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1.
J. coloproctol. (Rio J., Impr.) ; 41(1): 63-69, Jan.-Mar. 2021. tab, graf
Article in English | LILACS | ID: biblio-1286971

ABSTRACT

Abstract Objective Type-I collagen (Col-I) is one of the main macromolecules of the extracellular matrix, and it is involved in the desmoplastic stromal reaction, an indicator of worse prognosis in cases of colorectal cancer (CRC). The purpose of the present study was to investigate Col-I expression in cases of CRC and adenoma and to correlate with the clinical data and the data regarding the lifestyle of the patients. Methods A retrospective study including 22 patients with adenoma and 15 with CRC treated at a coloproctology service. The clinical and lifestyle data were obtained through medical records, and Col-I expression was investigated by immunohistochemistry. Results Women represented most cases of adenoma (63.64%), whereas CRC was found mainly in men (73.33%) (p=0.0448). Immunoexpression of Col-I showed a basement membrane thickening in areas of lining of epithelium and around the glands in both lesions. The cases of CRC had a quite evident fibrosis process in the stroma. The quantitative analysis demonstrated a higher protein expression in CRCs compared to adenomas (p=0.0109), as well as in female patients (p=0.0214), patients aged ≥ 50 years (p=0.0400), and in those with a positive family history of colorectal disease (p=0.0292). These results suggested a remodeling of the microenvironment of the Worked developed at the Department of Morphology, Centro de Ciências da Saúde, Universidade Federal do Espírito Santo, ES, Brazil. Conclusion The immunohistochemical analysis encourages the performance of more comprehensive studies to ascertain if our results could be a tool for the diagnosis and monitoring of the patients.


Resumo Objetivo O colágeno tipo I (Col-I) é uma das principais macromoléculas da matriz extracelular, e está envolvido na reação desmoplástica estromal, um indicador de pior prognóstico em casos de câncer colorretal (CCR). O objetivo foi investigar a expressão do Col-I emcasos de CCR e adenoma, e correlacioná-la comdados clínicos e de estilo de vida dos pacientes. Metodologia Foi realizado umestudoretrospectivo com22pacientes comadenoma e 15 comCCR tratadosemumserviço de coloproctologia.Os dados dos pacientes foramobtidos dos prontuários médicos, e a expressão do Col-I foi investigada por imunohistoquímica. Resultados As mulheres representaram a maioria dos casos de adenomas (63,64%), enquanto o CCR (73,33%) (p=0,0448) foi mais comum entre os homens. A imunoexpressão de Col-I mostrou espessamento da membrana basal em áreas de revestimento do epitélio e em volta de glândulas em ambas as lesões. O CCR apresentou fibrose no estroma. As análises quantitativas demonstraram maior expressão proteica no CCR (p=0,0109), assim como em mulheres (p=0,0214), pacientes com idade ≥ 50 anos (p=0,0400), e em pacientes com histórico positivo de doença colorretal na família (p=0,0292). Estes resultados sugerem a remodelação do microambiente tumoral na carcinogênese do CCR. As correlações clínico-patológicas positivas mostram uma ligação plausível entre o perfil do paciente e os achados imunohistoquímcos, o que indica uma possível forma de estratificação dos pacientes. Conclusão As análises imunohistoquímicas estimulam a execução de estudos mais abrangentes para confirmar se nossos resultados poderão ser uma ferramenta para o diagnóstico e o monitoramento dos pacientes.


Subject(s)
Humans , Male , Female , Colorectal Neoplasms/metabolism , Colorectal Neoplasms/pathology , Adenocarcinoma/diagnosis , Biomarkers, Tumor/metabolism , Gene Expression Regulation, Neoplastic , Collagen Type I/genetics , Extracellular Matrix/metabolism , Tumor Microenvironment/immunology
2.
Article in English | WPRIM | ID: wpr-879956

ABSTRACT

Epigenetics concerns gene regulatory mechanisms beyond DNA sequence,such as DNA methylation,histone modification,chromatin remodeling,and non-coding RNA. Epigenetic mechanisms play a key role in development,cell fate decision and tumorigenesis. Chromatin modifications and its high order structure across our genome are major forms of epigenetic information,and its establishment and maintenance are closely related to cell metabolism. Metabolic changes in cancer cells include aerobic glycolysis,increased glucose uptake,abnormally active glutamine metabolism,and the use of non-conventional energy supply. These changes meet the vigorous energy and matter needs for the development and spread of cancer,and help tumor cells adapt to hypoxia microenvironment for their survival,proliferation,invasion and migration. There is a complex relationship between epigenetic modifications and cell metabolism in tumor. On the one hand,metabolites in tumor cells may act as cofactors,modification donors or antagonists of epigenetic enzymes,thus modulating the epigenetic landscape. On the other hand,epigenetic modifications can directly regulate the expression of metabolic enzymes,transporters,signaling pathway and transcription factors to affect cell metabolism. This article reviews the crosstalk between epigenetics and cancer metabolism,to explore their potential future applications in the treatment of tumors.


