RESUMEN
Breast cancer is a heterogeneous disease that arises as a multi-stage process involving multiple cell types. Patients diagnosed with the same clinical stage and pathological classification may have different prognoses and therapeutic responses due to alterations in molecular genetics. As an essential marker for the molecular subtyping of breast cancer, long non-coding RNAs (lncRNAs) play a crucial role in gene expression regulation, cell differentiation, and the maintenance of genomic stability. Here, we developed a modular framework for lncRNA identification and applied it to a breast cancer cohort to identify novel lncRNAs not previously annotated. To investigate the potential biological function, regulatory mechanisms, and clinical relevance of the novel lncRNAs, we elucidated the genomic and chromatin features of these lncRNAs, along with the associated protein-coding genes and putative enhancers involved in the breast cancer regulatory networks. Furthermore, we uncovered that the expression patterns of novel and annotated lncRNAs identified in breast cancer were related to the hormone response in the PAM50 subtyping criterion, as well as the immune response and progression states of breast cancer across different immune cells and immune checkpoint genes. Collectively, the comprehensive identification and functional analysis of lncRNAs revealed that these lncRNAs play an essential role in breast cancer by altering gene expression and participating in the regulatory networks, contributing to a better insight into breast cancer heterogeneity and potential avenues for therapeutic intervention.
Asunto(s)
Neoplasias de la Mama , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Redes Reguladoras de Genes , ARN Largo no Codificante , Humanos , ARN Largo no Codificante/genética , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Femenino , Transcriptoma , Biomarcadores de Tumor/genética , PronósticoRESUMEN
Responsive thermochromic fiber materials capable of miniaturization and integrating comfortably and compliantly onto the soft and dynamically deforming human body are promising materials for visualized personal health monitoring. However, their development is hindered by monotonous colors, low-contrast color changes, and poor reversibility. Herein, full-color "off-on" thermochromic fluorescent fibers are prepared based on self-crystallinity phase change and Förster resonance energy transfer for long-term and passive body-temperature monitoring, especially for various personalized customization purposes. The off-on switching luminescence characteristic is derived from the reversible conversion of the dispersion state and fluorescent emission by fluorophores and quencher molecules, which are embedded in the matrix of a phase-change material, during the crystallizing/melting processes. The achievement of full-color fluorescence is attributed to the large modulation range of fluorescence colors according to primary color additive theory. These thermochromic fluorescent fibers exhibit good mechanical properties, fluorescent emission contrast, and reversibility, showing their great potential in flexible smart display devices. Moreover, the response temperature of the thermochromic fibers is controllable by adjusting the phase-change material, enabling body-temperature-triggered luminescence; this property highlights their potential for human body-temperature monitoring and personalized customization. This work presents a new strategy for designing and exploring flexible sensors with higher comprehensive performances.
Asunto(s)
Dispositivos Electrónicos Vestibles , Humanos , Monitoreo Fisiológico/instrumentación , Monitoreo Fisiológico/métodos , Color , TemperaturaRESUMEN
CD8+ T cells are critical for host antitumor responses, whereas persistent antigenic stimulation and excessive inflammatory signals lead to T cell dysfunction or exhaustion. Increasing early memory T cells can improve T cell persistence and empower T cell-mediated tumor eradication, especially for adoptive cancer immunotherapy. Here, it is reported that tumor-associated monocytes (TAMos) are highly correlated with the accumulation of CD8+ memory T cells in human cancers. Further analysis identifies that TAMos selectively reprogram CD8+ T cells into T central memory-like (TCM-like) cells with enhanced recall responses. L-NMMA, a pan nitric oxide synthase inhibitor, can mitigate TAMo-mediated inhibition of T cell proliferation without affecting TCM-like cell generation. Moreover, the modified T cells by TAMo exposure and L-NMMA treatment exhibit long-term persistence and elicit superior antitumor effects in vivo. Mechanistically, the transmembrane protein CD300LG is involved in TAMo-mediated TCM-like cell polarization in a cell-cell contact-dependent manner. Thus, the terminally differentiated TAMo subset (CD300LGhighACElow) mainly contributes to TCM-like cell development. Taken together, these findings establish the significance of TAMos in boosting T-cell antitumor immunity.
