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Clinical Epigenetics Jun 2024Gastrointestinal malignancies encompass a diverse group of cancers that pose significant challenges to global health. The major histocompatibility complex (MHC) plays a... (Review)
Review
BACKGROUND
Gastrointestinal malignancies encompass a diverse group of cancers that pose significant challenges to global health. The major histocompatibility complex (MHC) plays a pivotal role in immune surveillance, orchestrating the recognition and elimination of tumor cells by the immune system. However, the intricate regulation of MHC gene expression is susceptible to dynamic epigenetic modification, which can influence functionality and pathological outcomes.
MAIN BODY
By understanding the epigenetic alterations that drive MHC downregulation, insights are gained into the molecular mechanisms underlying immune escape, tumor progression, and immunotherapy resistance. This systematic review examines the current literature on epigenetic mechanisms that contribute to MHC deregulation in esophageal, gastric, pancreatic, hepatic and colorectal malignancies. Potential clinical implications are discussed of targeting aberrant epigenetic modifications to restore MHC expression and 0 the effectiveness of immunotherapeutic interventions.
CONCLUSION
The integration of epigenetic-targeted therapies with immunotherapies holds great potential for improving clinical outcomes in patients with gastrointestinal malignancies and represents a compelling avenue for future research and therapeutic development.
Topics: Humans; Gastrointestinal Neoplasms; Epigenesis, Genetic; Major Histocompatibility Complex; Gene Expression Regulation, Neoplastic; Immunotherapy; DNA Methylation; Tumor Escape
PubMed: 38915093
DOI: 10.1186/s13148-024-01698-8 -
PloS One 2024This study aimed to evaluate the effects of sarcopenia and inflammation on the prognosis of patients with pancreatic cancer after pancreaticoduodenectomy.
BACKGROUND
This study aimed to evaluate the effects of sarcopenia and inflammation on the prognosis of patients with pancreatic cancer after pancreaticoduodenectomy.
METHODS
Eighty patients who had undergone pancreaticoduodenectomy for pancreatic cancer between July 2010 and December 2023 were included in this study. The psoas muscle index was used to assess sarcopenia. The C-reactive protein-to-albumin ratio, prognostic nutritional index, neutrophil-to-lymphocyte ratio, and platelet-to-lymphocyte ratio were used to calculate the preoperative inflammatory marker levels. The prognostic factors for overall survival were determined using Cox regression analysis.
RESULTS
Twenty-four patients were diagnosed with sarcopenia. Sarcopenia showed a significant association with advanced tumor stage. Univariate analysis revealed a significant reduction in overall survival in patients with a prognostic nutritional index of <45, C-reactive protein-to-albumin ratio of ≥0.047, cancer antigen 19-9 levels of ≥130 U/mL, sarcopenia, lymph node metastasis, and vascular invasion. Multivariate analysis revealed that a C-reactive protein-to-albumin ratio of ≥0.047 (hazards ratio, 3.383; 95% confidence interval: 1.384-8.689; p< 0.001), cancer antigen 19-9 levels of ≥130 U/mL (hazards ratio, 2.720; 95% confidence interval: 1.291-6.060; p = 0.008), sarcopenia (hazards ratio, 3.256; 95% confidence interval: 1.535-7.072; p = 0.002) and vascular invasion (hazards ratio, 2.092; 95% confidence interval: 1.057-4.170; p = 0.034) were independent predictors of overall survival. Overall survival in the sarcopenia and high C-reactive protein-to-albumin ratio groups was significantly poorer than that in the non-sarcopenia and low C-reactive protein-to-albumin ratio and sarcopenia or high C-reactive protein-to-albumin ratio groups.
CONCLUSION
Sarcopenia and a high C-reactive protein-to-albumin ratio are independent prognostic factors in patients with pancreatic cancer after pancreaticoduodenectomy. Thus, sarcopenia may have a better prognostic value when combined with the C-reactive protein-to-albumin ratio.
