Orthotopic transplantation models of pancreatic adenocarcinoma derived from cell lines and primary tumors and displaying varying metastatic activity.
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.
Loukopoulos
Panayiotis
P
Pathology Division, National Cancer Center Research Institute, Tokyo, Japan.
Kanetaka
Kengo
K
Takamura
Masaaki
M
Shibata
Tatsuhiro
T
Sakamoto
Michiie
M
Hirohashi
Setsuo
S
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
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)