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Essential gene pathways for glioblastoma stem cells: clinical implications for prevention of tumor recurrence.

Yamada K, Tso J, Ye F, Choe J, Liu Y, Liau LM, Tso CL - Cancers (Basel) (2011)

Bottom Line: In contrast to the hyperproliferative and hyperangiogenic phenotype of glioblastoma tumors, GSC possess neuroectodermal properties and express genes associated with neural stem cells, radial glial cells, and neural crest cells, as well as portray a migratory, quiescent, and undifferentiated phenotype.To prevent tumor recurrence, a strategy targeting essential gene pathways of GSC must be identified and incorporated into the standard treatment regimen.Identifying intrinsic and extrinsic cues by which GSC maintain stemness properties and sustain both tumorigenesis and anti-apoptotic features may provide new insights into potentially curative strategies for treating brain cancers.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery/Surgical Oncology, David Geffen School of Medicine, University of California Los Angeles, 13-260 Factor building, 10833 Le Conte Avenue, Los Angeles, California 90095, USA. ctso@mednet.ucla.edu.

ABSTRACT
Glioblastoma (World Health Organization/WHO grade IV) is the most common and most aggressive adult glial tumor. Patients with glioblastoma, despite being treated with gross total resection and post-operative radiation/chemotherapy, will almost always develop tumor recurrence. Glioblastoma stem cells (GSC), a minor subpopulation within the tumor mass, have been recently characterized as tumor-initiating cells and hypothesized to be responsible for post-treatment recurrence because of their enhanced radio-/chemo-resistant phenotype and ability to reconstitute tumors in mouse brains. Genome-wide expression profile analysis uncovered molecular properties of GSC distinct from their differentiated, proliferative progeny that comprise the majority of the tumor mass. In contrast to the hyperproliferative and hyperangiogenic phenotype of glioblastoma tumors, GSC possess neuroectodermal properties and express genes associated with neural stem cells, radial glial cells, and neural crest cells, as well as portray a migratory, quiescent, and undifferentiated phenotype. Thus, cell cycle-targeted radio-chemotherapy, which aims to kill fast-growing tumor cells, may not completely eliminate glioblastoma tumors. To prevent tumor recurrence, a strategy targeting essential gene pathways of GSC must be identified and incorporated into the standard treatment regimen. Identifying intrinsic and extrinsic cues by which GSC maintain stemness properties and sustain both tumorigenesis and anti-apoptotic features may provide new insights into potentially curative strategies for treating brain cancers.

No MeSH data available.


Related in: MedlinePlus

A theoretical model of a growing, treatment-resistant glioblastoma tumor. Glioblastoma stem cells (GSC) use both symmetric and asymmetric division to achieve sustained self-renewal and proliferative differentiation to initiate and maintain a tumor. GSC contain both quiescent and active cell types; the quiescent GSC are slow-cycling, poorly differentiated, radio-chemoresistant, and capable of unlimited self-renewal. The differentiated GSC progeny form a tumor containing a heterogeneous population in different states of differentiation, and are fast-growing, angiogenic, and radio-chemosensitive. GSC can escape from radio-chemotherapy and continually replenish tumor cells, leading to sustained tumorigenesis.
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f1-cancers-03-01975: A theoretical model of a growing, treatment-resistant glioblastoma tumor. Glioblastoma stem cells (GSC) use both symmetric and asymmetric division to achieve sustained self-renewal and proliferative differentiation to initiate and maintain a tumor. GSC contain both quiescent and active cell types; the quiescent GSC are slow-cycling, poorly differentiated, radio-chemoresistant, and capable of unlimited self-renewal. The differentiated GSC progeny form a tumor containing a heterogeneous population in different states of differentiation, and are fast-growing, angiogenic, and radio-chemosensitive. GSC can escape from radio-chemotherapy and continually replenish tumor cells, leading to sustained tumorigenesis.

