title: Laminin alpha 2 enables glioblastoma stem cell growth.
abstract: OBJECTIVE
  Glioblastomas (GBMs) are lethal cancers that display cellular hierarchies parallel to normal brain. At the apex are GBM stem cells (GSCs), which are relatively resistant to conventional therapy. Interactions with the adjacent perivascular niche are an important driver of malignancy and self-renewal in GSCs. Extracellular matrix (ECM) cues instruct neural stem/progenitor cell-niche interactions, and the objective of our study was to elucidate its composition and contribution to GSC maintenance in the perivascular niche.
  
  
  METHODS
  We interrogated human tumor tissue for immunofluorescence analysis and derived GSCs from tumor tissues for functional studies. Bioinformatics analyses were conducted by mining publicly available databases.
  
  
  RESULTS
  We find that laminin ECM proteins are localized to the perivascular GBM niche and inform negative patient prognosis. To identify the source of laminins, we characterized cellular elements within the niche and found that laminin α chains were expressed by nonstem tumor cells and tumor-associated endothelial cells (ECs). RNA interference targeting laminin α2 inhibited GSC growth and self-renewal. In co-culture studies of GSCs and ECs, laminin α2 knockdown in ECs resulted in decreased tumor growth.
  
  
  CONCLUSIONS
  Our studies highlight the contribution of nonstem tumor cell-derived laminin juxtracrine signaling. As laminin α2 has recently been identified as a molecular marker of aggressive ependymoma, we propose that the brain vascular ECM promotes tumor malignancy through maintenance of the GSC compartment, providing not only a molecular fingerprint but also a possible therapeutic target.
authors.affiliation: Department of Cell Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA. lathiaj@ccf.org
authors.forename: Justin D
authors.initials: JD
authors.lastname: Lathia
authors.forename: Meizhang
authors.initials: M
authors.lastname: Li
authors.forename: Peter E
authors.initials: PE
authors.lastname: Hall
authors.forename: Joseph
authors.initials: J
authors.lastname: Gallagher
authors.forename: James S
authors.initials: JS
authors.lastname: Hale
authors.forename: Qiulian
authors.initials: Q
authors.lastname: Wu
authors.forename: Monica
authors.initials: M
authors.lastname: Venere
authors.forename: Emily
authors.initials: E
authors.lastname: Levy
authors.forename: M R Sandhya
authors.initials: MR
authors.lastname: Rani
authors.forename: Ping
authors.initials: P
authors.lastname: Huang
authors.forename: Eunnyung
authors.initials: E
authors.lastname: Bae
authors.forename: Julia
authors.initials: J
authors.lastname: Selfridge
authors.forename: Lin
authors.initials: L
authors.lastname: Cheng
authors.forename: Hacer
authors.initials: H
authors.lastname: Guvenc
authors.forename: Roger E
authors.initials: RE
authors.lastname: McLendon
authors.forename: Ichiro
authors.initials: I
authors.lastname: Nakano
authors.forename: Andrew E
authors.initials: AE
authors.lastname: Sloan
authors.forename: Heidi S
authors.initials: HS
authors.lastname: Phillips
authors.forename: Albert
authors.initials: A
authors.lastname: Lai
authors.forename: Candece L
authors.initials: CL
authors.lastname: Gladson
authors.forename: Markus
authors.initials: M
authors.lastname: Bredel
authors.forename: Shideng
authors.initials: S
authors.lastname: Bao
authors.forename: Anita B
authors.initials: AB
authors.lastname: Hjelmeland
authors.forename: Jeremy N
authors.initials: JN
authors.lastname: Rich
mesh_terms: D000071916:AC133 Antigen; D000704:Analysis of Variance; D015703:Antigens, CD / Q000378:metabolism; D001932:Brain Neoplasms / Q000401:mortality / Q000473:pathology*; D002470:Cell Survival / Q000187:drug effects; D018920:Coculture Techniques; D019295:Computational Biology; D004307:Dose-Response Relationship, Radiation; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D005909:Glioblastoma / Q000401:mortality / Q000473:pathology*; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D053208:Kaplan-Meier Estimate; D007797:Laminin / Q000235:genetics / Q000378:metabolism*; D008279:Magnetic Resonance Imaging; D008297:Male; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D010455:Peptides / Q000378:metabolism; D034622:RNA Interference / Q000502:physiology; D034741:RNA, Small Interfering / Q000494:pharmacology; D011827:Radiation; D012044:Regression Analysis; D013997:Time Factors; D046888:Tissue Array Analysis; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment / Q000502:physiology
chemical_list: D000071916:AC133 Antigen; D015703:Antigens, CD; D006023:Glycoproteins; D007797:Laminin; D010455:Peptides; D034741:RNA, Small Interfering; C102645:laminin alpha 2