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Alternative TrkAIII splicing: a potential regulated tumor-promoting switch and therapeutic target in neuroblastoma

    Antonella Tacconelli

    University of L'Aquila, Department of Experimental Medicine, Via Vetoio, Coppito 2, 67100 L'Aquila, Italy

    ,
    Antonietta R Farina

    University of L'Aquila, Department of Experimental Medicine, Via Vetoio, Coppito 2, 67100 L'Aquila, Italy

    ,
    Lucia Cappabianca

    University of L'Aquila, Department of Experimental Medicine, Via Vetoio, Coppito 2, 67100 L'Aquila, Italy

    ,
    Alberto Gulino

    University of Rome, Department of Experimental Medicine and Pathology, ‘La Sapienza’,Rome, Italy

    Neuromed Institute, 86077 Pozzilli, Italy

    &
    Andrew R Mackay

    † Author for correspondence

    University of L'Aquila, Department of Experimental Medicine, Via Vetoio, Coppito 2, 67100 L'Aquila, Italy.

    Published Online:https://doi.org/10.2217/14796694.1.5.689

    An association between elevated tyrosine kinase receptor (Trk)-A expression and better prognosis; the absence of mutation-activated TrkA oncogenes; the induction of apoptosis, growth arrest, morphological differentiation and inhibition of xenograft growth; and angiogenesis by TrkA gene transduction, provide the basis for the current concept of an exclusively tumor-suppressor role for TrkA in the aggressive pediatric tumor, neuroblastoma. This concept, however, has recently been challenged by the discovery of a novel hypoxia-regulated alternative TrkAIII splice variant, initial data for which suggest predominant expression in advanced-stage neuroblastoma. TrkAIII exhibits neuroblastoma xenograft tumor-promoting activity associated with the induction of a more angiogenic and stress-resistant neuroblastoma phenotype and antagonises nerve growth factor/TrkAI antioncogenic signaling. In this short review, the authors integrate this novel information into a modified concept that places alternative TrkA splicing as a potential pivotal regulator of neuroblastoma behavior and identifies the TrkAIII alternative splice variant as a potential biomarker of patient prognosis and novel therapeutic target.

    Papers of special note have been highlighted as either of interest (•) or of considerable interest (••) to readers.

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