RESUMEN

Cuproptosis is a new kind of cell death that depends on delivering copper ions into mitochondria to trigger the aggradation of tricarboxylic acid (TCA) cycle proteins and has been observed in various cancer cells. However, whether cuproptosis occurs in cancer stem cells (CSCs) is unexplored thus far, and CSCs often reside in a hypoxic tumor microenvironment (TME) of triple negative breast cancers (TNBC), which suppresses the expression of the cuproptosis protein FDX1, thereby diminishing anticancer efficacy of cuproptosis. Herein, a ROS-responsive active targeting cuproptosis-based nanomedicine CuET@PHF is developed by stabilizing copper ionophores CuET nanocrystals with polydopamine and hydroxyethyl starch to eradicate CSCs. By taking advantage of the photothermal effects of CuET@PHF, tumor hypoxia is overcome via tumor mechanics normalization, thereby leading to enhanced cuproptosis and immunogenic cell death in 4T1 CSCs. As a result, the integration of CuET@PHF and mild photothermal therapy not only significantly suppresses tumor growth but also effectively inhibits tumor recurrence and distant metastasis by eliminating CSCs and augmenting antitumor immune responses. This study presents the first evidence of cuproptosis in CSCs, reveals that disrupting hypoxia augments cuproptosis cancer therapy, and establishes a paradigm for potent cancer therapy by simultaneously eliminating CSCs and boosting antitumor immunity.

Asunto(s)

Cobre , Nanomedicina , Células Madre Neoplásicas , Neoplasias de la Mama Triple Negativas , Microambiente Tumoral , Neoplasias de la Mama Triple Negativas/patología , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/terapia , Microambiente Tumoral/efectos de los fármacos , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/metabolismo , Animales , Femenino , Nanomedicina/métodos , Cobre/química , Cobre/farmacología , Línea Celular Tumoral , Ratones , Nanopartículas/química , Ratones Endogámicos BALB C , Terapia Fototérmica/métodos , Humanos , Polímeros/química , Indoles/farmacología

RESUMEN

The notorious tumor microenvironment (TME) usually becomes more deteriorative during phototherapeutic progress that hampers the antitumor efficacy. To overcome this issue, we herein report the ameliorative and adaptive nanoparticles (TPASIC-PFH@PLGA NPs) that simultaneously reverse hypoxia TME and switch photoactivities from photothermal-dominated state to photodynamic-dominated state to maximize phototherapeutic effect. TPASIC-PFH@PLGA NPs are designed by incorporating oxygen-rich liquid perfluorohexane (PFH) into the intraparticle microenvironment to regulate the intramolecular motions of AIE photosensitizer TPASIC. TPASIC exhibits a unique aggregation-enhanced reactive oxygen species (ROS) generation feature. PFH incorporation affords TPASIC the initially dispersed state, thus promoting active intramolecular motions and photothermal conversion efficiency. While PFH volatilization leads to nanoparticle collapse and the formation of tight TPASIC aggregates with largely enhanced ROS generation efficiency. As a consequence, PFH incorporation not only currently promotes both photothermal and photodynamic efficacies of TPASIC and increases the intratumoral oxygen level, but also enables the smart photothermal-to-photodynamic switch to maximize the phototherapeutic performance. The integration of PFH and AIE photosensitizer eventually delivers more excellent antitumor effect over conventional phototherapeutic agents with fixed photothermal and photodynamic efficacies. This study proposes a new nanoengineering strategy to ameliorate TME and adapt the treatment modality to fit the changed TME for advanced antitumor applications.

Asunto(s)

Fluorocarburos , Nanopartículas , Fotoquimioterapia , Fármacos Fotosensibilizantes , Especies Reactivas de Oxígeno , Microambiente Tumoral , Nanopartículas/química , Microambiente Tumoral/efectos de los fármacos , Animales , Fotoquimioterapia/métodos , Especies Reactivas de Oxígeno/metabolismo , Fluorocarburos/química , Fluorocarburos/farmacología , Línea Celular Tumoral , Fármacos Fotosensibilizantes/uso terapéutico , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/química , Humanos , Ratones , Neoplasias/terapia , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Ratones Endogámicos BALB C , Terapia Fototérmica/métodos , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Fototerapia/métodos , Femenino

