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Nature Communications Dec 2023Early diagnosis of hepatocellular carcinoma (HCC) lacks highly sensitive and specific protein biomarkers. Here, we describe a staged mass spectrometry (MS)-based...
Early diagnosis of hepatocellular carcinoma (HCC) lacks highly sensitive and specific protein biomarkers. Here, we describe a staged mass spectrometry (MS)-based discovery-verification-validation proteomics workflow to explore serum proteomic biomarkers for HCC early diagnosis in 1002 individuals. Machine learning model determined as P4 panel (HABP2, CD163, AFP and PIVKA-II) clearly distinguish HCC from liver cirrhosis (LC, AUC 0.979, sensitivity 0.925, specificity 0.915) and healthy individuals (HC, AUC 0.992, sensitivity 0.975, specificity 1.000) in an independent validation cohort, outperforming existing clinical prediction strategies. Furthermore, the P4 panel can accurately predict LC to HCC conversion (AUC 0.890, sensitivity 0.909, specificity 0.877) with predicting HCC at a median of 11.4 months prior to imaging in prospective external validation cohorts (No.: Keshen 2018_005_02 and NCT03588442). These results suggest that proteomics-driven serum biomarker discovery provides a valuable reference for the liquid biopsy, and has great potential to improve early diagnosis of HCC.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Biomarkers, Tumor; Proteomics; Prospective Studies; alpha-Fetoproteins; Biomarkers; Early Detection of Cancer
PubMed: 38110372
DOI: 10.1038/s41467-023-44255-2 -
Nature Communications Sep 2023The durable response rate to immune checkpoint blockade such as anti-programmed cell death-1 (PD-1) antibody remains relatively low in hepatocellular carcinoma (HCC),...
The durable response rate to immune checkpoint blockade such as anti-programmed cell death-1 (PD-1) antibody remains relatively low in hepatocellular carcinoma (HCC), mainly depending on an immunosuppressive microenvironment with limited number of CD8 T cells, especially stem-like CD8 T cells, in tumor tissues. Here we develop engineered microparticles (MPs) derived from alpha-fetoprotein (AFP)-overexpressing macrophages to load resiquimod (R848@M2pep-MPs) for enhanced anti-PD-1 therapy in HCC. R848@M2pep-MPs target and reprogram immunosuppressive M2-like tumor-associated macrophages (TAMs) into M1-like phenotype. Meanwhile, R848@M2pep-MPs-reprogrammed TAMs act as antigen-presenting cells, not only presenting AFP antigen to activate CD8 T cell-mediated antitumor immunity, but also providing an intra-tumoral niche to maintain and differentiate stem-like CD8 T cells. Combination immunotherapy with anti-PD-1 antibody generates strong antitumor immune memory and induces abundant stem-like CD8 T cell proliferation and differentiation to terminally exhausted CD8 T cells for long-term immune surveillance in orthotopic and autochthonous HCC preclinical models in male mice. We also show that the R848-loaded engineered MPs derived from macrophages overexpressing a model antigen ovalbumin (OVA) can improve anti-PD-1 therapy in melanoma B16-OVA tumor-bearing mice. Our work presents a facile and generic strategy for personalized cancer immunotherapy to boost anti-PD-1 therapy.
Topics: Male; Animals; Mice; Tumor-Associated Macrophages; alpha-Fetoproteins; Carcinoma, Hepatocellular; CD8-Positive T-Lymphocytes; Liver Neoplasms; Immunosuppressive Agents; Antigens, Neoplasm; Tumor Microenvironment
PubMed: 37704614
DOI: 10.1038/s41467-023-41438-9 -
Indian Journal of Surgical Oncology May 2024Liver cancer is one of the most prevalent types of cancer and a major contributor to the socioeconomic burden worldwide. The pathogenesis of hepatocellular carcinoma... (Review)
Review
Liver cancer is one of the most prevalent types of cancer and a major contributor to the socioeconomic burden worldwide. The pathogenesis of hepatocellular carcinoma (HCC) is contributed by various etiological factors like virus infection, excessive alcohol consumption, exposure to toxins, or metabolic disorders. Majority of patients are diagnosed with late-stage HCC, which restricts its management to only palliative care. HCC, if diagnosed early, increases the survival and quality of life. Currently available biomarker (alpha-fetoproteins) have several limitations, that impede the early diagnosis and staging of cancer. This warrants the continous search in pursuit of a novel biomarker. Several research works in diverse areas have contributed to the identification of various novel biomarkers that have shown multifaceted application in early disease diagnosis, which further aid in targeted and effective therapy that can prevent cancer progression. This improves the overall health status of the patient along with significant reduction in caretaker's burden. With the aid of novel technologies, several biomarkers have been investigated and validated in mutliple preliminary research works. Therefore in this review, we have outlined various novel biomarkers that showed promising outcomes in their trials and we have highlighted the developing areas that act as game changers in cancer diagnosis and management.
PubMed: 38817995
DOI: 10.1007/s13193-023-01858-x -
Clinical and Experimental Hypertension... Dec 2023To evaluate the correlation between elevated maternal serum alpha-fetoprotein (AFP) in the second trimester and ischemic placental disease (IPD).
