title: Monocytes promote liver carcinogenesis in an oncogene-specific manner.
abstract: OBJECTIVE
  The leukocyte composition of tumors is heterogeneous, as is the involvement of each leukocyte subset in promoting or restraining tumorigenesis. This heterogeneity reflects the tissue of origin, tumor stage, and the functional state of leukocyte activation, but its biological roots remain poorly understood. Since tumorigenesis is driven by various genetic events, we assessed the role of driver genes in shaping the profiles and the roles of leukocytes in tumorigenesis.
  
  
  METHODS
  Mouse liver tumors were induced by hepatic overexpression of either MYC or the combination of myristoylated AKT and NRAS(V12) oncogenes via hydrodynamic transfection. A comparative, flow cytometry- and histology-based immunophenotyping of liver-infiltrating leukocytes was performed at various stages of liver tumorigenesis. The roles of the most abundant leukocyte subsets in tumorigenesis were addressed by immunodepletion. The contribution of liver injury was assessed by comparing the injury-inducing hydrodynamic transfection model to a model in which MYC is an inducible transgene.
  
  
  RESULTS
  Myristoylated AKT and NRAS(V12) promoted a marked recruitment of CD11b(+)Ly6G(hi)Ly6C(int) neutrophils and CD11b(+)Ly6G(-)Ly6C(hi) monocytes to the liver, but their immunodepletion did not alter tumorigenesis. In contrast, despite minimal invasion by monocytes/neutrophils during MYC-driven tumorigenesis, immunodepletion of these cells reduced MYC tumor burden and extended survival. MYC-driven tumor initiation was augmented specifically by Ly6C+ monocytes and their ability to promote liver injury.
  
  
  CONCLUSIONS
  Our results demonstrate that leukocyte profiles do not necessarily predict their involvement in tumorigenesis, the functional role of leukocytes can be shaped by oncogenes, and that monocyte-dependent tissue injury selectively cooperates with MYC during tumorigenesis.
authors.affiliation: GW Hooper Research Foundation, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: vladi.juric@gilead.com.
authors.forename: Vladislava
authors.initials: V
authors.lastname: Juric
authors.affiliation: Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Ruffell
authors.affiliation: Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Kimberley J
authors.initials: KJ
authors.lastname: Evason
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA 94143, USA; School of Pharmacy, Hubei University of Chinese Medicine, Wuhan, Hubei, PR China.
authors.forename: Junjie
authors.initials: J
authors.lastname: Hu
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA 94143, USA; Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, PR China.
authors.forename: Li
authors.initials: L
authors.lastname: Che
authors.affiliation: Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Linlin
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA 94143, USA; School of Pharmacy, Hubei University of Chinese Medicine, Wuhan, Hubei, PR China.
authors.forename: Xin
authors.initials: X
authors.lastname: Chen
authors.affiliation: GW Hooper Research Foundation, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: J Michael
authors.initials: JM
authors.lastname: Bishop
mesh_terms: D000818:Animals; D000950:Antigens, Ly / Q000032:analysis; D005260:Female; D016259:Genes, myc / Q000502:physiology*; D011905:Genes, ras; D008114:Liver Neoplasms, Experimental / Q000209:etiology*; D051379:Mice; D009000:Monocytes / Q000502:physiology*; D020556:Neutrophil Infiltration; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics; D019707:Receptors, Chemokine / Q000032:analysis
chemical_list: D000950:Antigens, Ly; C503133:Gr-1 protein, mouse; C494192:Ly-6C antigen, mouse; D019707:Receptors, Chemokine; D051057:Proto-Oncogene Proteins c-akt
keywords: AKT; Inflammation; Liver injury; MYC; Monocytes; Neutrophils; Oncogenes; RAS; Tumor