Accelerated orthotopic hepatocellular carcinomas growth is linked to increased expression of pro-angiogenic and prometastatic factors in murine liver fibrosis.
BACKGROUND
Most experimental therapy studies are performed in mice that bear subcutaneous or orthotopic hepatoma but are otherwise healthy. We questioned whether a pre-existing fibrosis affects tumour development of implanted syngenic hepatoma cells. To further investigate a selected panel of factors involved in tumour growth, tumour organ samples were characterized for gene expression of vascular endothelial growth factor (VEGF)-A/-C, VEGF receptors Flt1, Flk-1, Flt-4 and for VEGF-A protein levels.


RESULTS
The presented data show that tumour sizes were 3.7-fold increased and fibrotic livers had numerous satellites. Increased tumour sizes were associated with elevated intratumoral VEGF-A protein amounts and intratumoral increased VEGF receptor gene expression levels in tumour tissue from fibrotic livers as compared with non-fibrotic livers. Additionally, intratumoral gene expression levels of matrix metalloproteinase-2 (MMP-2) and MMP-9 were elevated in fibrotic mice.


CONCLUSIONS
Our results indicate that liver fibrosis stimulates tumour development of implanted syngenic hepatoma cells. Accelerated tumour growth was going along with elevated intratumoral VEGF-A and VEGF-A receptor status, which most probably mediated pro-angiogenic and prometastatic effects in this model. Furthermore, advanced tumour spread was associated with increased MMP-2/-9 expression. These data suggest that the intratumoral VEGF-A proteins levels and VEGF receptor status contribute to accelerated hepatocellular carcinoma development in fibrotic mice and that elevated MMP-2, MMP-9 and VEGF-C levels could promote tumour metastasis in this model.
Kornek
Miroslaw
M
Department of Internal Medicine I, University Hospital, Bonn, Germany.
Raskopf
Esther
E
Tolba
Rene
R
Becker
Ursula
U
Klöckner
Maren
M
Sauerbruch
Tilman
T
Schmitz
Volker
V
D042702:Angiopoietin-2 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology*; D018076:DNA, Complementary / Q000032:analysis; D004195:Disease Models, Animal; D018450:Disease Progression; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D008103:Liver Cirrhosis / Q000378:metabolism / Q000473:pathology*; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008809:Mice, Inbred C3H; D011336:Probability; D012334:RNA, Neoplasm / Q000032:analysis; D011897:Random Allocation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012680:Sensitivity and Specificity; D018709:Statistics, Nonparametric; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics / Q000378:metabolism*
D042702:Angiopoietin-2; D014408:Biomarkers, Tumor; D018076:DNA, Complementary; D012334:RNA, Neoplasm; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1