Research Papers:

Tumor-initiating cell frequency is relevant for glioblastoma aggressiveness

Cristina Richichi, Daniela Osti, Massimiliano Del Bene, Lorenzo Fornasari, Monica Patanè, Bianca Pollo, Francesco DiMeco and Giuliana Pelicci _

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Oncotarget. 2016; 7:71491-71503. https://doi.org/10.18632/oncotarget.11600

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Cristina Richichi1, Daniela Osti1, Massimiliano Del Bene2, Lorenzo Fornasari1, Monica Patanè3, Bianca Pollo3, Francesco DiMeco2,4, Giuliana Pelicci1,5

1Department of Experimental Oncology, European Institute of Oncology, 20139, Milan, Italy

2Department of Neurosurgery, IRCCS Foundation Neurological Institute “C. Besta”, 20133, Milan, Italy

3Department of Neuropathology, IRCCS Foundation Neurological Institute “C. Besta”, 20133, Milan, Italy

4Department of Neurosurgery, Johns Hopkins University, Baltimore, MD 21218, USA

5Department of Translational Medicine, Piemonte Orientale University “Amedeo Avogadro”, 28100 Novara, Italy

Correspondence to:

Giuliana Pelicci, email: [email protected]

Keywords: glioblastoma, tumor-initiating cell frequency, neurosphere, limiting dilution assay, tumorigenicity

Received: March 03, 2016    Accepted: August 13, 2016    Published: August 25, 2016


Glioblastoma (GBM) is maintained by a small subpopulation of tumor-initiating cells (TICs). The arduous assessment of TIC frequencies challenges the prognostic role of TICs in predicting the clinical outcome in GBM patients. We estimated the TIC frequency in human GBM injecting intracerebrally in mice dissociated cells without any passage in culture.

All GBMs contained rare TICsand were tumorigenic in vivo but only 54% of them grew in vitro as neurospheres. We demonstrated that neurosphere formation in vitro did not foretell tumorigenic ability in vivo and frequencies calculated in vitro overestimated the TIC content.

Our findings assert the pathological significance of GBM TICs. TIC number correlated positively with tumor incidence and inversely with survival of tumor-bearing mice. Stratification of GBM patients according to TIC content revealed that patients with low TIC frequency experienced a trend towards a longer progression free survival. The expression of either putative stem-cell markers or markers associated with different GBM molecular subtypes did not associate with either TIC content or neurosphere formation underlying the limitations of TIC identification based on the expression of some putative stem cell-markers.

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