Topics: Humans; Sarcopenia; Pancreatic Neoplasms; Pancreaticoduodenectomy; Male; Female; Middle Aged; Aged; Prognosis; C-Reactive Protein; Inflammation; Retrospective Studies; Biomarkers, Tumor
PubMed: 38913646
DOI: 10.1371/journal.pone.0305844 -
JCI Insight May 2024The regulated glycosylation of the proteome has widespread effects on biological processes that cancer cells can exploit. Expression of N-acetylglucosaminyltransferase V...
The regulated glycosylation of the proteome has widespread effects on biological processes that cancer cells can exploit. Expression of N-acetylglucosaminyltransferase V (encoded by Mgat5 or GnT-V), which catalyzes the addition of β1,6-linked N-acetylglucosamine to form complex N-glycans, has been linked to tumor growth and metastasis across tumor types. Using a panel of murine pancreatic ductal adenocarcinoma (PDAC) clonal cell lines that recapitulate the immune heterogeneity of PDAC, we found that Mgat5 is required for tumor growth in vivo but not in vitro. Loss of Mgat5 results in tumor clearance that is dependent on T cells and dendritic cells, with NK cells playing an early role. Analysis of extrinsic cell death pathways revealed Mgat5-deficient cells have increased sensitivity to cell death mediated by the TNF superfamily, a property that was shared with other non-PDAC Mgat5-deficient cell lines. Finally, Mgat5 knockout in an immunotherapy-resistant PDAC line significantly decreased tumor growth and increased survival upon immune checkpoint blockade. These findings demonstrate a role for N-glycosylation in regulating the sensitivity of cancer cells to T cell killing through classical cell death pathways.
Topics: Animals; Glycosylation; Mice; N-Acetylglucosaminyltransferases; Carcinoma, Pancreatic Ductal; Pancreatic Neoplasms; Cell Line, Tumor; Humans; T-Lymphocytes; Dendritic Cells; Killer Cells, Natural; Mice, Knockout
PubMed: 38912584
DOI: 10.1172/jci.insight.178804 -
DEN Open Apr 2025Endoscopic ultrasound-guided tissue acquisition (EUS-TA), including fine-needle aspiration (EUS-FNA) and fine-needle biopsy (EUS-FNB), has revolutionized specimen... (Review)
Review
Endoscopic ultrasound-guided tissue acquisition (EUS-TA), including fine-needle aspiration (EUS-FNA) and fine-needle biopsy (EUS-FNB), has revolutionized specimen collection from intra-abdominal organs, especially the pancreas. Advances in personalized medicine and more precise treatment have increased demands to collect specimens with higher cell counts, while preserving tissue structure, leading to the development of EUS-FNB needles. EUS-FNB has generally replaced EUS-FNA as the procedure of choice for EUS-TA of pancreatic cancer. Various techniques have been tested for their ability to enhance the diagnostic performance of EUS-TA, including multiple methods of sampling at the time of puncture, on-site specimen evaluation, and specimen processing. In addition, advances in next-generation sequencing have made comprehensive genomic profiling of EUS-TA samples feasible in routine clinical practice. The present review describes updates in EUS-TA sampling techniques of pancreatic lesions, as well as methods for their evaluation.
PubMed: 38911353
DOI: 10.1002/deo2.399 -
Signal Transduction and Targeted Therapy Jun 2024Pancreatic cancer is one of the deadly malignancies with a significant mortality rate and there are currently few therapeutic options for it. The tumor microenvironment...
