Holopainen Tanja, Huang Huilian, Chen Caiping, Kim Kyung Eun, Zhang Luqing, Zhou Fei, Han Wencan, Li Chaojun, Yu Jun, Wu Jun, Koh Gou Young, Alitalo Kari, He Yulong
Molecular/Cancer Biology Laboratory, Biomedicum Helsinki, Department of Pathology, Haartman Institute and Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland.
Cancer Res. 2009 Jun 1;69(11):4656-64. doi: 10.1158/0008-5472.CAN-08-4654.
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.
已知血管生成素-1（Ang1）/Tie2信号通路在血管成熟调节和血管完整性维持中发挥重要作用。在本研究中，我们研究了全身性Tie2激活或抑制对肿瘤生长和转移的影响。我们发现，通过腺病毒载体递送Ang1进行治疗可促进皮下植入肿瘤向肺部转移。Ang1治疗并未显著增加肿瘤中的血管密度，但可诱导肿瘤组织和正常组织中的血管扩张，这增加了肿瘤细胞向血液循环中的扩散。当通过尾静脉将肿瘤细胞注入循环系统时，Ang1还增强了肺部转移灶的形成。通过同时用可溶性形式的Tie2（sTie2）进行治疗验证了Ang1对转移的作用，这导致抑制了Ang1诱导的肿瘤转移增加。此外，使用高转移性肿瘤模型，我们证实全身性sTie2治疗可抑制肿瘤向肺部和淋巴结的转移，而肿瘤相关的血管生成和淋巴管生成未受到显著影响。这表明Ang1/Tie2信号通过增加肿瘤细胞的血管进入和流出促进肿瘤播散和转移灶的形成，从而促进肿瘤进展。
