogle Scholar
  78. Pucilowska JB, Davenport ML, Kabir I, Clemmons DR, Thissen JP, Butler T, Underwood LE (1993) The effect of dietary protein supplementation on insulin-like growth factors (IGFs) and IGF-binding proteins in children with shigellosis. J Clin Endocrinol Metab 77:1516–1521PubMedGoogle Scholar
  79. Brandt K, Lundell K, Brismar K (2011) Neutrophil-derived azurocidin cleaves insulin-like growth factor-binding protein-1, −2 and −4. Growth Hormon IGF Res 21:167–173Google Scholar
  80. DeGraff DJ, Malik M, Chen Q, Miyako K, Rejto L, Aguiar AA, Bancroft DRE, Cohen P, Sikes RA (2007) Hormonal regulation of IGFBP-2 proteolysis is attenuated with progression to androgen insensitivity in the LNCaP progression model. J Cell Physiol 213:261–268PubMedGoogle Scholar
  81. Russo VC, Andaloro E, Fornaro SA, Najdovska S, Newgreen DF, Bach LA, Werther GA (2004) Fibroblast growth factor-2 over-rides insulin-like growth factor-I induced proliferation and cell survival in human neuroblastoma cells. J Cell Physiol 199:371–380PubMedGoogle Scholar
  82. Hoeflich A, Reisinger R, Schuett BS, Elmlinger MW, Russo VC, Vargas GA, Jehle PM, Lahm H, Renner-Muller I, Wolf E (2004) Peri/nuclear localization of intact insulin-like growth factor binding protein-2 and a distinct carboxyl-terminal IGFBP-2 fragment in vivo. Biochem Biophys Res Commun 324:705–710PubMedGoogle Scholar
  83. Si M, Nakamura M, Yano K, Ishii G, Hasebe T, Endoh Y, Sangai T, Maeda H, Shi-chuang Z, Chiba T, Ochiai A (2007) Matrix metalloproteinase-7 triggers the matricrine action of insulin-like growth factor-II via proteinase activity on insulin-like growth factor binding protein 2 in the extracellular matrix. Cancer Sci 98:685–691Google Scholar
  84. Sunderic M, Miljus G, Nedic O (2013) Interaction of insulin-like growth factor-binding protein 2 with alpha2-macroglobulin in the circulation. Protein J 32:138–142PubMedGoogle Scholar
  85. Gerard N, Delpuech T, Oxvig C, Overgaard M, Monget P (2004) Proteolytic degradation of IGF-binding protein (IGFBP)-2 in equine ovarian follicles: involvement of pregnancy-associated plasma protein-A (PAPP-A) and association with dominant but not subordinated follicles. J Endocrinol 182:457–466PubMedGoogle Scholar
  86. Qin X, Wergedal JE, Rehage M, Tran K, Newton J, Lam P, Baylink DJ, Mohan S (2006) Pregnancy-associated plasma protein-A increases osteoblast proliferation in vitro and bone formation in vivo. Endocrinology 147:5653–5661PubMedCentralPubMedGoogle Scholar
  87. Ruoslahti E (1996) RGD and other recognition sequences for integrins. Annu Rev Cell Dev Biol 12:697–715PubMedGoogle Scholar
  88. Schutt B, Langkamp M, Rauschnabel U, Ranke M, Elmlinger M (2004) Integrin-mediated action of insulin-like growth factor binding protein-2 in tumor cells. J Mol Endocrinol 32:859–868PubMedGoogle Scholar
  89. Mendes KN, Wang GK, Fuller GN, Zhang W (2010) JNK mediates insulin-like growth factor binding protein 2/integrin alpha5-dependent glioma cell migration. Int J Oncol 37:143–153PubMedGoogle Scholar
  90. Uzoh CC, Holly JM, Biernacka KM, Persad RA, Bahl A, Gillatt D, Perks CM (2011) Insulin-like growth factor-binding protein-2 promotes prostate cancer cell growth via IGF-dependent or -independent mechanisms and reduces the efficacy of docetaxel. Br J Cancer 104:1587–1593PubMedCentralPubMedGoogle Scholar