RESUMEN

Infiltration of immunosuppressive cells into the breast tumor microenvironment (TME) is associated with suppressed effector T cell (Teff) responses, accelerated tumor growth, and poor clinical outcomes. Previous studies from our group and others identified infiltration of immunosuppressive myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) as critical contributors to immune dysfunction in the orthotopic claudin-low tumor model, limiting the efficacy of adoptive cellular therapy. However, approaches to target these cells in the TME are currently lacking. To overcome this barrier, polymeric micellular nanoparticles (PMNPs) were used for the co-delivery of small molecule drugs activating Toll-like receptors 7 and 8 (TLR7/8) and inhibiting PI3K delta (PI3Kδ). The immunomodulation of the TME by TLR7/8 agonist and PI3K inhibitor led to type 1 macrophage polarization, decreased MDSC accumulation and selectively decreased tissue-resident Tregs in the TME, while enhancing the T and B cell adaptive immune responses. PMNPs significantly enhanced the anti-tumor activity of local radiation therapy (RT) in mice bearing orthotopic claudin-low tumors compared to RT alone. Taken together, these data demonstrate that RT combined with a nanoformulated immunostimulant diminished the immunosuppressive TME resulting in tumor regression. These findings set the stage for clinical studies of this approach.

Asunto(s)

Nanopartículas , Receptor Toll-Like 7 , Receptor Toll-Like 8 , Microambiente Tumoral , Animales , Microambiente Tumoral/efectos de los fármacos , Receptor Toll-Like 7/agonistas , Femenino , Nanopartículas/química , Ratones , Receptor Toll-Like 8/agonistas , Inmunomodulación/efectos de los fármacos , Línea Celular Tumoral , Fosfatidilinositol 3-Quinasa Clase I , Células Supresoras de Origen Mieloide/efectos de los fármacos , Células Supresoras de Origen Mieloide/inmunología , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/inmunología , Ratones Endogámicos BALB C , Micelas , Humanos

RESUMEN

Photodynamic therapy (PDT) is an appealing modality for cancer treatments. However, the limited tissue penetration depth of external-excitation light makes PDT impossible in treating deep-seated tumors. Meanwhile, tumor hypoxia and intracellular reductive microenvironment restrain the generation of reactive oxygen species (ROS). To overcome these limitations, a tumor-targeted self-illuminating supramolecular nanoparticle T-NPCe6-L-N is proposed by integrating photosensitizer Ce6 with luminol and nitric oxide (NO) for chemiluminescence resonance energy transfer (CRET)-activated PDT. The high H2O2 level in tumor can trigger chemiluminescence of luminol to realize CRET-activated PDT without exposure of external light. Meanwhile, the released NO significantly relieves tumor hypoxia via vascular normalization and reduces intracellular reductive GSH level, further enhancing ROS abundance. Importantly, due to the different ROS levels between cancer cells and normal cells, T-NPCe6-L-N can selectively trigger PDT in cancer cells while sparing normal cells, which ensured low side effect. The combination of CRET-based photosensitizer-activation and tumor microenvironment modulation overcomes the innate challenges of conventional PDT, demonstrating efficient inhibition of orthotopic and metastatic tumors on mice. It also provoked potent immunogenic cell death to ensure long-term suppression effects. The proof-of-concept research proved as a new strategy to solve the dilemma of PDT in treatment of deep-seated tumors.

Asunto(s)

Nanopartículas , Fotoquimioterapia , Fármacos Fotosensibilizantes , Microambiente Tumoral , Fotoquimioterapia/métodos , Microambiente Tumoral/efectos de los fármacos , Animales , Nanopartículas/química , Fármacos Fotosensibilizantes/uso terapéutico , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/farmacología , Humanos , Ratones , Línea Celular Tumoral , Especies Reactivas de Oxígeno/metabolismo , Transferencia de Energía , Neoplasias/tratamiento farmacológico , Neoplasias/terapia , Ratones Endogámicos BALB C , Luz , Ratones Desnudos , Óxido Nítrico/metabolismo

RESUMEN

The challenges generated by insufficient T cell activation and infiltration have constrained the application of immunotherapy. Making matters worse, the complex tumor microenvironment (TME), resistance to apoptosis collectively poses obstacles for cancer treatment. The carrier-free small molecular self-assembly strategy is a current research hotspot to overcome these challenges. This strategy can transform multiple functional agents into sustain-released hydrogel without the addition of any excipients. Herein, a coordination and hydrogen bond mediated tricomponent hydrogel (Cel hydrogel) composed of glycyrrhizic acid (GA), copper ions (Cu2+) and celastrol (Cel) was initially constructed. The hydrogel can regulate TME by chemo-dynamic therapy (CDT), which increases reactive oxygen species (ROS) in conjunction with GA and Cel, synergistically expediting cellular apoptosis. What's more, copper induced cuproptosis also contributes to the anti-tumor effect. In terms of regulating immunity, ROS generated by Cel hydrogel can polarize tumor-associated macrophages (TAMs) into M1-TAMs, Cel can induce T cell proliferation as well as activate DC mediated antigen presentation, which subsequently induce T cell proliferation, elevate T cell infiltration and enhance the specific killing of tumor cells, along with the upregulation of PD-L1 expression. Upon co-administration with aPD-L1, this synergy mitigated both primary and metastasis tumors, showing promising clinical translational value.

