Efficacy of Mesenchymal Stem Cells in Suppression of Hepatocarcinorigenesis in Rats: Possible Role of Wnt Signaling

Abstract

BackgroundThe 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.MethodsNinety 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 CCl4, 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.ResultsHistopathological examination of liver tissue from animals which received DENA-CCl4 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.ConclusionsAdministration 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.

Novel protective role of curcumin and taurine combination against experimental hepatocarcinogenesis

“…At 6 weeks, the DENA-injected rat liver tissues showed dysplastic changes, including disorganized hepatic tissue. These results were consistent with a previous study, in which hepatocarcinogenesis was shown to be induced in rats at 6 weeks following injection with DENA and weekly subcutaneous injection of CCL4 (65). In the present study, DENA injection for 8 weeks resulted in malignant changes of the liver tissues, including disorganized and irregularly arranged hepatocytes.…”

Adipose derived mesenchymal stem cells transplantation via portal vein improves microcirculation and ameliorates liver fibrosis induced by CCl4 in rats

“…MSCs have also been proved to be a potential solution in severe liver injury such as ischemia-reperfusion injury [23], acute liver failure [24], or hepatocellular carcinoma [25]. …”

Bone Marrow Cell Therapy on 1,2-Dimethylhydrazine (DMH)-Induced Colon Cancer in Rats

“…Another mechanism may be that the BMCs provide cytokines and growth factors in their microenvironment that enhance epithelial cells functions by paracrine mechanisms [40]. BMCs promote tissue renewing and repairing through synergistic down regulation of proinflammatory cytokines and increased production of soluble factors with antioxidant property.…”

“…Furthermore, cancer cells may produce proteins that can activate signaling pathways that facilitate and attract BMCs migration to the tumor site. As a result of injury, tissues produce chemokines attracting the circulated BMCs, and can produce circulating microvesicles including RNA, proteins and a variety of signals argument the tumor growth [40]. …”