title: Serum-based tracking of de novo initiated liver cancer progression reveals early immunoregulation and response to therapy.
abstract: OBJECTIVE
  Liver inflammatory diseases associated with cancer promoting somatic oncogene mutations are increasing in frequency. Preclinical cancer models that allow for the study of early tumor progression are often protracted, which limits the experimental study parameters due to time and expense. Here we report a robust inexpensive approach using Sleeping Beauty transposition (SBT) delivery of oncogenes along with Gaussia Luciferase expression vector GLuc, to assess de novo liver tumor progression, as well as the detection of innate immune responses or responses induced by therapeutic intervention.
  
  
  METHODS
  Tracking de novo liver tumor progression with GLuc was demonstrated in models of hepatocellular carcinoma (HCC) or adenoma (HCA) initiated by hydrodynamic delivery of SBT oncogenes.
  
  
  RESULTS
  Rising serum luciferase levels correlated directly with increasing liver tumor burden and eventual morbidity. Early detection of hepatocyte apoptosis from mice with MET+CAT transfected hepatocytes was associated with a transient delay in HCC growth mediated by a CD8(+) T-cell response against transformed hepatocytes. Furthermore, mice that lack B cells or macrophages had an increase in TUNEL(+) hepatocytes following liver MET transfection demonstrating that these cells provide protection from MET-induced hepatocyte apoptosis. Treatment with IL-18+IL-12 of mice displaying established HCC decreased tumor burden which was associated with decreased levels of serum luciferase.
  
  
  CONCLUSIONS
  Hydrodynamic delivery of the SBT vector GLuc to hepatocytes serves as a simple blood-based approach for real-time tracking of pathologically distinct types of liver cancer. This revealed tumor-induced immunologic responses and was beneficial in monitoring the efficacy of therapeutic interventions.
authors.affiliation: Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, United States.
authors.forename: Jeff J
authors.initials: JJ
authors.lastname: Subleski
authors.affiliation: Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, United States.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Scarzello
authors.affiliation: Statistical Consulting, Data Management Services, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, United States.
authors.forename: W Gregory
authors.initials: WG
authors.lastname: Alvord
authors.affiliation: Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, United States.
authors.forename: Qun
authors.initials: Q
authors.lastname: Jiang
authors.affiliation: Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, United States.
authors.forename: Jimmy K
authors.initials: JK
authors.lastname: Stauffer
authors.affiliation: Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, United States.
authors.forename: Anthony
authors.initials: A
authors.lastname: Kronfli
authors.affiliation: Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, United States.
authors.forename: Bahara
authors.initials: B
authors.lastname: Saleh
authors.affiliation: Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, United States.
authors.forename: Timothy
authors.initials: T
authors.lastname: Back
authors.affiliation: Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, United States.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Weiss
authors.affiliation: Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, United States. Electronic address: wiltrour@mail.nih.gov.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Wiltrout
mesh_terms: D018248:Adenoma, Liver Cell / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D000818:Animals; D017209:Apoptosis; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D018450:Disease Progression; D022781:Hepatocytes / Q000473:pathology; D007111:Immunity, Cellular; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D018664:Interleukin-12 / Q000627:therapeutic use; D020382:Interleukin-18 / Q000627:therapeutic use; D008113:Liver Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D008156:Luciferases / Q000097:blood*; D008279:Magnetic Resonance Imaging; D051379:Mice; D008810:Mice, Inbred C57BL; D011994:Recombinant Proteins / Q000627:therapeutic use*; D015398:Signal Transduction
chemical_list: D020382:Interleukin-18; D011994:Recombinant Proteins; D018664:Interleukin-12; D008156:Luciferases
keywords: Gaussia Luciferase; HCA; HCC; Real-time tracking; Sleeping Beauty Transposition; Treatment