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Cancer is a leading cause of death worldwide and, despite new targeted therapies and immunotherapies, many patients with advanced-stage- or high-risk cancers still die, owing to metastatic disease. Adoptive T-cell therapy, involving the autologous or allogeneic transplant of tumour-infiltrating lymphocytes or genetically modified T cells expressing novel T-cell receptors or chimeric antigen receptors, has shown promise in the treatment of cancer patients, leading to durable responses and, in some cases, cure. Technological advances in genomics, computational biology, immunology and cell manufacturing have brought the aspiration of individualised therapies for cancer patients closer to reality. This new era of cell-based individualised therapeutics challenges the traditional standards of therapeutic interventions and provides opportunities for a paradigm shift in our approach to cancer therapy. Invited speakers at a 2020 symposium discussed three areas-cancer genomics, cancer immunology and cell-therapy manufacturing-that are essential to the effective translation of T-cell therapies in the treatment of solid malignancies. Key advances have been made in understanding genetic intratumour heterogeneity, and strategies to accurately identify neoantigens, overcome T-cell exhaustion and circumvent tumour immunosuppression after cell-therapy infusion are being developed. Advances are being made in cell-manufacturing approaches that have the potential to establish cell-therapies as credible therapeutic options. T-cell therapies face many challenges but hold great promise for improving clinical outcomes for patients with solid tumours.
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Inmunoterapia Adoptiva , Neoplasias/terapia , Linfocitos T/trasplante , Animales , Humanos , Tolerancia Inmunológica/genética , Inmunoterapia Adoptiva/métodos , Inmunoterapia Adoptiva/tendencias , Linfocitos Infiltrantes de Tumor/fisiología , Neoplasias/inmunología , Neoplasias/patología , Receptores de Antígenos de Linfocitos T/genética , Receptores de Antígenos de Linfocitos T/metabolismo , Receptores Quiméricos de Antígenos/genética , Receptores Quiméricos de Antígenos/metabolismo , Linfocitos T/fisiologíaRESUMEN
Circulating plasma proteins play key roles in human health and can potentially be used to measure biological age, allowing risk prediction for age-related diseases, multimorbidity and mortality. Here we developed a proteomic age clock in the UK Biobank (n = 45,441) using a proteomic platform comprising 2,897 plasma proteins and explored its utility to predict major disease morbidity and mortality in diverse populations. We identified 204 proteins that accurately predict chronological age (Pearson r = 0.94) and found that proteomic aging was associated with the incidence of 18 major chronic diseases (including diseases of the heart, liver, kidney and lung, diabetes, neurodegeneration and cancer), as well as with multimorbidity and all-cause mortality risk. Proteomic aging was also associated with age-related measures of biological, physical and cognitive function, including telomere length, frailty index and reaction time. Proteins contributing most substantially to the proteomic age clock are involved in numerous biological functions, including extracellular matrix interactions, immune response and inflammation, hormone regulation and reproduction, neuronal structure and function and development and differentiation. In a validation study involving biobanks in China (n = 3,977) and Finland (n = 1,990), the proteomic age clock showed similar age prediction accuracy (Pearson r = 0.92 and r = 0.94, respectively) compared to its performance in the UK Biobank. Our results demonstrate that proteomic aging involves proteins spanning multiple functional categories and can be used to predict age-related functional status, multimorbidity and mortality risk across geographically and genetically diverse populations.
