title: Reactive glia are recruited by highly proliferative brain metastases of breast cancer and promote tumor cell colonization.
abstract: Interactions between tumor cells and the microenvironment are crucial to tumor formation and metastasis. The central nervous system serves as a "sanctuary" site for metastasis, resulting in poor prognosis in diagnosed patients. The incidence of brain metastasis is increasing; however, little is known about interactions between the brain and metastatic cells. Brain pathology was examined in an experimental model system of brain metastasis, using a subline of MDA-MB-231 human breast cancer cells. The results were compared with an analysis of sixteen resected human brain metastases of breast cancer. Experimental metastases formed preferentially in specific brain regions, with a distribution similar to clinical cases. In both the 231-BR model, and in human specimens, Ki67 expression indicated that metastases were highly proliferative (approximately 50%). Little apoptosis was observed in either set of tumors. In the model system, metastases elicited a brain inflammatory response, with extensive reactive gliosis surrounding metastases. Similarly, large numbers of glial cells were found within the inner tumor mass of human brain metastases. In vitro co-cultures demonstrated that glia induced a approximately 5-fold increase in metastatic cell proliferation (P<0.001), suggesting that brain tissue secretes factors conducive to tumor cell growth. Molecules used to signal between tumor cells and the surrounding glia could provide a new avenue of therapeutic targets for brain metastases.
authors.affiliation: Women's Cancers Section, Laboratory of Molecular Pharmacology, National Cancer Institute, Building 37, Room 1126, National Institutes of Health, Bethesda, MD 20892, USA. fitzgeda@mail.nih.gov
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Fitzgerald
authors.forename: Diane
authors.initials: D
authors.lastname: Palmieri
authors.forename: Emily
authors.initials: E
authors.lastname: Hua
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Hargrave
authors.forename: Jeanne M
authors.initials: JM
authors.lastname: Herring
authors.forename: Yongzhen
authors.initials: Y
authors.lastname: Qian
authors.forename: Eleazar
authors.initials: E
authors.lastname: Vega-Valle
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Weil
authors.forename: Andreas M
authors.initials: AM
authors.lastname: Stark
authors.forename: Alexander O
authors.initials: AO
authors.lastname: Vortmeyer
authors.forename: Patricia S
authors.initials: PS
authors.lastname: Steeg
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D017209:Apoptosis; D001932:Brain Neoplasms / Q000556:secondary*; D001943:Breast Neoplasms / Q000473:pathology*; D039481:CD11b Antigen / Q000032:analysis; D002465:Cell Movement; D049109:Cell Proliferation; D005260:Female; D006801:Humans; D017493:Leukocyte Common Antigens / Q000032:analysis; D051379:Mice; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D009457:Neuroglia / Q000502:physiology*
chemical_list: D039481:CD11b Antigen; D017493:Leukocyte Common Antigens