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BACKGROUND: Alternative splicing of pre-mRNA is a fundamental regulatory process in multicellular eukaryotes, significantly contributing to the diversification of the human proteome. RNA-binding fox-1 homologue 2 (RBFOX2), a member of the evolutionarily conserved RBFOX family, has emerged as a critical splicing regulator, playing a pivotal role in the alternative splicing of pre-mRNA. This review provides a comprehensive analysis of RBFOX2, elucidating its splicing activity through direct and indirect binding mechanisms. RBFOX2 exerts substantial influence over the alternative splicing of numerous transcripts, thereby shaping essential cellular processes such as differentiation and development. MAIN BODY OF THE ABSTRACT: Dysregulation of RBFOX2-mediated alternative splicing has been closely linked to a spectrum of cardiovascular diseases and malignant tumours, underscoring its potential as a therapeutic target. Despite significant progress, current research faces notable challenges. The complete structural characterisation of RBFOX2 remains elusive, limiting in-depth exploration beyond its RNA-recognition motif. Furthermore, the scarcity of studies focusing on RBFOX2-targeting drugs poses a hindrance to translating research findings into clinical applications. CONCLUSION: This review critically assesses the existing body of knowledge on RBFOX2, highlighting research gaps and limitations. By delineating these areas, this analysis not only serves as a foundational reference for future studies but also provides strategic insights for bridging these gaps. Addressing these challenges will be instrumental in unlocking the full therapeutic potential of RBFOX2, paving the way for innovative and effective treatments in various diseases.

Asunto(s)

Neoplasias , Factores de Empalme de ARN , Humanos , Factores de Empalme de ARN/genética , Factores de Empalme de ARN/metabolismo , Neoplasias/genética , Neoplasias/metabolismo , Cardiomiopatías/genética , Cardiomiopatías/metabolismo , Proteínas Represoras/metabolismo , Proteínas Represoras/genética , Progresión de la Enfermedad , Empalme Alternativo/genética , Empalme del ARN/genética

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PRF1 (perforin 1) is a key cytotoxic molecule that plays a crucial role in the killing function of natural killer (NK) cells and cytotoxic T lymphocytes (CTLs). Recent studies have focused on PRF1's role in cancer development, progression, and prognosis. Studies have shown that aberrant PRF1 expression has a significant role to play in cancer development and progression. In some cancers, high expression of the PRF1 gene is associated with a better prognosis for patients, possibly because it helps enhance the body's immune response to tumors. However, some studies have also shown that the absence of PRF1 may make it easier for tumors to evade the body's immune surveillance, thus affecting patient survival. Furthermore, recent studies have explored therapeutic strategies based on PRF1, such as enhancing the ability of immune cells to kill cancer cells by boosting PRF1 activity. In addition, they have improved the efficacy of immunotherapy by modulating its expression to enhance the effectiveness of the treatment. Based on these findings, PRF1 may be a valuable biomarker both for the treatment of cancer and for its prognosis in the future. To conclude, PRF1 has an important biological function and has clinical potential for the treatment of cancer, which indicates that it deserves more research and development in the future.

Asunto(s)

Neoplasias , Perforina , Humanos , Perforina/metabolismo , Perforina/genética , Neoplasias/terapia , Neoplasias/inmunología , Neoplasias/genética , Neoplasias/metabolismo , Inmunoterapia , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Animales , Pronóstico , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Linfocitos T Citotóxicos/inmunología , Regulación Neoplásica de la Expresión Génica

