Clinico‐histological and molecular features of hepatocellular carcinoma from nonalcoholic fatty liver disease

Abstract

Patients with nonalcoholic fatty liver disease (NAFLD) continue to increase with the epidemics of obesity, and NAFLD is estimated to become the most prevalent etiology of hepatocellular carcinoma (HCC). Recently, NAFLD‐HCC has been recognized to have clinico‐histologically and molecularly distinct features from those from other etiologies, including a lower incidence rate of HCC and less therapeutic efficacy to immune checkpoint inhibitors (ICIs). Consistent with the clinical observations that up to 50% of NAFLD‐HCC occurs in the absence of cirrhosis, the imbalance of pro‐ and antitumorigenic hepatic stellate cells termed as myHSC and cyHSC can contribute to the creation of an HCC‐prone hepatic environment, independent of the absolute fibrosis abundance. Immune deregulations by accumulated metabolites in NAFLD‐affected livers, such as a fatty‐acid‐induced loss of cytotoxic CD4 T cells serving for immune surveillance and “auto‐aggressive” CXCR6+ CD8 T cells, may promote hepatocarcinogenesis and diminish therapeutic response to ICIs. Steatohepatitic HCC (SH‐HCC), characterized by the presence of fat accumulation in tumor cells, ballooned tumor cells, Mallory–Denk body, interstitial fibrosis, and intratumor immune cell infiltration, may represent a metabolic reprogramming for adapting to a lipid‐rich tumor microenvironment by downregulating CPT2 and leveraging its intermediates as an “oncometabolite.” Genome‐wide analyses suggested that SH‐HCC may be more responsive to ICIs given its mutual exclusiveness with β‐catenin mutation/activation that promotes immune evasion. Thus, further understanding of NAFLD‐specific hepatocarcinogenesis and HCC would enable us to improve the current daily practice and eventually the prognoses of patients with NAFLD.

Emerging Roles of Spatial Transcriptomics in Liver Research

“…94 Therefore, accurate prediction of future HCC development from MASLD is crucial; however, it is still an unmet medical need. 95 We previously identified and validated a hepatic transcriptome-based 133-gene signature, named Prognostic Liver Signature for MASLD (PLS-MASLD), by analyzing human liver tissues in an unbiased manner. 35 To explore the biological aspects of PLS-MASLD, we performed a meta-analysis of human sc/snRNA-seq datasets with >100,000 cells encompassing almost all hepatic cell types, and subsequently integrated it with an spatial transcriptome data from human MASLD-affected liver using SPOTlight cell deconvolution algorithm.…”

Squalene Epoxidase: Its Regulations and Links with Cancers

“…NAFLD can progress to nonalcoholic steatohepatitis (NASH) in 20-30% of cases, and approximately 20-25% of NASH cases progress to cirrhosis, which is the leading risk factor for HCC development [131][132][133][134]. During the past years, patients with NAFLD have continued to increase with the epidemics of obesity, with an estimate of one-third of the global adult population developing NAFLD, and NAFLD is estimated to become the most prevalent etiology of HCC [135,136]. It is reported that the addition of high cholesterol in high-fat diets can cause NASH in mice and augment carcinogenesis by increasing the multiplicity and size of tumors [106].…”

Combination Therapy of Immune Checkpoint Inhibitors with Locoregional Therapy for Hepatocellular Carcinoma

“…Zhu et al performed integrated molecular analyses of HCC samples (n = from patients enrolled in the phase 1b or IMbrave150 phase 3 clinical trial of atezoliz and bevacizumab to identify potential biomarkers for predicting clinical outcomes existing immunity characterized by intratumoral CD8 T cell density, high expressi CD274 encoding PD-L1, and T-effector signature was favorably associated with the come, whereas a high regulatory T cell to effector T cell ratio and high expression o cofetal genes (GPC3 and AFP) were associated with reduced benefit from the combin therapy. A variety of underlying mechanisms that promote T cell accumulation w tumors have been revealed in animal models and comprehensive human HCC ana [23]. Ruiz de Galarreta et al showed that β-catenin activation promotes immune e by defecting dendritic cell recruitment and impairing T cell activity [24].…”