Asunto(s)

Cobre , Hidrogeles , Inhibidores de Puntos de Control Inmunológico , Inmunoterapia , Activación de Linfocitos , Triterpenos Pentacíclicos , Especies Reactivas de Oxígeno , Linfocitos T , Microambiente Tumoral , Triterpenos Pentacíclicos/farmacología , Hidrogeles/química , Animales , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Inmunoterapia/métodos , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Ratones , Activación de Linfocitos/efectos de los fármacos , Cobre/química , Microambiente Tumoral/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Línea Celular Tumoral , Humanos , Ratones Endogámicos C57BL , Ácido Glicirrínico/farmacología , Ácido Glicirrínico/química , Femenino , Triterpenos/farmacología , Triterpenos/química

RESUMEN

PURPOSE: To construct a comprehensive model for predicting the prognosis of patients with glioblastoma (GB) using a radiomics method and integrating clinical risk factors, tumor microenvironment (TME), and imaging characteristics. MATERIALS AND METHODS: In this retrospective study, we included 148 patients (85 males and 63 females; median age 53 years) with isocitrate dehydrogenase-wildtype GB between January 2016 and April 2022. Patients were randomly divided into the training (n = 104) and test (n = 44) sets. The best feature combination related to GB overall survival (OS) was selected using LASSO Cox regression analyses. Clinical, radiomics, clinical-radiomics, clinical-TME, and clinical-radiomics-TME models were established. The models' concordance index (C-index) was evaluated. The survival curve was drawn using the Kaplan-Meier method, and the prognostic stratification ability of the model was tested. RESULTS: LASSO Cox analyses were used to screen the factors related to OS in patients with GB, including MGMT (hazard ratio [HR] = 0.642; 95% CI 0.414-0.997; P = 0.046), TERT (HR = 1.755; 95% CI 1.095-2.813; P = 0.019), peritumoral edema (HR = 1.013; 95% CI 0.999-1.027; P = 0.049), tumor purity (TP; HR = 0.982; 95% CI 0.964-1.000; P = 0.054), CD163 + tumor-associated macrophages (TAMs; HR = 1.049; 95% CI 1.021-1.078; P < 0.001), CD68 + TAMs (HR = 1.055; 95% CI 1.018-1.093; P = 0.004), and the six radiomics features. The clinical-radiomics-TME model had the best survival prediction ability, the C­index was 0.768 (0.717-0.819). The AUC of 1­, 2­, and 3­year OS prediction in the test set was 0.842, 0.844, and 0.795, respectively. CONCLUSION: The clinical-radiomics-TME model is the most effective for predicting the survival of patients with GB. Radiomics features, TP, and TAMs play important roles in the prognostic model.

RESUMEN

AIMS: This research developed a prognostic model for OS patients based on the Mechanistic Target of Rapamycin Complex 1 (mTORC1) signature. BACKGROUND: The mTORC1 signaling pathway has a critical role in the maintenance of cellular homeostasis and tumorigenesis and development through the regulation of cell growth, metabolism and autophagy. However, the mechanism of action of this signaling pathway in Osteosarcoma (OS) remains unclear. OBJECTIVE: The datasets including the TARGET-OS and GSE39058, and 200 mTORC1 genes were collected. METHODS: The mTORC1 signaling-related genes were obtained based on the Molecular Signatures Database (MSigDB) database, and the single sample gene set enrichment analysis (ssGSEA) algorithm was utilized in order to calculate the mTORC1 score. Then, the WGCNA were performed for the mTORC1-correlated gene module, the un/multivariate and lasso Cox regression analysis were conducted for the RiskScore model. The immune infiltration analysis was performed by using the ssGSEA method, ESTIMATE tool and MCP-Count algorithm. KM survival and Receiver Operating Characteristic (ROC) Curve analysis were performed by using the survival and timeROC package. RESULTS: The mTORC1 score and WGCNA with ß = 5 screened the mTORC1 positively correlated skyblue2 module that included 67 genes, which are also associated with the metabolism and hypoxia pathways. Further narrowing of candidate genes and calculating the regression coefficient, we developed a useful and reliable RiskScore model, which can classify the patients in the training and validation set into high and low-risk groups based on the median value of RiskScore as an independent and robust prognostic factor. High-risk patients had a significantly poor prognosis, lower immune infiltration level of multiple immune cells and prone to cancer metastasis. Finally, we a nomogram model incorporating the metastasis features and RiskScore showed excellent prediction accuracy and clinical practicability. CONCLUSION: We developed a useful and reliable risk prognosis model based on the mTORC1 signaling signature.

