Function and mutual interaction of BiP-, PERK- and IRE1α -dependent signalling pathways in vascular tumours.

Spontaneously regressing infantile haemangiomas and aggressive angiosarcomas are vascular tumours with excessive angiogenesis. When analysing haemangiomas and angiosarcomas immunohistochemically with respect to their chaperone profiles we found that angiosarcomas have significantly elevated protein levels of BiP and PERK with concomitant attenuated IRE1alpha levels while haemangioma tissue exhibits the same pattern as embryonal skin tissue. We show that BiP is essential for the maintenance of VEGFR2 protein, which is expressed in endothelium of both tumour types. When studying the effects of BiP, the IRE1alpha/Xbp1 -, and PERK/ATF4-signalling pathways on migration and tube-forming potential of endothelial cells we show that downregulation of BiP, as well as inhibition of the kinase activity of IRE1alpha, inhibit in vitro angiogenesis. Downregulation of PERK levels promotes Xbp1 splicing in ER-stressed cells, indicating that in angiosarcoma the elevated PERK levels might result in high levels of unspliced Xbp1, which have been reported to promote cell proliferation and increase tumour malignancy. The data presented in this study revealed that besides BiP or PERK, the kinase domain of IRE1alpha and Xbp1 could be potential targets for the development of novel therapeutic approaches for treating angiosarcomas and to control tumour angiogenesis. This article is protected by copyright. All rights reserved.