Rapid xenograft tumor progression in beta-arrestin1 transgenic mice due to enhanced tumor angiogenesis

β-arrestins (β-Arrs) are known to be associated with tumor signaling pathways such as transforming growth factor-β1 (TGF-β1), P53/Murine double minute (MDM2) and NF-κB. To investigate the role of β-Arr in tumor progression in vivo, we generated β-Arr transgenic mice by subcutaneously inoculating tumor cells in them. We found that the xenograft tumor initiated earlier and grew more rapidly in β-Arr1 transgenic mice than in both the β-Arr2 transgenic and wild-type mice after inoculating murine liver cancer Hepa1–6 cells or lymphoma EL4 cells. Moreover, matrix metalloproteinase 9 (MMP9) activity, vascular endothelial growth factor (VEGF) concentration in plasma and new small blood vessel formation in tumor tissues were enhanced in β-Arr1 transgenic mice compared with those in control mice. In addition, injection of MMP9 inhibitors in β-Arr1 transgenic mice abrogated all these effects and suppressed rapid tumor progression. Similar results were observed in human microvascular endothelial cells, where overexpr...