RESUMEN

Anaplastic thyroid carcinoma (ATC) is the most aggressive thyroid cancer, and it has a poor prognosis and high probability of metastatic recurrence. The long-term survival of cancer cells depends on their ability to settle in a favorable environment. Cancer cells interact with other cells in the tumor microenvironment to shape the "soil" and make it suitable for cell growth by forming an extremely complex tumor ecosystem. The extracellular matrix (ECM) is an essential component of the tumor ecosystem, and its biological and mechanical changes strongly affect tumor invasion, metastasis, immune escape and drug resistance. Compared to normal tissues, biological processes, such as collagen synthesis and ECM signaling, are significantly activated in ATC tissues. However, how ATC triggers changes in the properties of the ECM and its interaction with the ECM remain poorly characterized. Therefore, an in-depth study of the regulatory mechanism of the abnormal activation of ECM signaling in ATC is highly important for achieving the therapeutic goal of exerting antitumor effects by destroying the "soil" in which cancer cells depend for survival. In this research, we revealed the aberrant activation state of ECM signaling in ATC progression and attempted to uncover the potential mechanism of action of ECM components in ATC, with the aim of providing new drug targets for ATC therapy.

Asunto(s)

Matriz Extracelular , Carcinoma Anaplásico de Tiroides , Neoplasias de la Tiroides , Microambiente Tumoral , Carcinoma Anaplásico de Tiroides/patología , Carcinoma Anaplásico de Tiroides/tratamiento farmacológico , Carcinoma Anaplásico de Tiroides/metabolismo , Humanos , Matriz Extracelular/metabolismo , Neoplasias de la Tiroides/patología , Neoplasias de la Tiroides/tratamiento farmacológico , Neoplasias de la Tiroides/metabolismo , Transducción de Señal

RESUMEN

OBJECTIVES: MET exon 14 skipping alterations (METex14+) represent a heterogeneous subgroup of non-small cell lung cancer (NSCLC) with distinct biological and genomic features. We characterized this heterogeneity in a large cohort, integrating genomic and transcriptomic profiling with clinical outcomes, to elucidate the histologic and molecular traits and survival patterns of METex14+ NSCLC. MATERIALS AND METHODS: NSCLC tissue samples (n = 28,739) underwent DNA-based next-generation sequencing (592 genes, NextSeq) or whole-exome sequencing (NovaSeq), RNA-sequencing including whole transcriptome sequencing (WTS, NovaSeq), and PD-L1 IHC (Dako 22C3) at Caris Life Sciences. Immune cell fractions were estimated from bulk RNA sequencing (quanTIseq). Real-world survival data (mOS) was calculated from insurance claims. Statistical analyses employed Chi-square, Fisher's exact, or Mann-Whitney U and log-rank tests and were corrected for hypothesis testing where applicable. RESULTS: A total of 711 METex14+ cases were detected. Of 575 cases of defined histology, 77 (13.6 %) were squamous (Sq), 474 (82.3 %) were nSq (non-squamous), and 24 (4.1 %) were adenosquamous. Mutations in POT1 and BRCA2 were enriched, and amplifications in MDM2, HMGA2, CDK4, and MET were common in METex14+ tumors. TMB-high and TP53 mutated tumors were reduced in METex14+ independent of histology. KEAP1 (2.1 vs 14.7 %) and STK11 mutations (0.8 vs 17.1 %) were reduced only in METex14+ nSq (vs METex14+ Sq, q < 0.05). While the prevalence of PD-L1 high tumors was enriched in METex14+ independent of histology, T-cell inflamed tumors were enriched only in nSq METex14+. B-cells and CD8+ T-cells (1.07-1.43-fold) were enriched in nSq METex14+, and dendritic cells (0.32 fold) were reduced only in METex14+ Sq. METex14+ tumors had a modest improvement in mOS compared to METex14- tumors (mOS = 22.9 m vs 18.6 m, HR = 0.914, p = 0.04). Moreover, METex14+ tumors who received immunotherapy (IO) had a modest improvement in survival (mOS = 27.5 m vs 21.8 m; HR = 0.803, p = 0.03) compared to those who did not receive IO. METex14+ nSq tumors were associated with improved mOS compared to METex14+ Sq tumors (mOS = 27.7 vs 8.9 m, HR = 0.493, p < 0.0001). CONCLUSION: METex14+ alterations are a heterogeneous subgroup of NSCLC. Our analysis reveals that METex14+ nSq exhibit improved survival compared to METex14+ Sq. The distinct genomic and transcriptomic variations across histologies warrant clinical consideration.