Pancreatic cancer is one of the deadly malignancies with a significant mortality rate and there are currently few therapeutic options for it. The tumor microenvironment (TME) in pancreatic cancer, distinguished by fibrosis and the existence of cancer-associated fibroblasts (CAFs), exerts a pivotal influence on both tumor advancement and resistance to therapy. Recent advancements in the field of engineered extracellular vesicles (EVs) offer novel avenues for targeted therapy in pancreatic cancer. This study aimed to develop engineered EVs for the targeted reprogramming of CAFs and modulating the TME in pancreatic cancer. EVs obtained from bone marrow mesenchymal stem cells (BMSCs) were loaded with miR-138-5p and the anti-fibrotic agent pirfenidone (PFD) and subjected to surface modification with integrin α5-targeting peptides (named IEVs-PFD/138) to reprogram CAFs and suppress their pro-tumorigenic effects. Integrin α5-targeting peptide modification enhanced the CAF-targeting ability of EVs. miR-138-5p directly inhibited the formation of the FERMT2-TGFBR1 complex, inhibiting TGF-β signaling pathway activation. In addition, miR-138-5p inhibited proline-mediated collagen synthesis by directly targeting the FERMT2-PYCR1 complex. The combination of miR-138-5p and PFD in EVs synergistically promoted CAF reprogramming and suppressed the pro-cancer effects of CAFs. Preclinical experiments using the orthotopic stroma-rich and patient-derived xenograft mouse models yielded promising results. In particular, IEVs-PFD/138 effectively reprogrammed CAFs and remodeled TME, which resulted in decreased tumor pressure, enhanced gemcitabine perfusion, tumor hypoxia amelioration, and greater sensitivity of cancer cells to chemotherapy. Thus, the strategy developed in this study can improve chemotherapy outcomes. Utilizing IEVs-PFD/138 as a targeted therapeutic agent to modulate CAFs and the TME represents a promising therapeutic approach for pancreatic cancer.
Topics: Pancreatic Neoplasms; Extracellular Vesicles; Humans; Cancer-Associated Fibroblasts; Mice; MicroRNAs; Animals; Tumor Microenvironment; Cellular Reprogramming; Cell Line, Tumor; Mesenchymal Stem Cells; Neoplasm Proteins; Gemcitabine
PubMed: 38910148
DOI: 10.1038/s41392-024-01872-7 -
Human Pathology Jun 2024Pancreatic neuroendocrine tumors (PanNETs) comprise a heterogeneous group of neoplasms in terms of biological behavior. This study aims to develop a practical algorithm...
Pancreatic neuroendocrine tumors (PanNETs) comprise a heterogeneous group of neoplasms in terms of biological behavior. This study aims to develop a practical algorithm based on emerging biomarkers, including chromatin-remodeling molecules DAXX/ATRX/H3K36me3, in conjunction with established prognostic factors, such as WHO grade and size. In immunohistochemical analyses, 18 of the 111 (16.2%) primary PanNETs showed DAXX or ATRX loss in a mutually exclusive manner. DAXX/ATRX loss was significantly correlated with higher recurrence risk and better predicted postoperative recurrence than WHO grade. We proposed a novel algorithm for stratifying patients with resectable PanNET into three groups according to recurrence risk: (A) WHO Grade 1 and ≤ 2 cm (very low-risk); for the others, (B) retained DAXX/ATRX (low-risk) and (C) DAXX/ATRX complete/heterogeneous loss (high-risk). Furthermore, we elucidated the intratumoral heterogeneities of PanNETs. Among cases with DAXX or ATRX loss, nine cases demonstrated heterogeneous loss of expression of DAXX/ATRX/H3K36me3. The majority of cases with DAXX/ATRX loss, either homogeneous or heterogeneous loss, showed uniform α-cell-like phenotype (ARX1+/PDX1-). In cases of metastatic or recurrent tumors, the expression pattern was identical to that observed in at least part of the primary tumor. In some instances, the expression pattern differed among different metastatic or recurrent tumors of the same patient. In summary, we propose a clinically useful and practical algorithm for postoperative recurrence risk stratification in PanNETs, by combining DAXX/ATRX status with WHO grade and size. Moreover, our findings highlighted the frequent spatiotemporal heterogeneity of chromatin-remodeling molecule expression in PanNETs with an α-cell phenotype, offering insights into tumorigenesis.
PubMed: 38909708
DOI: 10.1016/j.humpath.2024.06.015 -
Scientific Reports Jun 2024Pancreatic cancer is one of the most aggressive forms of cancer, and treatment options are limited. One therapeutic approach is to use nanoparticles to deliver the...
