Cimmino, Flora (2010) Discovery of new therapeutic targets in Neuroblastoma by means of proteomic approach and functional studies. [Tesi di dottorato] (Unpublished)

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Neuroblatoma (NB) is an embryonal tumor of the sympathetic nervous system which arises from the neural crest cells. This disease rappresents the most common extracranial tumor in infants, accounting for 8% to 10% of all childhood cancer and for approximately 15% of cancer deaths in children. NB is a heterogeneous tumor for which biology dictates clinical behaviour. It comprises cases with divergent outcome ranging from spontaneous differentiation to metastatic forms with poor prognosis. The deep knowledge of NB biology is imperative toward the development of novel therapy. The most favourable subset of NB (stage 4S) can spontaneously differentiate in neurons or regress to a benign tumour phenotype. Retinoic Acid (RA) is a known neural differentiation-inducing agent actually used in NB therapy. In order to get new insights in the molecular mechanism driving neuronal differentiation in vitro, two-Dimensional Differential In-Gel Electrophoresis (2D-DIGE) analyse was performed on the cytosolic and nuclear protein expression patterns of NB cells following RA treatment. The combination of a proteomic approach and sub-cellular fractionation of the proteome provides the identification of 33 differentially expressed proteins during RA treatment in NB. The identified proteins have important roles in a variety of pathways which may have role on NB development and in NB RA-induced differentiation. The results also strength the use of proteomics to discover new putative protein targets in cancer. Expression of Trk receptors is an important prognostic factor in NB. TrkB and its ligand BDNF (brain derived neurotrophin factor) are preferentially expressed in NB with poor prognosis, conferring invasive and metastatic potential to the tumor cells as well as enhancing therapy resistance. TrkA in contrast is high expressed in tumor with good outcome. Galectin-1 (Gal-1), a very promising cancer target, is involved in modulating cell proliferation, cell death and cell migration and was found to be up-regulated in patients with aggressive, relapsing NB. Gal-1 is a down-stream mediator of TrkB signalling, since its espression is increased in human SY5Y NB cells upon activation of ectopically expressed TrkB (SY5Y-TrkB), but not TrkA (SY5Y-TrkA). Functional studies here presented underlined the Gal-1 role to mediate invasion and migration in TrkB over-expressing NB cells, thus being activated by BDNF. This establishes Gal-1 as a potential therapeutic marker in high-risk TrkB-expressing NB.

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