Cancer Cell International最新文献

Cancer immunotherapy has reshaped the landscape of cancer treatment over the past decades. Genetic manipulation of T cells to express synthetic receptors, known as chimeric antigen receptors (CAR), has led to the creation of tremendous commercial and therapeutic success for the treatment of certain hematologic malignancies. However, since the engagement of CAR-T cells with their respective antigens is solely what triggers their cytotoxic reactions against target cells, the slightest changes to the availability and/or structure of the target antigen often result in the incapacitation of CAR-T cells to enforce tumoricidal responses. This results in the resistance of tumor cells to a particular CAR-T cell therapy that requires meticulous heeding to sustain remissions in cancer patients. In this review, we highlight the antigen-dependent resistance mechanisms by which tumor cells dodge being recognized and targeted by CAR-T cells. Moreover, since substituting the target antigen is the most potent strategy for overcoming antigen-dependent disease relapse, we tend to highlight the current status of some target antigens that might be considered suitable alternatives to the currently available antigens in various cancers. We also propose target antigens whose targeting might reduce the off-tumor adverse events of CAR-T cells in certain malignancies.

Prostate cancer (PCa) ranks as the second most common malignancy and the fifth leading cause of cancer-related deaths among men. A critical challenge lies in accurately identifying those patients at high risk for transitioning rapidly from hormone-sensitive PCa (HSPC) to lethal castration-resistant PCa (CRPC). In our study, we employed a multiomics approach involving bioinformatics analysis on datasets GSE2443 and GSE35988, along with proteomics studies, to discover that cysteine- and glycine-rich protein 1 (CSRP1) expression significantly impacts the progression of HSPC. This hypothesis was substantiated through experiments using PC3 and LNCaP prostate cancer cells, where we conducted scratch assays and apoptosis assays, all of which confirmed CSRP1's role in suppressing tumor growth. Furthermore, we elucidated the inhibitory effect of CSRP1 on tumors by performing xenograft experiments on castrated mice models. To solidify these findings in a clinical context, we constructed a nomogram model integrating CSRP1's immunohistochemistry data and clinical parameters from an actual patient cohort with HSPC. This model revealed that low CSRP1 expression indeed promotes the advancement towards CRPC. In conclusion, the level of CSRP1 expression can serve as a valuable biomarker for clinicians to predict disease progression in their patients. It has the potential to guide personalized clinical management and decision-making strategies, thereby contributing to more effective and targeted treatment approaches for HSPC patients.

Objective: Oral malignancies are among the common head and neck cancers. Various therapeutic modalities are used for targeting oral cancers. It was shown that quercetin (a flavonoid) has an anti-cancer effect on different cancers. In the current study, the anti-cancer potentials of quercetin against oral cancer cells were summarized.

Methods: The current systematic review was conducted in accordance with the PRISMA guideline for the identification of relevant studies in various electronic databases up to April 2023. After reviewing and screening 193 articles, 18 were chosen for this study based on our inclusion and exclusion criteria.

Results: It was shown that quercetin significantly reduced cancer cell proliferation, cell viability, tumor volume, invasion, metastasis and migration. This anti-cancer agent induced oxidative stress and apoptosis in the cancer cells. Quercetin treatment could also induce some biochemical alterations in the cancer cells.

Conclusion: According to the results, it can be mentioned that quercetin administration has an anti-cancer effect against oral cancer cells. This agent exerts its anticancer effects via reduced cell viability and different mechanisms, including induce oxidative damage, apoptosis, and reduced invasion and metastasis. However, suggesting the use of quercetin as a therapeutic agent of oral cancer patients requires further clinical studies due to its poor absorption rates, and the exact molecular mechanisms are still not well understood.

Pancreatic cancer (PC) is a malignancy of gastrointestinal tract threatening the life of people around the world. In spite of the advances in the treatment of PC, the overall survival of this disease in advanced stage is less than 12%. Moreover, PC cells have aggressive behaviour in proliferation and metastasis as well as capable of developing therapy resistance. Therefore, highlighting the underlying molecular mechanisms in PC pathogenesis can provide new insights for its treatment. In the present review, inflammation and related pathways as well as role of gut microbiome in the regulation of PC pathogenesis are highlighted. The various kinds of interleukins and chemokines are able to regulate angiogenesis, metastasis, proliferation, inflammation and therapy resistance in PC cells. Furthermore, a number of molecular pathways including NF-κB, TLRs and TGF-β demonstrate dysregulation in PC aggravating inflammation and tumorigenesis. Therapeutic regulation of these pathways can reverse inflammation and progression of PC. Both chronic and acute pancreatitis have been shown to be risk factors in the development of PC, further highlighting the role of inflammation. Finally, the composition of gut microbiota can be a risk factor for PC development through affecting pathways such as NF-κB to mediate inflammation.

