Activation of tumor cell integrin αvβ₃ controls angiogenesis and metastatic growth in the brain

• Published in: Proceedings of the National Academy of Sciences - PNAS 2009-06, Vol.106 (26), p.10666-10671
• Main Authors: Lorger, Mihaela, Krueger, Joseph S, O'Neal, Melissa, Staflin, Karin, Felding-Habermann, Brunhilde
• Format: Article
• Language: English
• Subjects: Biological Sciences
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0903035106

The incidence of brain metastasis is rising and poses a severe clinical problem, as we lack effective therapies and knowledge of mechanisms that control metastatic growth in the brain. Here we demonstrate a crucial role for high-affinity tumor cell integrin αvβ₃ in brain metastatic growth and recruitment of blood vessels. Although αvβ₃ is frequently up-regulated in primary brain tumors and metastatic lesions of brain homing cancers, we show that it is the αvβ₃ activation state that is critical for brain lesion growth. Activated, but not non-activated, tumor cell αvβ₃ supports efficient brain metastatic growth through continuous up-regulation of vascular endothelial growth factor (VEGF) protein under normoxic conditions. In metastatic brain lesions carrying activated αvβ₃, VEGF expression is controlled at the post-transcriptional level and involves phosphorylation and inhibition of translational respressor 4E-binding protein (4E-BP1). In contrast, tumor cells with non-activated αvβ₃ depend on hypoxia for VEGF induction, resulting in reduced angiogenesis, tumor cell apoptosis, and inefficient intracranial growth. Importantly, the microenvironment critically influences the effects that activated tumor cell αvβ₃ exerts on tumor cell growth. Although it strongly promoted intracranial growth, the activation state of the receptor did not influence tumor growth in the mammary fat pad as a primary site. Thus, we identified a mechanism by which metastatic cells thrive in the brain microenvironment and use the high-affinity form of an adhesion receptor to grow and secure host support for proliferation. Targeting this molecular mechanism could prove valuable for the inhibition of brain metastasis.