Cellular Oncology最新文献

Background: The most common type of lung cancer is non-small cell lung cancer (NSCLC), accounting for 85% of all cases. Programmed cell death (PCD), an important regulatory mechanism for cell survival and homeostasis, has become increasingly prominent in cancer research in recent years. As such, exploring the role of PCD in NSCLC may help uncover new mechanisms for therapeutic targets.

Methods: We utilized the GEO database and TCGA NSCLC gene data to screen for co-expressed genes. To delve deeper, single-cell sequencing combined with spatial transcriptomics was employed to study the intrinsic mechanisms of programmed cell death in cells and their interaction with the tumor microenvironment. Furthermore, Mendelian randomization was applied to screen for causally related genes. Prognostic models were constructed using various machine learning algorithms, and multi-cohort multi-omics analyses were conducted to screen for genes. In vitro experiments were then carried out to reveal the biological functions of the genes and their relationship with apoptosis.

Results: Cells with high programmed cell death activity primarily activate pathways related to apoptosis, cell migration, and hypoxia, while also exhibiting strong interactions with smooth muscle cells in the tumor microenvironment. Based on a set of programmed cell death genes, the prognostic model NSCLCPCD demonstrates strong predictive capabilities. Moreover, laboratory experiments confirm that SLC7A5 promotes the proliferation of NSCLC cells, and the knockout of SLC7A5 significantly increases tumor cell apoptosis.

Conclusions: Our data indicate that programmed cell death is predominantly associated with pathways related to apoptosis, tumor metastasis, and hypoxia. Additionally, it suggests that SLC7A5 is a significant risk indicator for the prognosis of non-small cell lung cancer (NSCLC) and may serve as an effective target for enhancing apoptosis in NSCLC tumor cells.

BRCA1 (Breast Cancer 1) is a tumor suppressor gene with a role in DNA repair by Homologous Recombination (HR), and maintenance of genomic stability that is frequently investigated in breast, prostate, and ovarian cancers. BRCA1 mutations or dysregulation in glioblastoma can lead to impaired DNA repair mechanisms, resulting in tumor progression and resistance to standard therapies. Several studies have shown that BRCA1 expression is altered, albeit rarely, in glioblastoma, leading to poor prognosis and increased tumor aggressiveness. In addition, the communication of BRCA1 with other molecular pathways such as p53 and PTEN further complicates its role in glioblastoma pathogenesis. Targeting BRCA1-related pathways in these cases has shown the potential to improve the efficacy of standard treatments, including radiotherapy and chemotherapy. The development of (Poly (ADP-ribose) Polymerase) PARP inhibitors that exploit the lack of HR also offers a therapeutic approach to glioblastoma patients with BRCA1 mutations. Despite these advances, the heterogeneity of glioblastoma and its complex tumor microenvironment make the translation of such approaches into clinical practice still challenging, and there is an "unmet need". This review discusses the current mechanisms of etiology and potential treatment of BRCA1-related glioblastoma.

Background: Gastric cancer, characterized by its high morbidity and mortality rates, exhibits low levels of RAB37. The role and molecular mechanisms of RAB37, a small GTPase, in the pathogenesis of gastric cancer are still unclear.

Methods: We assessed RAB37 expression in gastric cancer cells using quantitative Polymerase Chain Reaction (qPCR), Western blot, and immunohistochemical staining (IHC), and analyzed EMT marker proteins and autophagy changes via Western blot, immunofluorescence (IF), and transmission electron microscopy (TEM). Co-immunoprecipitation (co-IP) was used to identify protein-protein interactions. We studied the migration and invasion of gastric cancer cells using wound healing and transwell assays in vitro and a mouse pulmonary metastasis model in vivo.

Results: Overexpression of RAB37 suppressed EMT, invasion, and migration while enhancing autophagy in gastric cancer cells, which was dependent on its GTPase activity. However, all these effects could be reversed by the autophagy inhibitor chloroquine. Regarding the molecular mechanism, RAB37 strengthened the interaction between p62 and β-catenin, which consequently enhanced the p62-mediated autophagic degradation of β-catenin. Furthermore, RAB37 curbed the pulmonary metastasis of both general and cisplatin-resistant gastric cancer cells.

Conclusion: The low level of RAB37 reduces interaction between p62 and β-catenin and then the autophagic degradation of β-catenin, thereby promoting the EMT, invasion, and migration in gastric cancer cells. The low expression of RAB37 in gastric cancer suggests a potential therapeutic target, especially for cisplatin-resistant gastric cancer.

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.

Ovarian cancer, a leading cause of gynecological cancer deaths globally, poses significant treatment challenges. Cisplatin (CDDP) is the first treatment choice for ovarian cancer and it is initially effective. However, 80% of ovarian cancer patients eventually relapse and develop resistance, resulting in chemotherapy failure. Therefore, finding new treatment combinations to overcome ovarian cancer resistance can provide a new tactic to improve the ovarian cancer patients' survival rate. We first identified activation of the Unfolded Protein Response (UPR) in CDDP-resistant ovarian cancer cells, implicating the IRE1α/XBP1 pathway in promoting resistance. Our findings demonstrate that inhibiting IRE1α signaling can re-sensitizes resistant cells to CDDP in vivo and in vitro, suggesting that IRE1α inhibitor used in conjunction with CDDP presumably could merge as a novel therapeutic strategy. Here, our research highlights the critical role of IRE1α signaling in mediating CDDP resistance, and paves the way for improved treatment options through combinatorial therapy.

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.

Purpose: Phosphoglycerate dehydrogenase (PHGDH), a pivotal enzyme in serine synthesis, plays a key role in the malignant progression of tumors through both its metabolic activity and moonlight functions. This study aims to elucidate the non-canonical function of PHGDH in promoting hepatocellular carcinoma (HCC) metastasis through its interaction with methyltransferase-like 3 (METTL3), potentially uncovering a novel therapeutic target.

Methods: Western blot was used to study PHGDH expression changes under anoikis and cellular functional assays were employed to assess its role in HCC metastasis. PHGDH-METTL3 interactions were explored using GST pull-down, Co-immunoprecipitation and immunofluorescence assays. Protein stability and ubiquitination assays were performed to understand PHGDH's impact on METTL3. Flow cytometry, cellular assays and nude mice model were used to confirm PHGDH's effects on anoikis resistance and HCC metastasis in vitro and in vivo.

Results: PHGDH is upregulated under anoikis conditions, thereby enhancing the metastatic potential of HCC cells. By interacting with METTL3, PHGDH prevents its ubiquitin-dependent degradation, resulting in higher METTL3 protein levels. This interaction upregulates epithelial-mesenchymal transition related genes, contributing to anoikis resistance and HCC metastasis. Nude mice model confirms that PHGDH's interaction with METTL3 is crucial for driving HCC metastasis.

Conclusion: Our research presents the first evidence that PHGDH promotes HCC metastasis by interacting with METTL3. The PHGDH-METTL3 axis may serve as a potential clinical therapeutic target, offering new insights into the multifaceted roles of PHGDH in HCC metastasis.

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.