Oncogenic driver genes and tumor microenvironment determine the type of liver cancer

Abstract

Primary liver cancer (PLC) may be mainly classified as the following four types: hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (ICC), hepatoblastoma (HB), and combined hepatocellular carcinoma and intrahepatic cholangiocarcinoma (cHCC-ICC). The majority of PLC develops in the background of tumor microenvironment, such as inflammatory microenvironments caused by viral hepatitis, alcoholic or nonalcoholic steatohepatitis, carbon tetrachloride (CCl₄), 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC), and necroptosis-associated hepatic cytokine microenvironment caused by necroptosis of hepatocytes. However, the impact of different types of microenvironments on the phenotypes of PLC generated by distinct oncogenes is still unclear. In addition, the cell origin of different liver cancers have not been clarified, as far as we know. Recent researches show that mature hepatocytes retain phenotypic plasticity to differentiate into cholangiocytes. More importantly, our results initially demonstrated that HCC, ICC, and cHCC-ICC could originate from mature hepatocytes rather than liver progenitor cells (LPCs), hepatic stellate cells (HSCs) and cholangiocytes in AKT-driven, AKT/NICD-driven and AKT/CAT-driven mouse PLC models respectively by using hydrodynamic transfection methodology. Therefore, liver tumors originated from mature hepatocytes embody a wide spectrum of phenotypes from HCC to CC, possibly including cHCC-ICC and HB. However, the underlying mechanism determining the cancer phenotype of liver tumors has yet to be delineated. In this review, we will provide a summary of the possible mechanisms for directing the cancer phenotype of liver tumors (i.e., ICC, HCC, and cHCC-ICC) in terms of oncogenic driver genes and tumor microenvironment. Moreover, this study initially revealed the cell origin of different types of liver cancer.

Fig. 1. ICC could originate from hepatocytes.

a Immunohistochemical staining (IHC) showed that some scattered HA-tag strongly positive hepatocytes were detected in AKT/NICD-injected livers after 7 days. b IHC results showed that HA-tag protein was also expressed in ICC tissues after 4 weeks. c IHC results showed that some HA-stained hepatocytes and biliary duct cells appeared after 2 weeks. ICC: intrahepatic cholangiocarcinoma (scale bars, 50 μm).

Fig. 2. Schematic representation of regulatory molecules and tumor microenvironment that commit hepatocyte-derived ICC formation.

ICC: intrahepatic cholangiocarcinoma.

Fig. 3. HCC and ICC components of cHCC-ICC could both originate from hepatocytes.

a–c The moribund livers (5%) following 2 months of AKT and CAT injection displayed a pathological characteristics of cHCC-ICC containing both HCC and ICC two components. d, e IHC showed that some scattered HA-tag strongly positive hepatocytes were detected in AKT/CAT -injected livers after 7 days. f IHC showed that HA-tag protein was also expressed in both HCC and ICC two components of cHCC-ICC tumor tissues after 90 days. HCC: hepatocellular carcinoma; ICC: intrahepatic cholangiocarcinoma; cHCC-ICC: combined hepatocellular carcinoma and intrahepatic cholangiocarcinoma; IHC: immunohistochemical staining (scale bars, 50 μm).

Fig. 4. Schematic representation of regulatory molecules and tumor microenvironment that may commit hepatocyte-derived cHCC-ICC formation.

cHCC-ICC: combined hepatocellular carcinoma and intrahepatic cholangiocarcinoma.

Fig. 5. IHC showed that TGF-β and Notch signalings were activated in the ICC components of human cHCC-ICC.

ICC: intrahepatic cholangiocarcinoma; cHCC-ICC: combined hepatocellular carcinoma and intrahepatic cholangiocarcinoma; IHC: immunohistochemical staining (scale bars, 50 μm).

Fig. 6. HCC could originate from hepatocytes.

a IHC showed that some scattered HA-tag strongly positive hepatocytes were detected in AKT-injected livers after 7 days. b IHC results showed that HA-tag protein was also expressed in HCC tumor tissues after 6 months. c HE staining showed that AKT-initiated tumors were characterized by lipid rich droplets. d IHC results showed that PCNA protein was highly expressed in HCC tumor tissues after 6 months. HCC: hepatocellular carcinoma; IHC: immunohistochemical staining; HE: hematoxylin-eosin staining (scale bars, 50 μm).

Fig. 7. Schematic representation of regulatory molecules and tumor microenvironment that may commit hepatocyte-derived HCC formation.

HCC: hepatocellular carcinoma.

Fig. 8. Oncogenic driver genes and tumor microenvironment determine the type of liver cancer.

HCC: hepatocellular carcinoma; ICC: intrahepatic cholangiocarcinoma; cHCC-ICC: combined hepatocellular carcinoma and intrahepatic cholangiocarcinoma.