Involvement of midkine in neuroblastoma tumourigenesis



Midkine is highly expressed in various cancers, including neuroblastoma, one of the most malignant paediatric solid tumours known. Also, it has been shown to be useful as a tumour marker, a prognosis factor and a target of molecular therapy. Several molecular tools (e.g. siRNA, antibodies and RNA aptamer) have been used to establish a midkine-targeted therapy. The involvement of midkine in tumourigenesis has been demonstrated in vivo in a mouse neuroblastoma model, where targeting it with an RNA aptamer was shown to be an effective treatment for xenografted tumours. Chemoresistance is one of the notable phenotypes regulated by midkine in various cancer cell types. In pancreatic tumours and glioma cells, midkine is expressed in chemoresistant cells and is involved in the survival of these cells in the presence of anticancer drugs. In contrast to these tumours, midkine was found to be expressed in every neuroblastoma cell line tested and the knockdown of midkine alone was sufficient to suppress their growth. These results indicate that neuroblastoma cells are highly dependent on midkine and that a midkine-targeted therapy could exert a significant effect in these cells. However, to achieve a midkine-targeted therapy for high-risk neuroblastoma patients, the further refinement of the RNA aptamer or antibody as tools and the elucidation of midkine signalling are immediate issues that need to be resolved. Regarding the latter, although it has been shown that Notch2 functions as a receptor in neuroblastoma cells, it is likely that other receptors (e.g. anaplastic lymphoma kinase) are also involved in midkine signalling.

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