Abstract
Tumor growth is not solely a consequence of autonomous tumor cell properties. Rather, tumor cells act upon and are acted upon by their microenvironment. It is tumor tissue biology that ultimately determines tumor growth. Thus, we developed a compound library screen for agents that could block essential tumor-promoting effects of the glioblastoma (GBM) perivascular stem cell niche (PVN). We modeled the PVN with three-dimensional primary cultures of human brain microvascular endothelial cells in Matrigel. We previously demonstrated stimulated growth of GBM cells in this PVN model and used this to assay PVN function. We screened the Microsource Spectrum Collection library for drugs that specifically blocked PVN function, without any direct effect on GBM cells themselves. Three candidate PVN-disrupting agents, Iridin, Tigogenin and Triacetylresveratrol (TAR), were identified and evaluated in secondary in vitro screens against a panel of primary GBM isolates as well as in two different in vivo intracranial models. Iridin and TAR significantly inhibited intracranial tumor growth and prolonged survival in these mouse models. Together these data identify Iridin and TAR as drugs with novel GBM tissue disrupting effects and validate the importance of preclinical screens designed to address tumor tissue function rather than the mechanisms of autonomous tumor cell growth.
Highlights
Despite decades of clinical and basic research, a diagnosis of glioblastoma (GBM) continues to carry a dismal prognosis, and new approaches to cure are needed
Recent studies have identified a sub-population of tumor cells with enhanced tumor-initiating capability, known as cancer “stem-like” cells (CSCs)
To better define the mechanisms by which endothelial cells drive GBM growth, and to provide a system for high throughput screening for drugs that can disrupt the functions of the peri-vascular niche (PVN), we developed a co-culture system in which we could measure the tumor-promoting effects of endothelial cells on GBM cells [8]
Summary
Despite decades of clinical and basic research, a diagnosis of glioblastoma (GBM) continues to carry a dismal prognosis, and new approaches to cure are needed. CSCs are thought to drive tumor growth and recurrence [1,2,3,4,5], and CSC-directed therapy may provide a long-awaited critical advance in GBM care. CSCs are localized to a specialized domain that surrounds the tumor microvasculature, often referred to as the peri-vascular niche (PVN). The PVN is a complex structure composed of tumor cells, microglia, www.impactjournals.com/oncotarget astrocytes, pericytes, and endothelial cells [6, 7]. Each component cell type may play a role in the maintenance of the CSC phenotype, thereby promoting tumor growth and therapeutic resistance [8,9,10,11].
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