Targeting Alpha V Beta 3 And Alpha V Beta 5 Integrins Inhibits Pulmonary Metastasis In An Intratibial Xenograft Osteosarcoma Mouse Model

Osteosarcoma is an aggressive bone cancer that has a high propensity for metastasis to the lungs. Patients with metastatic disease face a very poor prognosis. Therefore, novel therapeutics, efficiently suppressing the metastatic process, are urgently needed. Integrins play a pivotal role in tumor cell adhesion, motility and metastasis. Here, we evaluated alpha v beta 3 and av beta 5 integrin inhibition with cilengitide as a novel metastasis-suppressive therapeutic approach in osteosarcoma. Immunohistochemical analysis of alpha v beta 3 and alpha v beta 5 integrins expression in a tissue microarray of tumor specimens collected from osteosarcoma patients revealed that alpha v beta 5 integrin is mainly found on tumor cells, whereas alpha v beta 3 is predominantly expressed by stromal cells. In vitro functional assays demonstrated that cilengitide dose-dependently inhibited de novo adhesion, provoked detachment and inhibited migration of osteosarcoma cell lines. Cilengitide induced a decline in cell viability, blocked the cell cycle in the G1 phase and caused anoikis by activation of the Hippo pathway. In a xenograft orthotopic mouse model cilengitide minimally affected intratibial primary tumor growth but, importantly, suppressed pulmonary metastasis. The data demonstrate that targeting alpha v beta 3 and alpha v beta 5 integrins in osteosarcoma should be considered as a novel therapeutic option for patients with metastatic disease.