Subject(s)
Carcinogenesis , DNA Methylation , Epigenesis, Genetic , Gene Expression Regulation , Humans , Neoplasms/genetics , Tumor Microenvironment
3.
Article in English | WPRIM | ID: wpr-879954

ABSTRACT

Cholesterol is an important lipid in the body of mammals and an essential component of membrane structures. Cholesterol homeostasis is critical for the maintenance of cellular and body activities, and is mainly regulated by the balance of cholesterol biosynthesis and the exogenous cholesterol uptake. Aberrantly regulated cholesterol metabolism promotes tumor cell proliferation,survival,invasion and metastasis,and their adaptability into the tumor microenvironment. Therefore,targeting cholesterol biosynthesis and reduction of plasma cholesterol levels and cholesterol esterification will provide new strategies for cancer treatment. This review summarizes the current understanding in cholesterol homeostasis regulation and its function in the occurence and development of cancer,as well as current metabolism-targeted cancer treatments.


Subject(s)
Animals , Cell Proliferation , Cholesterol , Homeostasis , Lipid Metabolism , Neoplasms , Tumor Microenvironment
4.
Article in English | WPRIM | ID: wpr-879944

ABSTRACT

The metabolic reprogramming of tumor cells is characterized by increased uptake of various nutrients including glutamine. Glutamine metabolism provides the required substances for glycolysis and oxidative phosphorylation and affects the homeostasis of carbohydrate,fat and protein metabolism to induce the chemoresistance of tumor cells. Combination of chemotherapeutic agents with inhibitors specific to different components of glutamine metabolic pathway has obtained favorable clinical results on various tumors. Glutamine metabolic pathway plays a role in drug resistance of tumor cells in various ways. Firstly,the dynamic change of glutamine transporters can directly affect intracellular glutamine content thereby causing drug resistance; secondly,tumor stromal cells including adipocyte,fibroblast and metabolite from tumor microenvironment would give rise to immune-mediated drug resistance; thirdly,the expression and activity of key enzymes in glutamine metabolism also has a critical role in drug resistance of tumors. This article reviews the effects of glutamine metabolic pathway in the development of tumor chemoresistance,in terms of transporters,tumor microenvironment and metabolic enzymes,to provide insight for improving the therapeutic efficacy for drug-resistant tumors.


Subject(s)
Cell Line, Tumor , Drug Resistance, Neoplasm , Glutamine/metabolism , Glycolysis , Humans , Neoplasms/drug therapy , Oxidative Phosphorylation , Tumor Microenvironment
5.
Article in English | WPRIM | ID: wpr-880866

ABSTRACT

As an important component of the tumor microenvironment, cancer-associated fibroblasts (CAFs) secrete energy metabolites to supply energy for tumor progression. Abnormal regulation of long noncoding RNAs (lncRNAs) is thought to contribute to glucose metabolism, but the role of lncRNAs in glycolysis in oral CAFs has not been systematically examined. In the present study, by using RNA sequencing and bioinformatics analysis, we analyzed the lncRNA/mRNA profiles of normal fibroblasts (NFs) derived from normal tissues and CAFs derived from patients with oral squamous cell carcinoma (OSCC). LncRNA H19 was identified as a key lncRNA in oral CAFs and was synchronously upregulated in both oral cancer cell lines and CAFs. Using small interfering RNA (siRNA) strategies, we determined that lncRNA H19 knockdown affected proliferation, migration, and glycolysis in oral CAFs. We found that knockdown of lncRNA H19 by siRNA suppressed the MAPK signaling pathway, 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) and miR-675-5p. Furthermore, the lncRNA H19/miR-675-5p/PFKFB3 axis was involved in promoting the glycolysis pathway in oral CAFs, as demonstrated by a luciferase reporter system assay and treatment with a miRNA-specific inhibitor. Our study presents a new way to understand glucose metabolism in oral CAFs, theoretically providing a novel biomarker for OSCC molecular diagnosis and a new target for antitumor therapy.


