Journal
CANCER RESEARCH
Volume 77, Issue 15, Pages 4171-4184Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-16-3094
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Funding
- National Science Foundation Division of Mathematical Sciences
- UC-MEXUS fellowship
- Miguel Velez fellowship at UCI
- NIH [U54CA143907, R01HL60067, R01CA180122, P50GM76516]
- National Institute for Neurological Diseases and Stroke Award (NINDS/NIH) [NS072234]
- Chao Family Comprehensive Cancer Center at University of California, Irvine, through an NCI Center Grant [P30CA062203]
- Direct For Mathematical & Physical Scien [1263796] Funding Source: National Science Foundation
- Division Of Mathematical Sciences [1263796] Funding Source: National Science Foundation
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Glioblastoma (GBM), the most aggressive brain tumor in human patients, is decidedly heterogeneous and highly vascularized. Glioma stem/initiating cells (GSC) are found to play a crucial role by increasing cancer aggressiveness and promoting resistance to therapy. Recently, cross-talk between GSC and vascular endothelial cells has been shown to significantly promote GSC self-renewal and tumor progression. Furthermore, GSC also transdifferentiate into bona fide vascular endothelial cells (GEC), which inherit mutations present in GSC and are resistant to traditional antiangiogenic therapies. Here we use three-dimensional mathematical modeling to investigate GBM progression and response to therapy. The model predicted that GSCs drive invasive fingering and that GEC spontaneously form a network within the hypoxic core, consistent with published experimental findings. Standard-of-care treatments using DNA-targeted therapy (radiation/chemo) together with antiangiogenic therapies reduced GBM tumor size but increased invasiveness. Anti-GEC treatments blocked the GEC support of GSCs and reduced tumor size but led to increased invasiveness. Anti-GSC therapies that promote differentiation or disturb the stem cell niche effectively reduced tumor invasiveness and size, but were ultimately limited in reducing tumor size because GECs maintain GSCs. Our study suggests that a combinatorial regimen targeting the vasculature, GSCs, and GECs, using drugs already approved by the FDA, can reduce both tumor size and invasiveness and could lead to tumor eradication. (C)2017 AACR.
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