1. ¹Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy
2. ²Institutes of Neurosurgery, Catholic University of Rome, Rome, Italy
3. ³Pathological Anatomy, Catholic University of Rome, Rome, Italy
4. ⁴Mediterranean Institute of Oncology, Catania, Italy

Correspondence: R De Maria, Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Viale Regina Elena 299, Rome 00161, Italy. Tel: +39 064 990 3121; Fax: +39 064 990 3683; E-mail: demaria@iss.it

⁵These authors contributed equally to the study.

Received 31 January 2008; Revised 4 April 2008; Accepted 8 April 2008; Published online 23 May 2008.

Abstract

Glioblastoma multiforme is a severe form of cancer most likely arising from the transformation of stem or progenitor cells resident in the brain. Although the tumorigenic population in glioblastoma is defined as composed by cancer stem cells (CSCs), the cellular target of the transformation hit remains to be identified. Glioma stem cells (SCs) are thought to have a differentiation potential restricted to the neural lineage. However, using orthotopic versus heterotopic xenograft models and in vitro differentiation assays, we found that a subset of glioblastomas contained CSCs with both neural and mesenchymal potential. Subcutaneous injection of CSCs or single CSC clones from two of seven patients produced tumor xenografts containing osteo-chondrogenic areas in the context of glioblastoma-like tumor lesions. Moreover, CSC clones from four of seven cases generated both neural and chondrogenic cells in vitro. Interestingly, mesenchymal differentiation of the tumor xenografts was associated with reduction of both growth rate and mitotic index. These findings suggest that in a subclass of glioblastomas the tumorigenic hit occurs on a multipotent stem cell, which may reveal its plasticity under specific environmental stimuli. The discovery of such biological properties might provide considerable information to the development of new therapeutic strategies aimed at forcing glioblastoma stem cell differentiation.