Cellular Oncology最新文献

A substance integral to the sustenance and functionality of virtually all forms of life is manganese (Mn), classified as an essential trace metal. Its significance lies in its pivotal role in facilitating metabolic processes crucial for survival. Additionally, Mn exerts influence over various biological functions including bone formation and maintenance, as well as regulation within systems governing immunity, nervous signaling, and digestion. Manganese nanoparticles (Mn-NP) stand out as a beacon of promise within the realm of immunotherapy, their focus honed on intricate mechanisms such as triggering immune pathways, igniting inflammasomes, inducing immunogenic cell death (ICD), and sculpting the nuances of the tumor microenvironment. These minuscule marvels have dazzled researchers with their potential in reshaping the landscape of cancer immunotherapy - serving as potent vaccine enhancers, efficient drug couriers, and formidable allies when paired with immune checkpoint inhibitors (ICIs) or cutting-edge photodynamic/photothermal therapies. Herein, we aim to provide a comprehensive review of recent advances in the application of Mn and Mn-NP in the immunotherapy of cancer. We hope that this review will display an insightful view of Mn-NPs and provide guidance for design and application of them in immune-based cancer therapies.

Metastasis, the leading cause of cancer-related deaths, underscores the critical need to understand its regulatory mechanisms to improve prevention and treatment strategies for late-stage tumors. Hematogenous dissemination is a key route of metastasis. However, as the gatekeeper of vessels, the role of pericytes in hematogenous metastasis remains largely unknown. In this review, we comprehensively explore the contributions of pericytes throughout the metastatic cascade, particularly their functions that extend beyond influencing tumor angiogenesis. Pericytes should not be perceived as passive bystanders, but rather as active participants in various stages of the metastatic cascade. Pericytes-targeted therapy may provide novel insights for preventing and treating advanced-stage tumor.

Purpose: There is a lack of clinical evidence on whether further clinical strategies are needed after TURBT combined with immediate bladder instillation. This study intends to establish a reliable quantitative assay for active urinary cancer cells (AUCC) and to investigate the clinical efficacy of continuous saline bladder irrigation (CSBI) as a feasible option by analyzing the perioperative AUCC changes in TURBT.

Methods: An AUCC assay was developed and its reliability was verified by single-cell whole genome sequencing. Bladder cancer patients (N = 324) diagnosed by cystoscopy and pathologic biopsy and control individuals (N = 92) were included from 2021 to 2023 in the study. Enrolled patients with non-muscle invasive bladder cancer (NMIBC) underwent TURBT followed by immediate bladder instillation of epirubicin, after subgroups received CSBI or not, and AUCCs were tested on the first and fifth postoperative day. The patients were followed up for two years for postoperative recurrence.

Results: The AUCC assay achieved good detection accuracy, with a sensitivity of 0.821 and specificity of 0.902. AUCC increased on the first day after TURBT in combination with immediate bladder instillation, regardless of whether or not the patient received CSBI. However, AUCCs decreased more rapidly on the fifth day in patients treated with CSBI, and patients with concomitant risk factors benefited more from CSBI. The two-year follow-up results showed that high-risk patients with complex surgeries could benefit significantly from CSBI.

Conclusions: We pioneered a quantitative assay for AUCC and provided laboratory evidence that TURBT causes tumor cell dissemination and CSBI can be a further clinical strategy to reduce the risk of potential recurrence.

Purpose: Post-translational modifications, such as lactylation, are emerging as critical regulators of metabolic enzymes in cancer progression. Mitochondrial malic enzyme 2 (ME2), a key enzyme in the TCA cycle, plays a pivotal role in maintaining redox homeostasis and supporting tumor metabolism. However, the functional significance of ME2 lactylation and its regulatory mechanisms remain unclear. This study investigates the role of ME2 K352 lactylation in modulating enzymatic activity, redox balance, and tumor progression.

Methods: Immunoprecipitation and western blotting were used to assess ME2 lactylation and its interaction with Sirtuin 3 (SIRT3). Mass spectrometry identified the lactylation site on ME2. Enzymatic activity was measured using NADH production assays. The functional effects of ME2 K352 lactylation were analyzed by measuring ROS levels, NADP⁺/NADPH ratios, metabolic intermediates, and mitochondrial respiration parameters. Cell proliferation was evaluated via CCK-8 and colony formation assays. Xenograft tumor models and Ki-67 immunohistochemical staining were used to assess tumor growth and proliferation in vivo.

Results: Mass spectrometry identified K352 as the primary lactylation site on ME2. Sodium lactate treatment enhanced ME2 lactylation and enzymatic activity, while SIRT3-mediated delactylation at K352 reduced ME2 activity, disrupting redox homeostasis. Cells expressing the K352R mutant exhibited elevated ROS levels, higher NADP⁺/NADPH ratios, and altered levels of metabolic intermediates, including increased malate and lactate with reduced pyruvate. Additionally, re-expression of ME2 K352R in HCT116 cells significantly impaired proliferation and colony formation. In vivo, xenograft models demonstrated that ME2 K352R expression suppressed tumor growth, as evidenced by reduced tumor volume, weight, and Ki-67 staining.

