Glioblastoma cancer stem-like cells: implications for pathogenesis and treatment

Abstract

Glioblastoma remains one of the deadliest forms of cancer. Infiltrating cancer cells in the surrounding brain prevent complete resection, and tumor cell resistance to chemoradiation results in the poor prognosis of the glioblastoma (GBM) patient. Much research has been devoted over the years to the pathogenesis and treatment of GBM. The tumor stem cell hypothesis, which was initially described in hematopoietic cell malignancies, may explain the resistance of these tumors to conventional therapies. In this model, a certain subset of tumor cells, with characteristics similar to normal stem cells, is capable of producing the variety of cell types, which constitute the bulk of a tumor. As these tumor cells have properties distinct from those constituting the bulk of the tumor, a different approach may be required to eradicate these residual cells within the brain. Here we outline the history behind the theory of GBM cancer stem-like cells, as they are now referred to. We will also discuss the implications of their existence on commonly held beliefs about GBM pathogenesis and how they might influence future treatment strategies.

Figure 1

Locations of multipotent cells within the brain. Orange areas denote regions that contain NSCs. X’s show areas inhabited by glial progenitor cells (one group has also noted NSCs in these areas (22)) Coronal brain pathology slide provided by The Brain Biodiversity Bank at Michigan State University, with permission, funded by the National Science Foundation, https://www.msu.edu/~brains

Figure 2

This diagram illustrates the various symbiotic relationships between CSCs and its vascular niche. A. Endothelial cells have been found to secrete Nitrous Oxide among other factors which support the stemness of CSCs in a Notch-dependent manner. B. VEGF secreted by CSCs stimulates angiogenesis C. Endothelial cell Notch ligands also support the stem cell qualities of CSCs. D. CSCs may differentiate into CD133 positive endothelial cells, further enriching the vascular niche.

Figure 3

An overview of the various theories of the genesis of GBM. Initially, it was thought that mature glial cells mutated to form the various equivalent tumor cells of the GBM A.), any of which would be capable of regenerating the mass. More recent theories for inciting events include B.) the mutation of mature cells into the TIC, C. the mutation of immature stem cells into a multipotent tumor initiating cell, which then develops into CSCs, D.) the mutation of the numerous glial progenitor cells into the TIC or even E.) the dedifferentiation of mature glial cells into a less differentiated state (progenitor cells) which then transforms into a TIC

Figure 4

Therapies targeting CSCs. A. Conventional therapies target the mature GBM cells, leaving the multipotent, self-renewing CSCs within the brain to cause recurrence. B. Differentiating the CSCs may enable conventional therapies to be more effective. C. Developing therapies targeted toward unique CSC markers may prevent these cells from evading treatment. D. Immunotherapy targeted at CSC specific surface antigens can use the body’s innate defense mechanisms to kill these invasive cells

Figure 5

Differentiation pathways of CSCs. A. The Bone morphogenic protein pathway, through the activation of the various bone morphogenic protein receptors increases the activity of PS-SMAD1/5/8, leading to an increase in Id1, Id3 and Hes1 expression, ultimately leading to differentiation. B. The STAT3 pathway is similarly activated by CNTF in a manner mediated by BMPR1B, also leading to differentiation. C. Inhibition of the mTOR pathway, either by direct inhibition with Rapamycin or by inhibition of the upstream PI3K pathway leads to decreased phosphorylation of p70S6K, also driving differentiation. D. As a result of the above pathways, the CSC differentiates, losing Nestin, Sox2 and Yb-1 expression and gaining GFAP