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Journal of Nanobiotechnology Jun 2024Tumor-associated macrophages (TAMs) are a promising target for cancer immunotherapy, but delivering therapeutic agents to TAMs within the tumor microenvironment (TME) is...
Tumor-associated macrophages (TAMs) are a promising target for cancer immunotherapy, but delivering therapeutic agents to TAMs within the tumor microenvironment (TME) is challenging. In this study, a photosensitive, dual-targeting nanoparticle system (M.RGD@Cr-CTS-siYTHDF1 NPs) was developed. The structure includes a shell of DSPE-modified RGD peptides targeting integrin receptors on tumor cells and carboxymethyl mannose targeting CD206 receptors on macrophages, with a core of chitosan adsorbing m6A reading protein YTHDF1 siRNA and chromium nanoparticles (Cr NPs). The approach is specifically designed to target TAM and cancer cells, utilizing the photothermal effect of Cr NPs to disrupt the TME and deliver siYTHDF1 to TAM. In experiments with tumor-bearing mice, M.RGD@Cr-CTS-siYTHDF1 NPs, when exposed to laser irradiation, effectively killed tumor cells, disrupted the TME, delivered siYTHDF1 to TAMs, silenced the YTHDF1 gene, and shifted the STAT3-STAT1 equilibrium by reducing STAT3 and enhancing STAT1 expression. This reprogramming of TAMs towards an anti-tumor phenotype led to a pro-immunogenic TME state. The strategy also suppressed immunosuppressive IL-10 production, increased expression of immunostimulatory factors (IL-12 and IFN-γ), boosted CD8 + T cell infiltration and M1-type TAMs, and reduced Tregs and M2-type TAMs within the TME. In conclusion, the dual-targeting M.RGD@Cr-CTS-siYTHDF1 NPs, integrating dual-targeting capabilities with photothermal therapy (PTT) and RNA interference, offer a promising approach for molecular targeted cancer immunotherapy with potential for clinical application.
Topics: Animals; Mice; Immunotherapy; RNA, Small Interfering; Humans; Liver Neoplasms; Cell Line, Tumor; Tumor Microenvironment; Tumor-Associated Macrophages; RNA-Binding Proteins; Nanoparticles; Metal Nanoparticles; Photosensitizing Agents
PubMed: 38898486
DOI: 10.1186/s12951-024-02612-3 -
International Journal of... 2024Hepatocellular carcinoma (HCC) is the most common and fatal primary liver cancer. Genetic variants of DNA repair systems can reduce DNA repair capability and increase...
Hepatocellular carcinoma (HCC) is the most common and fatal primary liver cancer. Genetic variants of DNA repair systems can reduce DNA repair capability and increase HCC risk. This study aimed to examine, in Egyptian hepatitis C virus (HCV) patients, the relationship between the X-ray repair cross-complementing group 1 (XRCC1) rs1799782 single nucleotide polymorphism (SNP) and HCC susceptibility. We included 100 adult HCV-positive patients with HCC and 100 adult HCV-positive patients with liver cirrhosis as pathological controls. XRCC1 rs1799782 SNP genotyping was done in both groups using quantitative real-time PCR (qPCR). The distribution of genotypes in patients and controls was compared using several inheritance models. We found that the CT genotype, when analyzed under both the co-dominant (OR (95 % CI): 2.147 (1.184-3.893), = .012) and the over-dominant (OR (95 % CI): 2.055 (1.153-3.660), = .015) models, as well as the combined CT and TT genotypes under the dominant model (OR (95 % CI) of 1.991 (1.133-3.497), = .017), were associated with increased susceptibility to HCC. The frequency of the T allele was higher among HCC participants (32%) compared to those with cirrhosis (23.5%) and carrying the T allele increased the risk of HCC by 1.532 times, however, these associations did not reach statistical significance (-values >0.05). Moreover, the variant T allele was associated with worse clinical manifestations and laboratory results among the HCC group, but AFP levels were not affected significantly. Egyptians with XRCC1 rs1799782 SNP may have a higher risk of HCV-related HCC. More extensive multi-center prospective investigations must confirm this association.
