Validation of a Preclinical Model of Diethylnitrosamine-Induced Hepatic Neoplasia in Yucatan Miniature Pigs.
OBJECTIVE
The purpose of this study was to reduce the time to tumor onset in a diethylnitrosamine (DEN)-induced hepatocellular carcinoma (HCC) swine model via partial liver embolization (PLE) and to characterize the model for use in translational research.


METHODS
Eight Yucatan miniature pigs were injected intraperitoneally with either saline (n = 2) or DEN (n = 6) solution weekly for 12 weeks. Three of the DEN-treated pigs underwent PLE. The animals underwent periodic radiological evaluation, liver biopsy, and blood sampling, and full necropsy was performed at study termination (∼29 months).


RESULTS
All DEN-treated pigs developed hepatic adenoma and HCC. PLE accelerated the time to adenoma development but not to HCC development. Biomarker analysis results showed that IGF1 levels decreased in all DEN-treated pigs as functional liver capacity decreased with progression of HCC. VEGF and IL-6 levels were positively correlated with disease progression. Immunohistochemical probing of HCC tissues demonstrated the expression of several important survival-promoting proteins.


CONCLUSIONS
To our knowledge, we are the first to demonstrate an accelerated development of hepatic neoplasia in Yucatan miniature pigs. Our HCC swine model closely mimics the human condition (i.e., progressive disease stages and expression of relevant molecular markers) and is a viable translational model.
Department of Veterinary Medicine and Surgery, The University of Texas MD Anderson Cancer Center, Houston, Tex., USA.
Jennifer
J
Mitchell
Peggy T
PT
Tinkey
Rony
R
Avritscher
Carolyn
C
Van Pelt
Ghazaleh
G
Eskandari
Suraj
S
Konnath George
Lianchun
L
Xiao
Erik
E
Cressman
Jeffrey S
JS
Morris
Asif
A
Rashid
Ahmed O
AO
Kaseb
Hesham M
HM
Amin
Rajesh
R
Uthamanthil
D000236:Adenoma / Q000097:blood* / Q000139:chemically induced / Q000473:pathology*; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000097:blood* / Q000139:chemically induced / Q000473:pathology; D004052:Diethylnitrosamine; D004195:Disease Models, Animal; D004617:Embolism / Q000139:chemically induced; D005260:Female; D013006:Growth Hormone / Q000097:blood; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D015850:Interleukin-6 / Q000097:blood; D053614:Janus Kinase 2 / Q000032:analysis; D008114:Liver Neoplasms, Experimental / Q000097:blood* / Q000139:chemically induced / Q000473:pathology*; D011169:Portal Vein; D017451:Receptors, Somatomedin / Q000032:analysis; D050796:STAT3 Transcription Factor / Q000032:analysis; D050799:STAT5 Transcription Factor / Q000032:analysis; D013552:Swine; D013556:Swine, Miniature; D013997:Time Factors; D042461:Vascular Endothelial Growth Factor A / Q000097:blood; D000509:alpha-Fetoproteins / Q000378:metabolism
D015850:Interleukin-6; D017451:Receptors, Somatomedin; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; D042461:Vascular Endothelial Growth Factor A; D000509:alpha-Fetoproteins; D004052:Diethylnitrosamine; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone; D053614:Janus Kinase 2