title: Imaging of Tumor-Associated Macrophages in a Transgenic Mouse Model of Orthotopic Ovarian Cancer.
abstract: Tumor-associated macrophages (TAMs) are often associated with a poor prognosis in cancer. To gain a better understanding of cellular recruitment and dynamics of TAM biology during cancer progression, we established a novel transgenic mouse model for in vivo imaging of luciferase-expressing macrophages.
  
  
  
  B6.129P2-Lyz2tm1(cre)Ifo/J mice, which express Cre recombinase under the control of the lysozyme M promoter (LysM) were crossed to Cre-lox Luc reporter mice (RLG), to produce LysM-LG mice whose macrophages express luciferase. Cell-type-specific luciferase expression in these mice was verified by flow cytometry, and via in vivo bioluminescence imaging under conditions where macrophages were either stimulated with lipopolysaccharide or depleted with clodronate liposomes. The distribution of activated macrophages was longitudinally imaged in two immunocompetent LysM-LG mouse models with either B16 melanoma or ID8 ovarian cancer cells.
  
  
  
  In vivo imaging of LysM-LG mice showed luciferase activity was generated by macrophages. Clodronate liposome-mediated depletion of macrophages lowered overall bioluminescence while lipopolysaccharide injection increased macrophage bioluminescence in both the B16 and ID8 models. Tracking macrophages weekly in tumor-bearing animals after intraperitoneal (i.p.) or intraovarian (i.o.) injection resulted in distinct, dynamic patterns of macrophage activity. Animals with metastatic ovarian cancer after i.p. injection exhibited significantly higher peritoneal macrophage activity compared to animals after i.o. injection.
  
  
  
  The LysM-LG model allows tracking of macrophage recruitment and activation during disease initiation and progression in a noninvasive manner. This model provides a tool to visualize and monitor the benefit of pharmacological interventions targeting macrophages in preclinical models.
authors.affiliation: Departments of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, CA, 94305, USA.
authors.forename: Huanhuan
authors.initials: H
authors.lastname: He
authors.affiliation: Departments of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, CA, 94305, USA.
authors.forename: Alan C
authors.initials: AC
authors.lastname: Chiu
authors.affiliation: Departments of Pediatrics, Stanford University School of Medicine, Stanford, CA, 94305, USA.
authors.forename: Masamitsu
authors.initials: M
authors.lastname: Kanada
authors.affiliation: Departments of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, CA, 94305, USA.
authors.forename: Bruce T
authors.initials: BT
authors.lastname: Schaar
authors.affiliation: Departments of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, CA, 94305, USA.
authors.forename: Venkatesh
authors.initials: V
authors.lastname: Krishnan
authors.affiliation: Departments of Pediatrics, Stanford University School of Medicine, Stanford, CA, 94305, USA.|Departments of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, 94305, USA.|Departments of Radiology, Stanford University School of Medicine, Stanford, CA, 94305, USA.
authors.forename: Christopher H
authors.initials: CH
authors.lastname: Contag
authors.affiliation: Departments of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, CA, 94305, USA. odorigo@stanford.edu.
authors.forename: Oliver
authors.identifier: 0000-0002-5749-2742
authors.initials: O
authors.lastname: Dorigo
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D017930:Genes, Reporter; D008163:Luminescent Measurements; D008262:Macrophage Activation; D008264:Macrophages / Q000473:pathology*; D008545:Melanoma / Q000473:pathology; D008822:Mice, Transgenic; D057054:Molecular Imaging / Q000379:methods*; D009113:Muramidase / Q000235:genetics; D010051:Ovarian Neoplasms / Q000473:pathology*; D011401:Promoter Regions, Genetic / Q000235:genetics
chemical_list: D009113:Muramidase
keywords: Bioluminescence; Macrophages; Ovarian cancer; Transgenic mice