Cytomegalovirus-infected neuroblastoma cells exhibit augmented invasiveness mediated by beta 1 alpha 5 integrin (VLA-5)

Previously, experimental in vivo results showed that the productively and p ersistently human cytomegalovirus (HCMV)-infected neuroblastoma cell line U KF-NB-4(AD169) exhibits a more malignant phenotype than the non-infected va riant UKF-NB-4. To prove the assumption that enhanced malignancy may be due to enhanced invasive potential of the infected cells we studied interactio ns of both lines with monolayers of cultured endothelial cells. UKF-NB-4(AD 169) cells adhered to and transmigrated through endothelial monolayer to a significantly higher extent compared with UKF-NB-4. Furthermore, the adhesi on of UKF-NB-4(AD169) but not of UKF-NB-4 resulted in focal disruption of t he monolayer integrity which facilitates tumor cell transmigration, Blockin g antibodies directed against the beta 1 integrin chain as well as beta 1 a lpha 5 on the tumor cells specifically inhibited adhesion in a concentratio n-dependent manner. When UKF-NB-4 were pretreated with a beta 1 integrin ac tivating antibody, focal disruption of the endothelial integrity also occur red. These findings lead us to suggest that HCMV infection activates beta 1 alpha 5 in the host neuroblastoma cell which in turn enables these cells t o tightly adhere to endothelial cells. In the presence of the protease inhi bitor phenantroline, beta 1 alpha 5-mediated adhesion was not impaired wher eas UKF-NB-4(AD169)-mediated endothelial monolayer permeabilization was dos e dependently inhibited. We conclude that human cytomegalovirus infection c ontributes to augmented neuroblastoma invasiveness via adhesion of activate d beta 1 alpha 5 and subsequent matrix digestion by proteases.