Displaying publications 61 - 80 of 91 in total

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  1. Adenosine Receptors as Novel Targets for the Treatment of Various Cancers
    Gorain B, Choudhury H, Yee GS, Bhattamisra SK
    Curr Pharm Des, 2019;25(26):2828-2841.
    PMID: 31333092 DOI: 10.2174/1381612825666190716102037
    Adenosine is a ubiquitous signaling nucleoside molecule, released from different cells within the body to act on vasculature and immunoescape. The physiological action on the proliferation of tumour cell has been reported by the presence of high concentration of adenosine within the tumour microenvironment, which results in the progression of the tumour, even leading to metastases. The activity of adenosine exclusively depends upon the interaction with four subtypes of heterodimeric G-protein-coupled adenosine receptors (AR), A1, A2A, A2B, and A3-ARs on the cell surface. Research evidence supports that the activation of those receptors via specific agonist or antagonist can modulate the proliferation of tumour cells. The first category of AR, A1 is known to play an antitumour activity via tumour-associated microglial cells to prevent the development of glioblastomas. A2AAR are found in melanoma, lung, and breast cancer cells, where tumour proliferation is stimulated due to inhibition of the immune response via inhibition of natural killer cells cytotoxicity, T cell activity, and tumourspecific CD4+/CD8+ activity. Alternatively, A2BAR helps in the development of tumour upon activation via upregulation of angiogenin factor in the microvascular endothelial cells, inhibition of MAPK and ERK 1/2 phosphorylation activity. Lastly, A3AR is expressed in low levels in normal cells whereas the expression is upregulated in tumour cells, however, agonists to this receptor inhibit tumour proliferation through modulation of Wnt and NF-κB signaling pathways. Several researchers are in search for potential agents to modulate the overexpressed ARs to control cancer. Active components of A2AAR antagonists and A3AR agonists have already entered in Phase-I clinical research to prove their safety in human. This review focused on novel research targets towards the prevention of cancer progression through stimulation of the overexpressed ARs with the hope to protect lives and advance human health.
    Matched MeSH terms: Tumor Microenvironment
  2. Targeting Legumain As a Novel Therapeutic Strategy in Cancers
    Mai CW, Chung FF, Leong CO
    Curr Drug Targets, 2017;18(11):1259-1268.
    PMID: 27993111 DOI: 10.2174/1389450117666161216125344
    BACKGROUND: Recent reports indicate that the tumor microenvironment plays a pivotal role in cancer development and progression, leading to a paradigm shift in the way cancer is studied and targeted. In contrast to traditional approaches, where only tumor cells are targeted for the treatment, an emerging approach is to develop therapeutics which target the tumor microenvironment while complementing or enhancing current treatments. Legumain (LGMN) is a newly identified target which is highly expressed in the tumor microenvironment and in tumor cells, and holds potential both as a biomarker and as a therapeutic target.

    CONCLUSION: This review will be the first to summarize the expression of LGMN in common cancers, as well as its roles in tumorigenesis and metastasis. This review also discusses the current developments and future prospects of targeting LGMN through the development of DNA vaccines, azopeptides, small molecule inhibitors and LGMN activated prodrugs, highlighting the potential of LGMN as a target for cancer therapeutics.

    Matched MeSH terms: Tumor Microenvironment
  3. Hydrogel-based methods for engineering cellular microenvironment with spatiotemporal gradients
    Wang L, Li Y, Huang G, Zhang X, Pingguan-Murphy B, Gao B, et al.
    Crit Rev Biotechnol, 2016 Jun;36(3):553-65.
    PMID: 25641330 DOI: 10.3109/07388551.2014.993588
    Natural cellular microenvironment consists of spatiotemporal gradients of multiple physical (e.g. extracellular matrix stiffness, porosity and stress/strain) and chemical cues (e.g. morphogens), which play important roles in regulating cell behaviors including spreading, proliferation, migration, differentiation and apoptosis, especially for pathological processes such as tumor formation and progression. Therefore, it is essential to engineer cellular gradient microenvironment incorporating various gradients for the fabrication of normal and pathological tissue models in vitro. In this article, we firstly review the development of engineering cellular physical and chemical gradients with cytocompatible hydrogels in both two-dimension and three-dimension formats. We then present current advances in the application of engineered gradient microenvironments for the fabrication of disease models in vitro. Finally, concluding remarks and future perspectives for engineering cellular gradients are given.