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Clinical Decision Support Systems (CDSS) provide an efficient way to diagnose the presence of diseases such as breast cancer using ultrasound images (USIs). Globally, breast cancer is one of the major causes of increased mortality rates among women. Computer-Aided Diagnosis (CAD) models are widely employed in the detection and classification of tumors in USIs. The CAD systems are designed in such a way that they provide recommendations to help radiologists in diagnosing breast tumors and, furthermore, in disease prognosis. The accuracy of the classification process is decided by the quality of images and the radiologist's experience. The design of Deep Learning (DL) models is found to be effective in the classification of breast cancer. In the current study, an Ensemble Deep-Learning-Enabled Clinical Decision Support System for Breast Cancer Diagnosis and Classification (EDLCDS-BCDC) technique was developed using USIs. The proposed EDLCDS-BCDC technique was intended to identify the existence of breast cancer using USIs. In this technique, USIs initially undergo pre-processing through two stages, namely wiener filtering and contrast enhancement. Furthermore, Chaotic Krill Herd Algorithm (CKHA) is applied with Kapur's entropy (KE) for the image segmentation process. In addition, an ensemble of three deep learning models, VGG-16, VGG-19, and SqueezeNet, is used for feature extraction. Finally, Cat Swarm Optimization (CSO) with the Multilayer Perceptron (MLP) model is utilized to classify the images based on whether breast cancer exists or not. A wide range of simulations were carried out on benchmark databases and the extensive results highlight the better outcomes of the proposed EDLCDS-BCDC technique over recent methods.
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The conduits of life; the animal oviducts and human fallopian tubes are of paramount importance for reproduction in amniotes. They connect the ovary with the uterus and are essential for fertility. They provide the appropriate environment for gamete maintenance, fertilization and preimplantation embryonic development. However, serious pathologies, such as ectopic pregnancy, malignancy and severe infections, occur in the oviducts. They can have drastic effects on fertility, and some are life-threatening. Despite the crucial importance of the oviducts in life, relatively little is known about the molecular drivers underpinning the embryonic development of their precursor structures, the Müllerian ducts, and their successive differentiation and maturation. The Müllerian ducts are simple rudimentary tubes comprised of an epithelial lumen surrounded by a mesenchymal layer. They differentiate into most of the adult female reproductive tract (FRT). The earliest sign of Müllerian duct formation is the thickening of the anterior mesonephric coelomic epithelium to form a placode of two distinct progenitor cells. It is proposed that one subset of progenitor cells undergoes partial epithelial-mesenchymal transition (pEMT), differentiating into immature Müllerian luminal cells, and another subset undergoes complete EMT to become Müllerian mesenchymal cells. These cells invaginate and proliferate forming the Müllerian ducts. Subsequently, pEMT would be reversed to generate differentiated epithelial cells lining the fully formed Müllerian lumen. The anterior Müllerian epithelial cells further specialize into the oviduct epithelial subtypes. This review highlights the key established molecular and genetic determinants of the processes involved in Müllerian duct development and the differentiation of its upper segment into oviducts. Furthermore, an extensive genome-wide survey of mouse knockout lines displaying Müllerian or oviduct phenotypes was undertaken. In addition to widely established genetic determinants of Müllerian duct development, our search has identified surprising associations between loss-of-function of several genes and high-penetrance abnormalities in the Müllerian duct and/or oviducts. Remarkably, these associations have not been investigated in any detail. Finally, we discuss future directions for research on Müllerian duct development and oviducts.