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BACKGROUND: In spite of significant advancements in theraputic modalities for hepatocellular carcinoma (HCC), there is still a high annual mortality rate with a rising incidence. Major challenges in the HCC clinical managment are related to the development of therapy resistance, and evasion of tumor cells apoptosis which leading unsatisfactory outcomes in HCC patients. Previous investigations have shown that autophagy plays crucial role in contributing to drug resistance development in HCC. Although, miR-29a is known to counteract authophagy, increasing evidence revealed a down-regulation of miR-29a in HCC patients which correlates with poor prognosis. Beside, evidences showed that miR-29a serves as a negative regulator of autophagy in other cancers. In the current study, we aim to investigate the impact of miR-29a on the autophagy and apoptosis in HCC cells using extracellular vesicles (EVs) as a natural delivery system given their potential in the miRNA delivery both in vitro and in vivo. METHOD: Human Wharton's Jelly mesenchymal stromal cell-derived extracellular vesicles were lately isolated through 20,000 or 110,000 × g centrifugation (EV20K or EV110K, respectively), characterized by western blot (WB), scanning electron microscopy (SEM), and dynamic light scattering (DLS). miR-29a was subsequently loaded into these EVs and its loading efficiency was evaluated via RT-qPCR. Comprehensive in vitro and in vivo assessments were then performed on Huh-7 and HepG2 cell lines. RESULTS: EV20K-miR-29a treatment significantly induces cell apoptosis and reduces both cell proliferation and colony formation in Huh-7 and HepG2 cell lines. In addition, LC3-II/LC3-I ratio was increased while the expression of key autophagy regulators TFEB and ATG9A were downregulated by this treatment. These findings suggest an effective blockade of autophagy by EV20K-miR-29a leading to apoptosis in the HCC cell lines through concomitant targeting of critical mediators within each pathway.

Asunto(s)

Apoptosis , Autofagia , Carcinoma Hepatocelular , Vesículas Extracelulares , Neoplasias Hepáticas , MicroARNs , Humanos , MicroARNs/genética , MicroARNs/metabolismo , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/tratamiento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/tratamiento farmacológico , Vesículas Extracelulares/metabolismo , Animales , Línea Celular Tumoral , Ratones , Células Hep G2 , Ratones Desnudos , Proliferación Celular/efectos de los fármacos

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BACKGROUND: Liver cirrhosis is a chronic and progressive liver disease with significant global health implications. Recent evidence suggests an association between serum vitamin D levels and the severity of liver cirrhosis, potentially serving as a therapeutic target. This study aimed to investigate the relationship between serum vitamin D status and the severity of liver cirrhosis in a population of Nigerian patients. METHODS: This analytical, cross-sectional study involved 201 participants, including 103 with liver cirrhosis and 98 age- and sex-matched controls. Serum vitamin D was measured using ELISA, with deficiency defined as < 20 ng/ml. Cirrhosis severity was assessed using Child-Pugh and MELD scores. Spearman's correlation was used to assess the relationship between vitamin D and severity of liver cirrhosis while ordinal regression analysis assessed its performance as an indicator of the disease severity. RESULT: Among cirrhotic patients, 36.9% were deficient, 31.1% insufficient, and 32.0% had sufficient vitamin D levels. Serum vitamin D showed strong negative correlations with Child-Pugh and MELD scores (r = -0.696, p < 0.001; r = -0.734, p < 0.001, respectively). Ordinal regression showed that higher vitamin D levels were associated with lower severity scores (Child-Pugh: OR = 0.856, 95% CI: 0.815-0.900, p < 0.001; MELD: OR = 0.875, 95% CI: 0.837-0.915, p < 0.001). CONCLUSION: Lower serum vitamin D levels correlated with increased liver cirrhosis severity, suggesting its potential as both a prognostic marker and therapeutic target. Further studies should investigate the efficacy of vitamin D supplementation in improving cirrhosis outcomes.

Asunto(s)

Cirrosis Hepática , Índice de Severidad de la Enfermedad , Deficiencia de Vitamina D , Vitamina D , Humanos , Cirrosis Hepática/sangre , Masculino , Femenino , Nigeria , Estudios Transversales , Vitamina D/sangre , Vitamina D/análogos & derivados , Persona de Mediana Edad , Deficiencia de Vitamina D/sangre , Deficiencia de Vitamina D/complicaciones , Deficiencia de Vitamina D/tratamiento farmacológico , Adulto , Estudios de Casos y Controles , Anciano , Biomarcadores/sangre

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Osteoporosis, a systemic skeletal disorder marked by diminished bone mass and compromised bone microarchitecture, is becoming increasingly prevalent due to an aging population. The underlying pathophysiology of osteoporosis is attributed to an imbalance between osteoclast-mediated bone resorption and osteoblast-mediated bone formation. Osteoclasts play a crucial role in the development of osteoporosis through various molecular pathways, including the RANK/RANKL/OPG signaling axis, cytokines, and integrins. Notably, the calcium signaling pathway is pivotal in regulating osteoclast activation and function, influencing bone resorption activity. Disruption in calcium signaling can lead to increased osteoclast-mediated bone resorption, contributing to the progression of osteoporosis. Emerging research indicates that calcium-permeable channels on the cellular membrane play a critical role in bone metabolism by modulating these intracellular calcium pathways. Here, we provide an overview of current literature on the regulation of plasma membrane calcium channels in relation to bone metabolism with particular emphasis on their dysregulation during the progression of osteoporosis. Targeting these calcium channels may represent a potential therapeutic strategy for treating osteoporosis.