Pancreatic cancer is one of the most aggressive forms of cancer, and treatment options are limited. One therapeutic approach is to use nanoparticles to deliver the active agent directly to pancreatic cancer cells. Nanoparticles can be designed to specifically target cancer cells, minimizing damage to healthy tissues. Silver nanoparticles have the unique ability to absorb light, especially in the near-infrared (NIR) region. In this study, silver nanoparticles functionalized with IgG molecules were synthesized and administered to pancreatic cancer cell lines. Subsequently, the cells were photo-excited using a 2 W 808 nm laser and further examined in PANC-1 pancreatic cancer cell lines. Flow cytometry and confocal microscopy combined with immunochemical staining were used to examine the interaction between photo-excited silver nanoparticles and pancreatic cancer cells. The photothermal therapy based on IgG-functionalized silver nanoparticles in pancreatic cancer induces dysfunction in the Golgi apparatus, leading to the activation of the caspase-3 apoptotic pathway and ultimately resulting in cellular apoptosis. These findings suggest that our proposed IgG nanoparticle laser treatment could emerge as a novel approach for the therapy of pancreatic cancer.
Topics: Pancreatic Neoplasms; Humans; Silver; Metal Nanoparticles; Immunoglobulin G; Cell Line, Tumor; Photothermal Therapy; Apoptosis; Caspase 3; Phototherapy
PubMed: 38909066
DOI: 10.1038/s41598-024-63142-4 -
Cell Death & Disease Jun 2024TBX3 behaves as a tumor suppressor or oncoprotein across cancer. However, TBX3 function remains undetermined in intrahepatic cholangiocarcinoma (iCCA), a deadly primary...
TBX3 behaves as a tumor suppressor or oncoprotein across cancer. However, TBX3 function remains undetermined in intrahepatic cholangiocarcinoma (iCCA), a deadly primary liver malignancy with few systemic treatment options. This study sought to investigate the impact of TBX3 on iCCA. We found that overexpression of TBX3 strongly inhibited human iCCA cell growth. In the Akt/FBXW7ΔF mouse iCCA model, overexpression of Tbx3 reduced cholangiocarcinogenesis in vivo, while inducible genetic knockout of Tbx3 accelerated iCCA growth. RNA-seq identified MAD2L1 as a downregulated gene in TBX3-overexpressing cells, and ChIP confirmed that TBX3 binds to the MAD2L1 promoter. CRISPR-mediated knockdown of Mad2l1 significantly reduced the growth of two iCCA models in vivo. Finally, we found that TBX3 expression is upregulated in ~20% of human iCCA samples, and its high expression is associated with less proliferation and better survival. MAD2L1 expression is upregulated in most human iCCA samples and negatively correlated with TBX3 expression. Altogether, our findings suggest that overexpression of TBX3 suppresses CCA progression via repressing MAD2L1 expression.
Topics: Cholangiocarcinoma; T-Box Domain Proteins; Humans; Animals; Mice; Bile Duct Neoplasms; Carcinogenesis; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; Cell Proliferation
PubMed: 38909034
DOI: 10.1038/s41419-024-06839-8 -
Medicina 2024Multiple Endocrine Neoplasia type 1 (MEN1) is an autosomal dominant inherited disease with an estimated prevalence of 2-10:100 000. The main locations of tumors are...
INTRODUCTION
Multiple Endocrine Neoplasia type 1 (MEN1) is an autosomal dominant inherited disease with an estimated prevalence of 2-10:100 000. The main locations of tumors are parathyroid glands (HPT), gastroenteropancreatic tract (GEPT), and anterior pituitary gland (PT). The aim of our investigation was to describe the phenotype and genotype of Argentinian patients with MEN1.
METHODS
A total of 68 index patients diagnosed with at least two of the three main tumors or one tumor and a relative with MEN1, and 84 first-degree relatives were studied. We sequenced the coding region (exons 2-10); the promoter, exon 1; and the flanking intronic regions of the MEN1 gene, following the Sanger method. We used MLPA in index patients without mutation.