RESUMEN

The intricate origins, subsets, and characteristics of TCR (T Cell Receptor) s, along with the mechanisms underpinning the antitumor response of tumor-infiltrating T lymphocytes within the tumor microenvironment (TME) remain enigmatic. Recently, the advent of single-cell RNA+TCR-sequencing (scRNA+TCR seq) has revolutionized TME analysis, providing unprecedented insight into the origins, cell subsets, TCR CDR3 compositions, and the expression patterns of response/depletion factors within individual tumor-infiltrating T lymphocytes. Our analysis of the shared scRNA+TCR seq dataset revealed a substantial presence of dual TCR T cells, characterized by clonal hyperplasia and remarkable migratory prowess across various tissues, including blood, normal, peritumoral, and tumor tissues in non-small cell lung cancer patients. Notably, dual TCR CD8+T cells predominantly fell within the CXCL13+subset, displaying potent antitumor activity and a strong preference for tumor tissue residency. Conversely, dual TCR CD4+T cells were predominantly classified as CD5+ or LMNA+subsets, exhibiting a more even distribution across diverse tissue types. By harnessing scRNA+TCR seq and other cutting-edge technologies, we can delve deeper into the effects and mechanisms that regulate the antitumor response or tolerance of dual TCR T cells. This innovative approach holds immense promise in offering fresh perspectives and avenues for advancing research on TIL (Tumor infiltrating lymphocyte)s within the TME.

Asunto(s)

Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Receptores de Antígenos de Linfocitos T , Microambiente Tumoral , Humanos , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Carcinoma de Pulmón de Células no Pequeñas/genética , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Microambiente Tumoral/inmunología , Receptores de Antígenos de Linfocitos T/metabolismo , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo , Análisis de la Célula Individual/métodos

RESUMEN

OBJECTIVE: Pancreatic cancer is an incurable malignant disease with extremely poor prognosis and a complex tumor microenvironment. We sought to characterize the role of Annexin A1 (ANXA1) in pancreatic cancer, including its ability to promote efferocytosis and antitumor immune responses. METHODS: The tumor expression of ANXA1 and cleaved Caspase-3 (c-Casp3) and numbers of tumor-infiltrating CD68+ macrophages in 151 cases of pancreatic cancer were examined by immunohistochemistry and immunofluorescence. The role of ANXA1 in pancreatic cancer was investigated using myeloid-specific ANXA1-knockout mice. The changes in tumor-infiltrating immune cell populations induced by ANXA1 deficiency in macrophages were assessed by single-cell RNA sequencing and flow cytometry. RESULTS: ANXA1 expression in pancreatic cancer patient samples correlated with the number of CD68+ macrophages. The percentage of ANXA1+ tumor-infiltrating macrophages negatively correlated with c-Casp3 expression and was significantly associated with worse survival. In mice, myeloid-specific ANXA1 deficiency inhibited tumor growth and was accompanied by the accumulation of apoptotic cells in pancreatic tumor tissue caused by inhibition of macrophage efferocytosis, which was dependent on cGAS-STING pathway-induced type I interferon signaling. ANXA1 deficiency significantly remodeled the intratumoral lymphocyte and macrophage compartments in tumor-bearing mice by increasing the number of effector T cells and pro-inflammatory macrophages. Furthermore, combination therapy of ANXA1 knockdown with gemcitabine and anti-programmed cell death protein-1 antibody resulted in synergistic inhibition of pancreatic tumor growth. CONCLUSION: This research uncovers a novel role of macrophage ANXA1 in pancreatic cancer. ANXA1-mediated regulation of efferocytosis by tumor-associated macrophages promotes antitumor immune response via STING signaling, suggesting potential treatment strategies for pancreatic cancer.

Asunto(s)

Anexina A1 , Macrófagos , Proteínas de la Membrana , Nucleotidiltransferasas , Neoplasias Pancreáticas , Microambiente Tumoral , Neoplasias Pancreáticas/inmunología , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/metabolismo , Animales , Humanos , Ratones , Microambiente Tumoral/inmunología , Anexina A1/metabolismo , Anexina A1/genética , Macrófagos/metabolismo , Macrófagos/inmunología , Nucleotidiltransferasas/metabolismo , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genética , Transducción de Señal , Femenino , Masculino , Ratones Noqueados , Eferocitosis

RESUMEN

Breast cancer stands as the most prevalent cancer diagnosed worldwide, often leading to brain metastasis, a challenging complication characterized by high mortality rates and a grim prognosis. Understanding the intricate mechanisms governing breast cancer brain metastasis (BCBM) remains an ongoing challenge. The unique microenvironment in the brain fosters an ideal setting for the colonization of breast cancer cells. The tumor microenvironment (TME) in brain metastases plays a pivotal role in the initiation and progression of BCBM, shaping the landscape for targeted therapeutic interventions. Current research primarily concentrates on unraveling the complexities of the TME in BCBM, with a particular emphasis on neuroglia and immune cells, such as microglia, monocyte-derived macrophages (MDMs), astrocytes and T cells. This comprehensive review delves deeply into these elements within the TME of BCBM, shedding light on their interplay, mechanisms, and potential as therapeutic targets to combat BCBM.

