Angiopoietin-1 overexpression modulates vascular endothelium to facilitate tumor cell dissemination and metastasis establishment.
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.
Holopainen
Tanja
T
Molecular/Cancer Biology Laboratory, Biomedicum Helsinki, Department of Pathology, Haartman Institute and Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland.
Huang
Huilian
H
Chen
Caiping
C
Kim
Kyung Eun
KE
Zhang
Luqing
L
Zhou
Fei
F
Han
Wencan
W
Li
Chaojun
C
Yu
Jun
J
Wu
Jun
J
Koh
Gou Young
GY
Alitalo
Kari
K
He
Yulong
Y
D042683:Angiopoietin-1 / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology; D000818:Animals; D002199:Capillary Permeability / Q000235:genetics; D002465:Cell Movement / Q000235:genetics*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008168:Lung / Q000187:drug effects / Q000473:pathology; D008175:Lung Neoplasms / Q000556:secondary; D051379:Mice; D016513:Mice, SCID; D009362:Neoplasm Metastasis / Q000235:genetics* / Q000473:pathology; D009360:Neoplastic Cells, Circulating / Q000187:drug effects / Q000473:pathology*; D042787:Receptor, TIE-2 / Q000037:antagonists & inhibitors / Q000502:physiology; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000502:physiology; D023041:Xenograft Model Antitumor Assays
D042683:Angiopoietin-1; D042787:Receptor, TIE-2