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PATHOLOGICAL ANGIOGENESIS IN VASCULAR TUMORS IS DRIVEN BY AKT1 AND INHIBITED BY TOPICAL RAPAMYCIN

Vascular tumors are lesions of dysregulated angiogenesis of neoplastic endothelial cells (EC). To date, the mechanisms leading to EC tumorigenesis are poorly understood. We found increased endothelial Akt activation in benign and malignant human vascular tumors such as hemangioma and angiosarcoma. Expression of constitutively active Akt1 in vascular EC in mice resulted in hemangioma formation with recruitment of bone marrow‐derived precursor cells. Loss of Akt1 significantly inhibited sprouting angiogenesis, cell migration and proliferation in response to VEGF‐A in primary human hemangioma EC. Furthermore, loss of Akt1 but not Akt2 and Akt3 isoforms significantly reduced the growth of mouse hemangioendothelioma cells in vivo. Inhibition of mTOR activity downstream of Akt with rapamycin blocked VEGF‐induced angiogenesis in hemangioma EC. Rapamycin, given i.p. or topically, strongly inhibited the growth of subcutaneous vascular tumors in vivo. In neoplastic EC, rapamycin inhibited both TORC1 activity, which activates S6 kinase downstream of mTOR, and TORC2 activity, which activates Akt in a feedback regulatory loop. In summary, these studies show that endothelial Akt1 activation is important in vascular tumor formation, and demonstrate the possible clinical utility of topical rapamycin or other Akt/mTOR pathway inhibitors in the treatment of cutaneous vascular tumors. Funding source: NHLBI.