Background: Angiogenesis is one of the important factors related to tumorigenesis, invasion, and metastasis. Cancer-secreted exosomes are essential mediators of intercellular cross-talk and participate in angiogenesis and metastasis. Unveiling the mechanism of angiogenesis is an important way to develop anti-angiogenesis therapeutic strategies to against cancer progression.

Methods: miR-1825 expression and relationship with microvascular density were validated in colorectal cancer (CRC) by in situ hybridization (ISH) staining and immunohistochemistry (IHC). Sequential differential centrifugation, transmission electron microscopy, and western blotting analysis were used to extract and characterize exosomes. The effort of exosomal miR-1825 on endothelial cells was examined by transwell assay, wound healing assay, tube formation assay, and aortic ring assay. The relationship of miR-1825, ING1 and the downstream pathway were analyzed by western blot, RT-PCR, Immunofluorescence, and dual-luciferase reporter system analysis.

Results: Exosomal miR-1825 is associated with angiogenesis in CRC and is enriched in exosomes extracted from the serum of CRC patients. The CRC-secreted exosomal miR-1825 can be transferred into vascular endothelial cells, promoting endothelial cell migration and tube formation in vitro, and facilitating angiogenesis and tumor metastasis in vivo. Mechanistically, exosomal miR-1825 regulates angiogenesis and tumor metastasis by suppressing inhibitor of growth family member 1 (ING1) and activating the TGF-β/Smad2/Smad3 signaling pathway in the recipient HUVECs.

Conclusions: Our study demonstrated the CRC-secreted exosomal miR-1825 could be transferred to vascular endothelial cells, subsequently leads to the inhibition of ING1 and the activation of the TGF-β/Smad2/Smad3 signaling pathway, thereby promoting angiogenesis and liver metastasis in CRC. Exosomal miR-1825 is thus a potential diagnostic and therapeutic target for CRC patients.

Background: High heterogeneity in gastric cancer (GC) remains a challenge for standard treatments and prognosis prediction. Dysregulation of sialic acid metabolism (SiaM) is recognized as a key metabolic hallmark of tumor immune evasion and metastasis. Herein, we aimed to develop a SiaM-based metabolic classification in GC.

Methods: SiaM-related genes were obtained from the MsigDB database. Bulk and single-cell transcriptional data of 956 GC patients were acquired from the GEO, TCGA, and MEDLINE databases. Proteomic profiles of 20 GC samples were derived from our institution. The consensus clustering algorithm was applied to identify SiaM-based clusters. The SiaM-based model was established via LASSO regression and evaluated via Kaplan‒Meier curve and ROC curve analyses. In vitro and in vivo experiments were conducted to explore the function of ST3GAL1 in GC.

Results: Three SiaM clusters presented distinct patterns of clinicopathological features, transcriptomic alterations, and tumor immune microenvironment landscapes in GC. Compared with clusters A and B, cluster C presented elevated SiaM activity, higher metastatic potential, more abundant immunosuppressive features, and a worse prognosis. Based on the differentially expressed genes between these clusters, a risk model for six genes (ARHGAP6, ST3GAL1, ADAM28, C7, PLCL1, and TTC28) was then constructed. The model exhibited robust performance in predicting peritoneal metastasis and prognosis in four independent cohorts. As a hub gene in the model, ST3GAL1 promoted GC cell migration and invasion in vitro and in vivo.

Conclusions: Our study proposed a novel SiaM-based classification that identified three metabolic subtypes with distinct characteristics of tumor microenvironment and clinical outcomes in GC.

Colorectal cancer (CRC) is a serious threat to human health with the third morbidity and the second cancer-related mortality worldwide. It is urgent to explore more effective strategy for CRC because of the acquired treatment resistance from the non-surgical conventional therapies, including radiation, chemotherapy, targeted therapy and immunotherapy. Ferroptosis is a novel form of programmed cell death characterized by iron-dependent lipid peroxidation species (ROS) accumulation and has been identified as a promising target for cancer treatment, especially for those with treatment resistance. In this review, we mainly summarize the recent studies on the influence and regulation of ferroptosis by which (including gut microbiota) modulating the metabolism of iron, amino acid and lipid. Thus this analysis may provide potential targets for inducing CRC ferroptosis and shed lights on the future application of ferroptosis in CRC.

