A novel orthotopic tumor model to study growth factors and oncogenes in hepatocarcinogenesis.
An orthotopic xenograft tumor model of hepatocellular carcinoma was created by injection of Hep 3B cells directly into the liver parenchyma of nude mice. Tumors were localized primarily in the injected lobe of the liver, beginning from the third week after tumor cell implantation. Thereafter, tumors grew rapidly, and animals usually died from hepatocellular carcinoma within 2 months. Insulin-like growth factor II, an embryonic growth factor and mitogen, is overexpressed in these tumors at both mRNA and protein levels. Oncogenes, such as c-myc, c-fos, and c-jun, are also up-regulated in this model. alpha-Fetal protein can be detected shortly after implantation and correlates with tumor growth, and measurement of serum alpha-fetal protein serves as an early biomarker to monitor the effect of antitumor therapy. Using this model, we have shown that inhibition of insulin-like growth factor II expression by a short methylated oligonucleotide prolongs survival. This in situ tumor model thus provides a fast, reliable, and reproducible means to study the therapeutic effect of inhibitors of growth factors and oncogenes in liver cancer.
Yao
Xiaoming
X
Medical Service, VA Palo Alto Health Care System and Division of Endocrinology, Department of Medicine, Stanford University, Palo Alto, California 94304, USA. arhoffman@stanford.edu
Hu
Ji-Fan
JF
Daniels
Mark
M
Yien
Huifan
H
Lu
Hongqi
H
Sharan
Hadas
H
Zhou
Xiangjun
X
Zeng
Zhilan
Z
Li
Tao
T
Yang
Youwen
Y
Hoffman
Andrew R
AR
D000818:Animals; D015415:Biomarkers; D006528:Carcinoma, Hepatocellular / Q000473:pathology*; D002455:Cell Division; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D006133:Growth Substances / Q000378:metabolism*; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000378:metabolism; D008099:Liver / Q000473:pathology; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009841:Oligonucleotides / Q000494:pharmacology; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis; D016755:Proto-Oncogene Proteins c-jun / Q000096:biosynthesis; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors; D015854:Up-Regulation; D000509:alpha-Fetoproteins / Q000096:biosynthesis
D015415:Biomarkers; D006133:Growth Substances; D009841:Oligonucleotides; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D000509:alpha-Fetoproteins; D007335:Insulin-Like Growth Factor II