title: Cessation of CCL2 inhibition accelerates breast cancer metastasis by promoting angiogenesis.
abstract: Secretion of C-C chemokine ligand 2 (CCL2) by mammary tumours recruits CCR2-expressing inflammatory monocytes to primary tumours and metastatic sites, and CCL2 neutralization in mice inhibits metastasis by retaining monocytes in the bone marrow. Here we report a paradoxical effect of CCL2 in four syngeneic mouse models of metastatic breast cancer. Surprisingly, interruption of CCL2 inhibition leads to an overshoot of metastases and accelerates death. This is the result of monocyte release from the bone marrow and enhancement of cancer cell mobilization from the primary tumour, as well as blood vessel formation and increased proliferation of metastatic cells in the lungs in an interleukin (IL)-6- and vascular endothelial growth factor (VEGF)-A-dependent manner. Notably, inhibition of CCL2 and IL-6 markedly reduced metastases and increased survival of the animals. CCL2 has been implicated in various neoplasias and adopted as a therapeutic target. However, our results call for caution when considering anti-CCL2 agents as monotherapy in metastatic disease and highlight the tumour microenvironment as a critical determinant of successful anti-metastatic therapy.
authors.affiliation: 1] Friedrich Miescher Institute for Biomedical Research (FMI), Basel 4058, Switzerland [2] Novartis Institutes for Biomedical Research, 4002 Basel, Switzerland.
authors.forename: Laura
authors.initials: L
authors.lastname: Bonapace
authors.affiliation: Friedrich Miescher Institute for Biomedical Research (FMI), Basel 4058, Switzerland.
authors.forename: Marie-May
authors.initials: MM
authors.lastname: Coissieux
authors.affiliation: Friedrich Miescher Institute for Biomedical Research (FMI), Basel 4058, Switzerland.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Wyckoff
authors.affiliation: 1] Department of Pathology, University Hospital Zurich, 8006 Zurich, Switzerland [2] Institute of Pathology Liestal, Cantonal Hospital Baselland, 4410 Liestal, Switzerland.
authors.forename: Kirsten D
authors.initials: KD
authors.lastname: Mertz
authors.affiliation: Department of Pathology, University Hospital Zurich, 8006 Zurich, Switzerland.
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Varga
authors.affiliation: Novartis Institutes for Biomedical Research, 4002 Basel, Switzerland.
authors.forename: Tobias
authors.initials: T
authors.lastname: Junt
authors.affiliation: Friedrich Miescher Institute for Biomedical Research (FMI), Basel 4058, Switzerland.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Bentires-Alj
mesh_terms: D000818:Animals; D001808:Blood Vessels / Q000166:cytology / Q000187:drug effects / Q000254:growth & development; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D049109:Cell Proliferation / Q000187:drug effects; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D015850:Interleukin-6 / Q000378:metabolism; D008175:Lung Neoplasms / Q000098:blood supply / Q000473:pathology / Q000556:secondary; D051379:Mice; D009000:Monocytes / Q000166:cytology / Q000378:metabolism; D009362:Neoplasm Metastasis / Q000188:drug therapy; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D016019:Survival Analysis; D059016:Tumor Microenvironment; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000378:metabolism; D000093242:Interleukin-6 Inhibitors
chemical_list: D018932:Chemokine CCL2; D015850:Interleukin-6; D042461:Vascular Endothelial Growth Factor A; D000093242:Interleukin-6 Inhibitors