Asunto(s)

Canales de Calcio , Osteoporosis , Humanos , Osteoporosis/metabolismo , Canales de Calcio/metabolismo , Animales , Resorción Ósea/metabolismo , Osteoclastos/metabolismo , Señalización del Calcio/fisiología

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Tumor microenvironment (TME) in head and neck squamous cell carcinoma (HNSCC) has a major influence on disease progression and therapy response. One of the predominant stromal cell types in the TME of HNSCC is cancer-associated fibroblasts (CAF). CAF constitute a diverse cell population and we are only at the beginning of characterizing and understanding the functions of various CAF subsets. CAF have been shown to interact with tumor cells and other components of the TME to shape mainly a favourable microenvironment for HNSCC progression, although some studies report existence of tumor-restraining CAF subtypes. The numerous pathways used by CAF to promote tumorigenesis may represent potential therapeutic targets. This review summarizes current knowledge on the origins, subtypes and mechanisms employed by CAF in HNSCC. The aim is to contribute to the understanding on how CAF actively influence the TME and modulate different immune cell types, as well as cancer cells, to establish a conducive setting for cancer growth. Although CAF are currently a promising therapeutic target for the treatment of other types of cancer, there is no significant therapeutic advancement in HNSCC.

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This review focuses on the expression and function of voltage-gated sodium channel subtype NaV1.7 in various cancers and explores its impact on the metastasis driving cell functions such as proliferation, migration, and invasiveness. An overview of its structural characteristics, drug binding sites, inhibitors and their likely mechanisms of action are presented. Despite the lack of clarity on the precise mechanism by which NaV1.7 contributes to cancer progression and metastasis; many studies have suggested a connection between NaV1.7 and proteins involved in multiple signaling pathways such as PKA and EGF/EGFR-ERK1/2. Moreover, the functional activity of NaV1.7 appears to elevate the expression levels of MACC1 and NHE-1, which are controlled by p38 MAPK activity, HGF/c-MET signaling and c-Jun activity. This cascade potentially enhances the secretion of extracellular matrix proteases, such as MMPs which play critical roles in cell migration and invasion activities. Furthermore, the NaV1.7 activity may indirectly upregulate Rho GTPases Rac activity, which is critical for cytoskeleton reorganization, cell adhesion, and actin polymerization. The relationship between NaV1.7 and cancer progression has prompted researchers to investigate the therapeutic potential of targeting NaV1.7 using inhibitors. The positive outcome of such studies resulted in the discovery of several inhibitors with the ability to reduce cancer cell migration, invasion, and tumor growth underscoring the significance of NaV1.7 as a promising pharmacological target for attenuating cancer cell proliferation and metastasis. The research findings summarized in this review suggest that the regulation of NaV1.7 expression and function by small molecules and/or by genetic engineering is a viable approach to discover novel therapeutics for the prevention and treatment of metastasis of cancers with elevated NaV1.7 expression.

RESUMEN

AIMS: Pannexin-1 (PANX1) is a hemichannel that releases ATP upon opening, initiating inflammation, cell proliferation, and migration. However, the role of PANX1 channels in colon cancer remains poorly understood, thus constituting the focus of this study. MAIN METHODS: PANX1 mRNA expression was analyzed using multiple cancer databases. PANX1 protein expression and distribution were evaluated by immunohistochemistry on primary tumor tissue and non-tumor colonic mucosa from colon cancer patients. PANX1 inhibitors (probenecid or 10Panx) were used to assess colon cancer cell lines viability. To study the role of PANX1 in vivo, a subcutaneous xenograft model using HCT116 cells was performed in BALB/c NOD/SCID immunodeficient mice to evaluate tumor growth under PANX1 inhibition using probenecid. KEY FINDINGS: PANX1 mRNA was upregulated in colon cancer tissue compared to non-tumor colonic mucosa. Elevated PANX1 mRNA expression in tumors correlated with worse disease-free survival. PANX1 protein abundance was increased on tumor cells compared to epithelial cells in paired samples, in a cancer stage-dependent manner. In vitro and in vivo experiments indicated that blocking PANX1 reduced cell viability and tumor growth. SIGNIFICANCE: PANX1 can be used as a biomarker of colon cancer progression and blocking PANX1 channel opening could be used as a potential therapeutic strategy against this disease.

