271 Critical role of Aquaporin-1 and telocytes in infantile hemangioma response to propranolol beta blockade

Abstract

Propranolol is currently the first-line treatment for severe infantile hemangioma (IH), the most frequent tumor in childhood. Neither the molecular mechanism of action nor the cellular target of the drug has been identified with a strong proof of concept. We showed that propranolol antitumor activity was associated with alteration of Aquaporin 1 (AQP1), a water and ion channel involved in tumor cell migration and angiogenesis. In pathological context, elevated AQP1 is involved in the development and progression of tumors and associated with poor prognosis. We developed an IH in vitro model using lesional patient-derived endothelial cells (EC), pericytes (PER) and CD34+/ PDGFR-α+ stromal cells named telocytes (TC) that we first described in IH. Thus, we investigated the role of these perivascular cells in the antiangiogenic effect of propranolol in IH and tested AQP1 as a marker and target of the beta-blockade response in IH. Immunuhistofluorescence staining revealed a unique AQP1 expression in IH-TC compared to normal dermis. IH-TC maintain high in vitro AQP1 protein levels compared to foreskin control-TC. We performed a Matrigel based tube formation assay including IH-EC, IH-PER and IH-TC, which highlights migration and cell-cell interaction alterations. This 3D model has a unique response to low doses of propranolol. Indeed 3 μM of propranolol highly decreased IH angiogenesis in our in vitro model and this effect is abolished when control foreskin-TC are used instead of IH-TC. Interestingly, the knockdown of AQP1 in IH-TC shows the same anti-angiogenic effect as propranolol and the combination is not additive. Moreover, we show that this beta-blockade downregulates AQP1 in patient derived telocytes. All together, these data suggest that IH sensitivity to propranolol rely at least in part to a cross talk between lesional vascular cells and stromal telocytes and reveal a critical role of AQP1 in this antitumor response.