CD133 expression is associated with poor outcome in neuroblastoma via chemoresistance mediated by the AKT pathway

Aims: Neuroblastoma is a frequent childhood cancer with a heterogeneous prognosis. CD133 expression is an independent prognostic marker for a low survival rate in several cancers. The aim of this study was to determine the prognostic value of CD133 expression in a large cohort of neuroblastoma cases, to define the chemoresistance of neuroblastoma cells expressing CD133, and to determine whether this chemoresistance is regulated by activation of the AKT pathway. Methods and results: Two hundred and eighty samples of neuroblastoma were screened for CD133 expression. The sensitivity of purified CD133+ neuroblastoma cells isolated from two human cell lines to doxorubicin, vincristine and cisplatin, as single agents or in combination with LY294002, an AKT inhibitor, was evaluated invitro. CD133 expression was found in 100 of 280 tumours. There was a significant association between CD133 expression and the following poor prognosis covariates: age, International Neuroblastoma Staging System stage, MYCN amplification, and phospho-AKT (pAKT) expression. Patients with CD133- tumours had significantly better 3-year event-free and overall survival than patients with CD133+ tumours. In a multivariate model, CD133 expression was independently associated with decreased overall survival. CD133 ^high neuroblastoma cells were significantly resistant to chemotherapy as compared with CD133 ^low cells. Treatment of unsorted neuroblastoma cells with the three anticancer drugs significantly enriched the CD133+ subpopulation. CD133 ^high cells expressed significantly higher levels of pAKT than CD133 ^low cells. LY294002 treatment abolished the preferential survival of CD133 ^high cells. Conclusions: CD133 is associated with in-vitro resistance to chemotherapy involving activation of the AKT pathway.