Asunto(s)

Neoplasias del Colon , Conexinas , Progresión de la Enfermedad , Proteínas del Tejido Nervioso , Animales , Femenino , Humanos , Masculino , Ratones , Biomarcadores de Tumor/metabolismo , Biomarcadores de Tumor/genética , Línea Celular Tumoral , Proliferación Celular , Supervivencia Celular , Neoplasias del Colon/patología , Neoplasias del Colon/metabolismo , Neoplasias del Colon/genética , Conexinas/metabolismo , Conexinas/genética , Regulación Neoplásica de la Expresión Génica , Células HCT116 , Ratones Endogámicos BALB C , Ratones Endogámicos NOD , Ratones SCID , Proteínas del Tejido Nervioso/metabolismo , Proteínas del Tejido Nervioso/genética , Probenecid/farmacología , Ensayos Antitumor por Modelo de Xenoinjerto

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CONTEXT: Computational modeling involves the use of computer simulations and models to study and understand real-world phenomena. Its application is particularly relevant in the study of potential interactions between biological elements. It is a promising approach to understand complex biological processes and predict their behavior under various conditions. METHODOLOGY: This paper is a review of the recent literature on computational modeling of biological systems. Our study focuses on the field of oncology and the use of artificial intelligence (AI) and, in particular, agent-based modeling (ABM), between 2010 and May 2023. RESULTS: Most of the articles studied focus on improving the diagnosis and understanding the behaviors of biological entities, with metaheuristic algorithms being the models most used. Several challenges are highlighted regarding increasing and structuring knowledge about biological systems, developing holistic models that capture multiple scales and levels of organization, reproducing emergent behaviors of biological systems, validating models with experimental data, improving computational performance of models and algorithms, and ensuring privacy and personal data protection are discussed.

Asunto(s)

Inteligencia Artificial , Simulación por Computador , Modelos Biológicos , Humanos , Algoritmos , Oncología Médica/métodos , Neoplasias/terapia , Análisis de Sistemas

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Non-small cell lung carcinoma (NSCLC) accounts for 85% of lung cancers, the leading cause of cancer associated deaths in the US and worldwide. Within NSCLC tumors, there is a subpopulation of cancer cells termed cancer stem cells (CSCs) which exhibit stem-like properties that drive NSCLC progression, metastasis, relapse, and therapeutic resistance. Extracellular vesicles (EVs) are membrane-bound nanoparticles secreted by cells that carry vital messages for short- and long-range intercellular communication. Numerous studies have implicated NSCLC CSC-derived EVs in the factors associated with NSCLC lethality. In this review, we have discussed mechanisms of EV-directed cross-talk between CSCs and cells of the tumor microenvironment that promote stemness, tumor progression and metastasis in NSCLC. The mechanistic studies discussed herein have provided insights for developing novel NSCLC diagnostic and prognostic biomarkers and strategies to therapeutically target the NSCLC CSC niche.

Asunto(s)

Carcinoma de Pulmón de Células no Pequeñas , Vesículas Extracelulares , Neoplasias Pulmonares , Células Madre Neoplásicas , Microambiente Tumoral , Humanos , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Vesículas Extracelulares/metabolismo , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/metabolismo , Animales , Biomarcadores de Tumor/metabolismo , Comunicación Celular

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The epidermal growth factor receptor (EGFR) family is a class of transmembrane proteins, highly regarded as anticancer targets due to their pivotal role in various malignancies. Standard cancer treatments targeting the ErbB receptors include tyrosine kinase inhibitors (TKIs) and monoclonal antibodies (mAbs). Despite their substantial survival benefits, the achievement of curative outcomes is hindered by acquired resistance. Recent advancements in anti-ErbB approaches, such as inhibitory peptides, nanobodies, targeted-protein degradation strategies, and bispecific antibodies (BsAbs), aim to overcome such resistance. More recently, emerging insights into the cell surface interactome of the ErbB family open new avenues for modulating ErbB signaling by targeting specific domains of ErbB partners. Here, we review recent progress in ErbB targeting and elucidate emerging paradigms that underscore the significance of EGF domain-containing proteins (EDCPs) as new ErbB-targeting pathways.

