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.

Melatonin as an Antitumor Agent against Liver Cancer: An Updated Systematic Review

“…Moreover, the high mortality associated with liver cancer is related to its lack of sensitivity and development of resistance to a few treatments that lead to the chemotherapy failure. These drawbacks may be explained, at least in part, by the various phenotypes and histological characteristics of tumor liver cells and their microenvironment [ 5 ]. Furthermore, the high refractoriness of liver cancer to treatments has been associated with the interaction of very complex and diverse mechanisms of chemoresistance, which can act synergistically to protect tumor cells from the chemotherapy agents [ 3 ].…”

Immune infiltrating cells in cholangiocarcinoma may become clinical diagnostic markers: based on bioinformatics analysis

“…Recent studies have shown that the tumor microenvironment can regulate the occurrence and development of tumors. This study is dedicated to finding more markers that can diagnose ICC by finding the differential tumor microenvironment cells between tumors and normal tissues [ 3 ].…”

Update on the Genetics of and Systemic Therapy Options for Combined Hepatocellular Cholangiocarcinoma

“…The dependence of tumor development on the TME is supported by the identification of associations between clinical/environmental factors and patterns of mutations in cHCC-ICC ( 57 ). To date, no data has been published for either the immune component of the TME nor tumor mutational burden in cHCC-ICC ( 58 ).…”

“…The detailed roles of oncogenic driver mutations are still poorly understood in all forms of PLC, especially cHCC-ICC. However TGF-β, Wnt, AKT, N-RAS, Notch-Hedgehog pathway activation and NF-κB pathway inactivation have all been implicated in pathogenesis, as has signaling through AXIN1, KMT2D, RB1, PTEN, FGFR, nestin, ARID1A, KEAP1, IDH1, versican, EpCAM, Erbb2, and TERT ( 2 , 19 , 47 , 53 , 58 , 61 – 63 ). A number of these are potential drug targets being evaluated in early phase clinical trials.…”