Cancer Stem cells and their cellular origins in primary liver and biliary tract cancers

Abstract

Liver and biliary tract cancers are highly aggressive, are heterogeneous in their phenotypic traits, and result in clinical outcomes that are difficult to manage. Cancers have subpopulations of cells termed "cancer stem cells" (CSCs) that share common intrinsic signaling pathways for self-renewal and differentiation with normal stem cells. These CSCs likely have the potential to evolve over time and to give rise to new genetically and functionally diverse subclones by accumulating genetic mutations. Extrinsic signaling from the tumor microenvironment, including the CSC niche, has been implicated in tumor initiation/progression and heterogeneity through dynamic crosstalk. CSCs have become recognized as pivotal sources of tumor initiation/progression, relapse/metastasis, and chemoresistance. Conclusion: The origins of CSCs are hypothesized to derive from the transformation of normal stem/progenitors and/or from the reprogramming of adult cells that converts them to stem/progenitor traits; however, the precise mechanisms have not yet been fully elucidated. (HEPATOLOGY 2016;64:645-651)

Activation of pluripotent genes in hepatic progenitor cells in the transition of nonalcoholic steatohepatitis to pre-malignant lesions

“…8,19 The remaining question is what these pluripotent transcription factors will do when they are activated in vivo such as in hepatic progenitor cells or steatotic hepatocytes in an inflammatory environment, since both hepatic progenitor cells and steatotic hepatocytes are thought to be possible origins of NASH-HCC. 20,21 Growing evidence from hepatitis virus-positive specimens has shown that c-Myc, KLF-4, Nanog, and Oct-4, as well as a morphogenic gene Gli-1 are highly expressed in HCC with HBV infection, and may serve as an indication of poor prognosis. 22,23 However, no studies are seen whether these factors are activated in NASH-HCC, and the influences of these factors on hepatic progenitor cells in the transition from NASH to HCC remain unexplored.…”

Pathology of intrahepatic cholangiocarcinoma

“…Recent research has brought up several new insights into the cellular origin of iCC (referring to a normal cell that acquires the first cancer-initiating mutation), indicative of possible multiple cell lineages origin (32,33). Histogenesis complexity and different molecular mechanisms underlying the diverse growth patterns of this malignancy is an object of clinical concern.…”

“…iCC may develop from intrahepatic epithelial lining of small to large BD and PBGs (32,33), from malignant transformation of ductules, from HPCs of canal of Hering or periductal glands stem niche or through oncogenic reprogramming of adult hepatocytes. However, these conclusions are largely based on reliance on results from murine models of lineage tracing systems which have some known technical limitations.…”

“…In human, it is today considered that iCC arises from topographically heterogeneous cholangiocytes within the different levels of the biliary tree (32,(34)(35)(36). Cylindrical mucin-producing cholangiocytes border large BDs while cuboidal non-mucin-producing cholangiocytes compose ductules, where bipotential hepatic progenitor cells (HPCs) are also located (stem cell niche).…”

Stem-like plasticity and heterogeneity of circulating tumor cells: current status and prospect challenges in liver cancer

“…Primary liver cancer (PLC) is one of the most common cancers worldwide and second leading cause of cancer-related mortality [1, 2]. Primary liver tumors are grossly classified in hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) [1, 3–5].…”