Asunto(s)
Linfocitos T CD8-positivos , Monocitos , Linfocitos T CD8-positivos/inmunología , Ratones , Animales , Monocitos/inmunología , Humanos , Células T de Memoria/inmunología , Memoria Inmunológica/inmunología , Modelos Animales de Enfermedad , Neoplasias/inmunología , Neoplasias/terapia , Ratones Endogámicos C57BL , Línea Celular Tumoral , Inmunoterapia Adoptiva/métodosRESUMEN
Immune checkpoint blockade has become an effective approach to reverse the immune tolerance of tumor cells. Indoleamine 2,3-dioxygenase 1 (IDO1) is frequently upregulated in many types of cancers and contributes to the establishment of an immunosuppressive cancer microenvironment, which has been thought to be a potential target for cancer therapy. However, the development of IDO1 inhibitors for clinical application is still limited. Here, we isolated a DNA aptamer with a strong affinity and inhibitory activity against IDO1, designated as IDO-APT. By conjugating with nanoparticles, in situ injection of IDO-APT to CT26 tumor-bearing mice significantly suppresses the activity of regulatory T cells and promotes the function of CD8+ T cells, leading to tumor suppression and prolonged survival. Therefore, this functional IDO1-specific aptamer with potent anti-tumor effects may serve as a potential therapeutic strategy in cancer immunotherapy. Our data provide an alternative way to target IDO1 in addition to small molecule inhibitors.
RESUMEN
Aptamers associated with cancer targeting therapy are commonly focused on cell membrane proteins; however, the study of intracellular, particularly, nuclear proteins is limited. The nuclear phosphatase PAC1 has been reported to be a potential T cell-related immunotherapeutic target. Here, we identified an aptamer, designated as PA5, with high affinity and specificity for PAC1 through the systematic evolution of ligands by exponential enrichment (SELEX) procedure. We then developed a dual-module aptamer PAC1-AS consisting of a cell-internalizing module and a targeting module, which can recognize PAC1 in the nucleus under physiological conditions. This modularized aptamer raises the possibility of manipulating endosomes and provides insights into the exploration and development of an efficient cancer immunotherapy approach.
Asunto(s)
Aptámeros de Nucleótidos , Aptámeros de Nucleótidos/metabolismo , Técnica SELEX de Producción de Aptámeros/métodos , Ligandos , Proteínas Nucleares , Linfocitos TRESUMEN
Background: To investigate reliable associations between dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) features and gene expression characteristics in breast cancer (BC) and to develop and validate classifiers for predicting PAM50 subtypes and prognosis from DCE-MRI non-invasively. Methods: Two radiogenomics cohorts with paired DCE-MRI and RNA-sequencing (RNA-seq) data were collected from local and public databases and divided into discovery (n = 174) and validation cohorts (n = 72). Six external datasets (n = 1,443) were used for prognostic validation. Spatial-temporal features of DCE-MRI were extracted, normalized properly, and associated with gene expression to identify the imaging features that can indicate subtypes and prognosis. Results: Expression of genes including RBP4, MYBL2, and LINC00993 correlated significantly with DCE-MRI features (q-value < 0.05). Importantly, genes in the cell cycle pathway exhibited a significant association with imaging features (p-value < 0.001). With eight imaging-associated genes (CHEK1, TTK, CDC45, BUB1B, PLK1, E2F1, CDC20, and CDC25A), we developed a radiogenomics prognostic signature that can distinguish BC outcomes in multiple datasets well. High expression of the signature indicated a poor prognosis (p-values < 0.01). Based on DCE-MRI features, we established classifiers to predict BC clinical receptors, PAM50 subtypes, and prognostic gene sets. The imaging-based machine learning classifiers performed well in the independent dataset (areas under the receiver operating characteristic curve (AUCs) of 0.8361, 0.809, 0.7742, and 0.7277 for estrogen receptor (ER), human epidermal growth factor receptor 2 (HER2)-enriched, basal-like, and obtained radiogenomics signature). Furthermore, we developed a prognostic model directly using DCE-MRI features (p-value < 0.0001). Conclusions: Our results identified the DCE-MRI features that are robust and associated with the gene expression in BC and displayed the possibility of using the features to predict clinical receptors and PAM50 subtypes and to indicate BC prognosis.
