Search

Cervical cancer can be detected at an early stage through the changes occurring in biochemical and morphological properties of epithelium layer. Fluorescence spectroscopy has the ability to identify these subtle changes non‐invasively and in real time with good accuracy in comparison with conventional techniques. In this paper, we report the usage of a custom designed spatially resolved fibre‐optic probe (SRFOP), which consists of 77 fibres in two concentric rings, for the detection of cervical cancer using fluorescence spectroscopy technique. The aim of this study is to classify different grades of cervical precancer on the basis of their fluorescence spectra followed by a robust classification algorithm. Fluorescence spectra of 28 cervical tissue samples of different categories have been recorded using six detector fibres of FOP at different spatial locations with the source fibre (SF). A 405 nm laser diode source has been utilised to excite the samples and a USB 4000 Ocean Optics spectrometer to collect the output spectra in the wavelength range 400–700 nm. Principal component analysis (PCA) was applied to the collected spectra to reduce the dimensionality of the data while preserving the most significant features for classification. The first 10 principal components, which captured the majority of the variance in the spectra, were selected as input features for the classification model. Classification was then performed using an artificial neural network (ANN) with a specific architecture, including an input layer, hidden layers, and a softmax activation function in the output layer. Experimental and classification results both demonstrate that proximal fibres (PFs) perform better than distal fibres (DFs) in capturing the discriminatory features present in the epithelium layer of cervical tissue samples as PF collect most of the signal from the epithelium layer. The combined approach of spatially resolved fluorescence spectroscopy and PCA‐ANN classification techniques is able to discriminate different grades of cervical precancer and normal with an average sensitivity, specificity and accuracy of 93.33%, 96.67% and 95.57%, respectively. [ABSTRACT FROM AUTHOR]

Ovarian cancer most commonly presents at an advanced stage where survival is approximately 30% compared with >80% if diagnosed and treated before disease spreads. Diagnostic capabilities have progressed from surgical staging via laparotomy to image-guided biopsies and immunohistochemistry staining, along with advances in technology and medicine. Despite improvements in diagnostic capabilities, population-level screening for ovarian cancer is not recommended. Extracellular vesicles (EVs) are 40–150 nm structures formed when the cellular lipid bilayer invaginates. These structures function in cell signaling, immune responses, cancer progression, and establishing the tumor microenvironment. EVs are found in nearly every bodily fluid, including serum, plasma, ascites, urine, and effusion fluid, and contain molecular cargo from their cell of origin. This cargo can be analyzed to yield information about a possible malignancy. In this review we describe how the cargo of EVs has been studied as biomarkers in ovarian cancer. We bring together studies analyzing evidence for various cargos as ovarian cancer biomarkers. Then, we describe the role of EVs in modulation of the tumor microenvironment. This review also summarizes the therapeutic and translational potential of EVs for their optimal utilization as non-invasive biomarkers for novel treatments against cancer.

Engineered T cell therapy has shown remarkable efficacy in hematologic malignancies and has the potential for application to common epithelial cancers. Diverse T cell therapy strategies including adoptive transfer of tumor-infiltrating lymphocytes, chimeric antigen receptor (CAR)-T cells, and T cell receptor (TCR)-T cells have been studied in clinical trials. Recent research has established treatment of human papillomavirus (HPV)-associated cancers with TCR-T cells as a model for proof-of-principle studies in epithelial cancers. These studies and others have provided critical insight into mechanisms of tumor regression, therapeutic targets, treatment safety, treatment design, and barriers to curative cell therapies for common types of cancer. This perspective will review and consolidate understanding gained from clinical trials to treat viral and non-viral epithelial cancers with cell and gene therapy and will examine how past experience may guide future strategy in treatment and biomarker discovery. [ABSTRACT FROM AUTHOR]

Ovarian cancer is one of the most prevalent pathologies in gynaecology. This malignancy can be divided into 2 large groups: epithelial and non-epithelial. Because epithelial ovarian cancers (EOC) are the most commonly diagnosed, this paper focuses on the latest therapies associated with this disease. Due to the difficult diagnosis, EOC is frequently detected in the advanced stage. The treatment is usually complex and requires specialist knowledge. Advances and new ideas, such as identification of various genes and molecules that can serve as prognostic factors, might increase patients’ chances of survival; they may contribute to optimization of patients’ treatment, deciding whether to use aggressive treatment strategies, and predicting chemoresistance. Moreover, new strategies might also improve the quality of life of patients. The study aimed to analyse and discuss the latest reports on new methods of managing EOC.

