Universität zu Köln

Anspach, Laura, Tsaryk, Roman, Seidmann, Larissa, Unger, Ronald E., Jayasinghe, Caren, Simiantonaki, Nektaria, Kirkpatrick, C. James and Proels, Felicitas (2020). Function and mutual interaction of BiP-, PERK-, and IRE1 alpha-dependent signalling pathways in vascular tumours. J. Pathol., 251 (2). S. 123 - 135. HOBOKEN: WILEY. ISSN 1096-9896

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Abstract

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 binding immunoglobulin protein (BIP) and PERK with concomitant attenuated IRE1 alpha levels, whereas 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 the endothelium of both tumour types. When studying the effects of BiP, the IRE1 alpha/Xbp1 -, and PERK/ATF4-signalling pathways on the migration and tube-forming potential of endothelial cells, we show that downregulation of BiP, as well as inhibition of the kinase activity of IRE1 alpha, inhibit in vitro angiogenesis. Downregulation of PERK (PKR-like kinase; PKR = protein kinase R) levels promotes Xbp1 splicing in endoplasmic reticulum (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 in addition to BiP or PERK, the kinase domains of IRE1 alpha and Xbp1 could be potential targets for the development of novel therapeutic approaches for treating angiosarcomas and to control tumour angiogenesis. (c) 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Anspach, Laura UNSPECIFIED UNSPECIFIED UNSPECIFIED Tsaryk, Roman UNSPECIFIED UNSPECIFIED UNSPECIFIED Seidmann, Larissa UNSPECIFIED UNSPECIFIED UNSPECIFIED Unger, Ronald E. UNSPECIFIED UNSPECIFIED UNSPECIFIED Jayasinghe, Caren UNSPECIFIED UNSPECIFIED UNSPECIFIED Simiantonaki, Nektaria UNSPECIFIED UNSPECIFIED UNSPECIFIED Kirkpatrick, C. James UNSPECIFIED UNSPECIFIED UNSPECIFIED Proels, Felicitas UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-334038
DOI:	10.1002/path.5423
Journal or Publication Title:	J. Pathol.
Volume:	251
Number:	2
Page Range:	S. 123 - 135
Date:	2020
Publisher:	WILEY
Place of Publication:	HOBOKEN
ISSN:	1096-9896
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language UNFOLDED PROTEIN RESPONSE; ER CHAPERONE GRP78/BIP; ENDOTHELIAL-CELLS; REGULATOR GRP78/BIP; IN-VITRO; EXPRESSION; ANGIOGENESIS; GROWTH; XBP1; RECEPTORS Multiple languages Oncology; Pathology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/33403