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1.
ACS Appl Mater Interfaces ; 16(8): 9968-9979, 2024 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-38358298

RESUMO

Foreseen as foundational in forthcoming oncology interventions are multimodal therapeutic systems. Nevertheless, the tumor microenvironment (TME), marked by heightened glucose levels, hypoxia, and scant concentrations of endogenous hydrogen peroxide could potentially impair their effectiveness. In this research, two-dimensional (2D) Ti3C2 MXene nanosheets are engineered with CeO2 nanozymes and glucose oxidase (GOD), optimizing them for TME, specifically targeting cancer therapy. Following our therapeutic design, CeO2 nanozymes, embodying both peroxidase-like and catalase-like characteristics, enable transformation of H2O2 into hydroxyl radicals for catalytic therapy while also producing oxygen to mitigate hypoxia. Concurrently, GOD metabolizes glucose, thereby augmenting H2O2 levels and disrupting the intracellular energy supply. When subjected to a near-infrared laser, 2D Ti3C2 MXene accomplishes photothermal therapy (PTT) and photodynamic therapy (PDT), additionally amplifying cascade catalytic treatment via thermal enhancement. Empirical evidence demonstrates robust tumor suppression both in vitro and in vivo by the CeO2/Ti3C2-PEG-GOD nanocomposite. Consequently, this integrated approach, which combines PTT/PDT and enzymatic catalysis, could offer a valuable blueprint for the development of advanced oncology therapies.


Assuntos
Hipertermia Induzida , Neoplasias , Nitritos , Elementos de Transição , Humanos , Glucose Oxidase , Peróxido de Hidrogênio , Titânio/farmacologia , Hipertermia , Neoplasias/terapia , Glucose , Hipóxia , Microambiente Tumoral , Linhagem Celular Tumoral
2.
ACS Appl Mater Interfaces ; 16(8): 9680-9689, 2024 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-38364813

RESUMO

Nitric oxide (NO) generated within the tumor microenvironment is an established driver of cancer progression and metastasis. Recent efforts have focused on leveraging this feature to target cancer through the development of diagnostic imaging agents and activatable chemotherapeutics. In this context, porphyrins represent an extraordinarily promising class of molecules, owing to their demonstrated use within both modalities. However, the remodeling of a standard porphyrin to afford a responsive chemical that can distinguish elevated NO from physiological levels has remained a significant research challenge. In this study, we employed a photoinduced electron transfer strategy to develop a panel of NO-activatable porphyrin photosensitizers (NOxPorfins) augmented with real-time fluorescence monitoring capabilities. The lead compound, NOxPorfin-1, features an o-phenylenediamine trigger that can effectively capture NO (via N2O3) to yield a triazole product that exhibits a 7.5-fold enhancement and a 70-fold turn-on response in the singlet oxygen quantum yield and fluorescence signal, respectively. Beyond demonstrating excellent in vitro responsiveness and selectivity toward NO, we showcase the potent photodynamic therapy (PDT) effect of NOxPorfin-1 in murine breast cancer and human non-small cellular lung cancer cells. Further, to highlight the in vivo efficacy, two key studies were executed. First, we utilized NOxPorfin-1 to ablate murine breast tumors in a site-selective manner without causing substantial collateral damage to healthy tissue. Second, we established a nascent human lung cancer model to demonstrate the unprecedented ability of NOxPorfin-1 to halt tumor growth and progression completely. The results of the latter study have tremendous implications for applying PDT to target metastatic lesions.


Assuntos
Neoplasias Pulmonares , Fotoquimioterapia , Porfirinas , Humanos , Animais , Camundongos , Óxido Nítrico , Porfirinas/farmacologia , Porfirinas/química , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêutico , Fármacos Fotossensibilizantes/química , Neoplasias Pulmonares/tratamento farmacológico , Linhagem Celular Tumoral , Microambiente Tumoral
3.
Sheng Wu Gong Cheng Xue Bao ; 40(2): 391-418, 2024 Feb 25.
Artigo em Chinês | MEDLINE | ID: mdl-38369829

RESUMO

Tumor is one of the most serious diseases that threaten human health and social development, and it is the second most common cause of death worldwide. The latest statistics show that malignant tumors have surpassed cardiovascular disease as the leading cause of death in developed countries. Drug resistance, metastasis, and recurrence of tumors continue to present urgent challenges in clinical treatment. Tumor stem cells (TSCs) are a specific subset of cells that possess high capabilities of self-renewal, differentiation potential, tumorigenicity and drug resistance. They are resistant to non-specific treatment methods such as chemotherapy and radiotherapy, and play a crucial role in tumor initiation, metastasis, drug resistance, and recurrence. The surface markers, stemness maintenance mechanisms, microenvironment, and metabolic reprogramming of TSCs have become areas of intense research focus. The latest research results provide novel targets and strategies for the identification of TSCs and targeted therapy. This paper reviews the surface markers (CD133, CD44, etc.), self-renewal and epithelial mesenchymal transition (EMT) signaling pathways (Wnt/ß-catenin, Hedgehog, etc.), microenvironment characteristics, metabolic reprogramming (glycolysis, oxidative phosphorylation, etc.) and their roles in the initiation, development, metastasis and drug resistance of TSCs.


