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BMC Cancer Jul 2023CXC-chemokine receptor 2 (CXCR2) expression was found to be down-regulated on circulating monocytes of cancer patients. Here, we analyze the percentage of CD14CXCR2...
BACKGROUND
CXC-chemokine receptor 2 (CXCR2) expression was found to be down-regulated on circulating monocytes of cancer patients. Here, we analyze the percentage of CD14CXCR2 monocyte subsets in hepatocellular carcinoma (HCC) patients, and investigate the mechanisms that regulate CXCR2 surface expression on monocytes and its biological function.
METHODS
Flow cytometry was used to analyze the proportion of the CD14CXCR2 subset from the total circulating monocytes of HCC patients. Interleukin 8 (IL-8) levels were measured from serum and ascites, and their correlation with the CD14CXCR2 monocyte subset proportion was calculated. THP-1 cells were cultured in vitro and treated with recombinant human IL-8 and CXCR2 surface expression was analyzed. CXCR2 was knocked down to examine how it affects the antitumor activity of monocytes. Finally, a monoacylglycerol lipase (MAGL) inhibitor was added to analyze its effect on CXCR2 expression.
RESULTS
A decrease in the proportion of the CD14CXCR2 monocyte subset was observed in HCC patients compared with healthy controls. CXCR2 monocyte subset proportion was associated with the AFP value, TNM stage, and liver function. Overexpression of IL-8 was observed in the serum and ascites of HCC patients, and negatively correlated with CXCR2 monocyte proportion. IL-8 decreased CXCR2 expression in THP-1 cells, contributing to decreased antitumor activity toward HCC cells. MAGL expression in THP-1 cells was up-regulated after IL-8 treatment, and the MAGL inhibitor partially reversed the effects of IL-8 on CXCR2 expression.
CONCLUSIONS
Overexpression of IL-8 drives CXCR2 down-regulation on circulating monocytes of HCC patients, which could be partially reversed by a MAGL inhibitor.
Topics: Humans; Ascites; Carcinoma, Hepatocellular; Down-Regulation; Immunologic Factors; Interleukin-8; Lipopolysaccharide Receptors; Liver Neoplasms; Monoacylglycerol Lipases; Monocytes
PubMed: 37403022
DOI: 10.1186/s12885-023-11109-5 -
BMC Genomics Jun 2024Peritoneal carcinomatosis was the main reason leading to gastric cancer (GC)-related death. We aimed to explore the roles of dysregulated microRNAs (miRNAs) and related...
BACKGROUND
Peritoneal carcinomatosis was the main reason leading to gastric cancer (GC)-related death. We aimed to explore the roles of dysregulated microRNAs (miRNAs) and related immune regulation activities in GC-associated malignant ascites.
METHODS
GSE126399 were downloaded from GEO database. Differentially expressed miRNAs in GC ascites samples was firstly screened, and critical miRNAs were further investigated by LASSO (least absolute shrinkage and selection operator) logistic regression and random forest (RF) algorithm. Receiver operating characteristic of critical miRNAs was also constructed. Moreover, functional analysis, immune cell infiltration associated with differentially expressed mRNAs were further analyzed. After selecting key modules by weighted gene co-expression network analysis, mRNAs related with survival performance and transcription factor (TF)-miRNA-mRNA network were constructed.
RESULTS
Hsa-miR-181b-5p was confirmed as critical differentially expressed miRNAs in GC ascites. Then, the tumor samples were divided into high- and low- expression groups divided by mean expression levels of hsa-miR-181b-5p, and subjects with high hsa-miR-181b-5p levels had better survival outcomes. In total, 197 differentially expressed mRNAs associated with hsa-miR-181b-5p levels were obtained, and these mRNAs were mainly enriched in muscle activity and vascular smooth muscle contraction. Hsa-miR-181b-5 was positively related with activated CD4 T cells and negatively related with eosinophil. 17 mRNAs were selected as mRNAs significantly related with prognosis of GC, such as PDK4 and RAMP1. Finally, 75 TF-miRNA-mRNA relationships were obtained, including 15 TFs, hsa-miR-181b-5p, and five mRNAs.
CONCLUSION
Our data suggest that the differentially expressed hsa-miR-181b-5p in ascites samples of GC patients may be a valuable prognostic marker and a potential target for therapeutic intervention, which should be validated in the near future.
Topics: Humans; MicroRNAs; Stomach Neoplasms; Ascites; Prognosis; Biomarkers, Tumor; Gene Expression Profiling; Gene Regulatory Networks; Gene Expression Regulation, Neoplastic; RNA, Messenger
PubMed: 38914980
DOI: 10.1186/s12864-024-10359-2 -
Cureus Aug 2023Malignant peritoneal mesothelioma (MPM) is a rare tumor of the serous membranes of the peritoneum and has been linked to exposure to asbestos and other risk factors. The...