Asunto(s)

Neoplasias Encefálicas , Neoplasias de la Mama , Microambiente Tumoral , Humanos , Microambiente Tumoral/inmunología , Neoplasias de la Mama/patología , Neoplasias de la Mama/inmunología , Neoplasias Encefálicas/secundario , Neoplasias Encefálicas/inmunología , Neoplasias Encefálicas/patología , Femenino , Neuroglía/patología , Neuroglía/inmunología , Animales

RESUMEN

INTRODUCTION: Colorectal cancer (CRC) remains one of the leading causes of cancer-related morbidity and mortality worldwide. This disease is complex and heterogeneous, influenced by a variety of genetic, epigenetic, and environmental factors that drive CRC initiation and progression. Despite advances in therapeutic strategies, the five-year survival rate for metastatic CRC is alarmingly low. Traditional two-dimensional (2D) cell culture systems have been the foundation of cancer research, but their inability to replicate the complex tumor microenvironment (TME) limits their effectiveness. AREAS COVERED: This paper explores the evolution of CRC models, starting with the limitations of traditional 2D cell culture systems and the significant advancements offered by 3D models. Additionally, it highlights 3D bioprinting and on-chip CRC models, which have enhanced the ability to mimic in vivo conditions. EXPERT OPINION: The transition to advanced 3D models represents a pivotal shift in CRC research, offering considerable improvements over the established 2D models. These models hold promise for the development of patient-specific models that better mimic in vivo conditions. However, the inherent complexity of CRC continues to pose challenges in developing models that can fully capture the disease's multifaceted nature. This complexity and high costs associated with these technologies, along with the need for standardized protocols, pose significant challenges to their widespread adoption.

RESUMEN

Neoadjuvant intratumoral (IT) therapy could amplify the weak responses to checkpoint blockade therapy observed in breast cancer (BC). In this study, we administered neoadjuvant IT anti-canine PD-1 therapy (IT acPD-1) alone or combined with IT cowpea mosaic virus therapy (IT CPMV/acPD-1) to companion dogs diagnosed with canine mammary cancer (CMC), a spontaneous tumor resembling human BC. CMC patients treated weekly with acPD-1 (n = 3) or CPMV/acPD-1 (n = 3) for four weeks or with CPMV/acPD-1 (n = 3 patients not candidates for surgery) for up to 11 weeks did not experience immune-related adverse events. We found that acPD-1 and CPMV/acPD-1 injections resulted in tumor control and a reduction in injected tumors in all patients and in noninjected tumors located in the ipsilateral and contralateral mammary chains of treated dogs. In two metastatic CMC patients, CPMV/acPD-1 treatments resulted in the control and reduction of established lung metastases. CPMV/acPD-1 treatments were associated with altered gene expression related to TLR1-4 signaling and complement pathways. These novel therapies could be effective for CMC patients. Owing to the extensive similarities between CMC and human BC, IT CPMV combined with approved anti-PD-1 therapies could be a novel and effective immunotherapy to treat local BC and suppress metastatic BC.

Asunto(s)

Comovirus , Inmunoterapia , Neoplasias Pulmonares , Neoplasias Mamarias Animales , Nanopartículas , Terapia Neoadyuvante , Receptor de Muerte Celular Programada 1 , Animales , Perros , Femenino , Inmunoterapia/métodos , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/secundario , Nanopartículas/química , Neoplasias Mamarias Animales/terapia , Neoplasias Mamarias Animales/patología , Humanos

