Angiopoietin-3 inhibits pulmonary metastasis by inhibiting tumor angiogenesis.
Angiopoietins (Ang-1, Ang-2, and Ang-3) are the ligands of Tie-2 receptor tyrosine kinase. The essential roles of Ang-1 and Tie-2 in embryonic angiogenesis have been established, and studies have demonstrated the involvement of Ang-1 and Ang-2 in tumor angiogenesis. However, the role of Ang-3 in tumor angiogenesis and metastasis and the mechanism underlying its function are totally unknown. We have shown recently that Ang-3 is tethered on cell surface via heparan sulfate proteoglycans. In our current study, we have demonstrated that overexpression of Ang-3 inhibits pulmonary metastasis of Lewis lung carcinoma and TA3 mammary carcinoma (TA3) cells by inhibiting tumor angiogenesis and promoting apoptosis of the tumor cells. In addition, we have demonstrated that the binding of Ang-3 to the cell surface is required for the effective inhibition of Ang-3 on tumor metastasis and that Ang-3 inhibits endothelial cell proliferation and survival and blocks Ang-1- and vascular endothelial growth factor-induced activation of extracellular signal-regulated kinase 1/2 and Akt kinases, which likely underlie the Ang-3-mediated inhibition on tumor angiogenesis and metastasis.
Xu
Yin
Y
Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Liu
Yao-Juan
YJ
Yu
Qin
Q
D000091304:Angiopoietin-Like Protein 1; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D018827:Carcinoma, Lewis Lung / Q000098:blood supply / Q000235:genetics / Q000517:prevention & control*; D002455:Cell Division / Q000502:physiology; D019070:Cell Lineage; D002462:Cell Membrane / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D008175:Lung Neoplasms / Q000098:blood supply / Q000235:genetics / Q000517:prevention & control* / Q000556:secondary*; D008325:Mammary Neoplasms, Experimental / Q000098:blood supply / Q000235:genetics / Q000473:pathology* / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000473:pathology; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D014162:Transfection
C117578:ANGPTL1 protein, human; D000091304:Angiopoietin-Like Protein 1; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins; D036341:Intercellular Signaling Peptides and Proteins; D011518:Proto-Oncogene Proteins; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases