Journal of Pathology J Pathol 2009; 217: 469–482 Published online 13 November 2008 in Wiley InterScience (www.interscience.wiley.com) DOI: 10.1002/path.2499 Review Article The insulin-like growth factor system and sarcomas Bart Rikhof, 1 * Steven de Jong, 1 Albert JH Suurmeijer, 2 Coby Meijer 1 and Winette TA van der Graaf 3 1 Department of Medical Oncology, University Medical Centre Groningen, University of Groningen, The Netherlands 2 Department of Pathology, University Medical Centre Groningen, University of Groningen, The Netherlands 3 Department of Medical Oncology, Radboud University, Nijmegen Medical Centre, The Netherlands *Correspondence to: Bart Rikhof, Department of Medical Oncology, University Medical Centre Groningen, PO Box 30.001, 9700 RB Groningen, The Netherlands. E-mail: b.rikhof@int.umcg.nl No conflicts of interest were declared. Received: 15 September 2008 Revised: 15 September 2008 Accepted: 6 November 2008 Abstract Sarcomas are a diverse group of malignant mesenchymal tumours arising from bone and soft tissues. The identification of critical cellular signalling pathways in sarcomas is an important issue for the development of new targeted therapies. This review highlights the experimental and clinical evidence supporting the role of the insulin-like growth factor (IGF) signalling system in the cellular transformation and progression of several types of sarcoma, including rhabdomyosarcoma, synovial sarcoma, leiomyosarcoma, Ewing’s sarcoma and osteosarcoma. Preclinical data suggest that the IGF system could be a promising target for therapy in these sarcomas. Currently, therapies interrupting IGF signalling have been or are being developed. In recent phase 1 clinical studies with humanized monoclonal antibodies directed against IGF receptor type 1 (IGF-1R), objective tumour responses were observed in several patients with Ewing’s sarcoma, encouraging further clinical testing in Ewing’s sarcoma and other sarcoma (sub)types. Moreover, the occasional occurrence of paraneoplastic hypoglycaemia as a result of the secretion of incompletely processed forms of pro-IGF-II by sarcomas is discussed. Copyright  2008 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Keywords: sarcoma; soft-tissue; bone; insulin-like growth factor; insulin-like growth factor receptor type 1; insulin receptor; targeted therapy Introduction Sarcomas are rare tumours of mesenchymal origin, comprising about 1% of all adult malignancies and 12% of paediatric cancers [1,2]. They form a het- erogeneous group of solid tumours arising from soft tissue or bone. There are more than 50 histological (sub)types of soft tissue and bone sarcomas. These subtypes display different biological characteristics, clinical behaviour and therapeutic options [1]. On the basis of cytogenetics, sarcomas have been divided into two major classes. The first class consists of sar- comas with simple karyotypes and specific genetic alterations, including chromosomal translocations or specific gene mutations. The second category is char- acterized by a complex unbalanced karyotype with non-specific genetic alterations [3]. Overall, there is a poor response of sarcomas from both categories to chemotherapy. Recent advances in the treatment of gastrointestinal stromal tumours (GISTs) with the tyrosine kinase inhibitor imatinib [4], and Ewing’s sar- coma with the insulin-like growth factor receptor type 1 (IGF-1R) antagonist R1507 [5], have shown that understanding of the biology of sarcomas, and iden- tification of critical signalling pathways involved in the aetiology and progression of these tumours, can lead to the recognition of molecular targets for ther- apy. Research performed in the last two decades has demonstrated that the insulin-like growth factor (IGF) system plays an important role in the tumourigenesis of several sarcoma (sub)types. Therefore, this system could be a target for antisarcoma therapy. Furthermore, mesenchymal neoplasms are occasionally associated with paraneoplastic hypoglycaemias as a result of pro- IGF-II secretion by the tumour. The purpose of this review is to highlight the biological, therapeutic and clinical role of the IGF system in sarcoma. Components of the IGF signalling system The IGF system consists of three ligands (IGF-I, IGF- II and insulin), four cell-membrane receptors [IGF-1R, insulin receptor isoform A (IR-A), hybrid receptors and IGF receptor type 2 (IGF-2R)] and six IGF- binding proteins (IGFBP-1–6; Figure 1). IGFs The majority of circulating IGF-I is produced by the liver and its expression is stimulated by growth hormone (GH). Other organs can also produce IGF-I. In this way, IGF-I functions as an endocrine growth Copyright  2008 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. www.pathsoc.org.uk