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PURPOSE: Tumor-associated macrophages (TAMs) are important biomarkers of tumor invasion and prognosis in patients with glioblastoma. We combined the imaging and radiomics features of preoperative MRI to predict CD68+ macrophage infiltration. METHODS: Clinical, MRI image, and pathology data of 188 patients with glioblastoma were analyzed. Overall, 143 patients were included in the training (n = 101) and validation (n = 42) sets, whereas 45 patients were included in an independent test set. The optimal cut-off value (14.8%) was based on the minimum p-value formed by the Kaplan-Meier survival analysis and log-rank tests which divided patients into groups with high CD68+ TAMs (≥ 14.8%) and low CD68+ TAMs (< 14.8%). Regions of interest and radiomics features extraction were based on contrast-enhanced T1-weighted images (CE-T1WI) and T2WI. Multi-parameter stepwise regression was used to create the clinical, radiomics, and combined models, each evaluated using the receiver operating characteristic curve. Decision curve analysis was used to assess the clinical applicability of the nomogram. RESULTS: A clinical model based on the minimum apparent diffusion coefficient (ADCmin) revealed an area under the curve (AUC) of 0.768, 0.764, and 0.624 for the training set, validation set, and test set, respectively. The 2D radiomics model, based on two features, revealed an AUC of 0.783, 0.724, and 0.789 for the training, validation, and test sets, respectively. The 3D radiomics model, based on three features, revealed AUCs of 0.823, 0.811, and 0.787 for the training, validation, and test sets, respectively. The combined model, with ADCmin and radiomics features, showed the best performance, with AUCs of 0.865, 0.822, and 0.776 for the training, validation, and test sets, respectively. The calibration curve of the combined model nomogram showed good agreement between the estimated and actual probabilities. CONCLUSION: The combined model constructed using ADCmin, a quantitative imaging parameter, combined with five key radiomics features can be used to evaluate the extent of CD68+ macrophages before surgery.

RESUMEN

Focal adhesion kinase (FAK) expression has been linked to tumor growth, immunosuppression, metastasis, angiogenesis, and therapeutic resistance through kinase-dependent and kinase scaffolding functions in the nucleus and cytoplasm. Hence, targeting FAK alone or with other agents has gained attention as a potential therapeutic strategy. Moreover, mounting evidence shows that FAK activity can influence the tumor immune microenvironment crosstalk to support tumor progression. Recently, tumor immune microenvironment interaction orchestrators have shown to be promising therapeutic agents for cancer immunotherapies. Therefore, this review highlights how FAK regulates the tumor immune microenvironment interplay to promote tumor immune evasive mechanisms and their potential for combination therapies with standard cancer treatments.

RESUMEN

Hepatocellular carcinoma (HCC), a major subtype of liver cancer, poses significant therapeutic challenges due to its late diagnosis and rapid progression. The evolving landscape of immunotherapy offers a beacon of hope, with natural killer (NK) cells emerging as pivotal players in combating HCC. NK cells are unique cytotoxic lymphocytes that are essential in the fight against infections and malignancies. Phenotypic and functional NK cell abnormalities have been shown in HCC patients, indicating their significance as a component of the innate immune system against cancer. This review elucidates the critical role of NK cells in combating HCC, focusing on their interaction with the tumor microenvironment, the development of NK cell-based therapies, and the innovative strategies to enhance their efficacy in the immunosuppressive milieu of HCC. The review delves into the various therapeutic strategies, including autologous and allogeneic NK cell therapies, genetic engineering to improve NK cell resilience and targeting, and the integration of NK cells with other immunotherapeutic approaches like checkpoint inhibitors and oncolytic virotherapy. By highlighting recent advancements and the ongoing challenges in the field, this review sets the stage for future research directions that could unlock the full potential of NK cell-based immunotherapy for HCC, offering a beacon of hope for patients battling this formidable cancer.

RESUMEN

This study evaluated the cellular heterogeneity and molecular mechanisms of hepatocellular carcinoma (HCC). Single cell RNA sequencing (scRNA-seq), transcriptomic data, histone lactylation-related genes were collected from public databases. Cell-cell interaction, trajectory, pathway, and spatial transcriptome analyses were executed. Differential expression and survival analyses were conducted. Western blot, Real-time reverse transcription PCR (qRT-PCR), and Cell Counting Kit 8 (CCK8) assay were used to detect the expression of αSMA, AKR1B10 and its target genes, and verify the roles of AKR1B10 in HCC cells. Hepatic stellate cell (HSC) subgroups strongly interacted with tumor cell subgroups, and their spatial distribution was heterogeneous. Two candidate prognostic genes (AKR1B10 and RMRP) were obtained. LONP1, NPIPB3, and ZSWIM6 were determined as AKR1B10 targets. Besides, the expression levels of AKR1B10 and αSMA were significantly increased in LX-2 + HepG2 and LX-2 + HuH7 groups compared to those in LX-2 group, respectively. sh-AKR1B10 significantly inhibited the HCC cell proliferation and change the expression of AKR1B10 target genes, Bcl-2, Bax, Pan Kla, and H3K18la at protein levels. Our findings unveil the pivotal role of HSCs in HCC pathogenesis through regulating histone lactylation.

