Expression of cancer stem cell biomarkers as a tool for a correct therapeutic approach to hepatocellular carcinoma

Abstract

Liver cancer is the fifth most commonly diagnosed malignancy and the second most frequent cause of cancer death in men worldwide. Amongst liver cancers, hepatocellular carcinoma (HCC) represents the major histological subtype and it is one of the most common malignant human tumors worldwide. Research into the molecular biology of hepatocarcinogenesis has identified several biomarkers, which could provide additional informations in order to better understand the biology of HCC. A large number of biomarkers have been shown to have potential predictive significance and a wide variety of molecular markers have been proven to be excellent diagnostic tools for HCC but it is difficult to characterize HCC with a single biomarker. Thus, signatures of a combination of biomarkers may be more valuable for the diagnosis, staging and prognosis of HCC. Specifically, a correlation of HCC-CSCs phenotype to specific hepatic cancer subtypes and to specific clinical and pathological features has not yet been reported in human liver tumors. In this view we will first discuss the possible sources of liver stem cells and their relation with liver cancer development and we will secondly focus on the prognostic significance of clinical and pathological features of HCC.

Keywords: biomarkers; clinic-pathological; early diagnosis; hepatocellular carcinoma; prognosis.

Figure 1. The cancer stem cell hypothesis (adapted from Lobo et al, 2007)

Tumors are not viewed as homogeneous masses of proliferating cells but as heterogeneous aberrant tissues containing a hierarchy of cells that originate from a single cancer stem cell (CSC). The CSC hypothesis postulates that a small subpopulation of cancer cells drives tumor growth and metastasis. CSCs are rare, quiescent, and capable of self-renewing and maintaining tumor growth and heterogeneity. Moreover, CSCs share more resistance to therapies, due to antiapoptotic activity and drug resistance (increased levels of drug efflux pumps and multi-drug resistance).

Figure 2. Hepatic stem cells in liver regeneration and HCC (adapted from Yin C et al, 2013; Carpino G et al, 2012)

(A) Normal cellular hierarchy comprising hepatic stem cells that progressively generate more restricted progenitor cells, yielding all the mature cell types that constitute the liver. Although the some hepatic stem cells have also been proposed to contribute to HCC development, potentially through dysregulation of some aspects of liver regeneration. The accumulation of further epigenetic mutations during neoplastic progression may result in the emergence of CSC, which propagates the tumor. (B) Liver fibrosis is the generic response to chronic liver injury. Most evidence suggests that fibrosis promotes HCC by involvement of inflammatory cells, integrin signaling, growth factor interactions with the ECM and communication between activated hepatic stem cells and tumor cells. In this case, hepatic stem cells (present between endothelial cells and cancer cell trabeculae in HCC patients) increases proliferation and migration of human HCC cells.

Figure 3. Anatomical location and differentiation capability of hepatic stem cells (adapted from Kruitwagen et al, 2014)

Schematic representation of the anatomical location of the hepatic stem cell in the canal of Hering. Upon activation the normally quiescent stem cells proliferate. Depending on the disease, the progenitor cells differentiate into either hepatocytes or chlangiocytes.

Figure 4. Stem cell therapies for liver failure and cirrhosis (adapted from Zhang Z and Wang FS, 2013)

(A) Liver failure and cirrhosis are characterized by massive inflammation, necrosis and accumulation of scar tissue. Different stem cell types have various putative functional roles. MSCs are gifted with immunomodulatory, anti-fibrotic and pro-regenerative capabilities. MSCs have been demonstrated to play an immunomodulatory role through producing inhibitory cytokines or inducing the development of regulatory T cells. MSCs have also an anti-fibrotic role for the potential to differentiate into myofibroblasts, which act as scar-forming cells within the liver. The last realistic target of MSC therapy is to replace damaged hepatocytes with exogenous functional hepatocytes in patients with liver failure or cirrhosis. In this regard, MSCs have a pro-regenerative role in fact have been shown to be most capable of producing large numbers of functional hepatocyte-like cells. (B) The use of stem cells transplantation may offer novel therapeutic interventions for liver failure and cirrhosis. Several critical issues in clinical protocols require further investigation, such as the optimal type of ASCs, the optimal therapeutic timing, the most effective number of stem cells.