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1.
Front Oncol ; 11: 722999, 2021.
Article in English | MEDLINE | ID: mdl-34881173

ABSTRACT

Pathogens or genotoxic agents continuously affect the human body. Acute inflammatory reaction induced by a non-sterile or sterile environment is triggered for the efficient elimination of insults that caused the damage. According to the insult, pathogen-associated molecular patterns, damage-associated molecular patterns, and homeostasis-altering molecular processes are released to facilitate the arrival of tissue resident and circulating cells to the injured zone to promote harmful agent elimination and tissue regeneration. However, when inflammation is maintained, a chronic phenomenon is induced, in which phagocytic cells release toxic molecules damaging the harmful agent and the surrounding healthy tissues, thereby inducing DNA lesions. In this regard, chronic inflammation has been recognized as a risk factor of cancer development by increasing the genomic instability of transformed cells and by creating an environment containing proliferation signals. Based on the cancer immunoediting concept, a rigorous and regulated inflammation process triggers participation of innate and adaptive immune responses for efficient elimination of transformed cells. When immune response does not eliminate all transformed cells, an equilibrium phase is induced. Therefore, excessive inflammation amplifies local damage caused by the continuous arrival of inflammatory/immune cells. To regulate the overstimulation of inflammatory/immune cells, a network of mechanisms that inhibit or block the cell overactivity must be activated. Transformed cells may take advantage of this process to proliferate and gradually grow until they become preponderant over the immune cells, preserving, increasing, or creating a microenvironment to evade the host immune response. In this microenvironment, tumor cells resist the attack of the effector immune cells or instruct them to sustain tumor growth and development until its clinical consequences. With tumor development, evolving, complex, and overlapping microenvironments are arising. Therefore, a deeper knowledge of cytokine, immune, and tumor cell interactions and their role in the intricated process will impact the combination of current or forthcoming therapies.

2.
Biology (Basel) ; 9(11)2020 Nov 05.
Article in English | MEDLINE | ID: mdl-33167343

ABSTRACT

Cytokines, key contributors to tumorigenesis, are mediators between inflammatory immune or nonimmune and cancer cells. Here, IL-6 production by tumor cells was assessed in a cohort of patients with lung adenocarcinoma treated with conventional therapy. IL-6 levels and neutrophil-lymphocyte ratio (NLR) or systemic immune-inflammation index (SII) markers were evaluated. Changes in pro- and anti-inflammatory cytokines, HMGB1 concentration, and CD4+ and CD8+ T-lymphocyte populations and their subpopulations were investigated. IL-6 expression was detected immunohistochemically in lung adenocarcinoma biopsies. Cytokines were quantified using the cytometric bead array, and TGF-ß and HMGB-1 through ELISA. Clinical parameters were collected to assess NLR and SII. CD4+ and CD8+ T-lymphocytes and naïve, memory, and effector subpopulations were quantified by flow cytometry. The data obtained were associated with patients' median overall survival (OS). IL-6 showed the highest increase, probably because the lung adenocarcinoma cells produced IL-6. Patients with higher OS had lower NLR and SII from the third cycle of chemotherapy. Patients with lower OS had significantly lower percentages of CD8+ T-lymphocyte and its effector subpopulations, with a concomitant increase in the naïve subpopulation. This study suggests that in addition to the known inflammatory markers, IL-6, CD8+ T-lymphocytes and their effector and naïve subpopulations could be useful as predictive markers in lung adenocarcinoma.

3.
Front Genet ; 10: 79, 2019.
Article in English | MEDLINE | ID: mdl-30881375

ABSTRACT

Epigenetic mechanisms control gene expression during normal development and their aberrant regulation may lead to human diseases including cancer. Natural phytochemicals can largely modulate mammalian epigenome through regulation of mechanisms and proteins responsible for chromatin remodeling. Phytochemicals are mainly contained in fruits, seeds, and vegetables as well as in foods supplements. These compounds act as powerful cellular antioxidants and anti-carcinogens agents. Several dietary compounds such as catechins, curcumin, genistein, quercetin and resveratrol, among others, exhibit potent anti-tumor activities through the reversion of epigenetic alterations associated to oncogenes activation and inactivation of tumor suppressor genes. In this review, we summarized the actual knowledge about the role of dietary phytochemicals in the restoration of aberrant epigenetic alterations found in cancer cells with a particular focus on DNA methylation and histone modifications. Furthermore, we discussed the mechanisms by which these natural compounds modulate gene expression at epigenetic level and described their molecular targets in diverse types of cancer. Modulation of epigenetic activities by phytochemicals will allow the discovery of novel biomarkers for cancer prevention, and highlights its potential as an alternative therapeutic approach in cancer.

