Cellular Oncology最新文献

Purpose: We aimed to explore the curative effects of hepatic arterial infusion chemotherapy (HAIC) combined with Tislelizumab and Lenvatinib on unresectable hepatocellular carcinoma (HCC).

Patients and methods: From September 2021 to September 2023, 42 patients with unresectable HCC who were treated in the First Affiliated Hospital of Chongqing Medical University were enrolled in this retrospective single-arm study. They received HAIC combined with Tislelizumab and lenvatinib. Baseline characteristics, laboratory indicators before and after treatment, and imaging findings were collected from medical records. The primary endpoint was objective response rate (ORR), and the secondary endpoints included disease control rate (DCR), overall survival (OS), progression-free survival (PFS), and safety indicators.

Results: A total of 199 HAIC treatments were performed, with a median of 5.5 times (3.75-6.0 times). Based on the mRECIST and RECIST1.1 criterion, the ORR was 71.4% and 57.1%, the DCR was 92.9% and 92.9%. Up to the follow-up date of October 1, 2024, the median PFS was 14.0 months (95% CI, 11.6-16.4 months), and the median OS was 26.0 months.The incidence of any grade of adverse events was 97.6%. The most commonly reported treatment-related grade 3-4 adverse events included thrombocytopenia (28.6%), elevated total bilirubin (19%), and abdominal pain (16.7%). There was no treatment-related death.

Conclusion: For unresectable HCC, HAIC combined with tirelizumab and lenvatinib has good anti-tumor efficacy and acceptable adverse reactions.

Immunotherapy resistance poses a significant challenge in oncology, necessitating novel strategies to enhance the therapeutic efficacy. Immunogenic cell death (ICD), including necroptosis, pyroptosis and ferroptosis, triggers the release of tumor-associated antigens and numerous bioactive molecules. This release can potentiate a host immune response, thereby overcoming resistance to immunotherapy. Nanoparticles (NPs) with their biocompatible and immunomodulatory properties, are emerging as promising vehicles for the delivery of ICD-inducing agents and immune-stimulatory adjuvants to enhance immune cells tumoral infiltration and augment immunotherapy efficacy. This review explores the mechanisms underlying immunotherapy resistance, and offers an in-depth examination of ICD, including its principles and diverse modalities of cell death that contribute to it. We also provide a thorough overview of how NPs are being utilized to trigger ICD and bolster antitumor immunity. Lastly, we highlight the potential of NPs in combination with immunotherapy to revolutionize cancer treatment.

Although accounting for only a small amount of skin cancers, melanoma contributes prominently to skin cancer-related deaths, which are mostly caused by metastatic diseases, and lymphatic metastasis constitutes the main route. In this review, we concentrate on the metabolic mechanisms of tumor lymph node (LN) metastasis in melanoma. Two hypotheses of melanoma LN metastasis are introduced, which are the premetastatic niche (PMN) and parallel progression model. Dysregulation of oxidative stress, lactic acid concentration, fatty acid synthesis, amino acid metabolism, autophagy, and ferroptosis construct the metabolic mechanisms in LN metastasis of melanoma. Moreover, melanoma cells also promote LN metastasis by interacting with non-tumor cells through metabolic reprogramming in TIME. This review will deepen our understanding of the mechanism of lymph node metastasis in melanoma.

Purpose: Neoadjuvant immunochemotherapy is emerging as a promising regimen for patients with locally advanced gastric and gastroesophageal junction (G/GEJ) adenocarcinoma. However, it remains unclear whether immunochemotherapy will bring more adverse events (AEs) leading to a delay or even cancellation of surgeries. We aimed to provide a comprehensive analysis of the toxicity profiles for immune checkpoint inhibitors (ICIs) combined with chemotherapy among patients with G/GEJ adenocarcinoma.

Methods: Published trials up to January 2024 were identified on Web of Science, Cochrane Library, Embase, and PubMed. Single-group and controlled clinical trials with ICIs in combination with chemotherapy in patients with G/GEJ adenocarcinoma were included. Two reviewers independently extracted data including incidence rate of AEs. The primary outcomes included the proportion of patients with adverse events leading to treatment discontinuation, grade 3 or higher adverse events, and serious adverse events. This study is registered with PROSPERO (CRD42023492676).

