Metastasis is a severe cause of cancer death. Even if we remove the primary tumor by surgery, cancer cells escaping from the primary tumor may circulate in the bloodstream and develop the tumor in a distant location. Then, how can we prevent metastasis? For the cancer cells to metastasize in a distant location, they need to cross the border of the blood vessels. The endothelial cells form a barrier like a border security to limit the entry of strangers.
Cancer cells secrete vascular endothelial growth factor (VEGF). VEGF can loosen the endothelial barrier via activating cell surface receptor VEGFR2. We previously showed that trafficking of VEGFR2 to the cell surface is mediated by a kinesin-3 family molecular motor, KIF13B. Then, we hypothesized that VEGF-induced endothelial barrier opening could be reduced by inhibition of the function of KIF13B. We developed a peptide inhibitor KAI, which disrupts the interaction between KIF13B and VEGFR2, thus, inhibits VEGFR2 trafficking to the cell surface. This manuscript showed that inhibition of VEGFR2 trafficking by KAI inhibited cancer metastasis in the lung. Using endothelial-specific KIF13B knockout mice, we demonstrated that KIF13B is necessary to regulate VEGF-induced vascular leakage. Similar to KAI treatment, endothelial-specific deletion of KIF13B also inhibited cancer metastasis in the lung. Therefore, KIF13B-mediated VEGFR2 trafficking to the cell surface is essential for VEGF-induced vascular leakage, and it can be a novel therapeutic target to prevent cancer metastasis.
2021 Waters S. B., Dominguez J.R., Cho, H.D., Sarich, N.A., Malik A. B., Yamada K. H.KIF13B-mediated VEGFR2 Trafficking is Essential for Vascular Leakage and Metastasis in vivo. Life Science Alliance