Malignant peritoneal mesothelioma (MPM) is a rare tumor of the serous membranes of the peritoneum and has been linked to exposure to asbestos and other risk factors. The clinical manifestations are vague, with a wide clinical spectrum, predominantly related to the abdominal involvement of the disease. Localized mesothelioma is an uncommon manifestation of the disease. Common symptoms include abdominal pain or abdominal distention, nausea, anorexia, and weight loss. Rarely, patients present with paraneoplastic syndrome. Due to the nonspecific symptoms, many patients already have advanced disease at the time of diagnosis. The authors report a case of a 75-year-old female patient who presented with symptoms of asthenia, anorexia, progressive paleness, and weight loss lasting five months. She reports later new-onset symptoms of diffuse abdominal pain and diarrhea associated with nausea. Laboratory tests showed anemia, mild leukocytosis, thrombocytosis, elevated C-reactive protein (CRP), and elevated liver enzymes. An abdominal and pelvic computed tomography (CT) scan revealed marked tissue thickening of an irregular and striated configuration of the leaflets and peritoneal reflections in an omental cake pattern, and a chest CT scan showed multiple bilateral pulmonary nodules, suggesting diffuse malignant disease. A CT-guided biopsy of a peritoneal implant was performed, establishing the diagnosis of malignant peritoneal mesothelioma. Due to rapid clinical deterioration, the patient did not receive any systemic treatment, surgery, or radiotherapy and was transitioned to comfort care. As in the presented case, most cases of MPM have diffuse peritoneal involvement at the time of diagnosis, although extra-abdominal involvement is very rare. This disease presentation is associated with high morbidity and mortality compared to cases of localized disease. There is no specific imaging diagnostic modality or valuable tumor markers for MPM. Although a CT scan remains important in the diagnostic approach, the changes found are not specific. Radiographically, MPM may present as mesenteric or parietal peritoneal nodules, visceral peritoneal thickening, ascites, or omental masses. Although these features may raise suspicion of MPM, a biopsy is necessary to confirm the diagnosis. Therefore, due to the rarity of this disease and its nonspecific signs or symptoms, MPM is difficult to diagnose, and the prognosis remains poor.
PubMed: 37664365
DOI: 10.7759/cureus.42902 -
Frontiers in Immunology 2023Despite predicted efficacy, immunotherapy in epithelial ovarian cancer (EOC) has limited clinical benefit and the prognosis of patients remains poor. There is thus a... (Observational Study)
Observational Study
INTRODUCTION
Despite predicted efficacy, immunotherapy in epithelial ovarian cancer (EOC) has limited clinical benefit and the prognosis of patients remains poor. There is thus a strong need for better identifying local immune dynamics and immune-suppressive pathways limiting T-cell mediated anti-tumor immunity.
METHODS
In this observational study we analyzed by immunohistochemistry, gene expression profiling and flow cytometry the antigenic landscape and immune composition of 48 EOC specimens, with a focus on tumor-infiltrating lymphocytes (TILs).
RESULTS
Activated T cells showing features of partial exhaustion with a CD137CD39PD-1TIM-3CD45RACD62LCD95 surface profile were exclusively present in EOC specimens but not in corresponding peripheral blood or ascitic fluid, indicating that the tumor microenvironment might sustain this peculiar phenotype. Interestingly, while neoplastic cells expressed several tumor-associated antigens possibly able to stimulate tumor-specific TILs, macrophages provided both co-stimulatory and inhibitory signals and were more abundant in TILs-enriched specimens harboring the CD137CD39PD-1TIM-3CD45RACD62LCD95 signature.
CONCLUSION
These data demonstrate that EOC is enriched in CD137CD39PD-1TIM-3CD45RACD62LCD95 T lymphocytes, a phenotype possibly modulated by antigen recognition on neoplastic cells and by a combination of inhibitory and co-stimulatory signals largely provided by infiltrating myeloid cells. Furthermore, we have identified immunosuppressive pathways potentially hampering local immunity which might be targeted by immunotherapeutic approaches.
Topics: Humans; Female; T-Lymphocytes; Hepatitis A Virus Cellular Receptor 2; Programmed Cell Death 1 Receptor; Carcinoma, Ovarian Epithelial; Leukocyte Common Antigens; Ovarian Neoplasms; Myeloid Cells; Tumor Microenvironment
PubMed: 37868997
DOI: 10.3389/fimmu.2023.1212444 -
Journal of Obstetrics and Gynaecology :... Dec 2023Peritoneal effusion is a common event in ovarian cancer (OC) patients. LncRNA H19 and vascular endothelial growth factor (VEGF) are implicated in cancer progression. The...