Asunto(s)

Receptores ErbB , Neoplasias , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Neoplasias/inmunología , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/metabolismo , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Terapia Molecular Dirigida , Transducción de Señal/efectos de los fármacos

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Pediatric neoplasms represent a complex group of malignancies that pose unique challenges in terms of diagnosis, treatment, and understanding of the underlying molecular pathogenetic mechanisms. Erythropoietin-producing hepatocellular receptors (EPHs), the largest family of receptor tyrosine kinases and their membrane-tethered ligands, ephrins, orchestrate short-distance cell-cell signaling and are intricately involved in cell-pattern morphogenesis and various developmental processes. Unraveling the role of the EPH/ephrin signaling pathway in the pathophysiology of pediatric neoplasms and its clinical implications can contribute to deciphering the intricate landscape of these malignancies. The bidirectional nature of the EPH/ephrin axis is underscored by emerging evidence revealing its capacity to drive tumorigenesis, fostering cell-cell communication within the tumor microenvironment. In the context of carcinogenesis, the EPH/ephrin signaling pathway prompts a reevaluation of treatment strategies, particularly in pediatric oncology, where the modest progress in survival rates and enduring treatment toxicity necessitate novel approaches. Molecularly targeted agents have emerged as promising alternatives, prompting a shift in focus. Through a nuanced understanding of the pathway's intricacies, we aim to lay the groundwork for personalized diagnostic and therapeutic strategies, ultimately contributing to improved outcomes for young patients grappling with neoplastic challenges.

Asunto(s)

Relevancia Clínica , Neoplasias Hematológicas , Humanos , Niño , Transducción de Señal , Comunicación Celular , Carcinogénesis , Efrinas , Receptores de Eritropoyetina , Microambiente Tumoral

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Pregnancy-associated breast cancer (PABC) presents unique challenges due to its occurrence during or shortly after pregnancy. Pregnancy-associated plasma protein A (PAPP-A) has emerged as a potential biomarker and regulator in PABC. This comprehensive review examines the role of PAPP-A in PABC, highlighting its involvement in tissue remodeling and cancer progression. Molecular mechanisms linking PAPP-A to breast cancer, including signaling pathways and interactions with other molecules, are explored. The review also discusses the diagnostic and therapeutic implications of PAPP-A dysregulation in PABC, emphasizing the need for further research to elucidate underlying mechanisms and develop targeted therapies. Collaborative efforts among researchers, clinicians, and industry stakeholders are essential for translating findings into clinically relevant interventions to improve outcomes for PABC patients.

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Navigating the intricate landscape of the tumor microenvironment (TME) unveils a pivotal arena for cancer therapeutics, where cytokines and soluble mediators emerge as double-edged swords in the fight against cancer. This review ventures beyond traditional perspectives, illuminating the nuanced interplay of these elements as both allies and adversaries in cancer dynamics. It critically evaluates the evolving paradigms of TME reprogramming, spotlighting innovative strategies that target the sophisticated network of cytokines and mediators. Special focus is placed on unveiling the therapeutic potential of novel cytokines and mediators, particularly their synergistic interactions with extracellular vesicles, which represent underexplored conduits for therapeutic targeting. Addressing a significant gap in current research, we explore the untapped potential of these biochemical players in orchestrating immune responses, tumor proliferation, and metastasis. The review advocates for a paradigm shift towards exploiting these dynamic interactions within the TME, aiming to transcend conventional treatments and pave the way for a new era of precision oncology. Through a critical synthesis of recent advancements, we highlight the imperative for innovative approaches that harness the full spectrum of cytokine and mediator activities, setting the stage for breakthrough therapies that offer heightened specificity, reduced toxicity, and improved patient outcomes.

