350 rub
Journal №12 for 2011 г.
Article in number:
The System of Insulin-Like Growth Factors
Keywords: IGF proliferation differentiation carcinogenesis
Authors:
N.E. Kushlinskii, Yu.S. Timofeev
Abstract:
The insulin-like growth factors induce a signal network, which is vital to modulation of different cell processes, like growth, cell survival, proliferation and differentiation. IGF-system consists of ligands (IGF-I, IGF-II, insulin) receptors, like IGF-IR, IGF-IIR, IR and hybrid receptor, insuline-like growth factor binding proteins (IGFBP-1-6) and proteases (PAPP-A, MMPs etc.). IGF-IR has complex downstream pathways, including MAPK-patway and PI3-K pathway, through which its biological effects are realized. Diverse effects of IGF-axis provide regenerative, regulatory, protective functions in many tissues and organs in human. However the deviations of IGF-system may provide carcinogenesis through upregulation of cyclin D1, CDK4 and inhibition of PTEN, which affects cell cycle. Interactions with bcl-2 system increase cell survival. IGF-system is also involved in tumor angiogenesis and lympangiogenesis, through induction of HIF-1α expression and activation of VEGF. Another effect of IGF-system is intensification of invasion and metastasis, as a result of regulation of MMPs and uPAR/uPA-system. In bone tumors IGF axis plays important role in tumorogenesis. Overexpression of IGF-I, IGF-II and IGF-IR has been found in osteosarcoma. In Ewing's sarcoma transformed cells depend on IGF-IR signalization, аnd cell survival is linked with IGFs. In DSRCT cells expression of IGF-IR is stimulated by some isoforms of EWS-WT1 protein. IGF-system causes non-islet hypoglycemia in malignant fibrous histiocytoma. IGF-I-II plays role of autoctine factor of differentiation in chondrosarcoma cell line HCS 2/8. Accordingly, the IGF-system can be an important target in diagnostics, detection, prognosis and treatment of cancer.
Pages: 3-24
References
  1. Salmon W.D. Jr., Daughaday W.H. Ahormonally controlled serum factor which stimulates sulfatein corporation by cartilage in vitro // J. Lab. Clin. Med. 1957. V. 49. № 6. P. 825-836.
  2. George Vardatsikos., Anita Sahu., Ashok K. Srivastava. The Insulin-Like Growth Factor Family: Molecular Mechanisms // Redox Regulation, and Clinical Implications. Antioxidants&Redoxsignaling. 2009. V. 11. № 5. P.1165.
  3. Hanahan D., Weinberg R.A. Hallmarks of Cancer: The Next Generation // Cell. 2011. V. 144. P. 648.
  4. Daughaday W.H., Hall K., Raben M.S., Salmon W.D. Jr., vanden Brande J.L., van Wyk J.J. Somatomedin: proposed designation for sulphation factor // Nature. 1972. V. 235. № 5333. P. 107.
  5. Froesch E.R., Buergi H., Ramseier E.B., Bally P., Labhart A. Antibody-suppressible and nonsuppressible insulin-like activities in human serum and their physiologics ignificance. An insulin as say with adipose tissue of increased precision and specificity // J. Clin. Invest. 1963. V. 42. P. 1816-1834.
  6. Klapper D.G., Svoboda M.E.,Van Wyk J.J. Sequence analysis of somatomedin-c: confirmation of identity with insulin-likegrowth factor-i // Endocrinology. 1983. V. 112. № 6. P. 2215-2217.
  7. Clemmons D.R. Value of insulin-likegrowth factor system markers in the assessment of growth hormone status // Endocrinol. Metab. Clin. North. Am. 2007. V. 36. P. 109-129.
  8. Clemmons D.R. Modifying IGF1 activity: an approach to treaten edocrine disorders, atherosclerosis and cancer. Nat Rev Drug Discov. 2007. V. 6. P. 821-833.
  9. GeorgeVardatsikos., Anita Sahu., Ashok K. Srivastava. The Insulin-Like Growth Factor Family: Molecular Mechanisms Redox Regulation, and Clinical Implications // Antioxidants&Redoxsignaling. 2009. V. 11. № 5.
  10. Heldin C.H., Ostman A. Ligand-induced dimerization of growth factor receptors: variations on the theme // Cytokine Growth Factor Rev. 1996. V.7(1). P. 3-10.