    Matched MeSH terms: Tumor Microenvironment
  4. Regulating tumor microenvironments by a lymph node-targeting adjuvant via tumor-specific CTL-derived IFNγ
    Xu X, Yi C, Feng T, Ge Y, Liu M, Wu C, et al.
    Clin Immunol, 2023 Aug;253:109685.
    PMID: 37406980 DOI: 10.1016/j.clim.2023.109685
    Inducing tumor-specific T cell responses and regulating suppressive tumor microenvironments have been a challenge for effective tumor therapy. CpG (ODN), the Toll-like receptor 9 agonist, has been widely used as adjuvants of cancer vaccines to induce T cell responses. We developed a novel adjuvant to improve the targeting of lymph nodes. CpG were modified with lipid and glycopolymers by the combination of photo-induced RAFT polymerization and click chemistry, and the novel adjuvant was termed as lipid-glycoadjuvant@AuNPs (LCpG). OVA protein was used as model antigen and melanoma model was established to test the immunotherapy effect of the adjuvant. In tumor model, the antitumor effect and mechanism of LCpG on the response of CTLs were examined by flow cytometry and cell cytotoxicity assay. The effects of LCpG on macrophage polarization and Tregs differentiation in tumor microenvironment were also studied by cell depletion assay and cytokine neutralization assay. We also tested the therapeutic effect of the combination of the adjuvant and anti-PD-1 treatment. LCpG could be rapidly transported to and retained longer in the lymphoid nodes than unmodified CpG. In melanoma model, LCpG controlled both primary tumor and its metastasis, and established long-term memory. In spleen and tumor draining lymphoid nodes, LCpG activated tumor-specific Tc1 responses, with increased CD8+ T-cell proliferation, antigen-specific Tc1 cytokine production and specific-tumor killing capacity. In tumor microenvironments, antigen-specific Tc1 induced by the LCpG promoted CTL infiltration, skewed tumor associated macrophages to M1 phenotype, regulated Treg and induced proinflammatory cytokines production in a CTL-derived IFN-γ-dependent manner. In vivo cell depletion and adoptive transfer experiments confirmed that antitumor activity of LCpG included vaccine was mainly dependent on CTL-derived IFN-γ. The anti-tumor efficacy of LCpG was dramatically enhanced when combined with anti-PD1 immunotherapy. LCpG was a promising adjuvant for vaccine formulation which could augment tumor-specific Tc1 activity, and regulate tumor microenvironments.
    Matched MeSH terms: Tumor Microenvironment
  5. Fulltext Harnessing the power of memory-like NK cells to fight cancer
    Foo YY, Tiah A, Aung SW
    Clin Exp Immunol, 2023 Jun 05;212(3):212-223.
    PMID: 36866467 DOI: 10.1093/cei/uxad030
    Natural killer (NK) cells possess the innate ability to eliminate cancerous cells effectively. Their crucial role in immunosurveillance has been widely recognized and exploited for therapeutic intervention. Despite the fast-acting nature of NK cells, NK adoptive cell transfer lacks favorable response in some patients. Patient NK cells often display diminished phenotype in preventing cancer progression resulting in poor prognosis. Tumor microenvironment plays a significant role in causing the downfall of NK cells in patients. The release of inhibitory factors by tumor microenvironment hinders normal function of NK cells against tumor. To overcome this challenge, therapeutic strategies such as cytokine stimulation and genetic manipulation are being investigated to improve NK tumor-killing capacity. One of the promising approaches includes generation of more competent NK cells via ex vivo cytokines activation and proliferation. Cytokine-induced ML-NK demonstrated phenotypic alterations such as enhanced expression of activating receptors which help elevate their antitumor response. Previous preclinical studies showed enhanced cytotoxicity and IFNγ production in ML-NK cells compared to normal NK cells against malignant cells. Similar effects are shown in clinical studies in which MK-NK demonstrated encouraging results in treating hematological cancer. However, there is still a lack of in-depth studies using ML-NK in treating different types of tumors and cancers. With convincing preliminary response, this cell-based approach could be used to complement other therapeutic modalities to achieve better clinical outcomes.
