Cancer stem cells and hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide, with a median survival of 6-16 m. Factors responsible for the poor prognosis include late onset diagnosis, underlying cirrhosis and resistance to chemotherapy; 40% of HCCs are clonal and therefore potentially arise from progenitor/stem cells. New insights are provided from several signaling pathways, such as STAT3, NOTCH, hedgehog and transforming growth factor-beta (TGFbeta), which are involved in stem cell renewal, differentiation, survival, and are commonly deregulated in HCC. Control of stem cell proliferation by the TGFbeta, Notch, Wnt and Hedgehog pathways to suppress hepatocellular cancer and to form the endoderm suggest a dual role for this pathway in tumor suppression as well as progression of differentiation from a stem or progenitor stage. This review provides a rationale for detecting and analyzing tumor stem cells as one of the most effective ways to treat cancers such as hepatocellular cancer.

Figure 1

Liver stem cell and TGFβ signaling via Smad proteins in liver development. (A) H&E staining for hepatic lobule; (B) Schematic representation of hepatic lobule and oval cell (liver progenitor cell); (C) Schematic diagram of TGFβ signaling in hepatocyte precursors directs development and differentiation. Smad 2, 3 and β2-SPECTRIN expression increases through development. Liver progenitor cells (LPCs) and rodent oval cells express phenotypic markers of both (immature) hepatocytes (α-fetoprotein and albumin) and bile duct cells (such as biliary-type CKs, oval cell marker 6, CK7, CK14 and CK19) as well as hematopoietic markers (such as the receptor for stem cell factor, c-kit and CD34). Another TGFβ adaptor protein, PRAJA, and c-kit expression decrease through development.

Figure 2

Directed stem cell renewal and liver differentiation by multiple signaling pathways. Proteins that direct self-renewal of embryonic stem cells and then differentiation of stem cells into mature hepatocytes and cholangiocytes. The mechanisms directing transformation of stem cells to cancer stem cells and hepatocellular cancer, however, remain to be elucidated.

Figure 3

TGF ligands signal through distinct receptors and Smads that are modulated by adaptor proteins and ubiquitinators. TGF binds to serine threonine kinase receptor complexes that phosphorylate R-Smads (Smad2/Smad3) as well as adaptor proteins such as 2-spectrin (2SP). R-Smads, 2-spectrin and Smad4 form a heteromeric complex, and translocate to the nucleus, activating target genes. At all levels, Smad modulation occurs through adaptor proteins as well as E3 ligases such as PRAJA and Smurfs, generating the diverse and complex signals. Arrows indicate signal flow and are color coded: black for ligand and receptor activation, red for Smad and receptor activation, olive green for Smad and receptor inactivation and formation of a transcriptional complex, and blue for Smad nucleocytoplasmic shuttling. Phosphate groups and ubiquitin (Ub) are represented by red stars and dark red circles, respectively.