Assuntos
Neoplasias , Humanos , Neoplasias/tratamento farmacológico , Transdução de Sinais , Diferenciação Celular , Transição Epitelial-Mesenquimal , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Microambiente Tumoral
4.
Front Immunol ; 15: 1331841, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38370403

RESUMO

Background: Breast cancer (BRCA) is a common malignancy in women, and its resistance to immunotherapy is a major challenge. Abnormal expression of genes is important in the occurrence and development of BRCA and may also affect the prognosis of patients. Although many BRCA prognosis model scores have been developed, they are only applicable to a limited number of disease subtypes. Our goal is to develop a new prognostic score that is more accurate and applicable to a wider range of BRCA patients. Methods: BRCA patient data from The Cancer Genome Atlas database was used to identify breast cancer-related genes (BRGs). Differential expression analysis of BRGs was performed using the 'limma' package in R. Prognostic BRGs were identified using co-expression and univariate Cox analysis. A predictive model of four BRGs was established using Cox regression and the LASSO algorithm. Model performance was evaluated using K-M survival and receiver operating characteristic curve analysis. The predictive ability of the signature in immune microenvironment and immunotherapy was investigated. In vitro experiments validated POLQ function. Results: Our study identified a four-BRG prognostic signature that outperformed conventional clinicopathological characteristics in predicting survival outcomes in BRCA patients. The signature effectively stratified BRCA patients into high- and low-risk groups and showed potential in predicting the response to immunotherapy. Notably, significant differences were observed in immune cell abundance between the two groups. In vitro experiments demonstrated that POLQ knockdown significantly reduced the viability, proliferation, and invasion capacity of MDA-MB-231 or HCC1806 cells. Conclusion: Our 4-BRG signature has the potential as an independent biomarker for predicting prognosis and treatment response in BRCA patients, complementing existing clinicopathological characteristics.


Assuntos
Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/genética , Neoplasias da Mama/terapia , Prognóstico , Mama , Biologia Computacional , Imunoterapia , Microambiente Tumoral/genética
5.
Front Immunol ; 15: 1308070, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38370407

RESUMO

Lysosomes are intracellular digestive organelles that participate in various physiological and pathological processes, including the regulation of immune checkpoint molecules, immune cell function in the tumor microenvironment, antigen presentation, metabolism, and autophagy. Abnormalities or dysfunction of lysosomes are associated with the occurrence, development, and drug resistance of tumors. Lysosomes play a crucial role and have potential applications in tumor immunotherapy. Targeting lysosomes or harnessing their properties is an effective strategy for tumor immunotherapy. However, the mechanisms and approaches related to lysosomes in tumor immunotherapy are not fully understood at present, and further basic and clinical research is needed to provide better treatment options for cancer patients. This review focuses on the research progress related to lysosomes and tumor immunotherapy in these.


Assuntos
Neoplasias , Humanos , Apresentação de Antígeno , Lisossomos/metabolismo , Imunoterapia , Autofagia , Microambiente Tumoral
6.
Front Immunol ; 15: 1334348, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38370413

RESUMO

Background: Immunohistochemistry (IHC) is a widely used laboratory technique for cancer diagnosis, which selectively binds specific antibodies to target proteins in tissue samples and then makes the bound proteins visible through chemical staining. Deep learning approaches have the potential to be employed in quantifying tumor immune micro-environment (TIME) in digitized IHC histological slides. However, it lacks of publicly available IHC datasets explicitly collected for the in-depth TIME analysis. Method: In this paper, a notable Multiplex IHC Histopathological Image Classification (MIHIC) dataset is created based on manual annotations by pathologists, which is publicly available for exploring deep learning models to quantify variables associated with the TIME in lung cancer. The MIHIC dataset comprises of totally 309,698 multiplex IHC stained histological image patches, encompassing seven distinct tissue types: Alveoli, Immune cells, Necrosis, Stroma, Tumor, Other and Background. By using the MIHIC dataset, we conduct a series of experiments that utilize both convolutional neural networks (CNNs) and transformer models to benchmark IHC stained histological image classifications. We finally quantify lung cancer immune microenvironment variables by using the top-performing model on tissue microarray (TMA) cores, which are subsequently used to predict patients' survival outcomes. Result: Experiments show that transformer models tend to provide slightly better performances than CNN models in histological image classifications, although both types of models provide the highest accuracy of 0.811 on the testing dataset in MIHIC. The automatically quantified TIME variables, which reflect proportions of immune cells over stroma and tumor over tissue core, show prognostic value for overall survival of lung cancer patients. Conclusion: To the best of our knowledge, MIHIC is the first publicly available lung cancer IHC histopathological dataset that includes images with 12 different IHC stains, meticulously annotated by multiple pathologists across 7 distinct categories. This dataset holds significant potential for researchers to explore novel techniques for quantifying the TIME and advancing our understanding of the interactions between the immune system and tumors.


