Anaplastic lymphoma kinase proteins in growth control and cancer

Abstract

The normal functions of full-length anaplastic lymphoma kinase (ALK) remain to be completely elucidated. Although considered to be important in neural development, recent studies in Drosophila also highlight a role for ALK in gut muscle differentiation. Indeed, the Drosophila model offers a future arena for the study of ALK, its ligands and signalling cascades. The discovery of activated fusion forms of the ALK tyrosine kinase in anaplastic large cell lymphoma (ALCL) has dramatically improved our understanding of the pathogenesis of these lymphomas and enhanced the pathological diagnosis of this subtype of non-Hodgkin's lymphoma (NHL). Likewise, the realisation that a high percentage of inflammatory myofibroblastic tumours express activated-ALK fusion proteins has clarified the causation of these mesenchymal neoplasms and provided for their easier discrimination from other mesenchymal-derived inflammatory myofibroblastic tumour (IMT) mimics. Recent reports of ALK expression in a range of carcinoma-derived cell lines together with its apparent role as a receptor for PTN and MK, both of which have been implicated in tumourigenesis, raise the possibility that ALK-mediated signalling could play a role in the development and/or progression of a number of common solid tumours. The therapeutic targeting of ALK may prove to have efficacy in the treatment of many of these neoplasms.

Anaplastic lymphoma kinase is expressed in different subtypes of human breast cancer

“…In samples from patients with Paget's disease of the breast, ALK is expressed in very high levels in the cytoplasm and in nuclei of stromal fibroblasts and in the inflammatory cells, whereas in the epithelial cells ALK is localized in the cytoplasm ( Figure 2H). These extraordinary differences in the patterns of expression of ALK in breast cancer has been previously described in studies of the different ALK fusion oncogenic proteins that characteristically are observed in ALCLs [24] and differ very significantly from normal breast tissues.…”

Exon Array Profiling Detects EML4-ALK Fusion in Breast, Colorectal, and Non–Small Cell Lung Cancers

“…Translocations linking ALK to multiple fusion partners were subsequently identified in ALCL as well as in other malignancies, including neuroblastomas and myofibroblastic tumors (11). A novel gene fusion of ALK and the echinoderm microtubule-associated protein-like 4 (EML4) was recently identified in non-small cell lung cancer (NSCLC; ref.…”

Functional validation of the anaplastic lymphoma kinase signature identifies CEBPB and Bcl2A1 as critical target genes

“…A discrete subset of ALCLs is characterized by specific chromosome translocations, in which the anaplastic lymphoma kinase (ALK) gene, on chromosome 2, is fused to several partners, most frequently to the nucleophosmin (NPM) gene (2,3). The presence of ALK fusions in inflammatory myofibroblastic tumors as well as lymphoma implies that ALK is involved in oncogenesis of both nonhematopoietic and hematopoietic tumors (4). Moreover, the deregulated expression of the ALK receptor has been documented in a subset of nonlymphoid tumors, including sarcomas, neuroblastomas, and gliomas (5-7).…”

“…However, the precise mechanisms by which NPM-ALK mediates cellular transformation and its requirements for tumor growth and survival are still unclear. Activated ALK chimeras bind multiple adaptor proteins capable of firing different pathways regulating cell proliferation, survival, and transformation (4,13,14). The known adaptors include Grb2, Shc, IRS-1, phospholipase Cγ (PLC-γ) PI3K, and Jak3, which activate numerous downstream molecules, including cyclin D, ERK1/2, STAT, and AKT (3,(14)(15)(16).…”