    Matched MeSH terms: Tumor Microenvironment
  6. Fulltext Hydroxychloroquine: Key therapeutic advances and emerging nanotechnological landscape for cancer mitigation
    Low LE, Kong CK, Yap WH, Siva SP, Gan SH, Siew WS, et al.
    Chem Biol Interact, 2023 Dec 01;386:110750.
    PMID: 37839513 DOI: 10.1016/j.cbi.2023.110750
    Hydroxychloroquine (HCQ) is a unique class of medications that has been widely utilized for the treatment of cancer. HCQ plays a dichotomous role by inhibiting autophagy induced by the tumor microenvironment (TME). Preclinical studies support the use of HCQ for anti-cancer therapy, especially in combination with conventional anti-cancer treatments since they sensitize tumor cells to drugs, potentiating the therapeutic activity. However, clinical evidence has suggested poor outcomes for HCQ due to various obstacles, including non-specific distribution, low aqueous solubility and low bioavailability at target sites, transport across tissue barriers, and retinal toxicity. These issues are addressable via the integration of HCQ with nanotechnology to produce HCQ-conjugated nanomedicines. This review aims to discuss the pharmacodynamic, pharmacokinetic and antitumor properties of HCQ. Furthermore, the antitumor performance of the nanoformulated HCQ is also reviewed thoroughly, aiming to serve as a guide for the HCQ-based enhanced treatment of cancers. The nanoencapsulation or nanoconjugation of HCQ with nanoassemblies appears to be a promising method for reducing the toxicity and improving the antitumor efficacy of HCQ.
    Matched MeSH terms: Tumor Microenvironment
  7. miRNAs as key modulators between normal cells and tumor microenvironment interactions
    Nour SM, Abbasi N, Sadi S, Ravan N, Alipourian A, Yarizadeh M, et al.
    Chem Biol Drug Des, 2023 Oct;102(4):939-950.
    PMID: 37402595 DOI: 10.1111/cbdd.14285
    The tumor microenvironment (TME) is well-defined target for understanding tumor progression and various cell types. Major elements of the tumor microenvironment are the followings: endothelial cells, fibroblasts, signaling molecules, extracellular matrix, and infiltrating immune cells. MicroRNAs (miRNAs) are a group of small noncoding RNAs with major functions in the gene expression regulation at post-transcriptional level that have also appeared to exerts key functions in the cancer initiation/progression in diverse biological processes and the tumor microenvironment. This study summarized various roles of miRNAs in the complex interactions between the tumor and normal cells in their microenvironment.
    Matched MeSH terms: Tumor Microenvironment/genetics
  8. DNA Morphology: Global Alteration of DNA Topological States Induced by Chemotherapeutic Agents and Its Implication in Cancer
    Ahammed KS, Pachal S, Majumdar P, Dutta S
    Chembiochem, 2023 Apr 17;24(8):e202200715.
    PMID: 36747378 DOI: 10.1002/cbic.202200715
    The dynamic topological states of chromosomal DNA regulate many cellular fundamental processes universally in all three domains of life, that is, bacteria, archaea, and eukaryotes. DNA-binding proteins maintain the regional and global supercoiling of the chromosome and thereby regulate the chromatin architecture that ultimately influences the gene expression network and other DNA-centric molecular events in various microenvironments and growth phases. DNA-binding small molecules are pivotal weapons for treating a wide range of cancers. Recent advances in single-molecule biophysical tools have uncovered the fact that many DNA-binding ligands not only alter the regional DNA supercoiling but also modulate the overall morphology of DNA. Here we provide insight into recent advances in atomic force microscopy (AFM) acquired DNA structural change induced by therapeutically important mono- and bis-intercalating anticancer agents as well as DNA-adduct-forming anticancer drugs. We also emphasize the growing evidence of the mechanistic relevance of changes in DNA topology in the anticancer cellular responses of DNA-targeting chemotherapeutic agents.
    Matched MeSH terms: Tumor Microenvironment
  9. The multifaceted role of exosomes in cancer progression: diagnostic and therapeutic implications [corrected]
    Sundararajan V, Sarkar FH, Ramasamy TS
    Cell Oncol (Dordr), 2018 06;41(3):223-252.