Assuntos
Neoplasias Pulmonares , Humanos , Redes Neurais de Computação , Imuno-Histoquímica , Microambiente Tumoral
7.
Aging (Albany NY) ; 16(3): 2591-2616, 2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-38305808

RESUMO

BACKGROUND: Mounting studies indicate that oxidative stress (OS) significantly contributes to tumor progression. Our study focused on bladder urothelial cancer (BLCA), an escalating malignancy worldwide that is growing rapidly. Our objective was to verify the predictive precision of genes associated with overall survival (OS) by constructing a model that forecasts outcomes for bladder cancer and evaluates the prognostic importance of these genetic markers. METHODS: Transcriptomic data were obtained from TCGA-BLCA and GSE31684, which are components of the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO), respectively. To delineate distinct molecular subtypes, we employed the non-negative matrix factorization (NMF)method. The significance of OS-associated genes in predicting outcomes was assessed using lasso regression, multivariate Cox analysis, and univariate Cox regression analysis. For external validation, we employed the GSE31684 dataset. CIBERSORT was utilized to examine the tumor immune microenvironment (TIME). A nomogram was created and verified using calibration and receiver operating characteristic (ROC) curves, which are based on risk signatures. We examined variations in clinical characteristics and tumor mutational burden (TMB) among groups classified as high-risk and low-risk. To evaluate the potential of immunotherapy, the immune phenomenon score (IPS) was computed based on the risk score. In the end, the pRRophetic algorithm was employed to forecast the IC50 values of chemotherapy medications. RESULTS: In our research, we examined the expression of 275 genes associated with OS in 19 healthy and 414 cancerous tissues of the bladder obtained from the TCGA database. As a result, a new risk signature was created that includes 4 genes associated with OS (RBPMS, CRYAB, P4HB, and PDGFRA). We found two separate groups, C1 and C2, that showed notable variations in immune cells and stromal score. According to the Kaplan-Meier analysis, patients classified as high-risk experienced a considerably reduced overall survival in comparison to those categorized as low-risk (P<0.001). The predictive capability of the model was indicated by the area under the curve (AUC) of the receiver operating characteristic (ROC) curve surpassing 0.6. Our model showed consistent distribution of samples from both the GEO database and TCGA data. Both the univariate and multivariate Cox regression analyses validated the importance of the risk score in relation to overall survival (P < 0.001). According to our research, patients with a lower risk profile may experience greater advantages from using a CTLA4 inhibitor, whereas patients with a higher risk profile demonstrated a higher level of responsiveness to Paclitaxel and Cisplatin. In addition, methotrexate exhibited a more positive outcome in patients with low risk compared to those with high risk. CONCLUSIONS: Our research introduces a novel model associated with OS gene signature in bladder cancer, which uncovers unique survival results. This model can assist in tailoring personalized treatment approaches and enhancing patient therapeutic effect in the management of bladder cancer.


Assuntos
Carcinoma de Células de Transição , Neoplasias da Bexiga Urinária , Humanos , Prognóstico , Bexiga Urinária , Neoplasias da Bexiga Urinária/genética , Cisplatino , Microambiente Tumoral/genética
8.
Aging (Albany NY) ; 16(3): 2517-2541, 2024 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-38305786

RESUMO

With the global rise in cancer incidence and mortality rates, research on the topic has become increasingly urgent. Among the significant players in this field are heat shock proteins (HSPs), particularly HSPA4 from the HSP70 subfamily, which has recently garnered considerable interest for its role in cancer progression. However, despite numerous studies on HSPA4 in specific cancer types, a comprehensive analysis across all cancer types is lacking. This study employs various bioinformatics techniques to delve into the role of HSPA4 in pan-cancer. Our objective is to assess its potential in clinical diagnosis, prognosis, and as a future molecular target for therapy. The research findings reveal significant differences in HSPA4 expression across different cancer types, suggesting its diagnostic value and close association with cancer staging and patient survival rates. Furthermore, genetic variations and methylation status of HSPA4 play critical roles in tumorigenesis. Lastly, the interaction of HSPA4 with immune cells is linked to the tumor microenvironment (TME) and immunotherapy. In summary, HSPA4 emerges as a promising cancer biomarker and a vital member of the HSPs family, holding potential applications in diagnosis, prognosis, and immunotherapy.


