Pathological Angiogenesis In Vascular Tumors Is Driven By Endothelial Akt1 And Inhibited By Rapamycin

Vascular tumors are abnormal angiogenic proliferations of neoplastic endothelial cells with a wide spectrum of clinical diseases ranging from common hemangioma in children to malignant angiosarcoma in adults. To date, the mechanisms leading to vascular tumor formation are poorly understood and under-investigated. We found reduction in PTEN levels and increased Akt activation in benign and malignant human vascular tumors. Akt1 promoted the proliferation and migration of vascular tumor cells. Expression of constitutively active Akt1 in vascular endothelial cells was sufficient to induce hemangioma formation in vivo, and sustained endothelial Akt1 activation was necessary to maintain tumor growth. Inhibition of mTOR activity downstream of Akt1 with rapamycin blocked VEGF-induced angiogenesis in vascular tumor cells and tumor growth in animals. In vascular tumors, rapamycin inhibited the activities of both TORC1 (which phosphorylates p70 S6-Kinase downstream of mTOR) and TORC2 (which phosphorylates Akt) and may provide a mechanism for the high efficacy of rapamycin in these tumors. As a topical agent, rapamycin was effective in inhibiting cutaneous vascular tumors with minimal systemic blood levels of the drug. In summary, these studies showed that endothelial Akt1 plays a key role in vascular tumor formation, and topical rapamycin holds promising clinical utility in the treatment of cutaneous vascular tumors. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2393.