    PMID: 29667069 DOI: 10.1007/s13402-018-0378-4
    BACKGROUND: Recent advances in cancer biology have highlighted the relevance of exosomes and nanovesicles as carriers of genetic and biological messages between cancer cells and their immediate and/or distant environments. It has been found that these molecular cues may play significant roles in cancer progression and metastasis. Cancer cells secrete exosomes containing diverse molecules that can be transferred to recipient cells and/or vice versa to induce a plethora of biological processes, including angiogenesis, metastasis formation, therapeutic resistance, epithelial-mesenchymal transition and epigenetic/stemness (re)programming. While exosomes interact with cells within the tumour microenvironment to promote tumour growth, these vesicles can also facilitate the process of distant metastasis by mediating the formation of pre-metastatic niches. Next to their tumour promoting effects, exosomes have been found to serve as potential tools for cancer diagnosis and therapy. The ease of isolating exosomes and their content from different body fluids has led to the identification of diagnostic and prognostic biomarker signatures, as well as to predictive biomarker signatures for therapeutic responses. Exosomes can also be used as cargos to deliver therapeutic anti-cancer drugs, and they can be engineered to serve as vaccines for immunotherapy. Additionally, it has been found that inhibition of exosome secretion, and thus the transfer of oncogenic molecules, holds promise for inhibiting tumour growth. Here we provide recent information on the diverse roles of exosomes in various cellular and systemic processes governing cancer progression, and discuss novel strategies to halt this progression using exosome-based targeted therapies and methods to inhibit exosome secretion and the transfer of pro-tumorigenic molecules.

    CONCLUSIONS: This review highlights the important role of exosomes in cancer progression and its implications for (non-invasive) diagnostics and the development of novel therapeutic strategies, as well as its current and future applications in clinical trials.

    Matched MeSH terms: Tumor Microenvironment
  10. Fulltext CD36-Fatty Acid-Mediated Metastasis via the Bidirectional Interactions of Cancer Cells and Macrophages
    Zaidi NE, Shazali NAH, Leow TC, Osman MA, Ibrahim K, Cheng WH, et al.
    Cells, 2022 Nov 10;11(22).
    PMID: 36428985 DOI: 10.3390/cells11223556
    Tumour heterogeneity refers to the complexity of cell subpopulations coexisting within the tumour microenvironment (TME), such as proliferating tumour cells, tumour stromal cells and infiltrating immune cells. The bidirectional interactions between cancer and the surrounding microenvironment mark the tumour survival and promotion functions, which allow the cancer cells to become invasive and initiate the metastatic cascade. Importantly, these interactions have been closely associated with metabolic reprogramming, which can modulate the differentiation and functions of immune cells and thus initiate the antitumour response. The purpose of this report is to review the CD36 receptor, a prominent cell receptor in metabolic activity specifically in fatty acid (FA) uptake, for the metabolic symbiosis of cancer-macrophage. In this review, we provide an update on metabolic communication between tumour cells and macrophages, as well as how the immunometabolism indirectly orchestrates the tumour metastasis.
    Matched MeSH terms: Tumor Microenvironment
  11. Fulltext Cephalomannine inhibits hypoxia-induced cellular function via the suppression of APEX1/HIF-1α interaction in lung cancer
    Ullah A, Leong SW, Wang J, Wu Q, Ghauri MA, Sarwar A, et al.
    Cell Death Dis, 2021 05 14;12(5):490.
    PMID: 33990544 DOI: 10.1038/s41419-021-03771-z
    Lung cancer (LC) is one of the leading causes of cancer-related death. As one of the key features of tumor microenvironment, hypoxia conditions are associated with poor prognosis in LC patients. Upregulation of hypoxic-induced factor-1α (HIF-1α) leads to the activation of various factors that contribute to the increased drug resistance, proliferation, and migration of tumor cells. Apurinic/apyrimidinic endonuclease-1 (APEX1) is a multi-functional protein that regulates several transcription factors, including HIF-1α, that contribute to tumor growth, oxidative stress responses, and DNA damage. In this study, we explored the mechanisms underlying cell responses to hypoxia and modulation of APEX1, which regulate HIF-1α and downstream pathways. We found that hypoxia-induced APEX1/HIF-1α pathways regulate several key cellular functions, including reactive oxygen species (ROS) production, carbonic anhydrase 9 (CA9)-mediated intracellular pH, migration, and angiogenesis. Cephalomannine (CPM), a natural compound, exerted inhibitory effects in hypoxic LC cells via the inhibition of APEX1/HIF-1α interaction in vitro and in vivo. CPM can significantly inhibit cell viability, ROS production, intracellular pH, and migration in hypoxic LC cells as well as angiogenesis of HUVECs under hypoxia through the inhibition of APEX1/HIF-1α interaction. Taken together, CPM could be considered as a promising compound for LC treatment.