Results: Twenty studies were included for a total of 6692 patients. In patients receiving immunochemotherapy, 17% (95% confidence interval (CI), 11-23%) had adverse events leading to treatment discontinuation, 23% (95% CI, 19-27%) had serious adverse events, and 64% (95% CI, 58-70%) had grade 3 or higher adverse events. Compared with patients receiving chemotherapy alone, patients with immunochemotherapy were associated with higher rates of adverse events leading to discontinuation (RR, 1.45; 95% CI, 1.32-1.60), serious adverse events (RR, 1.27; 95% CI, 1.04-1.57), and grade 3 or higher adverse events (RR, 1.15; 95% CI, 1.07-1.23).

Conclusions: In conclusion, the incidence of adverse events leading to discontinuation, serious adverse events, and grade 3 or higher adverse events were higher in patients receiving immunochemotherapy compared to those with chemotherapy.

Purpose: Lactate is a key metabolite produced by glycolytic metabolism, yet it also serves as an energy source for cancer cells. Lactate accumulation in the tumor microenvironment (TME) has been demonstrated to correlate with immunosuppressive TME and tumor progression. As a highly glycolytic tumor, it is crucial to decipher the underlying mechanism in pancreatic ductal adenocarcinoma (PDAC).

Methods: Bioinformation analysis was used to identify lactate mediated carbonic anhydrase IX (CA9) upregulation. CCK-8, colony formation and mouse xenograft assay were utilized to study the effect of CA9 in PDAC. ECAR, OCR and pHi measurement confirmed the impacts of CA9 in Warburg phenotype. Using confocal microscopy, flow cytometry, qRT-PCR, co-IP, we validated the signaling pathways in PDAC to regulate reactive oxygen species (ROS) production.

Results: We confirmed that CA9 is highly expressed in PDAC and positively regulated by lactate levels. CA9 can enhance the proliferative and migratory capabilities of PDAC cells. Pharmacologic inhibition or knockdown of CA9 significantly reduce pHi, increase the intracellular lactate and reverse the Warburg phenotype. The intracellular lactate accumulation caused by CA9 knockdown upregulates ROS and mitochondrial dysfunction. Furthermore, it was discovered that the competitive binding of CA9 with FUS inhibits the facilitation of FUS on NOX4 pre-mRNA splicing.

Conclusion: Collectively, our data illustrate that CA9 has a direct regulatory role in pHi homeostasis and ROS production, providing a potential therapeutic target for PDAC treatment.

Purpose: Our study aims to develop and validate a novel molecular marker for the prognosis and diagnosis of hepatocellular carcinoma (HCC) MATERIALS & METHODS: We retrospectively analyzed mRNA expression profile and clinicopathological data of HCC patients fetched from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO) and The International Cancer Genome Consortium (ICGC) datasets. Univariate Cox regression analysis was performed to collect differentially expressed mRNA (DEmRNAs) from HCC and non-tumor tissues, and YEATS2, a prognostic marker, was identified by further analysis. ROC curve, survival analysis and multivariate Cox regression analysis as well as nomograms were used to evaluate the prognosis of this gene. Finally, the biological function of this gene was preliminarily discussed by using single gene Gene Set Enrichment Analysis (GSEA), and the YEATS2 overexpression and knockdown hepatoma cell line was used to verify the results in vitro and in vivo.

Results: Based on the clinical information of HCC in TCGA, GEO and ICGC databases, the gene YEATS2 with significant differences from HCC was identified. There was a statistical difference in the survival prognosis between the two databases and the ROC curve showed that the survival of HCC in both TCGA, GSE14520 and ICGC groups had a satisfactory predictive effect. Univariate and multivariate Cox regression analysis showed that YEATS2 was an independent prognostic factor for HCC, and Nomograms, which combined this prognostic feature with significant clinical features, provided an important reference for the clinical prognostic diagnosis of HCC. Next, we constructed overexpression and knockdown YEATS2 cell line in Hep3B and LM3 cells, and further proved that overexpression YEATS2 promote the proliferation and migration of HCC cells by CCK8, colony formation experiment, and transwell assays, and knockdown YEATS2 inhibited the proliferation and migration of HCC cells by CCK8, colony formation experiment, and transwell assays. Finally, the biological function of YEATS2 was preliminarily explored through GSEA analysis of a single gene, and it was found that it was significantly correlated with cell cycle and DNA repair, which provided us with ideas for further analysis. Furthermore, the knockdown of YEATS2 promoted radiation-induced DNA damage, enhanced radiosensitivity, and ultimately inhibited the proliferation of hepatocellular carcinoma cells in vitro and in vivo.

