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Brain cancer stem cells: current status on glioblastoma multiforme.

Facchino S, Abdouh M, Bernier G - Cancers (Basel) (2011)

Bottom Line: GBM tumors are highly heterogeneous.Hence, previously identified molecular pathways regulating neural stem cell biology were found to represent the cornerstone of GBM stem cell self-renewal mechanism.GBM tumors are also notorious for their resistance to radiation therapy.

View Article: PubMed Central - PubMed

Affiliation: Developmental Biology Laboratory, Hopital Maisonneuve-Rosemont, 5415 Boul. l'Assomption, Montreal, H1T 2M4, Canada. gbernier.hmr@ssss.gouv.qc.ca.

ABSTRACT
Glioblastoma multiforme (GBM), an aggressive brain tumor of astrocytic/neural stem cell origin, represents one of the most incurable cancers. GBM tumors are highly heterogeneous. However, most tumors contain a subpopulation of cells that display neural stem cell characteristics in vitro and that can generate a new brain tumor upon transplantation in mice. Hence, previously identified molecular pathways regulating neural stem cell biology were found to represent the cornerstone of GBM stem cell self-renewal mechanism. GBM tumors are also notorious for their resistance to radiation therapy. Notably, GBM "cancer stem cells" were also found to be responsible for this radioresistance. Herein, we will analyze the data supporting or not the cancer stem cell model in GBM, overview the current knowledge regarding GBM stem cell self-renewal and radioresistance molecular mechanisms, and discuss the potential therapeutic application of these findings.

No MeSH data available.


Related in: MedlinePlus

Oncogenic functions of BMI1 in Glioblastoma multiforme (GBM). BMI1 regulates multiple molecular pathways in order to maintain GBM cancer stem cells (CSCs) self-renewal capacity and promote tumor invasion. Previously identified BMI1 target genes are delineated by blue bars. Confirmed (orange bar) and potentially new target genes (purple bars) are also shown. Based on work from [70,145-147].
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f2-cancers-03-01777: Oncogenic functions of BMI1 in Glioblastoma multiforme (GBM). BMI1 regulates multiple molecular pathways in order to maintain GBM cancer stem cells (CSCs) self-renewal capacity and promote tumor invasion. Previously identified BMI1 target genes are delineated by blue bars. Confirmed (orange bar) and potentially new target genes (purple bars) are also shown. Based on work from [70,145-147].

Mentions: In a panel of 305 grade II, III and IV astrocytomas and oligodendrogliomas, BMI1 expression was detected in 302 tumors (99%) [90]. Work from the Van Lohuizen laboratory revealed that BMI1 is highly expressed in human GBM samples and that Bmi1 deficiency reduces the invasiveness of malignant mouse astrocytes carrying a mutation in the Ink4a/Arf locus [91]. Using INK4A/ARF- human GBM specimens, we showed that BMI1 is enriched in CD133+ cells and required to sustain their self-renewal through prevention of CD133+ cells apoptosis and/or differentiation into neurons and astrocytes [70]. Out of 21 NOD/SCID mice transplanted with 1 × 105 GBM cells, none developed brain tumors when BMI1 was inactivated. Gene expression profile analysis revealed that one-way BMI1 promotes GBM cell survival and growth is through transcriptional repression of tumor-suppressor genes (such as P18INK4C) that attempt to compensate for INK4A/ARF deletion and PI3K/AKT hyper-activity (Figure 2). The robust expression of BMI1 in nearly all GBM samples analyzed and the extreme sensitivity of GBM cells to BMI1 inactivation further suggests that GBM stem cells have acquired an oncogenic addiction over BMI1 activity. Oncogenic addiction distinguishes CSCs from normal stem cells and can be viewed as a survival mechanism to overcome mutations affecting cancer cells viability [92,93]. This situation may render GBM stem cells more sensitive to BMI1 inhibition than normal stem cells present in the brain, and thus could be exploited in a therapeutic context. Other pathways involved in stem cell biology and also critical for GBM stem cells self-renewal, such as Notch, Sonic Hedgehog, Bone Morphogenic Protein, STAT3 and SOX2, have also been described [57,94-97]. Interestingly, it was also reported that the C-MYC oncogene is preferentially expressed in CD133+ GBM cells and required for CSCs survival and brain tumor engraftment in NOD/SCID mice [98]. C-MYC is the molecular cornerstone establishing the similarity between embryonic stem cells and cancer cells, and c-myc is negatively regulated by p53 and Pten in a murine model of GBM [99,100]. The identification of specific inhibitors against these factors, especially those involved in oncogenic addiction, may open new avenues to directly target CSCs for the treatment of GBM while preserving normal stem cell populations.


