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A Target for Antiangiogenic Therapy: Vascular Endothelium Derived from Glioblastoma

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A Target for Antiangiogenic Therapy: Vascular Endothelium Derived from Glioblastoma COMMENTARY A target for antiangiogenic therapy: Vascular endothelium derived from glioblastoma Adília Hormigoa,b,c, Bi-Sen Dinga, and Shahin Rafiia,1 aHoward Hughes Medical Institute, Ansary Stem Cell Institute, and Department of Genetic Medicine, Weill Cornell Medical College, New York, NY 10021; bDepartment of Neurology and Brain Tumor Center, Memorial Sloan-Kettering Cancer Center, New York, NY 10065; and cDepartment of Neurology, Weill Cornell Medical College, New York, NY 10021 lioblastoma is the most fre- EC-dependent tube formation in Matrigel quent primary brain tumor in or in vivo tumor growth. Notably, although G the adult, accounting for 53.8% TDECs exhibit high expression of FGFR1, of all gliomas (http://www. the main endothelial receptor of bFGF, cbtrus.org), and it is one of the most dual inhibition of both VEGFR and deadly among all human tumors. Despite FGFR1 failed to cause substantial effects aggressive treatment at diagnosis, consist- in inhibiting tube formation of TDECs. ing of resection followed by radiation with Therefore, TDECs have a unique VEGF- concurrent and subsequent adjuvant che- A, bFGF-independent angiogeneic mech- motherapy with temozolomide, the tumor anism that potentially accounts for the almost invariably recurs or progresses, resistance to anti-VEGF-A therapy in with a patient median survival of 14.6 mo glioblastoma treatment. (1). The hallmark of glioblastoma that Furthermore, cord formation by TDECs distinguishes it from all of the other glial continues to occur under hypoxia con- tumors is microvascular proliferation in Fig. 1. Model of glioblastoma cells transdif- ditions, when VEGF-A autocrine function conjunction with necrosis. Therefore, ferentiating into endothelial cells. Glioblastoma is blocked by neutralizing antibody or treatment with antiangiogenic agents are a source of TDECs. The formation of TDECs is enhanced by HIF-1α induced by hypoxia and in- when autophosphorylation of VEGFR ty- holds great promise to block the growth of dependent of VEGF and FGF inhibition. EC, endo- rosine kinase is inhibited by an antagonist, this most vascularized tumor. The best- thelial cell; GBM, glioblastoma. suggesting that transdifferentiation of tu- known antiangiogenic agents are inhibitors mor cells into endothelial cells is VEGF- of VEGF-A, an indispensable angiogenic A-independent. This observation is con- factor during developmental organogene- and colleagues reveal a new paradigm for firmed in vivo by showing that survival sis and growth of numerous tumors. glioblastoma angiogenesis whose main does not change for the animals treated However, treatment with bevacizumab, contribution is transdifferentiation of with this antagonist. In the treated ani- a neutralizing antibody to VEGF-A, at glioblastoma cells into endothelial cells mals, TDECs increase, more at the tumor relapse only confers transient benefit and a (11) (Fig. 1). Notably, these tumor-derived margins than in deep areas, supporting marginal increase in survival, indicating at endothelial cells (TDECs) are refractory a role for TDECs in offering resistance to tumor progression a VEGF-independent to inhibition of both VEGF-A and basic anti-VEGF treatment of glioblastoma. angiogenic mechanism of glioblastoma fibroblast growth factor (bFGF, FGF-2) TDECs were also found in human glio- resistance (2). Several mechanisms have pathways. By mapping GFP+ p53-deficient blastoma specimens. These TDECs been implicated in angiogenesis. One is glioblastoma established in glial-specific express FGFR1 but do not express the sprouting of capillaries from preexist- Cre mice (GFAP-Cre) (12), Soda et al. VEGFR1, VEGFR2, or VEGFR3. The ing blood vessels by endothelial prolif- find that tumor cells can directly trans- lack of VEGF receptors is a plausible ex- eration (3). Another is the cooption of differentiate into CD31+CD34+ endothe- planation for resistance of TDECs to preexisting blood vessels by tumor cells, lial cells that lack VEGF-A receptors antiangiogenesis treatment. Are there leading to expression of angiopoietin-2 by (VEGFR), constituting over 20% of total other alternate pathways of resistance to + + those vessels’ endothelial cells and tumor CD31 CD34 tumor endothelial popula- anti-VEGF-A treatment that implicates cell proliferation, followed later by in- tion. These TDECs are capable of forming TDECs? Tumor stromal cells including volution of preexisting vessels in the core patent vessels. Moreover, further analysis myeloid cells and bone marrow-derived of the tumor, massive tumor cell apopto- by hypoxyprobe unraveled their preferen- cells are known to contribute to tumor sis, organization of remaining tumor cells tial