RESULTS
Prevalence of tumors: HPT 87.5%, GEPT 49% (p< 0.001). No statistical differences in the prevalence of HPT vs. PT (68%). Prevalence of pathogenic variants: 90% in familial cases and 51% in sporadic cases. Of the different 36 pathogenic variants, 13 (36.2%) were frameshift micro-rearrangement, 8 (22.2%) were missense, 9 (25%) were nonsense, 3 (8.3%) were mutations in splicing sites, 2 (5.5%) were large deletions and, 1 in-frame micro-rearrangement. We found 7 novel pathogenic variants. Thirty-nine percent (n = 33) of first-degree relatives of 23 families were found to be mutation carriers.
CONCLUSION
The phenotype and genotype of Argentinian patients was similar to other MEN1 populations. A high frequency of PT and the identification of seven novel mutations are underscored.
Topics: Humans; Argentina; Male; Multiple Endocrine Neoplasia Type 1; Phenotype; Female; Adult; Genotype; Middle Aged; Adolescent; Young Adult; Child; Aged; Mutation; Child, Preschool; Parathyroid Neoplasms; Proto-Oncogene Proteins
PubMed: 38907957
DOI: No ID Found -
BMC Medical Genomics Jun 2024Collagen (COL) genes, play a key role in tumor invasion and metastasis, are involved in tumor extracellular matrix (ECM)-receptor interactions and focal adhesion...
BACKGROUND
Collagen (COL) genes, play a key role in tumor invasion and metastasis, are involved in tumor extracellular matrix (ECM)-receptor interactions and focal adhesion pathways. However, studies focusing on the diagnostic value of the COL4 family in stomach adenocarcinoma (STAD) are currently lacking.
METHODS
The TCGA database was employed to retrieve the clinical features and RNA sequencing expression profiles of patients with STAD. We conducted an investigation to examine the expression disparities between STAD and adjacent normal tissues. Kaplan-Meier survival analysis was utilized to assess their prognostic significance, while Spearman correlation analysis was employed to determine their association with immune checkpoint genes and immunomodulatory molecules. Furthermore, GO and KEGG analyses were performed on the COL4s-related genes, revealing potential biological pathways through gene set enrichment analysis (GSEA). Subsequently, we explored the extent of immune infiltration of the COL4 family in STAD using the TIMER database. Lastly, the expression levels of the COL4 family in STAD were further validated through quantitative PCR (qPCR) and western blot techniques.
RESULTS
The expression levels of COL4A1/2 were significantly upregulated, while COL4A5/6 were conspicuously downregulated in STAD. The survival analysis revealed that the upregulated COL4s indicated poorer overall survival, first progression and post-progression survival outcomes. Additionally, our findings demonstrated a positive correlation between the expressions of COL4A1/2/3/4 and the infiltration of immune cells, including CD8 + T cells, dendritic cells, macrophages, neutrophils and CD4 + T cells. Further correlation analysis uncovered a favorable association between the expression of COL4A1/2/3/4 and various crucial immunomodulatory molecules, immunological checkpoint molecules, and chemokines. Quantitative PCR analysis confirmed that the expression patterns of COL4A1/3/4/6 genes aligned with the finding from the TCGA database. However, gastric cancer cells exhibited downregulation of COL4A2. Consistently, the protein level of COL4A1 was elevated, whereas the protein level of COL4A2 was reduced in the gastric cancer cell lines.
CONCLUSION
COL4s could potentially serve as biomarkers for diagnosing and predicting the prognosis of STAD.
Topics: Stomach Neoplasms; Humans; Adenocarcinoma; Prognosis; Collagen Type IV; Gene Expression Regulation, Neoplastic; Male; Female; Biomarkers, Tumor; Middle Aged; Kaplan-Meier Estimate
PubMed: 38907304
DOI: 10.1186/s12920-024-01934-3