    Matched MeSH terms: Tumor Microenvironment
  12. Dual role of mesenchymal stem/stromal cells and their cell-free extracellular vesicles in colorectal cancer
    Saadh MJ, Mohamed AH, Almoyad MAA, Allela OQB, Amin AH, Malquisto AA, et al.
    Cell Biochem Funct, 2024 Mar;42(2):e3962.
    PMID: 38491792 DOI: 10.1002/cbf.3962
    Colorectal cancer (CRC) is one of the main causes of cancer-related deaths. However, the surgical control of the CRC progression is difficult, and in most cases, the metastasis leads to cancer-related mortality. Mesenchymal stem/stromal cells (MSCs) with potential translational applications in regenerative medicine have been widely researched for several years. MSCs could affect tumor development through secreting exosomes. The beneficial properties of stem cells are attributed to their cell-cell interactions as well as the secretion of paracrine factors in the tissue microenvironment. For several years, exosomes have been used as a cell-free therapy to regulate the fate of tumor cells in a tumor microenvironment. This review discusses the recent advances and current understanding of assessing MSC-derived exosomes for possible cell-free therapy in CRC.
    Matched MeSH terms: Tumor Microenvironment
  13. Fulltext Is targeting autophagy mechanism in cancer a good approach? The possible double-edge sword effect
    Lim SM, Mohamad Hanif EA, Chin SF
    Cell Biosci, 2021 Mar 20;11(1):56.
    PMID: 33743781 DOI: 10.1186/s13578-021-00570-z
    Autophagy is a conserved cellular process required to maintain homeostasis. The hallmark of autophagy is the formation of a phagophore that engulfs cytosolic materials for degradation and recycling to synthesize essential components. Basal autophagy is constitutively active under normal conditions and it could be further induced by physiological stimuli such as hypoxia, nutrient starvation, endoplasmic reticulum stress,energy depletion, hormonal stimulation and pharmacological treatment. In cancer, autophagy is highly context-specific depending on the cell type, tumour microenvironment, disease stage and external stimuli. Recently, the emerging role of autophagy as a double-edged sword in cancer has gained much attention. On one hand, autophagy suppresses malignant transformation by limiting the production of reactive oxygen species and DNA damage during tumour development. Subsequently, autophagy evolved to support the survival of cancer cells and promotes the tumourigenicity of cancer stem cells at established sites. Hence, autophagy is an attractive target for cancer therapeutics and researchers have been exploiting the use of autophagy modulators as adjuvant therapy. In this review, we present a summary of autophagy mechanism and controlling pathways, with emphasis on the dual-role of autophagy (double-edged sword) in cancer. This is followed by an overview of the autophagy modulation for cancer treatment and is concluded by a discussion on the current perspectives and future outlook of autophagy exploitation for precision medicine.
    Matched MeSH terms: Tumor Microenvironment
  14. Fulltext The effect of environmental chemicals on the tumor microenvironment
    Casey SC, Vaccari M, Al-Mulla F, Al-Temaimi R, Amedei A, Barcellos-Hoff MH, et al.
    Carcinogenesis, 2015 Jun;36 Suppl 1:S160-83.