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PURPOSE: Using RNA sequencing, we recently developed the 52-gene-based Oxford classifier of carcinoma of the ovary (Oxford Classic, OxC) for molecular stratification of serous ovarian cancers (SOCs) based on the molecular profiles of their cell of origin in the fallopian tube epithelium. Here, we developed a 52-gene NanoString panel for the OxC to test the robustness of the classifier. EXPERIMENTAL DESIGN: We measured the expression of the 52 genes in an independent cohort of prospectively collected SOC samples (n = 150) from a homogenous cohort who were treated with maximal debulking surgery and chemotherapy. We performed data mining of published expression profiles of SOCs and validated the classifier results on tissue arrays comprising 137 SOCs. RESULTS: We found evidence of profound nongenetic heterogeneity in SOCs. Approximately 20% of SOCs were classified as epithelial-to-mesenchymal transition-high (EMT-high) tumors, which were associated with poor survival. This was independent of established prognostic factors, such as tumor stage, tumor grade, and residual disease after surgery (HR, 3.3; P = 0.02). Mining expression data of 593 patients revealed a significant association between the EMT scores of tumors and the estimated fraction of alternatively activated macrophages (M2; P < 0.0001), suggesting a mechanistic link between immunosuppression and poor prognosis in EMT-high tumors. CONCLUSIONS: The OxC-defined EMT-high SOCs carry particularly poor prognosis independent of established clinical parameters. These tumors are associated with high frequency of immunosuppressive macrophages, suggesting a potential therapeutic target to improve clinical outcome.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/análisis , Cistadenocarcinoma Seroso/patología , Procedimientos Quirúrgicos de Citorreducción/métodos , Transición Epitelial-Mesenquimal , Terapia de Inmunosupresión , Neoplasias Ováricas/patología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Terapia Combinada , Cistadenocarcinoma Seroso/inmunología , Cistadenocarcinoma Seroso/terapia , Femenino , Estudios de Seguimiento , Humanos , Persona de Mediana Edad , Neoplasias Ováricas/inmunología , Neoplasias Ováricas/terapia , Pronóstico , Estudios Prospectivos , Adulto JovenRESUMEN
Similar to tumor-initiating cells (TICs), minimal residual disease (MRD) is capable of reinitiating tumors and causing recurrence. However, the molecular characteristics of solid tumor MRD cells and drivers of their survival have remained elusive. Here we performed dense multiregion transcriptomics analysis of paired biopsies from 17 ovarian cancer patients before and after chemotherapy. We reveal that while MRD cells share important molecular signatures with TICs, they are also characterized by an adipocyte-like gene expression signature and a portion of them had undergone epithelial-mesenchymal transition (EMT). In a cell culture MRD model, MRD-mimic cells showed the same phenotype and were dependent on fatty acid oxidation (FAO) for survival and resistance to cytotoxic agents. These findings identify EMT and FAO as attractive targets to eradicate MRD in ovarian cancer and make a compelling case for the further testing of FAO inhibitors in treating MRD.
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Adipocitos/metabolismo , Carcinoma Epitelial de Ovario/genética , Transición Epitelial-Mesenquimal/genética , Neoplasia Residual/genética , Células Madre Neoplásicas/metabolismo , Neoplasias Ováricas/genética , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carboplatino/administración & dosificación , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Carcinoma Epitelial de Ovario/metabolismo , Línea Celular Tumoral , Procedimientos Quirúrgicos de Citorreducción , Ácidos Grasos/metabolismo , Femenino , Humanos , Persona de Mediana Edad , Terapia Neoadyuvante , Neoplasia Residual/metabolismo , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/metabolismo , Oxidación-Reducción , Paclitaxel/administración & dosificación , TranscriptomaRESUMEN
The epigenetic silencing of tumor suppressor genes (TSGs) is a common finding in several solid and hematological tumors involving various epigenetic readers and writers leading to enhanced cell proliferation and defective apoptosis. Thymoquinone (TQ), the major biologically active compound of black seed oil, has demonstrated anticancer activities in various tumors by targeting several pathways. However, its effects on the epigenetic code of cancer cells are largely unknown. In the present study, we performed RNA sequencing to investigate the anticancer mechanisms of TQ-treated T-cell acute lymphoblastic leukemia cell line (Jurkat cells) and examined gene expression using different tools. We found that many key epigenetic players, including ubiquitin-like containing plant homeodomain (PHD) and really interesting new gene (RING) finger domains 1 (UHRF1), DNMT1,3A,3B, G9A, HDAC1,4,9, KDM1B, and KMT2A,B,C,D,E, were downregulated in TQ-treated Jurkat cells. Interestingly, several TSGs, such as DLC1, PPARG, ST7, FOXO6, TET2, CYP1B1, SALL4, and DDIT3, known to be epigenetically silenced in various tumors, including acute leukemia, were upregulated, along with the upregulation of several downstream pro-apoptotic genes, such as RASL11B, RASD1, GNG3, BAD, and BIK. Data obtained from RNA sequencing were confirmed using quantitative reverse transcription polymerase chain reaction (RT-qPCR) in Jurkat cells, as well as in a human breast cancer cell line (MDA-MB-468 cells). We found that the decrease in cell proliferation and in the expression of UHRF1, DNMT1, G9a, and HDAC1 genes in both cancer cell (Jurkat cells and MDA-MB-468 cells) lines depends on the TQ dose. Our results indicate that the use of TQ as an epigenetic drug represents a promising strategy for epigenetic therapy for both solid and blood tumors by targeting both DNA methylation and histone post-translational modifications.
