Glioma Stem Cells Remodel the Perivascular Tumor Microenvironment

Pericytes are required to protect endothelial cells (EC) and maintain vessel structure and function and have been implicated in therapeutic resistance in tumors. Recent studies suggest that glioma stem cells (GSC) localize to perivascular niches and promote angiogenesis in highly vascularized glioblastoma multiforme (GBM) tumors, potentially through differentiation into endothelial cells. Alternatively, GSCs can undergo mesenchymal differentiation and, similar to normal neural stem cells, may differentiate into tumor pericytes. In support of this idea, Cheng and colleagues found that a fraction of GSCs isolated from primary tumors differentiated into cells expressing pericyte lineage markers, including α-smooth muscle actin (α-SMA), in vitro. Additionally, lineage tracing analysis in vivo using constitutive or cell lineage–specific fluorescence reporters showed that GSCs gave rise to the majority of vascular pericytes in GBM xenografts but did not generate tumor ECs. These GSC-derived cells expressed a panel of pericyte markers but no longer expressed putative GSC markers, indicative of commitment to the pericyte lineage. Moreover, in contrast with tumor ECs, pericytes isolated from primary human GBMs or xenografts harbored the same genetic alterations as matched GSCs, further suggesting that vascular pericytes predominantly derive from neoplastic cells. The differentiation of GSCs into pericytes was induced, at least in part, by TGF-β signaling from ECs and was dependent on recruitment by EC-secreted stromal cell–derived factor 1 (SDF-1), which signaled through chemokine (C-X-C motif) receptor 4 (CXCR4) expressed on GSCs. Selective elimination of GSC-derived pericytes in tumor-bearing mice disrupted tumor vessel structure and impaired vascular function, resulting in inhibition of tumor growth and prolonged survival. These results show that GSC-mediated remodeling of the perivascular niche facilitates GBM progression and suggest that targeting of these GSC-derived vascular pericytes may suppress tumor growth and limit resistance to current antiangiogenic therapies.

Cheng L, Huang Z, Zhou W, Wu Q, Donnola S, Liu JK, et al. Glioblastoma stem cells generate vascular pericytes to support vessel function and tumor growth. Cell 2013 Mar 28 [Epub ahead of print].