Topics: Humans; Carcinoma, Hepatocellular; X-ray Repair Cross Complementing Protein 1; Liver Neoplasms; Male; Case-Control Studies; Egypt; Female; Polymorphism, Single Nucleotide; Genetic Predisposition to Disease; Middle Aged; Pilot Projects; Adult; Hepatitis C; Risk Factors; Genotype
PubMed: 38898405
DOI: 10.1177/03946320241265263 -
Medical Oncology (Northwood, London,... Jun 2024Low-density lipoprotein receptor (LDLR)-related protein 6 (LRP6), a member of the LDLR superfamily of cell surface receptors, is most widely known as a crucial... (Review)
Review
Low-density lipoprotein receptor (LDLR)-related protein 6 (LRP6), a member of the LDLR superfamily of cell surface receptors, is most widely known as a crucial co-receptor in the activation of canonical Wnt/β-catenin signaling. This signaling pathway is implicated in multiple biological processes, such as lipoprotein metabolism, protease regulation, cell differentiation, and migration. LRP6 is frequently overexpressed in a variety of tumors, including liver cancer, colorectal cancer, and prostate cancer, and is generally considered an oncogene that promotes tumor proliferation, migration, and invasion. However, there are exceptions; some studies have reported that LRP6 inhibits lung metastasis of breast cancer through its ectodomain (LRP6N), and patients with low LRP6 expression tend to have a poor prognosis. Thus, the role of LRP6 in tumors remains controversial. Although limited studies have shown that LRP6 is associated with the expression and roles of a variety of immune cells in tumors, the interaction of LRP6 with the tumor microenvironment (TME) is not fully understood. Furthermore, it is crucial to acknowledge that LRP6 can engage with alternative pathways, including the mTORC1, CXCL12/CXCR4, and KRAS signaling pathways mentioned earlier, resulting in the regulation of biological functions independent of canonical Wnt/β-catenin signaling. Due to the potential of LRP6 as a molecular target for cancer therapy, various treatment modalities have been developed to directly or indirectly inhibit LRP6 function, demonstrating promising anti-cancer effects across multiple cancer types. This review will concentrate on exploring the expression, function, and potential therapeutic applications of LRP6 in different cancer types, along with its influence on the TME.
Topics: Humans; Low Density Lipoprotein Receptor-Related Protein-6; Neoplasms; Molecular Targeted Therapy; Tumor Microenvironment; Wnt Signaling Pathway; Animals
PubMed: 38898247
DOI: 10.1007/s12032-024-02399-1 -
Arquivos de Gastroenterologia 2024Recently, significant associations between non-alcoholic fatty liver disease (NAFLD) and extra-hepatic cancer have been reported. (Review)
Review
BACKGROUND
Recently, significant associations between non-alcoholic fatty liver disease (NAFLD) and extra-hepatic cancer have been reported.
OBJECTIVE
To carry out a comprehensive review of the current evidence in the literature on the association between NAFLD and extra-hepatic cancer.
METHODS
A narrative literature review was performed through an online search for the MeSH terms "fatty liver" and "cancer" in MEDLINE (via PubMed) and LILACS (via BVS). Original studies that described the impact of NAFLD on different types of extra-hepatic malignancies were included.
RESULTS
After careful analysis, nine prospective cohort studies, one retrospective cohort study, three case-control studies, and three cross-sectional studies were selected.
CONCLUSION
There is consistent evidence on the association between NAFLD and extra-hepatic carcinogenesis, especially in relation to colorectal, gastric, pancreatic, breast, prostate, and bladder cancers.
Topics: Humans; Non-alcoholic Fatty Liver Disease; Neoplasms; Risk Factors; Male; Female
PubMed: 38896570
DOI: 10.1590/S0004-2803.24612023-027 -
ELife Jun 2024Untargeted metabolomic profiling through liquid chromatography-mass spectrometry (LC-MS) measures a vast array of metabolites within biospecimens, advancing drug...