  91. Arai T, Clarke J, Parker A, Busby W Jr, Nam T, Clemmons DR (1996) Substitution of specific amino acids in insulin-like growth factor (IGF) binding protein 5 alters heparin binding and its change in affinity for IGF-I response to heparin. J Biol Chem 271:6099–6106PubMedGoogle Scholar
  92. Kiepe D, Van Der Pas A, Ciarmatori S, Standker L, Schutt B, Hoeflich A, Hugel U, Oh J, Tonshoff B (2008) Defined carboxy-terminal fragments of insulin-like growth factor (IGF) binding protein-2 exert similar mitogenic activity on cultured rat growth plate chondrocytes as IGF-I. Endocrinology 149:4901–4911PubMedGoogle Scholar
  93. Xi G, Solum MA, Wai C, Maile LA, Rosen CJ, Clemmons DR (2013) The heparin-binding domains of IGFBP-2 mediate its inhibitory effect on preadipocyte differentiation and fat development in male mice. Endocrinology 154:4146–4157PubMedCentralPubMedGoogle Scholar
  94. Shitara K, Yamada H, Watanabe K, Shimonaka M, Yamaguchi Y (1994) Brain-specific receptor-type protein-tyrosine phosphatase RPTP beta is a chondroitin sulfate proteoglycan in vivo. J Biol Chem 269:20189–20193PubMedGoogle Scholar
  95. Sabin MA, Russo VC, Azar WJ, Yau SW, Kiess W, Werther GA (2011a) IGFBP-2 at the interface of growth and metabolism–implications for childhood obesity. Pediatr Endocrinol Rev 8:382–393PubMedGoogle Scholar
  96. Nam SY, Lee EJ, Kim KR, Cha BS, Song YD, Lim SK, Lee HC, Huh KB (1997a) Effect of obesity on total and free insulin-like growth factor (IGF)-1, and their relationship to IGF-binding protein (BP)-1, IGFBP-2, IGFBP-3, insulin, and growth hormone. Int J Obes Relat Metab Disord 21:355–359PubMedGoogle Scholar
  97. Heald AH, Kaushal K, Siddals KW, Rudenski AS, Anderson SG, Gibson JM (2006) Insulin-like growth factor binding protein-2 (IGFBP-2) is a marker for the metabolic syndrome. Exp Clin Endocrinol Diabetes 114:371–376PubMedGoogle Scholar
  98. Li Z, Picard F (2010a) Modulation of IGFBP2 mRNA expression in white adipose tissue upon aging and obesity. Horm Metab Res 42:787–791PubMedGoogle Scholar
  99. Krassas GE (2003) Endocrine abnormalities in Anorexia Nervosa. Pediatr Endocrinol Rev 1:46–54PubMedGoogle Scholar
  100. Counts DR, Gwirtsman H, Carlsson LM, Lesem M, Cutler GB (1992) The effect of anorexia nervosa and refeeding on growth hormone-binding protein, the insulin-like growth factors (IGFs), and the IGF-binding proteins. J Clin Endocrinol Metab 75:762–767PubMedGoogle Scholar
  101. Bereket A, Lang CH, Wilson TA (1999) Alterations in the growth hormone-insulin-like growth factor axis in insulin dependent diabetes mellitus. Horm Metab Res 31:172–181PubMedGoogle Scholar
  102. Frystyk J, Bek T, Flyvbjerg A, Skjærbæk C, Ørskov H (2003) The relationship between the circulating IGF system and the presence of retinopathy in Type 1 diabetic patients. Diabet Med 20:269–276PubMedGoogle Scholar
  103. Street ME, Smerieri A, Montanini L, Predieri B, Iughetti L, Valenzise M, De Luca F, Vigone M, Weber G, Maghnie M, Bernasconi S (2013) Interactions among pro-inflammatory cytokines, IGF system and thyroid function in pre-pubertal obese subjects. J Biol Regul Homeost Agents 27:259–266PubMedGoogle Scholar
  104. Smerieri A, Petraroli M, Ziveri MA, Volta C, Bernasconi S, Street ME (2011) Effects of cord serum insulin, IGF-II, IGFBP-2, IL-6 and cortisol concentrations on human birth weight and length: pilot study. PLoS One 6:e29562PubMedCentralPubMedGoogle Scholar
