Limits...
Efficacy of mesenchymal stem cells in suppression of hepatocarcinorigenesis in rats: possible role of Wnt signaling.

Abdel aziz MT, El Asmar MF, Atta HM, Mahfouz S, Fouad HH, Roshdy NK, Rashed LA, Sabry D, Hassouna AA, Taha FM - J. Exp. Clin. Cancer Res. (2011)

Bottom Line: Gene expression in rat liver tissue demonstrated that MSCs downregulated β-catenin, proliferating cell nuclear antigen (PCNA), cyclin D and survivin genes expression in liver tissues after HCC induction.Amelioration of the liver status after administration of MSCs has been inferred by the significant decrease of ALT, AST and Alpha fetoprotein serum levels.Administration of MSCs before HCC induction did not show any tumor suppressive or protective effect.

View Article: PubMed Central - HTML - PubMed

Affiliation: Unit of Biochemistry and Molecular Biology, Department of Medical Biochemistry, Faculty of Medicine, Cairo University, Cairo, Egypt.

ABSTRACT

Background: The present study was conducted to evaluate the tumor suppressive effects of bone marrow derived mesenchymal stem cells (MSCs) in an experimental hepatocellular carcinoma (HCC) model in rats and to investigate the possible role of Wnt signaling in hepato-carcinogenesis.

Methods: Ninety rats were included in the study and were divided equally into: Control group, rats which received MSCs only, rats which received MSCs vehicle only, HCC group induced by diethylnitroseamine (DENA) and CCl(4), rats which received MSCs after HCC induction, rats which received MSCs before HCC induction. Histopathological examination and gene expression of Wnt signaling target genes by real time, reverse transcription-polymerase chain reaction (RT-PCR) in rat liver tissue, in addition to serum levels of ALT, AST and alpha fetoprotein were performed in all groups.

Results: Histopathological examination of liver tissue from animals which received DENA-CCl(4) only, revealed the presence of anaplastic carcinoma cells and macro-regenerative nodules type II with foci of large and small cell dysplasia. Administration of MSCs into rats after induction of experimental HCC improved the histopathological picture which showed minimal liver cell damage, reversible changes, areas of cell drop out filled with stem cells. Gene expression in rat liver tissue demonstrated that MSCs downregulated β-catenin, proliferating cell nuclear antigen (PCNA), cyclin D and survivin genes expression in liver tissues after HCC induction. Amelioration of the liver status after administration of MSCs has been inferred by the significant decrease of ALT, AST and Alpha fetoprotein serum levels. Administration of MSCs before HCC induction did not show any tumor suppressive or protective effect.

Conclusions: Administration of MSCs in chemically induced HCC has tumor suppressive effects as evidenced by down regulation of Wnt signaling target genes concerned with antiapoptosis, mitogenesis, cell proliferation and cell cycle regulation, with subsequent amelioration of liver histopathological picture and liver function.

Show MeSH

Related in: MedlinePlus

Hepatocellular carcinoma cells. (×400) Characterized by large anaplastic carcinoma cells with eosinophilic cytoplasm, large hyperchromatic nuclei and prominent nucleoli. The normal trabecular structure of the liver is distorted.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3113743&req=5

Figure 5: Hepatocellular carcinoma cells. (×400) Characterized by large anaplastic carcinoma cells with eosinophilic cytoplasm, large hyperchromatic nuclei and prominent nucleoli. The normal trabecular structure of the liver is distorted.

Mentions: Histopathology of liver tissues of the animals that received DENA and CCl4 only showed cells with neoplastic changes, anaplastic carcinoma cells, characterized by large cells with eosinophilic cytoplasm, large hyperchromatic nuclei and prominent nucleoli (Figure 5) and macroregenerative nodules typeII (borderline nodules) with foci of large and small cell dysplasia (Figure 6). Improvement of histopathological picture after the administration of MSCs into rats with HCC is demonstrated in figure(7); with minimal reversible liver cell damage in form of ballooning degeneration, areas of cell drop out filled with stem cells, normal areas with sinusoidal dilatation and congestion and absence of fibrous thickening of portal tracts, inflammation, dysplasia and absence of regenerative nodules. Figure (8) shows MSCs labeled with PKH26 fluorescent dye detected in the hepatic tissue, confirming that these cells homed into the liver tissue. Data obtained from the group which received MSCs only and the one which received MSCs solvent were similar to data obtained from healthy controls. On the other hand, HCC rat group and the rat group injected with stem cells prior to induction of HCC (the prophylactic group) showed significant increase in gene expression of all four genes when compared to controls (p < 0.05) (Figure 9), whereas no significant difference in the gene expression was detected in liver tissues of MSCs-treated HCC rats and control group. As regards serum levels of alpha fetoprotein (Figure 10), as well as ALT and AST (Figure 11); significant increase was found in HCC and the prophylactic group(p < 0.05), whereas no significant difference was detected in the HCC rats group treated with MSCs when compared to the control group.


