-
Best Practice & Research. Clinical... Oct 2014When hepatocellular carcinoma presents with symptoms cure is seldom possible and death usually follows within months. However, it is possible to detect HCC early, at... (Review)
Review
When hepatocellular carcinoma presents with symptoms cure is seldom possible and death usually follows within months. However, it is possible to detect HCC early, at which stage it is curable. This requires a surveillance program. The components of such a program include: identification of the at risk population, provision of appropriate surveillance tests, and an appropriate method of determining whether the abnormalities found on screening are cancer or not. Surveillance for liver cancer meets all these criteria. Unfortunately high quality evidence showing benefit of liver cancer surveillance is lacking, but lesser quality evidence is plentiful, including several cost efficacy analyses that all show that surveillance does decrease mortality. Therefore all the continental liver disease societies and all national liver disease societies have recommended that surveillance should be undertaken.
Topics: Carcinoma, Hepatocellular; Cost-Benefit Analysis; Early Detection of Cancer; Humans; Liver Neoplasms; Population Surveillance; alpha-Fetoproteins
PubMed: 25260308
DOI: 10.1016/j.bpg.2014.08.008 -
Fetal and Pediatric Pathology Feb 2017Elevations of serum alpha-fetoprotein (sAFP) have been reported in fetal and infant states of anemia. Fanconi anemia (FA) belongs to a family of genetic instability... (Review)
Review
Elevations of serum alpha-fetoprotein (sAFP) have been reported in fetal and infant states of anemia. Fanconi anemia (FA) belongs to a family of genetic instability disorders which lack the capability to repair DNA breaks. The lesion occurs at a checkpoint regulatory step of the G2 to mitotic transition, allowing FA cells to override cell-cycle arrest. FA DNA repair pathways contain complementation groups known as FANC proteins. FANC proteins form multi-protein complexes with BRCA proteins and are involved in homologous DNA repair. An impaired cascade in these events imparts an increased breast cancer susceptibility to female FA patients. Elevations of sAFP have availed this fetal protein to serve as a biomarker for FA disease. However, the origin of the synthesis of sAFA has not been determined in FA patients. We hypothesize that hematopoietic multipotent progenitor stem cells in the bone marrow are the source of sAFP production in FA patients.
Topics: Adolescent; Adult; BRCA2 Protein; Biomarkers; Breast Neoplasms; Cell Cycle; Child; Child, Preschool; Chromosomes; DNA Repair; Fanconi Anemia; Fanconi Anemia Complementation Group Proteins; Female; Genetic Complementation Test; Genetic Predisposition to Disease; Humans; Infant; Male; Middle Aged; Stem Cells; Young Adult; alpha-Fetoproteins
PubMed: 27690720
DOI: 10.1080/15513815.2016.1225873 -
World Journal of Surgical Oncology Oct 2022The prognosis of hepatocellular carcinoma (HCC) varies considerably among patients with the same disease stage and characteristics, and only about two thirds show high...
BACKGROUND
The prognosis of hepatocellular carcinoma (HCC) varies considerably among patients with the same disease stage and characteristics, and only about two thirds show high levels of α-fetoprotein (AFP), a common prognostic indicator for HCC. Here, we assessed whether the combination of presurgical serum levels of AFP and carbohydrate antigen 19-9 (CA19-9) can predict the prognosis of HCC patients after hepatectomy.
METHODS
The clinicopathological characteristics and post-hepatectomy outcomes of 711 HCC patients were retrospectively reviewed. The patients were classified into three groups based on whether their preoperative serum levels of both AFP and CA19-9 were higher than the respective cut-offs of 400 ng/ml and 37 U/ml [double positive (DP)], the level of only one marker was higher than the cut-off [single positive (SP)], or neither level was higher than the cut-off [negative (N)]. The overall survival (OS) and recurrence-free survival (RFS) rates were estimated using Kaplan-Meier curves. Univariate and multivariate survival analyses were performed to identify the clinicopathological factors significantly associated with HCC prognosis.
RESULTS
The 1-year, 3-year, and 5-year RFS and OS rates in the N group were significantly higher than those in the SP group, while the DP group showed the lowest rates. Multivariate Cox regression analysis showed that large tumor size (> 5 cm), multiple tumors (≥ 2), incomplete tumor capsule, positive microvascular invasion, Barcelona Clinic Liver Cancer C stage, and CA19-9 level > 37 U/mL were independent risk factors for RFS and OS in HCC patients. Moreover, aspartate aminotransferase levels > 40 U/L proved to be an independent prognostic factor for OS.