Abstract: The holy grail of cancer therapeutics is the destruction of cancer cells while avoiding harm to normal cells. Cancer is unique from normal tissues because of the presence of somatic mutations that accumulate during tumorigenesis. Some nonsynonymous mutations can give rise to mutated peptide antigens (hereafter referred to as neoantigens) that can be specifically recognized by T cells. Thus, the immunological targeting of neoantigens represents a safe and promising strategy to treat patients with cancer. This article reviews the clinical application of adoptive cell therapy targeting neoantigens in patients with epithelial cancers. [ABSTRACT FROM AUTHOR]

Abstract The Epstein-Barr virus (EBV) is a ubiquitous γ-herpesvirus related to various types of cancers, including epithelial nasopharyngeal carcinoma, gastric carcinoma, and lymphoma. Long noncoding RNAs (lncRNAs) are expressed extensively in mammalian cells and play crucial roles in regulating various cellular processes and multiple cancers. Cellular lncRNAs can be differentially expressed induced by EBV infection. The dysregulated lncRNAs probably modulate the host immune response and other biological functions. At present, lncRNAs have been found to be significantly increased or decreased in EBV-infected cells, exosomes and EBV-associated cancers, suggesting their potential function and clinical application as biomarkers. In addition, EBV-encoded lncRNAs, BART and BHLF1 lncRNAs, may play roles in the viral oncogenesis. Analysis of the specific lncRNAs involved in interactions with the EBV machinery will provide information on their potential mechanism of action during multiple steps of EBV tumorigenesis. Here, we review the current knowledge regarding EBV-related lncRNAs and their possible roles in the pathogenesis of EBV-associated cancers.

Ovarian cancer is one of the most prevalent pathologies in gynaecology. This malignancy can be divided into 2 large groups: epithelial and non-epithelial. Because epithelial ovarian cancers (EOC) are the most commonly diagnosed, this paper focuses on the latest therapies associated with this disease. Due to the difficult diagnosis, EOC is frequently detected in the advanced stage. The treatment is usually complex and requires specialist knowledge. Advances and new ideas, such as identification of various genes and molecules that can serve as prognostic factors, might increase patients' chances of survival; they may contribute to optimization of patients' treatment, deciding whether to use aggressive treatment strategies, and predicting chemoresistance. Moreover, new strategies might also improve the quality of life of patients. The study aimed to analyse and discuss the latest reports on new methods of managing EOC. [ABSTRACT FROM AUTHOR]

Abstract Background There is increasing evidence that inflammation-based biomarkers are associated with tumor microenvironment which plays important roles in cancer progression. A high lymphocyte-to-monocyte ratio (LMR), has been suggested to indicate favorable prognoses in various epithelial cancers. We performed a meta-analysis to quantify the prognostic value of LMR in advanced-stage epithelial cancers undergoing various treatment. Methods We searched PubMed, EMBASE, Web of science and Cochrane Library up to July 2018 for relevant studies. We included studies assessing the prognostic impact of pretreatment LMR on clinical outcomes in patients with advanced-stage epithelial cancers. The primary outcome was overall survival (OS) and the secondary outcome was progression free survival (PFS). The summary hazard ratio (HR) and 95% confidence interval (CI) were calculated. Results A total of 8984 patients from 35 studies were included. A high pretreatment LMR was associated with favorable OS (HR = 0.578, 95% CI 0.522–0.641, P