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Though used widely in cancer therapy, paclitaxel only elicits a response in a fraction of patients. A strong determinant of paclitaxel tumor response is the state of microtubule dynamic instability. However, whether the manipulation of this physiological process can be controlled to enhance paclitaxel response has not been tested. Here, we show a previously unrecognized role of the microtubule-associated protein CRMP2 in inducing microtubule bundling through its carboxy terminus. This activity is significantly decreased when the FER tyrosine kinase phosphorylates CRMP2 at Y479 and Y499. The crystal structures of wild-type CRMP2 and CRMP2-Y479E reveal how mimicking phosphorylation prevents tetramerization of CRMP2. Depletion of FER or reducing its catalytic activity using sub-therapeutic doses of inhibitors increases paclitaxel-induced microtubule stability and cytotoxicity in ovarian cancer cells and in vivo. This work provides a rationale for inhibiting FER-mediated CRMP2 phosphorylation to enhance paclitaxel on-target activity for cancer therapy.
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Péptidos y Proteínas de Señalización Intercelular/metabolismo , Microtúbulos/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Neoplasias Ováricas/tratamiento farmacológico , Paclitaxel/farmacología , Proteínas Tirosina Quinasas/genética , Tratamiento con ARN de Interferencia , Moduladores de Tubulina/farmacología , Animales , Línea Celular Tumoral , Femenino , Humanos , Ratones , Ratones Desnudos , Microscopía Confocal , Microscopía Fluorescente , Microtúbulos/efectos de los fármacos , Microtúbulos/ultraestructura , Simulación de Dinámica Molecular , Terapia Molecular Dirigida , Trasplante de Neoplasias , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/ultraestructura , Fosforilación/efectos de los fármacos , Fosforilación/genética , Multimerización de Proteína/efectos de los fármacos , Multimerización de Proteína/genética , Proteínas Tirosina Quinasas/metabolismo , ARN Interferente PequeñoRESUMEN
BACKGROUND: High plasma concentration of low-density lipoprotein cholesterol (LDL-c) plays a significant role in the incidence of atherosclerosis and coronary heart diseases (CHD). MATERIALS AND METHODS: The purpose of this study was to investigate the mechanism by which citrus flavonoids, naringenin regulate the LDL receptor (LDLr) gene in human liver using the human hepatoma cell line, HepG2 as a model. RESULTS: Time-course transient transfection of HepG2 cells with luciferase reporter-gene constructs incorporating the promoters of SREBP-1a,-1c, -2 and LDLr, revealed that in lipoprotein-deficient medium (LPDM), only SREBP-1a promoter activity was increased significantly after 4h exposure to 200µM naringenin respectively. However, after 24h incubation with 200µM naringenin the gene expression activities of all the SREBP-1a, -1c, -2 and LDLr promoter-constructs were increased significantly. The effects of both 200µM naringenin on elevating LDLr mRNA are possibly due to regulation of gene transcription by SREBP-la and SREBP-2. However, the suppression effect of 200µM naringenin on hepatic SREBP-1c mRNA expression is likely associated with the reduction in mRNA expression of both acetyl-CoA carboxylase and fatty acid synthase in human hepatoma HepG2 cells. It was found that, 200µM naringenin was likely to stimulate LDLr gene expression via increase phosphorylation of PI3K and ERK1/2 which enhance the transcription factors SREBP-1a and SREBP-2 mRNA levels and increased their protein maturation in human hepatoma HepG2 cell. CONCLUSION: Diets supplemented with naringenin could effectively reduce mortality and morbidity from coronary heart diseases and as cardio-protective effects in humans.
