Editors' ChoiceCancer Biology

Stress-Induced Angiogenesis

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Science Signaling  07 Sep 2010:
Vol. 3, Issue 138, pp. ec270
DOI: 10.1126/scisignal.3138ec270

Gliomas are the most common type of brain tumor and are characterized by high proliferative, angiogenic, and invasive activity. Therapies that inhibit angiogenesis are used to treat gliomas but may induce a phenotypic switch to invasive cell behavior. Inositol-requiring enzyme 1 (IRE1), an endoplasmic reticulum–localized protein that mediates transcriptional responses to stress, including hypoxia, had been implicated previously in hypoxic responses in cancer cells, and Auf et al. examined the effect of inhibiting IRE1 activity on glioma development and progression in vivo. Animals engrafted intracranially with U87 cells expressing a dominant-negative form of IRE1 (U87dn) had smaller tumors and survived longer than those engrafted with control U87 cells (U87ctrl) or with U87 cells expressing wild-type IRE1 (U87wt). Invasive cells from U87dn tumors, but not those from U87ctrl tumors, coopted and migrated along preexisting blood vessels. Compared with U87ctrl tumors, U87dn tumors showed lower total and functional blood vessel density and produced lower concentrations of angiogenic factors, such as interleukin-1β (IL-1β), IL-6, IL-8, and vascular endothelial growth factor A (VEGF-A). U87wt and U87ctrl cells implanted onto chicken chorioallantoic membranes developed into tumors that were vascularized and noninvasive, whereas tumors that developed from U87dn cells were smaller, nonvascularized, and invasive and produced lower amounts of IL-6 and VEGF-A. The authors propose that IRE1 activity promotes angiogenesis and tumor progression, particularly in ischemic tumor microenvironments.

G. Auf, A. Jabouille, S. Guérit, R. Pineau, M. Delugin, M. Bouchecareilh, N. Magnin, A. Favereaux, M. Maitre, T. Gaiser, A. von Deimling, M. Czabanka, P. Vajkoczy, E. Chevet, A. Bikfalvi, M. Moenner, Inositol-requiring enzyme 1α is a key regulator of angiogenesis and invasion in malignant glioma. Proc. Natl. Acad. Sci. U.S.A. 107, 15553–15558 (2010). [Abstract] [Full Text]