  11. Marta Annunziata., Riccarda Granata., Ezio Ghigo. The IGF system // Acta Diabetol. 2011. V. 48. P. 1-9.
  12. Ward C.W., Garrett T.P.J., McKern N.M., Lou M., Cosgrove L.J., Sparrow L.G., Frenkel M.J., Hoyne P.A., Elleman T.C., Adams T.E., Lovrecz G.O., Lawrence L.J., Tulloch P.A. The three dimensional structure of the type I insulin-like growth factor receptor // Mol. Pathol. 2001. V. 54. P. 125-132.
  13. De Meyts P., Whittaker J. Structural biology of insulin and IGF1 receptors: implications for drug design // Nat. Rev. Drug Disc. 2002. V. 1. P. 769-783.
  14. White M.F. IRS proteins and the common patht of diabetes // Am. J. Physiol. Endocrinol. Metab. 2002. V. 283. P. E413-E422.
  15. Saltiel A., Rand Kahn C.R. Insulin signal lingand the regulation of glucose and lipid metabolism // Nature. 2001. V. 414. P. 799-806.
  16. Kyosseva S.V. Mitogen-activated proteinkinase signaling // Int. Rev. Neurobiol. 2004. V. 59. P. 201-220.
  17. Clark J.E., Sarafraz N., Marber M.S. Potential of p38 MAPK inhibitors in the treatment of ischaemic heart disease // Pharmacol. Ther. 2007. V. 116. P. 192-206.
  18. Chang F., Steelman L.S., Lee J.T., Shelton J.G., Navolanic P.M., Blalock W.L., Franklin R.A., McCubrey J.A. Signal Transduction mediated by the Ras=Raf=MEK=ERK pathway from cytokine receptors to transcription factors: potential targeting for therapeutic intervention // Leukemia. 2003. V. 17. P. 263-1293.
  19. White M.F. IRS proteins and the common path to diabetes // Am. J. Physiol. Endocrinol. Metab. 2002. V. 283. P. E413-E422.
  20. Kanzaki M. Insulin receptor signals regulating GLUT4 translocation and actin dynamics // Endocr. J. 2006. V. 53. P. 267-293.
  21. Cantley L.C. The phosphoinositide 3-kinase pathway // Science. 2002. V. 296. Р. 1655-1657.
  22. Sale E.M., Sale G.J. Proteinkinase B: Signalling roles and therapeutic targeting // Cell Mol. Life. Sci. 2008. V. 65. P. 113-127.
  23. Nakae J., Kido Y., Accili D. Distinct and overlapping functions of insulinand IGF-Ireceptors // Endocr. Rev. V. 22(6). P. 818-835. 2001.
  24. Clemmons D.R. Role of igf-I in skeletal muscle mass maintenance // Trends Endocrinol. Metab. 2009. V. 20(7). P. 349-356.
  25. Hadsell D.L. Genetic manipulation of mammary gland development and lactation // Adv. Exp. Med. Bio. 2004. V. l554. P. 229-251.
  26. Torres-Aleman I. Toward acomprehensive neurobiology of igf-i // Dev. Neurobiol. 2010. V. 70(5). P. 384-396.
  27. Llorens-Martin M., Torres-Aleman I., Trejo J.L. Mechanisms mediating brain plasticity: igf1 and adul thippocampal neurogenesis // Neuroscientist. 2009. V. 15(2). P. 134-148.
  28. Colao A. The gh-igf-I axis and the cardiovascular system: clinical implications // Clin. Endocrinol. (Oxf). 2008. V. 69(3). P. 347-358.
  29. Arnqvist H.J. The role of igf-system in vascular insulin resistance // Horm. Metab. Res. 2008. V. 40(9). P. 588-592.
  30. Smith T.J. Insulin-like growth factor-iregulation of Immune function: a potential therapeutic targeting autoimmune diseases - // Pharmacol. Rev. 2010. V. 62(2). P. 199-236.
  31. Higashi Y., Sukhanov S., Anwar A., Shai S.Y., Delafontaine P. Igf-1, oxidative stress and atheroprotection // Trends Endocrinol. Metab. 2010. V. 21(4). P. 245-254.
  32. Ren H., Yin P., Duan C. Igf bp-5 regulates muscle cell differentiation by binding to igf-ii and switching on the igf-ii auto-regulation loop // J. Cell Biol. 2008. V. 82(5). P. 979-991.