Subject(s)
Cancer-Associated Fibroblasts/metabolism , Carcinoma, Squamous Cell/genetics , Cell Line, Tumor , Cell Proliferation , Gene Expression Regulation, Neoplastic , Glycolysis , Head and Neck Neoplasms , Humans , MicroRNAs/metabolism , Mouth Neoplasms/genetics , Phosphofructokinase-2/genetics , RNA, Long Noncoding/genetics , Signal Transduction , Tumor Microenvironment
6.
Article in English | WPRIM | ID: wpr-880693

ABSTRACT

Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) can effectively inhibit the growth of EGFR-dependent mutant non-small cell lung cancer (NSCLC). Unfortunately, NSCLC patients often develop severe drug resistance after long-term EGFR-TKI treatment. Studies have shown that the disorder of energy metabolism in tumor cells can induce EGFR-TKI resistance. Due to the drug action, gene mutation and other factors, tumor cells undergo metabolic reprogramming, which increases the metabolic rate and intensity of tumor cells, promotes the intake and synthesis of nutrients (such as sugar, fat and glutamine), forms a microenvironment conducive to tumor growth, enhances the bypass activation, phenotype transformation and abnormal proliferation of tumor cells, and inhibits the activity of immune cells and apoptosis of tumor cells, ultimately leading to drug resistance of tumor cells to EGFR-TKI. Therefore, targeting energy metabolism of NSCLC may be a potential way to alleviate TKI resistance.


Subject(s)
Carcinoma, Non-Small-Cell Lung/genetics , Cell Line, Tumor , Drug Resistance, Neoplasm/genetics , Epidermal Growth Factor , ErbB Receptors/genetics , Humans , Lung Neoplasms/genetics , Mutation , Protein Kinase Inhibitors/therapeutic use , Tumor Microenvironment
7.
Acta Physiologica Sinica ; (6): 197-207, 2021.
Article in English | WPRIM | ID: wpr-878248

ABSTRACT

Pancreatic cancer (PC) is a devastating malignant tumor with high incidence and mortality rate worldwide. Meanwhile, the surgical approaches and drugs of this disease remain challenging. In recent years, reactive oxygen species (ROSs) study has become a hotspot in the field of PC research. ROSs may regulate tumor mic roenvironment (TME), cancer stem cells (CSCs) renewal and epithelial-mesenchymal transition (EMT), which result in drug-resistance and recurrence of the PC. Currently, TME that includes immune infiltrates, fibroblasts, vascular vessels and extracellular matrix has become a hotspot in the cancer research. Meanwhile, numerous researches have shown that ROSs-mediated TME plays a central role in the occurrence and development of PC. Targeting ROSs may be promising therapeutic treatments for the PC patients. Therefore, the purposes of the review were manifold: (1) to summarize the regulations of ROSs in tumorigenesis and drug-resistance of PC; (2) to investigate the modulation of ROSs in signaling cascades in PC; (3) to study the effects of ROSs in stromal cells in PC; (4) to generalize the potent therapies targeting ROSs in PC. Overall, this review summarized the current status of ROSs in PC research and suggested some potential anti-PC drugs that may target ROSs.


Subject(s)
Epithelial-Mesenchymal Transition , Humans , Neoplastic Stem Cells , Pancreatic Neoplasms , Reactive Oxygen Species , Tumor Microenvironment
8.
Ciencia Tecnología y Salud ; 8(2): 166-183, 2021. il 27 c
Article in Spanish | LILACS-Express | LILACS, LIGCSA, DIGIUSAC | ID: biblio-1353093

ABSTRACT

El cáncer gástrico (CG) es la neoplasia del tubo digestivo más prevalente en el mundo, asociada a factores genéticos del hospedero y externos, como infección por Helicobacter pylori. La patogénesis incluye inflamación crónica mediada por citocinas del microambiente tumoral, detectables sistémicamente. Estudios previos reportan niveles séricos de citocinas y su contribución al diagnóstico de CG. El presente estudio analiza el perfil de citocinas del tipo de Th1(IFNγ), Th2(IL-4 e IL-10), Th17(Th-17A) y otras pro inflamatorias: IL-1ß, IL-6 y TNF-α, en plasma de 70 casos de pacientes con CG comparándolos con 132 sujetos sanos equiparables en edad y sexo. Los casos provinieron del Hospital Roosevelt e Instituto Nacional de Cancerología de Guatemala (Incan) y formaron parte de un estudio previo. Se analizó la base de datos clínicos, patológicos y epidemiológicos. Se midieron los niveles de citocinas utilizando el sistema "MSD MULTI-SPOT Assay System". La edad promedio de los casos fue 59.5 años, (DE 13.0), 51%, eran positivos para IgG anti H. pylori. Un 71% presentó adenocarcinoma grado III (Borrman), según clasificación de Lauren 55% tenían tipo intestinal. Las siete citocinas cuantificadas se encontraron significativamente elevadas (p < .05) en el plasma de los casos respecto a sus controles. Los casos de CG tipo difuso presentaron niveles de IFNγ significativa-mente elevados. Por regresión logística, las citocinas IL-6 e IL-10, están asociadas significativamente a CG (p < .05) independientemente del estatus de infección por H. pylori. Se destacan la IL-6 e IL-10 como las principales citocinas asociadas a la presencia de CG.


