Hypoxia-inducible factor and cellular senescence in pulmonary aging and disease

Biogerontology, Journal Year: 2025, Volume and Issue: 26(2)

Published: Feb. 26, 2025

Abstract Cellular senescence and hypoxia-inducible factor (HIF) signaling are crucial in pulmonary aging age-related lung diseases such as chronic obstructive disease idiopathic fibrosis cancer. HIF plays a pivotal role cellular adaptation to hypoxia, regulating processes like angiogenesis, metabolism, inflammation. Meanwhile, leads irreversible cell cycle arrest, triggering the senescence-associated secretory phenotype which contributes inflammation, tissue remodeling, fibrosis. Dysregulation of these pathways accelerates progression by promoting oxidative stress, mitochondrial dysfunction, epigenetic alterations. Recent studies indicate that interact at multiple levels, where can both induce suppress senescence, depending on conditions. While transient activation supports repair stress resistance, dysregulation exacerbates pathologies. Furthermore, emerging evidence suggests targeting could offer new therapeutic strategies mitigate diseases. This review explores intricate crosstalk between mechanisms, shedding light how their interplay influences progression. Additionally, we discuss potential interventions, including senolytic therapies modulators, enhance health longevity.

Language: Английский

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Cancer stem cells and tumor-associated macrophages as mates in tumor progression: mechanisms of crosstalk and advanced bioinformatic tools to dissect their phenotypes and interaction

Frontiers in Immunology, Journal Year: 2025, Volume and Issue: 16

Published: Feb. 6, 2025

Cancer stem cells (CSCs) are a small subset within the tumor mass significantly contributing to cancer progression through dysregulation of various oncogenic pathways, driving growth, chemoresistance and metastasis formation. The aggressive behavior CSCs is guided by several intracellular signaling pathways such as WNT, NF-kappa-B, NOTCH, Hedgehog, JAK-STAT, PI3K/AKT1/MTOR, TGF/SMAD, PPAR MAPK kinases, well extracellular vesicles exosomes, molecules cytokines, chemokines, pro-angiogenetic growth factors, which finely regulate CSC phenotype. In this scenario, microenvironment (TME) key player in establishment permissive niche, where engage intricate communications with diverse immune cells. "oncogenic" mainly represented B T lymphocytes, NK cells, dendritic Among macrophages exhibit more plastic adaptable phenotype due their different subpopulations, characterized both immunosuppressive inflammatory phenotypes. Specifically, tumor-associated (TAMs) create an milieu production plethora paracrine factors (IL-6, IL-12, TNF-alpha, TGF-beta, CCL1, CCL18) promoting acquisition stem-like, invasive metastatic TAMs have demonstrated ability communicate via direct ligand/receptor (such CD90/CD11b, LSECtin/BTN3A3, EPHA4/Ephrin) interaction. On other hand, exhibited capacity influence creating favorable for progression. Interestingly, bidirectional TME leads epigenetic reprogramming sustains malignant transformation. Nowadays, integration biological computational data obtained cutting-edge technologies (single-cell RNA sequencing, spatial transcriptomics, trajectory analysis) has improved comprehension biunivocal multicellular dialogue, providing comprehensive view heterogeneity dynamics CSCs, uncovering alternative mechanisms evasion therapeutic resistance. Moreover, combination biology will lead development innovative target therapies dampening CSC-TME Here, we aim elucidate most recent insights on complex interactions specifically TAMs, tracing exhaustive scenario from primary

Language: Английский

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Emerging Role of Extracellular pH in Tumor Microenvironment as a Therapeutic Target for Cancer Immunotherapy

