part of 305 ISSN 1479-6694 10.2217/FON.13.184 © 2014 Future Medicine Ltd Future Oncol. (2014) 10(2), 305–321 ABSTRACT Since the discovery of ALK-positive anaplastic large-cell lymphoma in 1994 many other types of tumors showing ALK expression were disclosed. They form a heterogeneous group, including lung, renal and soft tissue tumors. The biological function of ALK, its role in carcinogenesis and impact exerted on the clinical outcome have been studied by many research groups. New drugs speciically dedicated for ALK inhibition, for example, crizotinib, have been synthesized and have become a viable treatment option for ALK-positive lung adenocarcinoma, and potentially for other ALK-positive cancers. This review summarizes the current state of knowledge concerning ALK-positive neoplasms, focusing on the clinical aspects of the subject. 1 Department of Pathomorphology, Medical University of Gdańsk, Mariana Smoluchowskiego 17, 80-214, Gdańsk, Poland 2 Department of Molecular Biology, University of Gdańsk, Gdańsk, Poland 3 Institute of Pathology, Comprehensive Cancer Center, University of Tübingen, Tübingen, Germany *Author for correspondence: biernat@gumed.edu.pl ALK-positive cancer: still a growing entity REVIEW Adam Gorczyński 1 , Monika Prełowska 2 , Patrick Adam 3 , Piotr Czapiewski 1 & Wojciech Biernat* 1 KEYWORDS • alkoma • anaplastic large-cell lymphoma • anaplastic lymphoma kinase • crizotinib • neuroblastoma • renal cell carcinoma ALK and its role in pathogenesis of anaplastic large-cell lymphoma (ALCL) was originally described in 1994 by Morris et al. [1]. Since then, it has been a subject of numerous clinical and laboratory studies, which proved that expression of ALK tyrosine kinase can have an impact on morphology, clinical presentation and pathogenesis of many types of cancers, including ALCL [1], non-small-cell lung cancer (NSCLC) [2], neuroblastoma [3], inflammatory myofibroblastic tumors [4] and, most recently, also renal carcinoma. A number of variants of fusion genes were discovered in the past two decades, some of which are used as targets for therapy using newly developed ALK inhibitors. ALK structure & function The ALK gene is located on the 2p23 human chromosome. It encodes a 1620-amino acid protein with a predicted final mass of approximately 200 kDa [5]. ALK is a receptor tyrosine kinase that belongs to the insulin receptor (IR) superfamily. IRs share the specific domains, such as an extracel- lular ligand-binding domain, a transmembrane domain and a cytoplasmic kinase catalytic region which activates the subsequent signaling pathway. ALK has been described as a large, single-chain membrane-spanning receptor tyrosine kinase. In humans the ALK gene is transiently expressed in the CNS. In mice, in situ hybridization studies have detected the murine Alk mRNA expression in multiple regions such as the thalamus, mid-brain and ganglia during the embryonal stage [6]. Thus, it has been suggested to exert an important role in the development of the CNS. Based on murine knockout experiments, Bilsland et al. identified the role of ALK in neurogenesis and cognitive processes. Loss of ALK expression increased the basal hippocampal progenitor proliferation and ALK knockout mice showed an anti- depressant profile. ALK was also suggested as a regulator in the frontal cortex and hippocampus dopaminergic signaling system [7]. For reprint orders, please contact: reprints@futuremedicine.com