12,828 results on '"*TUMOR microenvironment"'
Search Results
2. Single-cell analyzing of tumor microenvironment and cell adhesion between early and late-stage lung cancer.
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Zhu, Chaonan, Chen, Zhiquan, Wang, Shuai, Cao, Junmei, Cheng, Yuan, and Zheng, Maogen
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CELL adhesion , *TUMOR microenvironment , *CELL adhesion molecules , *LUNG cancer , *GENE expression , *RNA sequencing , *CELL cycle - Abstract
Lung adenocarcinoma (LUAD) is a highly heterogeneous disease that threaten human life with serious incidence and high mortality. High heterogeneity of tumor microenvironment (TME) was reported in multiple studies. However, the factor of controlling the tumor migration progression between eary and late-stage LUAD is still not fully understood. In this study, we conducted a comprehensive analysis of single-cell RNA sequencing (scRNA-seq) data of LUAD obtained from the GEO database. The identification of cell clusters revealed significant expansion of epithelial cells in late-stage patients. Interpretation of the cell-cell communication results between early-stage and late-stage patient samples indicated that early tumor cells may interact with epithelial cells through the TGF-β pathway to promote tumor progression. The cell cycle analysis demonstrated a significant increase in the number of cells in the G2 and M phases in late-stage lung cancer. Further analysis using Non-negative Matrix Factorization (NMF) revealed early-stage cell-specific gene features involved in cell adhesion-related biological processes. Among these, the Tensin (TNS) gene family, particularly TNS1, showed high expression in epithelial cells and fibroblasts of early-stage samples, specifically associated with cell adhesion. Survival analysis using TCGA database for LUAD demonstrated that patients with high expression of TNS1 exhibited significantly higher overall survival rates compared to those with low expression. Immunofluorescence experiments have demonstrated co-expression of TNS1 with fibroblast and tumor cell markers (α-SMA and EPCAM). Immunohistochemistry experiments further validated the significantly higher expression levels of TNS1 in early-stage LUAD tissues compared to late-stage lung cancer tissues (P<0.05). Pathway experiments have shown that early-stage tumor patients with high expression of TNS1 exhibit stronger phosphorylation levels of Akt and mTOR, indicating a more potent activation of the Akt/mTOR signaling pathway. In conclusion, the results of this study demonstrate that TNS1 is an adhesive molecule in the immune microenvironment of early-stage tumor cells, and it may serve as a novel prognostic marker for lug cancer. • Single-cell RNA sequencing results showed that light on the highly heterogeneous nature of the TME in LUAD. • Our study provides more evidence for the heterogeneity of LUAD's TME. • We present compelling evidence for the role of the Tensin (TNS) gene family, particularly TNS1, in early-stage LUAD. [ABSTRACT FROM AUTHOR]
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- 2024
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3. CAR T therapy from haematological malignancies to aging‐related diseases: An ever‐expanding universe.
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Ramoni, Davide, Montecucco, Fabrizio, and Carbone, Federico
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CHIMERIC antigen receptors , *KILLER cells , *AEROBIC capacity , *TUMOR microenvironment , *GENOME editing - Abstract
Background: Short but impactful, the two‐decade story of gene editing allowed a significant breakthrough in the treatment of haematological malignancies. However, despite different generations of chimeric antigen receptor T (CAR T), such a successful therapy has not yet been replicated in solid tumours and non‐oncological diseases. Methods: This narrative review discusses how CAR T therapy still faces challenges in overcoming the complexity of the solid tumour microenvironment and the concerns that its long‐term activity raises about potential unknown and unpredictable consequences in non‐oncological diseases. Results: In the most recent studies, the senolytic potential of CAR T is becoming an exciting field of research. Still, experimental but promising results indeed indicate the clearance of senescent cells as an effective strategy to improve exercise capacity and metabolic dysfunction in physiological ageing, with long‐term therapeutic and preventive effects. However, an effective expansion of a CAR T population requires a lympho‐depleting chemotherapy prior to infusion. While this procedure sounds reasonable for rescue therapy of oncological diseases, it poses genotoxic risks that may not be justified for non‐malignant diseases. Those represent the leading gaps for applying CAR T therapy in non‐oncological diseases. Conclusion: More is expected from current studies on the other classes of CAR cells now under investigation. Engineering NK cells and macrophages are candidates to improve cytotoxic and immunomodulating properties, potentially able to broaden application in solid tumours and non‐oncological diseases. Finally, engineering autologous T cells in old individuals may generate biologically deteriorated CAR T clones with impaired function and unpredictable effects on cytokine release. [ABSTRACT FROM AUTHOR]
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- 2024
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4. RAD23B mediated proteasomal degradation occurs through p38 MAPK/ATF‐2/RAD23B axis under nutrient‐deprived conditions in breast cancer.
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Sriaishwarya, Sukumaran and Lakshmi, Baddireddi Subhadra
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BREAST cancer , *METABOLIC reprogramming , *GENETIC transcription , *SLEEP deprivation , *TUMOR microenvironment , *CELL survival , *PROTEOLYSIS , *CANCER cell physiology - Abstract
Metabolic reprogramming in cancer occurs due to interaction of cells with the surrounding tumor microenvironment. In the microenvironment of solid tumors, nutrient deprivation is induced by high consumption of nutrients and insufficient vasculature. Tumor cells alter their metabolic strategies to adapt to the microenvironment. To understand the role of these metabolic changes, in the current study, we have mimicked nutrient deprivation condition in vitro to evaluate the associated signaling pathways in breast cancer cells. In our study, we have shown that nutritional deprivation activated p38 MAPK and activating transcription factor‐2 (ATF‐2) by increased phosphorylation of Thr180/Tyr182 and Thr71, respectively, in breast cancer cells. Pharmacological inhibition of p38 MAPK showed increased cell viability and reduced expression of ATF‐2 and RAD23B under nutrient starvation conditions. Further, silencing of ATF‐2 showed increased cell viability and decreased expression of RAD23B under nutrient starvation conditions. This suggests the involvement of p38 MAPK/ATF‐2/RAD23B axis as a signaling pathway under nutrition starvation in breast cancer cells. The RAD23B mediated proteasome activity was shown to be much higher under stress conditions indicating a crucial role of RAD23B as a target for breast cancer. [ABSTRACT FROM AUTHOR]
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- 2024
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5. Macrophages, IL-10, and nitric oxide increase, induced by hyperglycemic conditions, impact the development of murine melanoma B16F10-Nex2.
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Sellani, Tarciso A., Tomaz, Samanta L., Gonçalves, Jéssica M., Lima, Adriana, de Amat Herbozo, Carolina C., Silva, Gabrielli N., Gambero, Mônica, Longo-Maugéri, Ieda M., Simon, Karin A., Monteiro, Hugo P., and Rodrigues, Elaine G.
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INTERLEUKIN-10 , *NITRIC oxide , *MELANOMA , *MACROPHAGES , *BRAF genes , *NITRIC-oxide synthases - Abstract
Epidemiological studies show a strong correlation between diabetes and the increased risk of developing different cancers, including melanoma. In the present study, we investigated the impact of a streptozotocin (STZ)-induced hyperglycemic environment on B16F10-Nex2 murine melanoma development. Hyperglycemic male C57Bl/6 mice showed increased subcutaneous tumor development, partially inhibited by metformin. Tumors showed increased infiltrating macrophages, and augmented IL-10 and nitric oxide (NO) concentrations. In vivo neutralization of IL-10, NO synthase inhibition, and depletion of macrophages reduced tumor development. STZ-treated TLR4 KO animals showed delayed tumor development; the transfer of hyperglycemic C57Bl/6 macrophages to TLR4 KO reversed this effect. Increased concentrations of IL-10 present in tumor homogenates of hyperglycemic mice induced a higher number of pre-angiogenic structures in vitro , and B16F10-Nex2 cells incubated with different glucose concentrations in vitro produced increased levels of IL-10. In summary, our findings show that a hyperglycemic environment stimulates murine melanoma B16F10-Nex2 primary tumor growth, and this effect is dependent on tumor cell stimulation, increased numbers of macrophages, and augmented IL-10 and NO concentrations. These findings show the involvement of tumor cells and other components of the tumor microenvironment in the development of subcutaneous melanoma under hyperglycemic conditions, defining novel targets for melanoma control in diabetic patients. [Display omitted] • Hyperglycemic mice showed increased subcutaneous melanoma development. • Macrophages, IL-10 and NO are augmented in hyperglycemic tumors. • Tumor cells are stimulated to produce IL-10 in hyperglycemic conditions. • IL-10 increased tumor angiogenesis. • Depletion of macrophages, IL-10 or NO in hyperglycemic animals reduced tumor development. [ABSTRACT FROM AUTHOR]
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- 2024
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6. Liver metastases across cancer types sharing tumor environment immunotolerance can impede immune response therapy and immune monitoring.
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Gao, Yuzhen, Chen, Shipeng, Wang, Hao, Wu, Chenghao, An, Rui, Li, Guoli, Yang, Min, Zhou, Ying, Zhou, Yundong, Xie, Xinyou, Yu, Hong, and Zhang, Jun
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LIVER metastasis , *TUMOR microenvironment , *IMMUNOLOGICAL tolerance , *IMMUNE response , *METASTASIS - Abstract
[Display omitted] • The prognosis of patients with liver metastasis is worse than that of other metastatic cancers across cancer types. • Part of patients with liver metastasis have common tumor environment immunotolerance. • The immunotolerance with low immune cells expression contributed the main features of liver metastasis across cancer types. • Liver metastasis common features score guides immunotherapy/prognosis of liver metastasis, with KRT19 playing a key role. Hepatic immune tolerance might contribute to the development of therapeutic resistance to immunotherapy. However, addressing this issue is challenging since the efficacy of immunotherapy in the context of liver metastasis (LM) remains poorly studied. Here, we aimed to establish an LM common immune feature (LMCIF) score to quantify the characteristics of LM immunotolerance across cancer types for assisting clinical disease management. Large-scale clinical data were collected to identify the prognosis of LM. Multi-omics datasets of metastatic cancers with LM special immune-related pathways (LMSIPs) from the Molecular Signatures Database (MSigDB) were used to obtain an LMCIF cluster. Based on differential expression genes (DEGs), a novel LMCIF score for the LMCIF cluster was constructed. In addition, multi-omics, and immunohistochemistry (IHC) data from the public and in-house cohorts were used to explore the features of LM, and LMCIF score. Patients with LM had a worse prognosis and significantly lower infiltration of immune cells than patients with metastasis to other organs when analyzed with combined clinical and RNA sequencing data. After extracting the LMCIF cluster from 373 samples by utilizing 29 LMSIPs and validating them in a microarray cohort, an LMCIF score was established to confirm the role of the immunosuppressive environment as a contributor to the poor prognosis of LM across cancer types. Moreover, this LMCIF score could be used to predict the immune response of cancer patients undergoing immunotherapy. Finally, we identified that the majority of the 31 LMCIF genes exhibited a negative correlation with TME cells in LM patients, one of them, KRT19, which possessed the strongest positive correlation with LMCIF score, was confirmed to have an immunosuppressive effect through IHC analysis. Our results suggest that LM across cancer types share similar immunological profiles that induce immunotolerance and escape from immune monitoring. The novel LMCIF score represents a common liver metastasis immune cluster for predicting immunotherapy response, the results of which might benefit clinical disease management. [ABSTRACT FROM AUTHOR]
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- 2024
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7. A zebrafish xenotransplant model of anaplastic thyroid cancer to study tumor microenvironment and innate immune cell interactions in vivo.
