Abstract
Glioblastomas (GBM) may contain a variable proportion of active cancer stem cells (CSCs) capable of self-renewal, of aggregating into CD133+ neurospheres, and to develop intracranial tumors that phenocopy the original ones. We hypothesized that nucleostemin may contribute to cancer stem cell biology as these cells share characteristics with normal stem cells. Here we report that nucleostemin is expressed in GBM-CSCs isolated from patient samples, and that its expression, conversely to what it has been described for ordinary stem cells, does not disappear when cells are differentiated. The significance of nucleostemin expression in CSCs was addressed by targeting the corresponding mRNA using lentivirally transduced short hairpin RNA (shRNA). In doing so, we found an off-target nucleostemin RNAi (shRNA22) that abolishes proliferation and induces apoptosis in GBM-CSCs. Furthermore, in the presence of shRNA22, GBM-CSCs failed to form neurospheres in vitro or grow on soft agar. When these cells are xenotransplanted into the brains of nude rats, tumor development is significantly delayed. Attempts were made to identify the primary target/s of shRNA22, suggesting a transcription factor involved in one of the MAP-kinases signaling-pathways or multiple targets. The use of this shRNA may contribute to develop new therapeutic approaches for this incurable type of brain tumor.
Highlights
Glioblastoma multiforme is one of the most malignant and common of all astrocytic tumors [1]
Cells with stem-like properties were initially identified in acute myeloid leukaemia [4], and at present their existence has been confirmed in breast cancer [5], medulloblastoma and glioblastoma [6], prostate cancer [7], melanoma [8], ovarian cancer [9], head and neck squamous carcinomas [10], colon cancer [11], pancreatic cancer [12] and lung cancer [13], among others
Two cultures enriched for cancer stem cells were derived from human brain tumor specimens
Summary
Glioblastoma multiforme is one of the most malignant and common of all astrocytic tumors [1]. The cancer stem cell hypothesis suggests that tumors are organized in a hierarchy with a subpopulation of CSCs responsible for tumor progression, maintenance, and recurrence [3]. Relapses normally follow treatment, probably because CSCs are highly infiltrative, selectively resistant to radiotherapies, chemotherapies [14,15,16], immunotherapies [17], and promote angiogenic activity. Chemo- and radio- therapies may prime brain tumor CSCs to enhance their stem-cell-like characteristics [18]. This population of CSCs is highly tumorigenic and phenocopy the original tumor in rodent xenograft models [19,20]. Understanding the basic biology of cancer stem cells is a key feature before moving into putative treatments to eliminate them
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