Somatic activating mutations within the PIK3CA gene have been recently detected in sporadic lymphatic and venous malformations, and in vascular malformations (VM) associated to overgrowth syndromes, such as CLOVES and Klippel–Trenaunay syndrome. Although VM are often limited to specific tissue areas and can be well treated, in extended or recurrent lesions novel therapeutic approaches are needed. We generated a mouse model of VM by local expression of PIK3CA-activating mutation in endothelial cells. PIK3CA-driven lesions are characterized by large areas of hemorrhage, hyperplastic vessels, infiltrates of inflammatory cells, and elevated endothelial cell density. Such vascular lesions are ameliorated by administration of dual PI3K/mTOR inhibitor, BEZ235, and mTOR inhibitor, Everolimus. Unexpectedly, the expression of PIK3CA-activating mutations in human endothelial cells results in both increased proliferation rates and senescence. Moreover, active forms of PIK3CA strongly promote the angiogenic sprouting. Treatment with PI3K/mTOR inhibitors restores normal endothelial cell proliferation rate and reduces the amount of senescent cells, whereas treatment with Akt inhibitor is less effective. Our findings reveal that PIK3CA mutations have a key role in the pathogenesis of VM and PIK3CA-driven experimental lesions can be effectively treated by PI3K/mTOR inhibitors.

The concept that blood supply is required and necessary for cancer growth and spreading is intuitive and was firstly formalized by Judah Folkman in 1971, when he demonstrated that cancer cells release molecules able to promote the proliferation of endothelial cells and the formation of new vessels. This seminal result has initiated one of the most fascinating story of the medicine, which is offering a window of opportunity for cancer treatment based on the use of molecules inhibiting tumor angiogenesis and in particular vascular-endothelial growth factor (VEGF), which is the master gene in vasculature formation and is the commonest target of anti-angiogenic regimens. However, the clinical results are far from the remarkable successes obtained in pre-clinical models. The reasons of this discrepancy have been partially understood and well addressed in many reviews (Bergers and Hanahan, 2008; Bottsford-Miller et al., 2012; El-Kenawi and El-Remessy, 2013; Wang et al., 2015; Jayson et al., 2016). At present anti-angiogenic regimens are not used as single treatments but associated with standard chemotherapies. Based on emerging knowledge of the biology of VEGF, here we sustain the hypothesis of the efficacy of a dual approach based on targeting pro-angiogenic pathways and other druggable targets such as mutated oncogenes or the immune system.

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