title: Orthotopic transplantation models of pancreatic adenocarcinoma derived from cell lines and primary tumors and displaying varying metastatic activity.
abstract: OBJECTIVE
  To establish a series of clinically relevant orthotopic transplantation models of human pancreatic adenocarcinoma from both cell lines and primary tumors under uniform experimental conditions.
  
  
  METHODS
  Ten pancreatic cancer cell lines and 12 primary tumors were orthotopically transplanted in SCID mice. The cell lines and xenografts were characterized for K-ras, BRAF, p53, p16, and DPC4 aberrations employing direct sequencing, immunohistochemistry, and Western blotting.
  
  
  RESULTS
  All xenografts showed high intrapancreatic tumorigenicity and extensive local tumor growth, and each showed a unique behavioral and genetic profile. Tumor characteristics were retained during serial passaging. The cell line-derived xenografts represented the entire expected range of histologic differentiation. Although the overall metastatic rate was moderate to high, the metastatic pattern varied; 4 cell lines showed a high metastatic rate to the liver. The primary tumor-derived xenografts retained their similarity to the corresponding original donor tumors with regard to histologic presentation and biologic behavior. K-ras, p53, p16, and DPC4 aberrations were revealed in 80%, 70%, 50%, and 40% of cell lines and 100%, 33%, 75%, and 58% of primary tumor derived xenografts, respectively. No BRAF mutations were present. The metastatic behavior of the xenografts was significantly associated with the degree of histologic differentiation, number of genes altered, and p53 status.
  
  
  CONCLUSIONS
  The new models reflected the wide range of patho-biological features and genetic alterations that characterize human pancreatic cancer and may be used collectively or selectively as a markedly improved in vivo tool for preclinical and molecular studies of pancreatic cancer.
authors.affiliation: Pathology Division, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Panayiotis
authors.initials: P
authors.lastname: Loukopoulos
authors.forename: Kengo
authors.initials: K
authors.lastname: Kanetaka
authors.forename: Masaaki
authors.initials: M
authors.lastname: Takamura
authors.forename: Tatsuhiro
authors.initials: T
authors.lastname: Shibata
authors.forename: Michiie
authors.initials: M
authors.lastname: Sakamoto
authors.forename: Setsuo
authors.initials: S
authors.lastname: Hirohashi
mesh_terms: D000230:Adenocarcinoma / Q000737:chemistry / Q000235:genetics / Q000473:pathology* / Q000556:secondary; D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation; D045744:Cell Line, Tumor / Q000637:transplantation; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000032:analysis; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000032:analysis / Q000235:genetics; D004268:DNA-Binding Proteins / Q000032:analysis / Q000235:genetics; D017353:Gene Deletion; D019942:Genes, p16; D016158:Genes, p53; D011905:Genes, ras; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000556:secondary; D008175:Lung Neoplasms / Q000235:genetics / Q000556:secondary; D008207:Lymphatic Metastasis / Q000235:genetics; D008297:Male; D051379:Mice; D016513:Mice, SCID; D020125:Mutation, Missense; D009363:Neoplasm Proteins / Q000032:analysis / Q000235:genetics; D009368:Neoplasm Transplantation / Q000379:methods*; D010179:Pancreas; D010190:Pancreatic Neoplasms / Q000737:chemistry / Q000235:genetics / Q000473:pathology*; D010534:Peritoneal Neoplasms / Q000235:genetics / Q000556:secondary; D016133:Polymerase Chain Reaction; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras) / Q000032:analysis; D051901:Smad4 Protein; D013047:Specific Pathogen-Free Organisms; D015534:Trans-Activators / Q000032:analysis / Q000235:genetics; D014183:Transplantation, Heterologous; D016159:Tumor Suppressor Protein p53 / Q000032:analysis
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D009363:Neoplasm Proteins; C497796:SMAD4 protein, human; D051901:Smad4 Protein; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)