Untargeted metabolomic profiling through liquid chromatography-mass spectrometry (LC-MS) measures a vast array of metabolites within biospecimens, advancing drug development, disease diagnosis, and risk prediction. However, the low throughput of LC-MS poses a major challenge for biomarker discovery, annotation, and experimental comparison, necessitating the merging of multiple datasets. Current data pooling methods encounter practical limitations due to their vulnerability to data variations and hyperparameter dependence. Here, we introduce GromovMatcher, a flexible and user-friendly algorithm that automatically combines LC-MS datasets using optimal transport. By capitalizing on feature intensity correlation structures, GromovMatcher delivers superior alignment accuracy and robustness compared to existing approaches. This algorithm scales to thousands of features requiring minimal hyperparameter tuning. Manually curated datasets for validating alignment algorithms are limited in the field of untargeted metabolomics, and hence we develop a dataset split procedure to generate pairs of validation datasets to test the alignments produced by GromovMatcher and other methods. Applying our method to experimental patient studies of liver and pancreatic cancer, we discover shared metabolic features related to patient alcohol intake, demonstrating how GromovMatcher facilitates the search for biomarkers associated with lifestyle risk factors linked to several cancer types.
Topics: Metabolomics; Humans; Chromatography, Liquid; Algorithms; Mass Spectrometry; Pancreatic Neoplasms; Liver Neoplasms; Metabolome
PubMed: 38896449
DOI: 10.7554/eLife.91597 -
Annals of Surgical Oncology Jun 2024Surgical resection, the only potentially curative treatment for gallbladder cancer (GBC), entails an extended cholecystectomy with portal lymphadenectomy. Lymph node...
BACKGROUND
Surgical resection, the only potentially curative treatment for gallbladder cancer (GBC), entails an extended cholecystectomy with portal lymphadenectomy. Lymph node dissection is a key staging procedure, but its therapeutic value is unclear. Additionally, it is technically challenging and potentially harmful. Methods for better assessment of lymph node status are needed. This report presents a case of indocyanine green (ICG)-guided sentinel lymph node biopsy (SNLB) for a patient with a gallbladder mass suspicious for GBC.
METHODS
An 81-year-old woman consulted for abdominal discomfort. Abdominal ultrasound showed an intraluminal gallbladder mass suspicious for GBC. Staging imaging did not show liver invasion, lymphadenopathy, or distant metastasis. Given the woman's advanced age and limited extent of disease, a laparoscopic extended cholecystectomy with an ICG-guided SLNB was performed. Injection of 1 ml of ICG (0.125 mg/mL) into the gallbladder bed was performed using a 22-gauge needle, avoiding direct injection into the gallbladder wall.
RESULTS
A near-infrared camera was used to visualize real-time ICG flow through the lymphatic vessels of the gallbladder toward the cystic node. Then, a sentinel lymph node posterolateral to the bile duct (station 12b) was identified. The node was resected and sent for permanent section. The procedure continued with an extended cholecystectomy. Pathology showed an intracholecystic papillary neoplasm with high-grade dysplasia. Cystic and sentinel lymph nodes were negative for malignancy.
CONCLUSION
For patients with gallbladder neoplasms, ICG-guided SLNB is a feasible technique that could allow for treatment de-escalation. Further evaluation in clinical trials is needed.
PubMed: 38896224
DOI: 10.1245/s10434-024-15625-x -
Molecular Biology Reports Jun 2024MG132, a proteasome inhibitor, is widely used to inhibit nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activity by proteasome-mediated...
BACKGROUND
MG132, a proteasome inhibitor, is widely used to inhibit nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activity by proteasome-mediated degradation of IκB. It has been marketed as a specific, reversible, cell-permeable and low-cost inhibitor. However, adverse effects of the compound have been reported in the literature. We recently discovered and characterised a point mutation in the acute phase protein serum amyloid A (SAA) in chickens, by overexpressing the protein in chicken hepatocellular carcinoma (LMH) cells. This serine to arginine exchange at amino acid position 90 (SAA.R90S) leads to intra- and extracellular accumulation of SAA, which is surprisingly counteracted by MG132 treatment, independent of SAA's intrinsic promoter.
