Showing papers in "Frontiers in Oncology in 2021"

The Crosstalk Between Tumor Cells and the Immune Microenvironment in Breast Cancer: Implications for Immunotherapy.

Abstract: Breast cancer progression is a complex process controlled by genetic and epigenetic factors that coordinate the crosstalk between tumor cells and the components of tumor microenvironment (TME). Among those, the immune cells play a dual role during cancer onset and progression, as they can protect from tumor progression by killing immunogenic neoplastic cells, but in the meanwhile can also shape tumor immunogenicity, contributing to tumor escape. The complex interplay between cancer and the immune TME influences the outcome of immunotherapy and of many other anti-cancer therapies. Herein, we present an updated view of the pro- and anti-tumor activities of the main immune cell populations present in breast TME, such as T and NK cells, myeloid cells, innate lymphoid cells, mast cells and eosinophils, and of the underlying cytokine-, cell-cell contact- and microvesicle-based mechanisms. Moreover, current and novel therapeutic options that can revert the immunosuppressive activity of breast TME will be discussed. To this end, clinical trials assessing the efficacy of CAR-T and CAR-NK cells, cancer vaccination, immunogenic cell death-inducing chemotherapy, DNA methyl transferase and histone deacetylase inhibitors, cytokines or their inhibitors and other immunotherapies in breast cancer patients will be reviewed. The knowledge of the complex interplay that elapses between tumor and immune cells, and of the experimental therapies targeting it, would help to develop new combination treatments able to overcome tumor immune evasion mechanisms and optimize clinical benefit of current immunotherapies.

Boron Neutron Capture Therapy: A Review of Clinical Applications

Abstract: Boron neutron capture therapy (BNCT) is an emerging treatment modality aimed at improving the therapeutic ratio for traditionally difficult to treat tumors. BNCT utilizes boronated agents to preferentially deliver boron-10 to tumors, which, after undergoing irradiation with neutrons, yields litihium-7 and an alpha particle. The alpha particle has a short range, therefore preferentially affecting tumor tissues while sparing more distal normal tissues. To date, BNCT has been studied clinically in a variety of disease sites, including glioblastoma multiforme, meningioma, head and neck cancers, lung cancers, breast cancers, hepatocellular carcinoma, sarcomas, cutaneous malignancies, extramammary Paget's disease, recurrent cancers, pediatric cancers, and metastatic disease. We aim to provide an up-to-date and comprehensive review of the studies of each of these disease sites, as well as a review on the challenges facing adoption of BNCT.

Mechanisms for Modulating Anoikis Resistance in Cancer and the Relevance of Metabolic Reprogramming.

Abstract: The attachment of cells to the extracellular matrix (ECM) is the hallmark of structure-function stability and well-being ECM detachment in localized tumors precedes abnormal dissemination of tumor cells culminating in metastasis Programmed cell death (PCD) is activated during tumorigenesis to clear off ECM-detached cells through "anoikis" However, cancer cells develop several mechanisms for abrogating anoikis, thus promoting their invasiveness and metastasis Specific factors, such as growth proteins, pH, transcriptional signaling pathways, and oxidative stress, have been reported as drivers of anoikis resistance, thus enhancing cancer proliferation and metastasis Recent studies highlighted the key contributions of metabolic pathways, enabling the cells to bypass anoikis Therefore, understanding the mechanisms driving anoikis resistance could help to counteract tumor progression and prevent metastasis This review elucidates the dynamics employed by cancer cells to impede anoikis, thus promoting proliferation, invasion, and metastasis In addition, the authors have discussed other metabolic intermediates (especially amino acids and nucleotides) that are less explored, which could be crucial for anoikis resistance and metastasis

Immune Checkpoint Inhibitors in Triple Negative Breast Cancer Treatment: Promising Future Prospects.

Abstract: Immunotherapy has emerged as the fifth pillar of cancer treatment alongside surgery, radiotherapy, chemotherapy, and targeted therapy. Immune checkpoint inhibitors are the current superheroes of immunotherapy, unleashing a patient's own immune cells to kill tumors and revolutionizing cancer treatment in a variety of cancers. Although breast cancer was historically believed to be immunologically silent, treatment with immune checkpoint inhibitors has been shown to induce modest responses in metastatic breast cancer. Given the inherent heterogeneity of breast tumors, this raised the question whether certain breast tumors might benefit more from immune-based interventions and which cancer cell-intrinsic and/or microenvironmental factors define the likelihood of inducing a potent and durable anti-tumor immune response. In this review, we will focus on triple negative breast cancer as immunogenic breast cancer subtype, and specifically discuss the relevance of tumor mutational burden, the plethora and diversity of tumor infiltrating immune cells in addition to the immunoscore, the presence of immune checkpoint expression, and the microbiome in defining immune checkpoint blockade response. We will highlight the current immune checkpoint inhibitor treatment options, either as monotherapy or in combination with standard-of-care treatment modalities such as chemotherapy and targeted therapy. In addition, we will look into the potential of immunotherapy-based combination strategies using immune checkpoint inhibitors to enhance both innate and adaptive immune responses, or to establish a more immune favorable environment for cancer vaccines. Finally, the review will address the need for unambiguous predictive biomarkers as one of the main challenges of immune checkpoint blockade. To conclude, the potential of immune checkpoint blockade for triple negative breast cancer treatment could be enhanced by exploration of aforementioned factors and treatment strategies thereby providing promising future prospects.

