Microarray profiling shows distinct differences between primary tumors and commonly used preclinical models in...

Area of Science:

• Oncology
• Translational Research
• Genomics

Background:

• Hepatocellular carcinoma (HCC) outcomes remain poor despite therapeutic advances.
• Effective systemic therapies are urgently needed for HCC.
• Preclinical models often fail to predict clinical efficacy due to functional differences from primary tumors.

Purpose of the Study:

• To compare gene expression profiles and tumor morphology between primary HCC tumors, xenografts, and cell lines.
• To assess the clinical relevance of commonly used HCC preclinical models.

Main Methods:

• HepG2 cell lines and patient tumor explants were implanted subcutaneously and orthotopically in mice.
• Gene expression profiling was performed on extracted RNA.
• Principal component analyses (PCA) and dendrograms were used for data analysis.

Main Results:

• HepG2 models and their xenografts significantly differed from primary HCC tumors.
• Patient-derived xenografts (PDXs) showed divergent expression profiles from their original primary tumors.
• Gene expression profiles of xenografts showed limited impact from implantation site (orthotopic vs. ectopic).

Conclusions:

• Commonly used HCC preclinical models, including HepG2 and PDXs, lack clinical representativeness.
• The site of implantation had minimal effect on xenograft gene expression.
• These findings challenge the utility of current preclinical models and the notion of orthotopic PDXs as the gold standard for HCC research.