A One-Man Show: Glioblastoma Constructs Its Own Niche

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Science Translational Medicine  24 Apr 2013:
Vol. 5, Issue 182, pp. 182ec70
DOI: 10.1126/scitranslmed.3006348

It is now well recognized that tumor initiation and progression relies on dynamic interactions between tumor cells and so-called “normal” cells within the tumor microenvironment, much like the star of a show depends on his supporting actors to put on a good performance. Among these normal cells, endothelial cells were the first specified to be required for progression, which led to Folkman’s hypothesis that targeting a tumor’s vasculature could halt tumor growth. Antiangiogenic therapies have yet to live up to their promise, however, in part because of the remarkable plasticity displayed by tumors in terms of how they interact with their microenvironment. In essence, tumors practice improv; they have no need for a script.

It turns out that in some instances, tumors may not need supporting actors, either. Not because they are unnecessary, but because the tumor is able to play multiple roles. This was shown first when Maniotis et al. described “vasculogenic mimicry”: the ability of tumor cells to form tubes that anastomose to the vascular supply and sustain the tumor. Now, Cheng and colleagues demonstrate that glioblastoma (GBM)–initiating cells can differentiate into vascular pericytes that stabilize tumor vessels and leave them less susceptible to antiangiogenic therapies. The authors isolated human GBM-initiating cells from a number of different surgical specimens and transplanted them into mice. A subset of these cells localized to the microvasculature and expressed a suite of pericyte markers. Lineage tracing and in situ hybridization confirmed that they phenotypically and functionally behaved as pericytes while retaining the characteristic genetic lesions of the tumor. Notably, introduction of a suicide gene driven specifically by a pericyte gene promoter revealed that selectively ablating GBM-derived pericytes inhibited tumor growth and delayed depletion of neurological function significantly.

This study provides additional motivation for the development of combinatorial therapeutic regimens that simultaneously target the tumor and its microenvironment in order to delay progression of a fatal tumor such as GBM. Given that tumor cells are able to play multiple roles, the targets may be one and the same.

L. Cheng et al., Glioblastoma stem cells generate vascular pericytes to support vessel function and tumor growth. Cell 153, 139–152 (2013). [abstract]

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