Tumor-Induced Inflammatory Cytokines and the Emerging Diagnostic Devices for Cancer Detection and Prognosis.

Abstract: Chronic inflammation generated by the tumor microenvironment is known to drive cancer initiation, proliferation, progression, metastasis, and therapeutic resistance. The tumor microenvironment promotes the secretion of diverse cytokines, in different types and stages of cancers. These cytokines may inhibit tumor development but alternatively may contribute to chronic inflammation that supports tumor growth in both autocrine and paracrine manners and have been linked to poor cancer outcomes. Such distinct sets of cytokines from the tumor microenvironment can be detected in the circulation and are thus potentially useful as biomarkers to detect cancers, predict disease outcomes and manage therapeutic choices. Indeed, analyses of circulating cytokines in combination with cancer-specific biomarkers have been proposed to simplify and improve cancer detection and prognosis, especially from minimally-invasive liquid biopsies, such as blood. Additionally, the cytokine signaling signatures of the peripheral immune cells, even from patients with localized tumors, are recently found altered in cancer, and may also prove applicable as cancer biomarkers. Here we review cytokines induced by the tumor microenvironment, their roles in various stages of cancer development, and their potential use in diagnostics and prognostics. We further discuss the established and emerging diagnostic approaches that can be used to detect cancers from liquid biopsies, and additionally the technological advancement required for their use in clinical settings.

Has COVID-19 Affected Cancer Screening Programs? A Systematic Review

Abstract: Background Health care services across the world have been enormously affected by the onset of the coronavirus disease 2019 (COVID-19). Services in oncology have been curtailed because medical services have been focused on preventing the spread of the virus and maximizing the number of available hospital beds. The present study was designed to investigate the impact of COVID-19 on cancer screening. Methods Databases such as Medline, Web of Science Core Collection (Indexes = SCI-EXPANDED, SSCI, A & HCI Timespan) and Scopus were searched comprehensively for articles published until January 2021. The keywords used were COVID-19 and cancer screening, Articles dealing with cancer screening in the COVID-19 pandemic were included in the review. Results The review comprised 17 publications. The impact of COVID-19 was categorized into four dimensions: a significant decline in cancer screening and pathology samples, the cancer diagnosis rate, an increase in advanced cancers, mortality rate and years of life lost (YLLs). Conclusion Cancer screening programs have been clearly interrupted since the onset of the COVID-19 disease. The anticipated outcomes include delayed diagnosis and marked increases in the numbers of avoidable cancer deaths. Urgent policy interventions are needed to handle the backlog of routine diagnostic services and minimize the harmful effects of the COVID-19 pandemic on cancer patients.

Knowledge Domain and Emerging Trends in Ferroptosis Research: A Bibliometric and Knowledge-Map Analysis.

Abstract: Objectives: To identify the cooperation and impact of authors, countries, institutions, and journals, evaluate the knowledge base, find the hotspots trends, and detect the emerging topics regarding ferroptosis research. Methods: The articles and reviews related to ferroptosis were obtained from the Web of Science Core Collection on November 1, 2020. Two scientometric software (CiteSpace 5.7 and VOSviewer 1.6.15) were used to perform bibliometric and knowledge-map analysis. Results: A total of 1,2521,267 papers were included, in 461 466 academic journals by 6,7866,867 authors in 437 438 institutions from 61 countries/regions. The ferroptosis-related publications were increasing rapidly. Cell Death & Disease published the most papers on ferroptosis, while Cell was the top1 co-cited journal, publication journals and co-cited journals were major in molecular and biology field. The United States and China were the most productive countries; meanwhile, the University of Pittsburgh, Columbia University and Guangzhou Medical University were the most active institutions. Brent R Stockwell published the most papers, while Scott J Dixon had the most co-citations; simultaneously, active cooperation existed in ferroptosis researchers. Ten references on reviews, mechanisms and diseases were regarded as the knowledge base. Five main aspects of ferroptosis research included regulation mechanisms, nervous system injury, cancer, relationships with other types of cell death, and lipid peroxidation. The latest hotspots were nanoparticle, cancer therapy, iron metabolism, and in-depth mechanism. Notability, Nrf2 might have turning significance. The emerging topics on ferroptosis research were the further molecule mechanism of ferroptosis and the wider application of ferroptosis-related disease with advanced technology. Conclusion: This study performed a full overview of the ferroptosis research using bibliometric and visual methods. The information would provide helpful references for scholars focusing on ferroptosis.