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Carcinoma Hepatocelular/genética , Flavanonas/farmacología , Neoplasias Hepáticas/genética , Receptores de LDL/genética , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Células Hep G2 , Humanos , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/metabolismo , Fosfatidilinositol 3-Quinasas/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Receptores de LDL/metabolismo , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/genética , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/metabolismo , Proteína 2 de Unión a Elementos Reguladores de Esteroles/genética , Proteína 2 de Unión a Elementos Reguladores de Esteroles/metabolismoRESUMEN
The adipocyte-rich microenvironment forms a niche for ovarian cancer metastasis, but the mechanisms driving this process are incompletely understood. Here we show that salt-inducible kinase 2 (SIK2) is overexpressed in adipocyte-rich metastatic deposits compared with ovarian primary lesions. Overexpression of SIK2 in ovarian cancer cells promotes abdominal metastasis while SIK2 depletion prevents metastasis in vivo. Importantly, adipocytes induce calcium-dependent activation and autophosphorylation of SIK2. Activated SIK2 plays a dual role in augmenting AMPK-induced phosphorylation of acetyl-CoA carboxylase and in activating the PI3K/AKT pathway through p85α-S154 phosphorylation. These findings identify SIK2 at the apex of the adipocyte-induced signaling cascades in cancer cells and make a compelling case for targeting SIK2 for therapy in ovarian cancer.
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Neoplasias Ováricas/genética , Neoplasias Ováricas/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Quinasas Activadas por AMP/metabolismo , Acetil-CoA Carboxilasa/metabolismo , Adipocitos/enzimología , Adipocitos/metabolismo , Adipocitos/patología , Animales , Femenino , Xenoinjertos , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Desnudos , Metástasis de la Neoplasia , Proteína Oncogénica v-akt/metabolismo , Neoplasias Ováricas/enzimología , Neoplasias Ováricas/patología , Fosfatidilinositol 3-Quinasas/metabolismo , Transducción de SeñalRESUMEN
Tamoxifen (TAM) is widely used in the treatment and prevention of breast cancer. Adverse effects of TAM include hepatotoxicity. Caffeic acid phenethyl ester (CAPE), an active component of propolis, has been used in folk medicine for diverse ailments. In the current study, the protective effects of CAPE against TAM-induced hepatotoxicity in female rats were evaluated. TAM (45 mg/kg/day, i.p., for 10 consecutive days) resulted in an elevation of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP), depletion of liver reduced glutathione (GSH) and accumulation of oxidized glutathione (GSSG) and lipid peroxidation (LPO). Also, TAM treatment resulted in inhibition of hepatic activity of glutathione reductase (GR), glutathione peroxidase (GPx), superoxide dismutase (SOD) and catalase (CAT). Further, it raised liver tumor necrosis factor-alpha (TNF-alpha) level and induced histopathological changes. Pretreatment with CAPE (2.84 mg/kg/day; i.p., for 20 consecutive days, starting 10 days before TAM injection) significantly prevented the elevation in serum activity of the assessed enzymes. CAPE significantly inhibited TAM-induced hepatic GSH depletion and GSSG and LPO accumulation. Consistently, CAPE normalized the activity of GR, GPx, SOD and CAT, inhibited the rise in TNF-alpha and ameliorated the histopathological changes. In conclusion, CAPE protects against TAM-induced hepatotoxicity.