The small GTPase RhoA regulates the endothelial barrier during metastasis

The endothelial barrier plays an active role in transendothelial tumor cell migration during metastasis, however, the endothelial regulatory elements of this step remain obscure. Here we show that endothelial RhoA activation is a determining factor during this process. Breast tumor cell-induced endothelial RhoA activation is the combined outcome of paracrine IL-8-dependent and cell-to-cell contact β1 integrin-mediated mechanisms, with elements of this pathway correlating with clinical data. Endothelial-specific RhoA blockade or in vivo deficiency inhibited the transendothelial migration and metastatic potential of human breast tumor and three murine syngeneic tumor cell lines, similar to the pharmacological blockade of the downstream RhoA pathway. These findings highlight endothelial RhoA as a potent, universal target in the tumor microenvironment for anti-metastatic treatment of solid tumors.

Dr. Mikelis is an Associate Professor of Physiology at the Department of Pharmacy at the University of Patras, in Greece and an Associate Professor at the School of Pharmacy of Texas Tech University Health Sciences Center, where he keeps an adjunct appointment. His postdoctoral training was on vascular and cancer biology, with a focus on GPCRs, at the National Institute of Dental and Craniofacial Research at NIH and his PhD from the University of Patras was focused on angiogenesis. His current research program both in the United States and Greece is focused on investigating the role of small GTPases on endothelial physiology and on cellular communication with endothelial cells in physiological and pathological conditions.