Asunto(s)

Vesículas Extracelulares , Neoplasias , Humanos , Neoplasias/terapia , Medicina de Precisión , Microambiente Tumoral , Citocinas

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Gliomas are diffusely infiltrating brain tumors whose prognosis is strongly influenced by their extent of invasion into the surrounding brain tissue. While lower-grade gliomas present more circumscribed borders, high-grade gliomas are aggressive tumors with widespread brain infiltration and dissemination. Glioblastoma (GBM) is known for its high invasiveness and association with poor prognosis. Its low survival rate is due to the certainty of its recurrence, caused by microscopic brain infiltration which makes surgical eradication unattainable. New insights into GBM biology at the single-cell level have enabled the identification of mechanisms exploited by glioma cells for brain invasion. In this review, we explore the current understanding of several molecular pathways and mechanisms used by tumor cells to invade normal brain tissue. We address the intrinsic biological drivers of tumor cell invasion, by tackling how tumor cells interact with each other and with the tumor microenvironment (TME). We focus on the recently discovered neuronal niche in the TME, including local as well as distant neurons, contributing to glioma growth and invasion. We then address the mechanisms of invasion promoted by astrocytes and immune cells. Finally, we review the current literature on the therapeutic targeting of the molecular mechanisms of invasion.

Asunto(s)

Neoplasias Encefálicas , Glioblastoma , Glioma , Humanos , Glioblastoma/metabolismo , Invasividad Neoplásica/patología , Glioma/metabolismo , Neoplasias Encefálicas/metabolismo , Astrocitos/metabolismo , Microambiente Tumoral

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The diverse and severe nature of neurological manifestations associated with coronavirus disease 2019 (Covid-19) has garnered increasing attention. Exploring the potential to decrease neurological complications in Covid-19 patients involves targeting the mammalian target of rapamycin (mTOR) pathway as a therapeutic strategy. The mTOR pathway, widely recognised for its central role in essential cellular processes like synthesising proteins, facilitating autophagy, and modulating immune responses, has implications in various neurological disorders. Drawing parallels between these disorders and the observed neurological complications in Covid-19, we present a comprehensive review on the current understanding of mTOR signalling in the context of severe acute respiratory syndrome coronavirus 2 infection and neuroinflammation.

Asunto(s)

COVID-19 , Enfermedades del Sistema Nervioso , Serina-Treonina Quinasas TOR , Humanos , COVID-19/complicaciones , Enfermedades del Sistema Nervioso/etiología , Transducción de Señal , Serina-Treonina Quinasas TOR/metabolismo

RESUMEN

Imprecise targeting of chemotherapeutic drugs often leads to severe toxicity during breast cancer therapy. To address this issue, we have devised a strategy to load dacarbazine (DC) into fucose-based carbon quantum dots (CQDs), which are subsequently coated with exosomes (Ex-DC@CQDs) derived from breast cancer cells. Nanoparticle tracking analysis and western blotting revealed that Ex-DC@CQDs retained the structural and functional characteristics of exosomes. We found that exosomes facilitated the transport of DC@CQDs to cancer cells via heparan sulfate proteoglycan (HSPG) receptors, followed by an augmented depolarization of the mitochondrial membrane potential, ROS generation, and induction of apoptosis leading to cell death. In vivo imaging and pharmacokinetic studies demonstrated enhanced antitumor targeting and efficacy compared to free DC which we attribute to an improved pharmacokinetic profile, a greater tumor accumulation via exosome-mediated- HSPG receptor-driven cell uptake, and sustained release of the Ex-DC@CQDs. Our findings may pave the way for the further development of biologically sourced nanocarriers for breast cancer targeting.

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Neoplasias de la Mama , Exosomas , Puntos Cuánticos , Humanos , Femenino , Puntos Cuánticos/química , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Exosomas/metabolismo , Dacarbazina , Proteoglicanos de Heparán Sulfato/metabolismo , Carbono/química

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The bone marrow (BM) is the primary site of adult haematopoiesis, where stromal elements (e.g. fibroblasts and mesenchymal stem cells [MSCs]) work in concert to support blood cell development. However, the establishment of an abnormal clone can lead to a blood malignancy, such as acute myeloid leukaemia (AML). Despite our increased understanding of the pathophysiology of the disease, patient survival remains suboptimal, mainly driven by the development of therapy resistance. In this review, we highlight the importance of bone marrow fibroblasts and MSCs in health and acute myeloid leukaemia and their impact on patient prognosis. We discuss how stromal elements reduce the killing effects of therapies via a combination of contact-dependent (e.g. integrins) and contact-independent (i.e. secreted factors) mechanisms, accompanied by the establishment of an immunosuppressive microenvironment. Importantly, we underline the challenges of therapeutically targeting the bone marrow stroma to improve acute myeloid leukaemia patient outcomes, due to the inherent heterogeneity of stromal cell populations. LINKED ARTICLES: This article is part of a themed issue on Cancer Microenvironment and Pharmacological Interventions. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v181.2/issuetoc.