Cells, Journal Year: 2024, Volume and Issue: 13(22), P. 1924 - 1924

Published: Nov. 20, 2024

Identifying definitive biomarkers that predict clinical response and resistance to immunotherapy remains a critical challenge. One emerging factor is extracellular acidosis in the tumor microenvironment (TME), which significantly impairs immune cell function contributes failure. However, acidic conditions TME disrupt interaction between cancer cells, driving tumor-infiltrating T cells NK into an inactivated, anergic state. Simultaneously, promotes recruitment activation of immunosuppressive such as myeloid-derived suppressor regulatory (Tregs). Notably, acidity enhances exosome release from Tregs, further amplifying immunosuppression. Tumor thus acts "protective shield," neutralizing anti-tumor responses transforming pro-tumor allies. Therefore, targeting lactate metabolism has emerged promising strategy overcome this barrier, with approaches including buffer agents neutralize pH inhibitors block production or transport, thereby restoring efficacy TME. Recent discoveries have identified genes involved (pHe) regulation, presenting new therapeutic targets. Moreover, ongoing research aims elucidate molecular mechanisms acidification develop treatments modulate levels enhance outcomes. Additionally, future studies are crucial validate safety pHe-targeted therapies patients. Thus, review explores regulation pHe its potential role improving immunotherapy.

Language: Английский

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Hybrid Cell Membrane‐Coated Nanoparticles for Synergizing Sonodynamic Therapy and Immunotherapy against Triple‐Negative Breast Cancer

Advanced Healthcare Materials, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 21, 2024

Tumor immunotherapy represents a highly promising modality for the treatment of triple-negative breast cancer (TNBC). Nevertheless, its therapeutic efficacy has been profoundly impacted by challenges such as low drug uptake, hypoxia, and immunosuppression. To address these problems, study develops strategy combining sonodynamic therapy (SDT) using biomimetic nanoparticles coated with hybrid membranes. The are loaded semiconducting polymers (PFODBT), Atovaquone (ATO), TMP195 to enhance biocompatibility, targeting ability, uptake retention at tumor site. In in vitro experiments, alleviate induce immunogenic cell death (ICD), prompt reprogramming tumor-associated macrophages (TAMs) from M2 type M1 type. vivo synergistic effects enhanced SDT-mediated ICD TAMs repolarization significantly inhibit proliferation primary distant 4T1 subcutaneous model, effectively attenuated metastasis lung liver. Moreover, immune responses further activated improving maturation dendritic cells, filtration CD8

Language: Английский

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The potential of Dayak tribal herbal leaves as an anti-breast cancer agent: In silico approach

BIO Web of Conferences, Journal Year: 2025, Volume and Issue: 153, P. 01006 - 01006

Published: Jan. 1, 2025

Breast cancer is one of the leading causes mortality among women worldwide, prompting exploration alternative, natural therapies. This study examines anti-breast potential traditional herbal plants used by Dayak tribe, particularly Kleinhovia hospita Linn. Through in silico approaches, investigates cytotoxic effects and binding affinities key compounds, such as Scopoletin, Quercetin, Eleutherol, with breast cancer-related proteins. Molecular docking analysis demonstrated that Quercetin Eleutherol exhibit high (−9 −8 kcal/mol, respectively) target proteins, indicating significant for inhibiting cell proliferation targeting proteins like EGFR, JNK, NUDT5. The drug-likeness confirmed meet criteria further therapeutic exploration. These findings suggest compounds from tribal could be viable anti-cancer agents, providing a scientific foundation developing culturally relevant effective treatments cancer. Further research recommended to isolate evaluate bioactive preclinical clinical settings. work supports medicine strategy against

Language: Английский

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Dual inhibitor of MDM2 and NFAT1 for experimental therapy of breast cancer: in vitro and in vivo anticancer activities and newly discovered effects on cancer metabolic pathways

Frontiers in Pharmacology, Journal Year: 2025, Volume and Issue: 16

Published: Feb. 19, 2025

The oncogene MDM2 has garnered attention not only for its role in cancer as a negative regulator of the tumor suppressor p53 but also p53-independent oncogenic activities. involves metabolic reprogramming, such serine metabolism, respiration, mitochondrial functions, folate cycle, and redox balance. Traditional inhibitors blocking protein-protein binding between have shown limited clinical success various stages trials, most likely due to low efficacy, drug toxicity, resistance, highlighting need novel, strategy inhibit MDM2. present study investigated antitumor effects MA242, novel NFAT1 inhibitor, breast models. anticancer activity underlying mechanisms MA242 were evaluated vitro using cell lines with different backgrounds vivo orthotopic patient-derived xenograft We demonstrated that significantly inhibited viability induced apoptosis cells, regardless status. Metabolic analysis revealed notably disrupted nicotinamide modified nucleotide elevated cellular oxidative stress by disturbing Furthermore, animal models, reduced expression effectively growth dependent on without causing host toxicity. These findings highlight potential modulator metabolism support further development therapeutic option aggressive cancers.