FDA-Approved and Emerging Next Generation Predictive Biomarkers for Immune Checkpoint Inhibitors in Cancer Patients

Abstract: A patient's response to immune checkpoint inhibitors (ICIs) is a complex quantitative trait, and determined by multiple intrinsic and extrinsic factors. Three currently FDA-approved predictive biomarkers (progra1mmed cell death ligand-1 (PD-L1); microsatellite instability (MSI); tumor mutational burden (TMB)) are routinely used for patient selection for ICI response in clinical practice. Although clinical utility of these biomarkers has been demonstrated in ample clinical trials, many variables involved in using these biomarkers have poised serious challenges in daily practice. Furthermore, the predicted responders by these three biomarkers only have a small percentage of overlap, suggesting that each biomarker captures different contributing factors to ICI response. Optimized use of currently FDA-approved biomarkers and development of a new generation of predictive biomarkers are urgently needed. In this review, we will first discuss three widely used FDA-approved predictive biomarkers and their optimal use. Secondly, we will review four novel gene signature biomarkers: T-cell inflamed gene expression profile (GEP), T-cell dysfunction and exclusion gene signature (TIDE), melanocytic plasticity signature (MPS) and B-cell focused gene signature. The GEP and TIDE have shown better predictive performance than PD-L1, and PD-L1 or TMB, respectively. The MPS is superior to PD-L1, TMB, and TIDE. The B-cell focused gene signature represents a previously unexplored predictive biomarker to ICI response. Thirdly, we will highlight two combined predictive biomarkers: TMB+GEP and MPS+TIDE. These integrated biomarkers showed improved predictive outcomes compared to a single predictor. Finally, we will present a potential nucleic acid biomarker signature, allowing DNA and RNA biomarkers to be analyzed in one assay. This comprehensive signature could represent a future direction of developing robust predictive biomarkers, particularly for the cold tumors, for ICI response.

Immunotherapy in Treating EGFR-Mutant Lung Cancer: Current Challenges and New Strategies.

Abstract: Lung cancer is the leading cause of cancer-related deaths worldwide. Immune checkpoint inhibitors, including monoclonal antibodies against programmed death-1 (PD-1) and programmed death ligand-1 (PD-L1), have dramatically improved the survival and quality of life of a subset of non-small cell lung cancer (NSCLC) patients. Multiple predictive biomarkers have been proposed to select the patients who may benefit from the immune checkpoint inhibitors. EGFR-mutant NSCLC is the most prevalent molecular subtype in Asian lung cancer patients. However, patients with EGFR-mutant NSCLC show poor response to anti-PD-1/PD-L1 treatment. While small-molecule EGFR tyrosine kinase inhibitors (TKIs) are the preferred initial treatment for EGFR-mutant NSCLC, acquired drug resistance is severely limiting the long-term efficacy. However, there is currently no further effective treatment option for TKIs-refractory EGFR-mutant NSCLC patients. The reasons mediating the poor response of EGFR-mutated NSCLC patients to immunotherapy are not clear. Initial investigations revealed that EGFR-mutated NSCLC has lower PD-L1 expression and a low tumor mutational burden, thus leading to weak immunogenicity. Moreover, the use of PD-1/PD-L1 blockade prior to or concurrent with osimertinib has been reported to increase the risk of pulmonary toxicity. Furthermore, emerging evidence shows that PD-1/PD-L1 blockade in NSCLC patients can lead to hyperprogressive disease associated with dismal prognosis. However, it is difficult to predict the treatment toxicity. New biomarkers are urgently needed to predict response and toxicity associated with the use of PD-1/PD-L1 immunotherapy in EGFR-mutated NSCLC. Recently, promising data have emerged to suggest the potentiation of PD-1/PD-L1 blockade therapy by anti-angiogenic agents and a few other novel therapeutic agents. This article reviews the current investigations about the poor response of EGFR-mutated NSCLC to anti-PD-1/PD-L1 therapy, and discusses the new strategies that may be adopted in the future.

Global Research Trends on Prostate Diseases and Erectile Dysfunction: A Bibliometric and Visualized Study.

Abstract: Objectives: To identify the cooperation of authors, countries, institutions and explore the hot topics prospects regarding research of prostate diseases and erectile dysfunction (ED). Methods: Publications on research of prostate diseases and ED were retrieved from the Web of Science Core Collection (WoSCC). Bibliometric analyses were performed using VOSviewer and CiteSpace software. Network maps were generated to evaluate the collaborations between different authors, countries, institutions and keywords. Results: A total of 2599 articles related to study of prostate diseases and ED were identified. We observed gradually increasing in the number of publications from 1998 to 2016, and the trend was to be relatively stable in the past three years. Journal of Sexual Medicine (243 papers) owned the highest number of publications and Journal of Urology was the most co-cited journal. Mulhall John P (52 papers) was the top most productive authors and Mcvary Kebin T with the largest numbers of citations (1589 co-citations) during the past decades. There were active collaborations among the top authors. The USA was the leading contributor in this field with 1078 papers. Active cooperation between countries and between institutions was observed. The main hot topics included matters related to erectile dysfunction, prostate cancer, quality-of-life, radical prpstatectomy, sexual function and BPH. Conclusion: Studies of prostate diseases and ED have gradually increasing after 1998 and were relatively stable in the past three years. The USA contributed the most publications. There were active cooperation between authors, countries, and institutions. Further research should expand and develop new topics such as treatment.

Immune Checkpoint Inhibitors in the Treatment of HCC.