Asunto(s)

Leucemia Mieloide Aguda , Células Madre Mesenquimatosas , Adulto , Humanos , Médula Ósea/patología , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/patología , Células Madre Mesenquimatosas/patología , Células del Estroma , Fibroblastos/patología , Microambiente Tumoral , Células de la Médula Ósea/patología

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BACKGROUND: Gallbladder cancer (GBC) is a prevalent and deadly biliary tract carcinoma, often diagnosed at advanced stages with limited treatment options. The 5-year survival rate varies widely from 4 to 60%, mainly due to differences in disease stage detection. With only a small fraction of patients having resectable tumors and a high incidence of metastasis, advanced GBC stages are characterized by significant chemoresistance. Identification of new therapeutic targets is crucial, and recent studies have shown that the Endothelin-1 (ET-1) signaling pathway, involving ETAR and/or ETBR receptors (ETRs), plays a crucial role in promoting tumor aggressiveness in various cancer models. Blocking one or both receptors has been reported to reduce invasiveness and chemoresistance in cancers like ovarian, prostate, and colon. Furthermore, transcriptomic studies have associated ET-1 levels with late stages of GBC; however, it remains unclear whether its signaling or its inhibition has implications for its aggressiveness. Although the role of ET-1 signaling in gallbladder physiology is minimally understood, its significance in other tumor models leads us to hypothesize its involvement in GBC malignancy. RESULTS: In this study, we investigated the expression of ET-1 pathway proteins in three GBC cell lines and a primary GBC culture. Our findings demonstrated that both ETAR and ETBR receptors are expressed in GBC cells and tumor samples. Moreover, we successfully down-regulated ET-1 signaling using a non-selective ETR antagonist, Macitentan, which resulted in reduced migratory and invasive capacities of GBC cells. Additionally, Macitentan treatment chemosensitized the cells to Gemcitabine, a commonly used therapy for GBC. CONCLUSION: For the first time, we reveal the role of the ET-1 pathway in GBC cells, providing insight into the potential therapeutic targeting of its receptors to mitigate invasion and chemoresistance in this cancer with limited treatment options. These findings pave the way for further exploration of Macitentan or other ETR antagonists as potential therapeutic strategies for GBC management. In summary, our study represents a groundbreaking contribution to the field by providing the first evidence of the ET 1 pathway's pivotal role in modulating the behavior and aggressiveness of GBC cells, shedding new light on potential therapeutic targets.

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The HOXA9 transcription factor serves as a molecular orchestrator in cancer stemness, epithelial-mesenchymal transition (EMT), metastasis, and generation of the tumor microenvironment in hematological and solid malignancies. However, the multiple modes of regulation, multifaceted functions, and context-dependent interactions responsible for the dual role of HOXA9 as an oncogene or tumor suppressor in cancer remain obscure. Hence, unravelling its molecular complexities, binding partners, and interacting signaling molecules enables us to comprehend HOXA9-mediated transcriptional programs and molecular crosstalk. However, it is imperative to understand its central role in fundamental biological processes such as embryogenesis, foetus implantation, hematopoiesis, endothelial cell proliferation, and tissue homeostasis before designing targeted therapies. Indeed, it presents an enormous challenge for clinicians to selectively target its oncogenic functions or restore tumor-suppressive role without altering normal cellular functions. In addition to its implications in cancer, the present review also focuses on the clinical applications of HOXA9 in recurrence and drug resistance, which may provide a broader understanding beyond oncology, open new avenues for clinicians for accurate diagnoses, and develop personalized treatment strategies. Furthermore, we have also discussed the existing therapeutic options and accompanying challenges in HOXA9-targeted therapies in different cancer types.