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

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

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  • Media type: E-Article
  • Title: ErbB signaling is a potential therapeutic target for vascular lesions with fibrous component
  • Contributor: Jauhiainen, Suvi; Ilmonen, Henna; Vuola, Pia; Rasinkangas, Heta; Pulkkinen, Heidi H; Keränen, Sara; Kiema, Miika; Liikkanen, Jade J; Laham-Karam, Nihay; Laidinen, Svetlana; Beter, Mustafa; Aavik, Einari; Lappalainen, Kimmo; Lohi, Jouko; Aronniemi, Johanna; Örd, Tiit; Kaikkonen, Minna U; Salminen, Päivi; Tukiainen, Erkki; Ylä-Herttuala, Seppo; Laakkonen, Johanna P
  • Published: eLife Sciences Publications, Ltd, 2023
  • Published in: eLife, 12 (2023)
  • Language: English
  • DOI: 10.7554/elife.82543
  • ISSN: 2050-084X
  • Origination:
  • Footnote:
  • Description: <jats:sec id="abs1"><jats:title>Background:</jats:title><jats:p>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.</jats:p></jats:sec><jats:sec id="abs2"><jats:title>Methods:</jats:title><jats:p>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.</jats:p></jats:sec><jats:sec id="abs3"><jats:title>Results:</jats:title><jats:p>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 proliferation. Oncogenic <jats:italic>PIK3CA</jats:italic> 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 <jats:italic>PIK3CA</jats:italic> p.H1047R variant and fibroblasts.</jats:p></jats:sec><jats:sec id="abs4"><jats:title>Conclusions:</jats:title><jats:p>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.</jats:p></jats:sec><jats:sec id="abs5"><jats:title>Funding:</jats:title><jats:p>Academy of Finland, Ella and Georg Ehnrooth foundation, the ERC grants, Sigrid Jusélius Foundation, Finnish Foundation for Cardiovascular Research, Jane and Aatos Erkko Foundation, GeneCellNano Flagship program, and Department of Musculoskeletal and Plastic Surgery, Helsinki University Hospital.</jats:p></jats:sec>
  • Access State: Open Access