Assuntos
Proteínas de Choque Térmico HSP110 , Neoplasias , Humanos , Proteínas de Choque Térmico HSP110/genética , Proteínas de Choque Térmico HSP110/metabolismo , Prognóstico , Neoplasias/diagnóstico , Neoplasias/genética , Neoplasias/terapia , Proteínas de Choque Térmico HSP70/genética , Proteínas de Choque Térmico/genética , Imunoterapia , Microambiente Tumoral/genética
9.
Aging (Albany NY) ; 16(3): 2715-2735, 2024 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-38309289

RESUMO

BACKGROUND: The relationship between clear cell renal cell carcinoma (ccRCC) and branched-chain amino acids (BCAA) metabolism has yet to be thoroughly explored. METHODS: The BCAA metabolism-related clusters were constructed using non-negative matrix factorization (NMF). The features of BCAA metabolism in ccRCC were evaluated by building a prognostic model using least absolute shrinkage and selection operator (LASSO) regression algorithm. Real-time quantitative PCR (RT-qPCR) was employed to analyze differential expression of branched-chain amino acid transaminase 1 (BCAT1) between cancer and paracancer tissues and between different cell lines. Cell counting kit-8, wound healing and Transwell chamber assays were conducted to determine changes in proliferative and metastatic abilities of A498 and 786-O cells. RESULTS: Two BCAA metabolism-related clusters with distinct prognostic and immune infiltration characteristics were identified in ccRCC. The BCAA metabolic signature (BMS) was capable of distinguishing immune features, tumor mutation burden, responses to immunotherapy, and drug sensitivity among ccRCC patients. RT-qPCR revealed overexpression of BCAT1 in ccRCC tissues and cell lines. Additionally, single-gene RNA sequencing analysis demonstrated significant enrichment of BCAT1 in macrophages and tumor cells. BCAT1 played tumor-promoting role in ccRCC and was closely associated with immunosuppressive cells and checkpoints. BCAT1 promoted ccRCC cell proliferation and metastasis. CONCLUSIONS: The BMS played a crucial role in determining the prognosis, tumor mutation burden, responses to immunotherapy and drug sensitivity of ccRCC patients, as well as the immune cell infiltration features. BCAT1 was linked to immunosuppressive microenvironments and may offer new sights into ccRCC immunotherapeutic targets.


Assuntos
Carcinoma de Células Renais , Carcinoma , Neoplasias Renais , Humanos , Carcinoma de Células Renais/genética , Prognóstico , Aminoácidos de Cadeia Ramificada , Imunossupressores , Neoplasias Renais/genética , Microambiente Tumoral/genética , Transaminases/genética
10.
Aging (Albany NY) ; 16(3): 2563-2590, 2024 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-38315450

RESUMO

Targeting Protein for Xenopus Kinesin Like Protein 2 (TPX2) serves as a microtubule associated protein for the regulation of spindle assembly and tumorigenesis. We aim to investigate the prognostic and immunological role of TPX2 in pan-cancer. TCGA database, Tumor Immune Single-cell Hub (TISCH), and Human Protein Atlas (HPA) were retrieved to evaluate the expression pattern of TPX2 as well as its diagnostic and prognostic value in solid tumors. Genomic alterations of TPX2 were assessed with cBioPortal database. In vitro experiments in lung adenocarcinoma (LUAD) were performed to confirm the potential role of TPX2. Overexpression of TPX2 was found in 22 types of cancers, and was positively related with copy number variations (CNV) and negative with methylation. Up-regulated TPX2 could predict worse outcomes in the majority of cancers. Single-cell analysis revealed that TPX2 was mainly distributed in malignant cells (especially in glioma) and proliferating T cells. Genomic alteration of TPX2 was common in different types of tumors, while with prognostic value in two types of cancers. Additionally, significant correlations were found between TPX2 expression and tumor microenvironment (including stromal cells and immune cells) as well as immune related genes across cancer types. Drug sensitivity analysis revealed that TPX2 could predict response to chemotherapy and immunotherapy. Functional analyses demonstrated close relationship of TPX2 with immune function and malignant phenotypes. Finally, it was confirmed that knockdown of TPX2 could reduce proliferation and migration ability of LUAD cells. In summary, TPX2 could serve as a diagnostic and prognostic biomarker and a potential immunotherapy marker.


