Abstract
Extracellular ATP accumulated in tumor microenvironment activates P2X7 receptor on cellular membrane of cancer cells. Recently, an importance of P2X7 receptor in cancer growth or malignancy has been suggested. We have reported an inhibitory effect of oxidized ATP (oxATP), which is an irreversible antagonist of P2X7 receptor, on melanoma growth. However, the mechanism has not yet been established. In this study, we investigated the effect of oxATP on angiogenesis in vitro and in vivo to reveal the mechanism of anti-tumor growth by oxATP. We found that oxATP strongly suppressed cell migration and wound healing in mouse endothelium b.End3 cells, indicating the suppressive effect of oxATP on angiogenesis in vitro. We further investigate the effect of oxATP on angiogenesis in vivo. We performed ligation of the femoral artery and vein of BALB/c mouse, and a laser doppler perfusion image analyzer recorded blood flow postoperatively. The blood flow of hind limb was significantly decreased by the operation and recovered within 1-2 weeks, indicating angiogenesis. However, administration of oxATP to mice significantly suppressed the recovery of blood flow. Increase of serum matrix metalloproteinases (MMPs) and vascular endothelial growth factor (VEGF) levels contribute to angiogenesis. The serum MMP-2, MMP-9, and VEGF levels were lower in oxATP-treated mice than in control mice. Moreover, production of VEGF in RBL-2H3 mast cells was suppressed by treatment with oxATP. These results suggest that oxATP inhibited angiogenesis in vivo via suppression of MMP-2, MMP-9 and VEGF production. We conclude that oxATP has an anti-angiogenic effect, which would contribute to suppression of cancer growth.
Highlights
Angiogenesis is a complex manner that is characterized by the 1) migration, 2) degradation of extracellular matrix, 3) proliferation, 4) morphogenesis/capillary tube formation of endothelial cells [1,2]
These results suggested that suppression of migration by oxidized ATP (oxATP) would be mediated by a mechanism except for blockade of P2X7 receptor
Serum concentrations of matrix metalloproteinases (MMPs)-2, MMP-9 and vascular endothelial growth factor (VEGF) in oxATP-treated group were lower (Figures 5B-D). These results indicate that oxATP would suppress blood flow recovery via blockade of MMP-2, 9 and VEGF release in hind limb ischemia mice
Summary
Angiogenesis is a complex manner that is characterized by the 1) migration, 2) degradation of extracellular matrix, 3) proliferation, 4) morphogenesis/capillary tube formation of endothelial cells [1,2]. The expression of P2X7 receptor is increased in thyroid cancer cells and activation of P2X7 receptor promotes release of interleukin (IL)-6, which may be correlated with malignancy [8,9]. The recent demonstration that P2X7 expression enhances cancer cell invasiveness in vivo is in keeping with its angiogenic activity and further stresses the possible role of this receptor in cancer [12]. Recent study has clearly revealed the importance of P2X7 receptor in cancer growth [13]; expression of P2X7 enhanced engraftment ability and in vivo growth rate, increased expression of proliferation markers, reduced apoptosis, and enhanced vascular endothelial growth factor (VEGF) release and angiogenesis [13]. We have recently reported that P2X7 receptor is involved in ATP release from melanoma in response to decrease of pH in the medium like a tumor microenvironment [14]. An important role of P2X7 receptor is suggested in cancer cells
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