Abstract: Hepatocellular carcinoma (HCC) is the typical inflammation-induced neoplasia. It often prospers where a chronic liver disease persists, thus leading a strong rationale for immune therapy. Several immune-based treatments, including immune checkpoint inhibitors (ICI), cytokines, adoptive cell transfer, and vaccines, have been tested in the treatment of HCC. In this review, we summarize the role of the ICI in HCC patients in various sets of treatment. As for advanced HCC, the anti-Programmed cell Death protein 1 (PD1) antibodies and the anti-Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) antibodies have been examined in patients with enthusiastic results in phase I-II-III studies. Overall, this led the Food and Drug Administration (FDA) to approve pembrolizumab, nivolumab, and nivolumab + ipilimumab in the second-line setting. The anti- Programmed Death-Ligand 1 (PDL-1) antibodies have also been evaluated. Thanks to the results obtained from phase III IMbrave study, atezolizumab + bevacizumab is now the standard of care in the first-line advanced setting of HCC. As for localized HCC, the putative immunological effect of locoregional therapies led to evaluate the combination strategy with ICI. This way, chemoembolization, ablation with radiofrequency, and radioembolization combined with ICI are currently under study. Likewise, the study of adjuvant immunotherapy following surgical resection is underway. In addition, the different ICI has been studied in combination with other ICI as well as with multikinase inhibitors and anti-angiogenesis monoclonal antibody. The evidence available suggests that combining systemic therapies and locoregional treatments with ICI may represent an effective strategy in this context.

Artificial Convolutional Neural Network in Object Detection and Semantic Segmentation for Medical Imaging Analysis

Abstract: In the era of digital medicine, a vast number of medical images are produced every day. There is a great demand for intelligent equipment for adjuvant diagnosis to assist medical doctors with different disciplines. With the development of artificial intelligence, the algorithms of convolutional neural network (CNN) progressed rapidly. CNN and its extension algorithms play important roles on medical imaging classification, object detection, and semantic segmentation. While medical imaging classification has been widely reported, the object detection and semantic segmentation of imaging are rarely described. In this review article, we introduce the progression of object detection and semantic segmentation in medical imaging study. We also discuss how to accurately define the location and boundary of diseases.

CAFs Interacting With TAMs in Tumor Microenvironment to Enhance Tumorigenesis and Immune Evasion

Abstract: Cancer associated fibroblasts (CAFs) and tumor associated macrophages (TAMs) are among the most important and abundant players of the tumor microenvironment. CAFs as well as TAMs are known to play pivotal supportive roles in tumor growth and progression. The number of CAF or TAM cells is mostly correlated with poor prognosis. Both CAFs and TAMs are in a reciprocal communication with the tumor cells in the tumor milieu. In addition to such interactions, CAFs and TAMs are also involved in a dynamic and reciprocal interrelationship with each other. Both CAFs and TAMs are capable of altering each other’s functions. Here, the current understanding of the distinct mechanisms about the complex interplay between CAFs and TAMs are summarized. In addition, the consequences of such a mutual relationship especially for tumor progression and tumor immune evasion are highlighted, focusing on the synergistic pleiotropic effects. CAFs and TAMs are crucial components of the tumor microenvironment; thus, they may prove to be potential therapeutic targets. A better understanding of the tri-directional interactions of CAFs, TAMs and cancer cells in terms of tumor progression will pave the way for the identification of novel theranostic cues in order to better target the crucial mechanisms of carcinogenesis.

Pyroptosis-Related Gene Signatures Can Robustly Diagnose Skin Cutaneous Melanoma and Predict the Prognosis.

Abstract: Skin cutaneous melanoma (SKCM) is a chronically malignant tumor with a high mortality rate. Pyroptosis, a kind of pro-inflammatory programmed cell death, has been linked to cancer in recent studies. However, the value of pyroptosis in the diagnosis and prognosis of SKCM is not clear. In this study, it was discovered that 20 pyroptosis-related genes (PRGs) differed in expression between SKCM and normal tissues, which were related to diagnosis and prognosis. Firstly, based on these genes, nine machine-learning algorithms were shown to perform well in constructing diagnostic classifiers, including K-Nearest Neighbor (KNN), logistic regression, Support Vector Machine (SVM), Artificial Neural Network (ANN), decision tree, random forest, XGBoost, LightGBM, and CatBoost. Secondly, the least absolute shrinkage and selection operator (LASSO) Cox regression analysis was applied and the prognostic model was constructed based on 9 PRGs. Subgroups in low and high risks determined by the prognostic model were shown to have different survival. Thirdly, functional enrichment analyses were performed by applying the gene set enrichment analysis (GSEA), and results suggested that the risk was related to immune response. In conclusion, the expression signatures of pyroptosis-related genes are effective and robust in the diagnosis and prognosis of SKCM, which is related to immunity.

An Inflammatory Response-Related Gene Signature Can Impact the Immune Status and Predict the Prognosis of Hepatocellular Carcinoma.

