title: Postsurgical adjuvant tumor therapy by combining anti-angiopoietin-2 and metronomic chemotherapy limits metastatic growth.
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.
authors.affiliation: Division of Vascular Oncology and Metastasis, German Cancer Research Center Heidelberg (DKFZ-ZMBH Alliance), 69121 Heidelberg, Germany.
authors.forename: Kshitij
authors.initials: K
authors.lastname: Srivastava
authors.affiliation: Division of Vascular Oncology and Metastasis, German Cancer Research Center Heidelberg (DKFZ-ZMBH Alliance), 69121 Heidelberg, Germany.
authors.forename: Junhao
authors.initials: J
authors.lastname: Hu
authors.affiliation: Division of Vascular Oncology and Metastasis, German Cancer Research Center Heidelberg (DKFZ-ZMBH Alliance), 69121 Heidelberg, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Korn
authors.affiliation: 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.
authors.forename: Soniya
authors.initials: S
authors.lastname: Savant
authors.affiliation: 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.
authors.forename: Martin
authors.initials: M
authors.lastname: Teichert
authors.affiliation: Division of Vascular Oncology and Metastasis, German Cancer Research Center Heidelberg (DKFZ-ZMBH Alliance), 69121 Heidelberg, Germany.
authors.forename: Stephanie S
authors.initials: SS
authors.lastname: Kapel
authors.affiliation: Small Animal Imaging Center, German Cancer Research Center Heidelberg, Heidelberg, Germany.
authors.forename: Manfred
authors.initials: M
authors.lastname: Jugold
authors.affiliation: Division of Vascular Oncology and Metastasis, German Cancer Research Center Heidelberg (DKFZ-ZMBH Alliance), 69121 Heidelberg, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Besemfelder
authors.affiliation: Roche Diagnostics, GmbH, 82377 Penzberg, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Thomas
authors.affiliation: 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.
authors.forename: Manolis
authors.initials: M
authors.lastname: Pasparakis
authors.affiliation: 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.
authors.forename: Hellmut G
authors.initials: HG
authors.lastname: Augustin
mesh_terms: D000277:Adjuvants, Pharmaceutic / Q000008:administration & dosage / Q000009:adverse effects; D059250:Administration, Metronomic; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000009:adverse effects; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000601:surgery; D045744:Cell Line, Tumor; D042783:Endothelial Cells / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008325:Mammary Neoplasms, Experimental; D020714:Maximum Tolerated Dose; D051379:Mice; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis / Q000188:drug therapy*; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000473:pathology; D017239:Paclitaxel / Q000008:administration & dosage / Q000009:adverse effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000277:Adjuvants, Pharmaceutic; D020533:Angiogenesis Inhibitors; D017239:Paclitaxel