METHODS AND RESULTS
To test, whether low proteasomal degradation of SAA.R90S is responsible for the observed intra- and extracellular SAA accumulation, we intended to inhibit the proteasome in SAA wild type (SAA.WT) overexpressing cells with MG132. However, we observed an unexpected drastic decrease in SAA protein expression at the transcript level. NF-κB gene expression was unchanged by MG132 at the measured time point.
CONCLUSIONS
The observed results demonstrate that MG132 inhibits SAA expression at the transcript level, independent of its endogenous promoter. Further, the data might indicate that NF-κB is not involved in the observed MG132-induced inhibition of SAA expression. We, consequently, question in this brief report whether MG132 should truly be categorised as a specific ubiquitin proteasome inhibitor and recommend the usage of alternative compounds.
Topics: Animals; Leupeptins; Chickens; Carcinoma, Hepatocellular; Cell Line, Tumor; Liver Neoplasms; Promoter Regions, Genetic; Serum Amyloid A Protein; NF-kappa B; Proteasome Endopeptidase Complex; Proteasome Inhibitors; Gene Expression Regulation, Neoplastic
PubMed: 38896168
DOI: 10.1007/s11033-024-09726-9 -
Journal of Cancer Research and Clinical... Jun 2024Metabolic reprogramming is an emerging hallmark that influences the tumour microenvironment (TME) by regulating the behavior of cancer cells and immune cells. The...
BACKGROUND
Metabolic reprogramming is an emerging hallmark that influences the tumour microenvironment (TME) by regulating the behavior of cancer cells and immune cells. The relationship between metabolism and immunity remains elusive. The purpose of this study was to explore the predictive value of immune- and metabolism-related genes in hepatocellular carcinoma (HCC) and their intricate interplay with TME.
METHODS
We established the immune- and metabolism-related signature (IMRPS) based on the LIHC cohort from The Cancer Genome Atlas (TCGA) dataset. Kaplan-Meier analysis, receiver operating characteristic (ROC) curve analysis and Cox regression analysis confirmed the prognostic value of IMRPS. We investigated differences in immune cell infiltration, clinical features, and therapeutic response between risk groups. The quantitative real-time PCR (qPCR) was used to confirm the expression of signature genes. Immunohistochemical staining was performed to evaluate immune infiltration features in HCC tissue samples. We conducted cell experiments including gene knockout, cell counting kit-8 (CCK-8), and flow cytometry to explore the role of the IMRPS key gene UCK2 in HCC. RNA-seq was used to further investigate the potential underlying mechanism involved.
RESULTS
The IMRPS, composed of four genes, SMS, UCK2, PFKFB4 and MAPT, exhibited significant correlations with survival, immune cell infiltration, clinical features, immune checkpoints and therapeutic response. The IMRPS was shown to be an excellent predictor of HCC prognosis. It could stratify patients appropriately and characterize the TME accurately. The high-risk HCC group exhibited an immunosuppressive microenvironment with abundant M-like macrophage infiltration, which was confirmed by the immunohistochemistry results. The results of qPCR revealed that the expression of signature genes in 20 HCC tissues was significantly greater than that in adjacent normal tissues. After the key gene UCK2 was knocked out, the proliferation of the Huh7 cell line was significantly inhibited, and monocyte-derived macrophages polarized towards an M1-like phenotype in the coculture system. RNA-seq and GSEA suggested that the phenotypes were closely related to the negative regulation of growth and regulation of macrophage chemotaxis.
CONCLUSIONS
This study established a new IMRS for the accurate prediction of patient prognosis and the TME, which is also helpful for identifying new targets for the treatment of HCC.
Topics: Carcinoma, Hepatocellular; Humans; Liver Neoplasms; Tumor Microenvironment; Prognosis; Biomarkers, Tumor; Female; Gene Expression Regulation, Neoplastic; Male; Middle Aged; Gene Expression Profiling; Transcriptome
PubMed: 38896142
DOI: 10.1007/s00432-024-05849-5 -
Hepatology Communications Jul 2024Serum AFP-L3%, AFP, and DCP are useful biomarkers for HCC detection, but their utility in assessing treatment response remains unknown. We aim to evaluate the accuracy...
