Stem Cell Microenvironments and Beyond

133

7.5 Future Directions

Standard forms of therapy have been ineffective in significantly increasing the over-
all survival of GBM patients and the failures of these therapies have been pinned on
the highly heterogeneous nature of GBMs. As summarized above, a wide variety of
studies that have investigated the existence of a stem-like GBM population within
tumors and their resistance to chemo- and radiation therapy. The expansion and re-
establishment of aggressive GBMs post therapy by these stem-like cells is thought
to be one of the major reasons for disease recurrence which is a major cause of
GBM patient mortality. It is therefore imperative to design therapeutics which can
effectively target GSCs which exist within hypoxic regions and invasive ends of
GBMs.
As mentioned above, recent reports have brought to light the gaps in knowledge
regarding cellular plasticity and the role played by the GBM microenvironment.
Studies have shown that non-stem GBM cells de-differentiate into GSCs along with
transdifferentiation of GSCs into cells of the perivascular niche. Therapies designed

GSC

GSCs

TACs

TDCs

2.5% O 2

1% O 2

0.5% O 2

0.1% O 2

Trans-differenaon

Blood vessels Endothelial Cells

Circulang

endothelial

cells

CD133+ GSCs Severe^

Hypoxia

Mild Hyp

ox

ia

Normoxia

HIF1α

HIF 2α

VEGF

SDF-1α

TAMs

NSCs, NPCs,

ChAT+ neurons

ECM

Fig. 7.2 Summary of interactions between GSCs and components of their microenvironment.
GSC glioblastoma stem cells; TAC transiently amplifying cells; TDC terminally differentiated
cells; NSC neural stem cells; NPC neural progenitor cells; ChAT choline acetyltransferase; TAM
tumor associated macrophages; ECM extracellular matrix; VEGF vascular endothelial growth fac-
tor; SDF-1 stromal derived factor-1; O 2 oxygen; HIF hypoxia inducible factor

7 Glioblastoma Stem Cells and Their Microenvironment