Conclusions: This study reveals that ME2 K352 lactylation is a critical regulatory mechanism that modulates enzymatic activity, mitochondrial function, and tumor progression. SIRT3-mediated delactylation of ME2 K352 disrupts redox homeostasis and inhibits tumor growth. These findings highlight the potential of targeting ME2 lactylation as a therapeutic strategy in cancer treatment.

Purpose: Gastric cancer (GC) remains a considerable global health concern, underscoring the necessity for dependable biomarkers for its diagnosis and treatment. This investigation seeks to investigate the clinical predictive value and functional roles of SPTSSA in GC.

Methods: The mRNA expression of SPT family molecules was analyzed through bioinformatics approaches. In vitro and in vivo studies assessed the function of SPTSSA in the malignant progression of GC. Additionally, SPTSSA protein levels in GC tissues and peripheral venous blood were measured using immunofluorescence staining and enzyme-linked immunosorbent assay, respectively. The link between SPTSSA expression and immune cell infiltration in GC was also evaluated by multiplex immunohistochemistry.

Results: Patients exhibiting elevated levels of SPTSSA mRNA experienced the poorest prognosis in comparison to other members of the SPT family. SPTSSA overexpression enhanced the malignant phenotype of GC in in vitro and in vivo experiments. Mechanistically, SPTSSA facilitated the accumulation of β-catenin and the transcription of programmed death ligand 1 (PD-L1) through the Wnt signaling pathway. SPTSSA protein levels were markedly elevated in both GC tissues and peripheral venous blood. Furthermore, increased expression of SPTSSA was linked to a reduction in CD8⁺ T cell infiltration, heightened M2 macrophage infiltration, and increased PD-L1 expression in GC patients.

Conclusion: SPTSSA promotes GC progression by modulating PD-L1 expression in immunomicroenvironment via the Wnt signaling pathway. Consequently, SPTSSA emerges as a promising new prognostic indicator and a potential therapeutic target for GC management.

Background: Non-small cell lung cancer (NSCLC) mainly includes lung squamous cell carcinoma and lung adenocarcinoma, and its extremely high morbidity and mortality are the main causes of poor prognosis in NSCLC patients. Therefore, it is particularly important to study the mechanisms associated with tumor proliferation and metastasis and explore new molecular targets of NSCLC. Studies have shown that Guanosine monophosphate synthase (GMPS) may serve as a potential drug target, but its biological function and molecular mechanism in NSCLC are still unknown. Therefore, it is urgently needed to investigate the molecular mechanisms of GMPS.

Methods: We first analyzed 30 cases of lung adenocarcinoma, lung squamous carcinoma and adjacent tissues; Then, lentiviral technology was used to construct overexpressed or knocked out cell lines to verify the function of GMPS. Then, RNA sequencing and Western blot experiments were carried out in animal experiments to explore the mechanism of GMPS. Our experimental results suggest that GMPS plays an important role in the progression of NSCLC.

Results: We found that GMPS was highly expressed in lung adenocarcinoma and lung squamous cell carcinoma tissues, and was associated with poor prognosis of patients. Down-regulation of GMPS inhibits tumor progression. And GMPS promotes lung cancer cell migration through the SERPINB2-uPA axis, and DNMT1 is an intermediate factor in GMPS regulating SERPINB2 expression. Our experimental results show that GMPS expression is associated with lung cancer invasion and migration.

Conclusions: Our findings revealed the correlation between GMPS and the prognosis of NSCLC at the tissue level. Secondly, GMPS can promote the progression of NSCLC. The molecular mechanism of GMPS affecting the metastasis of lung cancer cells was elucidated. These findings highlight the important role of GMPS in NSCLC, so as to provide new insights for the identification of new targets and lay a theoretical foundation for the clinical application of GMPS.

Background: Liver is one of the target organs bearing the most frequent distant metastasis of gastric cancer (GC), and patients with GC liver metastasis suffering from poor prognosis. According to "seed and soil" theory, important and complex interactions between disseminated tumor cells (DTCs) and metastasis tumor microenvironment (MTM) have played a vital role in waking the dormant DTCs and promoting their proliferation. We have discovered that the aberrantly activated cancer associated fibroblasts (CAFs) could significantly increase the enrichment and stiffness of extracellular matrix (ECM). ECM with high stiffness could facilitate the accumulation of Troponin T1, slow skeletal type (TNNT1) in cytoplasm for dormant DTCs awaking and proliferation.

Methods: We set off from observing the stiffness of ECM around liver metastatic niches of GC and performed in vivo and in vitro study for further study. Based on the gained information, we plan to further unveil the underlying mechanism and explore the clinical transformation value using the ex-vivo and patient derived xenograft (PDX) model.

Conclusion: Our study aims to illustrate the relationship between ECM stiffness and tumor dormancy awakening in liver metastasis of GC and provide reliable theoretical and research basis for treatment of GC liver metastasis.

Background: Gastric cancer (GC) ranks as the fourth leading cause of cancer-related deaths worldwide, with most patients diagnosed at advanced stages due to the absence of reliable early detection biomarkers.

