Activation of tumor cell integrin alphavbeta3 controls angiogenesis and metastatic growth in the brain.
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 alpha(v)beta(3) in brain metastatic growth and recruitment of blood vessels. Although alpha(v)beta(3) is frequently up-regulated in primary brain tumors and metastatic lesions of brain homing cancers, we show that it is the alpha(v)beta(3) activation state that is critical for brain lesion growth. Activated, but not non-activated, tumor cell alpha(v)beta(3) 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 alpha(v)beta(3), 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 alpha(v)beta(3) 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 alpha(v)beta(3) 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.
Lorger
Mihaela
M
Department of Molecular and Experimental Medicine, The Scripps Research Institute, MEM-150, La Jolla, CA 92037, USA.
Krueger
Joseph S
JS
O'Neal
Melissa
M
Staflin
Karin
K
Felding-Habermann
Brunhilde
B
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism / Q000556:secondary*; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000860:Hypoxia; D020287:In Situ Nick-End Labeling; D039302:Integrin alphaVbeta3 / Q000235:genetics / Q000378:metabolism*; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D016513:Mice, SCID; D009154:Mutation; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000473:pathology*; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014183:Transplantation, Heterologous; D047368:Tumor Burden; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; D039302:Integrin alphaVbeta3; D010750:Phosphoproteins; D042461:Vascular Endothelial Growth Factor A