Mentions: Cancer remains the third biggest killer worldwide. Although its survival rates are improving, it is still responsible for 13 percent of all deaths (according to the World Health Organization/WHO, 2010). To date, there is no approved effective treatment for relapsed advanced cancer. The mechanisms underlying persistent tumorigenesis and treatment resistance are still poorly understood, thereby making it difficult to develop an effective preclinical model for defining and predicting the efficacy of new treatments in patient trials. Among all human cancers, primary malignant brain tumors are one of the most challenging scientific and clinical problems in modern medicine. The tumor's location, its unique feature of high motility, and its protection by the blood brain barrier make certain therapies that are effective for some other cancers ineffective against brain tumors. In particular, glioblastoma remains virtually incurable despite extensive surgical excision and post-operative adjuvant radiotherapy and chemotherapy. The vast majority of glioblastoma patients will always develop tumor recurrence. The recent isolation and characterization of glioblastoma stem cells (GSC), a rare subpopulation within the tumor mass capable of unlimited self-renewal and sustenance of tumor growth, provides an excellent model to explain our inability to eradicate these tumors. Particularly, GSC isolated from recurrent glioblastoma tumors express molecular properties of a quiescent stem cell phenotype distinct from their proliferative progeny which make up the majority of tumor mass [1]. This suggests that they may evade standard cell cycle target-based therapy and continue seeding the new tumor, despite local treatment to the bulk tumor mass (Figure 1). Thus, identification of genes and pathways that confer the migratory ability, anti-apoptotic features, and tumorigenic capacity of GSC would be essential for a clear understanding of GSC and identifying potential targets in order to eradicate and prevent them from regenerating new tumors. This review summarizes signaling pathways that have been relatively well-studied in GSC and are essential for maintaining GSC stemness, tumorigenic potential, and anti-apoptotic features. Based on these reported signaling pathways relevant for maintaining GSC, we discuss and propose potential targeting strategies for future therapeutic developments in the treatment of brain cancer.


Essential gene pathways for glioblastoma stem cells: clinical implications for prevention of tumor recurrence.

Yamada K, Tso J, Ye F, Choe J, Liu Y, Liau LM, Tso CL - Cancers (Basel) (2011)

A theoretical model of a growing, treatment-resistant glioblastoma tumor. Glioblastoma stem cells (GSC) use both symmetric and asymmetric division to achieve sustained self-renewal and proliferative differentiation to initiate and maintain a tumor. GSC contain both quiescent and active cell types; the quiescent GSC are slow-cycling, poorly differentiated, radio-chemoresistant, and capable of unlimited self-renewal. The differentiated GSC progeny form a tumor containing a heterogeneous population in different states of differentiation, and are fast-growing, angiogenic, and radio-chemosensitive. GSC can escape from radio-chemotherapy and continually replenish tumor cells, leading to sustained tumorigenesis.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3757400&req=5