Assuntos
Variações do Número de Cópias de DNA , Neoplasias , Humanos , Microambiente Tumoral/genética , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Neoplasias/genética , Neoplasias/terapia , Prognóstico , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Imunoterapia , Proteínas Associadas aos Microtúbulos/genética
11.
Aging (Albany NY) ; 16(3): 2273-2298, 2024 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-38319706

RESUMO

BACKGROUND: Methods for predicting the outcome of lung adenocarcinoma (LUAD) in the clinic are limited. Anoikis is an important route to programmed cell death in LUAD, and the prognostic value of a model constructed with anoikis-related lncRNAs (ARlncRNAs) in LUAD is unclear. METHODS: Transcriptome and basic information for LUAD patients was obtained from the Cancer Genome Atlas. Coexpression and Cox regression analyses were utilized to identify prognostically significant ARlncRNAs and construct a prognostic signature. Furthermore, the signature was combined with clinical characteristics to create a nomogram. Finally, we performed principal component, enrichment, tumor mutation burden (TMB), tumor microenvironment (TME) and drug sensitivity analyses to evaluate the basic research and clinical merit of the signature. RESULTS: The prognostic signature developed with eleven ARlncRNAs can accurately predict that high-risk group patients have a worse prognosis, as proven by the receiver operating characteristic (ROC) curve (AUC: 0.718). Independent prognostic analyses indicated that the risk score is a significant independent prognostic element for LUAD (P<0.001). In the high-risk group, enrichment analysis demonstrated that glucose metabolism and DNA replication were the main enrichment pathways. TMB analysis indicated that the high-risk group had a high TMB (P<0.05). Drug sensitivity analyses can recognize drugs that are sensitive to different risk groups. Finally, 11 ARlncRNAs of this signature were verified by RT-qPCR analysis. CONCLUSIONS: A novel prognostic signature developed with 11 ARlncRNAs can accurately predict the OS of LUAD patients and offer clinical guidance value for immunotherapy and chemotherapy treatment.


Assuntos
Adenocarcinoma , Neoplasias Pulmonares , RNA Longo não Codificante , Humanos , Anoikis/genética , Prognóstico , RNA Longo não Codificante/genética , Pulmão , Neoplasias Pulmonares/genética , Microambiente Tumoral/genética
12.
Aging (Albany NY) ; 16(3): 2753-2773, 2024 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-38319721

RESUMO

BACKGROUND: Disulfidoptosis is an unconventional form of programmed cell death that distinguishes itself from well-established cell death pathways like ferroptosis, pyroptosis, and necroptosis. METHODS: Initially, we conducted a single-cell analysis of the GSE131907 dataset from the GEO database to identify disulfidoptosis-related genes (DRGs). We utilized differentially expressed DRGs to classify TCGA samples with an unsupervised clustering algorithm. Prognostic models were built using Cox regression and LASSO regression. RESULTS: Two DRG-related clusters (C1 and C2) were identified based on the DEGs from single-cell sequencing data analysis. In comparison to C1, C2 exhibited significantly worse overall prognosis, along with lower expression levels of immune checkpoint genes (ICGs) and chemoradiotherapy sensitivity-related genes (CRSGs). Furthermore, C2 displayed a notable enrichment in metabolic pathways and cell cycle-associated mechanisms. C2 was also linked to the development and spread of tumors. We created a prognostic risk model known as the DRG score, which relies on the expression levels of five DRGs. Patients were categorized into high-risk and low-risk groups depending on their DRG score, with the former group being linked to a poorer prognosis and higher TMB score. Moreover, the DRG score displayed significant correlations with CRSGs, ICGs, the tumor immune dysfunction and exclusion (TIDE) score, and chemotherapeutic sensitivity. Subsequently, we identified a significant correlation between the DRG score and monocyte macrophages. Additionally, crucial DRGs were additionally validated using qRT-PCR. CONCLUSIONS: Our new DRG score can predict the immune landscape and prognosis of LUAD, serving as a reference for immunotherapy and chemotherapy.


Assuntos
Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Humanos , Prognóstico , Adenocarcinoma de Pulmão/genética , Sequência de Bases , Análise de Sequência de RNA , Neoplasias Pulmonares/genética , Microambiente Tumoral
13.
Aging (Albany NY) ; 16(3): 2657-2678, 2024 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-38319724