Efficacy and safety of intraperitoneal bevacizumab combined with hyperthermic intraperitoneal chemotherapy in the treatment of patients with ovarian cancer and peritoneal effusion and the effect on serum lncRNA H19 and VEGF levels.
Peritoneal effusion is a common event in ovarian cancer (OC) patients. LncRNA H19 and vascular endothelial growth factor (VEGF) are implicated in cancer progression. The study evaluated the curative effect and safety of bevacizumab combined with hyperthermic intraperitoneal chemotherapy (HIPEC) in OC patients with peritoneal effusion and the effect on serum lncRNA H19/VEGF levels. Totally 248 OC patients with peritoneal effusion were treated with intraperitoneal bevacizumab + HIPEC (observation group) or abdominal paracentesis without HIPEC (control group). The clinical efficacy, quality of life, and adverse reactions were evaluated after two treatment cycles. The serum lncRNA H19 and VEGF levels pre-/post-treatment were determined by RT-qPCR and ELISA. The observation group exhibited better clinical efficacy than the control group, evidenced by a higher partial response rate, response rate, and disease control rate. The observation group exhibited reduced physical/cognitive/role/social/emotional function scores and total adverse reactions. LncRNA H19/VEGF levels showed no significant difference between the two groups before treatment but were significantly downregulated in the observation group after treatment. Summarily, intraperitoneal bevacizumab + HIPEC has significant efficacy in treating peritoneal effusion, improves the quality of life, and reduces serum lncRNA H19 and VEGF levels in OC patients, with fewer adverse reactions and higher safety.Impact statement The utilization of hyperthermic intraperitoneal chemotherapy (HIPEC) as an emerging treatment option for abdominal malignancies has garnered the attention of numerous researchers over the years, which has significant clinical effects on peritoneal effusion in ovarian cancer and can control patients' conditions and improve their signs and symptoms to a certain extent. In this paper, we investigated the efficacy and safety of intraperitoneal bevacizumab combined with hyperthermic intraperitoneal chemotherapy in the treatment of peritoneal effusion in ovarian cancer. Meanwhile, we compared serum lncRNA H19 and VEGF levels before and after treatment. Our findings may provide a clinically worthy method for the treatment of peritoneal effusion in ovarian cancer. The treatment method reduces serum lncRNA H19 and VEGF levels in patients, which provides a theoretical basis for further research.
Topics: Humans; Female; Bevacizumab; Vascular Endothelial Growth Factor A; Hyperthermic Intraperitoneal Chemotherapy; RNA, Long Noncoding; Ascitic Fluid; Quality of Life; Peritoneal Neoplasms; Hyperthermia, Induced; Antineoplastic Combined Chemotherapy Protocols; Ovarian Neoplasms; Combined Modality Therapy; Cytoreduction Surgical Procedures
PubMed: 37186893
DOI: 10.1080/01443615.2023.2204940 -
Cell Communication and Signaling : CCS Jan 2024Omental metastasis is the major cause of ovarian cancer recurrence and shortens patient survival, which can be largely attributed to the dynamic evolution of the fertile...
BACKGROUND
Omental metastasis is the major cause of ovarian cancer recurrence and shortens patient survival, which can be largely attributed to the dynamic evolution of the fertile metastatic microenvironment driven by cancer cells. Previously, we found that adipose-derived mesenchymal stem cells (ADSCs) undergoing a phenotype shift toward cancer-associated fibroblasts (CAFs) participated in the orchestrated omental premetastatic niche for ovarian cancer. Here, we aim to elucidate the underlying mechanisms.
METHODS
Small extracellular vesicles were isolated from ovarian cancer cell lines (ES-2 and its highly metastatic subline, ES-2-HM) and patient ascites using ultracentrifugation. Functional experiments, including Transwell and EdU assays, and molecular detection, including Western blot, immunofluorescence, and RT-qPCR, were performed to investigate the activation of ADSCs in vitro. High-throughput transcriptional sequencing and functional assays were employed to identify the crucial functional molecules inducing CAF-like activation of ADSCs and the downstream effector of miR-320a. The impact of extracellular vesicles and miR-320a-activated ADSCs on tumor growth and metastasis was assessed in subcutaneous and orthotopic ovarian cancer xenograft mouse models. The expression of miR-320a in human samples was evaluated using in situ hybridization staining.