CONCLUSION
The combination of serum AFP and CA19-9 levels may be a useful prognostic marker for HCC patients after hepatectomy.
Topics: Humans; Carcinoma, Hepatocellular; alpha-Fetoproteins; Hepatectomy; CA-19-9 Antigen; Prognosis; Liver Neoplasms; Retrospective Studies; Aspartate Aminotransferases; Carbohydrates
PubMed: 36258212
DOI: 10.1186/s12957-022-02806-9 -
Journal of Gastrointestinal Surgery :... Dec 2022Resection of Barcelona Clinic Liver Cancer (BCLC) intermediate-stage hepatocellular carcinoma (HCC) remains controversial. While not recommended by the BCLC algorithm,...
BACKGROUND
Resection of Barcelona Clinic Liver Cancer (BCLC) intermediate-stage hepatocellular carcinoma (HCC) remains controversial. While not recommended by the BCLC algorithm, some patients may indeed benefit from hepatectomy. We sought to identify that subset of patients who might derive long-term survival benefit from resection.
METHODS
Intermediate-stage HCC patients who underwent curative-intent resection were identified from an international multi-institutional database. Factors associated with long-term prognosis were identified using multivariate analysis and a risk score was developed and assessed.
RESULTS
Among 194 patients, most individuals had two tumors (n = 123, 63.4%) with a median size of 6.0 cm (IQR, 4.0-8.4) for a median tumor burden score (TBS) of 6.5 (IQR, 5.0-9.1); median alpha-fetoprotein (AFP) was 23.9 ng/mL (IQR, 5.0-503.2), and median overall survival (OS) was 69 months (IAR, 60.7-77.3). Factors associated with OS included AFP (referent ≤ 20 ng/mL, > 20 ng/mL: HR 1.78 95%CI, 1.09-2.89) and TBS (referent TBS ≤ 8.0, TBS > 8.0: HR 1.72 95%CI, 1.07-2.75). While 71 (36.6%) patients had neither risk factor, 79 (40.7%) and 44 (22.7%) had 1 or 2, respectively. A simplified score stratified patients relative to recurrence-free survival (RFS) (0: 33.6% vs. 1: 18.0% vs. 2: 14.7%) (AUC 0.60) and recurrence time (i.e., < 6 months after surgery) (0: 21.3% vs. 1: 43.1% vs. 2: 68.6%) (AUC 0.69) (both p < 0.001). Of note, a higher score was also associated with incrementally worse 5-year OS (0: 68.1% vs. 1: 61.0% vs. 2: 29.9%) (AUC 0.62) (p < 0.001).
CONCLUSION
Long-term OS and RFS outcomes varied considerably. Using a simple risk score, patients with low AFP and low TBS were identified as the subset of individuals most likely to benefit from resection.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; alpha-Fetoproteins; Tumor Burden; Neoplasm Staging; Hepatectomy; Prognosis; Retrospective Studies
PubMed: 36171471
DOI: 10.1007/s11605-022-05469-9 -
World Journal of Gastroenterology Jul 2022Endoplasmic reticulum (ER) stress contributes to the pathogenesis of chronic liver diseases, but how hepatocytes respond to ER stress has not been clarified....
BACKGROUND
Endoplasmic reticulum (ER) stress contributes to the pathogenesis of chronic liver diseases, but how hepatocytes respond to ER stress has not been clarified. Alpha-fetoprotein (AFP) is secreted by hepatoma cells and elevated levels of serum AFP are associated with development of liver malignancies.
AIM
To investigate whether and how AFP could regulate ER stress and hepatocyte injury.
METHODS
The distribution of AFP and the degrees of ER stress in liver tissues and liver injury were characterized by histology, immunohistochemistry, and Western blot in biopsied human liver specimens, two mouse models of liver injury and a cellular model. The levels of AFP in sera and the supernatants of cultured cells were quantified by chemiluminescence.
RESULTS
High levels of intracellular AFP were detected in liver tissues, particularly in the necrotic areas, from patients with chronic liver diseases and mice after carbon tetrachloride (CCl) administration or induction of ER stress, but not from the controls. The induced intracellular AFP was accompanied by elevated activating transcription factor-6 (ATF6) expression and protein kinase R-like ER kinase (PERK) phosphorylation in mouse livers. ER stress induced AFP expression in LO2 cells and decreased their viability. ATF6, but not PERK, silencing mitigated the ER-stress-induced AFP expression in LO2 cells. Conversely, AFP silencing deteriorated the ER stress-mediated LO2 cell injury and CCl administration-induced liver damages by increasing levels of cleaved caspase-3, the C/enhancer binding protein homologous protein expression, mixed lineage kinase domain-like pseudokinase and PERK phosphorylation, but decreasing ATF6 expression.
