Glioblastoma Stem Cells as a New Therapeutic Target for Glioblastoma

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Glioblastoma stem cells may represent a potential novel therapeutic target for glioblastoma, a form of brain cancer, according to a recent review.

Glioblastoma is one of the deadliest types of cancer. Currently, the most effective treatments against the bulk tumor in patients with glioblastoma are radiation and chemotherapy, but tumor recurrence attributed to glioma stem cell resistance continues to occur. Therefore, therapies that directly target glioma stem cells may result in durable responses. Possible targets within glioblastoma stem cells include epidermal growth factor (EGFR), VEGF receptors, Sonic hedgehog, STAT3, mTOR, microRNA, and many more.

Various studies have evaluated anti-stem cell therapies for the treatment of glioblastoma. One study assessing neural stem cells (NSCs) loaded with CRA-Survivin-pk7 given prior to chemoradiotherapy was more effective than combination therapy alone, suggesting that adenovirus infection is a powerful radiosensitizer in patients with glioblastoma receiving radiation and temozolomide. Another cancer stem cell-targeted study showed that cetuximab, a monoclonal antibody that targets EGFR, may be efficacious in glioblastoma tumors.

Combination treatment strategies may hold the greatest potential. Stem cells combined with conventional treatment may ultimately improve prognosis in patients with glioblastoma and glioblastoma stem cells from a patient’s own autologous stem cells in combination with suicidal gene therapies may also be a possibly effective approach.

Clinical Medicine Insights: Oncology
Clinical Medicine Insights: Oncology

ABSTRACT: Primary and secondary glioblastomas (GBMs) are two distinct diseases. The genetic and epigenetic background of these tumors is highly variable. The treatment procedure for these tumors is often unsuccessful because of the cellular heterogeneity and intrinsic ability of the tumor cells to invade healthy tissues. The fatal outcome of these tumors promotes researchers to find out new markers associated with the prognosis and treatment planning. In this communication, the role of glioblastoma stem cells in tumor progression and the malignant behavior of GBMs are summarized with attention to the signaling pathways and molecular regulators that are involved in maintaining the glioblastoma stem cell phenotype. A better understanding of these stem cell-like cells is necessary for designing new effective treatments and developing novel molecular strategies to target glioblastoma stem cells. We discuss hypoxia as a new therapeutic target for GBM. We focus on the inhibition of signaling pathways, which are associated with the hypoxia-mediated maintenance of glioblastoma stem cells, and the knockdown of hypoxia-inducible factors, which could be identified as attractive molecular target approaches for GBM therapeutics.

KEYWORDS: stem cell, glioblastoma stem cell, therapy, hypoxia, mutation  

CITATION: Kalkan R. Glioblastoma Stem Cells as a New Therapeutic Target for Glioblastoma. Clinical Medicine Insights: Oncology 2015:9 95–103 doi: 10.4137/CMO.S30271.

TYPE: Review

RECEIVED: June 07, 2015. RESUBMITTED: July 13, 2015. ACCEPTED FOR PUBLICATION: July 14, 2015.

ACADEMIC EDITOR: William C. S. Cho, Editor in Chief

PEER REVIEW: Four peer reviewers contributed to the peer review report. Reviewers' reports totaled 592 words, excluding any confidential comments to the academic editor.

FUNDING: Author discloses no funding sources.

COMPETING INTERESTS: Author discloses no potential conflicts of interest.


COPYRIGHT: © the authors, publisher and licensee Libertas Academica Limited. This is an open-access article distributed under the terms of the Creative Commons CC-BY-NC 3.0 License. 


Cancer stem cells, also known as tumor-initiating cells or tumor-propagating cells,1,2 have the ability to self-renew and differentiate into various cell types.3 These cells also show stem cell properties that include asymmetric cell division, infinite growth, and multipotency.4 Cancer stem cells have been iden­tified in various tumor types, such as prostate tumors, pan­creatic adenocarcinomas, colon carcinomas, hepatocellular carcinomas, melanoma, lung and breast cancers, osteosarco­mas, and brain tumors.5

In 2002 the stem cell properties of human cortical glial tumors were discovered and isolated precursor cells that are capable of forming neurosphere in vitro.4 Glioblastomas (GBMs) are the most common and lethal brain tumors. The current standard therapies include tumor resection, adjuvant chemotherapy, and chemoradiotherapy.1,6 GBMs express multipotent neural stem cell (NSC)-like cells that also contain neurons, astrocytes, and oligodendrocytes within the tumor mass.6 Cancer stem cells in malignant gliomas were called glioblastoma stem cells (GSCs). These cells have the potential to differentiate into astrocytes, oligodendrocytes, and neurons. The characteristics of glioblastoma cancer stem cells include self-renewal,6 pluripotency, neurosphere formation,5 proliferation, angiogenesis, invasion, modulation of immune response,6 marker expression, multilineage differentiation, and high motility (Table 1).7,8

Niches are important for self-renewal and undifferentiated state of normal stem cells. In this regard, GSCs were located in a perivascular niche in brain tumors that recapitulates a relationship between normal neural stem/progenitors and the vas­culature.1 After DNA damage, normal stem cells could assume a quiescent state and stop proliferating. However, glioma stem cells express various proteins that promote the survival of cells following cancer treatment procedures, which include the major drug resistance proteins, such as MGMT (O-6-methylguanine-DNA methyltransferase), and antiapoptotic genes, such as FLIP (FLICE-like inhibitory protein), BCL-2 (B-Cell CLL/Lymphoma 2), BCL-XL (B-cell lymphoma-extra large), and cIAP1 (cellular inhibitor of apoptosis protein-1).7  

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