Summary. In the last decades, the concept that Insulin- like Growth Factor (IGF) axis plays a key role in several steps of tumorigenesis, cancer growth and metastasis has been widely documented. The aberration of the IGF system has been described in many kinds of tumours, providing several lines of evidence in support of IGF receptor type 1 (IGF1R) as molecular target in cancer treatment. Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumor of the gastrointestinal tract, commonly characterized in most cases by KIT and PDGFRA gain mutations. Beyond to the well recognized KIT and PDGFRA gain mutations, in the last years other molecular aberrations have been investigated. Recently, several lines of evidence about the involvement of the IGF system in GIST have been accumulated. The aim of this review is to report all current data about the IGF system involvement in GIST, focusing on the current clinical implication and future perspectives. Key words: Gastrointestinal stromal tumors (GIST), Insulin growth factor receptor 1 (IGF1R), KIT/ PDGFRA, Wild-type, Succinate dehydrogenase (SDH). Introduction The Insulin-like Growth Factor (IGF) signalling system, composed of the IGF-receptor type 1 (IGF1R), the insuline receptor (IR), two ligands (IGF1 and IGF2), and six regulatory IGF-binding proteins (IGFBPs), is physiologically involved in the regulation of normal tissue growth and metabolism (LeRoith and Roberts, 2003). The activation of IGF1R via autophosphorylation after IGF1 and IGF2 binding, promotes cell proliferation and survival by the activation of downstream signalling molecules, such as phosphatidylinositol 3-kinase (PI3K), AKT, mTOR, S6 kinase and mitogen-activated protein kinase (MAPK) (Chitnis, et al., 2008) (Fig. 1). In the last decades, the concept that the IGF axis plays a key role in several steps of tumorigenesis, cancer growth and metastasis has been widely documented both on experimental models and population studies (Pollak, 2008; Samani et al., 2007; Seccareccia and Brodt, 2012). The aberration of the IGF system, even if the molecular mechanisms behind it are still not well clarified, has been described in many kinds of tumours, and several lines of evidence have been provided in support of IGF1R as a molecular target in cancer treatment (Gualberto and Pollak, 2009). Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumor of the gastrointestinal tract, commonly characterized in most cases by KIT and PDGFRA gain mutations. Beyond to the well recognized KIT and PDGFRA gain mutations, in the last years other molecular aberrations have been investigated, especially in that Review Insulin-like Growth Factor (IGF) system and gastrointestinal stromal tumours (GIST): present and future Margherita Nannini 1 , Guido Biasco 1,2 , Annalisa Astolfi 2 , Milena Urbini 2 and Maria A. Pantaleo 1,2 1 Department of Specialized, Experimental and Diagnostic Medicine, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy and 2 “Giorgio Prodi” Cancer Research Center, University of Bologna, Bologna, Italy Histol Histopathol (2014) 29: 167-175 Offprint requests to: Margherita Nannini, University of Bologna, Department of Hematology and Oncological Sciences "L.A.Seragnoli", S. Orsola-Malpighi Hospital, Via Massarenti 9, 40138 Bologna, Italy. e- mail: maggie.nannini@gmail.com http://www.hh.um.es Histology and Histopathology Cellular and Molecular Biology