CONCLUSION
ER stress upregulated intra-hepatocyte AFP expression by activating ATF6 during the process of liver injury and intracellular AFP attenuated hepatocyte apoptosis and necroptosis by alleviating ER stress.
Topics: Animals; Apoptosis; Endoplasmic Reticulum Stress; Hepatocytes; Humans; Liver Diseases; Mice; Necroptosis; alpha-Fetoproteins
PubMed: 36051342
DOI: 10.3748/wjg.v28.i26.3201 -
Mini Reviews in Medicinal Chemistry 2022Liver cancer is one of the most common malignant tumors, with limited treatment and 8.2% mortality. Liver cancer is the fourth leading cause of cancer-related deaths,... (Review)
Review
Liver cancer is one of the most common malignant tumors, with limited treatment and 8.2% mortality. Liver cancer is the fourth leading cause of cancer-related deaths, which seriously endangers human life and health. Approximately 70% of liver cancer patients show increased serum Alpha- Fetoprotein (AFP) levels. AFP is the main diagnostic and prognostic indicator of liver cancer. AFP, a key marker of liver cancer, plays a crucial role in regulating the proliferation of tumor cells, apoptosis, and induction of cellular immune escape. High levels of AFP during embryonic development protect the embryos from maternal immune attack. AFP also promotes immune escape of liver cancer cells by inhibiting Tumor-Infiltrating Lymphocytes (TILs), Natural Killer cells (NK), Dendritic Cells (DC), and macrophages; thus, it is also used as a target antigen in immunotherapy for liver cancer. AFP is highly expressed in liver cancer cells. In addition to being used in the diagnosis of liver cancer, it has become a target of immunotherapy for liver cancer as a tumor-associated antigen. In immunotherapy, it was also confirmed that early AFP response was positively correlated with the efficacy of immunotherapy. Early AFP responders had longer PFS and OS than non-responders. At present, the methods of immunotherapy for liver cancer mainly include Adoptive Cell Transfer Therapy (ACT), tumor vaccine therapy, immune checkpoint inhibitors (ICIs) therapy, etc. A large number of studies have shown that AFP mainly plays a role in ACT and liver cancer vaccines. This review presents the research progress of AFP and immunosuppression of liver cancer.
Topics: Cancer Vaccines; Carcinoma, Hepatocellular; Humans; Immunosuppression Therapy; Immunotherapy; Liver Neoplasms; alpha-Fetoproteins
PubMed: 35184712
DOI: 10.2174/1389557522666220218124816 -
Cancer Research May 2023α-Fetoprotein (AFP) is expressed by stem-like and poor outcome hepatocellular cancer tumors and is a clinical tumor biomarker. AFP has been demonstrated to inhibit...
UNLABELLED
α-Fetoprotein (AFP) is expressed by stem-like and poor outcome hepatocellular cancer tumors and is a clinical tumor biomarker. AFP has been demonstrated to inhibit dendritic cell (DC) differentiation and maturation and to block oxidative phosphorylation. To identify the critical metabolic pathways leading to human DC functional suppression, here, we used two recently described single-cell profiling methods, scMEP (single-cell metabolic profiling) and SCENITH (single-cell energetic metabolism by profiling translation inhibition). Glycolytic capacity and glucose dependence of DCs were significantly increased by tumor-derived, but not normal cord blood-derived, AFP, leading to increased glucose uptake and lactate secretion. Key molecules in the electron transport chain in particular were regulated by tumor-derived AFP. These metabolic changes occurred at mRNA and protein levels, with negative impact on DC stimulatory capacity. Tumor-derived AFP bound significantly more polyunsaturated fatty acids (PUFA) than cord blood-derived AFP. PUFAs bound to AFP increased metabolic skewing and promoted DC functional suppression. PUFAs inhibited DC differentiation in vitro, and ω-6 PUFAs conferred potent immunoregulation when bound to tumor-derived AFP. Together, these findings provide mechanistic insights into how AFP antagonizes the innate immune response to limit antitumor immunity.
SIGNIFICANCE
α-Fetoprotein (AFP) is a secreted tumor protein and biomarker with impact on immunity. Fatty acid-bound AFP promotes immune suppression by skewing human dendritic cell metabolism toward glycolysis and reduced immune stimulation.
Topics: Humans; alpha-Fetoproteins; Liver Neoplasms; Fatty Acids, Unsaturated; Fatty Acids; Biomarkers; Dendritic Cells
PubMed: 36847613
DOI: 10.1158/0008-5472.CAN-22-3551 -
Journal of Population Therapeutics and... 2022Liver-related death globally is caused mainly by cirrhosis. It is the final grade of extensive liver fibrosis, in which the hepatic architecture is modified. Cirrhosis...
