ErbB Signalling is a Potential Therapeutic Target for Vascular Lesions with Fibrous Component

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. ![Figure][1] Graphical abstract. Proposed model for the paracrine signaling of TGFA/VEGF-A in vascular lesion Schematic illustration showing the general structure of venous malformation or angiomatosis of soft tissue. Pathological vasculature in the lesion (dark blue) is surrounded by disorganized extracellular matrix (ECM) and intervascular stromal cells (SCs, orange). High magnification from the area close to vessel wall demonstrates the proposed model for crosstalk between endothelial cells (ECs) and SCs. A mutation in phosphatidylinositol-4,5-biphosphate 3-kinase catalytic subunit alpha (PIK3CA) gene ([1][2]) or other processes promote ECs to express high level of transforming growth factor A (TGFA) ([2][3]) . TGFA binds to epithelial growth factor receptor (EGFR) on the surface of adjacent SCs ([3][4]) . Activated EGFR-downstream signaling ([4][5]) promotes elevated expression of vascular endothelial growth factor (VEGF)-A in SCs and increases the expression of TGFA ([5][6]) . VEGF-A secreted from SCs ([6][7]) binds to VEGF-recetor-2 (VEGFR2) on surface of ECs ([7][8]) and together with TGFA activates angiogenic EC phenotype. TGFA secreted from the SCs ([8][9]) , can further activate EGFR and its downstream signaling. ### Competing Interest Statement The authors have declared no competing interest. [1]: pending:yes [2]: #ref-1 [3]: #ref-2 [4]: #ref-3 [5]: #ref-4 [6]: #ref-5 [7]: #ref-6 [8]: #ref-7 [9]: #ref-8