Efficacy of mesenchymal stem cells in suppression of hepatocarcinorigenesis in rats: possible role of Wnt signaling.

Abdel aziz MT, El Asmar MF, Atta HM, Mahfouz S, Fouad HH, Roshdy NK, Rashed LA, Sabry D, Hassouna AA, Taha FM - J. Exp. Clin. Cancer Res. (2011)

Hepatocellular carcinoma cells. (×400) Characterized by large anaplastic carcinoma cells with eosinophilic cytoplasm, large hyperchromatic nuclei and prominent nucleoli. The normal trabecular structure of the liver is distorted.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3113743&req=5

Figure 5: Hepatocellular carcinoma cells. (×400) Characterized by large anaplastic carcinoma cells with eosinophilic cytoplasm, large hyperchromatic nuclei and prominent nucleoli. The normal trabecular structure of the liver is distorted.
Mentions: Histopathology of liver tissues of the animals that received DENA and CCl4 only showed cells with neoplastic changes, anaplastic carcinoma cells, characterized by large cells with eosinophilic cytoplasm, large hyperchromatic nuclei and prominent nucleoli (Figure 5) and macroregenerative nodules typeII (borderline nodules) with foci of large and small cell dysplasia (Figure 6). Improvement of histopathological picture after the administration of MSCs into rats with HCC is demonstrated in figure(7); with minimal reversible liver cell damage in form of ballooning degeneration, areas of cell drop out filled with stem cells, normal areas with sinusoidal dilatation and congestion and absence of fibrous thickening of portal tracts, inflammation, dysplasia and absence of regenerative nodules. Figure (8) shows MSCs labeled with PKH26 fluorescent dye detected in the hepatic tissue, confirming that these cells homed into the liver tissue. Data obtained from the group which received MSCs only and the one which received MSCs solvent were similar to data obtained from healthy controls. On the other hand, HCC rat group and the rat group injected with stem cells prior to induction of HCC (the prophylactic group) showed significant increase in gene expression of all four genes when compared to controls (p < 0.05) (Figure 9), whereas no significant difference in the gene expression was detected in liver tissues of MSCs-treated HCC rats and control group. As regards serum levels of alpha fetoprotein (Figure 10), as well as ALT and AST (Figure 11); significant increase was found in HCC and the prophylactic group(p < 0.05), whereas no significant difference was detected in the HCC rats group treated with MSCs when compared to the control group.

Bottom Line: Gene expression in rat liver tissue demonstrated that MSCs downregulated β-catenin, proliferating cell nuclear antigen (PCNA), cyclin D and survivin genes expression in liver tissues after HCC induction.Amelioration of the liver status after administration of MSCs has been inferred by the significant decrease of ALT, AST and Alpha fetoprotein serum levels.Administration of MSCs before HCC induction did not show any tumor suppressive or protective effect.

View Article: PubMed Central - HTML - PubMed

Affiliation: Unit of Biochemistry and Molecular Biology, Department of Medical Biochemistry, Faculty of Medicine, Cairo University, Cairo, Egypt.

ABSTRACT

Background: The present study was conducted to evaluate the tumor suppressive effects of bone marrow derived mesenchymal stem cells (MSCs) in an experimental hepatocellular carcinoma (HCC) model in rats and to investigate the possible role of Wnt signaling in hepato-carcinogenesis.

Methods: Ninety rats were included in the study and were divided equally into: Control group, rats which received MSCs only, rats which received MSCs vehicle only, HCC group induced by diethylnitroseamine (DENA) and CCl(4), rats which received MSCs after HCC induction, rats which received MSCs before HCC induction. Histopathological examination and gene expression of Wnt signaling target genes by real time, reverse transcription-polymerase chain reaction (RT-PCR) in rat liver tissue, in addition to serum levels of ALT, AST and alpha fetoprotein were performed in all groups.

Results: Histopathological examination of liver tissue from animals which received DENA-CCl(4) only, revealed the presence of anaplastic carcinoma cells and macro-regenerative nodules type II with foci of large and small cell dysplasia. Administration of MSCs into rats after induction of experimental HCC improved the histopathological picture which showed minimal liver cell damage, reversible changes, areas of cell drop out filled with stem cells. Gene expression in rat liver tissue demonstrated that MSCs downregulated β-catenin, proliferating cell nuclear antigen (PCNA), cyclin D and survivin genes expression in liver tissues after HCC induction. Amelioration of the liver status after administration of MSCs has been inferred by the significant decrease of ALT, AST and Alpha fetoprotein serum levels. Administration of MSCs before HCC induction did not show any tumor suppressive or protective effect.

Conclusions: Administration of MSCs in chemically induced HCC has tumor suppressive effects as evidenced by down regulation of Wnt signaling target genes concerned with antiapoptosis, mitogenesis, cell proliferation and cell cycle regulation, with subsequent amelioration of liver histopathological picture and liver function.

Show MeSH
Related in: MedlinePlus