-
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 -
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 -
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 -
BMC Cancer Dec 2023Routine clinical staging for hepatocellular carcinoma (HCC) incorporates liver function, general health, and tumor morphology. Further refinement of prognostic...
Prognostic implications of alpha-fetoprotein and C-reactive protein elevation in hepatocellular carcinoma following resection (PACE): a large cohort study of 2770 patients.
BACKGROUND
Routine clinical staging for hepatocellular carcinoma (HCC) incorporates liver function, general health, and tumor morphology. Further refinement of prognostic assessments and treatment decisions may benefit from the inclusion of tumor biological marker alpha-fetoprotein (AFP) and systemic inflammation indicator C-reactive protein (CRP).
METHODS
Data from a multicenter cohort of 2770 HCC patients undergoing hepatectomy were analyzed. We developed the PACE risk score (Prognostic implications of AFP and CRP Elevation) after initially assessing preoperative AFP and CRP's prognostic value. Subgroup analyzes were performed in BCLC cohorts A and B using multivariable Cox analysis to evaluate the prognostic stratification ability of the PACE risk score and its complementary utility for BCLC staging.
RESULTS
Preoperative AFP ≥ 400ng/mL and CRP ≥ 10 mg/L emerged as independent predictors of poorer prognosis in HCC patients who underwent hepatectomy, leading to the creation of the PACE risk score. PACE risk score stratified patients into low, intermediate, and high-risk groups with cumulative 5-year overall (OS) and recurrence-free survival (RFS) rates of 59.6%/44.9%, 43.9%/38.4%, and 20.6%/18.0% respectively (all P < 0.001). Increased PACE risk scores correlated significantly with early recurrence and extrahepatic metastases frequency (all P < 0.001). The multivariable analysis identified intermediate and high-risk PACE scores as independently correlating with poor postoperative OS and RFS. Furthermore, the PACE risk score proficiently stratified the prognosis of BCLC stages A and B patients, with multivariable analyses demonstrating it as an independent prognostic determinant for both stages.
CONCLUSION
The PACE risk score serves as an effective tool for postoperative risk stratification, potentially supplementing the BCLC staging system.
Topics: Humans; alpha-Fetoproteins; C-Reactive Protein; Carcinoma, Hepatocellular; Cohort Studies; Hepatectomy; Liver Neoplasms; Neoplasm Staging; Prognosis; Retrospective Studies
PubMed: 38053048
DOI: 10.1186/s12885-023-11693-6 -
Digestive Diseases and Sciences Dec 2021The clinical value of alpha-fetoprotein (AFP) in patients with AFP-negative (< 20 ng/ml) hepatocellular carcinoma (HCC) who underwent curative resection remained...
BACKGROUND
The clinical value of alpha-fetoprotein (AFP) in patients with AFP-negative (< 20 ng/ml) hepatocellular carcinoma (HCC) who underwent curative resection remained controversial.
AIMS
To investigate clinical relevance and prognostic effect of preoperative serum AFP level in this subgroup.
METHODS
A total of 1879 patients with AFP-negative HCC who underwent curative resection were included in the study. Overall survival (OS) and disease-free survival (DFS) rate were displayed by Kaplan-Meier method and compared by log-rank test. Multivariate cox proportional hazard regression analysis was used to identify the independent prognostic factors. The prognostic predictive performance was analyzed by time-dependent areas under receiver operating characteristic curve (AUC).
RESULTS
Even in AFP-negative HCC, patients with high preoperative serum AFP level tended to have multiple tumor (P < 0.001), poorer differentiation of tumor cell (P < 0.001), presence of satellite nodules (P < 0.001), and MVI (P = 0.002). Kaplan-Meier analysis showed the adverse impact of AFP level on prognosis, especially for DFS. Multivariate analysis identified AFP as the independent unfavorable factor for OS and DFS (P < 0.001 for both). Time-dependent AUC analysis showed that the combination with AFP could improve the prognostic predictive performance of 8th AJCC and BCLC staging system.
CONCLUSIONS
AFP was still the surrogate of aggressive behavior of HCC and independent prognostic factor for patients with AFP-negative HCC underwent curative resection. Even combining with such a low level of AFP could significantly improve the predictive performance of conventional staging system.
Topics: Biomarkers; Carcinoma, Hepatocellular; Female; Hepatectomy; Humans; Liver Neoplasms; Male; Middle Aged; Prognosis; Retrospective Studies; alpha-Fetoproteins
PubMed: 33723698
DOI: 10.1007/s10620-020-06797-z -
World Journal of Gastroenterology May 2017Hepatocellular carcinoma is becoming an increasing indication for liver transplantation, but selection and allocation of patients are challenging because of organ...