Abstract: Background Hepatocellular carcinoma (HCC) is a highly heterogeneous disease, which makes the prognostic prediction challenging. As part of the active cross-talk between the tumor and the host, inflammatory response in the tumor or its microenvironment could affect prognosis. However, the prognostic value of inflammatory response-related genes in HCC remains to be further elucidated. Methods In this study, the mRNA expression profiles and corresponding clinical data of HCC patients were downloaded from the public database. The least absolute shrinkage and selection operator Cox analysis was utilized to construct a multigene prognostic signature in the TCGA cohort. HCC patients from the ICGC cohort were used for validation. Kaplan Meier analysis was used to compare the overall survival (OS) between high- and low-risk groups. Univariate and multivariate Cox analyses were applied to determine the independent predictors for OS. Single-sample gene set enrichment analysis was utilized to calculate the immune cell infiltration score and immune related pathway activity. Gene set enrichment analysis was implemented to conduct GO terms and KEGG pathways. The qRT-PCR and immunohistochemistry were utilized to perform the mRNA and protein expression of prognostic genes between HCC tissues and normal liver tissues respectively. Results An inflammatory response-related gene signature model was constructed by LASSO Cox regression analysis. Compared with the low-risk group, patients in the high-risk group showed significantly reduced OS. Receiver operating characteristic curve analysis confirmed the predictive capacity of the prognostic gene signature. Multivariate Cox analysis revealed that the risk score was an independent predictor for OS. Functional analysis indicated that immune status was definitely different between two risk groups, and cancer-related pathways were enriched in high-risk group. The risk score was significantly correlated with tumor grade, tumor stage and immune infiltrate types. The expression levels of prognostic genes were significantly correlated with sensitivity of cancer cells to anti-tumor drugs. Furthermore, the expression of prognostic genes showed significant difference between HCC tissues and adjacent non-tumorous tissues in the separate sample cohort. Conclusion A novel signature constructed with eight inflammatory response-related genes can be used for prognostic prediction and impact the immune status in HCC. Moreover, inhibition of these genes may be a therapeutic alternative.

Obesity, Type 2 Diabetes, and Cancer Risk.

Abstract: Obesity and type 2 diabetes have both been associated with increased cancer risk and are becoming increasingly prevalent. Metabolic abnormalities such as insulin resistance and dyslipidemia are associated with both obesity and type 2 diabetes and have been implicated in the obesity-cancer relationship. Multiple mechanisms have been proposed to link obesity and diabetes with cancer progression, including an increase in insulin/IGF-1 signaling, lipid and glucose uptake and metabolism, alterations in the profile of cytokines, chemokines, and adipokines, as well as changes in the adipose tissue directly adjacent to the cancer sites. This review aims to summarize and provide an update on the epidemiological and mechanistic evidence linking obesity and type 2 diabetes with cancer, focusing on the roles of insulin, lipids, and adipose tissue.

FOXM1 and Cancer: Faulty Cellular Signaling Derails Homeostasis.

Abstract: Forkhead box transcription factor, FOXM1 is implicated in several cellular processes such as proliferation, cell cycle progression, cell differentiation, DNA damage repair, tissue homeostasis, angiogenesis, apoptosis, and redox signaling. In addition to being a boon for the normal functioning of a cell, FOXM1 turns out to be a bane by manifesting in several disease scenarios including cancer. It has been given an oncogenic status based on several evidences indicating its role in tumor development and progression. FOXM1 is highly expressed in several cancers and has also been implicated in poor prognosis. A comprehensive understanding of various aspects of this molecule has revealed its role in angiogenesis, invasion, migration, self- renewal and drug resistance. In this review, we attempt to understand various mechanisms underlying FOXM1 gene and protein regulation in cancer including the different signaling pathways, post-transcriptional and post-translational modifications. Identifying crucial molecules associated with these processes can aid in the development of potential pharmacological approaches to curb FOXM1 mediated tumorigenesis.

The Current Treatment Paradigm for Pancreatic Ductal Adenocarcinoma and Barriers to Therapeutic Efficacy.

Abstract: Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis, with a median survival time of 10-12 months. Clinically, these poor outcomes are attributed to several factors, including late stage at the time of diagnosis impeding resectability, as well as multi-drug resistance. Despite the high prevalence of drug-resistant phenotypes, nearly all patients are offered chemotherapy leading to modest improvements in postoperative survival. However, chemotherapy is all too often associated with toxicity, and many patients elect for palliative care. In cases of inoperable disease, cytotoxic therapies are less efficacious but still carry the same risk of serious adverse effects, and clinical outcomes remain particularly poor. Here we discuss the current state of pancreatic cancer therapy, both surgical and medical, and emerging factors limiting the efficacy of both. Combined, this review highlights an unmet clinical need to improve our understanding of the mechanisms underlying the poor therapeutic responses seen in patients with PDAC, in hopes of increasing drug efficacy, extending patient survival, and improving quality of life.

The Role of the Transcription Factor EGR1 in Cancer.

Abstract: Early growth response factor 1 (EGR1) is a transcription factor that is mainly involved in the processes of tissue injury, immune responses, and fibrosis. Recent studies have shown that EGR1 is closely related to the initiation and progression of cancer and may participate in tumor cell proliferation, invasion, and metastasis and in tumor angiogenesis. Nonetheless, the specific mechanism whereby EGR1 modulates these processes remains to be elucidated. This review article summarizes possible mechanisms of action of EGR1 in tumorigenesis and tumor progression and may serve as a reference for clinical efficacy predictions and for the discovery of new therapeutic targets.

A Review of Newly Diagnosed Glioblastoma.

Abstract: Glioblastoma is an aggressive and inevitably recurrent primary intra-axial brain tumor with a dismal prognosis. The current mainstay of treatment involves maximally safe surgical resection followed by radiotherapy over a 6-week period with concomitant temozolomide chemotherapy followed by temozolomide maintenance. This review provides a summary of the epidemiological, clinical, histologic and genetic characteristics of newly diagnosed disease as well as the current standard of care and potential future therapeutic prospects.