  105. Giudice LC, de Zegher F, Gargosky SE, Dsupin BA, de las Fuentes L, Crystal RA, Hintz RL, Rosenfeld RG (1995) Insulin-like growth factors and their binding proteins in the term and preterm human fetus and neonate with normal and extremes of intrauterine growth. J Clin Endocrinol Metab 80:1548–1555PubMedGoogle Scholar
  106. Ko JM, Park HK, Yang S, Hwang IT (2012) Influence of catch-up growth on IGFBP-2 levels and association between IGFBP-2 and cardiovascular risk factors in Korean children born SGA. Endocr J 59:725–733PubMedGoogle Scholar
  107. de Kort SW, van Doorn J, van de Sande AG, Leunissen RW, Hokken-Koelega AC (2010) Serum insulin-like growth factor-binding protein-2 levels and metabolic and cardiovascular risk factors in young adults and children born small for gestational age. J Clin Endocrinol Metab 95:864–871PubMedGoogle Scholar
  108. Friedman JM, Halaas JL (1998) Leptin and the regulation of body weight in mammals. Nature 395:763–770PubMedGoogle Scholar
  109. Yau SW, Henry BA, Russo VC, McConell GK, Clarke IJ, Werther GA, Sabin MA (2014a) Leptin enhances insulin sensitivity by direct and sympathetic nervous system regulation of muscle Igfbp-2 expression - evidence from non-rodent models. Endocrinology 155:2133–2143PubMedGoogle Scholar
  110. Sabin MA, Yau SW, Russo VC, Clarke IJ, Dunshea FR, Chau J, Cox M, Werther GA (2011b) Dietary monounsaturated fat in early life regulates IGFBP2: implications for fat mass accretion and insulin sensitivity. Obesity 19:2374–2381PubMedGoogle Scholar
  111. Nam S, Lee E, Kim K, Cha B, Song Y, Lim S (1997b) Effect of obesity on total and free insulin-like growth factor (IGF)-1, and their relationship to IGF-binding protein (BP)-1, IGFBP-2, IGFBP-3, insulin, and growth hormone. Int J Obes Relat Metab Disord 21:355–359PubMedGoogle Scholar
  112. Claudio M, Benjamim F, Riccardo B, Massimiliano C, Francesco B, Luciano C (2010b) Adipocytes IGFBP-2 expression in prepubertal obese children. Obesity 18:2055–2057PubMedGoogle Scholar
  113. Li Z, Picard F (2010) Modulation of IGFBP2 mRNA expression in white adipose tissue upon aging and obesity. Horm Metab Res:787–791Google Scholar
  114. Wheatcroft S, Kearney M, Shah A, Ezzat V, Miell J, Modo M (2007b) IGF-binding protein-2 protects against the development of obesity and insulin resistance. Diabetes 56:284–294Google Scholar
  115. Yau SW, Russo VC, Clarke IJ, Dunshea FR, Werther GA, Sabin MA (2014b) IGFBP-2 inhibits adipogenesis and lipogenesis in human visceral, but not subcutaneous, adipocytes. Int J Obes. doi: 10.1038/ijo.2014.192 Google Scholar
  116. Reeve JG, Kirby LB, Brinkman A, Hughes SA, Schwander J, Bleehen NM (1992a) Insulin-like growth-factor-binding protein gene expression and protein production by human tumour cell lines. Int J Cancer 51:818–821PubMedGoogle Scholar
  117. Tennant MK, Thrasher JB, Twomey PA, Birnbaum RS, Plymate SR (1996) Insulin-like growth factor-binding protein-2 and −3 expression in benign human prostate epithelium, prostate intraepithelial neoplasia, and adenocarcinoma of the prostate. J Clin Endocrinol Metab 81:411–420PubMedGoogle Scholar
  118. Wex H, Vorwerk P, Mohnike K, Bretschneider D, Kluba U, Aumann V, Blum WF, Mittler U (1998) Elevated serum levels of IGFBP-2 found in children suffering from acute leukaemia is accompanied by the occurrence of IGFBP-2 mRNA in the tumour clone. Br J Cancer 78:515–520PubMedCentralPubMedGoogle Scholar
