ErbB signaling is a potential therapeutic target for vascular lesions with fibrous component

Suvi Jauhiainen, Henna Ilmonen, Pia Vuola, Heta Rasinkangas, Heidi H. Pulkkinen, Sara Keränen, Miika Kiema, Jade J. Liikkanen, Nihay Laham-Karam, Svetlana Laidinen, Mustafa Beter, Einari Aavik, Kimmo Lappalainen, Jouko Lohi, Johanna Aronniemi, Tiit Örd, Minna U. Kaikkonen, Päivi Salminen, Erkki Tukiainen, Seppo Ylä-HerttualaJohanna P. Laakkonen

Tutkimustuotos: ArtikkelijulkaisuArtikkeliTieteellinenvertaisarvioitu

Abstrakti

Background: Sporadic venous malformation (VM) and angiomatosis of soft tissue (AST) are benign, congenital vascular anomalies affecting venous vasculature. Depending on the size and location of the lesion, symptoms vary from motility disturbances to pain and disfigurement. Due to the high recurrence of the lesions, more effective therapies are needed. Methods: As targeting stromal cells has been an emerging concept in anti-angiogenic therapies, here, by using VM/AST patient samples, RNA-sequencing, cell culture techniques, and a xenograft mouse model, we investigated the crosstalk of endothelial cells (EC) and fibroblasts and its effect on vascular lesion growth. Results: We report, for the first time, the expression and secretion of transforming growth factor A (TGFA) in ECs or intervascular stromal cells in AST and VM lesions. TGFA induced secretion of vascular endothelial growth factor (VEGF-A) in paracrine fashion, and regulated EC prolifera-tion. Oncogenic PIK3CA variant in p.H1047R, a common somatic mutation found in these lesions, increased TGFA expression, enrichment of hallmark hypoxia, and in a mouse xenograft model, lesion size, and vascularization. Treatment with afatinib, a pan-ErbB tyrosine-kinase inhibitor, decreased vascularization and lesion size in a mouse xenograft model with ECs expressing oncogenic PIK3CA p.H1047R variant and fibroblasts. Conclusions: Based on the data, we suggest that targeting of both intervascular stromal cells and ECs is a potential treatment strategy for vascular lesions having a fibrous component.

Alkuperäiskielienglanti
Artikkelie82543
LehtieLife
Vuosikerta12
ISSN2050-084X
DOI - pysyväislinkit
TilaJulkaistu - toukok. 2023
OKM-julkaisutyyppiA1 Alkuperäisartikkeli tieteellisessä aikakauslehdessä, vertaisarvioitu

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Publisher Copyright:
© Jauhiainen, Ilmonen et al.

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