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Michael, Cassia, Mendonça-Gomes, Juliana Moreira, DePaolo, Clinton Walton, Di Cristofano, Antonio, and de Oliveira, Sofia
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ANAPLASTIC thyroid cancer , *TUMOR microenvironment , *BRACHYDANIO , *CELL cycle , *THYROID cancer , *CELL death - Abstract
Anaplastic thyroid cancer (ATC) is of the most aggressive thyroid cancer. While ATC is rare, it accounts for a disproportionately high number of thyroid cancer-related deaths. Here, we developed an ATC xenotransplant model in zebrafish larvae, where we can study tumorigenesis and therapeutic response in vivo. Using both mouse (T4888M) and human (C643)-derived fluorescently labeled ATC cell lines, we show these cell lines display different engraftment rates, mass volume, proliferation, cell death, angiogenic potential, and neutrophil and macrophage recruitment and infiltration. Next, using a PIP-FUCCI reporter to track proliferation in vivo, we observed cells in each phase of the cell cycle. Additionally, we performed long-term non-invasive intravital microscopy over 48 h to understand cellular dynamics in the tumor microenvironment at the single-cell level. Lastly, we tested two drug treatments, AZD2014 and a combination therapy of dabrafenib and trametinib, to show our model could be used as an effective screening platform for new therapeutic compounds for ATC. Altogether, we show that zebrafish xenotransplants make a great model to study thyroid carcinogenesis and the tumor microenvironment, while also being a suitable model to test new therapeutics in vivo. [ABSTRACT FROM AUTHOR]
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- 2024
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8. Prognostic Impact and Spatial Interplay of Immune Cells in Urothelial Cancer.
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Debatin, Nicolaus F., Bady, Elena, Mandelkow, Tim, Huang, Zhihao, Lurati, Magalie C.J., Raedler, Jonas B., Müller, Jan H., Vettorazzi, Eik, Plage, Henning, Samtleben, Henrik, Klatte, Tobias, Hofbauer, Sebastian, Elezkurtaj, Sefer, Furlano, Kira, Weinberger, Sarah, Giacomo Bruch, Paul, Horst, David, Roßner, Florian, Schallenberg, Simon, and Marx, Andreas H.
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BLADDER cancer , *TRANSITIONAL cell carcinoma , *TUMOR-infiltrating immune cells , *CYTOTOXIC T cells , *RECEIVER operating characteristic curves , *T cells - Abstract
Out of 52 immune-related parameters in muscle-invasive bladder cancer, 39 were significant, and of these, 16 were independent prognostic parameters. The strongest prognostic factor was the density of intraepithelial CD8+ T cells, representing the terminal end route of tumor cell killing. Quantity and the spatial relationship of specific immune cell types can provide prognostic information in bladder cancer. The objective of the study was to characterize the spatial interplay and prognostic role of different immune cell subpopulations in bladder cancer. A total of 2463 urothelial bladder carcinomas were immunostained with 21 antibodies using BLEACH&STAIN multiplex fluorescence immunohistochemistry in a tissue microarray format and analyzed using a framework of neuronal networks for an image analysis. Spatial immune parameters were compared with histopathological parameters and overall survival data. The identification of > 300 different immune cell subpopulations and the characterization of their spatial relationship resulted in numerous spatial interaction patterns. Thirty-nine immune parameters showed prognostic significance in univariate analyses, of which 16 were independent from pT, pN, and histological grade in muscle-invasive bladder cancer. Among all these parameters, the strongest association with prolonged overall survival was identified for intraepithelial CD8+ cytotoxic T cells (time-dependent area under receiver operating characteristic curve [AUC]: 0.70), while stromal CD8+ T cells were less relevant (AUC: 0.65). A favorable prognosis of inflamed cancers with high levels of "exhaustion markers" suggests that TIM3, PD-L1, PD-1, and CTLA-4 on immune cells do not hinder antitumoral immune response in tumors rich of tumor infiltrating immune cells. The density of intraepithelial CD8+ T cells was the strongest prognostic feature in muscle-invasive bladder cancer. Given that tumor cell killing by CD8+ cytotoxic T lymphocytes through direct cell-to-cell-contacts represents the "terminal end route" of antitumor immunity, the quantity of "tumor cell adjacent CD8+ T cells" may constitute a surrogate for the efficiency of cancer recognition by the immune system that can be measured straightaway in routine pathology as the CD8 labeling index. Quantification of intraepithelial CD8+ T cells, the strongest prognosticfeature identified in muscle-invasive bladder cancer, can easily be assessed by brightfield immunohistochemistry and is therefore "ready to use" for routine pathology. [ABSTRACT FROM AUTHOR]
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- 2024
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9. RNA M6A modification shaping cutaneous melanoma tumor microenvironment and predicting immunotherapy response.
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Wu, Yanhong, He, Hongying, Zheng, Kairong, Qin, Zhenxin, Cai, Naikun, Zuo, Shuguang, and Zhu, Xiao
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RNA modification & restriction , *TUMOR microenvironment , *IMMUNOTHERAPY , *MELANOMA , *PRINCIPAL components analysis - Abstract
Recent years have seen rising mortality rates linked to cutaneous melanoma (SKCM), despite advances in immunotherapy. Understanding RNA N6‐methyladenosine (M6A) significance in SKCM is crucial for prognosis, tumor microenvironment (TME), immune cell presence, and immunotherapy efficacy. We analyzed 23 M6A regulators using SKCM samples from TCGA and GEO databases, identifying three M6A modification patterns linked to TME cell infiltration. Principal component analysis (PCA) yielded an M6A score for individual tumors, utilizing patient gene expression profiles and CNV data from TCGA. M6A modification patterns play a crucial role in SKCM development and progression, influencing tumor attributes such as inflammatory stage, subtype, TME interstitial activity, and genetic mutations. The M6A score independently predicts patient outcomes and correlates with improved response to immunotherapy, validated across anti‐PD‐1 and anti‐PD‐L1 therapy cohorts. M6A modifications significantly impact the TME landscape, with the M6A score serving as a predictive marker for immunotherapy response. Integrating M6A‐related information into clinical practice could revolutionize SKCM management and treatment strategies. [ABSTRACT FROM AUTHOR]
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- 2024
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10. Epigenetic silencing of LDHB promotes hepatocellular carcinoma by remodeling the tumor microenvironment.
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Zhang, Peng, Wan, Yi, Ma, Jinrong, Gong, Jin, Zhong, Ziwei, Cui, Yuxin, Zhang, Hongli, Da, Yanyan, Ma, Junpeng, Li, Chenxi, Liu, Lijuan, Gong, Tian, Tan, Youwen, and Zhang, Chengsheng
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Lactate dehydrogenase B (LDHB) reversibly catalyzes the conversion of pyruvate to lactate or lactate to pyruvate and expressed in various malignancies. However, the role of LDHB in modulating immune responses against hepatocellular carcinoma (HCC) remains largely unknown. Here, we found that down-regulation of lactate dehydrogenase B (LDHB) was coupled with the promoter hypermethylation and knocking down the DNA methyltransferase 3A (DNMT 3A) restored LDHB expression levels in HCC cell lines. Bioinformatics analysis of the HCC cohort from The Cancer Genome Atlas revealed a significant positive correlation between LDHB expression and immune regulatory signaling pathways and immune cell infiltrations. Moreover, immune checkpoint inhibitors (ICIs) have shown considerable promise for HCC treatment and patients with higher LDHB expression responded better to ICIs. Finally, we found that overexpression of LDHB suppressed HCC growth in immunocompetent but not in immunodeficient mice, suggesting that the host immune system was involved in the LDHB-medicated tumor suppression. Our findings indicate that DNMT3A-mediated epigenetic silencing of LDHB may contribute to HCC progression through remodeling the tumor immune microenvironment, and LDHB may become a potential prognostic biomarker and therapeutic target for HCC immunotherapy. [ABSTRACT FROM AUTHOR]
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- 2024
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11. Overexpressing S100A9 ameliorates NK cell dysfunction in estrogen receptor-positive breast cancer.
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Liu, Yansong, Li, Mingcui, Fang, Zhengbo, Gao, Shan, Cheng, Weilun, Duan, Yunqiang, Wang, Xuelian, Feng, Jianyuan, Yu, Tianshui, Zhang, Jiarui, Wang, Ting, Hu, Anbang, Zhang, Hanyu, Rong, Zhiyuan, Shakila, Suborna S., Shang, Yuhang, Kong, Fanjing, Liu, Jiangwei, Li, Yanling, and Ma, Fei
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KILLER cells , *EPIDERMAL growth factor receptors , *BREAST cancer , *TRIPLE-negative breast cancer , *HORMONE receptor positive breast cancer , *CELL physiology - Abstract
Background: Estrogen receptor (ER) positive human epidermal growth factor receptor 2 (HER2) negative breast cancer (ER+/HER2−BC) and triple-negative breast cancer (TNBC) are two distinct breast cancer molecular subtypes, especially in tumor immune microenvironment (TIME). The TIME of TNBC is considered to be more inflammatory than that of ER+/HER2−BC. Natural killer (NK) cells are innate lymphocytes that play an important role of tumor eradication in TME. However, studies focusing on the different cell states of NK cells in breast cancer subtypes are still inadequate. Methods: In this study, single-cell mRNA sequencing (scRNA-seq) and bulk mRNA sequencing data from ER+/HER2−BC and TNBC were analyzed. Key regulator of NK cell suppression in ER+/HER2−BC, S100A9, was quantified by qPCR and ELISA in MCF-7, T47D, MDA-MB-468 and MDA-MB-231 cell lines. The prognosis predictability of S100A9 and NK activation markers was evaluated by Kaplan–Meier analyses using TCGA-BRAC data. The phenotype changes of NK cells in ER+/HER2−BC after overexpressing S100A9 in cancer cells were evaluated by the production levels of IFN-gamma, perforin and granzyme B and cytotoxicity assay. Results: By analyzing scRNA-seq data, we found that multiple genes involved in cellular stress response were upregulated in ER+/HER2−BC compared with TNBC. Moreover, TLR regulation pathway was significantly enriched using differentially expressed genes (DEGs) from comparing the transcriptome data of ER+/HER2−BC and TNBC cancer cells, and NK cell infiltration high/low groups. Among the DEGs, S100A9 was identified as a key regulator. Patients with higher expression levels of S100A9 and NK cell activation markers had better overall survival. Furthermore, we proved that overexpression of S100A9 in ER+/HER2-cells could improve cocultured NK cell function. Conclusion: In conclusion, the study we presented demonstrated that NK cells in ER+/HER2−BC were hypofunctional, and S100A9 was an important regulator of NK cell function in ER+BC. Our work contributes to elucidate the regulatory networks between cancer cells and NK cells and may provide theoretical basis for novel drug development. [ABSTRACT FROM AUTHOR]
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- 2024
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12. Cross‐talk between leukemic and immune cells at the tumor microenvironment in chronic lymphocytic leukemia: An update review.
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Taghiloo, Saeid and Asgarian‐Omran, Hossein
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CHRONIC lymphocytic leukemia , *TUMOR microenvironment , *B cell lymphoma , *CHRONIC leukemia , *THERAPEUTICS , *CANCER invasiveness - Abstract
Chronic lymphocytic leukemia (CLL) is a mature‐type B cell malignancy correlated with significant changes and defects in both the innate and adaptive arms of the immune system, together with a high dependency on the tumor microenvironment. Overall, the tumor microenvironment (TME) in CLL provides a supportive niche for leukemic cells to grow and survive, and interactions between CLL cells and the TME can contribute to disease progression and treatment resistance. Therefore, the increasing knowledge of the complicated interaction between immune cells and tumor cells, which is responsible for immune evasion and cancer progression, has provided an opportunity for the development of new therapeutic approaches. In this review, we outline tumor microenvironment‐driven contributions to the licensing of immune escape mechanisms in CLL patients. [ABSTRACT FROM AUTHOR]
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- 2024
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13. Tumour microenvironment-responded Fe-doped carbon dots-sensitized cubic Cu2O for Z-scheme heterojunction-enhanced sono-chemodynamic synergistic tumor therapy.
