title: Natural killer (NK) cells inhibit systemic metastasis of glioblastoma cells and have therapeutic effects against glioblastomas in the brain.
abstract: BACKGROUND
  Glioblastoma multiforme (GBM) is characterized by extensive local invasion, which is in contrast with extremely rare systemic metastasis of GBM. Molecular mechanisms inhibiting systemic metastasis of GBM would be a novel therapeutic candidate for GBM in the brain.
  
  
  METHODS
  Patient-derived GBM cells were primarily cultured from surgical samples of GBM patients and were inoculated into the brains of immune deficient BALB/c-nude or NOD-SCID IL2Rgamma(null) (NSG) mice. Human NK cells were isolated from peripheral blood mononucleated cells and expanded in vitro.
  
  
  RESULTS
  Patient-derived GBM cells in the brains of NSG mice unexpectedly induced spontaneous lung metastasis although no metastasis was detected in BALB/c-nude mice. Based on the difference of the innate immunity between two mouse strains, NK cell activities of orthotopic GBM xenograft models based on BALB/c-nude mice were inhibited. NK cell inactivation induced spontaneous lung metastasis of GBM cells, which indicated that NK cells inhibit the systemic metastasis. In vitro cytotoxic activities of human NK cells against GBM cells indicated that cytotoxic activity of NK cells against GBM cells prevents systemic metastasis of GBM and that NK cells could be effective cell therapeutics against GBM. Accordingly, NK cells transplanted into orthotopic GBM xenograft models intravenously or intratumorally induced apoptosis of GBM cells in the brain and showed significant therapeutic effects.
  
  
  CONCLUSIONS
  Our results suggest that innate NK immunity is responsible for rare systemic metastasis of GBM and that sufficient supplementation of NK cells could be a promising immunotherapeutic strategy for GBM in the brain.
authors.affiliation: Department of Anatomy and Cell Biology, Sungkyunkwan University School of Medicine, 2066, Seobu-ro, Jangan-gu, Suwon-si, Gyeonggi-do, 16419, South Korea. shc102@gmail.com.
authors.forename: Se Jeong
authors.initials: SJ
authors.lastname: Lee
authors.affiliation: Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Ilwon-Dong, Gangnam-Gu, Seoul, 06351, South Korea. liebe102@gmail.com.|Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, 50 Ilwon-Dong, Gangnam-Gu, Seoul, 06351, South Korea. liebe102@gmail.com.
authors.forename: Won Young
authors.initials: WY
authors.lastname: Kang
authors.affiliation: Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Ilwon-Dong, Gangnam-Gu, Seoul, 06351, South Korea. yoonyeup@gmail.com.|Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, 50 Ilwon-Dong, Gangnam-Gu, Seoul, 06351, South Korea. yoonyeup@gmail.com.
authors.forename: Yeup
authors.initials: Y
authors.lastname: Yoon
authors.affiliation: Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Ilwon-Dong, Gangnam-Gu, Seoul, 06351, South Korea. pkjinju@gmail.com.
authors.forename: Ju Youn
authors.initials: JY
authors.lastname: Jin
authors.affiliation: Department of Anatomy and Cell Biology, Sungkyunkwan University School of Medicine, 2066, Seobu-ro, Jangan-gu, Suwon-si, Gyeonggi-do, 16419, South Korea. sgppwls@gmail.com.
authors.forename: Hye Jin
authors.initials: HJ
authors.lastname: Song
authors.affiliation: Cell Therapy Team, Mogam Biotechnology Institute, Yongin, 16928, South Korea. hjh@mogam.re.kr.
authors.forename: Jung Hyun
authors.initials: JH
authors.lastname: Her
authors.affiliation: Cell Therapy Team, Mogam Biotechnology Institute, Yongin, 16928, South Korea. sm6220@greencross.com.
authors.forename: Sang Mi
authors.initials: SM
authors.lastname: Kang
authors.affiliation: Cell Therapy Team, Mogam Biotechnology Institute, Yongin, 16928, South Korea. ykhwang@greencross.com.
authors.forename: Yu Kyeong
authors.initials: YK
authors.lastname: Hwang
authors.affiliation: Department of Anatomy and Cell Biology, Sungkyunkwan University School of Medicine, 2066, Seobu-ro, Jangan-gu, Suwon-si, Gyeonggi-do, 16419, South Korea. kangk@skku.edu.
authors.forename: Kyeong Jin
authors.initials: KJ
authors.lastname: Kang
authors.affiliation: Department of Anatomy and Cell Biology, Sungkyunkwan University School of Medicine, 2066, Seobu-ro, Jangan-gu, Suwon-si, Gyeonggi-do, 16419, South Korea. kmjoo@skku.edu.|Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Ilwon-Dong, Gangnam-Gu, Seoul, 06351, South Korea. kmjoo@skku.edu.|Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, 50 Ilwon-Dong, Gangnam-Gu, Seoul, 06351, South Korea. kmjoo@skku.edu.|Department of Anatomy and Cell Biology, Sungkyunkwan University School of Medicine, 50 Ilwon-Dong, Gangnam-Gu, Seoul, 06351, South Korea. kmjoo@skku.edu.
authors.forename: Kyeung Min
authors.initials: KM
authors.lastname: Joo
authors.affiliation: Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Ilwon-Dong, Gangnam-Gu, Seoul, 06351, South Korea. nsnam@skku.edu.|Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, 50 Ilwon-Dong, Gangnam-Gu, Seoul, 06351, South Korea. nsnam@skku.edu.
authors.forename: Do-Hyun
authors.initials: DH
authors.lastname: Nam
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000276:immunology / Q000473:pathology* / Q000628:therapy; D005909:Glioblastoma / Q000276:immunology / Q000556:secondary* / Q000628:therapy; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology*; D008175:Lung Neoplasms / Q000276:immunology / Q000556:secondary*; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D008819:Mice, Nude; D016513:Mice, SCID; D023041:Xenograft Model Antitumor Assays