Gastric cancer (GC) is the most prevalent gastrointestinal neoplasm in the world, associated with host and external genetic factors, such as Helicobacter pylori infection. The pathogenesis includes chronic inflammation mediated by cytokines of the tumor microenvironment, systemically detectable. Previous studies report serum levels of cyto-kines and their contribution to the diagnosis of GC. The present study analyzes the profile of cytokines of the type Th1 (IFNγ), Th2 (IL-4 and IL-10), Th17 (Th-17A) and other pro-inflammatory: IL-1ß, IL-6 and TNF-α, in plasma of 70 cases of patients with GC compared with 132 healthy subjects comparable in age and sex. The cases came from the Roosevelt Hospital and the National Cancer Institute of Guatemala -Incan- and were part of a previous study. The clinical, pathological and epidemiological databases were analyzed. Cytokine levels were measured using the "MSD MULTI-SPOT Assay System". The average age of the cases was 59.5 years, (SD 13.0), 51% were positive for IgG anti H. pylori, 71% had grade III adenocarcinoma (Borrman), according to Laurenís classification, 55% had intestinal type. The seven cytokines quantified were found to be significantly elevated (p < .05) in the plasma of the cases compared to their controls. The diffuse GC cases presented significantly elevated IFNγ levels. By logistic regression, the cytokines IL-6 and IL-10 are significantly associated with GC (p < .05) regardless of the H. pylori infection status. IL-6 and IL-10 stand out as the main cytokines associated with the presence of GC.


Subject(s)
Humans , Male , Female , Adolescent , Adult , Middle Aged , Plasma/chemistry , Stomach Neoplasms/complications , Cytokines/analysis , Interleukin-6/analysis , Interleukin-1/analysis , Interleukin-10/analysis , Th2 Cells , Th17 Cells , Immunoglobulin G/analysis , Adenocarcinoma/complications , Biomarkers, Tumor/analysis , Helicobacter Infections/complications , Th1 Cells , Gastrointestinal Tract/pathology , Tumor Microenvironment , Neoplasms/complications
9.
Braz. j. med. biol. res ; 54(10): e11156, 2021. graf
Article in English | LILACS | ID: biblio-1285646

ABSTRACT

The objective of this study was to investigate the effect of human esophageal fibroblast-derived exosomal miR-21 on cisplatin sensitivity against esophageal squamous EC9706 cells. EC9706 cells were co-cultured indirectly with human esophageal fibroblasts (HEF) or miR-21 mimics transfected-HEF in the transwell system. The exosomes in HEF-culture conditioned medium were extracted by differential ultracentrifugation. EC9706 cells were co-cultured with HEF-derived exosomes directly. The cisplatin sensitivity against EC9706 cells was revealed via half maximal inhibitory concentration (IC50) values using MTT assay. The expressions of miR-21, programmed cell death 4 (PDCD4) mRNA, and gene of phosphate and tension homology deleted on chromosome ten (PTEN) mRNA were determined by qRT-PCR. The changes of the protein level were detected using western blot assay. IC50 values of cisplatin against EC9706 cells were increased after EC9706 cells were co-cultured with either HEF or exosomes derived from miR-21 mimics-transfected HEF. Following the increased level of miR-21, the mRNA expression and protein levels of PTEN and PDCD4 were decreased in EC9706 cells. The cisplatin sensitivity to EC9706 cells was reduced by HEF-derived exosomal miR-21 through targeting PTEN and PDCD4. This study suggested that non-tumor cells in the tumor micro-environment increased the tumor anti-chemotherapy effects through their exosomes.


Subject(s)
Humans , Esophageal Neoplasms/genetics , Esophageal Neoplasms/drug therapy , Carcinoma , MicroRNAs/genetics , Cisplatin/pharmacology , RNA-Binding Proteins , Apoptosis , Cell Line, Tumor , Cell Proliferation , Apoptosis Regulatory Proteins/metabolism , Tumor Microenvironment , Fibroblasts/metabolism
10.
Braz. j. med. biol. res ; 54(7): e10612, 2021. tab, graf
Article in English | LILACS | ID: biblio-1249314