  119. Wang H, Shen W, Huang H, Hu L, Ramdas L, Zhou YH, Liao WS, Fuller GN, Zhang W (2003) Insulin-like growth factor binding protein 2 enhances glioblastoma invasion by activating invasion-enhancing genes. Cancer Res 63:4315–4321PubMedGoogle Scholar
  120. Fukushima T, Kataoka H (2007) Roles of insulin-like growth factor binding protein-2 (IGFBP-2) in glioblastoma. Anticancer Res 27:3685–3692PubMedGoogle Scholar
  121. Becher OJ, Peterson KM, Khatua S, Santi MR, MacDonald TJ (2008) IGFBP2 is overexpressed by pediatric malignant astrocytomas and induces the repair enzyme DNA-PK. J Child Neurol 23:1205–1213PubMedCentralPubMedGoogle Scholar
  122. Moore LM, Holmes KM, Smith SM, Wu Y, Tchougounova E, Uhrbom L, Sawaya R, Bruner JM, Fuller GN, Zhang W (2009) IGFBP2 is a candidate biomarker for Ink4a-Arf status and a therapeutic target for high-grade gliomas. Proc Natl Acad Sci U S A 106:16675–16679PubMedCentralPubMedGoogle Scholar
  123. Fukushima T, Tezuka T, Shimomura T, Nakano S, Kataoka H (2007) Silencing of insulin-like growth factor-binding protein-2 in human glioblastoma cells reduces both invasiveness and expression of progression-associated gene CD24. J Biol Chem 282:18634–18644PubMedGoogle Scholar
  124. Heinlein CA, Chang C (2004) Androgen receptor in prostate cancer. Endocr Rev 25:276–308PubMedGoogle Scholar
  125. Karantanos T, Corn PG, Thompson TC (2013) Prostate cancer progression after androgen deprivation therapy: mechanisms of castrate resistance and novel therapeutic approaches. Oncogene 32:5501–5511PubMedCentralPubMedGoogle Scholar
  126. Kimura G, Kasuya J, Giannini S, Honda Y, Mohan S, Kawachi M, Akimoto M, Fujita-Yamaguchi Y (1996) Insulin-like growth factor (IGF) system components in human prostatic cancer cell-lines: LNCaP, DU145, and PC-3 cells. Intl J Urol : Off J Jpn Urol Assoc 3:39–46Google Scholar
  127. Cohen P, Peehl DM, Stamey TA, Wilson KF, Clemmons DR, Rosenfeld RG (1993) Elevated levels of insulin-like growth factor-binding protein-2 in the serum of prostate cancer patients. J Clin Endocrinol Metab 76:1031–1035PubMedGoogle Scholar
  128. Degraff DJ, Aguiar AA, Sikes RA (2009) Disease evidence for IGFBP-2 as a key player in prostate cancer progression and development of osteosclerotic lesions. Am J Transl Res 1:115–130PubMedCentralPubMedGoogle Scholar
  129. Wang H, Arun BK, Wang H, Fuller GN, Zhang W, Middleton LP, Sahin AA (2008) IGFBP2 and IGFBP5 overexpression correlates with the lymph node metastasis in T1 breast carcinomas. Breast J 14:261–267PubMedGoogle Scholar
  130. Juncker-Jensen A, Lykkesfeldt AE, Worm J, Ralfkiær U, Espelund U, Jepsen JS (2006) Insulin-like growth factor binding protein 2 is a marker for antiestrogen resistant human breast cancer cell lines but is not a major growth regulator. Growth Hormon IGF Res 16:224–239Google Scholar
  131. Sohn J, Do KA, Liu S, Chen H, Mills GB, Hortobagyi GN, Meric-Bernstam F, Gonzalez-Angulo AM (2013) Functional proteomics characterization of residual triple-negative breast cancer after standard neoadjuvant chemotherapy. Ann Oncol 24:2522–2526PubMedCentralPubMedGoogle Scholar
  132. Mireuta M, Darnel A, Pollak M (2010) IGFBP-2 expression in MCF-7 cells is regulated by the PI3K/AKT/mTOR pathway through Sp1-induced increase in transcription. Growth Factors 28:243–255PubMedGoogle Scholar