The recepteur d'origine nantais (RON) receptor tyrosine kinase, belonging to the mesenchymal-to-epithelial transition proto-oncogene family, has been implicated in the pathogenesis of cancers derived from the colon, lung, breast, and pancreas. These findings lay the foundation for targeting RON for cancer treatment. However, development of RON-targeted therapeutics has not gained sufficient attention for the last decade. Although therapeutic monoclonal antibodies (TMABs) targeting RON have been validated in preclinical studies, results from clinical trials have met with limited success. This outcome diminishes pharmaceutical enthusiasm for further development of RON-targeted therapeutics. Recently, antibody–drug conjugates (ADCs) targeting RON have drawn special attention owing to their increased therapeutic activity. The rationale for developing anti-RON ADCs is based on the observation that cancer cells are not sufficiently addicted to RON signaling for survival. Thus, TMAB-mediated inhibition of RON signaling is ineffective for clinical application. In contrast, anti-RON ADCs combine a target-specific antibody with potent cytotoxins for cancer cell killing. This approach not only overcomes the shortcomings in TMAB-targeted therapies but also holds the promise for advancing anti-RON ADCs into clinical trials. In this review, we discuss the latest advancements in the development of anti-RON ADCs for targeted cancer therapy including drug conjugation profile, pharmacokinetic properties, cytotoxic effect in vitro, efficacy in tumor models, and toxicological activities in primates. [ABSTRACT FROM AUTHOR]

The Epstein-Barr virus (EBV) is a ubiquitous γ-herpesvirus related to various types of cancers, including epithelial nasopharyngeal carcinoma, gastric carcinoma, and lymphoma. Long noncoding RNAs (lncRNAs) are expressed extensively in mammalian cells and play crucial roles in regulating various cellular processes and multiple cancers. Cellular lncRNAs can be differentially expressed induced by EBV infection. The dysregulated lncRNAs probably modulate the host immune response and other biological functions. At present, lncRNAs have been found to be significantly increased or decreased in EBV-infected cells, exosomes and EBV-associated cancers, suggesting their potential function and clinical application as biomarkers. In addition, EBV-encoded lncRNAs, BART and BHLF1 lncRNAs, may play roles in the viral oncogenesis. Analysis of the specific lncRNAs involved in interactions with the EBV machinery will provide information on their potential mechanism of action during multiple steps of EBV tumorigenesis. Here, we review the current knowledge regarding EBV-related lncRNAs and their possible roles in the pathogenesis of EBV-associated cancers. [ABSTRACT FROM AUTHOR]

In order to compare the clinicopathological characteristics and survival outcomes of patients with ovarian clear cell carcinoma (CCC) to other epithelial cancer types, a total of 27,290 patients were analyzed, including 2,424 patients with CCC (8.9%), 3,505 patients with endometrioid cancer (EC) (12.8%), 2,379 patients with mucinous cancer (MC) (8.7%) and 18,982 patients with serous cancer (SC) (69.6%). Patients with EC had the most favorable prognosis and patients with SC had the poorest prognosis among all epithelial ovarian cancers. Among patients with stage I cancer, patients with CCC had a more favorable prognosis compared with patients with SC, especially after 60 months (landmark analysis results, HR=2.079, P=0.001) and had a poorer prognosis compared with patients with MC [restricted mean survival time (RMST) difference, −3.434 months]. Among patients at stages III and IV, patients with CCC had a poorer prognosis compared with patients with SC (RMST difference in stage III, −7.588 months; RMST difference in stage IV, −15.445 months) and had a more favorable prognosis compared with patients with MC (RMST difference in stage III, 10.850 months; RMST difference in stage IV, 8.430 months). The present results suggested that most patients with CCC exhibited, high grade, an early stage, unilateral status and were of a young age. In general, patients with SC presented the poorest prognosis among all patients with epithelial ovarian cancer and no significant survival difference was found between patients with CCC and MC. However, after adjusting for stage using pairwise comparisons, the prognosis of patients with CCC was found to be more favorable compared with the patients with SC and worse compared with patients with MC at stage I; the results at stage III–IV were opposite and the prognosis of patients with CCC was worse compared with the patients with SC and more favorable compared with the patients with MC. [ABSTRACT FROM AUTHOR]