ABSTRACT

Genomic studies have provided insights into molecular subgroups and oncogenic drivers of pediatric brain tumors (PBT) that may lead to novel therapeutic strategies. Participants of the cohort Pediatric Brain Tumor Atlas: CBTTC (CBTTC cohort), were randomly divided into training and validation cohorts. In the training cohort, Kaplan-Meier analysis and univariate Cox regression model were applied to preliminary screening of prognostic genes. The LASSO Cox regression model was implemented to build a multi-gene signature, which was then validated in the validation and CBTTC cohorts through Kaplan-Meier, Cox, and receiver operating characteristic curve (ROC) analyses. Also, gene set enrichment analysis (GSEA) and immune infiltrating analyses were conducted to understand function annotation and the role of the signature in the tumor microenvironment. An eight-gene signature was built, which was examined by Kaplan-Meier analysis, revealing that a significant overall survival difference was seen, either in the training or validation cohorts. The eight-gene signature was further proven to be independent of other clinic-pathologic parameters via the Cox regression analyses. Moreover, ROC analysis demonstrated that this signature owned a better predictive power of PBT prognosis. Furthermore, GSEA and immune infiltrating analyses showed that the signature had close interactions with immune-related pathways and was closely related to CD8 T cells and monocytes in the tumor environment. Identifying the eight-gene signature (CBX7, JADE2, IGF2BP3, OR2W6P, PRAME, TICRR, KIF4A, and PIMREG) could accurately identify patients' prognosis and the signature had close interactions with the immunodominant tumor environment, which may provide insight into personalized prognosis prediction and new therapies for PBT patients.


Subject(s)
Humans , Child , Brain Neoplasms/genetics , Gene Expression Profiling , Prognosis , Gene Expression Regulation, Neoplastic , Cell Cycle Proteins , Kaplan-Meier Estimate , Tumor Microenvironment , Polycomb Repressive Complex 1
11.
Article in Chinese | WPRIM | ID: wpr-828527

ABSTRACT

Neutrophil extracellular traps(NET)is neutrophil-derived extracellular fiber web-like structure, composed of DNA scaffold studded with various active proteins. In addition to its bactericidal effect, NET is closely related to various diseases including immune disease, thrombosis and tumor. Recently, lots of researches have shown that NET is highly expressed in a variety of tumors, tumor cells and microenvironment can promote NET formation, whereas NET participates in tumor progression as well, and is closely related to tumor proliferation, metastasis and thrombosis, which provides new clinical thinking in tumor diagnosis as well as treatment indeed. This review will focus on the research progress of NET and tumor, meanwhile make a prospect for its clinical application value.


Subject(s)
Extracellular Traps , Genetics , Humans , Neoplasms , Neutrophils , Pathology , Tumor Microenvironment
12.
Frontiers of Medicine ; (4): 726-745, 2020.
Article in English | WPRIM | ID: wpr-880949

ABSTRACT

Chimeric antigen receptor (CAR) T cells have been indicated effective in treating B cell acute lymphoblastic leukemia and non-Hodgkin lymphoma and have shown encouraging results in preclinical and clinical studies. However, CAR T cells have achieved minimal success against solid malignancies because of the additional obstacles of their insufficient migration into tumors and poor amplification and persistence, in addition to antigen-negative relapse and an immunosuppressive microenvironment. Various preclinical studies are exploring strategies to overcome the above challenges. Mobilization of endogenous immune cells is also necessary for CAR T cells to obtain their optimal therapeutic effect given the importance of the innate immune responses in the elimination of malignant tumors. In this review, we focus on the recent advances in the engineering of CAR T cell therapies to restore the immune response in solid malignancies, especially with CAR T cells acting as cellular carriers to deliver immunomodulators to tumors to mobilize the endogenous immune response. We also explored the sensitizing effects of conventional treatment approaches, such as chemotherapy and radiotherapy, on CAR T cell therapy. Finally, we discuss the combination of CAR T cells with biomaterials or oncolytic viruses to enhance the anti-tumor outcomes of CAR T cell therapies in solid tumors.


Subject(s)
Humans , Immunotherapy, Adoptive , Neoplasms/therapy , T-Lymphocytes , Tumor Microenvironment
13.
Journal of Experimental Hematology ; (6): 2084-2088, 2020.
Article in Chinese | WPRIM | ID: wpr-880019

ABSTRACT

Exosomes are microvesicles that can be secreting in many kinds of cells, under the condition of normal and pathology. Exosomes contain abundant proteins, miRNAs and RNA fragments, which play an important role in communicating between cells, especially non-contact cells. The interaction between blood tumor cells and immune microenvironment is inseparable from the involvement of exosomes. Exosomes are involved in the interaction among tumor cells, NK cells, T cells, stromal cells and endothelial cells, such as promoting the proliferation of blood tumor cells, helping blood tumor cells to achieve immune evasion, promoting angiogenesis and migration of tumor cells. Therefore, exosomes are closely related to the diagnosis, treatment and prognosis of hematological tumors. In this review, the basic characteristics of exosomes, the important role of exosomes in the immune microenvironment of hematological tumors, and the research progress of exosomes in clinical applications was sammrized briefly.


