New version of tumor-suppressor linked to progression of childhood cancer

Researchers have discovered an unexpected role as a tumor promoter for a molecule that was previously thought to function exclusively as a cancer suppressor in neuroblastoma (NB), a highly aggressive and deadly childhood cancer. The study, published in the October issue of Cancer Cell, reveals new evidence about what stimulates progression of neuroblastoma and may provide a likely target for new anti-cancer therapies.

Neurotrophin tyrosine kinase receptor type I (TrkA) responds to nerve growth factor and plays a key role in the development of the nervous system. Mutated TrkA has been associated with many human cancers, including colon, thyroid and prostate cancers. However, previous studies have suggested that TrkA acts as a tumor-suppressor in NB. Dr. Andrew R. Mackay and colleagues from the University of L’Aquila in Italy found a previously undiscovered variant of TrkA, called TrkIII, which exhibits oncogenic properties in human NB cells. TrkIII levels are elevated in advanced stage NB tumors, suggesting that the molecule may play a role in cancer progression. The researchers found that the level of TrkIII resulting from altered splicing of TrkA transcripts is controlled in part by hypoxia, a condition where cells are deprived of oxygen that is known to contribute to cancer progression. The researchers found that TrkIII stimulated advancement of NB, in part, by interfering with the normal anti-oncogenic function of TrkA.

The researchers conclude that formation of TrkIII represents a tumor-promoting switch in NB. Preventing generation of TrkIII may serve to inhibit NB progression. “A potential mechanism for regulating NB progression based on alternative TrkAIII splicing rather than genetic TrkA abnormality would theoretically permit reversal by re-establishing regular TrkA (I/II) splicing, which would represent a potential therapeutic goal,” explains Dr. Mackay.

Antonella Tacconelli, Antonietta R. Farina, Lucia Cappabianca, Giuseppina DeSantis, Alessandra Tessitore, Antonella Vetuschi,1 Roberta Sferra, Nadia Rucci, Beatrice Argenti, Isabella Screpanti, Alberto Gulino, and Andrew R. Mackay: “TrkA alternative splicing: A regulated tumor-promoting switch in human neuroblastoma”