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- Title
Intratumoral Hypoxic Gradient Drives Stem Cells Distribution and MGMT Expression in Glioblastoma.
- Authors
Pistoli, Francesca; Abbadi, Sara; Rampazzo, Elena; Persano, Luca; Puppa, Alessandro Della; Frasson, Chiara; Sarto, Eva; Scienza, Renato; D'Avella, Domenico; Basso, Giuseppe
- Abstract
Glioblustoma multiforme (GBM) are highly proliferative tumors currently treuted by surgical removal, followed by radiotherapy and chemotherapy, which are counteracted by intratumoral hypoxia. Here we exploited image guided surgery to sample multiple intratumoral areas to deline potential cellular heterogeneity in correlation to the oxygen tensiim gradient within the GBM mass. Our results indicate that more immature cells are localized in the inner core and in the intermediate layer of the tumor mass, whereas more committed cells, expressing gliat fibrillary acidic protein and β-III-tubulin, are distributed along the peripheral and neo-vascularized area, where Smad 1/5/8 and Stat3 result to be activated. Moreover, GBM stem cells, identified with the stem cell marker CD133, express high level of DNA repair protein O6-meth-ylguanine-DNA- methyitransferase (MGMT) known to be involved in chemotherapy resistance and highly expressed in the inner core of the tumor mass. Importantly, these cells and, particularly, CD133+ cells result to be resistant to temozolomide (TMZ), tbe most used oral alkylating agent for the treatment of GUM, which specifically causes apoptosis only in GBM cells derived from the peripheral layer of the tumor mass. These results indicate a correlation between the intratumoral hypoxic gradient, the tumor cell phenotype, and the tumor resistance to chemotherapy leading to a novel concentric model of tumor stem cell niche, which may be useful to define the real localization of the chemoresistant GBM tumor cells in order to design more effective treatment strategies.
- Subjects
CANCER cells; STEM cell treatment; BRAIN tumor treatment; RADIOTHERAPY; DRUG therapy; CEREBRAL anoxia; DNA; PROTEINS; CANCER treatment
- Publication
Stem Cells, 2010, Vol 28, Issue 5, p851
- ISSN
1066-5099
- Publication type
Article
- DOI
10.1002/stem.415