In vivo cell lineage analysis during chemical hepatocarcinogenesis in rats using retroviral-mediated gene transfer: evidence for dedifferentiation of mature hepatocytes.
ABSTRACT Feeding adult rats with a diet containing 2-acetylaminofluorene (2-AAF) results in suppression of hepatocyte proliferation and stimulation of oval cell proliferation. Although oval cells may be facultative liver stem cells, the actual relationship between oval cells and liver cancer has not been clearly established in vivo. Our goal was to label hepatic cells in vivo using retroviral vectors and follow their fate during the early steps of chemically induced hepatocarcinogenesis. Oval cell proliferation was induced by continuous feeding with a carcinogenic diet containing 2-AAF. We used two different strategies to genetically label hepatic cells: (a) labeling of proliferating cells in rats fed 2-AAF by injecting recombinant retroviral vectors containing the beta-galactosidase gene either in a peripheral vein or in the common bile duct at the peak of oval cell proliferation and (b) prelabeling of hepatocytes by intravenously injecting recombinant vectors 1 day after partial hepatectomy and 1 week before subsequent administration of 2-AAF. Using the first strategy, transgene expression occurred in both oval cells and hepatocytes. Using the second strategy, we could selectively label, and hence study the fate of, differentiated hepatocytes. In the latter case, we observed clusters of beta-galactosidase-positive hepatocytes, some of them also expressing preneoplastic markers such as gamma-glutamyl transpeptidase as well as the placental form of glutathione-S-transferase. These results demonstrate that preneoplastic foci can originate from mature hepatocytes and are consistent with the hypothesis that dedifferentiation of mature hepatocytes may occur during the course of carcinogenic regimen.
- SourceAvailable from: Antonio Facciorusso[Show abstract] [Hide abstract]
ABSTRACT: The liver has 3 cell lineages able to proliferate after a hepatic injury: the mature hepatocyte, the ductular “bipolar” progenitor cell termed “oval cell” and the putative periductular stem cell. Hepatocytes can only produce other hepatocytes whereas ductular progenitor cells are considerate bipolar since they can give rise to biliary cells or hepatocytes. Periductular stem cells are rare in the liver, have a very long proliferation potential and may be multipotent, being this aspect still under investigation. They originate in the bone marrow since their progeny express genetic markers of donor hematopoietic cells after bone marrow transplantation. Since the liver is the hematopoietic organ of the fetus, it is possible that hematopoietic stem cells may reside in the liver of the adult. This assumption is proved by the finding that oval cells express hematopoietic markers like CD34, CD45, CD 109, Thy-1, c-kit, and others, which are also expressed by bone marrow-derived hematopoietic stem cells (BMSCs). Few and discordant studies have evaluated the role of BMSC in hepatocarcinogenesis so far and further studies in vitro and in vivo are warranted in order to definitively clarify such an issue.Hepatobiliary surgery and nutrition. 08/2014;
Article: Liver carcinogenesis[Show abstract] [Hide abstract]
ABSTRACT: Hepatocellular carcinoma occurs most commonly in the setting of cirrhosis, where the annual rate of cancer development approximates 3-7%. Most cases arise in the setting of impaired liver regeneration combined with chronic inflammation and fibrosis. Liver progenitor cells play an important role in cell renewal processes in the liver in the setting of chronic injury and have recently emerged as potential candidates in the carcinogenic pathway. There are two main hypotheses which have been proposed to explain hepatocellular carcinogenesis, namely the de-differentiation and the maturation arrest hypotheses. Understanding the carcinogenic pathways and the role of liver progenitor cells will provide greater understanding and novel approaches to preventative strategies.
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ABSTRACT: Primary hepatocellular carcinoma (HCC) is a common malignancy that has a poor prognosis because it is often diagnosed at an advanced stage. HCC normally develops as a consequence of underlying liver disease and is most often associated with cirrhosis. Surgical resection and liver transplantation are the current best options to treat liver cancer. However, problems associated with liver transplantation, such as shortage of donors, risk of immune rejection, and tissue damage following surgery provided the impetus for development of alternative therapies. The emerging field of stem cell therapy has raised hopes for finding curative options for liver cancer. Stem cells have the ability not only to proliferate after transplantation but also to differentiate into most mammalian cell types in vivo. In this review, progress on stem cell-derived technologies for the treatment of liver cancer is discussed.Stem Cells and Cloning: Advances and Applications 01/2010; 3:81-92.