Conclusions: Our study identified a promising prognostic marker for hepatocellular carcinoma that is useful for clinical decision-making and individualized treatment.

Background: The small leucine-rich proteoglycan decorin (DCN) is recognized for its diverse roles in tissue homeostasis and malignant progression. Nevertheless, the regulatory effects of DCN on bladder cancer stem cells (BCSCs) and the underlying mechanisms in muscle-invasive bladder cancer (MIBC) remain to be elucidated.

Methods: The study obtained data (including scRNA-seq, clinicopathological characteristics, and survival) were acquired from TCGA and GEO. The BCSCs were cultured by enriching the suspension culture in a serum-free medium, followed by flow cytometry sorting. Overexpression/knockdown was constructed by utilizing lentivirus. The surface biomarkers of cancer stem cells were identified via flow cytometry. Cell proliferation and self-renewal were evaluated by CCK8 and Sphere formation assays, and in vivo tumor growth was evaluated with subcutaneous xenografts.

Results: Total DCN expression was significantly elevated in muscle-invasive bladder cancer (MIBC) and was associated with poor prognosis. The ΔDCN isoform, which lacks glycosylation sites, was identified in bladder cancer stem cells (BCSCs) derived from clinical tissue samples and bladder cancer cell lines. Suppression of ΔDCN expression resulted in a reduction of BCSC stemness. Both in vitro and in vivo experiments indicated that overexpression of full-length DCN inhibited stemness within the extracellular matrix. Conversely, overexpression of ΔDCN and the introduction of exogenous recombinant decorin protein in ΔDCN-knockdown BCSC-SW780 cell lines enhanced stemness within the cytoplasm. The ΔDCN isoform exhibited resistance to gemcitabine chemotherapy in vitro.

Conclusion: Non-glycanated ΔDCN isoforms were identified in bladder cancer stem cells (BCSCs), where they exhibited differential cytoplasmic localization and promoted oncogenic effects by inducing a stemness phenotype and conferring resistance to gemcitabine chemotherapy. These oncogenic effects are in stark contrast to the anti-tumor functions of glycosylated DCN in the extracellular matrix. The ratio of ΔDCN isoforms to glycosylated DCN is pivotal in predicting tumor progression and therapeutic resistance.

Purpose: Leiomyosarcoma (LMS) is an aggressive mesenchymal malignant tumor with poor therapeutic options, but the molecular mechanisms underlying LMS remain largely unknown. Increasing evidence indicates that transient receptor potential vanilloid 4 (TRPV4) levels are closely related to the advancement of various malignant tumors through diverse molecular mechanisms. However, the roles and regulatory mechanisms of TRPV4 in LMS progression remain unclear.

Methods: Immunohistochemistry, Western blot, and immunofluorescence were used to investigate the relationship between TRPV4 expression and LMS. Survival analysis was conducted to evaluate the association between TRPV4 levels and prognosis in LMS patients. Intracellular Ca²⁺ measurement, colony formation, CCK-8, wound healing and Transwell assays and peritoneal metastasis mouse model were used to verify the effect of TRPV4 activity and expression on LMS proliferation and metastasis. RNA-seq and proteomics were performed to explore the underlying mechanism.

Results: TRPV4 was upregulated in LMS tissues and cells and served as a novel prognostic factor. Moreover, TRPV4 overexpression enhanced cell proliferation, cell migration and invasion of LMS cells in vitro, as well as promoted tumor metastasis in vivo, which could be blocked by HC067047 intervention or TRPV4 knockdown. Combined RNA-seq and proteomics analysis of KEGG pathway indicated that ECM receptor interaction was obviously activated. Extracellular matrix protein 1 (ECM1) was identified as downstream gene of TRPV4. Mechanistically, TRPV4 overexpression increased ECM1 level and activated the FAK/PI3K/AKT/GSK3β pathway, which could be reversed by TRPV4 knockdown or LY294002 treatment. Moreover, ECM1 overexpression enhanced the activation of FAK/PI3K/AKT/GSK3β pathway. And simultaneous overexpression of TRPV4 and ECM1 synergistically activated this pathway.

Conclusion: Our findings provide a novel mechanism by which TRPV4 directly activates Ca²⁺/FAK/PI3K/AKT/GSK3β pathway and further indirectly enhances the FAK/PI3K/AKT/GSK3β pathway through the promotion and secretion of ECM1 to promote LMS malignant progression. Targeting the TRPV4/FAK axis might be a promising potential strategy for prognosis and treatment of LMS.