    PMID: 26106136 DOI: 10.1093/carcin/bgv035
    Potentially carcinogenic compounds may cause cancer through direct DNA damage or through indirect cellular or physiological effects. To study possible carcinogens, the fields of endocrinology, genetics, epigenetics, medicine, environmental health, toxicology, pharmacology and oncology must be considered. Disruptive chemicals may also contribute to multiple stages of tumor development through effects on the tumor microenvironment. In turn, the tumor microenvironment consists of a complex interaction among blood vessels that feed the tumor, the extracellular matrix that provides structural and biochemical support, signaling molecules that send messages and soluble factors such as cytokines. The tumor microenvironment also consists of many host cellular effectors including multipotent stromal cells/mesenchymal stem cells, fibroblasts, endothelial cell precursors, antigen-presenting cells, lymphocytes and innate immune cells. Carcinogens can influence the tumor microenvironment through effects on epithelial cells, the most common origin of cancer, as well as on stromal cells, extracellular matrix components and immune cells. Here, we review how environmental exposures can perturb the tumor microenvironment. We suggest a role for disrupting chemicals such as nickel chloride, Bisphenol A, butyltins, methylmercury and paraquat as well as more traditional carcinogens, such as radiation, and pharmaceuticals, such as diabetes medications, in the disruption of the tumor microenvironment. Further studies interrogating the role of chemicals and their mixtures in dose-dependent effects on the tumor microenvironment could have important general mechanistic implications for the etiology and prevention of tumorigenesis.
    Matched MeSH terms: Tumor Microenvironment/drug effects*
  15. A miRNA-145/TGF-β1 negative feedback loop regulates the cancer-associated fibroblast phenotype
    Melling GE, Flannery SE, Abidin SA, Clemmens H, Prajapati P, Hinsley EE, et al.
    Carcinogenesis, 2018 05 28;39(6):798-807.
    PMID: 29506142 DOI: 10.1093/carcin/bgy032
    The dissemination of cancer cells to local and distant sites depends on a complex and poorly understood interplay between malignant cells and the cellular and non-cellular components surrounding them, collectively termed the tumour microenvironment. One of the most abundant cell types of the tumour microenvironment is the fibroblast, which becomes corrupted by locally derived cues such as TGF-β1 and acquires an altered, heterogeneous phenotype (cancer-associated fibroblasts, CAF) supportive of tumour cell invasion and metastasis. Efforts to develop new treatments targeting the tumour mesenchyme are hampered by a poor understanding of the mechanisms underlying the development of CAF. Here, we examine the contribution of microRNA to the development of experimentally-derived CAF and correlate this with changes observed in CAF derived from tumours. Exposure of primary normal human fibroblasts to TGF-β1 resulted in the acquisition of a myofibroblastic CAF-like phenotype. This was associated with increased expression of miR-145, a miRNA predicted in silico to target multiple components of the TGF-β signalling pathway. miR-145 was also overexpressed in CAF derived from oral cancers. Overexpression of miR-145 blocked TGF-β1-induced myofibroblastic differentiation and reverted CAF towards a normal fibroblast phenotype. We conclude that miR-145 is a key regulator of the CAF phenotype, acting in a negative feedback loop to dampen acquisition of myofibroblastic traits, a key feature of CAF associated with poor disease outcome.
    Matched MeSH terms: Tumor Microenvironment/physiology
  16. A single targeted gamma-ray irradiation induced an acute modulation of immune cells and related cytokines in EMT6 mouse-bearing tumour model
    Hasan N, Hasani NAH, Omar E, Sham FR, Fuad SBSA, Karim MKA, et al.
    Cancer Biomark, 2023;38(1):61-75.
    PMID: 37522193 DOI: 10.3233/CBM-220268
    BACKGROUND: A complicated interplay between radiation doses, tumour microenvironment (TME), and host immune system is linked to the active participation of immune response.

    OBJECTIVE: The effects of single targeted 2 Gy and 8 Gy gamma-ray irradiations on the immune cell population (lymphocytes, B-cells, T-cells, neutrophils, eosinophils, and macrophages) in EMT6 mouse-bearing tumour models was investigated.

    METHODS: The effects of both irradiation doses in early (96 hours) and acute phase (5 to 11 days) post-irradiation on immune parameters were monitored in blood circulation and TME using flow cytometry. Simultaneously, selected cytokines related to immune cells within the TME were measured using multiplex ELISA.