BACKGROUND
To evaluate the correlation between elevated maternal serum alpha-fetoprotein (AFP) in the second trimester and ischemic placental disease (IPD).
METHODS
A retrospective cohort study was conducted to analyze the data of 22,574 pregnant women who delivered in the Department of Obstetrics at Hangzhou Women's Hospital from 2018 to 2020, and were screened for maternal serum AFP and free beta-human chorionic gonadotropin (free β-hCG) in the second trimester. The pregnant women were divided into two groups: elevated maternal serum AFP group (n = 334, 1.48%); and normal group (n = 22,240, 98.52%). Mann-Whitney U-test or Chi-square test was used for continuous or categorical data. Modified Poisson regression analysis was used to calculate the relative risk (RR) and 95% confidence interval (CI) of the two groups.
RESULTS
The AFP MoM and free β-hCG MoM in the elevated maternal serum AFP group were higher than the normal group (2.25 vs. 0.98, 1.38 vs. 1.04) and the differences were all statistically significant (all < .001). Placenta previa, hepatitis B virus carrying status of pregnant women, premature rupture of membranes (PROM), advanced maternal age (≥35 years), increased free β-hCG MoM, female infants, and low birth weight (RR: 2.722, 2.247, 1.769, 1.766, 1.272, 0.624, 2.554 respectively) were the risk factors for adverse maternal pregnancy outcomes in the elevated maternal serum AFP group.
CONCLUSIONS
Maternal serum AFP levels during the second trimester can monitor IPD, such as IUGR, PROM, and placenta previa. Maternal women with high serum AFP levels are more likely to deliver male fetuses and low birth weight infants. Finally, the maternal age (≥35 years) and hepatitis B carriers also increased maternal serum AFP significantly.
Topics: Pregnancy; Infant; Humans; Female; Male; Adult; alpha-Fetoproteins; Placenta Previa; Retrospective Studies; Placenta; Chorionic Gonadotropin, beta Subunit, Human
PubMed: 36849437
DOI: 10.1080/10641963.2023.2175848 -
Molecular Cancer Oct 2023To address the shortcomings of current hepatocellular carcinoma (HCC) surveillance tests, we set out to find HCC-specific methylation markers and develop a highly...
To address the shortcomings of current hepatocellular carcinoma (HCC) surveillance tests, we set out to find HCC-specific methylation markers and develop a highly sensitive polymerase chain reaction (PCR)-based method to detect them in circulating cell-free DNA (cfDNA). The analysis of large methylome data revealed that Ring Finger Protein 135 (RNF135) and Lactate Dehydrogenase B (LDHB) are universally applicable HCC methylation markers with no discernible methylation level detected in any other tissue types. These markers were used to develop Methylation Sensitive High-Resolution Analysis (MS-HRM), and their diagnostic accuracy was tested using cfDNA from healthy, at-risk, and HCC patients. The combined MS-HRM RNF135 and LDHB analysis detected 57% of HCC, outperforming the alpha-fetoprotein (AFP) test's sensitivity of 45% at comparable specificity. Furthermore, when used with the AFP test, the methylation assay can detect 70% of HCC. Our findings suggest that the cfDNA methylation assay could be used for HCC liquid biopsy.
Topics: Humans; Carcinoma, Hepatocellular; alpha-Fetoproteins; Liver Neoplasms; DNA Methylation; Biomarkers, Tumor; Cell-Free Nucleic Acids; Ubiquitin-Protein Ligases
PubMed: 37803338
DOI: 10.1186/s12943-023-01872-1 -
JCI Insight Sep 2023Cancer stem cells (CSCs) are responsible for tumor progression and recurrence. However, the mechanisms regulating hepatocellular carcinoma (HCC) stemness remain unclear....
Cancer stem cells (CSCs) are responsible for tumor progression and recurrence. However, the mechanisms regulating hepatocellular carcinoma (HCC) stemness remain unclear. Applying a genome-scale CRISPR knockout screen, we identified that the H3K4 methyltransferase SETD1A and other members of Trithorax group proteins drive cancer stemness in HCC. SET domain containing 1A (SETD1A) was positively correlated with poor clinical outcome in patients with HCC. Combination of SETD1A and serum alpha fetoprotein substantially improved the accuracy of predicting HCC relapse. Mechanistically, SETD1A mediates transcriptional activation of various histone-modifying enzymes, facilitates deposition of trimethylated H3K4 (H3K4me3) and H3K27me3, and activates oncogenic enhancers and super-enhancers, leading to activation of oncogenes and inactivation of tumor suppressor genes simultaneously in liver CSCs. In addition, SETD1A cooperates with polyadenylate-binding protein cytoplasmic 1 to regulate H3K4me3 modification on oncogenes. Our data pinpoint SETD1A as a key epigenetic regulator driving HCC stemness and progression, highlighting the potential of SETD1A as a candidate target for HCC intervention and therapy.