  133. Karasik A, Menczer J, Pariente C, Kanety H (1994) Insulin-like growth factor-I (IGF-I) and IGF-binding protein-2 are increased in cyst fluids of epithelial ovarian cancer. J Clin Endocrinol Metab 78:271–276PubMedGoogle Scholar
  134. Kanety H, Kattan M, Goldberg I, Kopolovic J, Ravia J, Menczer J, Karasik A (1996) Increased insulin-like growth factor binding protein-2 (IGFBP-2) gene expression and protein production lead to high IGFBP-2 content in malignant ovarian cyst fluid. Br J Cancer 73:1069–1073PubMedCentralPubMedGoogle Scholar
  135. Wang H, Rosen DG, Wang H, Fuller GN, Zhang W, Liu J (2006) Insulin-like growth factor-binding protein 2 and 5 are differentially regulated in ovarian cancer of different histologic types. Mod Pathol 19:1149–1156PubMedGoogle Scholar
  136. Lee EJ, Mircean C, Shmulevich I, Wang H, Liu J, Niemisto A, Kavanagh JJ, Lee JH, Zhang W (2005) Insulin-like growth factor binding protein 2 promotes ovarian cancer cell invasion. Mol Cancer 4:7PubMedCentralPubMedGoogle Scholar
  137. Inaba H, Greaves M, Mullighan CG (2013) Acute lymphoblastic leukaemia. Lancet 381:1943–1955PubMedGoogle Scholar
  138. Lo Nigro L (2013) Biology of childhood acute lymphoblastic leukemia. J Pediatr Hematol Oncol 35:245–252PubMedGoogle Scholar
  139. Carroll WL, Raetz EA (2012) Clinical and laboratory biology of childhood acute lymphoblastic leukemia. J Pediatr 160:10–18PubMedGoogle Scholar
  140. Rivera GK, Crist WM, Sallan SE (1994) Biology and therapy of childhood acute lymphoblastic leukemia. Revista de investigacion clinica; organo del Hospital de Enfermedades de la Nutricion Suppl: 26–33Google Scholar
  141. Rodríguez-Vicente AE, Díaz MG, Hernández-Rivas JM (2013) Chronic lymphocytic leukemia: a clinical and molecular heterogenous disease. Cancer Genet 206:49–62PubMedGoogle Scholar
  142. Shanshal M, Haddad RY (2012) Chronic lymphocytic leukemia. Dis Mon 58:153–167PubMedGoogle Scholar
  143. Hillmen P (2011) Using the biology of chronic lymphocytic leukemia to choose treatment. ASH Educ Program Book 2011:104–109Google Scholar
  144. Estey EH (2013) Acute myeloid leukemia: 2013 update on risk-stratification and management. Am J Hematol 88:317–327Google Scholar
  145. Puumala SE, Ross JA, Aplenc R, Spector LG (2013) Epidemiology of childhood acute myeloid leukemia. Pediatr Blood Cancer 60:728–733PubMedCentralPubMedGoogle Scholar
  146. Gamis AS, Alonzo TA, Perentesis JP, Meshinchi S, COGAMLC (2013) Children’s Oncology Group’s 2013 blueprint for research: Acute myeloid leukemia. Pediatr Blood Cancer 60:964–971PubMedGoogle Scholar
  147. Jabbour E, Kantarjian H (2012) Chronic myeloid leukemia: 2012 update on diagnosis, monitoring, and management. Am J Hematol 87:1037–1045PubMedGoogle Scholar
  148. Maru Y (2012) Molecular biology of chronic myeloid leukemia. Cancer Sci 103:1601–1610PubMedGoogle Scholar
  149. Zhang Y, Rowley JD (2011) Chronic myeloid leukemia: current perspectives. Clin Lab Med 31:687–698PubMedGoogle Scholar
  150. Mohnike KL, Kluba U, Mittler U, Aumann V, Vorwerk P, Blum WF (1996) Serum levels of insulin-like growth factor-I, −II and insulin- like growth factor binding proteins −2 and −3 in children with acute lymphoblastic leukaemia. Eur J Pediatr 155:81–86PubMedGoogle Scholar