RESUMEN
Coefficients for translational and rotational diffusion characterize the Brownian motion of particles. Emerging X-ray photon correlation spectroscopy (XPCS) experiments probe a broad range of length scales and time scales and are well-suited for investigation of Brownian motion. While methods for estimating the translational diffusion coefficients from XPCS are well-developed, there are no algorithms for measuring the rotational diffusion coefficients based on XPCS, even though the required raw data are accessible from such experiments. In this paper, we propose angular-temporal cross-correlation analysis of XPCS data and show that this information can be used to design a numerical algorithm (Multi-Tiered Estimation for Correlation Spectroscopy [MTECS]) for predicting the rotational diffusion coefficient utilizing the cross-correlation: This approach is applicable to other wavelengths beyond this regime. We verify the accuracy of this algorithmic approach across a range of simulated data.
RESUMEN
Breast cancer is a highly heterogeneous disease, and there are many forms of categorization for breast cancer based on gene expression profiles. Gene expression profiles are variables and may show differences if measured at different time points or under different conditions. In contrast, biological networks are relatively stable over time and under different conditions. In this study, we used a gene interaction network from a new point of view to explore the subtypes of breast cancer based on individual-specific edge perturbations measured by relative gene expression value. Our study reveals that there are four breast cancer subtypes based on gene interaction perturbations at the individual level. The new network-based subtypes of breast cancer show strong heterogeneity in prognosis, somatic mutations, phenotypic changes and enriched pathways. The network-based subtypes are closely related to the PAM50 subtypes and immunohistochemistry index. This work helps us to better understand the heterogeneity and mechanisms of breast cancer from a network perspective.
Asunto(s)
Biomarcadores de Tumor/genética , Neoplasias de la Mama/clasificación , Neoplasias de la Mama/genética , Epistasis Genética , Regulación Neoplásica de la Expresión Génica , Redes Reguladoras de Genes , Femenino , HumanosRESUMEN
Cancer cells subvert immune surveillance through inhibition of T cell effector function. Elucidation of the mechanism of T cell dysfunction is therefore central to cancer immunotherapy. Here, we report that dual specificity phosphatase 2 (DUSP2; also known as phosphatase of activated cells 1, PAC1) acts as an immune checkpoint in T cell antitumor immunity. PAC1 is selectively upregulated in exhausted tumor-infiltrating lymphocytes and is associated with poor prognosis of patients with cancer. PAC1hi effector T cells lose their proliferative and effector capacities and convert into exhausted T cells. Deletion of PAC1 enhances immune responses and reduces cancer susceptibility in mice. Through activation of EGR1, excessive reactive oxygen species in the tumor microenvironment induce expression of PAC1, which recruits the Mi-2ß nucleosome-remodeling and histone-deacetylase complex, eventually leading to chromatin remodeling of effector T cells. Our study demonstrates that PAC1 is an epigenetic immune regulator and highlights the importance of targeting PAC1 in cancer immunotherapy.
Asunto(s)
Fosfatasa 2 de Especificidad Dual/inmunología , Neoplasias/inmunología , Linfocitos T/inmunología , Animales , Cromatina/genética , Cromatina/metabolismo , Fosfatasa 2 de Especificidad Dual/deficiencia , Fosfatasa 2 de Especificidad Dual/genética , Proteína 1 de la Respuesta de Crecimiento Precoz/metabolismo , Femenino , Humanos , Activación de Linfocitos , Linfocitos Infiltrantes de Tumor/inmunología , Masculino , Complejo Desacetilasa y Remodelación del Nucleosoma Mi-2/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos NOD , Ratones Noqueados , Ratones SCID , Neoplasias/genética , Neoplasias/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Microambiente Tumoral/genética , Microambiente Tumoral/inmunología , Regulación hacia ArribaRESUMEN
Background: Breast cancer (BC) is a highly heterogeneous cancer. The interaction between immune system and BC is complex, widespread yet unclear. In this study, we aimed to reveal the heterogeneity of host systemic immune response to BC and understand the possible mechanisms that may drive the heterogeneity using transcriptomic data from peripheral blood mononuclear cells (PBMCs). Methods: Transcriptome-wide gene expressions of PBMCs in 33 BC patients were generated by RNA sequencing. An unsupervised clustering algorithm was employed to discover PBMC transcriptome subtypes among BC patients. Association analysis between PBMC subtypes and age, clinical stage, abundance of immune cells, and other clinical factors was performed to understand the underlying biological processes that may drive this heterogeneity. Immune gene signature identification and in silico survival analysis were performed to investigate the potential clinical implications of these PBMC subtypes. The findings were validated using the whole blood transcriptomes of an independent cohort. Results: We observed that established BC subtypes were not associated with PBMC gene expression profiles. Instead, we discovered and validated two new BC subtypes using PBMC transcriptome, which have distinct immune cell proportions, especially for lymphocytes (P = 5.22 × 10-12) and neutrophils (P = 1.13 × 10-14). Enrichment analysis of differentially expressed genes revealed that these two subtypes had distinct patterns of immune responses, including osteoclast differentiation and interleukin-10 signaling pathway. We developed two immune gene signatures that can differentiate these two BC PBMC subtypes. Further analysis suggested they had the ability to predict the clinical outcome of BC patients. Conclusions: PBMC transcriptome profiles can classify BC patients into two distinct subtypes. These two subtypes are mainly shaped by different immune cell abundance, which may have implications on clinical outcomes.
RESUMEN
Background: Adequate recruitment of highly active tumor antigen-specific cytotoxic T lymphocytes (CTLs) remains a major challenge in cancer immunotherapy. Objective: To construct liposome (LP)-based nanocapsules with surface endoglin aptamer (ENG-Apt) encapsulating mouse interferon-inducible protein-10 (mIP-10), with the ability to target mouse tumor vascular endothelial cells (mTECs) and enhance CTLs targeting and recruitment to the tumor vasculature. Methods: ENG-Apt/mIP-10-LP nanocapsules were prepared by grafting DSPE-PEG2000-ENG-Apt on the surface of liposomes containing mIP-10 plasmids, characterized and assessed for the cell binding specificity in vitro. The tumor-targeting ability of ENG-Apt/mIP-10-LP nanocapsules was evaluated in vivo. The anti-tumor efficacy of ENG-Apt/mIP-10-LP nanocapsules treatment, as well as the combination treatment of ENG-Apt/mIP-10-LP nanocapsules and adoptive TRP2CD8+ T cells, were both tested in melanoma-bearing mice, by evaluation of the tumor volume and the mouse survival time. To discuss the anti-tumoral mechanism of ENG-Apt/mIP-10-LP nanocapsules-based therapies, IFN-γ secretion, proportion of TRP2CD8+ T cells among TILs, MDSCs in the tumor microenvironment and Tregs in the spleen, were determined after the treatments. Proliferation and apoptosis of tumor cells, and tumor angiogenesis were also assessed. Results: The prepared ENG-Apt/mIP-10-LP nanocapsules possess an adequate nanometric size, good stability, high specificity to mTECs and tumor sites, along with the ability to induce mIP-10 expression in vitro and in vivo. Treatment of ENG-Apt/mIP-10-LP nanocapsules demonstrated CTLs enrichment into the tumor site, which inhibited tumor cell proliferation and angiogenesis, as well as promoted tumor-cell apoptosis, leading to a decrease in tumor progression and prolonged survival time in melanoma tumor-bearing mice. In addition, the proportion of MDSCs and Tregs was found to decrease. The combination of ENG-Apt/mIP-10-LP nanocapsules with adoptive TRP2CD8+ T cells, showed stronger abilities in inhibiting tumor growth and increasing animal survival time, thereby displayed an enhanced anti-melanoma tumor efficacy, due to the recruitment of both endogenous CD8+ T cells and exogenous TRP2CD8+ T cells in vivo. Conclusion: ENG-Apt/mIP-10-LP nanocapsules could enhance the recruitment of both endogenous and exogenous CTLs specifically targeting melanoma tumor vasculatures and exert anti-tumoral effect, therefore provides a potentially novel strategy for tumor immunotherapy.
Asunto(s)
Endoglina/química , Liposomas/química , Linfocitos T Citotóxicos/metabolismo , Animales , Apoptosis/genética , Apoptosis/fisiología , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Línea Celular , Línea Celular Tumoral , Quimiocina CXCL10/genética , Quimiocina CXCL10/metabolismo , Ensayo de Cambio de Movilidad Electroforética , Células Endoteliales/inmunología , Células Endoteliales/metabolismo , Femenino , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Desnudos , Nanocápsulas/química , Plásmidos/química , Transducción de Señal , Linfocitos T Citotóxicos/inmunología , Microambiente Tumoral/fisiologíaRESUMEN
New therapeutic approaches are needed for hepatocellular carcinoma (HCC), which is the most common primary malignancy of the liver. Bispecific T-cell engagers (BiTE) can effectively redirect T cells against tumors and show a strong anti-tumor effect. However, the potential immunogenicity, complexity, and high cost significantly limit their clinical application. In this paper, we used the hepatoma cells-specific aptamer TLS11a and anti-CD3 for to establish an aptamer/antibody bispecific system (AAbs), TLS11a/CD3, which showed advantages over BiTE and can specifically redirect T cells to lyse tumor cells. TLS11a-SH and anti-CD3-NH2 were crosslinked with sulfosuccinimidyl 4-(N-maleimidomethyl) cyclohexane-1-carboxylate (sulfo-SMCC). T cell activation, proliferation, and cytotoxicity of TLS11a/CD3 were analyzed by flow cytometry. Cytokine array was used to detect cytokine released from activated T cells. Hepatoma xenograft model was used to monitor the tumor volume and survival. TLS11a/CD3 could specifically bind hepatoma cells (H22) and T cells, activated T cells to mediate antigen-specific lysis of H22 cells in vitro, and effectively inhibited the growth of implanted H22 tumors as well as prolonged mice survival. TLS11a/CD3 could simultaneously target hepatoma cells and T cells, specifically guide T cells to kill tumor cells, and enhance the anti-tumor effect of T cells both in vitro and in vivo.
Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Animales , Anticuerpos Biespecíficos , Complejo CD3 , Humanos , Activación de Linfocitos , RatonesRESUMEN
Cytotoxic compounds vincristine sulphate (VCR) is widely used to against hemato-oncology, and especially the acute lymphoblastic leukemia (ALL). However, VCR's full therapeutic potential has been limited by its dose-limiting neurotoxicity, classically resulting in autonomic and peripheral sensory-motor neuropathy. Therefore, we developed a targeted liposomal drug delivery system (sgc8/VCR-Lipo) for improving the therapeutic effects of VCR against leukemia and reducing its systematic adverse effects. sgc8/VCR-Lipo could specifically bind to CCRF-CEM cells and significantly inhibit proliferation of cancer cells in vitro and tumor growth in vivo. The sgc8/VCR-Lipo nanoparticles may improve the anti-tumor efficacy of VCR and reduce side effects induced by non-specific drug release. These results suggest that our findings provide scientific evidence for developing novel aptamer-based targeted drug delivery systems for leukemia treatment.