CCL2: An Important Mediator Between Tumor Cells and Host Cells in Tumor Microenvironment.

Abstract: Tumor microenvironment (TME) formation is a major cause of immunosuppression. The TME consists of a considerable number of macrophages and stromal cells that have been identified in multiple tumor types. CCL2 is the strongest chemoattractant involved in macrophage recruitment and a powerful initiator of inflammation. Evidence indicates that CCL2 can attract other host cells in the TME and direct their differentiation in cooperation with other cytokines. Overall, CCL2 has an unfavorable effect on prognosis in tumor patients because of the accumulation of immunosuppressive cell subtypes. However, there is also evidence demonstrating that CCL2 enhances the anti-tumor capability of specific cell types such as inflammatory monocytes and neutrophils. The inflammation state of the tumor seems to have a bi-lateral role in tumor progression. Here, we review works focusing on the interactions between cancer cells and host cells, and on the biological role of CCL2 in these processes.

YTHDF1 Is a Potential Pan-Cancer Biomarker for Prognosis and Immunotherapy.

Abstract: Background: YTH N6-methyladenosine RNA binding protein 1 (YTHDF1) has been indicated proven to participate in the cross-presentation of tumor antigens in dendritic cells and the cross-priming of CD8+ T cells. However, the role of YTHDF1 in prognosis and immunology in human cancers remains largely unknown. Methods: All original data were downloaded from TCGA and GEO databases and integrated via R 3.2.2. YTHDF1 expression was explored with the Oncomine, TIMER, GEPIA, and BioGPS databases. The effect of YTHDF1 on prognosis was analyzed via GEPIA, Kaplan-Meier plotter, and the PrognoScan database. The TISIDB database was used to determine YTHDF1 expression in different immune and molecular subtypes of human cancers. The correlations between YTHDF1 expression and immune checkpoints (ICP), tumor mutational burden (TMB), microsatellite instability (MSI), and neoantigens in human cancers were analyzed via the SangerBox database. The relationships between YTHDF1 expression and tumor infiltrated immune cells were analyzed via the TIMER and GEPIA databases. The relationships between YTHDF1 and marker genes of tumor infiltrated immune cells in urogenital cancers were analyzed for confirmation. The genomic alterations of YTHDF1 were investigated with the c-BioPortal database. The differential expression of YTHDF1 in urogenital cancers with different clinical characteristics was analyzed with the UALCAN database. YTHDF1 coexpression networks were studied by the LinkedOmics database. Results: In general, YTHDF1 expression was higher in tumors than in paired normal tissue in human cancers. YTHDF1 expression had strong relationships with prognosis, ICP, TMB, MSI, and neoantigens. YTHDF1 plays an essential role in the tumor microenvironment (TME) and participates in immune regulation. Furthermore, significant strong correlations between YTHDF1 expression and tumor immune infiltrated cells (TILs) existed in human cancers, and marker genes of TILs were significantly related to YTHDF expression in urogenital cancers. TYHDF1 coexpression networks mostly participated in the regulation of immune response and antigen processing and presentation. Conclusion: YTHDF1 may serve as a potential prognostic and immunological pan-cancer biomarker. Moreover, YTHDF1 could be a novel target for tumor immunotherapy.

Immunotherapy in Acute Myeloid Leukemia: Where We Stand.

Abstract: In the past few years, our improved knowledge of acute myeloid leukemia (AML) pathogenesis has led to the accelerated discovery of new drugs and the development of innovative therapeutic approaches. The role of the immune system in AML development, growth and recurrence has gained increasing interest. A better understanding of immunological escape and systemic tolerance induced by AML blasts has been achieved. The extraordinary successes of immune therapies that harness the power of T cells in solid tumors and certain hematological malignancies have provided new stimuli in this area of research. Accordingly, major efforts have been made to develop immune therapies for the treatment of AML patients. The persistence of leukemia stem cells, representing the most relevant cause of relapse, even after allogeneic stem cell transplant (allo-SCT), remains a major hurdle in the path to cure for AML patients. Several clinical trials with immune-based therapies are currently ongoing in the frontline, relapsed/refractory, post-allo-SCT and minimal residual disease/maintenance setting, with the aim to improve survival of AML patients. This review summarizes the available data with immune-based therapeutic modalities such as monoclonal antibodies (naked and conjugated), T cell engagers, adoptive T-cell therapy, adoptive-NK therapy, checkpoint blockade via PD-1/PD-L1, CTLA4, TIM3 and macrophage checkpoint blockade via the CD47/SIRPa axis, and leukemia vaccines. Combining clinical results with biological immunological findings, possibly coupled with the discovery of biomarkers predictive for response, will hopefully allow us to determine the best approaches to immunotherapy in AML.

Understanding Sources of Variation to Improve the Reproducibility of Radiomics.

