A novel animal model for in vivo study of liver cancer metastasis

AIM:To establish an animal model with human hepatocyte-repopulated liver for the study of liver cancer metastasis.METHODS:Cell transplantation into mouse livers was conducted using alpha-fetoprotein(AFP)-producing hu-man gastric cancer cells(h-GCCs) and h-hepatocytes as donor cells in a transgenic mouse line expressing urokinase-type plasminogen activator(uPA) driven by the albumin enhancer/promoter crossed with a severe combined immunodeficient(SCID) mouse line(uPA/SCID mice).Host mice were divided into two groups(A and B).Group A mice were transplanted with h-GCCs alone,and group B mice were transplanted with h-GCCs and h-hepatocytes together.The replacement index(RI),which is the ratio of transplanted h-GCCs and h-hepatocytes that occupy the examined area of a histological section,was estimated by measuring h-AFP and h-albumin concentrations in sera,respectively,as well as by immunohistochemical analyses of h-AFP and human cytokeratin 18 in histological sections.RESULTS:The h-GCCs successfully engrafted,repopulated,and colonized the livers of mice in group A(RI = 22.0% ± 2.6%).These mice had moderately differentiated adenocarcinomatous lesions with disrupted glandular structures,which is a characteristics feature of gastric cancers.The serum h-AFP level reached 211.0 ± 142.2 g/mL(range,7.1-324.2 g/mL).In group B mice,the h-GCCs and h-hepatocytes independently engrafted,repopulated the host liver,and developed colonies(RI = 12.0% ± 6.8% and 66.0% ± 12.3%,respectively).h-GCC colonies also showed typical adenocarcinomatous glandular structures around the h-hepatocyte-colonies.These mice survived for the full 56 day-study and did not exhibit any metastasis of h-GCCs in the extrahepatic regions during the observational period.The mice with an h-hepatocyte-repopulated liver possessed metastasized h-GCCs and therefore could be a useful humanized liver animal model for studying liver cancer metastasis in vivo.CONCLUSION:A novel animal model of human liver cancer metastasis was established using the uPA/SCID mouse line.This model could be useful for in vivo testing of anti-cancer drugs and for studying the mechanisms of human liver cancer metastasis.

Comparison between bioartificial and artificial liver for the treatment of acute liver failure in pigs

AIM: To characterize and evaluate the therapeuti efficacy of bioartificial liver (BAL) as compared to tha of continuous hemodiafiltration (CHDF) with plasma exchange (PE), which is the current standard therapy fo fulminant hepatic failure (FHF) in Japan. METHODS: Pigs with hepatic devascularization were divided into three groups: (1) a non-treatment group (NT; n = 4); (2) a BAL treatment group (BAL; n = 4) (3) a PE + CHDF treatment group using 1.5 L of norma porcine plasma with CHDF (PE + CHDF, n = 4). Our BA system consisted of a hollow fiber module with 0.2 μm pores and 1 x 1010 of microcarrier-attached hepatocyte inoculated into the extra-fiber space. Each treatment wa initiated 4 h after hepatic devascularization. RESULTS: The pigs in the BAL and the PE + CHD groups survived longer than those in the NT group. The elimination capacity of blood ammonia by both BAL and PE + CHDF was significantly higher than that in NT Aromatic amino acids (AAA) were selectively eliminated by BAL, whereas both AAA and branched chain amino acids, which are beneficial for life, were eliminated by PE + CHDF. Electrolytes maintenance and acid-base balance were better in the CPE + CHDF group than that in the BAL group. CONCLUSION: Our results suggest that PE + CHDF eliminate all factors regardless of benefits, wherea BAL selectively metabolizes toxic factors such as AAA However since PE + CHDF maintain electrolytes and acid-base balance, a combination therapy of BAL plu CPE + CHDF might be more effective for FHF.

mPGES-1 expression in non-cancerous liver tissue impacts on postoperative recurrence of HCC

AIM:To investigate whether microsomal prostaglandin E synthase-1 (mPGES-1) expression in hepatocellular carcinoma (HCC) and in non-cancerous liver affects HCC prognosis after hepatectomy. METHODS: The relationship between patient clinical prof iles, tumor factors, surgical determinants, and mPGES-1 expression and the recurrence-free survival rate were examined in 64 patients who underwent curative hepatectomy between March 2003 and December 2006. RESULTS: The scores for mPGES-1 expression were higher in well differentiated and moderately differentiated HCC tissues than in poorly differentiated HCC tissues (well differentiated, 5.1 ± 2.7; moderately differentiated, 5.1 ± 1.7; poorly differentiated, 3.0 ± 1.8). In noncancerous liver tissues, the mPGES-1 levels were higher in injured liver tissues than in normal tissues. Cirrhotic livers had higher mPGES-1 levels than livers with chronic hepatitis (normal livers, 3.3 ± 0.7; chronic hepatitic livers, 5.4 ± 1.9; cirrhotic livers, 6.4 ± 1.6). A univariate analysis revealed that the recurrence-free survival rate was signif icantly lower in patients with vascular invasion,a higher mPGES-1 level in non-cancerous liver tissue,a larger tumor diameter (≥5 cm), and a lower serum albumin level (≤3.7 g/dL). The mPGES-1 expression in HCC tissues did not correlate well with postoperative recurrence. A multivariate analysis demonstrated that the presence of vascular invasion and higher mPGES-1 levels were statistically significant independent predictors for early postoperative recurrence of HCC.CONCLUSION: Increased mPGES-1 expression in noncancerous liver tissues is closely associated with the early recurrence of HCC after curative resection.