title: Impact of tumor-associated macrophages in LH(BETA)T(AG) mice on retinal tumor progression: relation to macrophage subtype.
abstract: OBJECTIVE
  To determine the distribution of tumor-associated macrophages (TAMs) during retinoblastoma tumor development, examine the contribution of bone marrow-derived TAMs in retinoblastoma tumors, and evaluate the supportive role of TAMs in tumor growth in a transgenic retinoblastoma mouse model.
  
  
  METHODS
  The time course of macrophage infiltration in transgenic retinoblastoma tumors was assessed by immunohistochemistry at different time points in tumorigenesis. The origin of TAMs in transgenic retinoblastoma tumors was determined by transplanting 10(7) bone marrow cells from green fluorescent protein (GFP)-positive 16-week-old mice into age-matched, irradiated LH(BETA)T(AG) mice via tail vein injections. Macrophage depletion was performed by subconjunctival (SC) delivery of liposomal clodronate.
  
  
  RESULTS
  The density of TAMs increased from 4 to 12 weeks of age in mice with small to medium tumors (P = 0.037) and remained stable in the later stages of disease (i.e., 16 weeks old with large tumors; P = 0.20). In 16-week-old mice, 38% (2.5 +/- 3.2 cells per 400x high-power field) of TAMs were GFP-positive, bone marrow-derived macrophages. Total TAM depletion was associated with a significant decrease in the expression levels of MMP-9 (P = 0.014) and mature vessels (P < 0.001) and a nonsignificant decrease in the density of neovessels (P = 0.94). The density of M2-polarized TAMs did not change significantly after TAM depletion (P = 0.68). After M1-polarized TAM depletion, the tumor burden increased (P = 0.056).
  
  
  CONCLUSIONS
  This work extends understanding of the complex role that macrophages play in retinoblastoma. Macrophage modulation in the tumor microenvironment is a critical factor in retinoblastoma tumor progression.
authors.affiliation: Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL 33101, USA.
authors.forename: Yolanda
authors.initials: Y
authors.lastname: Piña
authors.forename: Hinda
authors.initials: H
authors.lastname: Boutrid
authors.forename: Timothy G
authors.initials: TG
authors.lastname: Murray
authors.forename: Martine J
authors.initials: MJ
authors.lastname: Jager
authors.forename: Colleen M
authors.initials: CM
authors.lastname: Cebulla
authors.forename: Amy
authors.initials: A
authors.lastname: Schefler
authors.forename: Long V
authors.initials: LV
authors.lastname: Ly
authors.forename: Armando
authors.initials: A
authors.lastname: Alegret
authors.forename: Magda
authors.initials: M
authors.lastname: Celdran
authors.forename: William
authors.initials: W
authors.lastname: Feuer
authors.forename: Maria-Elena
authors.initials: ME
authors.lastname: Jockovich
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D016026:Bone Marrow Transplantation; D002452:Cell Count; D004195:Disease Models, Animal; D018450:Disease Progression; D019084:Fluorescent Antibody Technique, Indirect; D006801:Humans; D008264:Macrophages / Q000502:physiology*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000166:cytology; D009389:Neovascularization, Pathologic / Q000473:pathology; D019572:Retinal Neoplasms / Q000098:blood supply / Q000473:pathology*; D012175:Retinoblastoma / Q000098:blood supply / Q000473:pathology*
chemical_list: D020780:Matrix Metalloproteinase 9