Abstract Detecting early‐stage epithelial cancers and their precursor lesions are challenging as lesions could be subtle and focally or heterogeneously distributed over large mucosal areas. Optical coherence tomography (OCT) that enables wide‐field imaging of subsurface microstructures in vivo is a promising screening tool for epithelial diseases. However, its diagnostic capability has not been fully appreciated since the optical reflectance contrast is poorly understood. We investigated the back‐scattered intensities from clustered or packed nanometer scale intracellular scatterers using finite‐difference time‐domain method and 1‐μm resolution form of OCT, and uncovered that there existed correlations between the reflectance contrasts and the ultrastructural clustering or packing states of these scatterers, which allows us to interpret the physiological state of the cells. Specifically, both polarized goblet cells and foveolar cells exhibited asymmetric reflectance contrast, but they could be differentiated by the optical intensity of the mucin cup due to the different ultrastructural make‐ups of the mucin granules; keratinocytes could demonstrate varied cytoplasmic intensity and their cytoplasmic contrast was closely correlated with the packing state of keratin filaments. Further preliminary study demonstrated that these new understandings of OCT image contrast enables the characterization of precancerous lesions, which could complement the current morphology‐based criteria in realizing “virtual histology” and would have a profound impact for the screening and surveillance of epithelial cancers.

Epstein‐Barr virus (EBV) is a prevalent γ‐herpesvirus associated with a variety of cancers, including epithelial nasopharyngeal carcinoma (NPC) and gastric carcinoma (GC). Long noncoding RNAs (lncRNAs) are emerging as powerful regulators that have demonstrated to play crucial roles in cancer development. In this approach, based on genome‐wide RNA sequencing, we examined the lncRNA expression profiles in four EBV genome‐infected and EBV‐negative 293 cells. A series of lncRNAs were found to be dysregulated in a comparative analysis. Then, eight typical lncRNAs were selected for validation of expression levels by real‐time quantitative polymerase chain reaction and were detected in EBV‐positive or EBV‐negative GC and NPC cells. The differential expression patterns of the eight lncRNAs for validation were fundamentally identical to those revealed in RNA sequencing. Particularly, the differential expression of these lncRNAs in GC and NPC cells indicated their possible roles in EBV infection and tumorigenesis. In addition, a predicted lncRNA‐microRNA‐messenger RNA network suggested their potential interactions. This study reveals the first lncRNAome related to EBV infection in the epithelial cells and provides novel clues for the study of viral role in epithelial cancers through the interaction between EBV and host lncRNAs. Highlight: Genome‐wide RNAseq revealed differential lncRNA expression profiles related to EBV latent infection.The data were validated in EBV‐positive epithelial cancer cells.An lncRNA‐microRNA‐mRNA network was constructed and analyzed.The dysregulation of lncRNAs by EBV provides novel clues for the related study. [ABSTRACT FROM AUTHOR]

• Neutrophils play important roles throughout the metastatic process. • Tumour progression and invasion are influenced by infiltrating neutrophils. • Signalling from neutrophils can enhance survival of circulating tumour cells. • Neutrophils play a key role in establishing the metastatic niche. The metastasis cascade is complex and comprises several stages including local invasion into surrounding tissue, intravasation and survival of tumour cells in the circulation, and extravasation and colonisation of a distant site. It is increasingly clear that these processes are driven not only by signals within the tumour cells, but are also profoundly influenced by stromal cells and signals in the tumour microenvironment. Amongst the many cell types within the tumour microenvironment, immune cells such as lymphocytes, macrophages and neutrophils play a prominent role in tumour development and progression. Neutrophils, however, have only recently emerged as important players, particularly in metastasis. Here we review the current evidence suggesting a multi-faceted role for neutrophils in the metastatic cascade. [ABSTRACT FROM AUTHOR]