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Feng, Chuanqi, Wang, Lumin, Zhang, Dashuai, Geng, Longlong, Zhou, Lianwen, Wang, Ling, Tian, Guanfeng, Tang, Qi, Hu, Jinyan, Geng, Bijiang, and Yan, Lang
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DOPING agents (Chemistry) , *COPPER , *HETEROJUNCTIONS , *TUMOR microenvironment , *CARBON - Abstract
[Display omitted] The efficacy of electron-hole separation in a single sonosensitizer and the complexities of the tumor microenvironment (TME) present significant challenges to the effectiveness of sonodynamic therapy (SDT). Designing efficient sonosensitizers to enhance electron-hole separation and alleviate TME resistance is crucial yet challenging. Herein, we introduce a novel Z-scheme heterojunctions (HJs) sonosensitizer using Fe-doped carbon dots (CDs) as auxiliary semiconductors to sensitize cubic Cu 2 O (Fe-CDs@Cu 2 O) for the first time. Fe-CDs@Cu 2 O demonstrated enhanced SDT effects due to improved electron-hole separation. Additionally, the introduction of Fe ions in CDs synergistically enhances Fenton-like reactions with Cu ions in Cu 2 O, resulting in enhanced chemodynamic therapy (CDT) effects. Moreover, Fe-CDs@Cu 2 O exhibited rapid glutathione (GSH) depletion, effectively mitigating TME resistance. With high rates of 1O 2 and OH generated by Fe-CDs@Cu 2 O, coupled with strong GSH depletion, single drug injection and ultrasound (US) irradiation effectively eliminate tumors. This innovative heterojunction sonosensitizer offers a promising pathway for clinical anti-tumor treatment. [ABSTRACT FROM AUTHOR]
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- 2024
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14. Tumor microenvironment activated mussel-inspired hollow mesoporous nanotheranostic for enhanced synergistic photodynamic/chemodynamic therapy.
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Tian Yan, Hao, Jang, Moon-Sun, Liu, Changling, Fu, Qiang, Wang, Bo, Fu, Yan, Hee Lee, Jung, and Yu Yang, Hong
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TUMOR microenvironment , *REACTIVE oxygen species , *MAGNETIC resonance imaging , *HYDROXYL group , *ETHYLENE glycol , *CONJUGATED polymers , *HYALURONIC acid - Abstract
[Display omitted] Anti-tumor therapies reliant on reactive oxygen species (ROS) as primary therapeutic agents face challenges due to a limited oxygen substrate. Photodynamic therapy (PDT) is particularly hindered by inherent hypoxia, while chemodynamic therapy (CDT) encounters obstacles from insufficient endogenous hydrogen peroxide (H 2 O 2) levels. In this study, we engineered biodegradable tumor microenvironment (TME)-activated hollow mesoporous MnO 2 -based nanotheranostic agents, designated as HAMnO 2 A. This construct entails loading artemisinin (ART) into the cavity and surface modification with a mussel-inspired polymer ligand, namely hyaluronic acid-linked poly(ethylene glycol)-diethylenetriamine-conjugated (3,4-dihydroxyphenyl) acetic acid, and the photosensitizer Chlorin e6 (mPEG-HA-Dien-(Dhpa/Ce6)), facilitating dual-modal imaging-guided PDT/CDT synergistic therapy. In vitro experimentation revealed that HAMnO 2 A exhibited ideal physiological stability and enhanced cellular uptake capability via CD44-mediated endocytosis. Additionally, it was demonstrated that accelerated endo -lysosomal escape through the pH-dependent protonation of Dien. Within the acidic and highly glutathione (GSH)-rich TME, the active component of HAMnO 2 A, MnO 2 , underwent decomposition, liberating oxygen and releasing both Mn2+ and ART. This process alleviates hypoxia within the tumor region and initiates a Fenton-like reaction through the combination of ART and Mn2+, thereby enhancing the effectiveness of PDT and CDT by generating increased singlet oxygen (1O 2) and hydroxyl radicals (•OH). Moreover, the presence of Mn2+ ions enabled the activation of T 1 -weighted magnetic resonance imaging. In vivo findings further validated that HAMnO 2 A displayed meaningful tumor-targeting capabilities, prolonged circulation time in the bloodstream, and outstanding efficacy in restraining tumor growth while inducing minimal damage to normal tissues. Hence, this nanoplatform serves as an efficient all-in-one solution by facilitating the integration of multiple functions, ultimately enhancing the effectiveness of tumor theranostics. [ABSTRACT FROM AUTHOR]
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- 2024
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15. "Four-in-One" Nanozyme for Amplified Catalytic-Photothermal Therapy.
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Zhang, Qing, Zhuang, Tinglong, Sun, Xiaohuan, Bao, Yanli, Zhu, Liqi, Zhang, Quan, Han, Jie, and Guo, Rong
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GLUCOSE oxidase , *PHOTOTHERMAL conversion , *REACTIVE oxygen species , *PHENYLENEDIAMINES , *TUMOR microenvironment , *HYDROGEN peroxide , *GENE amplification - Abstract
[Display omitted] The cancer therapeutic efficacy of the peroxidase (POD)-mimicking nanozyme-based monotherapy is significantly hindered due to insufficient intratumoral hydrogen peroxide (H 2 O 2) and glutathione (GSH) consumption effect on reactive oxygen species (ROS). In this study, we present the development of poly (o -phenylenediamine)@gold nanoparticles (AuNPs) (PoPD@Au) nanocomposites for multifunctional catalytic-photothermal therapy. These nanocomposites exhibit triple distinct nanozymatic activities, i.e. , POD-like activity that catalyzes H 2 O 2 to ROS, glucose oxidase (GOx)-like activity that supplements endogenous H 2 O 2 , and GSH depleting activity that decreases the ROS consumption efficiency. This open source and reduce expenditure strategy for ROS generation allows for the amplification of tumor oxidative stress, thereby enhancing anti-tumor efficiency. Additionally, the PoPD@Au nanocomposites demonstrate outstanding photothermal conversion efficiency, contributing to the synergistic effect between PoPD and AuNPs. Moreover, we reveal the improved photothermal performance of PoPD@Au triggered by the tumor microenvironment pH, which provides additional benefits for targeted catalytic-photothermal therapy. This "four-in-one" design of PoPD@Au enables efficient anti-tumor effects both in vitro and in vivo , making it a universal strategy for engineering catalytic-photothermal therapeutic nanoagents. [ABSTRACT FROM AUTHOR]
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- 2024
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16. Ti2C3 MXene-based nanocomposite as an intelligent nanoplatform for efficient mild hyperthermia treatment.
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Li, Bai, Fu, Gege, Liu, Chao, Lu, Yang, Mi, Yingqian, Yan, Dongmei, Wu, Jiahang, Dai, Xinhua, Cao, Dianbo, Liu, Wanchao, and Liu, Xiaomin
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HEAT shock proteins , *FEVER , *PHOTOTHERMAL conversion , *NANOCOMPOSITE materials , *TUMOR microenvironment - Abstract
The Ti 3 C 2 @Qu nanocomposites are constructed by utilizing the high photothermal conversion ability of Ti 3 C 2 nanosheets in combination with quercetin (Qu) as an inhibitor of heat shock protein 70 (HSP70). Qu molecules are loaded onto the nanoplatform in a pH-sensitive controlled release manner. The acidic environment of the tumor causes the burst-release of Qu molecules, which deplete the level of HSP70 in tumor cells and leave the tumor cells out from the protection of the heat-resistant survival pathway in advance, thus sensitizing the hyperthermia efficacy. [Display omitted] Photothermal therapy (PTT) has attracted much attention due to its less invasive, controllable and highly effective nature. However, PTT also suffers from intrinsic cancer resistance mediated by cell survival pathways. These survival pathways are regulated by a variety of proteins, among which heat shock protein (HSP) triggers thermotolerance and protects tumor cells from hyperthermia-induced apoptosis. Confronted by this challenge, we propose and validate here a novel MXene-based HSP-inhibited mild photothermal platform, which significantly enhances the sensitivity of tumor cells to heat-induced stress and thus improves the PPT efficacy. The Ti 3 C 2 @Qu nanocomposites are constructed by utilizing the high photothermal conversion ability of Ti 3 C 2 nanosheets in combination with quercetin (Qu) as an inhibitor of HSP70. Qu molecules are loaded onto the nanoplatform in a pH-sensitive controlled release manner. The acidic environment of the tumor causes the burst-release of Qu molecules, which deplete the level of heat shock protein 70 (HSP70) in tumor cells and leave the tumor cells out from the protection of the heat-resistant survival pathway in advance, thus sensitizing the hyperthermia efficacy. The nanostructure, photothermal properties, pH-responsive controlled release, synergistic photothermal ablation of tumor cells in vitro and in vivo, and hyperthermia effect on subcellular structures of the Ti 3 C 2 @Qu nanocomposites were systematically investigated. [ABSTRACT FROM AUTHOR]
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- 2024
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17. Mitochondria-targeted polyprodrug nanoparticles induce mitochondrial stress for immunogenic chemo-photodynamic therapy of ovarian cancer.
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Zhang, Wenjia, Chen, Gui, Chen, Ziqi, Yang, Xin, Zhang, Bingchen, Wang, Shengtao, Li, Zibo, Yang, Yuanyuan, Wu, Yifen, Liu, Zhigang, and Yu, Zhiqiang
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OVARIAN cancer , *MITOCHONDRIA , *CANCER treatment , *RHODAMINE B , *NANOPARTICLES , *PLANT mitochondria , *SEROUS fluids - Abstract
Hypoimmunogenicity and the immunosuppressive microenvironment of ovarian cancer severely restrict the capability of immune-mediated tumor killing. Immunogenic cell death (ICD) introduces a theoretical principle for antitumor immunity by increasing antigen exposure and presentation. Despite recent research progress, the currently available ICD inducers are still very limited, and many of them can hardly induce sufficient ICD based on traditional endoplasmic reticulum (ER) stress. Accumulating evidence indicates that inducing mitochondrial stress usually shows a higher efficiency in evoking large-scale ICD than that via ER stress. Inspired by this, herein, a mitochondria-targeted polyprodrug nanoparticle (named Mito-CMPN) serves as a much superior ICD inducer, effectively inducing chemo-photodynamic therapy-caused mitochondrial stress in tumor cells. The rationally designed stimuli-responsive polyprodrugs, which can self-assemble into nanoparticles, were functionalized with rhodamine B for mitochondrial targeting, cisplatin and mitoxantrone (MTO) for synergistic chemo-immunotherapy, and MTO also serves as a photosensitizer for photodynamic immunotherapy. The effectiveness and robustness of Mito-CMPNs in reversing the immunosuppressive microenvironment is verified in both an ovarian cancer subcutaneous model and a high-grade serous ovarian cancer model. Our results support that the induction of abundant ICD by focused mitochondrial stress is a highly effective strategy to improve the therapeutic efficacy of immunosuppressive ovarian cancer. A mitochondria-targeted polyprodrug nanoinducer (Mito-CMPN) was designed to simultaneously amplify immunogenic cell death of tumor cells and engineer the polarization of M2 to M1-like tumor-associated macrophages for both adaptive and innate immunity activation via immunogenic chemo-photodynamic therapy-induced mitochondrial stress to overcome the hypoimmunogenicity and immunosuppressive microenvironment of ovarian cancer. [Display omitted] • A mitochondria-targeted polyprodrug nanoinducer was developed as a superior ICD inducer to reprogram the immunosuppressive tumor microenvironment for ovarian cancer immunotherapy. • The superior nanoinducer could specifically target at mitochondria of tumor cells and induce mitochondrial stress by in situ photochemotherapy. • Such focused mitochondrial stress could induce large-scale ICD of tumor cells and trigger the polarization of M1 macrophages. [ABSTRACT FROM AUTHOR]
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- 2024
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18. Tumour‐associated neutrophils: Potential therapeutic targets in pancreatic cancer immunotherapy.