RESUMO

BACKGROUND: Multiple myeloma (MM) is an incurable B-cell malignancy, but with the emergence of immunotherapy, a potential cure is hopeful. The individualized interaction between the tumor and bone marrow (BM) microenvironment determines the response to immunotherapy. Angiogenesis is a constant hallmark of the BM microenvironment in MM. However, little is known about the potency ability of angiogenesis-associated genes (AAGs) to regulate the immune microenvironment of MM patients. METHODS: We comprehensively dissected the associations between angiogenesis and genomic landscapes, prognosis, and the immune microenvironment by integrating 36 AAGs. Immunohistochemistry was performed to verify the correlation between angiogenic factor expression and patient prognosis. Single-sample gene set enrichment analysis was applied to quantify the relative abundance of 28 infiltrating cells. The AAG score was constructed using the least absolute shrinkage and selection operator Cox regression model. RESULTS: Angiogenesis was closely correlated with MM patient prognosis, and the mutation intensity of the AAGs was low. Immunohistochemistry confirmed that high microvessel density predicted poor prognosis. Three AAG clusters and two gene clusters with distinct clinical outcomes and immune characteristics were identified. The established AAG_score model performed well in predicting patient prognosis and active immunotherapy response. The high-AAG_score subgroup was characterized by reduced immune cell infiltration, poor prognosis, and inactive immunotherapy response. Multivariate analyses indicated that the AAG_score was strongly robust and independent among the prognostic variables. CONCLUSION: This study revealed that angiogenesis is significantly related to MM patient prognosis and immune phenotype. Evaluating the AAG signature was conducive to predicting patient response to immunotherapy and guiding more efficacious immunotherapy strategies.


Assuntos
Mieloma Múltiplo , Humanos , Mieloma Múltiplo/genética , Mieloma Múltiplo/terapia , Fenômenos Fisiológicos Cardiovasculares , Genômica , Imunoterapia , Microambiente Tumoral/genética , Prognóstico
14.
Aging (Albany NY) ; 16(3): 2812-2827, 2024 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-38319718

RESUMO

BACKGROUND: Bladder cancer (BCa) is a common malignancy in the urinary system. Necroptosis, a recently discovered form of programmed cell death, is closely associated with the development and progression of various types of tumors. Targeting necroptosis through anti-cancer strategies has shown potential as a therapy for cancer. We aimed to develop a necroptosis-related lncRNAs (NRlncRNAs) risk model that can predict the survival and tumor immunity of BCa patients. METHODS: We analyzed sequencing data obtained from the TCGA database, and applied least absolute shrinkage and selection operator (LASSO) and Cox regression analysis to identify crucial NRlncRNAs for building a risk model. Using the risk score, we categorized patients into high- and low-risk groups, and assessed the accuracy with the area under the receiver operating characteristic (AUROC) and Kaplan-Meier curves. We performed the RT-qPCR to detect the expression differences of the genes based on the risk model. RESULTS: We identified a total of 296 NRlncRNAs, and 6 of them were included in the prognostic model. The AUC values for 1-, 3-, and 5-year predictions were 0.675, 0.726 and 0.734, respectively. Our risk model demonstrated excellent predictive performance and served as an independent predictor with high predictive power. Additionally, we performed PCA, TMB, GSEA analyses, and evaluated immune cell infiltration, to reveal significant differences between the high- and low-risk groups in functional signaling pathways, immunological status, and mutation profiles. Finally, we assessed the chemotherapeutic response of several drugs. According to the RT-qPCR results, we found that four NRlncRNAs of the risk model were more highly expressed in BCa cell lines than human immortalized uroepithelial cell line and regulated the occurrence and progression of bladder cancer. CONCLUSION: We constructed a novel NRlncRNAs-associated risk model, which could predict the prognosis and immune response of BCa patients.


Assuntos
RNA Longo não Codificante , Neoplasias da Bexiga Urinária , Humanos , RNA Longo não Codificante/genética , Necroptose/genética , Neoplasias da Bexiga Urinária/genética , Prognóstico , Apoptose , Microambiente Tumoral/genética
15.
J Exp Med ; 221(3)2024 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-38334978

RESUMO

An effective cancer therapy requires killing cancer cells and targeting the tumor microenvironment (TME). Searching for molecules critical for multiple cell types in the TME, we identified NR4A1 as one such molecule that can maintain the immune suppressive TME. Here, we establish NR4A1 as a valid target for cancer immunotherapy and describe a first-of-its-kind proteolysis-targeting chimera (PROTAC, named NR-V04) against NR4A1. NR-V04 degrades NR4A1 within hours in vitro and exhibits long-lasting NR4A1 degradation in tumors with an excellent safety profile. NR-V04 inhibits and frequently eradicates established tumors. At the mechanistic level, NR-V04 induces the tumor-infiltrating (TI) B cells and effector memory CD8+ T (Tem) cells and reduces monocytic myeloid-derived suppressor cells (m-MDSC), all of which are known to be clinically relevant immune cell populations in human melanomas. Overall, NR-V04-mediated NR4A1 degradation holds promise for enhancing anticancer immune responses and offers a new avenue for treating various types of cancers such as melanoma.


