A Link Between Liver Development, Regeneration, and Carcinogensis

The liver has long been recognized as having marked capacity for regeneration. However, it is only lately that we have been able to characterize and define the stem cell populations that contribute to the regeneration of the liver. Several new biomarkers have enabled a new understanding of human hepatic stem cells which has changed the way we think about the relationship between liver development, regeneration, and carcinogenesis. The following is a summary of recent advances in the field of stem cell biology relevant to liver pathology.

Research from the group of Lola M. Reid at the University of North Carolina is bringing the human hepatic stem cells (hHpSC) into clear focus. A study from 2008 published in Hepatology found hHpSC concentrated in the ductal plate during development and restricted to the terminal biliary ducts (canals of hering) in normal adult tissues.  hHpSC are a separate population from the Hepatoblast (HB) which had formerly been regarded as the only stem cell population in the liver. The article defines these two distinct cell populations...

The combination of antigens that uniquely defines hHpSCs (EpCAM, NCAM, CK19, and albumin, but not AFP) is evident in the ductal plates in fetal and neonatal livers and in the canals of Hering in adults. The combination of antigens uniquely defining hHBs (EpCAM, ICAM, CK19, albumin, AFP) is not in cells in the ductal plates but is present in cells throughout the parenchyma of fetal and neonatal livers and in individual cells or small groups of cells connecting to one end of, or adjacent to, a canal of Hering in pediatric and adult livers.

This new perspective allowed the further study of the role these primitive compartments play in the regeneration of human livers. The authors found that the biliary ductular reaction, the putative progenitors that arise from the canals of hering following liver injury, is an expansion of progenitors originating from the hHpSC and HB. Interestingly though, the population that gives rise to the ductular reaction differs depending on the type of injury.

The primary regenerative responses to liver necrosis involve expansion of the hHpSCs (Ep-CAM+, NCAM+, but AFP negative), whereas those in biliary cirrhosis involves presumptive hHBs (EpCAM+at the plasma membrane and ICAM+, AFP+). In hepatic cirrhosis, both populations can be involved.

In a studied carried out by another group, Zhou et al., (Hepatology 2007) showed that a similar set of markers was useful in distinguishing the lineages that the ductular reactions cells contribute to. This study generated beautiful images that depict the ductular reactions becoming bipolarized into hepatocytic and cholangiocytic lineages. An investigation into the transcription factors that are expressed in these ductular reactions confirmed that developmental genes are reactivated and similarly showed differences in expression profiles between injury groups.

I have previously posted on the role of stem cells in tumorigenesis, and hepatic stem cells are a prime suspect for the originating cell of hepatocellular carcinoma (HCC). Last year, Yamashita et al, found an aggressive subset of HCC that contains EpCAM+ cells with the molecular signature of hHpSC. The authors of this study further demonstrated that the EpCAM+ cells are a tumor initiating population and that molecular knockdown of the EpCAM-WNT signalling pathway can attenuate tumor growth. This provides a therapuetics strategy whereby a patient's HCC is assayed for EpCAM expression to determine if anti-EpCAM therapies are indicated. Adecatumumab, an Anti-EpCAM monclonal antibody, has already been used in clinical trials for breast and other cancers. This is an example of a personalized medicine/ targeted molecular therapeutics strategy that is similar to the algorithms now in use for Her2 positive breast cancers and EGFR+/K-Ras wild-type colon cancers.

A pattern is emerging that shows that some tissue stem cells re-express the molecular regulators that govern the embryonic development during regeneration. Further, our new understanding of this link between development and regeneration has opened up new therapeutic areas for cancers that exploit the molecular pathways and mechanisms of the stem cell state for tumor growth, invasions, and metastasis. This is just one area where our pursuit of stem cell research, both embryonic and adult, will lead to new therapeutics for diseases with few, if any, treatments that work.



Zhang L, Theise N, Chua M, & Reid LM (2008). The stem cell niche of human livers: symmetry between development and regeneration. Hepatology (Baltimore, Md.), 48 (5), 1598-607 PMID: 18972441

Zhou H, Rogler LE, Teperman L, Morgan G, & Rogler CE (2007). Identification of hepatocytic and bile ductular cell lineages and candidate stem cells in bipolar ductular reactions in cirrhotic human liver. Hepatology (Baltimore, Md.), 45 (3), 716-24 PMID: 17326146

Yamashita T, Ji J, Budhu A, Forgues M, Yang W, Wang HY, Jia H, Ye Q, Qin LX, Wauthier E, Reid LM, Minato H, Honda M, Kaneko S, Tang ZY, & Wang XW (2009). EpCAM-positive hepatocellular carcinoma cells are tumor-initiating cells with stem/progenitor cell features. Gastroenterology, 136 (3), 1012-24 PMID: 19150350

Limaye PB, Alarcón G, Walls AL, Nalesnik MA, Michalopoulos GK, Demetris AJ, & Ochoa ER (2008). Expression of specific hepatocyte and cholangiocyte transcription factors in human liver disease and embryonic development. Laboratory investigation; a journal of technical methods and pathology, 88 (8), 865-72 PMID: 18574450

Stem cell biology challenges traditional view of tumorigenesis

A very interesting aspect of stem cell biology is the hypothesis that stem cells and progenitors may be the origin of some cancers.  Below is an excerpt from the research group web page of Dr. Eva Hernando.  I believe this sums up the current views on this subject quite nicely.

Traditionally, mature cells in specific tissues and organs have been regarded as the cell-of-origin of the corresponding tumors. However, the observation that tumor cells need to accumulate genetic and phenotypic alterations over extended time periods has turned the view in recent years to stem cells or progenitors with a prolonged lifespan, broadly distributed in local reservoirs [1]. These cells, in charge of maintaining tissue homeostasis, are now considered as the potential target of neoplastic transformation.

Although this notion has been largely accepted for certain leukemias and lymphomas in which the corresponding hematopoietic progenitors are precisely defined, this theory has not yet permeated the field of solid tumors, with few exceptions [2-4]. The identification of maturation stages in non-hematopoietic (i.e., epithelial, mesenchymal) cell types is proving difficult due to the lack of distinctive markers and the low abundance of such intermediates in adult tissues, except after trauma-induced regeneration.

Our laboratory is studying whether certain sarcomas originate from mesenchymal progenitors [5, 6] and whether melanomas result from transformation of melanocytic precursors [7, 8]. Moreover, we hypothesize that alterations in the normal differentiation process of these progenitors act at early stages of tumor initiation, and that the retention or reactivation of stem cell properties may contribute to tumor progression and aggressive behavior (resistance to therapy, metastasis). A limitation for these studies is our partial understanding of the normal differentiation process of these two lineages.

The stem cell state and the process of differentiation are regulated in part by signalling pathways, many of which are a function of kinase activity.  Will we be able to target these stem cell specific pathways with small molecule inhibitors to prevent cancers?