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Cancer stem cells in glioblastoma

Lathia, Justin D., Mack, Stephen C., Mulkearns-Hubert, Erin E., Valentim, Claudia L.L., Rich, Jeremy N.·2015·Genes & Development
DOI 10.1101/gad.261982.115PMC PMC4495393
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Abstract

Tissues with defined cellular hierarchies in development and homeostasis give rise to tumors with cellular hierarchies, suggesting that tumors recapitulate specific tissues and mimic their origins. Glioblastoma (GBM) is the most prevalent and malignant primary brain tumor and contains self-renewing, tumorigenic cancer stem cells (CSCs) that contribute to tumor initiation and therapeutic resistance. As normal stem and progenitor cells participate in tissue development and repair, these developmental programs re-emerge in CSCs to support the development and progressive growth of tumors. Elucidation of the molecular mechanisms that govern CSCs has informed the development of novel targeted therapeutics for GBM and other brain cancers. CSCs are not self-autonomous units; rather, they function within an ecological system, both actively remodeling the microenvironment and receiving critical maintenance cues from their niches. To fulfill the future goal of developing novel therapies to collapse CSC dynamics, drawing parallels to other normal and pathological states that are highly interactive with their microenvironments and that use developmental signaling pathways will be beneficial.

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Figure 1. Functional criteria of CSCs. CSCs are defined by functional characteristics that include sustained self-renewal, persistent proliferation, and tumor initiation upon secondary transplantation, which is the definitive functional CSC assay. CSCs also share features with somatic stem cells, including frequency within a tissue (or tumor), stem cell marker expression (examples relevant to GBM and the brain are provided), and the ability to generate progeny of multiple lineages.
Figure 1. Functional criteria of CSCs. CSCs are defined by functional characteristics that include sustained self-renewal, persistent proliferation, and tumor initiation upon secondary transplantation, which is the definitive functional CSC assay. CSCs also share features with somatic stem cells, including frequency within a tissue (or tumor), stem cell marker expression (examples relevant to GBM and the brain are provided), and the ability to generate progeny of multiple lineages.CC BY-NC · PubMed Central
Figure 2. Regulation of CSCs. Cell-autonomous (intrinsic) and external (extrinsic) forces regulate the CSC state. Key intrinsic regulators include genetic, epigenetic, and metabolic regulation, while extrinsic regulators include interaction with the microenvironment, including niche factors and the immune system.
Figure 2. Regulation of CSCs. Cell-autonomous (intrinsic) and external (extrinsic) forces regulate the CSC state. Key intrinsic regulators include genetic, epigenetic, and metabolic regulation, while extrinsic regulators include interaction with the microenvironment, including niche factors and the immune system.CC BY-NC · PubMed Central
Figure 3. Proposed features of CSCs. Non-cell-autonomous aspects of CSCs may drive tumor growth but also serve as points of fragility. These include the increased ability to invade through the brain parenchyma, immune evasion, relationship with a niche, and promotion of angiogenesis.
Figure 3. Proposed features of CSCs. Non-cell-autonomous aspects of CSCs may drive tumor growth but also serve as points of fragility. These include the increased ability to invade through the brain parenchyma, immune evasion, relationship with a niche, and promotion of angiogenesis.CC BY-NC · PubMed Central

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Metadata

Authors
Lathia, J. D., Mack, S. C., Mulkearns-Hubert, E. E., Valentim, C. L. L., & Rich, J. N.
ORCID
Venue
Genes & Development
Publisher
Cold Spring Harbor Laboratory
Published
2015-06-15
Volume
29
Issue
12
Pages
1203-1217
ISSN
  • 0890-9369
  • 1549-5477
DOI
10.1101/gad.261982.115
PMC
PMC4495393
Cited by
1,520
References
13
Language
en
Funders
  • National Institutes of Health (CA154130, CA171652, CA169117, NS087913, NS089272, CA157948, NS083629)
  • Sontag Foundation
  • Cleveland Clinic
  • James S. McDonnell Foundation
  • Canadian Institutes of Health Research
  • Lerner Research Institute
  • Case Comprehensive Cancer Center
  • Voices Against Brain Cancer
  • Blast GBM
  • Ohio Cancer Research Associates
  • American Cancer Society (V Scholar Award)
  • V Foundation for Cancer Research (IRG-91-022-18)

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