αvβ3 integrin activation controls metastatic growth in the brain Free

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Although significant progress has been made in treating metastatic cancer, brain metastases present an increasing clinical problem as no therapies exist that effectively control this stage of the disease. In order to develop new approaches for prevention and treatment of brain metastases, we must gain a better understanding of the mechanisms that allow circulating tumor cells to colonize the brain. Previously, we identified the adhesion receptor integrin a_vβ₃ as an important regulator of tumor cell arrest in the circulation. Cancer cells that lack expression of α_vβ₃ (MDA-MB-435 β₃^- cells) do not arrest under blood flow conditions, but can be rescued by transfection with a constitutively activated form of the α_vβ₃ integrin, β3 D273R (MDA-MB-435 β₃^D273R cells). We found that cells lacking α_vβ₃ integrin (β₃^- cells) show an impaired ability to colonize the lungs of experimental mice after introducing the tumor cells into the venous circulation. However, it is not known if α_vβ₃ expression and activation promote metastatic activity solely by supporting tumor cell arrest in the circulation; or if the receptor also critically impacts tumor cell survival within target organs of metastasis. To directly examine if integrin α_vβ₃ contributes to tumor cell survival in the specific microenvironment of the brain, we implanted variants of MDA-MB-435 cells that either lack α_vβ₃ (β3^-), or which express α_vβ₃ wild type (β3^WT), or the constitutively activated form of the receptor (β3^D723R) directly into the forebrain of immune deficient mice and monitored tumor growth in vivo by non-invasive bioluminescence imaging. Our study revealed that cells lacking α_vβ₃ integrin (β₃^- cells) cannot efficiently establish tumors in the brain microenvironment, even when implanted directly into the forebrain. Any surviving cells that eventually grow in the brain microenvironment do so by regaining the ability to express α_vβ₃. Most importantly, cells that express the activated integrin, the β₃^D273R rescued cells, have a distinct growth advantage in the brain micro-environment over the parental or β₃ wild-type rescued cells (β₃^WT). Although MDA-MB-435 β₃^WT cells survive and proliferate in the brain micro-environment, they do not spread to distal regions of the brain as efficiently as the cells with constitutively activated α_vβ₃ integrin (β₃^D273R ). Thus, α_vβ₃ integrin expression and activation are critical determinants in the establishment, growth and spread of metastases within the brain micro-environment, regardless of the ability of α_vβ₃ to mediate tumor cell arrest in the circulation. These results identify tumor cell integrin α_vβ₃ as a critical mediator of cancer cell survival and proliferation during the development of brain metastases. Thus, this receptor is a potential target for effective prevention and treatment of metastatic brain lesions.