Hepatocellular carcinoma is becoming an increasing indication for liver transplantation, but selection and allocation of patients are challenging because of organ shortages. Conventional Milan criteria are the reference for the selection of patients worldwide, but many expanded criteria, like University of California San Francisco criteria and up-to-7 criteria, have demonstrated that survival and recurrence results are lower than those for restricted indications. Correct staging is crucial and should include surrogate markers of biological aggressiveness (α-fetoprotein, response to loco-regional treatments). Successful down-staging can select between patients with tumor burden initially beyond transplantation criteria those with a more favorable biology, provided a 3-mo stability in meeting the transplantation criteria. Allocation rules are constantly adjusted to minimize the imbalance between the priorities of candidates with and without hepatocellular carcinoma, and take into account local donor rate and waitlist dynamics. Recently, Mazzaferro et al proposed a benefit-oriented "adaptive approach", in which the selection and allocation of patients are based on their response to non-transplantation treatments: low priority for transplantation in case of complete response, high priority in case of partial response or recurrence, and no listing in case of progression beyond transplantation criteria.
Topics: Biomarkers; Carcinoma, Hepatocellular; Disease Progression; Europe; Humans; Liver Neoplasms; Liver Transplantation; Neoplasm Recurrence, Local; Neoplasm Staging; Patient Selection; Severity of Illness Index; Treatment Outcome; United States; alpha-Fetoproteins
PubMed: 28566879
DOI: 10.3748/wjg.v23.i18.3195 -
Cells Jan 2024Midkine (MDK) is a multifunctional secreted protein that can act as a cytokine or growth factor regulating multiple signaling pathways and being implicated in... (Review)
Review
Midkine (MDK) is a multifunctional secreted protein that can act as a cytokine or growth factor regulating multiple signaling pathways and being implicated in fundamental cellular processes, such as survival, proliferation, and migration. Although its expression in normal adult tissues is barely detectable, MDK serum levels are found to be elevated in several types of cancer, including hepatocellular carcinoma (HCC). In this review, we summarize the findings of recent studies on the role of MDK in HCC diagnosis and progression. Overall, studies show that MDK is a powerful biomarker for HCC early diagnosis, as it can differentiate not only between HCC patients and normal individuals but also between HCC patients and patients with other liver pathologies. It is correlated with high recurrence rates and was shown to be valuable for the diagnosis of early-stage HCC, even in patients negative for α-fetoprotein (AFP), the most commonly used biomarker for HCC diagnosis. A comparison with AFP reveals that MDK is inferior to AFP with regard to specificity but significantly superior with regard to sensitivity, which further indicates the need for using both biomarkers for more effective HCC diagnosis.
Topics: Adult; Humans; alpha-Fetoproteins; Biomarkers; Carcinoma, Hepatocellular; Liver Neoplasms; Midkine
PubMed: 38247828
DOI: 10.3390/cells13020136 -
World Journal of Gastroenterology Jul 2016Hepatocellular carcinoma (HCC) is one of the most common cancers in Eastern Asia, and its incidence is increasing globally. Numerous experimental models have been... (Review)
Review
Hepatocellular carcinoma (HCC) is one of the most common cancers in Eastern Asia, and its incidence is increasing globally. Numerous experimental models have been developed to better our understanding of the pathogenic mechanism of HCC and to evaluate novel therapeutic approaches. Molecular imaging is a convenient and up-to-date biomedical tool that enables the visualization, characterization and quantification of biologic processes in a living subject. Molecular imaging based on reporter gene expression, in particular, can elucidate tumor-specific events or processes by acquiring images of a reporter gene's expression driven by tumor-specific enhancers/promoters. In this review, we discuss the advantages and disadvantages of various experimental HCC mouse models and we present in vivo images of tumor-specific reporter gene expression driven by an alpha-fetoprotein (AFP) enhancer/promoter system in a mouse model of HCC. The current mouse models of HCC development are established by xenograft, carcinogen induction and genetic engineering, representing the spectrum of tumor-inducing factors and tumor locations. The imaging analysis approach of reporter genes driven by AFP enhancer/promoter is presented for these different HCC mouse models. Such molecular imaging can provide longitudinal information about carcinogenesis and tumor progression. We expect that clinical application of AFP-targeted reporter gene expression imaging systems will be useful for the detection of AFP-expressing HCC tumors and screening of increased/decreased AFP levels due to disease or drug treatment.
