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Purging of the Neuroblastoma Stem Cell Compartment and Tumor Regression on Exposure to Hypoxia or Cytotoxic Treatment

¹ Department of Experimental Pathology and Oncology, University of Florence, Florence, Italy and ² Department of Biotechnology and Biosciences, University of Milan-Bicocca, Milan, Italy

Requests for reprints: Massimo Olivotto, Dipartimento di Patologia e Oncologia Sperimentali, Viale G.B. Morgagni, 50, 50134 Florence, Italy. Phone: 39-55-459-8203; Fax: 39-55-459-8900; E-mail: olivotto{at}unifi.it.

We worked out an experimental protocol able to purge the stem cell compartment of the SH-SY5Y neuroblastoma clone. This protocol was based on the prolonged treatment of the wild-type cell population with either hypoxia or the antiblastic etoposide. Cell fate was monitored by immunocytochemical and electrophysiologic (patch-clamp) techniques. Both treatments produced the progressive disappearance of neuronal type (N) cells (which constitute the bulk of the tumor), leaving space for a special category of epithelial-like substrate-adherent cells (S₀). The latter represent a minimal cell component of the untreated population and are endowed with immunocytochemical markers (p75, c-kit, and CD133) and the electrophysiologic "nude" profile, typical of the neural crest stem cells. S₀ cells displayed a highly clonogenic potency and a substantial plasticity, generating both the N component and an alternative subpopulation terminally committed to the fibromuscular lineage. Unlike the N component, this lineage was highly insensitive to the apoptotic activity of hypoxia and etoposide and developed only when the neuronal option was abolished. Under these conditions, the fibromuscular progeny of S₀ expanded and progressed up to the exhaustion of the staminal compartment and to the extinction of the tumor. When combined, hypoxia and etoposide cooperated in abolishing the N cell generation and promoting the conversion of the tumor described. This synergy might mirror a natural condition in the ischemic areas occurring in cancer. These results have relevant implications for the understanding of the documented tendency of neuroblastomas to regress from a malignant to a benign phenotype, either spontaneously or on antiblastic treatment. [Cancer Res 2007;67(6):2402–7]