Methods: RNA-sequencing was conducted to identify the differentially expressed genes between GC tissues and adjacent normal tissues. CCK8, EdU, colony formation, transwell, flow cytometry and xenograft assays were adopted to explore the biological function of ZBTB10 and betulinic acid (BA) in GC progression. RNA-sequencing and phospho-proteomic profiling were performed to analyze the signaling pathways associated with ZBTB10-inhibiting GC progression. Chromatin immunoprecipitation, Co-immunoprecipitation and luciferase reporter assay were employed to elucidate the potential molecular regulatory mechanisms of ZBTB10 in GC.

Results: ZBTB10 was one of the most significantly downregulated genes in GC tissues, and higher expression levels of ZBTB10 was correlated with better prognosis in patients with GC. Functional studies revealed that ZBTB10 overexpression and BA inhibited GC progression both in vitro and in vivo. Mechanistically, ZBTB10 enhanced ARRDC3 expression by binding to a specific response element in the ARRDC3 promoter region. Elevated ARRDC3 then directly interacted with β-4 integrin (ITGB4), leading to its ubiquitination and degradation. This cascade ultimately resulted in the downregulation of PI3K and AKT phosphorylation level. Moreover, ZBTB10 was a key target for BA in GC and BA inhibited GC progression through regulating the ZBTB10/ARRDC3/ITGB4/PI3K/AKT axis.

Conclusions: Our findings reveal that BA holds promise as an effective therapeutic strategy for GC, and the ZBTB10/ARRDC3/ITGB4/PI3K/AKT axis may serve as a novel diagnostic and therapeutic target.

Objective: Predicting the therapeutic response before initiation of hepatic artery infusion chemotherapy (HAIC) with fluorouracil, leucovorin, and oxaliplatin (FOLFOX) remains challenging for patients with unresectable hepatocellular carcinoma (HCC). Herein, we investigated the potential of a contrast-enhanced CT-based habitat radiomics model as a novel approach for predicting the early therapeutic response to HAIC-FOLFOX in patients with unresectable HCC.

Methods: A total of 148 patients with unresectable HCC who received HAIC-FOLFOX combined with targeted therapy or immunotherapy at three tertiary care medical centers were enrolled retrospectively. Tumor habitat features were extracted from subregion radiomics based on CECT at different phases using k-means clustering. Logistic regression was used to construct the model. This CECT-based habitat radiomics model was verified by bootstrapping and compared with a model based on clinical variables. Model performance was evaluated using the area under the curve (AUC) and a calibration curve.

Results: Three intratumoral habitats with high, moderate, and low enhancement were identified to construct a habitat radiomics model for therapeutic response prediction. Patients with a greater proportion of high-enhancement intratumoral habitat showed better therapeutic responses. The AUC of the habitat radiomics model was 0.857 (95% CI: 0.798-0.916), and the bootstrap-corrected concordance index was 0.842 (95% CI: 0.785-0.907), resulting in a better predictive value than the clinical variable-based model, which had an AUC of 0.757 (95% CI: 0.679-0.834).

Conclusion: The CECT-based habitat radiomics model is an effective, visualized, and noninvasive tool for predicting the early therapeutic response of patients with unresectable HCC to HAIC-FOLFOX treatment and could guide clinical management and decision-making.

Background: Potassium channel tetramerization domain-containing 1 (KCTD1) plays a critical role in transcriptional regulation and adipogenesis, but its significance in hepatocellular cancer (HCC) has not been reported.

Methods: Immunohistochemistry, Western blotting and quantitative real-time PCR analysis were performed to assess the expression of KCTD1 and related genes in HCC cells. MTT assays, colony formation, cell migration, invasion and the in-vivo mouse models were utilized to evaluate the function of KCTD1 in HCC progression. Co-immunoprecipitation, chromatin immunoprecipitation and luciferase reporter assays were conducted to elucidate the molecular mechanisms of KCTD1 in HCC.

Results: KCTD1 expression was increased in human HCC tissues and closely associated with advanced tumor stages. KCTD1 overexpression enhanced growth, migration, and invasion of Huh7 and HepG2 cells both in vitro and in vivo, while KCTD1 knockdown reversed these effects in MHCC97H cells. Mechanistically, KCTD1 interacted with hypoxia-inducible factor 1 alpha (HIF-1α) and enhanced HIF-1α protein stability with the inhibited prolyl-hydroxylases (PHD)/Von Hippel-Lindau (VHL) pathway, consequently activating the Vascular Endothelial Growth Factor (VEGF)/VEGFR2 pathway in HCC cells. Sorafenib and KCTD1 knockdown synergistically inhibited intrahepatic tumor growth following in situ injection of MHCC97H cells. miR-129-5p downregulated KCTD1 by binding to KCTD1 3'UTR. Finally, 45 µg exosomes from miR-129-5p-overexpressing MHCC97H cells combined with 25 mg/kg sorafenib to decrease HCC tumor size.

Conclusions: These results suggested that KCTD1 protects HIF-1α from degradation and activates the VEGF signaling cascade to enhance HCC progression. Therefore, KCTD1 may serve as a novel target of HCC and pave the way for an efficient combined therapy in advanced HCC.