Topics: Animals; Carcinogens; Carcinoma, Hepatocellular; Disease Models, Animal; Enhancer Elements, Genetic; Gene Expression; Genes, Reporter; Genetic Engineering; Humans; Liver Neoplasms; Mice; Molecular Imaging; Neoplasm Transplantation; Promoter Regions, Genetic; alpha-Fetoproteins
PubMed: 27468205
DOI: 10.3748/wjg.v22.i27.6127 -
Clinical Chemistry and Laboratory... May 2019Background Measurement of α-fetoprotein (AFP) concentrations in the serum of infants is useful for the management of testicular germ cell tumors, hepatoblastoma and... (Review)
Review
Background Measurement of α-fetoprotein (AFP) concentrations in the serum of infants is useful for the management of testicular germ cell tumors, hepatoblastoma and hepatocellular carcinoma. Here, we provide a critical review of the available information about pediatric reference intervals (RI), focusing on their utility in interpreting AFP as an aid for cancer diagnosis. Content Evidence sources in the available literature were critically appraised. Out of 3873 retrieved papers, 24 were finally selected and carefully inspected, and six of them overcame exclusion criteria (i.e. methodological limitations in the study design, statistical gaps, drawbacks in traceability of the AFP assay to higher order materials and/or biased reporting of AFP results). Preterm and term infants up to the 3rd month of life exhibited the highest average AFP concentrations, but the attempt of defining RI by data pooling and partitioning for age intervals was impeded by the wide variability of data. The inability of defining robust RI in the first months of life made difficult, if not impossible, using upper reference limits for ruling out malignancies with a single AFP result. Evaluating the behavior of AFP concentrations 5 days from the baseline result, if this exceeds risk thresholds partitioned for age, according to the formula Xt=X0*2-t/HL (where: t=days elapsed for AFP retest; HL=AFP half-life according to age; X0=AFP baseline concentration, and Xt=predicted AFP concentration at day 5), could give a better information. Summary Novel studies defining AFP RI in infants based on robust methodology are warranted to improve the interpretation of AFP results in pediatric oncology. In the meantime, algorithms based on both serum AFP absolute concentrations and HL may aid in cancer diagnosis.
Topics: Age Factors; Carcinoma, Hepatocellular; Hepatoblastoma; Humans; Immunoassay; Liver Neoplasms; Neoplasms, Germ Cell and Embryonal; Reference Values; Sex Factors; Testicular Neoplasms; alpha-Fetoproteins
PubMed: 30367785
DOI: 10.1515/cclm-2018-0803 -
BMC Research Notes Nov 2023This study aims to describe the diagnostic performance of alpha-fetoprotein (AFP), alpha-fetoprotein L3 isoform (AFP-L3), protein induced by vitamin K absence II...
OBJECTIVE
This study aims to describe the diagnostic performance of alpha-fetoprotein (AFP), alpha-fetoprotein L3 isoform (AFP-L3), protein induced by vitamin K absence II (PIVKA-II), and combined biomarkers for non-B non-C hepatocellular carcinoma (NBNC-HCC).
RESULTS
A total of 681 newly-diagnosed primary liver disease subjects (385 non-HCC, 296 HCC) who tested negativity for the hepatitis B surface antigen (HBsAg) and hepatitis C antibody (anti-HCV) enrolled in this study. At the cut-off point of 3.8 ng/mL, AFP helps to discriminate HCC from non-HCC with an area under the curve (AUC) value of 0.817 (95% confidence interval [CI]: 0.785-0.849). These values of AFP-L3 (cut-off 0.9%) and PIVKA-II (cut-off 57.7 mAU/mL) were 0.758 (95%CI: 0.725-0.791) and 0.866 (95%CI: 0.836-0.896), respectively. The Bayesian Model Averaging (BMA) statistic identified the optimal model, including patients' age, aspartate aminotransferase, AFP, and PIVKA-II combination, which helps to classify HCC with better performance (AUC = 0.896, 95%CI: 0.872-0.920, P < 0.001). The sensitivity and specificity of the optimal model reached 81.1% (95%CI: 76.1-85.4) and 83.2% (95%CI: 78.9-86.9), respectively. Further analyses indicated that AFP and PIVKA-II markers and combined models have good-to-excellent performance detecting curative resected HCC, separating HCC from chronic hepatitis, dysplastic, and hyperplasia nodules.
Topics: Humans; Carcinoma, Hepatocellular; alpha-Fetoproteins; Liver Neoplasms; Vitamin K; Vitamins; Bayes Theorem; ROC Curve; Biomarkers; Biomarkers, Tumor
PubMed: 37932802
DOI: 10.1186/s13104-023-06600-y