ErbB signaling is a potential therapeutic target for vascular lesions with fibrous component
Author:
Jauhiainen Suvi1ORCID, Ilmonen Henna1, Vuola Pia23, Rasinkangas Heta1, Pulkkinen Heidi H1, Keränen Sara1, Kiema Miika1ORCID, Liikkanen Jade J1, Laham-Karam Nihay1ORCID, Laidinen Svetlana1, Beter Mustafa1, Aavik Einari1ORCID, Lappalainen Kimmo34, Lohi Jouko35, Aronniemi Johanna34, Örd Tiit1, Kaikkonen Minna U1ORCID, Salminen Päivi36, Tukiainen Erkki2, Ylä-Herttuala Seppo178ORCID, Laakkonen Johanna P1ORCID
Affiliation:
1. A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland 2. Department of Plastic Surgery, Helsinki University Hospital and University of Helsinki 3. VASCERN VASCA European Reference Centre, Helsinki University Hospital 4. Department of Radiology, HUS Diagnostic Center and Helsinki University Hospital and University of Helsinki 5. Department of Pathology, HUSLAB, Helsinki University Hospital and University of Helsinki 6. Department of Pediatric Surgery, New Children's Hospital, Helsinki University Hospital and University of Helsinki 7. Science Service Center, Kuopio University Hospital 8. Gene Therapy Unit, Kuopio University Hospital
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 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 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 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.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, GeneCellNano Flagship program, and Department of Musculoskeletal and Plastic Surgery, Helsinki University Hospital.
Funder
Academy of Finland Ella and Georg Ehnrooth Foundation CoE of Cardiovascular and Metabolic Disease GeneCellNano Flagship Program European Research Council Sigrid Jusélius Foundation Finnish Foundation for Cardiovascular Research Jane and Aatos Erkko Foundation Department of Musculosceletal and Plastic Surgery, Helsinki University Hospital
Publisher
eLife Sciences Publications, Ltd
Subject
General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience
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