Subject(s)
Endothelial Cells , Exosomes , Hematologic Neoplasms , Humans , Neovascularization, Pathologic , Research , Tumor Microenvironment
14.
Article in English | WPRIM | ID: wpr-828962

ABSTRACT

With the understanding of the complex interaction between the tumour microenvironment and immunotherapy, there is increasing interest in the role of immune regulators in the treatment of head and neck squamous cell carcinoma (HNSCC). Activation of T cells and immune checkpoint molecules is important for the immune response to cancers. Immune checkpoint molecules include cytotoxic T lymphocyte antigen 4 (CTLA-4), programmed death 1 (PD-1), T-cell immunoglobulin mucin protein 3 (TIM-3), lymphocyte activation gene 3 (LAG-3), T cell immunoglobin and immunoreceptor tyrosine-based inhibitory motif (TIGIT), glucocorticoid-induced tumour necrosis factor receptor (GITR) and V-domain Ig suppressor of T cell activation (VISTA). Many clinical trials using checkpoint inhibitors, as both monotherapies and combination therapies, have been initiated targeting these immune checkpoint molecules. This review summarizes the functional mechanism and use of various immune checkpoint molecules in HNSCC, including monotherapies and combination therapies, and provides better treatment options for patients with HNSCC.


Subject(s)
Head and Neck Neoplasms , Pathology , Therapeutics , Humans , Immunologic Factors , Therapeutic Uses , Immunotherapy , Methods , Squamous Cell Carcinoma of Head and Neck , Pathology , Therapeutics , Tumor Microenvironment
15.
Article in Chinese | WPRIM | ID: wpr-828890

ABSTRACT

OBJECTIVE@#To investigate whether interleukin-12 (IL-12) over-expression in malignant melanoma B16 cells affects the expression level of programmed death-1 (PD-1) on T cells in mice during immune microenvironment reconstruction.@*METHODS@#B16 cells were transfected with an IL-12 expression lentiviral vector, and IL-12 over-expression in the cells was verified qPCR and ELISA. Plate cloning assay was used to compare the cell proliferation activity between B16 cells and B16/IL-12 cells. The expression of IL-12 protein in B16/IL-12 cells-derived tumor tissue were detected by ELISA. C57BL/6 mice were inoculated with B16 cells or B16/IL-12 cells, and 14 days later the proportion of T cells with high expression of PD-1 in the tumor-draining lymph nodes was detected by flow cytometry. Mouse models of immune reconstitution established by 650 cGy X-ray radiation were inoculated with B16 (B16+RT group) or B16/IL-12 (B16/IL-12+RT group) cells, with the mice without X-ray radiation prior to B16 cell inoculation as controls. Tumor growth in the mice was recorded at different time points, and on day 14, flow cytometry was performed to detect the proportion of T cells with high PD-1 expression in the tumor-draining lymph nodes and in the tumor tissue.@*RESULTS@#B16 cells infected with the IL-12-overexpressing lentiviral vector showed significantly increased mRNA and protein levels of IL-12 ( < 0.001) without obvious changes in cell viability (>0.05). B16/IL-12 cells expressed higher levels of IL-12 than B16 cells ( < 0.01). In the tumor-bearing mouse models, the proportion of CD4 PD-1 T cells was significantly lower in B16/IL-12 group than in B16 group ( < 0.01). In the mice with X-ray radiation-induced immune reconstitution, PD-1 expressions on CD4 T cells ( < 0.05) and CD8+ T cells ( < 0.01) were significantly higher in B16+ RT group than in the control mice and in B16/IL-12+RT group ( < 0.01 or 0.001); the tumors grew more slowly in B16/IL-12+RT group than in B16 + RT group ( < 0.001).@*CONCLUSIONS@#During immune microenvironment reconstruction, overexpression IL-12 in the tumor microenvironment can reduce the percentage of PD-1 T cells and suppress the growth of malignant melanoma in mice.