Asunto(s)
Leucemia-Linfoma Linfoblástico de Células Precursoras , Sistemas de Liberación de Medicamentos , Liberación de Fármacos , Humanos , Liposomas , VincristinaRESUMEN
PURPOSE: Dendritic cell (DC)-based cancer vaccines is a newly emerging and potent form of immune therapy. As for any new technology, there are still considerable challenges that need to be addressed. Here, we investigate the antitumor potential of a novel liposomal vaccine, M/CpG-ODN-TRP2-Lipo. METHODS: We developed a vaccination strategy by assembling the DC-targeting mannose and immune adjuvant CpG-ODN on the surface of liposomes, which were loaded with melanoma-specific TRP2180-188 peptide as liposomal vaccine. M/CpG-ODN-TRP2-Lipo treatment was used to intendedly induce activation of DCs and antitumor- specific immune response in vivo. RESULTS: Our results demonstrated in vitro that the prepared liposomal particles were efficiently taken up by DCs. This uptake led to an enhanced activation of DCs, as measured by the upregulation of MHC II, CD80, and CD86. Furthermore, M/CpG-ODN-TRP2-Lipo effectively inhibited the growth of implanted B16 melanoma and prolonged the survival of mice. This therapy significantly reduced the number of myeloid-derived suppressor cells (MDSCs) and regulatory T cells, while simultaneously increasing the number of activated T cells, tumor antigen-specific CD8+ cytotoxic T cells, and interferon-γ-producing cells. At the same time, it was found to suppress tumor angiogenesis and tumor cell proliferation, as well as up-regulate their apoptosis. Interestingly, MyD88-knockout mice had significantly shorter median survival times compared to wild-type mice following the administration of M/CpG-ODN-TRP2-Lipo. CONCLUSIONS: The results suggested that the antitumor activities of the vaccine partially rely on the Myd88 signaling pathway. Interestingly, compared to whole tumor cell lysate-based vaccine, M/CpG-ODN-TRP2-Lipo, tumor specific antigen peptide-based vaccine, improved survival of tumor-bearing mice as well as enhanced their antitumor responses. All in all, we describe a novel vaccine formulation, M/CpG-ODN-TRP2-Lipo, with the aim of improving antitumor responses by alleviating the immunosuppressive environment in tumors.
Asunto(s)
Vacunas contra el Cáncer/farmacología , Células Dendríticas/efectos de los fármacos , Melanoma Experimental/terapia , Proteínas de la Membrana/inmunología , Oligodesoxirribonucleótidos/inmunología , Fragmentos de Péptidos/inmunología , Neoplasias Cutáneas/terapia , Linfocitos T Citotóxicos/efectos de los fármacos , Animales , Antígenos CD/genética , Antígenos CD/inmunología , Vacunas contra el Cáncer/química , Células Dendríticas/citología , Células Dendríticas/inmunología , Femenino , Expresión Génica , Antígenos de Histocompatibilidad Clase II/genética , Antígenos de Histocompatibilidad Clase II/inmunología , Inmunoterapia/métodos , Liposomas/química , Liposomas/farmacología , Activación de Linfocitos , Recuento de Linfocitos , Manosa/química , Melanoma Experimental/inmunología , Melanoma Experimental/mortalidad , Melanoma Experimental/patología , Proteínas de la Membrana/química , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Factor 88 de Diferenciación Mieloide/deficiencia , Factor 88 de Diferenciación Mieloide/genética , Factor 88 de Diferenciación Mieloide/inmunología , Células Supresoras de Origen Mieloide/efectos de los fármacos , Células Supresoras de Origen Mieloide/inmunología , Células Supresoras de Origen Mieloide/patología , Oligodesoxirribonucleótidos/química , Fragmentos de Péptidos/química , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/mortalidad , Neoplasias Cutáneas/patología , Análisis de Supervivencia , Linfocitos T Citotóxicos/citología , Linfocitos T Citotóxicos/inmunología , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/patologíaRESUMEN
Nanotechnology for early diagnosis and treatment of malignant tumor is a forefront topic in the international field of biotechnology and medicine. In order to improve the effect of cancer therapy, the timely and accurate detection of the cancer is important and necessary. Graphene and its derivatives have various excellent characteristics. For example, biological sensors based on graphene are good at amplifying detection signals, and its derivatives play an important role in the early diagnosis and cancer therapy. In view of this, we discussed the biological sensor application based on graphene and its derivatives in the detection and therapy of cancer.