Glioma is the most common primary malignant tumor of the central nervous system in adults, characterized by high mortality, low cure rate and high recurrence rate. Among gliomas, glioblastoma multiforme (GBM) is the most malignant subtype. Currently, the standard treatment for patients with GBM is maximum surgical excision combined with radiotherapy and chemotherapy. But only a small percentage of patients benefit from this standard treatment. The tumor microenvironment plays an important role in the occurrence and development of most tumors. It is primarily composed of tumor cells, peripheral blood vessels, extracellular matrix, signaling molecules, stromal cells, and immune cells. The role of stromal cells in GBM has emerged as the focus of current research. The interaction among tumor, stromal, and immune cells within the tumor microenvironment can influence tumor development. Traditional research and drug therapy in glioma mainly focus on the tumor cells themselves, but recent studies have found that targeting stromal cells in the tumor microenvironment can also modulate tumor progression in GBM. Here, we review the influence of stromal cells in the tumor microenvironment of GBM on tumor cells and its related mechanism, as well as related molecular targets and signaling pathways, providing new ideas for the treatment and prognosis of GBM.

Estrogen receptor-positive breast cancer (ERPBC) accounts for approximately 70% of breast cancers in women worldwide. The therapeutic strategy process for ERPBC is well-established and significantly reduces the mortality rate. The discovery of new therapeutic targets remains essential for ERPBC patients with metastasis or endocrine resistance. This study indicated that USP7 is highly expressed in ERBPC and promotes tumor progression and metastasis. Inhibition of USP7 activity repressed proliferation, induced apoptosis, suppressed migration and invasive activities, and reversed the epithelial-mesenchymal transition of ERPBC. Mass spectrometry analysis indicated that USP7 regulates CDK1 expression, which is highly expressed and correlates with a poor overall survival rate in ERPBC. USP7 directly interacts with CDK1 and regulates its stability. The combined inhibition of USP7 and CDK1 by GNE-6776 and Ro-3306 synergistically represses the malignant process and metastasis of ERPBC. These findings proved that targeting USP7 and CDK1 is a potential strategy for overcoming endocrine resistance in patients with advanced ERPBC.

Background: Pancreatic adenocarcinoma (PDAC) is the most fatal malignant tumor that focuses on men and the elderly (40-85 years) and is aggressive. Its surgical resection rate is only 10-44%, and the rate of local recurrence in the retroperitoneum 1 year after surgery is as high as about 60%. The main reason for local recurrence in the majority of patients is that PDAC is perineural invasion (PNI) and the cancer cells infiltrate and grow along the peripancreatic nerve bundles. The identification of biomarkers associated with the diagnosis of PDAC may help to improve the current difficulty in early diagnosis of pancreatic cancer and guide clinical treatment. We constructed a co-culture model system of Schwann and PDCA cells to determined that Stearoyl Coenzyme A Desaturase (SCD) is a key gene driving the progress of PDAC.

Methods: Single-cell data files for PDAC were analyzed to compare cellular composition and subpopulation-specific gene expression between control (n = 4) and pancreatic cancer (n = 6). Among 36,277 cells, we obtained a total of 16 subpopulations, including a Neurons subpopulation, by UMAP analysis. Further screening by Mendelian randomization analysis yielded three pairs of key genes corresponding to eQTL-positive outcome causally, the corresponding genes were, in order: the three genes COL18A1, RASSF4, and SCD. Among them, SCD was significantly positively correlated with with the malignant progression of pancreatic cancer, and enriched in signaling pathways such as MTORC1_SIGNALING and P53-PATHWAY. In this study, We further applied CRISPR-Cas9 technology to knock out SCD expression in Schwann cells under co culture system to detect the growth status of PDAC cells.

Results: Three genes (COL18A1, RASSF4, SCD) showed significant correlation with PDAC. The identified SCD genes were positively correlated with the development of PDAC. We further demonstrated through experiments that SCD is overexpressed in PDAC tissues, and knocking down SCD in neuronal cells reduces the PDAC cells growth rate and migration ability.

Conclusion: In this article, we demonstrated that the upregulation of SCD expression level in neuronal cells is related to the PDAC, and SCD may be a promising candidate for PDAC therapy.