Liver cancer: the role of stem cells

Abstract

Studies of aggregation chimaeras and X-linked polymorphisms strongly suggest that liver tumours are derived from single cells (monoclonal), but the important question is, which cell? Stem cell biology and cancer are inextricably linked. In continually renewing tissues such as the gut mucosa and epidermis, where a steady flux of cells occurs from the stem cell zone to the terminally differentiated cells that are imminently to be lost, it is widely accepted that cancer is a disease of stem cells, since these are the only cells that persist in the tissue for a sufficient length of time to acquire the requisite number of genetic changes for neoplastic development. In the liver the identity of the founder cells for the two major primary tumours, hepatocellular carcinoma and cholangiocarcinoma, is more problematic. The reason for this is that no such obvious unidirectional flux occurs in the liver, although it is held that the centrilobular hepatocytes may be more differentiated (polyploid) and closer to cell senescence than those cells closest to the portal areas. Moreover, the existence of bipotential hepatic progenitor cells, along with hepatocytes endowed with longevity and long-term repopulating potential suggests there may be more than one type of carcinogen target cell. Cell proliferation at the time of carcinogen exposure is pivotal for 'fixing' any genotoxic injury into a heritable form, thus any proliferative cell in the liver can be susceptible to neoplastic transformation. Hepatocytes are implicated in many instances of hepatocellular carcinoma, direct injury to the biliary epithelium implicates cholangiocytes in some cases of cholangiocarcinoma, while hepatic progenitor cell/oval cell activation accompanies many instances of liver damage irrespective of aetiology, making such cells very likely carcinogen targets. Of course, we must qualify this assertion by stating that many carcinogens are both cytotoxic and cytostatic, and that hepatic progenitor cell proliferation may be merely a bystander effect of this toxicity. An in-depth discussion of causes of cancer in the liver is beyond the scope of this review, but infectious agents (e.g. hepatitis B and C viruses) play a major role, not just in transactivating or otherwise disrupting cellular proto-oncogenes (hepatitis B virus), but also in causing chronic inflammation (hepatitis C and B viruses). Sustained epithelial proliferation in a milieu rich in inflammatory cells, growth factors and DNA-damaging agents (reactive oxygen and nitrogen species--produced to fight infection), will lead to permanent genetic changes in proliferating cells. Up-regulation of the transcription factor NF-kappaB in transformed hepatocytes, through the paracrine action of TNF-alpha from neighbouring endothelia and inflammatory cells, may be critical for tumour progression given the mitogenic and antiapoptotic properties of proteins encoded by many of NF-kappaB's target genes.

Figure 1

(a) An oval cell reaction in the rat liver. Oval cells, highlighted by cytokeratin 19 immunoexpression, branch out from the portal tract (PT). (b) An extensive ductular reaction in a human liver in response to parenchymal necrosis. Both hepatocytes and ductular cells express cytokeratin 18, but the strongest expression is in the ductular cells.

Figure 2

Ductular reaction in a case of massive hepatic necrosis due to acetaminophen toxicity, immunohistochemically stained for CK7. Note many intermediate cells still with a bilary‐type staining pattern (CK7 +), but with a morphology midway between cholangiocytes and hepatocytes (courtesy of Professsor Tania Roskams and with permission from John Wiley Publishers).

Figure 3

Schematic diagram of the various lineages that respond to specific cell damaging insults and therefore are likely founder cells for the tumours that subsequently develop. (1) The cells that normally respond to hepatocyte loss are the hepatocytes themselves; (2) potential stem cells may reside in the canal of Hering and they or their progeny (oval cells/hepatic progenitor cells) may give rise to most HCCs; (3) the interlobular bile duct epithelia may give rise to CCs associated with fluke infection; and (4) periductular cells are associated with experimental hepatocarcinogenesis when animals are fed ethionine in a choline‐deficient diet. Largely based on an idea by Stewart Sell.

Figure 4

An oval cell reaction in a Long Evans Cinnamon (LEC) rat. These animals develop HCC and CC with a high frequency.

Figure 5

(a) A multistep model for the progression to HCC in human liver. Chronic inflammation may not only initiate the carcinogenic process, but may also be important for subsequent progression via inflammatory cytokines such as TNFα, that through NF‐κB signalling cause (1) more oxidative cell damage (iNOS), (2) promoting cell growth (COX‐2) and (3) suppressing apoptosis (Bcl‐X_L and IAPs) – see Pikarsky et al. (2004). HPCs may be involved in the histogenesis of many HCCs and give rise to foci of small cell dysplasia. Further rounds of mutation and clonal expansion may give rise to other precancerous lesions such as ‘low grade dysplastic nodules’ (LGDN) and ‘high grade dysplastic nodules’ (HGDN) before HCC develops. (b) Cartoon of the morphological correlates of this process.

Figure 6

HPCs (arrowheads) in a hepatic adenoma immunoreactive for CK19 (a), OV‐6 (b) and chromogranin‐A (c). Intermediate hepatocyte‐like cells (arrows) positive for OV‐6 and chromogranin‐A surround the HPCs (courtesy of Professor Tania Roskams).