Assuntos
Melanoma , Células Supressoras Mieloides , Humanos , Linhagem Celular Tumoral , Imunoterapia , Melanoma/patologia , Células Supressoras Mieloides/patologia , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/metabolismo , Microambiente Tumoral , Quimera de Direcionamento de Proteólise
16.
Sci Rep ; 14(1): 3778, 2024 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-38355711

RESUMO

Our research found that vitamin D3 (VD3) treatment increased lung metastasis in mice with 4T1 murine breast cancer (BC). This study aims to investigate the impact of VD3 on the activation of tumor-associated macrophages (TAMs) in BC. Mice bearing 4T1, E0771, 67NR BC cells, and healthy mice, were fed diets with varying VD3 contents (100-deficient, 1000-normal, and 5000 IU/kg-elevated). Some mice in the 1000 and 100 IU/kg groups received calcitriol. We studied bone metastasis and characterized TAMs and bone marrow-derived macrophages (BMDMs). 4T1 cells had higher bone metastasis potential in the 5000 IU/kg and calcitriol groups. In the same mice, an elevated tumor osteopontin level and M2 polarization of TAMs (MHCIIlow CD44high phenotype) were observed. Gene expression analysis confirmed M2 polarization of 4T1 (but not 67NR) TAMs and BMDMs, particularly in the 100 IU + cal group (increased Mrc1, Il23, and Il6). This polarization was likely due to COX-2/PGE2 induction in 4T1 calcitriol-treated cells, leading to increased proinflammatory cytokines like IL-6 and IL-23. Future studies will explore COX-2/PGE2 as a primary mediator of calcitriol-stimulated inflammation in the BC microenvironment, especially relevant for BC patients with VD3 deficiency and supplementation.


Assuntos
Neoplasias da Mama , Glândulas Mamárias Humanas , Humanos , Animais , Camundongos , Feminino , Citocinas/metabolismo , Calcitriol/farmacologia , Macrófagos Associados a Tumor/metabolismo , Ciclo-Oxigenase 2/genética , Glândulas Mamárias Humanas/metabolismo , Linhagem Celular Tumoral , Neoplasias da Mama/patologia , Microambiente Tumoral
17.
Int J Biol Sci ; 20(3): 1110-1124, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38322116

RESUMO

At present, tumor metastasis still remains the leading contributor to high recurrence and mortality in cancer patients. There have been no clinically effective therapeutic strategies for treating patients with metastatic cancer. In recent years, a growing body of evidence has shown that the pre-metastatic niche (PMN) plays a crucial role in driving tumor metastasis. Nevertheless, a clear and detailed understanding of the formation of PMN is still lacking given the fact that PMN formation involves in a wealth of complicated communications and underlying mechanisms between primary tumors and metastatic target organs. Despite that the roles of numerous components including tumor exosomes and extracellular vesicles in influencing the evolution of PMN have been well documented, the involvement of cancer-associated fibroblasts (CAFs) in the tumor microenvironment for controlling PMN formation is frequently overlooked. It has been increasingly recognized that fibroblasts trigger the formation of PMN by virtue of modulating exosomes, metabolism and so on. In this review, we mainly summarize the underlying mechanisms of fibroblasts from diverse origins in exerting impacts on PMN evolution, and further highlight the prospective strategies for targeting fibroblasts to prevent PMN formation.


Assuntos
Fibroblastos Associados a Câncer , Exossomos , Vesículas Extracelulares , Neoplasias , Humanos , Estudos Prospectivos , Neoplasias/metabolismo , Exossomos/metabolismo , Vesículas Extracelulares/metabolismo , Fibroblastos/metabolismo , Fibroblastos Associados a Câncer/metabolismo , Microambiente Tumoral , Metástase Neoplásica/patologia
18.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 55(1): 6-12, 2024 Jan 20.
Artigo em Chinês | MEDLINE | ID: mdl-38322525

RESUMO

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths in the world. Due to the insidious onset and rapid progression and a lack of effective treatments, the prognosis of patients with HCC is extremely poor, with the average 5-year survival rate being less than 10%. The tumor microenvironment (TME), the internal environment in which HCC develops, can regulate the oncogenesis, development, invasion, and metastasis of HCC. During the process of cancer progression, HCC cells can regulate the biological behaviors of tumor cells, cancer-associated fibroblasts, cancer-associated immune cells, and other cells in the TME by releasing exosomes containing specific signals, thereby promoting cancer progression. However, the exact molecular mechanisms and the roles of exosomes in the specific cellular regulation of these processes are not fully understood. Herein, we summarized the TME components of HCC, the sources and the biological traits of exosomes in the TME, and the impact of mechanical factors on exosomes. In addition, special attention was given to the discussion of the effects of HCC-exosomes on different types of cells in the microenvironment. There are still many difficulties to be overcome before exosomes can be applied as carriers in clinical cancer treatment. First of all, the homogeneity of exosomes is difficult to ensure. Secondly, exosomes are mainly administered through subcutaneous injection. Although this method is simple and easy to implement, the absorption efficiency is not ideal. Thirdly, exosome extraction methods are limited in number and inefficient, making it difficult to prepare exosomes in large quantities. It is important to ensure that exosomes are used in sufficient quantities to trigger an effective tumor immune response, especially for exosome-mediated tumor immunotherapy. With the improvement in identification, isolation, and purification technology, exosomes are expected to be successfully used in the clinical diagnosis of early-stage HCC and the clinical treatment of liver cancer.


