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

Abstract

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.

Induction of liver fibrosis in a murine hepatoma model by thioacetamide is associated with enhanced tumor growth and suppressed antitumor immunity

“…A complex interaction or cross-regulation between the hepatoma microenvironment and immune surveillance exists. That fibrosis can enhance the orthotopic hepatoma growth in a fibrotic liver has been reported by Kuriyama et al 10 and Kornek et al 11 Hepatoma cells grow faster and invade a tumor mass after implantation into the liver, and a comparison of the intratumor factors that favor the tumor cell growth or invasion in either a normal or fibrotic liver reveal that the increases of proangiogenic and prometastatic factors are found to accelerate the hepatoma growth. However, the immune surveillance was not evaluated in the liver.…”

1,2-Dioleoyl-3-Trimethylammonium-Propane (DOTAP)-Formulated, Immune-Stimulatory Vascular Endothelial Growth Factor A Small Interfering RNA (siRNA) Increases Antitumoral Efficacy in Murine Orthotopic Hepatocellular Carcinoma with Liver Fibrosis

“…injections of thioacetamide (TAA) (Sigma-Aldrich, Taufkirchen, Germany; 0.15 mg/g body weight) three times per wk for up to 24 wks in combination with alcohol feeding in sweetened drinking water (10% vol/vol) according to a published protocol (8,15,16).…”

“…Laparotomy for syngenic tumor cell implantation was performed as described elsewhere. (17) Briefly, 64 fibrotic mice were laparotomized and orthotopic tumors were established by subcapsular intrahepatic injection of 1.25 × 10 5 hepatoma cells (Hepa129) suspended in 50 µL RPMI into the left liver lobe. Postinjection bleeding and tumor cell escape were avoided by local compression.…”

“…Notably, once cirrhosis is established there is no proven effective HCC prevention, yet (7). Recently, we showed that hepatic fibrosis relevantly accelerates orthotopic HCC tumor growth and metastasis in fibrotic C3H/He mice (8). Kuriyama et al (9) reported that fibrosis seemed to affect metastasis.…”

Characterisation of a novel cell line (CSQT-2) with high metastatic activity derived from portal vein tumour thrombus of hepatocellular carcinoma

“…In addition, the mortality due to liver cancer has shown the fastest rate of increase in the United States, even though overall cancer-related mortality has been declining (www.seer.cancer.gov). In fact, liver cancer metastasis and recurrence are known to be highly lethal (Kornek et al, 2008). Unfortunately, the poor understanding of the development of HCC metastasis has been the main obstacle for the improvement of HCC therapy (Shuqun et al, 2004;Sun et al, 2007;Amarapurkar et al, 2008;Lim et al, 2008;Ramaiah and Rittling, 2008).…”