Glioblastoma – Are Cancer Stem Cells The Ultimate Target?by Sara Adaes, PhD | October 19, 2015
A glioma is a type of tumor that arises from glial cells in the central nervous system. The yearly incidence of primary malignant brain tumors is around 5 or 6 in 100,000 people, of which about 80% are malignant gliomas. Although they may develop at any age, their peak incidence is in the fifth and sixth decades of life.
Glioblastoma, also known as glioblastoma multiforme or grade IV glioma, is the most common and most aggressive malignant primary brain tumor. It accounts for 52% of all brain tissue tumors and it is highly lethal: about 50% of the people diagnosed with glioblastoma die within one year, while 90% die within three years.
The clinical features of glioblastoma include headaches, focal neurologic deficits, confusion, memory loss, personality changes or seizures. Glioblastomas appear to be sporadic, with little genetic predisposition. There are some known risk factors that have been linked to glioblastoma development; these include environmental risk factors such as exposure to therapeutic ionizing radiation, pesticides, vinyl chloride (used to produce PVC), or work in petroleum refining or synthetic rubber industries.
Current treatment relies on maximal surgical removal, along with radiotherapy and chemotherapy. But the rate of recurrence and therapeutic resistance is extremely high and it remains an incurable disease.
Apart from the obvious difficulties associated with brain surgeries, why are glioblastomas so lethal and difficult to treat? The answer may lie on cancer stem cells.
Cancer stem cells
Organs with a high rate of cellular proliferation, such as the skin, contain at least two pools of stem cells: one quiescent, and another highly proliferative. Stem cells generate transient amplifying cells, which in turn differentiate into lineage-restricted cells, i.e., cells whose type is irreversibly determined. The central nervous system also contains its own pool of pluripotent cells; these neural stem and progenitor cells are capable of proliferation, self-renewal and differentiation.
What may be surprising is that tumors also contain a subset of cells with characteristics of stem cells – these cancer cells are able to self-renew and to differentiate into multiple cell types, originating all kinds of cells found in a tumor. They are therefore known as “cancer stem cells” and they can be a source of new tumor cells after tumor growth is therapeutically arrested.
Cancer stem cells were first isolated in the late 1990s. Since then, there has been an intensive search for these cells in many types of cancer. In the brain, tumor cells sharing the characteristics of neural stem and progenitor cells have been widely investigated. Many primary brain tumors have been shown to contain these self-renewing, tumor-inducing cells, including glioblastoma.
Cancer stem cells follow a similar pattern to regular stem cells – there is a relatively quiescent subset of cells that is responsible for sustaining long-term tumor growth through the production of transient populations of highly proliferative cells.
Brain cancer stem cells have been shown to contribute to tumor initiation and to resistance to chemotherapy and radiotherapy, greatly contributing also to disease progression and recurrence. For example, these cells have been shown to be able to contribute to therapeutic resistance by increasing the tumor cells’ ability to repair radiation-induced damage to their DNA. Cancer stem cells are hypothesized to persist in tumors as a distinct population and cause relapse and metastasis by giving rise to new tumors. They may initiate and maintain a tumor even after treatment.
Just as normal stem and progenitor cells participate in tissue development and repair, cancer stem cells also support the development and growth of tumors. They actively remodel and maintain the surrounding environment in such a way as to create the most favorable context for tumor growth.
Despite rarely metastasizing to other organs, a glioblastoma can widely invade the surrounding tissue in the brain, with a significant help from its stem-like cells. Besides promoting cell proliferation, glioma stem cells have also been shown to promote angiogenesis (the generation of new blood vessels) thus optimizing their environment for growth and survival.
These are tricky cells. And they are the key to the survival of many types of cancer, including the highly lethal glioblastoma. Understanding their molecular biology may therefore be the key to the development of effective therapies for glioblastoma and other brain cancers.
Alifieris C, & Trafalis DT (2015). Glioblastoma multiforme: Pathogenesis and treatment. Pharmacology & therapeutics, 152, 63-82 PMID: 25944528
Bao S, Wu Q, McLendon RE, Hao Y, Shi Q, Hjelmeland AB, Dewhirst MW, Bigner DD, & Rich JN (2006). Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature, 444 (7120), 756-60 PMID: 17051156
Chen J, Li Y, Yu TS, McKay RM, Burns DK, Kernie SG, & Parada LF (2012). A restricted cell population propagates glioblastoma growth after chemotherapy. Nature, 488 (7412), 522-6 PMID: 22854781
Ignatova TN, Kukekov VG, Laywell ED, Suslov ON, Vrionis FD, & Steindler DA (2002). Human cortical glial tumors contain neural stem-like cells expressing astroglial and neuronal markers in vitro. Glia, 39 (3), 193-206 PMID: 12203386
Lathia JD, Mack SC, Mulkearns-Hubert EE, Valentim CL, & Rich JN (2015). Cancer stem cells in glioblastoma. Genes & development, 29 (12), 1203-17 PMID: 26109046
Stupp R, Brada M, van den Bent MJ, Tonn JC, Pentheroudakis G, & ESMO Guidelines Working Group (2014). High-grade glioma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of oncology : official journal of the European Society for Medical Oncology / ESMO, 25 Suppl 3 PMID: 24782454
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