title: Tumor-associated macrophages in SHH subgroup of medulloblastomas.
abstract: OBJECTIVE
  Medulloblastoma in children can be categorized into at least four molecular subgroups, offering the potential for targeted therapeutic approaches to reduce treatment-related morbidities. Little is known about the role of tumor microenvironment in medulloblastoma or its contribution to these molecular subgroups. Tumor microenvironment has been shown to be an important source for therapeutic targets in both adult and pediatric neoplasms. In this study, we investigated the hypothesis that expression of genes related to tumor-associated macrophages (TAM) correlates with the medulloblastoma molecular subgroups and contributes to a diagnostic signature.
  
  
  METHODS
  Gene-expression profiling using human exon array (n = 168) was analyzed to identify medulloblastoma molecular subgroups and expression of inflammation-related genes. Expression of 45 tumor-related and inflammation-related genes was analyzed in 83 medulloblastoma samples to build a gene signature predictive of molecular subgroups. TAMs in medulloblastomas (n = 54) comprising the four molecular subgroups were assessed by immunohistochemistry (IHC).
  
  
  RESULTS
  A 31-gene medulloblastoma subgroup classification score inclusive of TAM-related genes (CD163 and CSF1R) was developed with a misclassification rate of 2%. Tumors in the Sonic Hedgehog (SHH) subgroup had increased expression of inflammation-related genes and significantly higher infiltration of TAMs than tumors in the Group 3 or Group 4 subgroups (P < 0.0001 and P < 0.0001, respectively). IHC data revealed a strong association between location of TAMs and proliferating tumor cells.
  
  
  CONCLUSIONS
  These data show that SHH tumors have a unique tumor microenvironment among medulloblastoma subgroups. The interactions of TAMs and SHH medulloblastoma cells may contribute to tumor growth revealing TAMs as a potential therapeutic target.
authors.affiliation: Children's Hospital Los Angeles and The Saban Research Institute, Los Angeles, California. Department of Pediatrics, Keck School of Medicine of University of Southern California, Los Angeles, California.
authors.forename: Ashley S
authors.initials: AS
authors.lastname: Margol
authors.affiliation: Children's Hospital Los Angeles and The Saban Research Institute, Los Angeles, California. Department of Pediatrics, Keck School of Medicine of University of Southern California, Los Angeles, California.
authors.forename: Nathan J
authors.initials: NJ
authors.lastname: Robison
authors.affiliation: Children's Hospital Los Angeles and The Saban Research Institute, Los Angeles, California.
authors.forename: Janahan
authors.initials: J
authors.lastname: Gnanachandran
authors.affiliation: Children's Hospital Los Angeles and The Saban Research Institute, Los Angeles, California.
authors.forename: Long T
authors.initials: LT
authors.lastname: Hung
authors.affiliation: Children's Hospital Los Angeles and The Saban Research Institute, Los Angeles, California.
authors.forename: Rebekah J
authors.initials: RJ
authors.lastname: Kennedy
authors.affiliation: Children's Hospital Los Angeles and The Saban Research Institute, Los Angeles, California.
authors.forename: Marzieh
authors.initials: M
authors.lastname: Vali
authors.affiliation: Children's Hospital Los Angeles and The Saban Research Institute, Los Angeles, California. Department of Pediatrics, Keck School of Medicine of University of Southern California, Los Angeles, California.
authors.forename: Girish
authors.initials: G
authors.lastname: Dhall
authors.affiliation: Children's Hospital Los Angeles and The Saban Research Institute, Los Angeles, California. Department of Pediatrics, Keck School of Medicine of University of Southern California, Los Angeles, California.
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Finlay
authors.affiliation: Children's Hospital Los Angeles and The Saban Research Institute, Los Angeles, California. Department of Pediatrics, Keck School of Medicine of University of Southern California, Los Angeles, California. Department of Pathology, Keck School of Medicine of University of Southern California, Los Angeles, California.
authors.forename: Anat
authors.initials: A
authors.lastname: Erdreich-Epstein
authors.affiliation: Children's Hospital Los Angeles and The Saban Research Institute, Los Angeles, California. Department of Pediatrics, Keck School of Medicine of University of Southern California, Los Angeles, California.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Krieger
authors.affiliation: Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Rachid
authors.initials: R
authors.lastname: Drissi
authors.affiliation: Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Maryam
authors.initials: M
authors.lastname: Fouladi
authors.affiliation: Children's Hospital Los Angeles and The Saban Research Institute, Los Angeles, California. Department of Pediatrics, Keck School of Medicine of University of Southern California, Los Angeles, California.
authors.forename: Floyd H
authors.initials: FH
authors.lastname: Gilles
authors.affiliation: Children's Hospital Los Angeles and The Saban Research Institute, Los Angeles, California. Department of Pathology, Keck School of Medicine of University of Southern California, Los Angeles, California.
authors.forename: Alexander R
authors.initials: AR
authors.lastname: Judkins
authors.affiliation: Children's Hospital Los Angeles and The Saban Research Institute, Los Angeles, California. Department of Pediatrics, Keck School of Medicine of University of Southern California, Los Angeles, California.
authors.forename: Richard
authors.initials: R
authors.lastname: Sposto
authors.affiliation: Children's Hospital Los Angeles and The Saban Research Institute, Los Angeles, California. Department of Pediatrics, Keck School of Medicine of University of Southern California, Los Angeles, California. Department of Pathology, Keck School of Medicine of University of Southern California, Los Angeles, California. sasgharzadeh@chla.usc.edu.
authors.forename: Shahab
authors.initials: S
authors.lastname: Asgharzadeh
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics; D002528:Cerebellar Neoplasms / Q000276:immunology* / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D005260:Female; D020869:Gene Expression Profiling; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000276:immunology; D008264:Macrophages / Q000276:immunology*; D008297:Male; D008527:Medulloblastoma / Q000276:immunology* / Q000473:pathology; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors; D059016:Tumor Microenvironment / Q000276:immunology*
chemical_list: D014408:Biomarkers, Tumor; D053823:Hedgehog Proteins; C509239:SHH protein, human; D016186:Receptor, Macrophage Colony-Stimulating Factor