    RESULTS: A temporary reduction in systemic total white blood count (TWBC) resulted from an early phase (96 hours) of gamma-ray irradiation at 2 Gy and 8 Gy compared to sham control group. No difference was obtained in the acute phase. Neutrophils dominated among other immune cells in TME in sham control group. Eosinophils in TME was significantly increased after 8 Gy treatment in acute phase compared to sham control (p< 0.005). Furthermore, the increment of tumour necrosis (TNF)-α, eotaxin and interleukin (IL)-7 (p< 0.05) in both treatment groups and phases were associated with anti-tumour activities within TME by gamma-ray irradiation.

    CONCLUSION: The temporary changes in immune cell populations within systemic circulation and TME induced by different doses of gamma-ray irradiation correlated with suppression of several pro-tumorigenic cytokines in mouse-bearing EMT6 tumour models.

    Matched MeSH terms: Tumor Microenvironment
  17. Fulltext Lipopolysaccharide (LPS) stimulation of Pancreatic Ductal Adenocarcinoma (PDAC) and macrophages activates the NLRP3 inflammasome that influences the levels of pro-inflammatory cytokines in a co-culture model
    Sivam HGP, Chin BY, Gan SY, Ng JH, Gwenhure A, Chan EWL
    Cancer Biol Ther, 2023 Dec 31;24(1):2284857.
    PMID: 38018872 DOI: 10.1080/15384047.2023.2284857
    Modified macrophages, tumor-associated macrophages (TAMs), are key contributors to the survival, growth, and metastatic behavior of pancreatic ductal adenocarcinoma (PDAC) cells. Central to the role of inflammation and TAMs lies the NLRP3 inflammasome. This study investigated the effects of LPS-stimulated inflammation on cell proliferation, levels of pro-inflammatory cytokines, and the NLRP3 inflammasome pathway in a co-culture model using PDAC cells and macrophages in the presence or absence of MCC950, a NLRP3-specific inhibitor. The effects of LPS-stimulated inflammation were tested on two PDAC cell lines (Panc 10.05 and SW 1990) co-cultured with RAW 264.7 macrophages. Cell proliferation was determined using the MTT assay. Levels of pro-inflammatory cytokines, IL-1β, and TNF-α were determined by ELISA. Western blot analyses were used to examine the expression of NLRP3 in both PDAC cells and macrophages. The co-culture and interaction between PDAC cell lines and macrophages led to pro-inflammatory microenvironment under LPS stimulation as evidenced by high levels of secreted IL-1β and TNF-α. Inhibition of the NLRP3 inflammasome by MCC950 counteracted the effects of LPS stimulation on the regulation of the NLRP3 inflammasome and pro-inflammatory cytokines in PDAC and macrophages. However, MCC950 differentially modified the viability of the metastatic vs primary PDAC cell lines. LPS stimulation increased PDAC cell viability by regulating the NLRP3 inflammasome and pro-inflammatory cytokines in the tumor microenvironment of PDAC cells/macrophages co-cultures. The specific inhibition of the NLRP inflammasome by MCC950 effectively counteracted the LPS-stimulated inflammation.
    Matched MeSH terms: Tumor Microenvironment
  18. Fulltext Role of exosomes as a proinflammatory mediator in the development of EBV-associated lymphoma
    Higuchi H, Yamakawa N, Imadome KI, Yahata T, Kotaki R, Ogata J, et al.
    Blood, 2018 06 07;131(23):2552-2567.
    PMID: 29685921 DOI: 10.1182/blood-2017-07-794529
    Epstein-Barr virus (EBV) causes various diseases in the elderly, including B-cell lymphoma such as Hodgkin's lymphoma and diffuse large B-cell lymphoma. Here, we show that EBV acts in trans on noninfected macrophages in the tumor through exosome secretion and augments the development of lymphomas. In a humanized mouse model, the different formation of lymphoproliferative disease (LPD) between 2 EBV strains (Akata and B95-8) was evident. Furthermore, injection of Akata-derived exosomes affected LPD severity, possibly through the regulation of macrophage phenotype in vivo. Exosomes collected from Akata-lymphoblastoid cell lines reportedly contain EBV-derived noncoding RNAs such as BamHI fragment A rightward transcript (BART) micro-RNAs (miRNAs) and EBV-encoded RNA. We focused on the exosome-mediated delivery of BART miRNAs. In vitro, BART miRNAs could induce the immune regulatory phenotype in macrophages characterized by the gene expressions of interleukin 10, tumor necrosis factor-α, and arginase 1, suggesting the immune regulatory role of BART miRNAs. The expression level of an EBV-encoded miRNA was strongly linked to the clinical outcomes in elderly patients with diffuse large B-cell lymphoma. These results implicate BART miRNAs as 1 of the factors regulating the severity of lymphoproliferative disease and as a diagnostic marker for EBV+ B-cell lymphoma.