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Wu, Qihang, Mao, Han, Jiang, Zhengting, and Tang, Dong
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PANCREATIC cancer , *IMMUNOTHERAPY , *DRUG target , *NEUTROPHILS , *TUMOR microenvironment - Abstract
Pancreatic cancer (PC) is a highly malignant tumour of the digestive system with poor therapeutic response and low survival rates. Immunotherapy has rapidly developed in recent years and has achieved significant outcomes in numerous malignant neoplasms. However, responses to immunotherapy in PC are rare, and the immunosuppressive and desmoplastic tumour microenvironment (TME) significantly hinders their efficacy in PC. Tumour‐associated neutrophils (TANs) play a crucial role in the PC microenvironment and exert a profound influence on PC immunotherapy by establishing a robust stromal shelter and restraining immune cells to assist PC cells in immune escape, which may subvert the current status of PC immunotherapy. The present review aims to offer a comprehensive summary of the latest progress in understanding the involvement of TANs in PC desmoplastic and immunosuppressive functions and to emphasise the potential therapeutic implications of focusing on TANs in the immunotherapy of this deleterious disease. Finally, we provide an outlook for the future use of TANs in PC immunotherapy. [ABSTRACT FROM AUTHOR]
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- 2024
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19. Analysis of tumor microenvironment alterations in partially responsive rectal cancer patients treated with neoadjuvant chemoradiotherapy.
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Chen, Hong, Zhang, Ji-Hong, Hao, Qin, Wu, Xin-Lin, Guo, Jia-Xing, Huang, Cong-Xiu, Zhang, Jun, Xing, Guo-Sheng, An, Zhi-Lin, Ling, Yu, Zhao, Jian-Guo, and Bao, Ying-Na
- Abstract
Purpose: Achieving a pathologic complete response (pCR) after neoadjuvant chemoradiotherapy (NCRT) remains a challenge for most patients with rectal cancer. Exploring the potential of combining NCRT with immunotherapy or targeted therapy for those achieving a partial response (PR) offers a promising avenue to enhance treatment efficacy. This study investigated the impact of NCRT on the tumor microenvironment in locally advanced rectal cancer (LARC) patients who exhibited a PR. Methods: This was a retrospective, observational study. Five patients demonstrating a PR after neoadjuvant treatment for LARC were enrolled in the study. Biopsy samples before treatment and resected specimens after treatment were stained with a panel of 26 antibodies targeting various immune and tumor-related markers, each labeled with distinct metal tags. The labeled samples were then analyzed using the Hyperion imaging system. Results: Heterogeneity within the tumor microenvironment was observed both before and after NCRT. Notably, tumor-associated macrophages, CD4 + T cells, CD8 + T cells, CD56 + natural killer cells, tumor-associated neutrophils, cytokeratin, and E-cadherin exhibited slight increase in abundance within the tumor microenvironment following treatment (change ratios = 0.78, 0.2, 0.27, 0.32, 0.17, 0.46, 0.32, respectively). Conversely, the number of CD14 + monocytes, CD19 + B cells, CD45 + CD4 + T cells, collagen I, α-smooth muscle actin, vimentin, and β-catenin proteins displayed significant decreases post-treatment (change ratios = 1.73, 1.92, 1.52, 1.25, 1.52, 1.12, 2.66, respectively). Meanwhile, Foxp3 + regulatory cells demonstrated no significant change (change ratio = 0.001). Conclusions: NCRT has diverse effects on various components of the tumor microenvironment in LARC patients who achieve a PR after treatment. Leveraging combination therapies may optimize treatment outcomes in this patient population. [ABSTRACT FROM AUTHOR]
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- 2024
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20. Metal–organic framework (MOF)-based materials for pyroptosis-mediated cancer therapy.
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Dou, You, Wang, Yuting, Tian, Shu, Song, Qiao, Deng, Yun, Zhang, Zhipeng, Chen, PeiYao, and Sun, Yao
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METAL-organic frameworks , *CANCER treatment , *PYROPTOSIS , *DRUG resistance , *TUMOR microenvironment - Abstract
Pyroptosis is regarded as a promising strategy to modulate tumor immune microenvironments for anticancer therapy. Although pyroptosis inducers have been extensively explored in the biomedical field, their drug resistance, off-targeting capacity, and adverse effects do not fulfill the growing demands of therapy. Nowadays, metal–organic frameworks (MOFs) with unique structures and facile synthesis/functionalization characteristics have shown great potential in anticancer therapy. The flexible choices of metal ions and ligands endow MOFs with inherent anti-cancer efficiency, whereas the porous structures in MOFs make them ideal vehicles for delivering various chemodrug-based pyroptosis inducers. In this review, we provide the latest advances in MOF-based materials to evoke pyroptosis and give a brief but comprehensive review of the different types of MOFs for pyroptosis-mediated cancer therapy. Finally, we also discuss the current challenges of MOF-based pyroptosis inducers and their future prospects in this field. [ABSTRACT FROM AUTHOR]
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- 2024
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21. A chiral trimethyl lock based on the vicinal disubstituent effect: prolonged release of camptothecin into cancer cells.
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Venturi, Silvia, Chiaradonna, Ferdinando, Gatti, Francesco G., La Ferla, Barbara, Palorini, Roberta, and Zerbato, Barbara
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CAMPTOTHECIN , *CANCER cells , *HYDROLASES , *TUMOR microenvironment , *PANCREATIC cancer , *ANTINEOPLASTIC agents - Abstract
Synthesis and in vitro testing of a prodrug designed for the controlled delivery of the anticancer drug camptothecin within pancreatic cancer cells are reported. Our study reveals a non-conventional pharmacokinetic release characterized by an exponential pattern before reaching the half-life (t1/2) and a linear pattern thereafter. The release mechanism was triggered either by hydrolytic enzymes and/or by the acid microenvironment of cancer cells. [ABSTRACT FROM AUTHOR]
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- 2024
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22. Tumor-associated characteristics and immune dysregulation in nasopharyngeal carcinoma under the regulation of m7G-related tumor microenvironment cells.
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Long, Zhen, Li, Xiaochen, Deng, Wenmin, Tan, Yan, and Liu, Jie
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Background: Nasopharyngeal carcinoma (NPC) is a type of malignant tumor with high morbidity. Aberrant levels of N7-methylguanosine (m7G) are closely associated with tumor progression. However, the characteristics of the tumor microenvironment (TME) in NPC associated with m7G modification remain unclear. Methods: A total of 68,795 single cells from single-cell RNA sequencing data derived from 11 NPC tumor samples and 3 nasopharyngeal lymphatic hyperplasia (NLH) samples were clustered using a nonnegative matrix factorization algorithm according to 61 m7G RNA modification regulators. Results: The m7G regulators were found differential expression in the TME cells of NPC, and most m7G-related immune cell clusters in NPC tissues had a higher abundance compared to non-NPC tissues. Specifically, m7G scores in the CD4+ and CD8+ T cell clusters were significantly lower in NPC than in NLH. T cell clusters differentially expressed immune co-stimulators and co-inhibitors. Macrophage clusters differentially expressed EIF4A1, and high EIF4A1 expression was associated with poor survival in patients with head and neck squamous carcinoma. EIF4A1 was upregulated in NPC tissues compared to the non-NPC tissues and mainly expressed in CD86+ macrophages. Moreover, B cell clusters exhibited tumor biological characteristics under the regulation of m7G-related genes in NPC. The fibroblast clusters interacted with the above immune cell clusters and enriched tumor biological pathways, such as FGER2 signaling pathway. Importantly, there were correlations and interactions through various ligand-receptor links among epithelial cells and m7G-related TME cell clusters. Conclusion: Our study revealed tumor-associated characteristics and immune dysregulation in the NPC microenvironment under the regulation of m7G-related TME cells. These results demonstrated the underlying regulatory roles of m7G in NPC. [ABSTRACT FROM AUTHOR]
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- 2024
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23. Constructing a prognostic model for colon cancer: insights from immunity-related genes.
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Li, Ansu, Li, Qi, Wang, Chaoshan, Bao, Xue, Sun, Feng, Qian, Xiaoping, and Sun, Wu
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COLON cancer , *PROGNOSTIC models , *CANCER relapse , *TERTIARY structure , *OVERALL survival , *COLECTOMY - Abstract
Background: Colon cancer (CC) is a malignancy associated with significant morbidity and mortality within the gastrointestinal tract. Recurrence and metastasis are the main factors affecting the prognosis of CC patients undergoing radical surgery; consequently, we attempted to determine the impact of immunity-related genes. Result: We constructed a CC risk model based on ZG16, MPC1, RBM47, SMOX, CPM and DNASE1L3. Consistently, we found that a significant association was found between the expression of most characteristic genes and tumor mutation burden (TMB), microsatellite instability (MSI) and neoantigen (NEO). Additionally, a notable decrease in RBM47 expression was observed in CC tissues compared with that in normal tissues. Moreover, RBM47 expression was correlated with clinicopathological characteristics and improved disease-free survival (DFS) and overall survival (OS) among patients with CC. Lastly, immunohistochemistry and co-immunofluorescence staining revealed a clear positive correlation between RBM47 and CXCL13 in mature tertiary lymphoid structures (TLS) region. Conclusion: We conclude that RBM47 was identified as a prognostic-related gene, which was of great significance to the prognosis evaluation of patients with CC and was correlated with CXCL13 in the TLS region. [ABSTRACT FROM AUTHOR]
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- 2024
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24. Mechanisms underlying neutrophils adhesion to triple-negative breast cancer cells via CD11b-ICAM1 in promoting breast cancer progression.
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Yang, Chenghui, Li, Lili, Ye, Zhiqiang, Zhang, Anqi, Bao, Yunjia, Wu, Xue, Ren, Guohong, Jiang, Chao, Wang, Ouchen, and Wang, Zhen
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TRIPLE-negative breast cancer , *CELL adhesion , *BREAST cancer , *CANCER cells , *NEUTROPHILS , *CANCER invasiveness - Abstract
Background: Triple-negative breast cancer (TNBC) is recognized as the most aggressive and immunologically infiltrated subtype of breast cancer. A high circulating neutrophil-to-lymphocyte ratio (NLR) is strongly linked to a poor prognosis among patients with breast cancer, emphasizing the critical role of neutrophils. Although the involvement of neutrophils in tumor metastasis is well documented, their interactions with primary tumors and tumor cells are not yet fully understood. Methods: Clinical data were analyzed to investigate the role of neutrophils in breast cancer. In vivo mouse model and in vitro co-culture system were used for mechanism researches. Blocking experiments were further performed to identify therapeutic agents against TNBC. Results: TNBC cells secreted GM-CSF to sustain the survival of mature neutrophils and upregulated CD11b expression. Through CD11b, neutrophils specifically binded to ICAM1 on TNBC cells, facilitating adhesion. Transcriptomic sequencing combined with human and murine functional experiments revealed that neutrophils, through direct CD11b-ICAM1 interactions, activated the MAPK signaling pathway in TNBC cells, thereby enhancing tumor cell invasion and migration. Atorvastatin effectively inhibited ICAM1 expression in tumor cells, and tumor cells with ICAM1 knockout or treated with atorvastatin were unresponsive to neutrophil activation. The MAPK pathway and MMP9 expression were significantly inhibited in the tumor tissues of TNBC patients treated with atorvastatin. Conclusions: Targeting CD11b-ICAM1 with atorvastatin represented a potential clinical approach to reduce the malignant characteristics of TNBC. [ABSTRACT FROM AUTHOR]
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- 2024
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25. Integrin-linked kinase-frizzled 7 interaction maintains cancer stem cells to drive platinum resistance in ovarian cancer.
