Cancer Letters
Volume 318, Issue 1 , Pages 26-33, 1 May 2012

DLK1, delta-like 1 homolog (Drosophila), regulates tumor cell differentiation in vivo

  • Asma Begum

      Affiliations

    • Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT 06510, USA
    • ,
  • Yuri Kim

      Affiliations

    • Department of Nutritional Science and Food Management, Ewha Womans University, Seoul 120-750, Republic of Korea
    • ,
  • Qun Lin

      Affiliations

    • Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT 06510, USA
    • ,
  • Zhong Yun

      Affiliations

    • Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT 06510, USA
    • Corresponding Author InformationCorresponding author. Address: Department of Therapeutic Radiology, Yale University School of Medicine, P.O. Box 208040, New Haven, CT 06520-8040, USA. Tel.: +1 203 737 2183; fax: +1 203 785 6309.

Received 4 August 2011; received in revised form 16 November 2011; accepted 25 November 2011. published online 29 December 2011.

Abstract 

The stem cell-like characteristics of tumor cells are not only essential for tumor development and malignant progression, but also significantly contribute to therapy resistance. However, it remains poorly understood how cancer cell differentiation or stemness is regulated in vivo. We investigated the role of the stem cell gene DLK1, or delta-like 1 homolog (Drosophila), in the regulation of cancer cell differentiation in vivo using neuroblastoma (NB) xenografts as a model. We found that loss-of-function mutants of DLK1 significantly enhanced NB cell differentiation in vivo likely by increasing the basal phosphorylation of MEK and ERK kinases, a mechanism that has been shown to facilitate neuronal differentiation. We also found that DLK1+ cells are preferentially located in hypoxic regions. These results clearly demonstrate that DLK1 plays an important role in the maintenance of undifferentiated, stem cell-like phenotypes of NB cells in vivo.

Keywords: Cancer stem cell, Differentiation, DLK1, Hypoxia, Neuroblastoma

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PII: S0304-3835(11)00733-6

doi:10.1016/j.canlet.2011.11.032

Cancer Letters
Volume 318, Issue 1 , Pages 26-33, 1 May 2012

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