    Matched MeSH terms: Tumor Microenvironment
  19. Functionalized chitosan for cancer nano drug delivery
    Zaiki Y, Iskandar A, Wong TW
    Biotechnol Adv, 2023 Oct;67:108200.
    PMID: 37331671 DOI: 10.1016/j.biotechadv.2023.108200
    Chitosan is a biotechnological derivative of chitin receiving a widespread pharmaceutical and biomedical applications. It can be used to encapsulate and deliver cancer therapeutics with inherent pH-dependent solubility to confer drug targeting at tumour microenvironment and anti-cancer activity synergizing cancer cytotoxic drug actions. To further reduce the off-target and by-stander adverse effects of drugs, a high targeted drug delivery efficiency at the lowest possible drug doses is clinically required. The chitosan has been functionalized with covalent conjugates or complexes and processed into nanoparticles to encapsulate and control drug release, to avoid premature drug clearance, to deliver drugs passively and actively to cancer site at tissue, cell or subcellular levels, and to promote cancer cell uptake of nanoparticles through membrane permeabilization at higher specificity and scale. Nanomedicine developed using functionalized chitosan translates to significant preclinical improvements. Future challenges related to nanotoxicity, manufacturability, selection precision of conjugates and complexes as a function of cancer omics and their biological responses from administration site to cancer target need critical assessments.
    Matched MeSH terms: Tumor Microenvironment
  20. Fulltext Molecular mechanisms underlying the clinical efficacy of panobinostat involve Stochasticity of epigenetic signaling, sensitization to anticancer drugs, and induction of cellular cell death related to cellular stresses
    El Omari N, Bakrim S, Khalid A, Abdalla AN, Almalki WH, Lee LH, et al.
    Biomed Pharmacother, 2023 Aug;164:114886.
    PMID: 37224752 DOI: 10.1016/j.biopha.2023.114886
    Panobinostat, also known as Farydak®, LBH589, PNB, or panobinostat lactate, is a hydroxamic acid that has been approved by the Food and Drug Administration (FDA) for its anti-cancer properties. This orally bioavailable drug is classified as a non-selective histone deacetylase inhibitor (pan-HDACi) that inhibits class I, II, and IV HDACs at nanomolar levels due to its significant histone modifications and epigenetic mechanisms. A mismatch between histone acetyltransferases (HATs) and HDACs can negatively affect the regulation of the genes concerned, which in turn can contribute to tumorigenesis. Indeed, panobinostat inhibits HDACs, potentially leading to acetylated histone accumulation, re-establishing normal gene expression in cancer cells, and helping to drive multiple signaling pathways. These pathways include induction of histone acetylation and cytotoxicity for the majority of tested cancer cell lines, increased levels of p21 cell cycle proteins, enhanced amounts of pro-apoptotic factors (such as caspase-3/7 activity and cleaved poly (ADP-ribose) polymerase (PARP)) associated with decreased levels of anti-apoptotic factors [B-cell lymphoma 2 (Bcl-2) and B-cell lymphoma-extra-large (Bcl-XL)], as well as regulation of immune response [upregulated programmed death-ligand 1 (PD-L1) and interferon gamma receptor 1 (IFN-γR1) expression] and other events. The therapeutic outcome of panobinostat is therefore mediated by sub-pathways involving proteasome and/or aggresome degradation, endoplasmic reticulum, cell cycle arrest, promotion of extrinsic and intrinsic processes of apoptosis, tumor microenvironment remodeling, and angiogenesis inhibition. In this investigation, we aimed to pinpoint the precise molecular mechanism underlying panobinostat's HDAC inhibitory effect. A more thorough understanding of these mechanisms will greatly advance our knowledge of cancer cell aberrations and, as a result, provide an opportunity for the discovery of significant new therapeutic perspectives through cancer therapeutics.
    Matched MeSH terms: Tumor Microenvironment
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