Asunto(s)
Grafito , Nanoestructuras , Nanotecnología , Técnicas Biosensibles , Biotecnología , Neoplasias/diagnóstico , Neoplasias/terapiaRESUMEN
Hepatocellular carcinoma (HCC) is one of the most common cancers around the world. Multiple etiologic factors such as virus and environment can lead to HCC. It is a challenge for us to successfully detect early HCC due to the lack of effective characterized and specific biomarkers. However, if the early diagnosis is successfully realized, it provides crucial chance for HCC patients to receive effective treatment as early as possible. Dickkopf-1 (DKK-1) is a secretary glycoprotein, which negatively regulates Wnt pathway through binding to surface receptors LRP5/6 and Kremen 1/2. The expression of DKK-1 is regulated by p53, V-Myc avian myelocytomatosis viral oncogene neuroblastoma derived homolog (MYCN), ß-catenin, etc. Ectopic expression of DKK-1 can inhibit cell proliferation, or induce apoptosis with apoptosis enhancing factors. DKK-1 is low-expressed in many tumors, but overexpressed in others. Growing evidences show that DKK-1 plays complex and different roles in tumorigenesis, tumor progression and metastasis of different cancers. We herein review the recent progress in the expression and function of DKK-1 in hepatocellular carcinoma.
Asunto(s)
Carcinoma Hepatocelular/metabolismo , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Neoplasias Hepáticas/metabolismo , Vía de Señalización Wnt , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/tratamiento farmacológico , Proliferación Celular , Humanos , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/tratamiento farmacológicoRESUMEN
Since the serendipitous discovery of heavy-chain antibodies in Camelidae 20 years ago, the smallest single-domain antigen-binding fragment, known as VHH or nanobody, has received growing attention. In comparison with traditional antibodies, VHHs performs equally high specificity and affinity and low toxicity to targets, and has the ability to inhibit the formation of enzymes and enter the receptor gap. Hence, VHHs has been recently regarded as the highly valued protein and applied in multiple fields, including fundamental research, diagnosis, therapeutics, food science, etc. Today, based on the past achievements, an increasing number of academic and industrial groups begin to explore innovative VHH applications. In this review, we make a thorough retrospect of the unique features and explore novel implementations of VHHs in diverse forms in different fields. In addition, we also propose the potential future issues and problems of VHHs in many fields.
Asunto(s)
Anticuerpos , Cadenas Pesadas de Inmunoglobulina , Especificidad de Anticuerpos , Enzimas , NanotecnologíaRESUMEN
Cytotoxic Tlymphocyte antigen4 (CTLA4) is a critical negative regulator of immune responses. CTLA4 is rapidly upregulated following Tcell activation, and then binds to B7 molecules with a higher affinity than CD28. CTLA4 may abolish the initiation of the responses of T cells by raising the threshold of signals required for full activation of T cells, and it also may terminate ongoing T-cell responses. This regulatory role has led to the development of monoclonal antibodies (mAbs) designed to block CTLA4 activity for enhancing immune responses against cancer. mAbs have several disadvantages including high production cost and unstable behavior. Nanobodies (Nbs) are singledomain antigenbinding fragments derived from the camelid heavychain antibodies, which are highly attractive in cancer immunotherapy due to their small size, high specificity, and stability. We selected CTLA4specific Nbs from a high quality dromedary camel immune library by phage display technology. Four positive colonies were sequenced and classified based on the amino acids sequences in the CDR3 region. These Nbs recognized unique epitopes on CTLA4 and displayed high binding rates when used on PHAstimulated human T cells. Treatment of B16 melanomabearing C57BL/6 mice with antiCTLA4 nanobody 16 (Nb16) delayed melanoma growth and prolonged the survival time of mice. These data indicate that antiCTLA4 Nbs selected from a high quality phage display library may be effective for the treatment of patients with tumors.