  33. Frystyk J. Free insulin-like growth factors-Measurements and relationships to growth hormone secretion and glucose homeostasis // Growth Horm IGF Res. 2004. V. 14. P. 337-375.
  34. Firth S.M., Baxter R.C. Cellular actions of the insulin-like Growth factor binding proteins // Endocr. Rev. 2002. V. 23. P. 824-854.
  35. Suem Firth, Robertc Baxter. Cellular Actions of the Insulin-Like Growth Factor Binding Proteins // Endocrine Reviews. 2002. V. 23. P. 824-854.
  36. Cheryl A. Conover. Insulin-like growth factor-binding proteins and bone Metabolism // Am. J. Physiol. Endocrinol. Metab. 2008. V. 294. P. E10-E14.
  37. Zhou R., Diehl D., Hoeflich A., Lahm H., Wolf E. IGF-bindingprotein-4: biochemical characteristics and functional consequences // J. Endocrinol. 2003. V. 178. P. 177-193.
  38. Bale L.K., Conover C.A. Disruption of insulin-like growth factor-II imprinting during embryonic development rescues the dwarf phenotype of mice null for pregnancy - associated plasmaprotein-A // J. Endocrinol. 2005. V. 186. P. 325-331.
  39. Salih D.A.M., Mohan S., Kasukawa Y., Tripathi G., Lovett F.A., Anderson N.F., Carter E.J., Wergedal J.E., Baylink D.J., Pell J.M. Insulin-like growth factor-binding protein-5induces a gender-related decrease in bone mineral Density in transgenic mice // Endocrinology. 2005. V. 146. P. 931-940.
  40. Mohan S., Thompson G.R., Amaar Y.G., Hathaway G., Tschesche H., Baylink D.J. ADAM-9 is an insulin-like growth factor binding protein-5 protease produced and secreted by human osteoblasts // Biochemistry. 2002. V. 41. P. 15394-15403.
  41. Andrea Taferner, Lucia Micutkova, Martin Hermann, Pidder Jansen-Durr, Haymo Pircher. Purification and characterization of native human insulin-like growth factor binding protein-6 // J. Cell Commun. Signal. 2011. DOI10.1007/s12079-011-0126-2.
  42. Fingleton B. Matrix metalloproteinases: roles in cancer and metastasis // Front Biosci. 2006. V. 11. P. 479-91.
  43. Sounni N.E., Noel A. Membrane type-matrix metalloproteinases and tumor progression // Biochimie. 2005. V. 87(3-4). P. 329-42.
  44. Chantrain C.F., Henriet P., Jodele S. Mechanisms of pericyte recruitment in tumour angiogenesis: a new role for metalloproteinases // Eur. J. Cancer. 2006. V. 42(3). P. 310-318.
  45. Zhang D., Bar-Eli M., Meloche S., Brodt P. Dual regulation of MMP-2 expression by the type 1 insulin-like growth factor receptor: the phosphatidylinositol 3- kinase/Akt and Raf/ERK pathways transmit opposing signals // J. Biol. Chem. 2004. V. 279(19). P. 19683-90.
  46. Zhuang D., Ceacareanu A.C., Lin Y., Ceacareanu B., Dixit M., Chapman K.E., Waters C.M., Rao G.N., Hassid A. Nitric oxide attenuate sinsulin-or IGF-I-stimulated aortics mooth muscle cell motility by decree sing H2O2 levels: Essential role of cGMP // Am. J. Physiol. Heart Circ. Physiol. 2004. V. 286. P. H2103-H2112.
  47. Linseman D.A., Phelps R.A., Bouchard R.J., Le S.S., Laessig T.A., McClure M.L., Heidenreich K.A. Insulin-like growth factor-I blocks Bcl-2 interacting mediator of cell death (Bim) induction and intrinsic death signaling in cerebellar granuleneurons // J. Neurosci. 2002. V. 22. P. 9287-9297.
  48. Lin C.W., Yang L.Y., Shen S.C., Chen Y.C. IGF-I plus E2 induces proliferation via activation of ROS-dependent ERKs and JNKs in human breast carcinoma cells // J. Cell. Physiol. 2007. V. 212. P. 666-674.
  49. Meng D., Lv D.D., Fang J. Insulin-like growth factor-I induces reactive oxygen species production and cell migration through Nox4 and Rac1 in vascular smooth muscle cells // Cardiovasc. Res. 2008. V. 80. P. 299-308.
