Alternative TrkAIII splicing: a potential regulated tumor-promoting switch and therapeutic target in neuroblastoma.
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.
Tacconelli
Antonella
A
University of L'Aquila, Department of Experimental Medicine, Via Vetoio, Coppito 2, 67100 L'Aquila, Italy.
Farina
Antonietta R
AR
Cappabianca
Lucia
L
Gulino
Alberto
A
Mackay
Andrew R
AR
D017398:Alternative Splicing / Q000235:genetics*; D000818:Animals; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009447:Neuroblastoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020917:Receptor, trkA / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction
D020917:Receptor, trkA