Subject(s)
Animals , CD8-Positive T-Lymphocytes , Cell Line, Tumor , Immune Reconstitution , Interleukin-12 , Melanoma, Experimental , Mice , Mice, Inbred C57BL , Tumor Microenvironment
16.
Article in Chinese | WPRIM | ID: wpr-828861

ABSTRACT

OBJECTIVE@#To investigate the expression of BUB1 gene in gastric cancer.@*METHODS@#Oncomine, GEPIA, BioGPS and Kaplan-Meier Plotter databases were used to analyze the difference of BUB1 gene expression between gastric cancer tissue and normal gastric tissue. The association of BUB1 expression level with the prognosis of gastric cancer patients was also analyzed. The Cancer Cell Line Encyclopedia (CCLE) was explored to analyze the expression of BUB1 in T cells and B cells in gastric cancer patients, and the String database was used to generate the network map of BUB1-related proteins and functional annotation of gene ontology (GO). The related pathways of KEGG were analyzed. Tumor immune assessment resource (TIMER) database was used to analyze the expression of BUB1 in immune infiltration and its effect on prognosis of gastric cancer patients. To further verify the results of gene chip analysis in Oncomine database, we collected 30 pairs of surgical specimens of gastric adenocarcinoma and adjacent tissues from patients admitted to the First Affiliated Hospital of Chengdu Medical College from March, 2018 to July, 2019. The results of BUB1 gene expression in Oncomine database were verified by PCR and immunohistochemistry.@*RESULTS@#Oncomine, GEPIA and BioGPS analyses showed that BUB1 was highly expressed in gastric cancer compared with normal gastric tissue. Kaplan-Meier survival analysis showed that the progression-free survival time (HR=0.52, 95% :0.41-0.67, < 0.05) and the overall survival time (HR=0.67, 95% :0.55-0.82, < 0.05) were prolonged in gastric cancer patients with a high expression of BUB1. Through String data collection, BUB1-related proteins were mainly enriched in 13 cellular components, 4 molecular functions and 12 biological processes, involving 4 signal pathways. TIMER database analysis showed that CD4 T cells and macrophages with high expressions of BUB1 mRNA in the immune microenvironment were associated with a favorable 5-year survival outcome of patients with gastric cancer. In the surgical specimens, real-time quantitative PCR showed that the expression level of BUB1 mRNA was significantly higher in gastric cancer tissues than in the adjacent gastric mucosa tissues, and immunohistochemical results demonstrated positive BUB1 staining in the gastric cancer tissues.@*CONCLUSIONS@#BUB1 gene is highly expressed in gastric cancer. BUB1 may reduce tumor immunosuppression and helps to evaluate the prognosis of patients with gastric cancer.


Subject(s)
Computational Biology , Humans , Kaplan-Meier Estimate , Prognosis , Protein-Serine-Threonine Kinases , Genetics , Stomach Neoplasms , Genetics , Tumor Microenvironment
17.
Chinese Medical Journal ; (24): 253-260, 2020.
Article in English | WPRIM | ID: wpr-877995

ABSTRACT

Although the first-line rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone regimen (R-CHOP) substantially improved outcomes for patients with diffuse large B-cell lymphoma (DLBCL), 40% of the patients suffered from relapsed/refractory disease and had poor survival outcomes. The detailed mechanism underlying R-CHOP resistance has not been well defined. For this review, we conducted a thorough search for literature and clinical trials involving DLBCL resistance. We discussed DLBCL biology, epigenetics, and aberrant signaling of the B-cell receptor (BCR), phosphatidylinositol 3-kinase (PI3K)/Akt, nuclear factor kappa light chain enhancer of activated B-cells (NF-κB), and the Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) pathways as defining mechanisms of DLBCL heterogeneity and R-CHOP resistance. The cell of origin, double- or triple-hit lymphoma and double-protein-expression, clonal evolution, tumor microenvironment, and multi-drug resistance help to contextualize DLBCL resistance in an (epi)genetically and biologically comparative manner. With better understanding of the biological and molecular landscape of DLBCL, a more detailed classification system and tailored treatments will ideally become available to further improve the prognosis of DLBCL patients.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Cyclophosphamide/therapeutic use , Doxorubicin/therapeutic use , Humans , Lymphoma, Large B-Cell, Diffuse/genetics , Phosphatidylinositol 3-Kinases , Prednisone/therapeutic use , Prognosis , Rituximab/therapeutic use , Tumor Microenvironment , Vincristine/therapeutic use
18.
Chinese Medical Journal ; (24): 334-343, 2020.
Article in English | WPRIM | ID: wpr-877961

