title: Carcinoma cells misuse the host tissue damage response to invade the brain.
abstract: The metastatic colonization of the brain by carcinoma cells is still barely understood, in particular when considering interactions with the host tissue. The colonization comes with a substantial destruction of the surrounding host tissue. This leads to activation of damage responses by resident innate immune cells to protect, repair, and organize the wound healing, but may distract from tumoricidal actions. We recently demonstrated that microglia, innate immune cells of the CNS, assist carcinoma cell invasion. Here we report that this is a fatal side effect of a physiological damage response of the brain tissue. In a brain slice coculture model, contact with both benign and malignant epithelial cells induced a response by microglia and astrocytes comparable to that seen at the interface of human cerebral metastases. While the glial damage response intended to protect the brain from intrusion of benign epithelial cells by inducing apoptosis, it proved ineffective against various malignant cell types. They did not undergo apoptosis and actually exploited the local tissue reaction to invade instead. Gene expression and functional analyses revealed that the C-X-C chemokine receptor type 4 (CXCR4) and WNT signaling were involved in this process. Furthermore, CXCR4-regulated microglia were recruited to sites of brain injury in a zebrafish model and CXCR4 was expressed in human stroke patients, suggesting a conserved role in damage responses to various types of brain injuries. Together, our findings point to a detrimental misuse of the glial damage response program by carcinoma cells resistant to glia-induced apoptosis.
authors.affiliation: Department of Hematology/Oncology, University Medical Center, Göttingen, Germany.
authors.forename: Han-Ning
authors.initials: HN
authors.lastname: Chuang
authors.forename: Denise
authors.initials: D
authors.lastname: van Rossum
authors.forename: Dirk
authors.initials: D
authors.lastname: Sieger
authors.forename: Laila
authors.initials: L
authors.lastname: Siam
authors.forename: Florian
authors.initials: F
authors.lastname: Klemm
authors.forename: Annalen
authors.initials: A
authors.lastname: Bleckmann
authors.forename: Michaela
authors.initials: M
authors.lastname: Bayerlová
authors.forename: Katja
authors.initials: K
authors.lastname: Farhat
authors.forename: Jörg
authors.initials: J
authors.lastname: Scheffel
authors.forename: Matthias
authors.initials: M
authors.lastname: Schulz
authors.forename: Faramarz
authors.initials: F
authors.lastname: Dehghani
authors.forename: Christine
authors.initials: C
authors.lastname: Stadelmann
authors.forename: Uwe-Karsten
authors.initials: UK
authors.lastname: Hanisch
authors.forename: Claudia
authors.initials: C
authors.lastname: Binder
authors.forename: Tobias
authors.initials: T
authors.lastname: Pukrop
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D017209:Apoptosis / Q000235:genetics; D001921:Brain / Q000276:immunology / Q000473:pathology*; D001932:Brain Neoplasms / Q000235:genetics / Q000276:immunology / Q000473:pathology*; D002277:Carcinoma / Q000235:genetics / Q000276:immunology / Q000473:pathology; D018920:Coculture Techniques; D004285:Dogs; D006801:Humans; D061986:MCF-7 Cells; D061985:Madin Darby Canine Kidney Cells; D051379:Mice; D008810:Mice, Inbred C57BL; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000276:immunology / Q000473:pathology*; D009924:Organ Culture Techniques; D015027:Zebrafish
keywords: astrocytes; brain metastasis; damage response; glia; invasion; microglia