Derya ÖZYÖRÜK, Suna EMİR, Esra KARAKUŞ, Ayper KAÇAR, Resul KARAKUŞ

Insulin-like growth factor-1 receptor expression in pediatric tumors: a comparative immunohistochemical study

Background/aim: Insulin-like growth factor-1 receptor (IGF-1R) is a pivotal receptor tyrosine kinase involved in the cell cycle andmalignant tumor transformation. It is differentially expressed in various types of tumors. We aimed to determine the expression of IGF1R in different pediatric tumors and to shed light on possible new indications of anti-IGF-1R treatment approaches.Materials and methods: A total of 147 specimens were analyzed according to their expression of IGF-1R. Specimens includedthose from rhabdomyosarcomas, Wilms tumors, Ewing sarcoma/primitive neuroectodermal tumors, peripheral neuroblastictumors, acute lymphoblastic lymphoma, Hodgkin lymphoma, Burkitt lymphoma, retinoblastoma, pleuropulmonary blastoma,Langerhans cell histiocytosis, endodermal sinus tumors (ESTs), and myeloid sarcoma. Analysis was performed on tissue sections byimmunohistochemically staining for IGF-1R expression.Results: All six specimens of EST cases showed positivity for IGF-R1. Additionally, about 56% of the Hodgkin lymphoma, 80% of therhabdomyosarcoma, and 70% of the Wilms tumor specimens showed positivity for IGF-R1 expression.Conclusion: All ESTs examined in our study expressed IGF-1R and to our knowledge this is the first report regarding ESTs and IGF-1Rexpression. IGF-1R could be included among confirmatory markers for ESTs and, from a therapeutic viewpoint, ESTs should also beexamined for IGF-1R expression for beneficial regimens.

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Reinmuth N, Kloos S, Warth A, Risch A, Muley T, Hoffmann H, Thomas M, Meister M. Insulin-like growth factor 1 pathway mutations and protein expression in resected non-small cell lung cancer. Hum Pathol 2014; 45: 1162-1168.
Tran TN, Selinger CI, Yu B, Ng CC, Kohonen-Corish MR, McCaughan B, Kennedy C, O’Toole SA, Cooper WA. Alterations of insulin-like growth factor-1 receptor gene copy number and protein expression are common in non-small cell lung cancer. J Clin Pathol 2014; 67: 985-991.
Hellawell GO, Turner GD, Davies DR, Poulsom R, Brewster SF, Macaulay VM. Expression of the type 1 insulin-like growth factor receptor is up-regulated in primary prostate cancer and commonly persists in metastatic disease. Cancer Res 2002; 62: 2942-2950.
Law JH, Habibi G, Hu K, Masoudi H, Wang MY, Stratford AL, Park E, Gee JM, Finlay P, Jones HE et al. Phosphorylated insulin-like growth factor-I/insulin receptor is present in all breast cancer subtypes and is related to poor survival. Cancer Res 2008; 68: 10238-10246.
LeRoy EC, Moore JH, Hu C, Martínez ME, Lance P, Duggan D, Thompson PA. Genes in the insulin and insulin-like growth factor pathway and odds of metachronous colorectal neoplasia. Hum Genet 2011; 129: 503-512.
Huang HJ, Angelo LS, Rodon J, Sun M, Kuenkele KP, Parsons HA, Trent JC, Kurzrock R. R1507, an anti-insulin-like growth factor-1 receptor (IGF-1R) antibody, and EWS/FLI-1 siRNA in Ewing’s sarcoma: convergence at the IGF/IGFR/Akt axis. PLoS One 2011; 6: e26060.
Pappo AS, Vassal G, Crowley JJ, Bolejack V, Hogendoorn PC, Chugh R, Ladanyi M, Grippo JF, Dall G, Staddon AP et al. A phase 2 trial of R1507, a monoclonal antibody to the insulinlike growth factor-1 receptor (IGF-1R), in patients with recurrent or refractory rhabdomyosarcoma, osteosarcoma, synovial sarcoma, and other soft tissue sarcomas: results of a Sarcoma Alliance for Research Through Collaboration study. Cancer 2014; 120: 2448-2456.
Gallagher EJ, LeRoith D. The proliferating role of insulin and insulin-like growth factors in cancer. Trends Endocrinol Metab 2010; 21: 610-618.
van Gaal JC, Roeffen MH, Flucke UE, van der Laak JA, van der Heijden G, de Bont ES, Suurmeijer AJ, Versleijen-Jonkers YM, van der Graaf WT. Simultaneous targeting of insulin-like growth factor-1 receptor and anaplastic lymphoma kinase in embryonal and alveolar rhabdomyosarcoma: a rational choice. Eur J Cancer 2013; 49: 3462-3470.
Natrajan R, Reis-Filho JS, Little SE, Messahel B, Brundler MA, Dome JS, Grundy PE, Vujanic GM, Pritchard-Jones K, Jones C. Blastemal expression of type I insulin-like growth factor receptor in Wilms’ tumors is driven by increased copy number and correlates with relapse. Cancer Res 2006; 66: 11148-11155.
Werner H, Re GG, Drummond IA, Sukhatme VP, Rauscher FJ 3rd, Sens DA, Garvin AJ, LeRoith D, Roberts CT Jr. Increased expression of the insulin-like growth factor I receptor gene, IGF1R, in Wilms tumor is correlated with modulation of IGF1R promoter activity by the WT1 Wilms tumor gene product. P Natl Acad Sci USA 1993; 90: 5828-5832.
Asmane I, Watkin E, Alberti L, Duc A, Marec-Berard P, RayCoquard I, Cassier P, Decouvelaere AV, Ranchère D, Kurtz JE et al. Insulin-like growth factor type 1 receptor (IGF-1R) exclusive nuclear staining: a predictive biomarker for IGF-1R monoclonal antibody (Ab) therapy in sarcomas. Eur J Cancer 2012; 48: 3027-3035.
Fleuren ED, Versleijen-Jonkers YM, Boerman OC, van der Graaf WT. Targeting receptor tyrosine kinases in osteosarcoma and Ewing sarcoma: current hurdles and future perspectives. Biochim Biophys Acta 2014; 1845: 266-276.
Kim B, van Golen CM, Feldman EL. Insulin-like growth factor-I signaling in human neuroblastoma cells. Oncogene 2004; 23: 130-141.
Wagner MJ, Maki RG. Type 1 insulin-like growth factor receptor targeted therapies in pediatric cancer. Front Oncol 2013; 3: 9.
Eppler E, Janas E, Link K, Weidmann L, Bischofberger H, Wenger M, Tinguely M, Schraml P, Moch H, Fellbaum C. Insulin-like growth factor I is expressed in classical and nodular lymphocyte-predominant Hodgkin’s lymphoma tumour and microenvironmental cells. Cell Tissue Res 2015; 359: 841-851.
Liang Z, Diepstra A, Xu C, van Imhoff G, Plattel W, Van Den Berg A, Visser L. Insulin-like growth factor 1 receptor is a prognostic factor in classical Hodgkin lymphoma. PLoS One 2014; 9: e87474.
Koh YW, Yoon DH, Suh C, Cha HJ, Huh J. Insulin-like growth factor-1 receptor is associated with better prognosis in classical Hodgkin’s lymphoma: correlation with MET expression. Int J Exp Pathol 2015; 96: 232-239.