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Atwani, Rula, Nagare, Rohit Pravin, Rogers, Amber, Prasad, Mayuri, Lazar, Virginie, Sandusky, George, Tong, Yan, Pin, Fabrizio, and Condello, Salvatore
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CANCER stem cells , *OVARIAN cancer , *THERAPEUTICS , *PLATINUM , *EXTRACELLULAR matrix , *PEMETREXED , *FIBRONECTINS , *ACTIVATED protein C resistance - Abstract
Background: Platinum-based chemotherapy regimens are a mainstay in the management of ovarian cancer (OC), but emergence of chemoresistance poses a significant clinical challenge. The persistence of ovarian cancer stem cells (OCSCs) at the end of primary treatment contributes to disease recurrence. Here, we hypothesized that the extracellular matrix protects CSCs during chemotherapy and supports their tumorigenic functions by activating integrin-linked kinase (ILK), a key enzyme in drug resistance. Methods: TCGA datasets and OC models were investigated using an integrated proteomic and gene expression analysis and examined ILK for correlations with chemoresistance pathways and clinical outcomes. Canonical Wnt pathway components, pro-survival signaling, and stemness were examined using OC models. To investigate the role of ILK in the OCSC-phenotype, a novel pharmacological inhibitor of ILK in combination with carboplatin was utilized in vitro and in vivo OC models. Results: In response to increased fibronectin secretion and integrin β1 clustering, aberrant ILK activation supported the OCSC phenotype, contributing to OC spheroid proliferation and reduced response to platinum treatment. Complexes formed by ILK with the Wnt receptor frizzled 7 (Fzd7) were detected in tumors and correlated with metastatic progression. Moreover, TCGA datasets confirmed that combined expression of ILK and Fzd7 in high grade serous ovarian tumors is correlated with reduced response to chemotherapy and poor patient outcomes. Mechanistically, interaction of ILK with Fzd7 increased the response to Wnt ligands, thereby amplifying the stemness-associated Wnt/β-catenin signaling. Notably, preclinical studies showed that the novel ILK inhibitor compound 22 (cpd-22) alone disrupted ILK interaction with Fzd7 and CSC proliferation as spheroids. Furthermore, when combined with carboplatin, this disruption led to sustained AKT inhibition, apoptotic damage in OCSCs and reduced tumorigenicity in mice. Conclusions: This "outside-in" signaling mechanism is potentially actionable, and combined targeting of ILK-Fzd7 may lead to new therapeutic approaches to eradicate OCSCs and improve patient outcomes. [ABSTRACT FROM AUTHOR]
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- 2024
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26. Metabolic dialogues: regulators of chimeric antigen receptor T cell function in the tumor microenvironment.
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Moraly, Josquin, Kondo, Taisuke, Benzaoui, Mehdi, DuSold, Justyn, Talluri, Sohan, Pouzolles, Marie C., Chien, Christopher, Dardalhon, Valérie, and Taylor, Naomi
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T cells , *CHIMERIC antigen receptors , *CELL physiology , *T cell receptors , *TUMOR microenvironment , *T cell differentiation - Abstract
Tumor‐infiltrating lymphocytes (TILs) and chimeric antigen receptor (CAR) T cells have demonstrated remarkable success in the treatment of relapsed/refractory melanoma and hematological malignancies, respectively. These treatments have marked a pivotal shift in cancer management. However, as “living drugs,” their effectiveness is dependent on their ability to proliferate and persist in patients. Recent studies indicate that the mechanisms regulating these crucial functions, as well as the T cell's differentiation state, are conditioned by metabolic shifts and the distinct utilization of metabolic pathways. These metabolic shifts, conditioned by nutrient availability as well as cell surface expression of metabolite transporters, are coupled to signaling pathways and the epigenetic landscape of the cell, modulating transcriptional, translational, and post‐translational profiles. In this review, we discuss the processes underlying the metabolic remodeling of activated T cells, the impact of a tumor metabolic environment on T cell function, and potential metabolic‐based strategies to enhance T cell immunotherapy. [ABSTRACT FROM AUTHOR]
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- 2024
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27. Programmed cell death disrupts inflammatory tumor microenvironment (TME) and promotes glioblastoma evolution.
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Liang, Tingyu, Gu, Lingui, Kang, Xiaoman, Li, Junlin, Song, Yixuan, Wang, Yu, and Ma, Wenbin
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APOPTOSIS , *TUMOR microenvironment , *BRAIN tumors , *GLIOBLASTOMA multiforme , *CELL death - Abstract
Glioblastoma (GBM) is the most common malignant brain tumor and has a dismal prognosis even under the current first-line treatment, with a 5-year survival rate less than 7%. Therefore, it is important to understand the mechanism of treatment resistance and develop new anti-tumor strategies. Induction of programmed cell death (PCD) has become a promising anti-tumor strategy, but its effectiveness in treating GBM remains controversial. On the one hand, PCD triggers tumor cell death and then release mediators to draw in immune cells, creating a pro-inflammatory tumor microenvironment (TME). One the other hand, mounting evidence suggests that PCD and inflammatory TME will force tumor cells to evolve under survival stress, leading to tumor recurrence. The purpose of this review is to summarize the role of PCD and inflammatory TME in the tumor evolution of GBM and promising methods to overcome tumor evolution. [ABSTRACT FROM AUTHOR]
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- 2024
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28. Metformin‐Mediated Immunosuppressive Microenvironment Remodeling in Combination with Chemotherapy via a Spatial‐Specific Multi‐Responsive Carrier‐Free Self‐Assembled Nanoparticle.
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Song, Yujun, Du, Yufan, Hu, Chuan, Lei, Lei, Yang, Lianyi, Wang, Xiaorong, Jiang, Chaoqing, and Gao, Huile
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NANOPARTICLES , *COMBINATION drug therapy , *METFORMIN , *INTEGRINS , *DRUG delivery systems , *TUMOR microenvironment , *PEPTIDES - Abstract
The complex tumor immune pathology requires a precise spatial‐control release of the combination drugs, but most multi‐drug loaded nanoparticles release all drugs simultaneously in the tumor microenvironment (TME), making them difficult to reach the exact action site. To address the spatial specific release of drugs, a carrier‐free self‐assembled multi‐responsive nanodrug delivery system is designed, in which p‐phthalaldehyde (p‐APA) and dithiodipropionic acid are used to connect metformin (MET) and 7‐ethyl‐10‐hydroxycamptothecin (SN38) through a matrix metalloproteinase‐2 (MMP‐2) responsive peptide, and dipyridamole (DIP) is further loaded (MA‐GPLGVRGDK‐SS‐SN38@DIP, MR NPs). The MR NPs first target tumor by enhanced permeability and retention effect, then the highly expressed MMP‐2 at tumor site cleaves GPLGVRGDK, breaking the nanoparticle into three parts—DIP, MA‐GPLG, and VRGDK‐SS‐SN38. DIP automatically binds with platelets in TME, inhibiting their function and restraining tumor metastasis. MA‐GPLG releases MET in response to the acidic TME to reverse the immunosuppressive networks through PD‐L1 downregulation and M2‐like macrophages repolarization. Moreover, VRGDK‐SS‐SN38 binds to the overexpressed integrin αvβ3 receptor to achieve tumor cells specific delivery and precise killing. Overall, this study offers an intelligent spatial‐specific multi‐responsive carrier‐free drug delivery system in breast cancer, which releases drug spatial specifically, therefore reverses the tumor immunosuppressive microenvironment and inhibits metastasis. [ABSTRACT FROM AUTHOR]
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- 2024
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29. Interaction between CAFs and apoptotic cancer cells promotes OSCC proliferation via STING signaling.
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Yu, Qiuya, Huang, Xiaofeng, Zhang, Fei, Jin, Wanyong, Li, Ke, Xiao, Tao, Jing, Yue, Zhang, Xiaoxin, Song, Yuxian, Wang, Shuai, Hu, Qingang, and Ni, Yanhong
- Abstract
Background Objectives Methods Results Conclusion Apoptosis can fuel oncogenesis by the education of surrounding stromal cells. However, the function of cancer‐associated fibroblasts (CAFs), which interacted with apoptotic cancer cells, in oral squamous cell carcinoma (OSCC) progression is still unknown.This study aimed to explore the prognostic value of apoptosis and the biological effects of CAFs, interacted with apoptotic cancer cells, on OSCC.A total of 166 samples from OSCC patients were stained via TUNEL reaction to evaluate the correlation between apoptosis and clinical characteristics. Cell viability and proliferation were assessed through flow cytometry and CCK‐8 assays, respectively. Levels of mRNA and protein were examined through qRT‐PCR, western blot and immunofluorescence.Higher percentage of apoptotic cancer cells in OSCC positively correlated with more Ki67+ cells and predicted poor clinical outcomes. Conditioned medium from CAFs exposed to apoptotic cancer cells significantly facilitated cell proliferation. Co‐culture CAFs with apoptotic cancer cells dampened the phosphorylation of STING/IRF3 signaling, as well as the production of type I interferon, which was required for the inhibition of OSCC cell proliferation.These results demonstrate the interplay between apoptotic cancer cells and CAFs promotes OSCC proliferation via STING signaling, identifying a potential therapy targeted CAFs surrounded with apoptotic cancer cells for OSCC. [ABSTRACT FROM AUTHOR]
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- 2024
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30. A Bioinformatic Analysis of Gut Microbiota Related with Immune Cell Infiltration in Colorectal Cancer.
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Liu, Dan, Zhou, Jiang, Fu, Qiong, Zhao, Yuanzhu, Wang, Panpan, Zheng, Yang, Cui, Meihong, and Zhang, Heng
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AbstractObjectiveMethodsResultsConclusionThe composition of microbiota which correlates with infiltrating immune cells and clinical signatures is not clarified in CRC.We applied 4 kinds of bioinformatic tools GSVA (version: 1.42.0), ESTIMATE (version: 1.0.13), CIBERSORT (version: 2.0), and immune-related genes.We found that a total of 8 types of microbiotas appeared in the three immune correlation analyses. Among these microbiotas, significant enrichments in relative abundances associated with immune cell infiltration can be found for the dominant phyla Proteobacteria, Firmicutes, and Actinobacteria. Moreover, there existed correlations between some of the 8 microbiotas and clinical-related indicators.We identified some novel microbiotas involved in immune regulation in CRC. [ABSTRACT FROM AUTHOR]
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- 2024
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31. Exploratory mapping of tumor associated macrophage nanoparticle article abstracts using an eLDA topic modeling machine learning approach.
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Brown, Chloe, Bilynsky, Colette S. M., Gainey, Melanie, Young, Sarah, Kitchin, John, and Wayne, Elizabeth C.
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NANOPARTICLES , *MACHINE learning , *COMBINED modality therapy , *MACROPHAGES , *TUMOR microenvironment - Abstract
The role of macrophages in regulating the tumor microenvironment has spurned the exponential generation of nanoparticle targeting technologies. With the large amount of literature and the speed at which it is generated it is difficult to remain current with the most up-to-date literature. In this study we performed a topic modeling analysis of 854 abstracts of peer-reviewed literature for the most common usages of nanoparticle targeting of tumor associated macrophages (TAMs) in solid tumors. The data spans 20 years of literature, providing a broad perspective of the nanoparticle strategies. Our topic model found 6 distinct topics: Immune and TAMs, Nanoparticles, Imaging, Gene Delivery and Exosomes, Vaccines, and Multi-modal Therapies. We also found distinct nanoparticle usage, tumor types, and therapeutic trends across these topics. Moreover, we established that the topic model could be used to assign new papers into the existing topics, thereby creating a Living Review. This type of "birds-eye-view" analysis provides a useful assessment tool for exploring new and emerging themes within a large field. [ABSTRACT FROM AUTHOR]
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- 2024
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32. IFIT1 + neutrophil is a causative factor of immunosuppressive features of poorly cohesive carcinoma (PCC).