f1-cancers-03-01975: A theoretical model of a growing, treatment-resistant glioblastoma tumor. Glioblastoma stem cells (GSC) use both symmetric and asymmetric division to achieve sustained self-renewal and proliferative differentiation to initiate and maintain a tumor. GSC contain both quiescent and active cell types; the quiescent GSC are slow-cycling, poorly differentiated, radio-chemoresistant, and capable of unlimited self-renewal. The differentiated GSC progeny form a tumor containing a heterogeneous population in different states of differentiation, and are fast-growing, angiogenic, and radio-chemosensitive. GSC can escape from radio-chemotherapy and continually replenish tumor cells, leading to sustained tumorigenesis.
Mentions: Cancer remains the third biggest killer worldwide. Although its survival rates are improving, it is still responsible for 13 percent of all deaths (according to the World Health Organization/WHO, 2010). To date, there is no approved effective treatment for relapsed advanced cancer. The mechanisms underlying persistent tumorigenesis and treatment resistance are still poorly understood, thereby making it difficult to develop an effective preclinical model for defining and predicting the efficacy of new treatments in patient trials. Among all human cancers, primary malignant brain tumors are one of the most challenging scientific and clinical problems in modern medicine. The tumor's location, its unique feature of high motility, and its protection by the blood brain barrier make certain therapies that are effective for some other cancers ineffective against brain tumors. In particular, glioblastoma remains virtually incurable despite extensive surgical excision and post-operative adjuvant radiotherapy and chemotherapy. The vast majority of glioblastoma patients will always develop tumor recurrence. The recent isolation and characterization of glioblastoma stem cells (GSC), a rare subpopulation within the tumor mass capable of unlimited self-renewal and sustenance of tumor growth, provides an excellent model to explain our inability to eradicate these tumors. Particularly, GSC isolated from recurrent glioblastoma tumors express molecular properties of a quiescent stem cell phenotype distinct from their proliferative progeny which make up the majority of tumor mass [1]. This suggests that they may evade standard cell cycle target-based therapy and continue seeding the new tumor, despite local treatment to the bulk tumor mass (Figure 1). Thus, identification of genes and pathways that confer the migratory ability, anti-apoptotic features, and tumorigenic capacity of GSC would be essential for a clear understanding of GSC and identifying potential targets in order to eradicate and prevent them from regenerating new tumors. This review summarizes signaling pathways that have been relatively well-studied in GSC and are essential for maintaining GSC stemness, tumorigenic potential, and anti-apoptotic features. Based on these reported signaling pathways relevant for maintaining GSC, we discuss and propose potential targeting strategies for future therapeutic developments in the treatment of brain cancer.

Bottom Line: In contrast to the hyperproliferative and hyperangiogenic phenotype of glioblastoma tumors, GSC possess neuroectodermal properties and express genes associated with neural stem cells, radial glial cells, and neural crest cells, as well as portray a migratory, quiescent, and undifferentiated phenotype.To prevent tumor recurrence, a strategy targeting essential gene pathways of GSC must be identified and incorporated into the standard treatment regimen.Identifying intrinsic and extrinsic cues by which GSC maintain stemness properties and sustain both tumorigenesis and anti-apoptotic features may provide new insights into potentially curative strategies for treating brain cancers.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery/Surgical Oncology, David Geffen School of Medicine, University of California Los Angeles, 13-260 Factor building, 10833 Le Conte Avenue, Los Angeles, California 90095, USA. ctso@mednet.ucla.edu.

ABSTRACT
Glioblastoma (World Health Organization/WHO grade IV) is the most common and most aggressive adult glial tumor. Patients with glioblastoma, despite being treated with gross total resection and post-operative radiation/chemotherapy, will almost always develop tumor recurrence. Glioblastoma stem cells (GSC), a minor subpopulation within the tumor mass, have been recently characterized as tumor-initiating cells and hypothesized to be responsible for post-treatment recurrence because of their enhanced radio-/chemo-resistant phenotype and ability to reconstitute tumors in mouse brains. Genome-wide expression profile analysis uncovered molecular properties of GSC distinct from their differentiated, proliferative progeny that comprise the majority of the tumor mass. In contrast to the hyperproliferative and hyperangiogenic phenotype of glioblastoma tumors, GSC possess neuroectodermal properties and express genes associated with neural stem cells, radial glial cells, and neural crest cells, as well as portray a migratory, quiescent, and undifferentiated phenotype. Thus, cell cycle-targeted radio-chemotherapy, which aims to kill fast-growing tumor cells, may not completely eliminate glioblastoma tumors. To prevent tumor recurrence, a strategy targeting essential gene pathways of GSC must be identified and incorporated into the standard treatment regimen. Identifying intrinsic and extrinsic cues by which GSC maintain stemness properties and sustain both tumorigenesis and anti-apoptotic features may provide new insights into potentially curative strategies for treating brain cancers.

No MeSH data available.


Related in: MedlinePlus