  50. Dupont J., Pierre A., Froment P., Moreau C. The insulin-like growth factor axis in cell cycle progression // Horm. Metab. Res. 2003. V. 35. P. 740-750.
  51. Fukuda R., Hirota K., Fan F., Jung Y.D., Ellis L.M., Semenza G.L. Insulin-like growth factor 1 induces hypoxia-inducible factor1-mediated vascular endothelial growth factor expression, which is dependent on MAP kinase and phosphatidylinositol 3-kinase signaling in colon cancer cells // J. Biol. Chem. 2002. V. 277. P. 38205-38211.
  52. Grulich-Henn J., Ritter J., Mesewinkel S., Heinrich U., Bettendorf M., Preissner K.T. Transport of insulin-like growth factor-I across endothelial cell monolayers and its binding to the subendothelial matrix // Exp. Clin. Endocrinol. Diabetes. 2002. V. 110. P. 67-73.
  53. Kondo T., Vicent D., Suzuma K., Yanagisawa M., King G.L., Holzenberger M., Kahn C.R. Knockout of insulin and IGF-1 receptors on vasculare endothelial cells protects against retinal neovascularization // J. Clin. Invest. 2003. V. 111(12). 1835-1842.
  54. Samani A.A., Yakar S., Le Roith D., Brodt P. The Role of the IGF System in Cancer Growth and Metastasis: Overview and Recent Insights Endocrine. // Reviews. 2007. V. 28(1). P. 20-47.
  55. Tang Y., Zhang D., Fallavollita L., Brodt P. Vascular endothelial growth factor C expression and lymph node metastasis are regulated by the type I insulin-like growth factor receptor // Cancer Res. 2003. V. 63. P. 1166-1171.
  56. Bjorndahl M., Cao R., Nissen L.J., Clasper S., Johnson L.A., Xue Y., Zhou Z., Jackson D., Hansen A.J., Cao Y. Insulin-like growth factors 1 and 2 induce lymphangiogenesis in vivo // Proc Natl Acad Sci USA. 2005. V. 102. P. 15593-15598.
  57. Zhang D., Brodt P. Type 1 insulin-like growth factor regulates MT1-MMP synthesis and tumor invasion via PI3-kinase/Akt signaling // Oncogene. 2003. V. 22. P. 974-982.
  58. Hemers E., Duval C., Mc Caig C., Handley M., Dockray G.J., Varro A. Insulin-like growth factor binding protein-5 is a target of matrix metalloproteinase-7: implications for epithelial-mesenchymal signaling // Cancer Res. 2005. V. 65. P. 7363-7369.
  59. Bauer T.W., Liu W., Fan F., Camp E.R., Yang A., Somcio R.J., Bucana C.D., Callahan J., Parry G.C., Evans D.B., Boyd D.D., Mazar A.P., Ellis L.M. Targeting of urokinase plasminogen activator receptor in human pancreatic carcinoma cells inhibits c-Met and insulin-like growth factor-I receptor-mediated migration and invasion and orthotopic tumor growth in mice // Cancer Res. 2005. V. 65. P. 7775-7781.
  60. Gallicchio M.A., Kaun C., Wojta J., Binder B., Bach L.A. Urokinase type plasminogen activator receptor is involved in insulin-like growth factor-induced migration of rhabdomyosarcoma cells in vitro // J. Cell. Physio. 2003. V. l197. P. 131-138.
  61. Cui H., Cruz-Correa M., Giardiello F.M., Hutcheon D.F., Kafonek D.R., Brandenburg S., Wu Y., He X., Powe N.R., Feinberg A.P. Loss of IGF2 imprinting: a potential marker of colorectal cancer risk // Science. 2003. V. 299. P. 1753-1755.
  62. Armengol G., Knuutila S., Lluis F., Capella G., Miro R., Caballin M.R. DNA copy number changes and evaluation of MYC, IGF1R, and FES amplification in xenografts of pancreatic adenocarcinoma // Cancer Genet Cyto genet. 2000. V. 116. P. 133-141.
  63. Bassi D.E., Fu J., Lopez de Cicco R., Klein-Szanto A.J. Proprotein convertases: "master switches" in the regulation of tumor growth and progression // Mol Carcinog. 2005. V. 44. P. 151-161.