BACKGROUND
Liver-related death globally is caused mainly by cirrhosis. It is the final grade of extensive liver fibrosis, in which the hepatic architecture is modified. Cirrhosis is a common disease worldwide and can be the end stage for several reasons such as obesity, non-alcoholic fatty liver, alcoholism, viral infection such as viral hepatitis, immune disorders, bile duct obstruction, and metabolic diseases. Alpha-fetoprotein (AFP) is defined as a protein secreted by the germinal yolk sac and liver. AFP level is used as a marker to diagnose inherited disorders and chromosomal anomaly, whereas the high-sensitivity C-reactive protein (hs-CRP) has a separate correlation with NAFLD. Therefore, hs-CRP can be used as a beneficial marker for identifying liver defects.
SUBJECTS AND METHODS
Thirty participants with liver cirrhosis and 30 healthy participants as control (male and female) were enrolled. The participants from Baghdad, Iraq, were enrolled in this study. Blood and serum samples were obtained for the estimation of hemoglobin, serum AFP, and hs-CRP levels.
RESULTS
The pooled data of participants showed that hs-CRP and alpha-fetoprotein levels in the participants with cirrhosis were significantly higher than in the control group, P<0.0001. There were no significant differences in the sexes while considering alpha-fetoprotein, whereas hs-CRP levels were higher in males compared with females.
CONCLUSION
This research shows a significantly high level of hs-CRP and alpha-fetoprotein in patients with liver cirrhosis compared with the control participants. There were non-significant gender differences concerning alpha-fetoprotein with significantly high level of hs-CRP in males compared with females.
Topics: Biomarkers; C-Reactive Protein; Female; Humans; Iraq; Liver Cirrhosis; Male; Non-alcoholic Fatty Liver Disease; alpha-Fetoproteins
PubMed: 36196934
DOI: 10.47750/jptcp.2022.905 -
Clinics in Liver Disease May 2015The incidence of cirrhosis-related hepatocellular carcinoma (HCC) is rising. Curative surgical options are available; outcomes are acceptable with early diagnosis. Lens... (Review)
Review
The incidence of cirrhosis-related hepatocellular carcinoma (HCC) is rising. Curative surgical options are available; outcomes are acceptable with early diagnosis. Lens culinaris agglutinin-reactive fraction of alpha-fetoprotein (AFP-L3) and des-gamma-carboxy prothrombin (DCP) are HCC risk markers. A high or increasing serum biomarker level can be predictive of the eventual development of HCC, large tumor size, advanced stage, extrahepatic metastases, portal vein thrombosis, and postoperative HCC recurrence. Based on FDA guidelines for HCC risk assessment, clinicians can consider using either the combination of AFP-L3 with DCP, or the combination of AFP-L3 with AFP and DCP.
Topics: Biomarkers; Biomarkers, Tumor; Carcinoma, Hepatocellular; Diagnosis, Differential; Glypicans; Humans; Liver Cirrhosis; Liver Neoplasms; Plant Lectins; Population Surveillance; Protein Precursors; Prothrombin; Risk Assessment; alpha-Fetoproteins
PubMed: 25921665
DOI: 10.1016/j.cld.2015.01.005 -
The Journal of Clinical Investigation Jan 2023Signaling circuits crucial to systemic physiology are widespread, yet uncovering their molecular underpinnings remains a barrier to understanding the etiology of many...
Signaling circuits crucial to systemic physiology are widespread, yet uncovering their molecular underpinnings remains a barrier to understanding the etiology of many metabolic disorders. Here, we identified a copper-linked signaling circuit activated by disruption of mitochondrial function in the murine liver or heart that resulted in atrophy of the spleen and thymus and caused a peripheral white blood cell deficiency. We demonstrated that the leukopenia was caused by α-fetoprotein, which required copper and the cell surface receptor CCR5 to promote white blood cell death. We further showed that α-fetoprotein expression was upregulated in several cell types upon inhibition of oxidative phosphorylation. Collectively, our data argue that α-fetoprotein may be secreted by bioenergetically stressed tissue to suppress the immune system, an effect that may explain the recurrent or chronic infections that are observed in a subset of mitochondrial diseases or in other disorders with secondary mitochondrial dysfunction.
Topics: Mice; Animals; Copper; alpha-Fetoproteins; Mitochondria; Mitochondrial Diseases; Immunosuppression Therapy
PubMed: 36301669
DOI: 10.1172/JCI154684