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Angiopoietin-1 Overexpression Modulates Vascular Endothelium to Facilitate Tumor Cell Dissemination and Metastasis Establishment

¹ Laboratory of Vascular and Cancer Biology, MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Institute, Nanjing University, Nanjing, China; ² Molecular/Cancer Biology Laboratory, Biomedicum Helsinki, Department of Pathology, Haartman Institute and Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland; ³ Biomedical Research Center and Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Korea; and ⁴ Shanghai Genomics, Inc., Shanghai, China

Requests for reprints: Yulong He, Nanjing University, 12 Xue-Fu Road, Nanjing 210061, China. Phone: 86-25-5864-1512; Fax: 86-25-5864-1500; E-mail: yhe20005{at}yahoo.com or Kari Alitalo, University of Helsinki, P.O.B. 63 (Haartmaninkatu 8), 00014 Helsinki, Finland. Phone: 358-9-1912-5511; Fax: 358-9-1912-5510; E-mail: kari.alitalo{at}helsinki.fi.

Key Words: Angiopoietin-1 • Tie2 • tumor metastasis • lymphangiogenesis • angiogenesis

The angiopoietin-1 (Ang1)/Tie2 signaling pathway is known to play an important role in the regulation of vascular maturation and maintenance of vessel integrity. In this study, we have investigated the effect of systemic Tie2 activation or inhibition on tumor growth and metastasis. We found that treatment with Ang1 delivered via an adenoviral vector promoted s.c. implanted tumor metastasis to the lungs. Ang1 treatment did not significantly increase vascular density in the tumors but induced enlargement of blood vessels in both the tumor and normal tissues, which increased tumor cell dissemination into the blood circulation. Ang1 also enhanced the formation of metastatic foci in the lungs when tumor cells were injected into the circulation via the tail vein. The effect of Ang1 on metastasis was validated by a simultaneous treatment with a soluble form of Tie2 (sTie2), which led to the suppression of Ang1-induced increase of tumor metastasis. Furthermore, using a highly metastatic tumor model, we confirmed that systemic treatment with sTie2 suppressed tumor metastasis to the lungs and lymph nodes, whereas tumor-associated angiogenesis and lymphangiogenesis were not significantly affected. This suggests that the Ang1/Tie2 signals contribute to tumor progression by increasing vascular entry and exit of tumor cells to facilitate tumor dissemination and establishment of metastases. [Cancer Res 2009;69(11):4656–64]

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				Correction: Article on Role of Angiopoietin-1 in Tumor Metastasis Cancer Res., July 1, 2009; 69(13): 5618 - 5618. [Full Text] [PDF]