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Liu, Yuan-jie, Li, Jie-pin, Han, Mei, Li, Jing-xiao, Ye, Qian-wen, Lin, Si-tian, Zhou, Jin-yong, Liu, Shen-lin, and Zou, Xi
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NEUTROPHILS , *CARCINOMA , *TUMOR microenvironment , *FIBROBLASTS , *STOMACH cancer - Abstract
The importance of the immune microenvironment in poorly cohesive carcinoma (PCC) has been highlighted due to its limited response rate to conventional therapy and emerging treatment resistance. A combination of clinical cohorts, bioinformatics analyses, and functional/molecular experiments revealed that high infiltration of Interferon Induced Protein with Tetratricopeptide Repeats 1 (IFIT1) + tumor-associated neutrophils (TANs) is a distinguishing feature of PCC patients. Upregulation of IFIT1 + TANs promote migration and invasion of gastric cancer (GC) cell lines (MKN45 and MKN74) and stimulates the growth of cell-derived xenograft models. Besides, by promoting macrophage secreted phosphoprotein 1 (SPP1) expression and facilitating cancer-associated fibroblast and endothelial cell recruitment and activation through TANs, IFIT1 promotes a mesenchymal phenotype, which is associated with a poor prognosis. Importantly, compared to non-PCC (NPCC), PCC tumors is more immunosuppressive. Mechanistically, IFIT1 can be stimulated by IFN-γ and contributes to the expression of Programmed Cell Death 1 Ligand (PDL1) in TANs. We demonstrated in mouse models that IFIT1 + PDL1 + TANs can induce acquired resistance to anti-PD-1 immunotherapy, which may be responsible for the difficulty of PCC patients to benefit from immunotherapy. This work highlights the role of IFIT1 + TANs in mediating the remodeling of the tumor immune microenvironment and immunotherapeutic resistance and introduces IFIT1 + TANs as a promising target for precision therapy of PCC. [ABSTRACT FROM AUTHOR]
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- 2024
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33. Tumor microenvironment responsive nano-herb and CRISPR delivery system for synergistic chemotherapy and immunotherapy.
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Jia, Yuanyuan, Yao, Yuhui, Fan, Lingyao, Huang, Qiqing, Wei, Guohao, Shen, Peiliang, Sun, Jia, Zhu, Gaoshuang, Sun, Zhaorui, Zhu, Chuandong, and Han, Xin
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TUMOR microenvironment , *DOXORUBICIN , *CRISPRS , *IMMUNOTHERAPY , *PHOSPHOPROTEIN phosphatases , *GENOME editing , *PROTEIN-tyrosine phosphatase - Abstract
Chemoresistance remains a significant challenge for effective breast cancer treatment which leads to cancer recurrence. CRISPR-directed gene editing becomes a powerful tool to reduce chemoresistance by reprogramming the tumor microenvironment. Previous research has revealed that Chinese herbal extracts have significant potential to overcome tumor chemoresistance. However, the therapeutic efficacy is often limited due to their poor tumor targeting and in vivo durability. Here we have developed a tumor microenvironment responsive nanoplatform (H-MnO2(ISL + DOX)-PTPN2@HA, M(I + D)PH) for nano-herb and CRISPR codelivery to reduce chemoresistance. Synergistic tumor inhibitory effects were achieved by the treatment of isoliquiritigenin (ISL) with doxorubicin (DOX), which were enhanced by CRISPR-based gene editing to target protein tyrosine phosphatase non-receptor type 2 (PTPN2) to initiate long-term immunotherapy. Efficient PTPN2 depletion was observed after treatment with M(I + D)PH nanoparticles, which resulted in the recruitment of intratumoral infiltrating lymphocytes and an increase of proinflammatory cytokines in the tumor tissue. Overall, our nanoparticle platform provides a diverse technique for accomplishing synergistic chemotherapy and immunotherapy, which offers an effective treatment alternative for malignant neoplasms. [ABSTRACT FROM AUTHOR]
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- 2024
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34. Disulfidptosis-related genes serve as potential prognostic biomarkers and indicate tumor microenvironment characteristics and immunotherapy response in prostate cancer.
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Zhou, Rongbin, Lu, Dingjin, Mi, Junhao, Wang, Chengbang, Lu, Wenhao, Wang, Zuheng, Li, Xiao, Wei, Chunmeng, Zhang, Huiyong, Ji, Jin, Zhang, Yifeng, Zhang, Duobing, and Wang, Fubo
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PROGNOSIS , *TREATMENT effectiveness , *TUMOR microenvironment , *DISEASE risk factors , *PROSTATE cancer , *PROSTATE-specific antigen , *TUMOR suppressor genes - Abstract
Disulfidptosis, a newly identified programmed cell death pathway in prostate cancer (PCa), is closely associated with intracellular disulfide stress and glycolysis. This study aims to elucidate the roles of disulfidptosis-related genes (DRGs) in the pathogenesis and progression of PCa, with the goal of improving diagnostic and therapeutic approaches. We analyzed PCa datasets and normal tissue transcriptome data from TCGA, GEO, and MSKCC. Using consensus clustering analysis and LASSO regression, we developed a risk scoring model, which was validated in an independent cohort. The model's predictive accuracy was confirmed through Kaplan–Meier curves, receiver operating characteristic (ROC) curves, and nomograms. Additionally, we explored the relationship between the risk score and immune cell infiltration, and examined the tumor microenvironment and somatic mutations across different risk groups. We also investigated responses to immunotherapy and drug sensitivity. Our analysis identified two disulfidosis subtypes with significant differences in survival, immune environments, and treatment responses. According to our risk score, the high-risk group exhibited poorer progression-free survival (PFS) and higher tumor mutational burden (TMB), associated with increased immune suppression. Functional enrichment analysis linked high-risk features to key cancer pathways, including the IL-17 signaling pathway. Moreover, drug sensitivity analysis revealed varied responses to chemotherapy, suggesting the potential for disulfidosis-based personalized treatment strategies. Notably, we identified PROK1 as a crucial prognostic marker in PCa, with its reduced expression correlating with disease progression. In summary, our study comprehensively assessed the clinical implications of DRGs in PCa progression and prognosis, offering vital insights for tailored precision medicine approaches. [ABSTRACT FROM AUTHOR]
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- 2024
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35. Multi-omics profiling reveal cells with novel oncogenic cluster, TRAP1low/CAMSAP3low, emerge more aggressive behavior and poor-prognosis in early-stage endometrial cancer.
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Mao, Xiaodan, Tang, Xiaoyue, Ye, Jingxuan, Xu, Shuxia, Wang, Yue, Liu, Xianhua, Wu, Qibin, Lin, Xite, Zhang, Maotong, Liu, Jiangfeng, Yang, Juntao, and Sun, Pengming
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ENDOMETRIAL cancer , *MULTIOMICS , *TUMOR necrosis factors , *ENDOMETRIAL tumors , *MYELOID cells , *SURVIVAL rate - Abstract
The clinical heterogeneity of early-stage endometrial cancer (EC) is worthy of further study to identify high-quality prognostic markers and their potential role in aggressive tumor behavior. Mutation of TP53 was considered as an important primary triage in modified molecular typing for EC, it still cannot precisely predict the prognosis of EC. After proteomic analysis of cancer and para-cancerous tissues from 24 early-stage endometrioid EC patients with different survival outcomes, 13 differentially expressed proteins were screen out while 2 proteins enriched in p53 signaling pathway were further identified by single-cell transcriptome (scRNA-seq). Interestingly, tumor necrosis factor type-1 receptor-associated protein (TRAP1) and calmodulin-regulated spectrin-associated protein family member 3 (CAMSAP3) were found to be significantly downregulated in the specific cell cluster. Expectedly, the signature genes of TRAP1low/CAMSAP3low cluster included classical oncogenes. Moreover, close cellular interactions were observed between myeloid cells and the TRAP1low/CAMSAP3low cluster after systematically elucidating their relationship with tumor microenvironment (TME). The expression of TRAP1 and CAMSAP3 was verified by immunohistochemistry. Thus, a novel prediction model combining TRAP1, CAMSAP3 and TP53 was construct by multi-omics. Compared with the area under the curve, it demonstrated a significantly improvemrnt in the diagnostic efficacy in EC patients from TCGA bank. In conclusion, this work improved the current knowledge regarding the prognosis of early-stage EC through proteomics and scRNA-seq. These findings may lead to improvements in precise risk stratification of early-stage EC patients. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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- View/download PDF
36. Single-cell analysis identifies PLK1 as a driver of immunosuppressive tumor microenvironment in LUAD.
- Author
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Kong, Yifan, Li, Chaohao, Liu, Jinpeng, Wu, Sai, Zhang, Min, Allison, Derek B., Hassan, Faisal, He, Daheng, Wang, Xinyi, Mao, Fengyi, Zhang, Qiongsi, Zhang, Yanquan, Li, Zhiguo, Wang, Chi, and Liu, Xiaoqi
- Subjects
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TUMOR microenvironment , *IMMUNOREGULATION , *ANTIGEN presentation , *MAJOR histocompatibility complex , *IMMUNE system , *T cell receptors - Abstract
PLK1 (Polo-like kinase 1) plays a critical role in the progression of lung adenocarcinoma (LUAD). Recent studies have unveiled that targeting PLK1 improves the efficacy of immunotherapy, highlighting its important role in the regulation of tumor immunity. Nevertheless, our understanding of the intricate interplay between PLK1 and the tumor microenvironment (TME) remains incomplete. Here, using genetically engineered mouse model and single-cell RNA-seq analysis, we report that PLK1 promotes an immunosuppressive TME in LUAD, characterized with enhanced M2 polarization of tumor associated macrophages (TAM) and dampened antigen presentation process. Mechanistically, elevated PLK1 coincides with increased secretion of CXCL2 cytokine, which promotes M2 polarization of TAM and diminishes expression of class II major histocompatibility complex (MHC-II) in professional antigen-presenting cells. Furthermore, PLK1 negatively regulates MHC-II expression in cancer cells, which has been shown to be associated with compromised tumor immunity and unfavorable patient outcomes. Taken together, our results reveal PLK1 as a novel modulator of TME in LUAD and provide possible therapeutic interventions. Author summary: Our research has pinpointed a vital protein, PLK1, in the development of lung cancer. Through the use of mouse models simulating the onset of lung cancer and genetic sequencing analysis, we've discovered that high level of PLK1 hinders the immune response, making it challenging for the patient's immune system to effectively eliminate lung cancer. Elevated PLK1 level specifically increases the presence of M2 macrophages, a type of immune cell, which, in turn, prevents the immune system from recognizing and attacking lung cancer cells. We've identified that this immune-suppressing effect is linked to PLK1's role in secreting a specific molecule called CXCL2. This molecule promotes the presence of M2 macrophages and hampers the recognition of cancer cells by decreasing the machinery that presents the cancer cells' signature to the immune system, known as MHC-II. These findings suggest that drugs targeting PLK1 could be a promising strategy for treating lung cancer patients. [ABSTRACT FROM AUTHOR]
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- 2024
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37. Epigenetic regulation of tumor immunity.
