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CANCER STEM CELLS

Cell Renewing in Neuroblastoma: Electrophysiological and Immunocytochemical Characterization of Stem Cells and Derivatives

^a Departments of Experimental Pathology and Oncology and
^b Human Anatomy, Histology and Legal Medicine, University of Florence, Florence, Italy;
^c Department of Biotechnology and Biosciences, University of Milan-Bicocca, Milan, Italy

Key Words. Neuroblastoma stem cells • Ion channels • Electrophysiological cluster of differentiation

Correspondence: Massimo Olivotto, M.D., Dipartimento di Patologia e Oncologia Sperimentali, Viale G.B. Morgagni 50, 50134 Firenze, Italy. Telephone: 39-055-4598203; Fax: 39-055-4598900; e-mail: olivotto{at}unifi.it

We explored the stem cell compartment of the SH-SY5Y neuroblastoma (NB) clone and its development by a novel approach, integrating clonal and immunocytochemical investigations with patch-clamp measurements of ion currents simultaneously expressed on single cells. The currents selected were the triad I_HERG, I_KDR, I_Na, normally expressed at varying mutual ratios during development of neural crest stem cells, from which NB derives upon neoplastic transformation. These ratios could be used as electrophysiological clusters of differentiation (ECDs), identifying otherwise indistinguishable stages in maturation. Subcloning procedures allowed the isolation of highly clonogenic substrate-adherent (S-type) cells that proved to be p75- and nestinpositive and were characterized by a nude electrophysiological profile (ECDS₀). These cells expressed negligible levels of the triad and manifested the capacity of generating the two following lineages: first, a terminally differentiating, smooth muscular lineage, positive for calponin and smooth muscle actin, whose electrophysiological profile is characterized by a progressive diminution of I_HERG, the increase of I_KDR and I_Na, and the acquisition of I_KIR (ECDS₂); second, a neuronal abortive pathway (NF-68 positive), characterized by a variable expression of I_HERG and I_KDR and a low expression of I_Na (ECDN_S). This population manifested a vigorous amplification, monopolizing the stem cell compartment at the expense of the smooth muscular lineage to such an extent that neuronal-like (N-type) cells must be continuously removed if the latter are to develop.

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