Accelerated orthotopic hepatocellular carcinomas growth is linked to increased expression of pro-angiogenic and prometastatic factors in murine liver fibrosis


Dr Volker Schmitz, Medizinische Klinik I, Sigmund-Freud-Str. 25, 53105 Bonn, Germany
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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.

Conclusion: 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.