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Lizhi Pang, Fei Zhou, Yang Liu, Heba Ali, Fatima Khan, Heimberger, Amy B., and Peiwen Chen
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IMMUNOREGULATION , *IMMUNE checkpoint inhibitors , *EPIGENETICS , *CANCER invasiveness , *TUMOR microenvironment - Abstract
Although cancer has long been considered a genetic disease, increasing evidence shows that epigenetic aberrations play a crucial role in affecting tumor biology and therapeutic response. The dysregulated epigenome in cancer cells reprograms the immune landscape within the tumor microenvironment, thereby hindering antitumor immunity, promoting tumor progression, and inducing immunotherapy resistance. Targeting epigenetically mediated tumor-immune crosstalk is an emerging strategy to inhibit tumor progression and circumvent the limitations of current immunotherapies, including immune checkpoint inhibitors. In this Review, we discuss the mechanisms by which epigenetic aberrations regulate tumorimmune interactions and how epigenetically targeted therapies inhibit tumor progression and synergize with immunotherapy. [ABSTRACT FROM AUTHOR]
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- 2024
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- View/download PDF
38. Manganese-derived biomaterials for tumor diagnosis and therapy.
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Huang, Peiying, Tang, Qinglai, Li, Mengmeng, Yang, Qian, Zhang, Yuming, Lei, Lanjie, and Li, Shisheng
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TUMOR diagnosis , *MAGNETIC resonance imaging , *ACOUSTIC imaging , *ULTRASONIC imaging , *BIOMATERIALS , *TUMOR microenvironment , *PHOTOACOUSTIC effect - Abstract
Manganese (Mn) is widely recognized owing to its low cost, non-toxic nature, and versatile oxidation states, leading to the emergence of various Mn-based nanomaterials with applications across diverse fields, particularly in tumor diagnosis and therapy. Systematic reviews specifically addressing the tumor diagnosis and therapy aspects of Mn-derived biomaterials are lacking. This review comprehensively explores the physicochemical characteristics and synthesis methods of Mn-derived biomaterials, emphasizing their role in tumor diagnostics, including magnetic resonance imaging, photoacoustic and photothermal imaging, ultrasound imaging, multimodal imaging, and biodetection. Moreover, the advantages of Mn-based materials in tumor treatment applications are discussed, including drug delivery, tumor microenvironment regulation, synergistic photothermal, photodynamic, and chemodynamic therapies, tumor immunotherapy, and imaging-guided therapy. The review concludes by providing insights into the current landscape and future directions for Mn-driven advancements in the field, serving as a comprehensive resource for researchers and clinicians. [ABSTRACT FROM AUTHOR]
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- 2024
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39. Unraveling the intricacies of cancer‐associated fibroblasts: a comprehensive review on metabolic reprogramming and tumor microenvironment crosstalk.
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Ahuja, Sana, Sureka, Niti, and Zaheer, Sufian
- Abstract
Cancer‐associated fibroblasts (CAFs) are crucial component of tumor microenvironment (TME) which undergo significant phenotypic changes and metabolic reprogramming, profoundly impacting tumor growth. This review delves into CAF plasticity, diverse origins, and the molecular mechanisms driving their continuous activation. Emphasis is placed on the intricate bidirectional crosstalk between CAFs and tumor cells, promoting cancer cell survival, proliferation, invasion, and immune evasion. Metabolic reprogramming, a cancer hallmark, extends beyond cancer cells to CAFs, contributing to the complex metabolic interplay within the TME. The ‘reverse Warburg effect’ in CAFs mirrors the Warburg effect, involving the export of high‐energy substrates to fuel cancer cells, supporting their rapid proliferation. Molecular regulations by key players like p53, Myc, and K‐RAS orchestrate this metabolic adaptation. Understanding the metabolic symbiosis between CAFs and tumor cells opens avenues for targeted therapeutic strategies to disrupt this dynamic crosstalk. Unraveling CAF‐mediated metabolic reprogramming provides valuable insights for developing novel anticancer therapies. This comprehensive review consolidates current knowledge, shedding light on CAFs' multifaceted roles in the TME and offering potential targets for future therapies. [ABSTRACT FROM AUTHOR]
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- 2024
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40. ALKBH5 promotes non-small cell lung cancer progression and susceptibility to anti-PD-L1 therapy by modulating interactions between tumor and macrophages.
- Author
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Hua, Xin, Xu, Qiuli, Wu, Ranpu, Sun, Wei, Gu, Yanli, Zhu, Suhua, Liu, Xin, Lv, Tangfeng, and Song, Yong
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NON-small-cell lung carcinoma , *CANCER invasiveness , *PROGRAMMED death-ligand 1 , *RNA methylation ,CANCER susceptibility - Abstract
Background: Understanding the mechanisms that mediate the interaction between tumor and immune cells may provide therapeutic benefit to patients with cancer. The N6-methyladenosine (m6A) demethylase, ALKBH5 (alkB homolog 5), is overexpressed in non-small cell lung cancer. However, its role in the tumor microenvironment is unknown. Methods: Datasets and tissue samples were used to determine the relationship between ALKBH5 expression and immunotherapy efficacy. Bioinformatic analysis, colorimetric assay to determine m6A RNA methylation, dual luciferase reporter assay, RNA/m6A-modified RNA immunoprecipitation, RNA stability assay, and RNA sequencing were used to investigate the regulatory mechanism of ALKBH5 in non-small cell lung cancer. In vitro and in vivo assays were performed to determine the contribution of ALKBH5 to the development of non-small cell lung cancer. Results: ALKBH5 was upregulated in primary non-small cell lung cancer tissues. ALKBH5 was positively correlated with programmed death-ligand 1 expression and macrophage infiltration and was associated with immunotherapy response. JAK2 was identified as a target of ALKBH5-mediated m6A modification, which activates the JAK2/p-STAT3 pathway to promote non-small cell lung cancer progression. ALKBH5 was found to recruit programmed death-ligand 1-positive tumor-associated macrophages and promote M2 macrophage polarization by inducing the secretion of CCL2 and CXCL10. ALKBH5 and tumor-associated macrophage-secreted IL-6 showed a synergistic effect to activate the JAK2/p-STAT3 pathway in cancer cells. Conclusions: ALKBH5 promotes non-small cell lung cancer progression by regulating cancer and tumor-associated macrophage behavior through the JAK2/p-STAT3 pathway and the expression of CCL2 and CXCL10, respectively. These findings suggest that targeting ALKBH5 is a promising strategy of enhancing the anti-tumor immune response in patients with NSCLC and that identifying ALKBH5 status could facilitate prediction of clinical response to anti-PD-L1 immunotherapy. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
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41. Using random forests to uncover the predictive power of distance-varying cell interactions in tumor microenvironments.
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VanderDoes, Jeremy, Marceaux, Claire, Yokote, Kenta, Asselin-Labat, Marie-Liesse, Rice, Gregory, and Hywood, Jack D.
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FALSE discovery rate , *TUMOR microenvironment , *RANDOM forest algorithms , *TRIPLE-negative breast cancer , *SURVIVAL analysis (Biometry) , *MACHINE learning , *STATISTICAL learning , *STATISTICAL significance , *SPECIFIC gravity - Abstract
Tumor microenvironments (TMEs) contain vast amounts of information on patient's cancer through their cellular composition and the spatial distribution of tumor cells and immune cell populations. Exploring variations in TMEs between patient groups, as well as determining the extent to which this information can predict outcomes such as patient survival or treatment success with emerging immunotherapies, is of great interest. Moreover, in the face of a large number of cell interactions to consider, we often wish to identify specific interactions that are useful in making such predictions. We present an approach to achieve these goals based on summarizing spatial relationships in the TME using spatial K functions, and then applying functional data analysis and random forest models to both predict outcomes of interest and identify important spatial relationships. This approach is shown to be effective in simulation experiments at both identifying important spatial interactions while also controlling the false discovery rate. We further used the proposed approach to interrogate two real data sets of Multiplexed Ion Beam Images of TMEs in triple negative breast cancer and lung cancer patients. The methods proposed are publicly available in a companion R package funkycells. Author summary: Spatial data on the tumor microenvironment (TME) are becoming more prevalent. Existing methods to interrogate such data often have several limitations: (1) they can rely on estimating the spatial relationships among cells by examining simple counts of cells within a single radius, (2) they may not come with ways to evaluate the statistical significance of any findings, or (3) they model individual interactions independently of other interactions. Our approach leverages techniques in spatial statistics and uses a benchmark ensemble machine learning method to address each of these deficiencies; it (1) uses K functions to encode the relative densities of cells over all radii up to a user-selected maximum radius, (2) employs permutation and cross-validation to evaluate the statistical significance of any findings on the spatial interactions in the TME, and (3) models multiple interactions simultaneously. Our approach is freely available with an R implementation called funkycells. In the analysis of two real data sets, we have seen that the method performs well, and gives the expected results. We think this will be a robust tool for researchers looking to interrogate TME data. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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42. Prognostic and predictive value of examined lymph node count in stage III colorectal cancer: a population based study.
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Wei, Ran, Zheng, Zifan, Li, Qinghai, Qian, Yan, Wu, Chong, Li, Yin, Wang, Mian, Chen, Jianhui, and He, Weiling
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- *
PROGNOSIS , *COLORECTAL cancer , *LYMPH nodes , *OVERALL survival , *DNA microarrays , *PROGRESSION-free survival , *IMMUNOTHERAPY - Abstract
Background: The role of tumor-draining lymph nodes in the progression of malignant tumors, including stage III colorectal cancer (CRC), is critical. However, the prognostic and predictive value of the number of examined lymph nodes (ELNs) are not fully understood. Methods: This population-based study retrospectively analyzed data from 106,843 patients with stage III CRC who underwent surgical treatment and registered in three databases from 2004 to 2021. The Surveillance, Epidemiology, and End Results (SEER) cohort was divided using into training and test cohorts at a ratio of 3:2. We employed restricted cubic spline (RCS) curves to explore nonlinear relationships between overall survival (OS) and ELNs counts and performed Cox regression to evaluate hazard ratios across different ELNs count subtypes. Additional validation cohorts were utilized from the First Affiliated Hospital, Sun Yat-sen University and The Cancer Genome Atlas (TCGA) under the same criteria. Outcomes measured included OS, cancer-specific survival (CSS), and progression-free survival (PFS). Molecular analyses involved differential gene expression using the "limma" package and immune profiling through CIBERSORT. Tissue microarray slides and multiplex immunofluorescence (MIF) were used to assess protein expression and immune cell infiltration. Results: Patients with higher ELNs counts (≥ 17) demonstrated significantly better long-term survival outcomes across all cohorts. Enhanced OS, CSS, and PFS were notably evident in the LN-ELN group compared to those with fewer ELNs. Cox regression models underscored the prognostic value of higher ELNs counts across different patient subgroups by age, sex, tumor differentiation, and TNM stages. Subtype analysis based on ELNs count revealed a marked survival benefit in patients treated with adjuvant chemotherapy in the medium and large ELNs counts (≥ 12), whereas those with fewer ELNs showed negligible benefits. RNA sequencing and MIF indicated elevated immune activation in the LN-ELN group, characterized by increased CD3+, CD4+, and CD8 + T cells within the tumor microenvironment. Conclusions: The number of ELNs independently predicts survival and the immunological landscape at the tumor site in stage III CRC, underscoring its dual prognostic and predictive value. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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43. Imaging at the nexus: how state of the art imaging techniques can enhance our understanding of cancer and fibrosis.
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Baniasadi, Alireza, Das, Jeeban P., Prendergast, Conor M., Beizavi, Zahra, Ma, Hong Y., Jaber, Muhammad Yaman, and Capaccione, Kathleen M.
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ART techniques , *MAGNETIC resonance imaging , *POSITRON emission tomography , *SECOND harmonic generation , *COMPUTED tomography - Abstract
Both cancer and fibrosis are diseases involving dysregulation of cell signaling pathways resulting in an altered cellular microenvironment which ultimately leads to progression of the condition. The two disease entities share common molecular pathophysiology and recent research has illuminated the how each promotes the other. Multiple imaging techniques have been developed to aid in the early and accurate diagnosis of each disease, and given the commonalities between the pathophysiology of the conditions, advances in imaging one disease have opened new avenues to study the other. Here, we detail the most up-to-date advances in imaging techniques for each disease and how they have crossed over to improve detection and monitoring of the other. We explore techniques in positron emission tomography (PET), magnetic resonance imaging (MRI), second generation harmonic Imaging (SGHI), ultrasound (US), radiomics, and artificial intelligence (AI). A new diagnostic imaging tool in PET/computed tomography (CT) is the use of radiolabeled fibroblast activation protein inhibitor (FAPI). SGHI uses high-frequency sound waves to penetrate deeper into the tissue, providing a more detailed view of the tumor microenvironment. Artificial intelligence with the aid of advanced deep learning (DL) algorithms has been highly effective in training computer systems to diagnose and classify neoplastic lesions in multiple organs. Ultimately, advancing imaging techniques in cancer and fibrosis can lead to significantly more timely and accurate diagnoses of both diseases resulting in better patient outcomes. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
44. Immune profiling of mouse lung adenocarcinoma paraffin tissues using multiplex immunofluorescence panel: a pilot study.