localization in deep hypoxic areas of angiogenesis by rendering the tumor re- into pseudopalisading that resides around the tumors. The hypoxic-associated distri- fractory to antiangiogenic treatment (13). areas of necrosis, and tumor rescue at bution of TDECs and elevated expres- We can speculate that glioblastoma- the margins by angiogenesis (4, 5). Ex- sion of HIF-1α, a hypoxia-induced trans- derived endothelial cells participate in the α pression of HIF-1 and up-regulation of cription factor, indicate the role of hypoxia recruitment of stromal cells that generate fi VEGF-A have been identi ed in hypoxic as the key determinant in forcing puta- a VEGF-A-independent pathway of tu- perinecrotic pseudopalisading tumor cells tive glioma cells to differentiate into mor resistance to antiangiogenic treat- – (4 6). Hypoxia induces elevated levels endothelial-like cells. ment. In fact, there is a growing concept of VEGF-A (6) and VEGF-A receptors Although TDECs share certain com- that endothelial cells are not merely that appear up-regulated in tumor endo- mon endothelial markers such as CD31, thelial cells but not in normal brain (7). CD34, vWF, and CD144, their special Another mechanism is the release of feature is demonstrated by the lacking Author contributions: A.H., B.-S.D., and S.R. wrote the angiogenic factors by the tumor that re- expression of VEGFR2, the major tyro- paper. cruit bone marrow-derived endothelial sine kinase receptor of VEGF-A. The The authors declare no conflict of interest. progenitors, hematopoietic stem and pro- absence of VEGFR is further illustrated See companion article on page 4274. genitor cells that participate in vessel for- by the negligible effect conferred by in- 1To whom correspondence should be addressed: E-mail: mation (8–10). In PNAS, Soda, Verma, hibition of all VEGF receptors in either srafi[email protected]. www.pnas.org/cgi/doi/10.1073/pnas.1019656108 PNAS | March 15, 2011 | vol. 108 | no. 11 | 4271–4272 Downloaded by guest on September 29, 2021 passive conduits but have an instructive endothelial marker? Strictly speaking mediates in this cell differentiation, the role, producing angiocrine factors, in- probably not, but rather refer to TDECs angiocrine modulators between tumor flammatory and protumorigenic at the that do not express either VEGFR1 or cells and endothelial cells, and whether vascular niche, leading to mobilization of VEGFR2 as vascular mimicry. The new the canonical or noncanonical HIF-1 other cells, promoting tumor growth and study also shows that in human glioblas- pathway leads to up-regulation of endo- modulation of response to treatment (14). toma, EGFR amplification found in glio- thelial-specific genes under hypoxia will be The concept that tumor cells could blastoma cells is also detected in some crucial to reveal mechanisms of tumor generate vascular channels was previously endothelial cells in the tumor but is absent resistance to antiangiogenic agents. introduced (15). Tube formation can be Are there other alternate pathways of produced by other nonendothelial cells, Soda, Verma, and resistance to anti-VEGF-A treatment that in a process known as vasculogenic mim- implicates TDECs? Tumor stromal cells icry. Endothelial-like cells derived from colleagues reveal a including myeloid cells and bone marrow- tumors such as melanoma lack the full derived cells are known to contribute to angiogenic repertoire of the endothelial new paradigm tumor angiogenesis by rendering the tu- cells. Recently, a tubular form of vasculo- mor refractory to antiangiogenic treat- genic mimicry was recognized for glio- + for glioblastoma ment (13). In particular, upon activation of blastoma, as CD133 glioblastoma stem- the Id pathway, endothelial progenitor like cells were found capable of trans- angiogenesis. cells (EPCs) mobilized from bone marrow differentiating into tubular vascular can initiate angiogenesis through release smooth muscle-like cells forming struc- of paracrine factors rather than structur- tures deprived of endothelial cells, despite in the endothelial cells in the normal ally incorporating into vessel wall (20). In immunoreactivity for collagen-IV, a com- brain. One might consider that EGFR fi addition, CXCR4 activation by stromal- ponent of vessel basement membrane ampli cation is a characteristic of tumor derived factor 1 has been shown to play an (16). In vitro, the CD133+ cells from cells, and that it does not belong to the essential role in the mobilization and re- glioblastoma that contain tumor cell-lined molecular signature of endothelial cells. vessels were capable of expressing endo- Alternatively, they might give indirect ev- cruitment of EPCs, which also might ex- thelium-associated genes, such as ephrin idence for a shared common lineage for plain the VEGF-A, bFGF-independent receptor, neuropilin-2, and laminin5γ2, but a subset of tumor-derived endothelial
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