  151. Dawczynski K, Kauf E, Zintl F (2003) Changes of serum growth factors (IGF-I,-II and IGFBP-2,-3) prior to and after stem cell transplantation in children with acute leukemia. Bone Marrow Transplant 32:411–415PubMedGoogle Scholar
  152. Elmlinger MW, Wimmer K, Biemer E, Blum WF, Ranke MB, Dannecker GE (1996) Insulin-like growth factor binding protein 2 is differentially expressed in leukaemic B- and T-cell lines. Growth Regul 6:152–157PubMedGoogle Scholar
  153. Attard-Montalto SP, Camacho-Hübner C, Cotterill AM, D’Souza-Li L, Daley S, Bartlett K, Halliday D, Eden OB (1998) Changes in protein turnover, IGF-I and IGF binding proteins in children with cancer. Acta Paediatr 87:54–60PubMedGoogle Scholar
  154. Vorwerk P, Mohnike K, Wex H, Rohl FW, Zimmermann M, Blum WF, Mittler U (2005) Insulin-like growth factor binding protein-2 at diagnosis of childhood acute lymphoblastic leukemia and the prediction of relapse risk. J Clin Endocrinol Metab 90:3022–3027PubMedGoogle Scholar
  155. Dawczynski K, Kauf E, Schlenvoigt D, Gruhn B, Fuchs D, Zintl F (2006) Elevated serum insulin-like growth factor binding protein-2 is associated with a high relapse risk after hematopoietic stem cell transplantation in childhood AML. Bone Marrow Transplant 37:589–594PubMedGoogle Scholar
  156. Hattori H, Matsuzaki A, Suminoe A, Koga Y, Tashiro K, Hara T (2006) Identification of novel genes with prognostic value in childhood leukemia using cDNA microarray and quantitative RT-PCR. Pediatr Hematol Oncol 23:115–127PubMedGoogle Scholar
  157. Dawczynski K, Steinbach D, Wittig S, Pfaffendorf N, Kauf E, Zintl F (2008) Expression of components of the IGF axis in childhood acute myelogenous leukemia. Pediatr Blood Cancer 50:24–28PubMedGoogle Scholar
  158. Kuhnl A, Kaiser M, Neumann M, Fransecky L, Heesch S, Radmacher M, Marcucci G, Bloomfield CD, Hofmann WK, Thiel E, Baldus CD (2011) High expression of IGFBP2 is associated with chemoresistance in adult acute myeloid leukemia. Leuk Res 35:1585–1590PubMedCentralPubMedGoogle Scholar
  159. Kitszel A, Krawczuk-Rybak M (2007) Are elevated serum levels of IGFBP-2 after intensive chemotherapy of childhood acute lymphoblastic leukemia a risk factor of relapse? Adv Med Sci 52:147–153PubMedGoogle Scholar
  160. Elmlinger M, Sanatani M, Bell M, Dannecker G, Ranke M (1998) Elevated insulin-like growth factor (IGF) binding protein (IGFBP)-2 and IGFBP-4 expression of leukemic T-cells is affected by autocrine/paracrine IGF-II action but not by IGF type I receptor expression. Eur J Endocrinol 138:337–343PubMedGoogle Scholar
  161. Jaques G, Kiefer P, Schoneberger HJ, Wegmann B, Kaiser U, Brandscheid D, Havemann K (1992) Differential expression of insulin-like growth factor binding proteins in human non-small cell lung cancer cell lines. Eur J Cancer 28A:1899–1904PubMedGoogle Scholar
  162. Reeve JG, Brinkman A, Hughes S, Mitchell J, Schwander J, Bleehen NM (1992b) Expression of Insulinlike Growth Factor (IGF) and IGF-binding protein genes in human lung tumor cell lines. J Natl Cancer Inst 84:628–634PubMedGoogle Scholar
  163. Hu Q, Huang L, Kuang X, Zhang H, Ling G, Chen X, Li K, Deng Z, Zhou J (2014) Is insulin-like growth factor binding protein 2 associated with metastasis in lung cancer? Clin Exp Metastasis 31:535–541PubMedGoogle Scholar