Language: Английский

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Impact of lactate on immune cell function in the tumor microenvironment: mechanisms and therapeutic perspectives

Frontiers in Immunology, Journal Year: 2025, Volume and Issue: 16

Published: March 26, 2025

Lactate has emerged as a key regulator in the tumor microenvironment (TME), influencing both progression and immune dynamics. As byproduct of aerobic glycolysis, lactate satisfies metabolic needs proliferating cells while reshaping TME to facilitate evasion. Elevated levels inhibit effector such CD8 + T natural killer cells, supporting immunosuppressive regulatory myeloid-derived suppressor thus fostering an environment. promotes epigenetic reprogramming, stabilizes hypoxia-inducible factor-1α, activates nuclear factor kappa B, leading further immunological dysfunction. In this review, we examined role suppression, treatment resistance. We also discuss promising therapeutic strategies targeting metabolism, including dehydrogenase inhibitors, monocarboxylate transporter neutralization methods, all which can restore function enhance immunotherapy outcomes. By highlighting recent advances, review provides theoretical foundation for integrating lactate-targeted therapies into clinical practice. highlight potential synergy between these current immunotherapeutic strategies, providing new avenues addressing TME-related challenges improving outcomes patients with cancer.

Language: Английский

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Cancer-associated fibroblasts secrete CSF3 to promote TNBC progression via enhancing PGM2L1-dependent glycolysis reprogramming

Cell Death and Disease, Journal Year: 2025, Volume and Issue: 16(1)

Published: April 4, 2025

Abstract Triple-negative breast cancer (TNBC) is characterized by a pronounced hypoxic tumor microenvironment, with cancer-associated fibroblasts (CAFs) serving as the predominant cellular component and playing crucial roles in regulating progression. However, mechanism which CAFs affect biological behavior of cells environment remain elusive. This study employed bead-based multiplex immunoassay to analyze panel cytokines/chemokines identified colony stimulating factor 3 (CSF3) significantly elevated secretome CAFs. We found that CSF3 promoted invasive TNBC activating downstream signaling pathway its receptor, CSF3R. RNA sequencing analysis further revealed phosphoglucomutase 2-like 1 (PGM2L1) target CSF3/CSF3R signaling, enhancing glycolysis providing energy support malignant phenotype cancer. In vivo, we confirmed promotes progression targeting PGM2L1. These findings suggest may represent potential therapeutic approach for TNBC.

Language: Английский

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Current Landscape of Hypoxia in Thyroid Cancer Pathogenesis and Treatment

Critical Reviews in Oncology/Hematology, Journal Year: 2025, Volume and Issue: unknown, P. 104719 - 104719

Published: April 1, 2025

Language: Английский

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Revisiting the role of cancer-associated fibroblasts in tumor microenvironment

Frontiers in Immunology, Journal Year: 2025, Volume and Issue: 16

Published: April 17, 2025

Cancer-associated fibroblasts (CAFs) are integral components of the tumor microenvironment playing key roles in progression, metastasis, and therapeutic resistance. However, challenges persist understanding their heterogeneity, origin, functional diversity. One major obstacle is lack standardized naming conventions for CAF subpopulations, with current systems failing to capture full complexity. Additionally, identification CAFs hindered by absence specific biomarkers, limiting precision diagnostic strategies. In vitro culture conditions often fail maintain vivo characteristics CAFs, which complicates study translation findings clinical practice. Although detection methods, such as antibodies, mRNA probes, single-cell transcriptomics, offer insights into biology, they standardization provide reliable quantitative measures. Furthermore, dynamic interactions between cells, immune cells within TME remain insufficiently understood, role evasion therapy resistance an area ongoing research. Understanding how influence drug response essential developing more effective cancer therapies. This review aims in-depth analysis research, propose future research directions, emphasize need improved CAF-targeted By addressing these gaps, it seeks highlight potential targets overcoming enhancing efficacy treatments.

Language: Английский

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