Abstract: Radiomics is the method of choice for investigating the association between cancer imaging phenotype, cancer genotype and clinical outcome prediction in the era of precision medicine. The fast dispersal of this new methodology has benefited from the existing advances of the core technologies involved in radiomics workflow: image acquisition, tumor segmentation, feature extraction and machine learning. However, despite the rapidly increasing body of publications, there is no real clinical use of a developed radiomics signature so far. Reasons are multifaceted. One of the major challenges is the lack of reproducibility and generalizability of the reported radiomics signatures (features and models). Sources of variation exist in each step of the workflow; some are controllable or can be controlled to certain degrees, while others are uncontrollable or even unknown. Insufficient transparency in reporting radiomics studies further prevents translation of the developed radiomics signatures from the bench to the bedside. This review article first addresses sources of variation, which is illustrated using demonstrative examples. Then, it reviews a number of published studies and progresses made to date in the investigation and improvement of feature reproducibility and model performance. Lastly, it discusses potential strategies and practical considerations to reduce feature variability and improve the quality of radiomics study. This review focuses on CT image acquisition, tumor segmentation, quantitative feature extraction, and the disease of lung cancer.

The Mevalonate Pathway, a Metabolic Target in Cancer Therapy

Abstract: A hallmark of cancer cells includes a metabolic reprograming that provides energy, the essential building blocks, and signaling required to maintain survival, rapid growth, metastasis, and drug resistance of many cancers. The influence of tumor microenviroment on cancer cells also results an essential driving force for cancer progression and drug resistance. Lipid-related enzymes, lipid-derived metabolites and/or signaling pathways linked to critical regulators of lipid metabolism can influence gene expression and chromatin remodeling, cellular differentiation, stress response pathways, or tumor microenviroment, and, collectively, drive tumor development. Reprograming of lipid metabolism includes a deregulated activity of mevalonate (MVA)/cholesterol biosynthetic pathway in specific cancer cells which, in comparison with normal cell counterparts, are dependent of the continuous availability of MVA/cholesterol-derived metabolites (i.e., sterols and non-sterol intermediates) for tumor development. Accordingly, there are increasing amount of data, from preclinical and epidemiological studies, that support an inverse association between the use of statins, potent inhibitors of MVA biosynthetic pathway, and mortality rate in specific cancers (e.g., colon, prostate, liver, breast, hematological malignances). In contrast, despite the tolerance and therapeutic efficacy shown by statins in cardiovascular disease, cancer treatment demands the use of relatively high doses of single statins for a prolonged period, thereby limiting this therapeutic strategy due to adverse effects. Clinically relevant, synergistic effects of tolerable doses of statins with conventional chemotherapy might enhance efficacy with lower doses of each drug and, probably, reduce adverse effects and resistance. In spite of that, clinical trials to identify combinatory therapies that improve therapeutic window are still a challenge. In the present review, we revisit molecular evidences showing that deregulated activity of MVA biosynthetic pathway has an essential role in oncogenesis and drug resistance, and the potential use of MVA pathway inhibitors to improve therapeutic window in cancer.

CAR-NK Cell: A New Paradigm in Tumor Immunotherapy.

Abstract: The tumor microenvironment (TME) is greatly multifaceted and immune escape is an imperative attribute of tumors fostering tumor progression and metastasis. Based on reports, the restricted achievement attained by T cell immunotherapy reflects the prominence of emerging other innovative immunotherapeutics, in particular, natural killer (NK) cells-based treatments. Human NK cells act as the foremost innate immune effector cells against tumors and are vastly heterogeneous in the TME. Currently, there exists a rapidly evolving interest in the progress of chimeric antigen receptor (CAR)-engineered NK cells for tumor immunotherapy. CAR-NK cells superiorities over CAR-T cells in terms of better safety (e.g., absence or minimal cytokine release syndrome (CRS) and graft-versus-host disease (GVHD), engaging various mechanisms for stimulating cytotoxic function, and high feasibility for ‘off-the-shelf’ manufacturing. These effector cells could be modified to target various antigens, improve proliferation and persistence in vivo, upturn infiltration into tumors, and defeat resistant TME, which in turn, result in a desired anti-tumor response. More importantly, CAR-NK cells represent antigen receptors against tumor-associated antigens (TAAs), thereby redirecting the effector NK cells and supporting tumor-related immunosurveillance. In the current review, we focus on recent progress in the therapeutic competence of CAR-NK cells in solid tumors and offer a concise summary of the present hurdles affecting therapeutic outcomes of CAR-NK cell-based tumor immunotherapies.

Current Triple-Negative Breast Cancer Subtypes: Dissecting the Most Aggressive Form of Breast Cancer.

Abstract: Triple-negative breast cancer (TNBC) is a highly heterogeneous disease defined by the absence of estrogen receptor (ER) and progesterone receptor (PR) expression, and human epidermal growth factor receptor 2 (HER2) overexpression that lacks targeted treatments, leading to dismal clinical outcomes. Thus, better stratification systems that reflect intrinsic and clinically useful differences between TNBC tumors will sharpen the treatment approaches and improve clinical outcomes. The lack of a rational classification system for TNBC also impacts current and emerging therapeutic alternatives. In the past years, several new methodologies to stratify TNBC have arisen thanks to the implementation of microarray technology, high-throughput sequencing, and bioinformatic methods, exponentially increasing the amount of genomic, epigenomic, transcriptomic, and proteomic information available. Thus, new TNBC subtypes are being characterized with the promise to advance the treatment of this challenging disease. However, the diverse nature of the molecular data, the poor integration between the various methods, and the lack of cost-effective methods for systematic classification have hampered the widespread implementation of these promising developments. However, the advent of artificial intelligence applied to translational oncology promises to bring light into definitive TNBC subtypes. This review provides a comprehensive summary of the available classification strategies. It includes evaluating the overlap between the molecular, immunohistochemical, and clinical characteristics between these approaches and a perspective about the increasing applications of artificial intelligence to identify definitive and clinically relevant TNBC subtypes.

