title: Tumor-associated macrophages in glioblastoma multiforme-a suitable target for somatostatin receptor-based imaging and therapy?
abstract: BACKGROUND
  Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults. Tumor-associated macrophages (TAM) have been shown to promote malignant growth and to correlate with poor prognosis. [1,4,7,10-tetraazacyclododecane-NN',N″,N'″-tetraacetic acid]-d-Phe1,Tyr3-octreotate (DOTATATE) labeled with Gallium-68 selectively binds to somatostatin receptor 2A (SSTR2A) which is specifically expressed and up-regulated in activated macrophages. On the other hand, the role of SSTR2A expression on the cell surface of glioma cells has not been fully elucidated yet. The aim of this study was to non-invasively assess SSTR2A expression of both glioma cells as well as macrophages in GBM.
  
  
  METHODS
  15 samples of patient-derived GBM were stained immunohistochemically for macrophage infiltration (CD68), proliferative activity (Ki67) as well as expression of SSTR2A. Anti-CD45 staining was performed to distinguish between resident microglia and tumor-infiltrating macrophages. In a subcohort, positron emission tomography (PET) imaging using 68Ga-DOTATATE was performed and the semiquantitatively evaluated tracer uptake was compared to the results of immunohistochemistry.
  
  
  RESULTS
  The amount of microglia/macrophages ranged from <10% to >50% in the tumor samples with the vast majority being resident microglial cells. A strong SSTR2A immunostaining was observed in endothelial cells of proliferating vessels, in neurons and neuropile. Only faint immunostaining was identified on isolated microglial and tumor cells. Somatostatin receptor imaging revealed areas of increased tracer accumulation in every patient. However, retention of the tracer did not correlate with immunohistochemical staining patterns.
  
  
  CONCLUSIONS
  SSTR2A seems not to be overexpressed in GBM samples tested, neither on the cell surface of resident microglia or infiltrating macrophages, nor on the surface of tumor cells. These data suggest that somatostatin receptor directed imaging and treatment strategies are less promising in GBM.
authors: Department of Nuclear Medicine, University Hospital Würzburg, Würzburg, Germany.
authors: Constantin
authors: C
authors: Lapa
authors: Department of Neurosurgery, University Hospital Würzburg, Würzburg, Germany.
authors: Thomas
authors: T
authors: Linsenmann
authors: Department of Nuclear Medicine, University Hospital Würzburg, Würzburg, Germany.
authors: Katharina
authors: K
authors: Lückerath
authors: Department of Nuclear Medicine, University Hospital Würzburg, Würzburg, Germany.
authors: Samuel
authors: S
authors: Samnick
authors: Department of Nuclear Medicine, University Hospital Würzburg, Würzburg, Germany.
authors: Ken
authors: K
authors: Herrmann
authors: Department of Neuropathology, Institute of Pathology, University of Würzburg, Würzburg, Germany.
authors: Carolin
authors: C
authors: Stoffer
authors: Department of Neurosurgery, University Hospital Würzburg, Würzburg, Germany.
authors: Ralf-Ingo
authors: RI
authors: Ernestus
authors: Department of Nuclear Medicine, University Hospital Würzburg, Würzburg, Germany.
authors: Andreas K
authors: AK
authors: Buck
authors: Department of Neurosurgery, University Hospital Würzburg, Würzburg, Germany.
authors: Mario
authors: M
authors: Löhr
authors: Department of Neuropathology, Institute of Pathology, University of Würzburg, Würzburg, Germany.
authors: Camelia-Maria
authors: CM
authors: Monoranu
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D001932:Brain Neoplasms / Q000000981:diagnostic imaging* / Q000188:drug therapy / Q000473:pathology; D005260:Female; D005909:Glioblastoma / Q000000981:diagnostic imaging* / Q000188:drug therapy / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D017493:Leukocyte Common Antigens / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism*; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009942:Organometallic Compounds / Q000737:chemistry; D049268:Positron-Emission Tomography; D011859:Radiography; D017481:Receptors, Somatostatin / Q000378:metabolism*; D012189:Retrospective Studies; D000097382:CD68 Molecule
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D017493:Leukocyte Common Antigens; D009942:Organometallic Compounds; D017481:Receptors, Somatostatin; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C513399:gallium Ga 68 dotatate; C093733:somatostatin receptor 2