Asunto(s)
Antígeno CTLA-4/antagonistas & inhibidores , Vacunas contra el Cáncer/administración & dosificación , Técnicas de Visualización de Superficie Celular/métodos , Melanoma Experimental/tratamiento farmacológico , Anticuerpos de Dominio Único/administración & dosificación , Animales , Antígeno CTLA-4/administración & dosificación , Antígeno CTLA-4/química , Camelus , Vacunas contra el Cáncer/metabolismo , Vacunas contra el Cáncer/farmacología , Proliferación Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Inmunización , Melanoma Experimental/inmunología , Ratones , Ratones Endogámicos C57BL , Anticuerpos de Dominio Único/metabolismo , Anticuerpos de Dominio Único/farmacología , Resultado del Tratamiento , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Background: Tumor vessels can potentially serve as diagnostic, prognostic and therapeutic targets for solid tumors. Fluorescent dyes are commonly used as biological indicators, while photobleaching seriously hinders their application. In this study, we aim to generate a fluorescent silica nanoparticles (FSiNPs) theranostic system marked by the mouse endgolin (mEND) aptamer, YQ26. Methods: A highly specific YQ26 was selected by using gene-modified cell line-based SELEX technique. FSiNPs were prepared via the reverse microemulsion method. The YQ26-FSiNPs theranostic system was developed by combining YQ26 with the FSiNPs for in vivo tumor imaging, treatment and monitoring. Results: Both in vitro experiments (i.e. cellular and tumor tissue targeting assays) and in vivo animal studies (i.e. in vivo imaging and antitumor efficacy of YQ26-FSiNPs) clearly demonstrated that YQ26-FSiNPs could achieve prominently high targeting efficiency and therapeutic effects via aptamer YQ26-mediated binding to endoglin (END) molecule. Conclusion: This simple, sensitive, and specific YQ26-FSiNPs theranostic system has a great potential for clinical tumor targeting imaging and treatment.
Asunto(s)
Aptámeros de Nucleótidos/farmacocinética , Endoglina/metabolismo , Nanopartículas/metabolismo , Neovascularización Patológica/terapia , Nanomedicina Teranóstica/métodos , Animales , Aptámeros de Nucleótidos/química , Aptámeros de Nucleótidos/uso terapéutico , Línea Celular Tumoral , Colorantes Fluorescentes/química , Células HEK293 , Humanos , Ratones , Ratones Endogámicos BALB C , Nanopartículas/química , Nanopartículas/uso terapéutico , Neovascularización Patológica/diagnóstico por imagen , Unión Proteica , Técnica SELEX de Producción de Aptámeros , Dióxido de Silicio/química , Distribución TisularRESUMEN
Dendritic cells (DC) and tumor cell fusion vaccine (DC/tumor cell fusion vaccine) is considered an effective approach in cancer biotherapy. However, its therapeutic effects in early clinical trials have been suboptimal partially due to the immunosuppressive tumor environment. In this study, we used nanoparticles of folate (FA)-modified chitosan, a non-viral vector capable of targeting tumor cells with high expression of FA receptors. FA-chitosan nanoparticles were used as biological carriers for the expression plasmid of the mouse interferon-induced protein-10 (mIP-10) gene, a potent chemoattractant for cytotoxic T cells. The combination of FA-chitosan/mIP-10 and DC/tumor cell fusion vaccine against hepatocellular carcinoma (HCC) effectively inhibited the growth of implanted HCC tumors and prolonged the survival of mice. The combination therapy significantly reduced myeloid-derived suppressor cells (MDSC) in mouse spleen, local tumor, and bone marrow while increasing tumor-specific IFN-γ responses. Furthermore, the combination therapy significantly inhibited tumor cell proliferation while promoting their apoptosis. Taken together, our data illustrate that the mIP-10 enhances the anti-tumor effect of DC/tumor cell fusion vaccine by alleviating the immunosuppressive tumor environment.