  64. Hakomori S. Glycosylation defining cancer malignancy: new wine in an old bottle // Proc Natl Acad Sci USA. 2002. V. 99. P. 10231-10233.
  65. Sciacca L., Mineo R., Pandini G., Murabito A., Vigneri R., Belfiore A. In IGF-I receptor-deficient leiomyosarcoma cells autocrine IGF-II induces cell invasion and protection from apoptosis via the Insulin receptor isoform A. // Oncogene. 2002. V. 21. P. 8240-8250.
  66. Renehan A.G., Zwahlen M., Minder C., O-Dwyer S.T., Shalet S.M., Egger M. Insulin-like growth factor (IGF)-I, IGF binding proteinprotein-3, and cancer risk: systematic review and meta-regression analysis // Lancet. 2004. V. 363. P. 1346-1353.
  67. Chang Y.S., Wang L., Liu D., Mao L., Hong W.K., Khuri F.R., Lee H.Y. 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. 2002. V. 8. P. 3669-3675.
  68. Kiepe D., Ciarmatori S., Hoeflich A., Wolf E., Tonshoff B. Insulin-like growth factor (IGF)-I stimulates cell proliferation and induces IGF binding protein (IGFBP)-3 and IGFBP-5 gene expression in cultured growth plate chondrocytes via distinct signaling pathways // Endocrinology. 2005. V. 146. P. 3096-310.
  69. Yi H.K., Kim S.Y., Hwang P.H., Kim C.Y., Yang D.H., Oh Y., Lee D.Y. Impact of PTEN on the expression of insulin-like growth factors (IGFs) and IGF-binding proteins in human gastric adenocarcinoma cells // Biochem. Biophys. Res. Commun. 2005. V. 330. P. 760-767.
  70. Kalli K.R., Falowo O.I., Bale L.K., Zschunke M.A., Roche P.C., Conover C.A. Functional insulin receptors on human epithelial ovarian carcinoma cells: implications for IGF-II mitogenic signaling // Endocrinology. 2002. V. 143. P. 3259-3267.
  71. Boissan M., Beurel E., Wendum D., Rey C., Lecluse Y., Housset C., Lacombe M.L., Desbois-Mouthon C. Overexpression of insulin receptor substrate-2 in human and murine hepatocellular carcinoma // Am. J. Pathol. 2005. V. 167. P. 869-877.
  72. Lee Y.I., Han Y.J., Lee S.Y., Park S.K., Park Y.J., Moon H.B., Shin J.H., Lee J.H. Activation of insulin-like growth factor II signaling by mutant type p53: physiological implications for potentiation of IGF-II signaling by p53 mutant 249 // Mol. Cell. Endocrinol. 2003. V. 203. P. 51-63.
  73. Yi H.K., Kim S.Y., Hwang P.H., Kim C.Y., Yang D.H.,Oh Y., Lee D.Y. Impact of PTEN on the expression of insulin-like growth factors(IGFs) and IGF-binding proteins in human gastric adenocarcinoma cells // Biochem. Biophys. Res. Commun. 2005. V. 330. P. 760-767.
  74. Hwang P.H., Kim S.Y., Lee J.C., Kim S.J., Yi H.K., Lee D.Y. PTEN/MMAC1 enhances the growth inhibition by anticancer drugs with downregulation of IGF-II expression in gastric cancer cells // Exp. Mol. Med. 2005. V. 37. P. 391-398.
  75. Li J., Sahagian G.G. Demonstration of tumor suppression by mannose 6-phosphate/insulin-like growth factor 2 receptor // Oncogene. 2004. V. 23. P. 9359-9368.
  76. Fletcher C.D.M., Unni K.K., Mertens F. World Health Organization Classification of Tumours: Pathology and Genetics of Tumours of Soft Tissue and Bone. Lyon. IARC Press. 2002.
  77. Rikhof B., de Jong S., Suurmeijer A.J., Meijer C., van der Graaf W.T. The insulin-like growth factor system and sarcomas // J. Pathol. 2009. V. 217. P. 469-482.
  78. Conover C.A. Insulin-like growth factor-binding proteins and bone metabolism // Am. J. Physiol. Endocrinol. Metab. 2008. V. 294. P. E10-14.
  79. Ulaner G.A, Vu T.H., Li T., Hu J.F., Yao X.M., Yang Y. Loss of imprinting of IGF2 and H19 in osteosarcoma is accompanied by reciprocal methylation changes of a CTCF-binding site // Hum. Mol. Genet. 2003. V. 12. P. 535-549.