Overexpression of mucin glycoproteins has been demonstrated in many epithelial-derived cancers. The significance of this overexpression remains uncertain. The aim of this paper was to define the association of mucin glycoproteins with apoptosis, cell growth, invasion, migration, adhesion, and clonogenicity in vitro as well as tumor growth, tumorigenicity, and metastasis in vivo in epithelial-derived cancers by performing a systematic review of all published data. A systematic review of PubMed, Embase, and the Cochrane Central Register of Controlled Trials was performed to identify all papers that evaluated the association between mucin glycoproteins with apoptosis, cell growth, invasion, migration, adhesion, and clonogenicity in vitro as well as tumor growth, tumorigenicity, and metastasis in vivo in epithelial-derived cancers. PRISMA guidelines were adhered to. Results of individual studies were extracted and pooled together based on the organ in which the cancer was derived from. The initial search revealed 2031 papers, of which 90 were deemed eligible for inclusion in the study. The studies included details on MUC1, MUC2, MUC4, MUC5AC, MUC5B, MUC13, and MUC16. The majority of studies evaluated MUC1. MUC1 overexpression was consistently associated with resistance to apoptosis and resistance to chemotherapy. There was also evidence that overexpression of MUC2, MUC4, MUC5AC, MUC5B, MUC13, and MUC16 conferred resistance to apoptosis in epithelial-derived cancers. The overexpression of mucin glycoproteins is associated with resistance to apoptosis in numerous epithelial cancers. They cause resistance through diverse signaling pathways. Targeting the expression of mucin glycoproteins represents a potential therapeutic target in the treatment of epithelial-derived cancers. [ABSTRACT FROM AUTHOR]

In the last few decades, the epithelial cell adhesion molecule (EpCAM) has received increased attention as the main membrane marker used in many enrichment technologies to isolate circulating tumor cells (CTCs). Although there has been a great deal of progress in the implementation of EpCAM-based CTC detection technologies in medical settings, several issues continue to limit their clinical utility. The biology of EpCAM and its role are not completely understood but evidence suggests that the expression of this epithelial cell-surface protein is crucial for metastasis-competent CTCs and may not be lost completely during the epithelial-to-mesenchymal transition. In this review, we summarize the most significant advantages and disadvantages of using EpCAM as a marker for CTC enrichment and its potential biological role in the metastatic cascade.

Many epithelial cancers show cell cycle dysfunction tightly correlated with the overexpression of the serine/threonine kinase Aurora A (AURKA). Its role in mitotic progression has been extensively characterised, and evidence for new AURKA functions emerges. Here, we reveal that AURKA is located and imported in mitochondria in several human cancer cell lines. Mitochondrial AURKA impacts on two organelle functions: mitochondrial dynamics and energy production. When AURKA is expressed at endogenous levels during interphase, it induces mitochondrial fragmentation independently from RALA. Conversely, AURKA enhances mitochondrial fusion and ATP production when it is over-expressed. We demonstrate that AURKA directly regulates mitochondrial functions and that AURKA over-expression promotes metabolic reprogramming by increasing mitochondrial interconnectivity. Our work paves the way to anti-cancer therapeutics based on the simultaneous targeting of mitochondrial functions and AURKA inhibition.

The epidermal growth factor (EGF)‐receptor ligand amphiregulin (AREG) is a potent growth factor implicated in proliferative skin diseases and in primary and metastatic epithelial cancers. AREG, synthesized as a propeptide, requires conversion to an active peptide by metalloproteases by a process known as ectodomain shedding. Although (ADAM17) a disintegrin and metalloprotease 17 is a key sheddase of AREG, ADAM8‐, ADAM15‐, and batimastat (broad metalloprotease inhibitor)‐sensitive metalloproteases have also been implicated in AREG shedding. In the present study, using a curly bare (Rhbdf2cub) mouse model that shows loss‐of‐hair, enlarged sebaceous gland, and rapid cutaneous wound‐healing phenotypes mediated by enhanced Areg mRNA and protein levels, we sought to identify the principal ectodomain sheddase of AREG. To this end, we generated Rhbdf2cub mice lacking ADAM17 specifically in the skin and examined the above phenotypes of Rhbdf2cub mice. We find that ADAM17 deficiency in the skin of Rhbdf2cub mice restores a full hair coat, prevents sebaceous gland enlargement, and impairs the rapid wound‐healing phenotype observed in Rhbdf2cub mice. Furthermore, in vitro, stimulated shedding of AREG is abolished in Rhbdf2cub mouse embryonic keratinocytes lacking ADAM17. Thus, our data support previous findings demonstrating that ADAM17 is the major ectodomain sheddase of AREG. [ABSTRACT FROM AUTHOR]