Topics: Humans; Carcinoma, Hepatocellular; Epigenesis, Genetic; Liver Neoplasms; Neoplasm Recurrence, Local; Stem Cells
PubMed: 37581938
DOI: 10.1172/jci.insight.168375 -
Journal of Clinical and Translational... Oct 2023Hepatocellular carcinoma (HCC) is a common malignant tumor with high incidence and cancer mortality worldwide. Post-translational modifications (PTMs) of proteins have a... (Review)
Review
Hepatocellular carcinoma (HCC) is a common malignant tumor with high incidence and cancer mortality worldwide. Post-translational modifications (PTMs) of proteins have a great impact on protein function. Almost all proteins can undergo PTMs, including phosphorylation, acetylation, methylation, glycosylation, ubiquitination, and so on. Many studies have shown that PTMs are related to the occurrence and development of cancers. The findings provide novel therapeutic targets for cancers, such as glypican-3 and mucin-1. Other clinical implications are also found in the studies of PTMs. Diagnostic or prognostic value, and response to therapy have been identified. In HCC, it has been shown that glycosylated alpha-fetoprotein (AFP) has a higher detection rate for early liver cancer than conventional AFP. In this review, we mainly focused on the diagnostic and prognostic value of PTM, in order to provide new insights into the clinical implication of PTM in HCC.
PubMed: 37577238
DOI: 10.14218/JCTH.2022.00006S -
Biosensors May 2024Hepatocellular carcinoma (HCC) is currently one of the most prevalent cancers worldwide. Associated risk factors include, but are not limited to, cirrhosis and... (Review)
Review
Hepatocellular carcinoma (HCC) is currently one of the most prevalent cancers worldwide. Associated risk factors include, but are not limited to, cirrhosis and underlying liver diseases, including chronic hepatitis B or C infections, excessive alcohol consumption, nonalcoholic fatty liver disease (NAFLD), and exposure to chemical carcinogens. It is crucial to detect this disease early on before it metastasizes to adjoining parts of the body, worsening the prognosis. Serum biomarkers have proven to be a more accurate diagnostic tool compared to imaging. Among various markers such as nucleic acids, circulating genetic material, proteins, enzymes, and other metabolites, alpha-fetoprotein (AFP) is a protein marker primarily used to diagnose HCC. However, current methods need a large sample and carry a high cost, among other challenges, which can be improved using biosensing technology. Early and accurate detection of AFP can prevent severe progression of the disease and ensure better management of HCC patients. This review sheds light on HCC development in the human body. Afterward, we outline various types of biosensors (optical, electrochemical, and mass-based), as well as the most relevant studies of biosensing modalities for non-invasive monitoring of AFP. The review also explains these sensing platforms, detection substrates, surface modification agents, and fluorescent probes used to develop such biosensors. Finally, the challenges and future trends in routine clinical analysis are discussed to motivate further developments.
Topics: Humans; Carcinoma, Hepatocellular; alpha-Fetoproteins; Liver Neoplasms; Biosensing Techniques; Early Detection of Cancer; Biomarkers, Tumor
PubMed: 38785709
DOI: 10.3390/bios14050235 -
Cancers Aug 2023Transarterial chemoembolization (TACE) is used as a bridging treatment in liver transplant candidates with hepatocellular carcinoma (HCC). Alpha-fetoprotein (AFP) is the...
Transarterial chemoembolization (TACE) is used as a bridging treatment in liver transplant candidates with hepatocellular carcinoma (HCC). Alpha-fetoprotein (AFP) is the main tumor marker used for HCC surveillance. The aim of this study was to assess the potential of using the AFP change after the first TACE in the prediction of complete tumor necrosis. The study comprised 101 patients with HCC who underwent liver transplantation (LT) after TACE in the period between January 2011 and December 2020. The ΔAFP was defined as the difference between the AFP value before the first TACE and AFP either before the second TACE or the LT. The receiver operator characteristics (ROC) curves were used to identify an optimal cut-off value. Complete tumor necrosis was found in 26.1% (18 of 69) and 6.3% (2 of 32) of patients with an initial AFP level under and over 100 ng/mL, respectively ( = 0.020). The optimal cut-off value of ΔAFP for the prediction of complete necrosis was a decline of ≥10.2 ng/mL and ≥340.5 ng/mL in the corresponding subgroups. Complete tumor necrosis rates were: 62.5% (5 of 8) in patients with an initial AFP < 100 ng/mL and decline of ≥10.2 ng/mL; 21.3% (13 of 61) in patients with an initial AFP < 100 ng/mL and decline of <10.2 ng/mL; 16.7% (2 of 12) in patients with an initial AFP > 100 ng/mL and decline of ≥340.5 ng/mL; and null in 20 patients with an initial AFP > 100 ng/mL and decline of <340.5 ng/mL, respectively ( = 0.003). The simple scoring system, based on the initial AFP and AFP decline after the first treatment, distinguished between a high, intermediate and low probability of complete necrosis, with an area under the ROC curve of 0.699 (95% confidence intervals 0.577 to 0.821, = 0.001). Combining the initial AFP with its change after the first treatment enables early identification of the efficacy of TACE.
PubMed: 37568778
DOI: 10.3390/cancers15153962