E-GEOD-44537 - Transient treatment with epigenetic modifiers yields stable neuroblastoma stem cells resembling aggressive large-cell neuroblastomas
Released on 2 April 2013, last updated on 2 June 2014
Cancer stem cells (CSCs) are plastic in nature, a characteristic that hampers cancer therapeutics. Neuroblastoma (NB) is a pediatric tumor of neural crest origin, and half of the cases are highly aggressive. By treating NB cell lines (SKNAS, SKNBE(2)C, CHP134, SY5Y) with epigenetic modifiers for a short time followed by sphere-forming culture conditions, we have established stem cell-like NB cells that are phenotypically stable for over a year. These cells are characterized by their high expression of stemness factors, stem cell markers, and open chromatin structure. We referred to these cells as induced CSC (iCSC). SKNAS iCSC and SKNBE(2)C iCSC clones (as few as 100 cells) injected subcutaneously into SCID/Beige mice formed tumors, and in one case, SKNBE(2)C iCSC metastasized to the adrenal gland, suggesting their increased metastatic potential. SKNAS iCSC xenografts showed the histologic appearance of totally undifferentiated “large-cell” NBs (LCNs), the most aggressive and deadly form of NB in humans. Immunohistochemical analyses showed that SKNAS iCSC xenografts expressed high levels of the stem cell marker CXCR4, while the SKNAS monolayer cell xenografts did not. The patterns of CXCR4 and MYC expression in SKNAS iCSC xenografts resembled those in the LCNs. The xenografts established from the NB iCSCs shared two common features: the LCN phenotype and high-level MYC/MYCN expression. These observations suggest that NB cells with large and vesicular nuclei, representing their open chromatin structure, are indicative of stem cell-like tumor cells, and that epigenetic changes may have contributed to the development of these most malignant NB cells. Gene expression profiles of SKNAS monolayer culture, sphere culture and iCSC culture were comparatively analyzed to examine the stem cell phenotype of each culture condition.
transcription profiling by array
Eric Rappaport <email@example.com>, Autumn M Fox, Eric F Rappaport, Hiroyuki Shimada, Joshua Jacobs, Naohiko Ikegaki, Paul L Regan, Sakeenah L Hicks, Xao X Tang
Transient treatment with epigenetic modifiers yields stable neuroblastoma stem cells resembling aggressive large-cell neuroblastomas. Ikegaki N, Shimada H, Fox AM, Regan PL, Jacobs JR, Hicks SL, Rappaport EF, Tang XX. , Europe PMC 23479628