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Cancer Cell. 2014 Dec 8;26(6):880-895. doi: 10.1016/j.ccell.2014.11.005.

Postsurgical adjuvant tumor therapy by combining anti-angiopoietin-2 and metronomic chemotherapy limits metastatic growth.

Author information

1
Division of Vascular Oncology and Metastasis, German Cancer Research Center Heidelberg (DKFZ-ZMBH Alliance), 69121 Heidelberg, Germany.
2
Division of Vascular Oncology and Metastasis, German Cancer Research Center Heidelberg (DKFZ-ZMBH Alliance), 69121 Heidelberg, Germany; Department of Vascular Biology and Tumor Angiogenesis (CBTM), Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany.
3
Small Animal Imaging Center, German Cancer Research Center Heidelberg, Heidelberg, Germany.
4
Roche Diagnostics, GmbH, 82377 Penzberg, Germany.
5
Institute for Genetics, Center for Molecular Medicine (CMMC), and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50923 Cologne, Germany.
6
Division of Vascular Oncology and Metastasis, German Cancer Research Center Heidelberg (DKFZ-ZMBH Alliance), 69121 Heidelberg, Germany; Department of Vascular Biology and Tumor Angiogenesis (CBTM), Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany; German Cancer Consortium, 69120 Heidelberg, Germany. Electronic address: augustin@angiogenese.de.

Abstract

Antiangiogenic tumor therapy has failed in the adjuvant setting. Here we show that inhibition of the Tie2 ligand angiopoietin-2 (Ang2) effectively blocks metastatic growth in preclinical mouse models of postsurgical adjuvant therapy. Ang2 antibody treatment combines well with low-dose metronomic chemotherapy (LDMC) in settings in which maximum-dose chemotherapy does not prove effective. Mechanistically, Ang2 blockade could be linked to quenching the inflammatory and angiogenic response of endothelial cells (ECs) in the metastatic niche. Reduced EC adhesion molecule and chemokine expression inhibits the recruitment of tumor-promoting CCR2(+)Tie2(-) metastasis-associated macrophages. Moreover, LDMC contributes to therapeutic efficacy by inhibiting the recruitment of protumorigenic bone marrow-derived myeloid cells. Collectively, these data provide a rationale for mechanism-guided adjuvant tumor therapies.

PMID:
25490450
DOI:
10.1016/j.ccell.2014.11.005
[Indexed for MEDLINE]
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