Humans experience higher rates of age-associated diseases than our closest living evolutionary relatives, chimpanzees. Environmental factors can explain many of these increases in disease risk, but species-specific genetic changes can also play a role. Alleles that confer increased disease susceptibility later in life can persist in a population in the absence of selective pressure if those changes confer positive adaptation early in life. One age-associated disease that disproportionately affects humans compared with chimpanzees is epithelial cancer. Here, we explored genetic differences between humans and chimpanzees in a well-defined experimental assay that mimics gene expression changes that happen during cancer progression: A fibroblast serum challenge. We used this assay with fibroblasts isolated from humans and chimpanzees to explore species-specific differences in gene expression and chromatin state with RNA-Seq and DNase-Seq. Our data reveal that human fibroblasts increase expression of genes associated with wound healing and cancer pathways; in contrast, chimpanzee gene expression changes are not concentrated around particular functional categories. Chromatin accessibility dramatically increases in human fibroblasts, yet decreases in chimpanzee cells during the serum response. Many regions of opening and closing chromatin are in close proximity to genes encoding transcription factors or genes involved in wound healing processes, further supporting the link between changes in activity of regulatory elements and changes in gene expression. Together, these expression and open chromatin data show that humans and chimpanzees have dramatically different responses to the same physiological stressor, and how a core physiological process can evolve quickly over relatively short evolutionary time scales. [ABSTRACT FROM AUTHOR]

Background: Genetic engineering of T-cells to express specific T cell receptors (TCR) has emerged as a novel strategy to treat various malignancies. More widespread utilization of these types of therapies has been somewhat constrained by the lack of closed culture processes capable of expanding sufficient numbers of T-cells for clinical application. Here, we evaluate a process for robust clinical grade manufacturing of TCR gene engineered T-cells.Methods: TCRs that target human papillomavirus E6 and E7 were independently tested. A 21 day process was divided into a transduction phase (7 days) and a rapid expansion phase (14 days). This process was evaluated using two healthy donor samples and four samples obtained from patients with epithelial cancers.Results: The process resulted in ~ 2000-fold increase in viable nucleated cells and high transduction efficiencies (64-92%). At the end of culture, functional assays demonstrated that these cells were potent and specific in their ability to kill tumor cells bearing target and secrete large quantities of interferon and tumor necrosis factor. Both phases of culture were contained within closed or semi-closed modules, which include automated density gradient separation and cell culture bags for the first phase and closed GREX culture devices and wash/concentrate systems for the second phase.Conclusion: Large-scale manufacturing using modular systems and semi-automated devices resulted in highly functional clinical-grade TCR transduced T-cells. This process is now in use in actively accruing clinical trials and the NIH Clinical Center and can be utilized at other cell therapy manufacturing sites that wish to scale-up and optimize their processing using closed systems. [ABSTRACT FROM AUTHOR]

Recessive dystrophic epidermolysis bullosa (RDEB) is a skin fragility disease caused by mutations that affect the function and/or the amount of type VII collagen (C7), the major component of anchoring fibrils. Hallmarks of RDEB are unremitting blistering and chronic wounds leading to tissue fibrosis and scarring. Nearly all patients with severe RDEB develop highly metastatic squamous cell carcinomas (SCC) which are the main cause of death. Accumulating evidence from a murine RDEB model and human RDEB cells demonstrates that lack of C7 also directly alters the wound healing process. Non-healing RDEB wounds are characterized by increased inflammation, high transforming growth factor-β1 (TGF-β1) levels and activity, and are heavily populated by myofibroblasts responsible for enhanced fibrogenesis and matrix stiffness. These changes make the RDEB stroma a microenvironment prone to cancer initiation, where cells with features of cancer-associated fibroblasts are found. Here, we discuss recent knowledge on microenvironment alterations in RDEB, highlighting possible therapeutic targets to prevent and/or delay fibrosis and SCC development. [ABSTRACT FROM AUTHOR]