Assuntos
Carcinoma Hepatocelular , Exossomos , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , Microambiente Tumoral , Comunicação Celular
19.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 55(1): 13-18, 2024 Jan 20.
Artigo em Chinês | MEDLINE | ID: mdl-38322528

RESUMO

Nanodrugs are widely utilized in the biomedical fields, exhibiting immense potential in cancer therapy in particular. However, tumors exist in an extremely complicated microenvironment where substances like collagen are continuously deposited and remodeled, leading to significant alterations in the mechanical properties of the extracellular matrix (ECM) during tumor development. Previous research has primarily focused on the specific physicochemical properties of nanodrugs, such as particle size, electric charge, shape, surface chemistry, etc., and their effects on cellular uptake, cytotoxicity, and in vivo pharmacokinetics. Limited studies have been done to explore the impact of ECM mechanical properties on nanodrug delivery. In this review, we systematically summarized the relevant research findings on this topic from the perspective of the characteristics and testing methods of tumor ECM mechanics. Additionally, we made a thorough discussion of the potential mechanical and biological mechanisms involved in nanodrug delivery. We proposed several noteworthy research directions. Regarding the overall strategy, there is a need to emphasize targeted delivery that combines ECM mechanics and nanomechanics to achieve precise drug delivery. Regarding the spatial aspect, attention should be given to the nonlinear spatial mechanical heterogeneity within the interior of solid tumors and the construction of mechanic microenvironment-adaptive nanocarriers to improve the delivery efficiency. Regarding the temporal aspect, emphasis should be placed on the dynamic development and changes in the mechanical microenvironment during solid tumor growth and treatment processes. Based on the stromal mechanical characteristics of the tumor tissues of individual patients, personalized treatment strategies can be formulated, which will enhance treatment specificity and efficacy. In addition, issues such as mechanically targeted nanodrug delivery, degradation, and metabolism under dynamic ECM mechanical conditions warrant further investigation.


Assuntos
Nanopartículas , Neoplasias , Humanos , Neoplasias/tratamento farmacológico , Sistemas de Liberação de Medicamentos/métodos , Nanopartículas/química , Matriz Extracelular/metabolismo , Matriz Extracelular/patologia , Microambiente Tumoral
20.
J Cancer Res Clin Oncol ; 150(2): 64, 2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-38300330

RESUMO

BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is the main type of renal cell carcinoma. Cyclin B2 (CCNB2) is a subtype of B-type cyclin that is associated with the prognosis of several cancers. This study aimed to identify the relationship between CCNB2 and progression of ccRCC and construct a novel lncRNAs-related model to predict prognosis of ccRCC patients. METHODS: The data were obtained from public databases. We identified CCNB2 in ccRCC using Kaplan-Meier survival analysis, univariate and multivariate Cox regression, and Gene Ontology analysis. External validation was then performed. The risk model was constructed based on prognostic lncRNAs by the LASSO algorithm and multivariate Cox regression. Receiver operating characteristics (ROC) curves were used to evaluate the model. Consensus clustering analysis was performed to re-stratify the patients. Finally, we analyzed the tumor-immune microenvironment and performed screening of potential drugs. RESULTS: CCNB2 associated with late clinicopathological parameters and poor prognosis in ccRCC and was an independent predictor for disease-free survival. In addition, CCNB2 shared the same expression pattern with known suppressive immune checkpoints. A risk model dependent on the expression of three prognostic CCNB2-related lncRNAs (SNHG17, VPS9D1-AS1, and ZMIZ1-AS1) was constructed. The risk signature was an independent predictor of ccRCC. The area under the ROC (AUC) curve for overall survival at 1-, 3-, 5-, and 8-year was 0.704, 0.702, 0.741, and 0.763. The high-risk group and cluster 2 had stronger immunogenicity and were more sensitive to immunotherapy. CONCLUSION: CCNB2 could be an important biomarker for predicting prognosis in ccRCC patients. Furthermore, we developed a novel lncRNAs-related risk model and identified two CCNB2-related molecular clusters. The risk model performed well in predicting overall survival and immunological microenvironment of ccRCC.


Assuntos
Carcinoma de Células Renais , Carcinoma , Neoplasias Renais , RNA Longo não Codificante , Humanos , Carcinoma de Células Renais/genética , RNA Longo não Codificante/genética , Ciclina B2/genética , Regulação para Cima , Prognóstico , Neoplasias Renais/genética , Microambiente Tumoral
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