  164. Reeve JG, Morgan J, Schwander J, Bleehen NM (1993) Role for membrane and secreted insulin-like growth factor- binding protein-2 in the regulation of insulin-like growth factor action in lung tumors. Cancer Res 53:4680–4685PubMedGoogle Scholar
  165. Dong F, Wu HB, Hong J, Rechler MM (2002) Insulin-like growth factor binding protein-2 mediates the inhibition of DNA synthesis by transforming growth factor-beta in mink lung epithelial cells. J Cell Physiol 190:63–73PubMedGoogle Scholar
  166. Lee DY, Kim SJ, Lee YC (1999) Serum insulin-like growth factor (IGF)-I and IGF-binding proteins in lung cancer patients. J Korean Med Sci 14:401–404PubMedCentralPubMedGoogle Scholar
  167. Guo C, Lu H, Gao W, Wang L, Lu K, Wu S, Pataer A, Huang M, El-Zein R, Lin T, Roth JA, Mehran R, Hofstetter W, Swisher SG, Wu X, Fang B (2013) Insulin-like growth factor binding protein-2 level is increased in blood of lung cancer patients and associated with poor survival. PLoS One 8:e74973PubMedCentralPubMedGoogle Scholar
  168. Yazawa T, Sato H, Shimoyamada H, Okudela K, Woo T, Tajiri M, Ogura T, Ogawa N, Suzuki T, Mitsui H, Ishii J, Miyata C, Sakaeda M, Goto K, Kashiwagi K, Masuda M, Takahashi T, Kitamura H (2009) Neuroendocrine cancer-specific up-regulating mechanism of insulin-like growth factor binding protein-2 in small cell lung cancer. Am J Pathol 175:976–987PubMedCentralPubMedGoogle Scholar
  169. Migita T, Narita T, Asaka R, Miyagi E, Nagano H, Nomura K, Matsuura M, Satoh Y, Okumura S, Nakagawa K, Seimiya H, Ishikawa Y (2010) Role of insulin-like growth factor binding protein 2 in lung adenocarcinoma: IGF-independent antiapoptotic effect via caspase-3. Am J Pathol 176:1756–1766PubMedCentralPubMedGoogle Scholar
  170. Zhang Y, Ying X, Han S, Wang J, Zhou X, Bai E, Zhang J, Zhu Q (2013) Autoantibodies against insulin-like growth factorbinding protein-2 as a serological biomarker in the diagnosis of lung cancer. Int J Oncol 42:93–100PubMedCentralPubMedGoogle Scholar
  171. Moser AR, Dove WF, Roth KA, Gordon JI (1992) The Min (multiple intestinal neoplasia) mutation: its effect on gut epithelial cell differentiation and interaction with a modifier system. J Cell Biol 116:1517–1526PubMedGoogle Scholar
  172. Burgess AW (1998) Growth control mechanisms in normal and transformed intestinal cells. Philos Trans R Soc Lond Ser B Biol Sci 353:903–909Google Scholar
  173. Rowan AJ, Lamlum H, Ilyas M, Wheeler J, Straub J, Papadopoulou A, Bicknell D, Bodmer WF, Tomlinson IPM (2000) APC mutations in sporadic colorectal tumors: A mutational “hotspot” and interdependence of the “two hits”. Proc Natl Acad Sci U S A 97:3352–3357PubMedCentralPubMedGoogle Scholar
  174. Valenta T, Hausmann G, Basler K (2012) The many faces and functions of beta-catenin. EMBO J 31:2714–2736PubMedCentralPubMedGoogle Scholar
  175. Naishiro Y, Yamada T, Idogawa M, Honda K, Takada M, Kondo T, Imai K, Hirohashi S (2005) Morphological and transcriptional responses of untransformed intestinal epithelial cells to an oncogenic [beta]-catenin protein. 24:3141–3153Google Scholar
  176. Ben-Shmuel A, Shvab A, Gavert N, Brabletz T, Ben-Ze’ev A (2013) Global analysis of L1-transcriptomes identified IGFBP-2 as a target of ezrin and NF-[kappa]B signaling that promotes colon cancer progression. Oncogene 32:3220–3230PubMedGoogle Scholar
