Intratumoral hypoxic gradient drives stem cells distribution and MGMT expression in glioblastoma

Stem Cells. 2010 May;28(5):851-62. doi: 10.1002/stem.415.


Glioblastoma multiforme (GBM) are highly proliferative tumors currently treated 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 define potential cellular heterogeneity in correlation to the oxygen tension 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 glial fibrillary acidic protein and beta-III-tubulin, are distributed along the peripheral and neo-vascularized area, where Smad1/5/8 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-methylguanine-DNA-methyltransferase (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), the most used oral alkylating agent for the treatment of GBM, 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AC133 Antigen
  • Adult
  • Antigens, CD / metabolism
  • Brain Neoplasms / enzymology
  • Brain Neoplasms / metabolism*
  • Brain Neoplasms / pathology*
  • Cell Dedifferentiation / physiology
  • DNA Modification Methylases / biosynthesis*
  • DNA Modification Methylases / genetics
  • DNA Repair Enzymes / biosynthesis*
  • DNA Repair Enzymes / genetics
  • Glioblastoma / enzymology
  • Glioblastoma / metabolism*
  • Glioblastoma / pathology*
  • Glycoproteins / metabolism
  • Humans
  • Hypoxia / enzymology
  • Hypoxia / pathology*
  • Infant, Newborn
  • Magnetic Resonance Imaging
  • Middle Aged
  • Neoplastic Stem Cells / enzymology
  • Neoplastic Stem Cells / metabolism*
  • Neoplastic Stem Cells / pathology
  • Neurosurgical Procedures
  • Peptides / metabolism
  • Tumor Cells, Cultured
  • Tumor Suppressor Proteins / biosynthesis*
  • Tumor Suppressor Proteins / genetics


  • AC133 Antigen
  • Antigens, CD
  • Glycoproteins
  • PROM1 protein, human
  • Peptides
  • Tumor Suppressor Proteins
  • DNA Modification Methylases
  • MGMT protein, human
  • DNA Repair Enzymes