RESULTS
Primary human ADSCs cocultured with small extracellular vesicles, especially those derived from ES-2-HM, exhibited boosted migration, invasion, and proliferation capacities and elevated α-SMA and FAP levels. Tumor-derived small extracellular vesicles increased α-SMA-positive stromal cells, fostered omental metastasis, and shortened the survival of mice harboring orthotopic ovarian cancer xenografts. miR-320a was abundant in highly metastatic cell-derived extracellular vesicles, evoked dramatic CAF-like transition of ADSCs, targeted the 3'-untranslated region of integrin subunit alpha 7 and attenuated its expression. miR-320a overexpression in ovarian cancer was associated with omental metastasis and shorter survival. miR-320a-activated ADSCs facilitated tumor cell growth and omental metastasis. Depletion of integrin alpha 7 triggered CAF-like activation of ADSCs in vitro. Video Abstract CONCLUSIONS: miR-320a in small extracellular vesicles secreted by tumor cells targets integrin subunit alpha 7 in ADSCs and drives CAF-like activation, which in turn facilitates omental metastasis of ovarian cancer.
Topics: Humans; Mice; Animals; Female; Neoplasm Recurrence, Local; Ovarian Neoplasms; Extracellular Vesicles; Cell Proliferation; Disease Models, Animal; MicroRNAs; Mesenchymal Stem Cells; Integrins; Cell Line, Tumor; Tumor Microenvironment
PubMed: 38233863
DOI: 10.1186/s12964-023-01413-9 -
Cancer Communications (London, England) Jan 2024Although the constitutively activated Wnt/β-catenin signaling pathway plays vital roles in gastric cancer (GC) progression, few Wnt inhibitors are approved for clinical...
BACKGROUND
Although the constitutively activated Wnt/β-catenin signaling pathway plays vital roles in gastric cancer (GC) progression, few Wnt inhibitors are approved for clinical use. Additionally, the clinical significance of long non-coding RNAs (lncRNAs) in GC intraperitoneal dissemination (IPD) remains elusive. Here, we investigated the function and therapeutic potential of Wnt-transactivated lncRNA, colon cancer-associated transcript 5 (CCAT5), in GC metastasis.
METHODS
LncRNA-sequencing assay was performed to document abundance changes of lncRNAs induced by Wnt family member 3A (Wnt3a) and degradation-resistant β-catenin (S33Y mutated) in ascites-derived GC cells with low Wnt activity. Luciferase reporter, Chromatin immunoprecipitation (ChIP)-re-ChIP assays were performed to determine how CCAT5 was transcribed. The clinical significance of CCAT5 was examined in 2 cohorts of GC patients. The biological function of CCAT5 was investigated through gain- and loss-of-function studies. The molecular mechanism was explored through RNA-sequencing, mass spectrometry, and CRISPR/Cas9-knocknout system. The therapeutic potential of CCAT5 was examined through RNAi-based cell xenograft model and patient-derived xenograft (PDX) model of IPD.
RESULTS
We identified a novel Wnt-regulated lncRNA, CCAT5, which was transactivated by the β-catenin/transcription factor 3 (TCF3) complex. CCAT5 was significantly upregulated in GC and predicted poor prognosis. Functional studies confirmed the promotive role of CCAT5 in GC growth and metastasis. Mechanistically, CCAT5 bound to the C-end domain of signal transducer and activator of transcription 3 (STAT3) and blocks Src homology 2 domain-containing protein tyrosine phosphatase 1 (SHP-1)-mediated STAT3 dephosphorylation, leading to STAT3 nuclear entry and transactivation, thus accelerating GC progression. Furthermore, we demonstrated that both Wnt3a and β-catenin acted as activator of STAT3 signaling pathway, and the interplay between CCAT5 and STAT3 was functionally essential for Wnt-drived STAT3 signaling and tumor evolution. Finally, we revealed in vivo si-CCAT5 selectively attenuated growth and metastasis of Wnt GC, but not Wnt GC. The combination of si-CCAT5 and oxaliplatin displayed obvious synergistic therapeutic effects on Wnt PDX mice.
CONCLUSIONS
We identified a novel Wnt-transactivated lncRNA, CCAT5. Our study revealed a mechanism of STAT3 signaling regulation via canonical Wnt signaling and the functional significance of CCAT5 as critical mediator. We provided conceptual advance that lncRNAs serve as therapeutic targets reversing GC progression.
Topics: Humans; Mice; Animals; RNA, Long Noncoding; Stomach Neoplasms; beta Catenin; Cell Line, Tumor; STAT3 Transcription Factor; Wnt Signaling Pathway; Colonic Neoplasms
PubMed: 38010289
DOI: 10.1002/cac2.12507 -
Molecular Therapy : the Journal of the... Jun 2024Malignant ascites is a common complication resulting from the peritoneal spread of malignancies, and currently lacks effective treatments. We conducted a phase II trial...