Brain cancer stem cells: current status on glioblastoma multiforme.

Facchino S, Abdouh M, Bernier G - Cancers (Basel) (2011)

Oncogenic functions of BMI1 in Glioblastoma multiforme (GBM). BMI1 regulates multiple molecular pathways in order to maintain GBM cancer stem cells (CSCs) self-renewal capacity and promote tumor invasion. Previously identified BMI1 target genes are delineated by blue bars. Confirmed (orange bar) and potentially new target genes (purple bars) are also shown. Based on work from [70,145-147].
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3757390&req=5

f2-cancers-03-01777: Oncogenic functions of BMI1 in Glioblastoma multiforme (GBM). BMI1 regulates multiple molecular pathways in order to maintain GBM cancer stem cells (CSCs) self-renewal capacity and promote tumor invasion. Previously identified BMI1 target genes are delineated by blue bars. Confirmed (orange bar) and potentially new target genes (purple bars) are also shown. Based on work from [70,145-147].
Mentions: In a panel of 305 grade II, III and IV astrocytomas and oligodendrogliomas, BMI1 expression was detected in 302 tumors (99%) [90]. Work from the Van Lohuizen laboratory revealed that BMI1 is highly expressed in human GBM samples and that Bmi1 deficiency reduces the invasiveness of malignant mouse astrocytes carrying a mutation in the Ink4a/Arf locus [91]. Using INK4A/ARF- human GBM specimens, we showed that BMI1 is enriched in CD133+ cells and required to sustain their self-renewal through prevention of CD133+ cells apoptosis and/or differentiation into neurons and astrocytes [70]. Out of 21 NOD/SCID mice transplanted with 1 × 105 GBM cells, none developed brain tumors when BMI1 was inactivated. Gene expression profile analysis revealed that one-way BMI1 promotes GBM cell survival and growth is through transcriptional repression of tumor-suppressor genes (such as P18INK4C) that attempt to compensate for INK4A/ARF deletion and PI3K/AKT hyper-activity (Figure 2). The robust expression of BMI1 in nearly all GBM samples analyzed and the extreme sensitivity of GBM cells to BMI1 inactivation further suggests that GBM stem cells have acquired an oncogenic addiction over BMI1 activity. Oncogenic addiction distinguishes CSCs from normal stem cells and can be viewed as a survival mechanism to overcome mutations affecting cancer cells viability [92,93]. This situation may render GBM stem cells more sensitive to BMI1 inhibition than normal stem cells present in the brain, and thus could be exploited in a therapeutic context. Other pathways involved in stem cell biology and also critical for GBM stem cells self-renewal, such as Notch, Sonic Hedgehog, Bone Morphogenic Protein, STAT3 and SOX2, have also been described [57,94-97]. Interestingly, it was also reported that the C-MYC oncogene is preferentially expressed in CD133+ GBM cells and required for CSCs survival and brain tumor engraftment in NOD/SCID mice [98]. C-MYC is the molecular cornerstone establishing the similarity between embryonic stem cells and cancer cells, and c-myc is negatively regulated by p53 and Pten in a murine model of GBM [99,100]. The identification of specific inhibitors against these factors, especially those involved in oncogenic addiction, may open new avenues to directly target CSCs for the treatment of GBM while preserving normal stem cell populations.

Bottom Line: GBM tumors are highly heterogeneous.Hence, previously identified molecular pathways regulating neural stem cell biology were found to represent the cornerstone of GBM stem cell self-renewal mechanism.GBM tumors are also notorious for their resistance to radiation therapy.

View Article: PubMed Central - PubMed

Affiliation: Developmental Biology Laboratory, Hopital Maisonneuve-Rosemont, 5415 Boul. l'Assomption, Montreal, H1T 2M4, Canada. gbernier.hmr@ssss.gouv.qc.ca.

ABSTRACT
Glioblastoma multiforme (GBM), an aggressive brain tumor of astrocytic/neural stem cell origin, represents one of the most incurable cancers. GBM tumors are highly heterogeneous. However, most tumors contain a subpopulation of cells that display neural stem cell characteristics in vitro and that can generate a new brain tumor upon transplantation in mice. Hence, previously identified molecular pathways regulating neural stem cell biology were found to represent the cornerstone of GBM stem cell self-renewal mechanism. GBM tumors are also notorious for their resistance to radiation therapy. Notably, GBM "cancer stem cells" were also found to be responsible for this radioresistance. Herein, we will analyze the data supporting or not the cancer stem cell model in GBM, overview the current knowledge regarding GBM stem cell self-renewal and radioresistance molecular mechanisms, and discuss the potential therapeutic application of these findings.

No MeSH data available.


Related in: MedlinePlus