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 IRE1α 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 IRE1α/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 IRE1α, 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 IRE1α and Xbp1 could be potential targets for the development of novel therapeutic approaches for treating angiosarcomas and to control tumour angiogenesis. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

中文翻译：

---

BiP，PERK和IRE1α依赖性信号通路在血管肿瘤中的功能和相互作用。

自发性退行性婴儿血管瘤和侵袭性血管肉瘤是血管生成过度的血管肿瘤。当通过免疫组织化学方法分析血管瘤和血管肉瘤的分子伴侣特征时，我们发现血管肉瘤的结合免疫球蛋白（BIP）和PERK蛋白水平显着升高，同时IRE1α水平降低，而血管瘤组织表现出与胚胎皮肤组织相同的模式。我们显示BiP对于维持VEGFR2蛋白至关重要，该蛋白在两种肿瘤类型的内皮中均表达。在研究BiP，IRE1α/ Xbp1-和PERK / ATF4信号通路对内皮细胞迁移和成管潜能的影响时，我们发现BiP的下调以及对IRE1α激酶活性的抑制，抑制体外血管生成。PERK的下调（PKR样激酶; PKR =蛋白激酶R）水平促进XBP1剪接内质网（ER）-stressed细胞，这表明在血管肉瘤升高的pERK水平可能导致高水平的未剪接的XBP1，已经报道促进细胞增殖并增加肿瘤恶性程度。这项研究中提供的数据表明，除了BiP或PERK，IRE1α和Xbp1的激酶结构域可能是开发治疗血管肉瘤和控制肿瘤血管生成的新型治疗方法的潜在靶标。©2020作者。该病理学杂志代表英国和爱尔兰的病理学学会出版由John Wiley父子有限公司。