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Cancer stem cells (CSCs) have the potential to self-renew and induce cancer, which may contribute to a poor prognosis by enabling metastasis, recurrence, and therapy resistance. Hence, this study was performed to identify the association between CSC-related genes and triple-negative breast cancer (TNBC) development. Stemness gene sets were downloaded from StemChecker. Based on the online databases, a consensus clustering algorithm was conducted for unsupervised classification of TNBC samples. The variations between subtypes were assessed with regard to prognosis, tumor immune microenvironment (TIME), and chemotherapeutic sensitivity. The stemness-related gene signature was established and random survival forest analysis was employed to identify the core gene for validation experiments and tumor sphere formation assays. 499 patients with TNBC were classified into three subgroups and the Cluster 1 had a better OS than others. After that, WGCNA study was performed to identify genes important for Cluster 1 subtype. Out of all 8 modules, the subtype of Cluster 1 and the yellow module with 103 genes demonstrated the largest positive association. After that, a four-gene stemness-related signature was established. Based on the yellow module, the 39 potential pivotal genes were subjected to the random forest survival analysis to find out the gene that was relatively important for OS. KIF15 was confirmed as the targeted gene by LASSO and random survival forest analyses. In vitro experiments, the downregulation of KIF15 promoted the stemness of TNBC cells. The expression levels of stem cell markers Nanog, SOX2, and OCT4 were found to be elevated in TNBC cell lines after KIF15 inhibition. A stemness-associated risk model was constructed to forecast the clinical outcomes of TNBC patients. The downregulation of KIF15 expression in a subpopulation of TNBC stem cells may promote stemness and possibly TNBC progression.

Asunto(s)

Biomarcadores de Tumor , Regulación Neoplásica de la Expresión Génica , Cinesinas , Aprendizaje Automático , Células Madre Neoplásicas , Neoplasias de la Mama Triple Negativas , Humanos , Neoplasias de la Mama Triple Negativas/genética , Neoplasias de la Mama Triple Negativas/patología , Neoplasias de la Mama Triple Negativas/metabolismo , Neoplasias de la Mama Triple Negativas/mortalidad , Cinesinas/genética , Cinesinas/metabolismo , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Femenino , Pronóstico , Microambiente Tumoral/genética , Línea Celular Tumoral , Perfilación de la Expresión Génica , Algoritmos

RESUMEN

IGFBP6, a member of the IGF binding protein (IGFBP) family, is a specific inhibitor of insulin-like growth factor II (IGF-II) and can inhibit the growth of malignant tumors overexpressing IGF-II. Type 2 diabetes (T2D) is a basic disorder of glucose metabolism that can be regulated by IGF-related pathways. We performed bioinformatics analysis of the TCGA database to explore the possible mechanism of IGFBP6 in breast cancer (BC) metabolism and prognosis and collected clinical samples from BC patients with and without T2D to compare and verify the prognostic effect of IGFBP6. In our study, the levels of IGFBP1-6 were positively correlated with overall survival (OS) in patients with breast cancer. IGFBP6 was upregulated in estrogen receptor (ER)-positive BC, and ER-positive and progesterone receptor (PR) positive patients had a higher expression level of IGFBP6 than ER-negative and PR-negative patients. IGFBP6 could be used as an independent prognostic factor in BC. The expression of IGFBP6 was decreased in BC tissue, and BC tissue from patients with T2D had lower IGFBP6 expression levels than BC tissue from patients without T2D. IGFBP6 is mainly involved in the PI3K-Akt and TGF-ß signaling pathways and tumor microenvironment regulation. In terms of metabolism, the expression of IGFBP6 was negatively correlated with that of most glucose metabolism-related genes. IGFBP6 expression was mainly correlated with mutations in TP53, PIK3CA, CDH1, and MAP3K1. In addition, the upregulation of IGFBP6 in BC increased the drug sensitivity to docetaxel, paclitaxel and gemcitabine. Overall, these results indicated that high expression of IGFBP6 is associated with a good prognosis in BC patients, especially in those without T2D. It is not only involved in the maintenance of the tumor microenvironment in BC but also inhibits the energy metabolism of cancer cells through glucose metabolism-related pathways. These findings may provide a new perspective on IGFBP6 as a potential prognostic marker for BC.

Asunto(s)

Biomarcadores de Tumor , Neoplasias de la Mama , Proteína 6 de Unión a Factor de Crecimiento Similar a la Insulina , Humanos , Femenino , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Neoplasias de la Mama/genética , Neoplasias de la Mama/mortalidad , Pronóstico , Biomarcadores de Tumor/metabolismo , Proteína 6 de Unión a Factor de Crecimiento Similar a la Insulina/metabolismo , Proteína 6 de Unión a Factor de Crecimiento Similar a la Insulina/genética , Regulación Neoplásica de la Expresión Génica , Biología Computacional/métodos , Transducción de Señal , Glucosa/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/patología , Persona de Mediana Edad , Estimación de Kaplan-Meier , Bases de Datos Genéticas