Malignant ascites is a common complication resulting from the peritoneal spread of malignancies, and currently lacks effective treatments. We conducted a phase II trial (NCT04771676) to investigate the efficacy and safety of oncolytic adenovirus H101 and virotherapy-induced immune response in 25 patients with malignant ascites. Oncolytic virotherapy achieved an increased median time to repeat paracentesis of 45 days (95% confidence interval 16.5-73.5 days), compared with the preset control value of 13 days. Therapy was well-tolerated, with pyrexia, fatigue, nausea, and abdominal pain as the most common toxicities. Longitudinal single-cell profiling identified marked oncolysis, early virus replication, and enhanced CD8 T cells-macrophages immune checkpoint crosstalk, especially in responsive patients. H101 also triggered a proliferative burst of CXCR6 and GZMKCD8 T cells with promoted tumor-specific cytotoxicity. Further establishment of oncolytic virus-induced T cell expansion signature (OiTE) implicated the potential benefits for H101-responsive patients from subsequent anti-PD(L)1 therapy. Patients with upregulated immune-signaling pathways in tumor cells and a higher proportion of CLEC10A dendritic cells and GZMKCD8 T cells at baseline showed a superior response to H101 treatment. Our study demonstrates promising clinical responses and tolerability of oncolytic adenovirus in treating malignant ascites and provides insights into the relevant cellular processes following oncolytic virotherapy.
Topics: Humans; Oncolytic Virotherapy; Oncolytic Viruses; Ascites; Female; Male; Middle Aged; Adenoviridae; Aged; Single-Cell Analysis; CD8-Positive T-Lymphocytes; Adult; Treatment Outcome; Longitudinal Studies; Virus Replication
PubMed: 38659226
DOI: 10.1016/j.ymthe.2024.04.029 -
Cureus Oct 2023Ascites is the accumulation of fluid in the abdominal cavity and is commonly attributed to various etiologies, including portal hypertension and peritoneal diseases....
Ascites is the accumulation of fluid in the abdominal cavity and is commonly attributed to various etiologies, including portal hypertension and peritoneal diseases. Hyperthyroidism is rarely associated with ascites, which is typically chylous and accompanied by high central venous pressure. We present a unique case of a 57-year-old woman with untreated hyperthyroidism who manifested non-chylous ascites without evidence of high venous pressure. Initially presenting with left lower leg pain, the patient presented with leg edema, abdominal distention, and diarrhea. A range of diagnostic tests ruled out common etiologies of ascites, such as liver cirrhosis, renal impairment, heart failure, infection, and malignancy. Ascites was characterized by low triglyceride levels, while no evidence of high venous pressure was found. Notably, the patient showed decreased levels of rapid turnover proteins, suggesting hypercatabolism and insufficient protein synthesis due to hyperthyroidism. Upon the initiation of antithyroid therapy, the patient's symptoms markedly improved. In conclusion, this report highlights a rare manifestation of hyperthyroidism that resulted in non-chylous ascites without high venous pressure. This underscores the need to include hyperthyroidism in the differential diagnosis of unexplained ascites, particularly in cases in which classical hyperthyroid symptoms are absent.
PubMed: 37942363
DOI: 10.7759/cureus.46657 -
BioRxiv : the Preprint Server For... Oct 2023Diffuse-type gastric adenocarcinoma (DGAC) is a deadly cancer often diagnosed late and resistant to treatment. While hereditary DGAC is linked to gene mutations,...
Diffuse-type gastric adenocarcinoma (DGAC) is a deadly cancer often diagnosed late and resistant to treatment. While hereditary DGAC is linked to gene mutations, causing E-Cadherin loss, its role in sporadic DGAC is unclear. We discovered CDH1 inactivation in a subset of DGAC patient tumors. Analyzing single-cell transcriptomes in malignant ascites, we identified two DGAC subtypes: DGAC1 (CDH1 loss) and DGAC2 (lacking immune response). DGAC1 displayed distinct molecular signatures, activated DGAC-related pathways, and an abundance of exhausted T cells in ascites. Genetically engineered murine gastric organoids showed that knock-out (KO), , KO (EKP) accelerates tumorigenesis with immune evasion compared to , KO (KP). We also identified EZH2 as a key mediator promoting CDH1 loss-associated DGAC tumorigenesis. These findings highlight DGAC's molecular diversity and potential for personalized treatment in CDH1-inactivated patients.
PubMed: 36993615
DOI: 10.1101/2023.03.23.533976