Cancer in Africa: The Untold Story

Abstract: Background Despite rising incidence and mortality rates in Africa, cancer has been given low priority in the research field and in healthcare services. Indeed, 57% of all new cancer cases around the world occur in low income countries exacerbated by lack of awareness, lack of preventive strategies, and increased life expectancies. Despite recent efforts devoted to cancer epidemiology, statistics on cancer rates in Africa are often dispersed across different registries. In this study our goal included identifying the most promising prevention and treatment approaches available in Africa. To do this, we collated and analyzed the incidence and fatality rates for the 10 most common and fatal cancers in 56 African countries grouped into 5 different regions (North, West, East, Central and South) over 16-years (2002-2018). We examined temporal and regional trends by investigating the most important risk factors associated to each cancer type. Data were analyzed by cancer type, African region, gender, measures of socioeconomic status and the availability of medical devices. Results We observed that Northern and Southern Africa were most similar in their cancer incidences and fatality rates compared to other African regions. The most prevalent cancers are breast, bladder and liver cancers in Northern Africa; prostate, lung and colorectal cancers in Southern Africa; and esophageal and cervical cancer in East Africa. In Southern Africa, fatality rates from prostate cancer and cervical cancer have increased. In addition, these three cancers are less fatal in Northern and Southern Africa compared to other regions, which correlates with the Human Development Index and the availability of medical devices. With the exception of thyroid cancer, all other cancers have higher incidences in males than females. Conclusion Our results show that the African continent suffers from a shortage of medical equipment, research resources and epidemiological expertise. While recognizing that risk factors are interconnected, we focused on risk factors more or less specific to each cancer type. This helps identify specific preventive and therapeutic options in Africa. We see a need for implementing more accurate preventive strategies to tackle this disease as many cases are likely preventable. Opportunities exist for vaccination programs for cervical and liver cancer, genetic testing and use of new targeted therapies for breast and prostate cancer, and positive changes in lifestyle for lung, colorectal and bladder cancers. Such recommendations should be tailored for the different African regions depending on their disease profiles and specific needs.

m5C RNA Methylation Regulators Predict Prognosis and Regulate the Immune Microenvironment in Lung Squamous Cell Carcinoma.

Abstract: RNA methylation is a novel epigenetic modification that can be used to evaluate tumor prognosis. However, the underlying mechanisms are unclear. This study aimed to investigate the genetic characteristics of 5-methylcytosine (m5C) and N1-methyladenosine (m1A) regulators in lung squamous cell carcinoma (LUSC) and the prognostic value and immune-related effects of m5C regulators. To this end, we selected the public LUSC dataset from the Cancer Genome Atlas and Gene Expression Omnibus. The least absolute shrinkage and selection operator regression model was used to identify prognostic risk signatures. We used the UALCAN and Human Protein Atlas databases to study the expression of target gene mRNA/protein expression. Furthermore, the Tumor Immune Single Cell Hub and the Tumor Immune Estimation Resource were used to evaluate the degree of immune cell infiltration. Most of the m5C and m1A regulators showed significantly different expression between LUSC and normal samples. The m5C regulators were associated with poor prognosis. In addition, a prognostic risk signature was developed based on two m5C regulators, NOP2/Sun RNA methyltransferase 3 (NSUN3), and NOP2/Sun RNA methyltransferase 4 (NSUN4). Compared with normal lung tissues, the expression of NSUN3 and NSUN4 in the LUSC TCGA dataset was increased, which was related to clinicopathological characteristics and survival. NSUN3 and NSUN4 were related to the infiltration of six major immune cells; especially NSUN3, which was closely related to CD8+ T cells, while NSUN4 was closely related to neutrophils. Our findings suggest that m5C regulators can predict the clinical prognosis risk and regulate the tumor immune microenvironment in LUSC.

The Metabolic Mechanisms of Breast Cancer Metastasis.

Abstract: Breast cancer is one of the most common malignancy among women worldwide. Metastasis is mainly responsible for treatment failure and is the cause of most breast cancer deaths. The role of metabolism in the progression and metastasis of breast cancer is gradually being emphasized. However, the regulatory mechanisms that conduce to cancer metastasis by metabolic reprogramming in breast cancer have not been expounded. Breast cancer cells exhibit different metabolic phenotypes depending on their molecular subtypes and metastatic sites. Both intrinsic factors, such as MYC amplification, PIK3CA, and TP53 mutations, and extrinsic factors, such as hypoxia, oxidative stress, and acidosis, contribute to different metabolic reprogramming phenotypes in metastatic breast cancers. Understanding the metabolic mechanisms underlying breast cancer metastasis will provide important clues to develop novel therapeutic approaches for treatment of metastatic breast cancer.