BACKGROUND
Serum AFP-L3%, AFP, and DCP are useful biomarkers for HCC detection, but their utility in assessing treatment response remains unknown. We aim to evaluate the accuracy of a biomarker model in the detection of posttreatment viable tumors.
METHODS
For model derivation, recipients with HCC undergoing liver transplant from 2018 to 2022 who had biomarkers collected within 3 months before transplant were included. We developed a generalized linear model for detecting posttreatment viable tumors with the 3 biomarkers as covariates, which we termed the "LAD Score." An independent cohort of 117 patients with HCC was used for external validation.
RESULTS
Among 205 recipients of transplant, 70.2% had evidence of viable tumor on explant. The median LAD score was higher among patients with viable versus nonviable tumors (1.06 vs. 0.465, p < 0.001). The LAD score had a sensitivity of 55.6% and a specificity of 85.1% at the cutoff of 0.927, which was more accurate than imaging for detecting posttreatment viable tumors (AUROC 0.736 vs. 0.643, respectively; p = 0.045). The superior performance of the LAD score over imaging is primarily driven by its greater accuracy in detecting tumors <2 cm in diameter (AUROC of the LAD score 0.721 vs. imaging 0.595, p = 0.02). In the validation data set, the LAD score had an AUROC of 0.832 (95% CI: 0.753, 0.911) with a sensitivity of 72.5% and a specificity of 89.4% at the cutoff of 0.927.
CONCLUSIONS
Our findings suggest the utility of LAD score in treatment response assessment after locoregional therapy for HCC, particularly in detecting small tumors. A larger prospective study is in progress to validate its accuracy and evaluate its performance in recurrence monitoring.
Topics: Humans; Liver Neoplasms; Carcinoma, Hepatocellular; Female; Male; Middle Aged; Biomarkers, Tumor; Liver Transplantation; alpha-Fetoproteins; Aged; Treatment Outcome; Sensitivity and Specificity; Retrospective Studies
PubMed: 38896084
DOI: 10.1097/HC9.0000000000000466 -
Landmark analysis of the risk of recurrence after resection or ablation for HCC: A nationwide study.Hepatology Communications Jul 2024The risk of HCC recurrence at particular landmarks since the initial treatment is unknown. With this registry-based study, we aimed to provide a nuanced description of...
BACKGROUND
The risk of HCC recurrence at particular landmarks since the initial treatment is unknown. With this registry-based study, we aimed to provide a nuanced description of the prognosis following resection or ablation for HCC, including landmark analyses.
METHODS
Using the Danish nationwide health care registries, we identified all patients who received resection or ablation in 2000-2018 as the first HCC treatment. HCC recurrence was defined as a new HCC treatment > 90 days after the first treatment. We conducted competing risk landmark analyses of the cumulative risk of recurrence and death.
RESULTS
Among 4801 patients with HCC, we identified 426 patients who received resection and 544 who received ablation. The 2 treatment cohorts differed in cirrhosis prevalence and tumor stage. The 5-year recurrence risk was 40.7% (95% CI 35.5%-45.8%) following resection and 60.7% (95% CI: 55.9%-65.1%) following ablation. The 1-year recurrence risk decreased over the landmarks from 20.4% (95% CI: 16.6%-24.6%) at the time of resection to 4.7% (95% CI: 0.9%-13.9%) at the 5-year landmark. For ablation, the risk decreased from 36.1% (95% CI: 31.9%-40.4%) at the time of treatment to 5.3% (95% CI: 0.4%-21.4%) at the 5-year landmark. The risk of death without recurrence was stable over the landmarks following both resection and ablation.
CONCLUSIONS
In conclusion, the risk of recurrence or death following resection or ablation for HCC is high from the treatment date, but the risk of recurrence decreases greatly over the survival landmarks. This information is valuable for clinicians and their patients.
Topics: Humans; Liver Neoplasms; Neoplasm Recurrence, Local; Carcinoma, Hepatocellular; Male; Female; Denmark; Middle Aged; Aged; Registries; Hepatectomy; Catheter Ablation; Risk Assessment; Prognosis; Risk Factors
PubMed: 38896083
DOI: 10.1097/HC9.0000000000000472