  80. Gorlick R., Anderson P., Andrulis I., Arndt C., Beardsley G.P., Bernstein M. Biology of childhood osteogenic sarcoma and potential targets for therapeutic development: meeting summary // Clin. Cancer. Res. 2003. V. 9. P. 5442-5453.
  81. Pinski J., Schally A.V., Halmos G., Szepeshazi K., Groot K. Somatostatin analog RC-160 inhibits the growth of human osteosarcomas in nude mice // Int. J. Cancer. 1996. V. 65. P. 870-874.
  82. Mansky P.J., Liewehr D.J., Steinberg S.M., Chrousos G.P., Avila N.A., Long L. Treatment of metastatic osteosarcoma with the somatostatin analog OncoLar: significant reduction of insulinlike growth factor-1 serum levels // J. Pediatr. Hematol. Oncol. 2002. V. 24. P. 440-446.
  83. Kolb E.A., Gorlick R., Houghton P.J., Morton C.L., Lock R., Carol H. Initial testing (stage 1) of a monoclonal antibody (SCH 717454) against the IGF-1 receptor by the pediatric preclinical testing program // Pediatr. Blood. Cancer. 2008. V. 50. P. 1190-1197.
  84. Savage S.A., Woodson K., Walk E., Modi W., Liao J., Douglass C. Analysis of genes critical for growth regulation identifies insulin-like growth factor 2 receptor variations with possible functional significance as risk factors for osteosarcoma // Cancer Epidemiol Biomarkers Prev. 2007. V. 16. P. 1667-1674.
  85. Arvand A., Denny C.T. Biology of EWS/ETS fusions in Ewing-s family tumors // Oncogene. 2001. V. 20. P. 5747-5754.
  86. Castillero-Trejo Y., Eliazer S., Xiang L., Richardson J.A., Ilaria R.L. Expression of the EWS/FLI-1 oncogene in murine primary bonederived cells. Results in EWS/FLI-1-dependent, ewing sarcomalike tumors // Cancer Res. 2005. V. 65. P. 8698-8705.
  87. Riggi N., Cironi L., Provero P., Suva M.L., Kaloulis K., Garcia-Echeverria C. Development of Ewing-s sarcoma from primary bone marrow-derived mesenchymal progenitor cells // Cancer Res. 2005. V. 65. P. 11459-11468.
  88. Manara M.C., Landuzzi L., Nanni P., Nicoletti G., Zambelli D., Lollini P.L. Preclinical in vivo study of new insulin-likegrowth factor-I receptor - specific inhibitor in Ewing-s sarcoma // Clin. Cancer. Res. 2007. V. 13. P. 1322-1330.
  89. Benini S., Manara M.C., Cerisano V., Perdichizzi S., Strammiello R., Serra M. Contribution of MEK-MAPK and PI3-K signaling pathway to the malignant behavior of Ewing-s sarcoma cells: therapeutic prospects // Int. J. Cancer. 2004. V. 108. P. 358-366.
  90. Prieur A., Tirode F., Cohen P., Delattre O. EWS/FLI-1 silencing and gene profiling of Ewing cells reveal downstream oncogenic pathways and a crucial role for repression of insulin-like growth factor binding protein 3 // Mol. Cell. Biol. 2004. V. 24. P. 7275-7283.
  91. Riggi N., Stamenkovic I. The Biology of Ewing sarcoma // Cancer Lett. 2007. V.254. P. 1-10.
  92. Finkeltov I., Kuhn S., Glaser T., Idelman G., Wright J.J., Roberts C.T. Transcriptional regulation of IGF-I receptor gene expression by novel isoforms of the EWS-WT1fusionprotein // Oncogene. 2002. V. 21. P. 1890-1898.
  93. Werner H., Idelman G., Rubinstein M., Pattee P., Nagalla S.R., Roberts C.T. A novel EWS-WT1 gene fusion product in desmoplastic small round cell tumor is a potent transactivator of the insulin-like growth factor-I receptor(IGF-IR) gene // Cancer Lett. 2007. V. 247. P. 84-90.
  94. Kageyama K., et al. Hypoglycemica Associated with Big Insulin-Like Growth Factor II Produced during Developmen og Malignant Gibrous Hisiocytoma End // J. 2003. V. 50(6). P. 753-758.