  177. Renehan AG, Painter JE, O’Halloran D, Atkin WS, Potten CS, O’Dwyer ST, Shalet SM (2000) Circulating insulin-like growth factor II and colorectal adenomas. J Clin Endocrinol Metab 85:3402–3408PubMedGoogle Scholar
  178. Mishra L, Bass B, Ooi BS, Sidawy A, Korman L (1998) Role of insulin-like growth factor-I (IGF-I) receptor, IGF-I, and IGF binding protein-2 in human colorectal cancers. Growth Horm IGF Res 8:473–479PubMedGoogle Scholar
  179. el Atiq F, Garrouste F, Remacle-Bonnet M, Sastre B, Pommier G (1994) Alterations in serum levels of insulin-like growth factors and insulin-like growth-factor-binding proteins in patients with colorectal cancer. Int J Cancer 57:491–497PubMedGoogle Scholar
  180. Liou J-M, Shun C-T, Liang J-T, Chiu H-M, Chen M-J, Chen CC, Wang H-P, Wu M-S, Lin J-T (2010) Plasma insulin-like growth factor-binding protein-2 levels as diagnostic and prognostic biomarker of colorectal cancer. J Clin Endocrinol Metab 95:1717–1725PubMedGoogle Scholar
  181. Miraki-Moud F, Jenkins PJ, Fairclough PD, Jordan S, Bustin SA, Jones AM, Lowe DG, Monson JP, Grossman AB, Besser GM, Camacho-Hubner C (2001) Increased levels of insulin-like growth factor binding protein-2 in sera and tumours from patients with colonic neoplasia with and without acromegaly. Clin Endocrinol (Oxford) 54:499–508Google Scholar
  182. Ben-Shmuel A, Shvab A, Gavert N, Brabletz T, Ben-Ze’ev A (2012) Global analysis of L1-transcriptomes identified IGFBP-2 as a target of ezrin and NF-[kappa]B signaling that promotes colon cancer progression. OncogeneGoogle Scholar
  183. Hoflich A, Lahm H, Blum W, Kolb H, Wolf E (1998) Insulin-like growth factor-binding protein-2 inhibits proliferation of human embryonic kidney fibroblasts and of IGF- responsive colon carcinoma cell lines. FEBS Lett 434:329–334PubMedGoogle Scholar
  184. Corkins MR, Vanderhoof JA, Slentz DH, MacDonald RG, Park JH (1995) Growth stimulation by transfection of intestinal epithelial cells with an antisense insulin-like growth factor binding protein-2 construct. Biochem Biophys Res Commun 211:707–713PubMedGoogle Scholar
  185. Michell NP, Langman MJ, Eggo MC (1997) Insulin-like growth factors and their binding proteins in human colonocytes: preferential degradation of insulin-like growth factor binding protein 2 in colonic cancers. Br J Cancer 76:60–66PubMedCentralPubMedGoogle Scholar
  186. Diehl D, Hessel E, Oesterle D, Renner-Muller I, Elmlinger M, Langhammer M, Gottlicher M, Wolf E, Lahm H, Hoeflich A (2009) IGFBP-2 overexpression reduces the appearance of dysplastic aberrant crypt foci and inhibits growth of adenomas in chemically induced colorectal carcinogenesis. Int J Cancer 124:2220–2225PubMedGoogle Scholar

Copyright information

© The International CCN Society 2015

Authors and Affiliations

  • Steven W. Yau
    • 1
    • 2
  • Walid J. Azar
    • 3
  • Matthew A. Sabin
    • 1
    • 2
  • George A. Werther
    • 1
    • 2
  • Vincenzo  C. Russo
    • 1
    • 2
    • 4
  1. 1.Deparment of Cell Biology, Hormone Research, Murdoch Childrens Research InstituteRoyal Children’s HospitalParkvilleAustralia
  2. 2.Department of PaediatricsUniversity of MelbourneParkvilleAustralia
  3. 3.Department of Cancer Genomics and Biochemistry, Cancer ResearchPeter MacCallum Cancer CentreMelbourneAustralia
  4. 4.Cell Biology, Murdoch Childrens Research InstituteRoyal Children’s HospitalParkvilleAustralia

Personalised recommendations