Biomarkers for hepatocellular carcinoma based on body fluids and feces

Novel non-/minimally-invasive and effective approaches are urgently needed to supplement and improve current strategies for diagnosis and management of hepatocellular carcinoma(HCC).Overwhelming evidence from published studies on HCC has documented that multiple molecular biomarkers detected in body fluids and feces can be utilized in early-diagnosis,predicting responses to specific therapies,evaluating prognosis before or after therapy,as well as serving as novel therapeutic targets.Detection and analysis of proteins,metabolites,circulating nucleic acids,circulating tumor cells,and extracellular vesicles in body fluids(e.g.,blood and urine)and gut microbiota(e.g.,in feces)have excellent capabilities to improve different aspects of management of HCC.Numerous studies have been devoted in identifying more promising candidate biomarkers and therapeutic targets for diagnosis,treatment,and monitoring responses of HCC to conventional therapies,most of which may improve diagnosis and management of HCC in the future.This review aimed to summarize recent advances in utilizing these biomarkers in HCC and discuss their clinical significance.

Early diagnosis and therapeutic strategies for hepatocellular carcinoma:From bench to bedside

Hepatocellular carcinoma(HCC)is the fourth leading cause of cancer-related deaths worldwide.The prognosis of patients with HCC remains poor largely due to the late diagnosis and lack of effective treatments.Despite being widely used,alpha-fetoprotein serology and ultrasonography have limited diagnostic performance for early-stage HCC.The emergence of omics strategies has contributed to significant advances in the development of non-invasive biomarkers for the early diagnosis of HCC including proteins,metabolites,circulating tumor deoxyribonucleic acid,and circulating non-coding ribonucleic acid.Early diagnosis is beneficial to patients as it increases the proportion who can be treated with curative treatment,thus prolonging survival outcomes.Currently,multiple clinical trials involving locoregional,systemic therapies,and combinations of these modalities are changing therapeutic strategies for different stage HCC.Success in several preclinical trials that involve immunotherapeutic innovations has created the potential to complement and enforce other treatment strategies in the future.This review summarizes the most recent advances in noninvasive early molecular detection,current therapy strategies,and potential immunotherapeutic innovations of HCC.

Alpha-fetoprotein,protein induced by vitamin K absence or antagonist-Ⅱ,lens culinaris agglutinin-reactive fraction of alpha-fetoprotein alone and in combination for early detection of hepatocellular carcinoma from nonalcoholic fatty liver disease:A multicenter analysis

Background:Current surveillance strategies for hepatocellular carcinoma(HCC)among patients with non-alcoholic fatty liver disease(NAFLD)are insufficient.This study aimed to investigate the diagnostic perfor-mance of alpha-fetoprotein(AFP),protein induced by vitamin K absence or antagonist-Ⅱ(PIVKA-Ⅱ),lens culinaris agglutinin-reactive fraction of AFP(AFP-L3),and their combinations in HCC underlying NAFLD patients.Methods:Serologic AFP,AFP-L3,and PIVKA-Ⅱ levels in NAFLD patients with and without HCC were mea-sured.By receiver operating characteristic(ROC)analyses,the area under the curve(AUC),sensitivity,and specificity were obtained to evaluate the diagnostic accuracy of each biomarker and their combinations.Results:This study was conducted on 139 patients with NAFLD-HCC and 345 NAFLD controls.The eleva-tion of these three biomarkers was observed in patients with NAFLD-HCC compared to those in NAFLD controls(all P<0.001).When they were analyzed individually,PIVKA-Ⅱ showed the best performance in diagnosing any-stage HCC with an AUC of 0.869,followed by AFP(0.763;vs.PIVKA-Ⅱ,P<0.001)and AFP-L3(0.689;vs.PIVKA-II,P<0.001).When they were analyzed in combination,AFP+PIVKA-Ⅱ yielded the highest AUC(0.906),followed by AFP+PIVKA-II+AFP-L3(0.904;vs.AFP+PIVKA-Ⅱ,P=0.086),PIVKA-Ⅱ+AFP-L3(0.881;vs.AFP+PIVKA-II,P<0.001),and AFP+AFP-L3(0.759;vs.AFP+PIVKA-II,P<0.001).Similar findings were obtained in the subgroup with early-stage NAFLD-HCC,as well as the non-cirrhotic subgroup.Conclusions:These data validated the better diagnostic ability of PIVKA-II than AFP or AFP-L3 alone for diagnosing any-stage HCC among patients with NAFLD,and the combination of AFP+PIVKA-II signifi-cantly improved the diagnostic accuracy of NAFLD-HCC.

Exosomes as mediators of tumor immune escape and immunotherapy in hepatocellular carcinoma

Hepatocellular carcinoma(HCC),a typical inflammatory-related cancer,mainly occurs in patients with chronic liver diseases.Moreover,the liver is an immunologically privileged apparatus with multiple immunosuppressive cell groups.The long process of inflammation-mediated carcinogenesis turns the HCC tumor microenvironment(TME)into one with strong immunosuppression,facilitating the immune escape of HCC cells.Accumulated data have manifested that tumor-associated cell-derived exosomes carry diverse molecular cargoes(e.g.,proteins and nucleic acids)for mediating cell-to-cell communication and are implicated in TME remodeling to promote tumor-infiltrating immune cell reprogramming,ultimately creating a tumor-friendly microenvironment.Characterized by several intrinsic attributes,such as good stability(bilayer-like structure)and high biocompatibility(cell secretion),exosomes can be modified or engineered as nanocarriers to deliver tumor-specific antigens or antitumor drugs to targeted cells or organs,thus effectively triggering the HCC cell elimination by the immune system.This review aimed to highlight the pivotal role of exosomes in regulating immune escape mechanisms in HCC and recent advances in exosome-mediated immunotherapy for HCC.