- Author
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Zhai, Jie, Tamegnon, Auriole, Jiang, Mei, Pandurengan, Renganayaki Krishna, and Parra, Edwin Roger
- Subjects
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LUNGS , *IMMUNOFLUORESCENCE , *PROGNOSIS , *IMMUNE checkpoint inhibitors , *CANCER cells , *PARAFFIN wax - Abstract
Background: Immune profiling has become an important tool for identifying predictive, prognostic and response biomarkers for immune checkpoint inhibitors from tumor microenvironment (TME). We aimed to build a multiplex immunofluorescence (mIF) panel to apply to formalin-fixed and paraffin-embedded tissues in mice tumors and to explore the programmed cell death protein 1/ programmed cell death 1 ligand 1 (PD-1/PD-L1) axis. Results: An automated eight-color mIF panel was evaluated to study the TME using seven antibodies, including cytokeratin 19, CD3e, CD8a, CD4, PD-1, PD-L1, F4-80 and DAPI, then was applied in six mice lung adenocarcinoma samples. Cell phenotypes were quantified by software to explore the co-localization and spatial distribution between immune cells within the TME. This mice panel was successfully optimized and applied to a small cohort of mice lung adenocarcinoma cases. Image analysis showed a sparse degree of immune cell expression pattern in this cohort. From the spatial analysis we found that T cells and macrophages expressing PD-L1 were close to the malignant cells and other immune cells. Conclusions: Comprehensive immune profiling using mIF in translational studies improves our ability to correlate the PD-1/PD-L1 axis and spatial distribution of lymphocytes and macrophages in mouse lung cancer cells to provide new cues for immunotherapy, that can be translated to human tumors for cancer intervention. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
45. Harnessing Metal Nanoparticles: Revolutionizing Cancer Therapy Through Targeted Drug Delivery and Tumor Microenvironment Modulation.
- Author
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Dudhat, Kiran
- Abstract
Cancer remains a significant global health burden, claiming countless lives annually and incurring substantial direct and indirect economic costs. Despite advancements in therapeutic modalities, conventional cancer treatments, including chemotherapy, radiotherapy and surgery, are often hampered by limitations such as insufficient efficacy, dose-dependent side effects, high costs and patient tolerability. This has spurred extensive research into novel therapeutic approaches for this life-threatening disease. Metal nanoparticles (MNPs) have emerged as promising tools in cancer therapy due to their unique physicochemical properties spanning the past two decades. Owing to their size similarity to biological molecules, MNPs possess the inherent ability to penetrate cellular barriers, making them ideal carriers for targeted drug delivery. These multifunctional nanoplatforms offer distinct advantages over conventional therapeutics by enabling targeted delivery of anticancer agents to specific tumor sites, thereby enhancing therapeutic efficacy and minimizing systemic side effects. Photodynamic therapy and sonodynamic therapy represent particularly promising strategies that leverage MNPs for cancer treatment. This review delves into the potential applications of MNPs in modulating the tumor microenvironment, paving the way for the exploration of this vast and rapidly evolving field of nanomedicine. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
46. PDE1B, a potential biomarker associated with tumor microenvironment and clinical prognostic significance in osteosarcoma.
- Author
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Chen, Qingzhong, Xing, Chunmiao, Zhang, Qiaoyun, Du, Zhijun, Kong, Jian, and Qian, Zhongwei
- Subjects
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OSTEOSARCOMA , *TUMOR suppressor genes , *TUMOR microenvironment , *GENE expression , *CALCIUM channels , *BIOMARKERS - Abstract
PDE1B had been found to be involved in various diseases, including tumors and non-tumors. However, little was known about the definite role of PDE1B in osteosarcoma. Therefore, we mined public data on osteosarcoma to reveal the prognostic values and immunological roles of the PDE1B gene. Three osteosarcoma-related datasets from online websites were utilized for further data analysis. R 4.3.2 software was utilized to conduct difference analysis, prognostic analysis, gene set enrichment analysis (GSEA), nomogram construction, and immunological evaluations, respectively. Experimental verification of the PDE1B gene in osteosarcoma was conducted by qRT-PCR and western blot, based on the manufacturer's instructions. The PDE1B gene was discovered to be lowly expressed in osteosarcoma, and its low expression was associated with poor OS (all P < 0.05). Experimental verifications by qRT-PCR and western blot results remained consistent (all P < 0.05). Univariate and multivariate Cox regression analyses indicated that the PDE1B gene had independent abilities in predicting OS in the TARGET osteosarcoma dataset (both P < 0.05). GSEA revealed that PDE1B was markedly linked to the calcium, cell cycle, chemokine, JAK STAT, and VEGF pathways. Moreover, PDE1B was found to be markedly associated with immunity (all P < 0.05), and the TIDE algorithm further shed light on that patients with high-PDE1B expression would have a better immune response to immunotherapies than those with low-PDE1B expression, suggesting that the PDE1B gene could prevent immune escape from osteosarcoma. The PDE1B gene was found to be a tumor suppressor gene in osteosarcoma, and its high expression was related to a better OS prognosis, suppressing immune escape from osteosarcoma. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
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47. Adipocyte pyroptosis occurs in omental tumor microenvironment and is associated with chemoresistance of ovarian cancer.
- Author
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Lin, Chang-Ni, Liang, Yu-Ling, Tsai, Hsing-Fen, Wu, Pei-Ying, Huang, Lan-Yin, Lin, Yu-Han, Kang, Chieh-Yi, Yao, Chao-Ling, Shen, Meng-Ru, and Hsu, Keng-Fu
- Subjects
- *
OVARIAN cancer , *PYROPTOSIS , *FAT cells , *TUMOR microenvironment , *DRUG resistance in cancer cells , *ADIPOSE tissue diseases - Abstract
Background: Ovarian carcinoma (OC) is a fatal malignancy, with most patients experiencing recurrence and resistance to chemotherapy. In contrast to hematogenous metastasizing tumors, ovarian cancer cells disseminate within the peritoneal cavity, especially the omentum. Previously, we reported omental crown-like structure (CLS) number is associated with poor prognosis of advanced-stage OC. CLS that have pathologic features of a dead or dying adipocyte was surrounded by several macrophages is well known a histologic hallmark for inflammatory adipose tissue. In this study, we attempted to clarify the interaction between metastatic ovarian cancer cells and omental CLS, and to formulate a therapeutic strategy for advanced-stage ovarian cancer. Methods: A three-cell (including OC cells, adipocytes and macrophages) coculture model was established to mimic the omental tumor microenvironment (TME) of ovarian cancer. Caspase-1 activity, ATP and free fatty acids (FFA) levels were detected by commercial kits. An adipocyte organoid model was established to assess macrophages migration and infiltration. In vitro and in vivo experiments were performed for functional assays and therapeutic effect evaluations. Clinical OC tissue samples were collected for immunochemistry stain and statistics analysis. Results: In three-cell coculture model, OC cells-derived IL-6 and IL-8 could induce the occurrence of pyroptosis in omental adipocytes. The pyroptotic adipocytes release ATP to increase macrophage infiltration, release FFA into TME, uptake by OC cells to increase chemoresistance. From OC tumor samples study, we demonstrated patients with high gasdermin D (GSDMD) expression in omental adipocytes is highly correlated with chemoresistance and poor outcome in advanced-stage OC. In animal model, by pyroptosis inhibitor, DSF, effectively retarded tumor growth and prolonged mice survival. Conclusions: Omental adipocyte pyroptosis may contribute the chemoresistance in advanced stage OC. Omental adipocytes could release FFA and ATP through the GSDMD-mediate pyroptosis to induce chemoresistance and macrophages infiltration resulting the poor prognosis in advanced-stage OC. Inhibition of adipocyte pyroptosis may be a potential therapeutic modality in advanced-stage OC with omentum metastasis. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
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48. Comprehensive characterization of B7 family members in breast cancer: B7-H5 switch reverses breast cancer from "immuno-cold" into "immuno-hot" status.
- Author
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Liu, Jiayu, Wang, Cenzhu, Jiang, Ying, Zhou, Yunxu, Chen, Lingyan, Qian, Zhiwen, Liu, Lu, Wu, Danping, and Zhang, Yan
- Subjects
- *
BREAST cancer , *IMMUNOTHERAPY , *BRCA genes , *RNA sequencing , *MICROARRAY technology , *TUMOR microenvironment , *FAMILIES - Abstract
The members of the classic B7 family regulate the immune microenvironment of several malignant tumors. However, the potential relationship between the B7 family and the breast cancer (BrCa) tumor immune microenvironment has remained elusive. In the present study, we provide a comprehensive explanation of the expression, clinical significance, mutation, and immune cell infiltration of B7 family molecules in BrCa. First, we recruited 10 patients with BrCa surgery from the Wuxi Maternal and Child Health Hospital and performed single-cell RNA sequencing (scRNA-seq) analysis to investigate the distribution of B7 family members in multiple immune cell subsets. We focused on B7-2, B7-H3, and B7-H5 molecules of the B7 family and constructed tumor microarrays by self-recruiting patients to perform multiple immunohistochemical (mIHC) analyses and study tumor expression of B7-2, B7-H3, B7-H5 and CD8+ immune cell infiltration. B7-H5 displayed a strong correlation with CD8+ immune cell infiltration. In summary, B7-H5 provides a new perspective for the identification of immunothermal subtypes of BrCa and could function as a switch to reverse BrCa from an "immunologically cold" state to an "immunologically hot" state. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
49. Artificial intelligence.
- Author
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Gerstung, Moritz, Liu, David, Ghassemi, Marzyeh, Zou, James, Chowell, Diego, Teuwen, Jonas, Mahmood, Faisal, and Kather, Jakob Nikolas
- Subjects
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ARTIFICIAL intelligence , *TUMOR microenvironment , *CELLULAR evolution , *CANCER cells - Abstract
Experts discuss the challenges and opportunities of using artificial intelligence (AI) to study the evolution of cancer cells and their microenvironment, improve diagnosis, predict treatment response, and ensure responsible implementation in the clinic. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
50. Tensile Strain‐Mediated Bimetallene Nanozyme for Enhanced Photothermal Tumor Catalytic Therapy.
- Author
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Wu, Jiandong, Liu, Qihui, Jiao, Dongxu, Tian, Bin, Wu, Qiong, Chang, Xin, Chu, Hongyu, Jiang, Shan, Yang, Qi, Liu, Tao, Zhang, Yue, Zhang, Wei, Fan, Jinchang, Cui, Xiaoqiang, and Chen, Fangfang
- Subjects
- *
PHOTOTHERMAL effect , *GEOMETRIC quantum phases , *GEOMETRIC analysis , *ELECTRON diffraction , *TUMOR microenvironment , *ENZYME kinetics , *ACETYLCOENZYME A - Abstract
Nanozymes have demonstrated significant potential in combating malignant tumor proliferation through catalytic therapy. However, the therapeutic effect is often limited by insufficient catalytic performance. In this study, we propose the utilization of strain engineering in metallenes to fully expose the active regions due to their ultrathin nature. Here, we present the first report on a novel tensile strain‐mediated local amorphous RhRu (la‐RhRu) bimetallene with exceptional intrinsic photothermal effect and photo‐enhanced multiple enzyme‐like activities. Through geometric phase analysis, electron diffraction profile, and X‐ray diffraction, it is revealed that crystalline‐amorphous heterophase boundaries can generate approximately 2 % tensile strain in the bimetallene. The ultrathin structure and in‐plane strain of the bimetallene induce an amplified strain effect. Both experimental and theoretical evidence support the notion that tensile strain promotes multiple enzyme‐like activities. Functioning as a tumor microenvironment (TME)‐responsive nanozyme, la‐RhRu exhibits remarkable therapeutic efficacy both in vitro and in vivo. This work highlights the tremendous potential of atomic‐scale tensile strain engineering strategy in enhancing tumor catalytic therapy. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
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