ErbB signalling is a potential therapeutic target for vascular lesions with fibrous component
- University of Eastern Finland, Finland
- Helsinki University Hospital, Finland
Abstract
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 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, expression and secretion of transforming growth factor A (TGFA) in ECs or intervascular stromal cells in AST and VM lesions. TGFA induced secretion of VEGF-A paracrinally, and regulated EC proliferation. 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 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.
Funding: Academy of Finland, Ella and Georg Ehnrooth foundation, the ERC grants, Sigrid Jusélius Foundation, Finnish Foundation for Cardiovascular Research, Jane and Aatos Erkko Foundation, and Department of Musculosceletal and Plastic Surgery, Helsinki University Hospital.
Data availability
RNA-seq data has been submitted to NCBI Gene Expression Omnibus under accession numbers GSE130807 and GSE196311 (GEO reviewer access tokens; wbivkayaxhojdqp and mbehiikgvtmfryh, respectively).
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Activation of Epidermal Growth Factor Receptor Pathway in Slow-Flow Vascular MalformationsNCBI Gene Expression Omnibus, GSE130807.
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Gene expression profiling of HUVEC-s expressing PIK3CA with H1047R point mutationNCBI Gene Expression Omnibus, GSE196311.
Article and author information
Author details
Seppo Ylä-Herttuala
Johanna P Laakkonen
Funding
Academy of Finland (328835)
- Johanna P Laakkonen
ERC grant (GA670951)
- Seppo Ylä-Herttuala
ERC grant (802825)
- Minna U Kaikkonen
Sigrid Jusélius Foundation
- Seppo Ylä-Herttuala
Sigrid Jusélius Foundation
- Minna U Kaikkonen
Finnish Foundation for Cardiovascular Research
- Johanna P Laakkonen
Finnish Foundation for Cardiovascular Research
- Seppo Ylä-Herttuala
Finnish Foundation for Cardiovascular Research
- Minna U Kaikkonen
Jane and Aatos Erkko Foundation
- Minna U Kaikkonen
Department of Musculosceletal and Plastic Surgery, Helsinki University Hospital
- Pia Vuola
Academy of Finland (321535)
- Johanna P Laakkonen
Academy of Finland (353376)
- Johanna P Laakkonen
Academy of Finland (287478)
- Minna U Kaikkonen
Academy of Finland (294073)
- Minna U Kaikkonen
Ella and Georg Ehnrooth foundation
- Johanna P Laakkonen
CoE of Cardiovascular and Metabolic Disease (307402)
- Seppo Ylä-Herttuala
GeneCellNano Flagship Program (337120)
- Johanna P Laakkonen
GeneCellNano Flagship Program (337120)
- Seppo Ylä-Herttuala
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: Animal experiments were approved by National Experimental Animal Board of Finland (Decision No Esavi-2019-004672) and carried out in accordance with guidelines of the Finnish Act on Animal Experimentation.
Human subjects: Patient sample collection was approved by the Ethical Committee of the Helsinki University hospital, Helsinki, Finland (Decision No 127/13/03/02/2010 and No 1394/2020). Control sample collection was approved by the Research Ethics Committee of the Northern Savo Hospital District, Kuopio, Finland (Decision No 139/2015). Umbilical cord collection for HUVEC isolation was performed with approval from the Research Ethics Committee of the Northern Savo Hospital District, Kuopio, Finland (Decision No 341/2015). Informed consent, and consent to publish, was obtained from all patients included in the study.
Copyright
© 2023, Jauhiainen et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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ErbB signalling is a potential therapeutic target for vascular lesions with fibrous component
eLife 12:e82543.
https://doi.org/10.7554/eLife.82543
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