title: Microglia promote colonization of brain tissue by breast cancer cells in a Wnt-dependent way.
abstract: Although there is increasing evidence that blood-derived macrophages support tumor progression, it is still unclear whether specialized resident macrophages, such as brain microglia, also play a prominent role in metastasis formation. Here, we show that microglia enhance invasion and colonization of brain tissue by breast cancer cells, serving both as active transporters and guiding rails. This is antagonized by inactivation of microglia as well as by the Wnt inhibitor Dickkopf-2. Proinvasive microglia demonstrate altered morphology, but neither upregulation of M2-like cytokines nor differential gene expression. Bacterial lipopolysacharide shifts tumor-educated microglia into a classical M1 phenotype, reduces their proinvasive function, and unmasks inflammatory and Wnt signaling as the most strongly regulated pathways. Histological findings in human brain metastases underline the significance of these results. In conclusion, microglia are critical for the successful colonization of the brain by epithelial cancer cells, suggesting inhibition of proinvasive microglia as a promising antimetastatic strategy.
authors.affiliation: Department of Hematology/Oncology, University of Göttingen, Göttingen, Germany. tobias.pukrop@med.uni-goettingen.de
authors.forename: Tobias
authors.initials: T
authors.lastname: Pukrop
authors.forename: Faramarz
authors.initials: F
authors.lastname: Dehghani
authors.forename: Han-Ning
authors.initials: HN
authors.lastname: Chuang
authors.forename: Raphaela
authors.initials: R
authors.lastname: Lohaus
authors.forename: Kathrin
authors.initials: K
authors.lastname: Bayanga
authors.forename: Stephan
authors.initials: S
authors.lastname: Heermann
authors.forename: Tommy
authors.initials: T
authors.lastname: Regen
authors.forename: Denise
authors.initials: D
authors.lastname: Van Rossum
authors.forename: Florian
authors.initials: F
authors.lastname: Klemm
authors.forename: Matthias
authors.initials: M
authors.lastname: Schulz
authors.forename: Laila
authors.initials: L
authors.lastname: Siam
authors.forename: Anja
authors.initials: A
authors.lastname: Hoffmann
authors.forename: Lorenz
authors.initials: L
authors.lastname: Trümper
authors.forename: Christine
authors.initials: C
authors.lastname: Stadelmann
authors.forename: Ingo
authors.initials: I
authors.lastname: Bechmann
authors.forename: Uwe-Karsten
authors.initials: UK
authors.lastname: Hanisch
authors.forename: Claudia
authors.initials: C
authors.lastname: Binder
mesh_terms: D050071:Bone Density Conservation Agents / Q000494:pharmacology; D001932:Brain Neoplasms / Q000473:pathology* / Q000556:secondary*; D001943:Breast Neoplasms / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004002:Clodronic Acid / Q000494:pharmacology; D018920:Coculture Techniques / Q000379:methods; D016207:Cytokines / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005260:Female; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007211:Indoles; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D046228:Microarray Analysis / Q000379:methods; D017628:Microglia / Q000502:physiology*; D018613:Microscopy, Confocal; D009361:Neoplasm Invasiveness; D015398:Signal Transduction / Q000502:physiology*; D013997:Time Factors; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D050071:Bone Density Conservation Agents; D016207:Cytokines; D007211:Indoles; D008070:Lipopolysaccharides; D051153:Wnt Proteins; D004002:Clodronic Acid; C007293:DAPI