Abstract
Ewing sarcoma (ES) is a highly aggressive pediatric cancer that may arise from neuronal precursors. Neurotrophins stimulate neuronal devlopment and plasticity. Here, we found that neurotrophins nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), as well as their receptors (TrkA and TrkB, respectively) are expressed in ES tumors. Treatment with TrkA (GW-441756) or TrkB (Ana-12) selective inhibitors decreased ES cell proliferation, and the effect was increased when the two inhibitors were combined. ES cells treated with a pan-Trk inhibitor, K252a, showed changes in morphology, reduced levels of β-III tubulin, and decreased mRNA expression of NGF, BDNF, TrkA and TrkB. Furthermore, combining K252a with subeffective doses of cytotoxic chemotherapeutic drugs resulted in a decrease in ES cell proliferation and colony formation, even in chemoresistant cells. These results indicate that Trk inhibition may be an emerging approach for the treatment of ES.
Highlights
Tumors of the Ewing sarcoma (ES) family are aggressive childhood cancers [1]
We showed that the pan-tropomyosin receptor kinase (Trk) inhibitor K252a can change ES cell morphology, leading to decreased expression of nerve growth factor (NGF), TrkA, brain-derived neurotrophic factor (BDNF), and TrkB
K252a reduced the proliferation and survival of ES cells, and produced a synergistic effect when used in combination with chemotherapeutic agents at low doses, even in chemoresistant cells
Summary
Tumors of the Ewing sarcoma (ES) family are aggressive childhood cancers [1]. ES remains the second most common primary bone malignancy in the pediatric population, with an annual incidence of almost 3 cases per million people in the USA [2]. These tumors are characterized by highly aggressive, small round blue cells of the bone and soft tissue, genetically marked by gene fusions involving, most commonly, the EWS gene and a gene of the ETS family (primarily FLI-1) [1, 3]. Only about 10% of patients with ES survived [1]. Despite many attempts to intensify treatments, survival remains poor in these patients
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