ABSTRACT

BACKGROUND@#High agglomeration of myeloid-derived suppressor cells (MDSCs) in neuroblastoma (NB) impeded therapeutic effects. This study aimed to investigate the role and mechanism of targeted inhibition of MDSCs by low-dose doxorubicin (DOX) to enhance immune efficacy in NB.@*METHODS@#Bagg albino (BALB/c) mice were used as tumor-bearing mouse models by injecting Neuro-2a cells, and MDSCs were eliminated by DOX or dopamine (DA) administration. Tumor-bearing mice were randomly divided into 2.5 mg/kg DOX, 5.0 mg/kg DOX, 50.0 mg/kg DA, and control groups (n = 20). The optimal drug and its concentration for MDSC inhibition were selected according to tumor inhibition. NB antigen-specific cytotoxic T cells (CTLs) were prepared. Tumor-bearing mice were randomly divided into DOX, CTL, anti-ganglioside (GD2), DOX+CTL, DOX+anti-GD2, and control groups. Following low-dose DOX administration, immunotherapy was applied. The levels of human leukocyte antigen (HLA)-I, CD8, interleukin (IL)-2 and interferon (IFN)-γ in peripheral blood, CTLs, T-helper 1 (Thl)/Th2 cytokines, perforin, granzyme and tumor growth were compared among the groups. The Wilcoxon two-sample test and repeated-measures analysis of variance were used to analyze results.@*RESULTS@#The slowest tumor growth (F = 6.095, P = 0.018) and strongest MDSC inhibition (F = 14.632, P = 0.001) were observed in 2.5 mg/kg DOX group. Proliferation of T cells was increased (F = 448.721, P < 0.001) and then decreased (F = 2.047, P = 0.186). After low-dose DOX administration, HLA-I (F = 222.489), CD8 (F = 271.686), Thl/Th2 cytokines, CD4+ and CD8+ lymphocytes, granzyme (F = 2376.475) and perforin (F = 488.531) in tumor, IL-2 (F = 62.951) and IFN-γ (F = 240.709) in peripheral blood of each immunotherapy group were all higher compared with the control group (all of P values < 0.05). The most significant increases in the aforementioned indexes and the most notable tumor growth inhibition were observed in DOX+anti-GD2 and DOX+CTL groups.@*CONCLUSIONS@#Low-dose DOX can be used as a potent immunomodulatory agent that selectively impairs MDSC-induced immunosuppression, thereby fostering immune efficacy in NB.


Subject(s)
Animals , Doxorubicin/therapeutic use , Mice , Mice, Inbred C57BL , Myeloid-Derived Suppressor Cells , Neuroblastoma/drug therapy , Tumor Microenvironment
19.
Chinese Medical Journal ; (24): 2444-2455, 2020.
Article in English | WPRIM | ID: wpr-877859

ABSTRACT

In recent years, the research of immune checkpoint inhibitors has made a great breakthrough in lung cancer treatment. Currently, a variety of immune checkpoint inhibitors have been applied into clinical practice, including antibodies targeting the programmed cell death-1, programmed cell death-ligand 1, and cytotoxic T-lymphocyte antigen 4, and so on. However, not all patients can benefit from the treatment. Abnormal antigen presentation, functional gene mutation, tumor microenvironment, and other factors can lead to primary or secondary resistance. In this paper, we reviewed the molecular mechanism of immune checkpoint inhibitor resistance and various combination strategies to overcome resistance, in order to expand the beneficial population and enable precision medicine.


Subject(s)
B7-H1 Antigen , CTLA-4 Antigen , Drug Resistance , Humans , Immune Checkpoint Inhibitors , Immunotherapy , Lung Neoplasms/drug therapy , Tumor Microenvironment
20.
Chinese Medical Journal ; (24): 2466-2475, 2020.
Article in English | WPRIM | ID: wpr-877853

ABSTRACT

Immune checkpoint inhibitors (ICIs) are widely used in lung cancer therapy due to their effectiveness and minimal side effects. However, only a few lung cancer patients benefit from ICI therapy, driving the need to develop alternative biomarkers. Programmed death-ligand 1 (PD-L1) molecules expressed in tumor cells and immune cells play a key role in the immune checkpoint pathway. Therefore, PD-L1 expression is a prognostic biomarker in evaluating the effectiveness of programmed death-1 (PD-1)/PD-L1 inhibitors. Nevertheless, adverse predictive outcomes suggest that other factors are implicated in the response. In this review, we present a detailed introduction of existing biomarkers concerning tumor abnormality and host immunity. PD-L1 expression, tumor mutation burden, neoantigens, specific gene mutations, circulating tumor DNA, human leukocyte antigen class I, tumor microenvironment, peripheral inflammatory cells, and microbiome are discussed in detail. To sum up, this review provides information on the current application and future prospects of ICI biomarkers.


Subject(s)
B7-H1 Antigen , Biomarkers, Tumor , Carcinoma, Non-Small-Cell Lung/drug therapy , Humans , Immune Checkpoint Inhibitors , Lung Neoplasms/drug therapy , Prospective Studies , Tumor Microenvironment
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