4.
Biomed Res Int ; 2015: 430943, 2015.
Article in English | MEDLINE | ID: mdl-26582240

ABSTRACT

Lung cancer is the leading cause of cancer death worldwide. Adenocarcinoma, the most commonly diagnosed histologic type of lung cancer, is associated with smoking. Cigarette smoke promotes inflammation on the airways, which might be mediated by Th17 cells. This inflammatory environment may contribute to tumor development. In contrast, some reports indicate that tumors may induce immunosuppressive Treg cells to dampen immune reactivity, supporting tumor growth and progression. Thus, we aimed to analyze whether chronic inflammation or immunosuppression predominates at the systemic level in lung adenocarcinoma patients, and several cytokines and Th17 and Treg cells were studied. Higher proportions of IL-17-producing CD4(+) T-cells were found in smoking control subjects and in lung adenocarcinoma patients compared to nonsmoking control subjects. In addition, lung adenocarcinoma patients increased both plasma concentrations of IL-2, IL-4, IL-6, and IL-10, and proportions of Latency Associated Peptide (LAP) TGF-ß subset of CD4(+)CD25(+)CD127(-) Treg cells, which overexpressed LAP TGF-ß. This knowledge may lead to the development of immunotherapies that could inhibit the suppressor activity mediated by the LAP TGF-ß subset of CD4(+)CD25(+)CD127(-) Treg cells to promote reactivity of immune cells against lung adenocarcinoma cells.


Subject(s)
Adenocarcinoma/blood , Inflammation/blood , Lung Neoplasms/blood , Peptides/blood , Protein Precursors/blood , T-Lymphocytes, Regulatory/metabolism , Transforming Growth Factor beta/blood , Adenocarcinoma/immunology , Adenocarcinoma/pathology , Adenocarcinoma of Lung , Adult , Aged , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/metabolism , Female , Humans , Immune Tolerance/genetics , Inflammation/immunology , Inflammation/pathology , Interleukin-10/biosynthesis , Interleukin-10/immunology , Interleukin-17/biosynthesis , Interleukin-17/immunology , Interleukin-2/blood , Interleukin-2 Receptor alpha Subunit/biosynthesis , Interleukin-2 Receptor alpha Subunit/immunology , Interleukin-4/blood , Interleukin-6/blood , Lung Neoplasms/immunology , Lung Neoplasms/pathology , Male , Middle Aged , Neoplasm Staging , T-Lymphocytes, Regulatory/immunology , Th17 Cells/immunology , Th17 Cells/metabolism , Th17 Cells/pathology
5.
Appl Immunohistochem Mol Morphol ; 22(2): 105-13, 2014.
Article in English | MEDLINE | ID: mdl-24752173

ABSTRACT

Lung cancer is the leading cause of cancer death worldwide and non-small cell lung carcinoma (NSCLC) is the most common type of lung carcinomas. In adenocarcinomas, the most frequent histologic type of NSCLC, dendritic cells (DCs) are localized in close contact with tumor cells, and tumor-infiltrating lymphocytes (TILs) are observed in the peritumoral zones. In NSCLC, no studies investigating the density of intratumoral DCs and their impact on the density of TILs have been performed. In addition, the role of the alarmin high-mobility group box1 (HMGB1) in intratumoral DCs recruitment has not been analyzed. In the present study, a total of 82 cases of advanced stages of NSCLC were included. Tissue samples were obtained from biopsies and autopsies. DCs in biopsies or combinations of DCs and NK cells, CD3 T lymphocytes, or CD8 T lymphocytes from autopsy specimens were quantified in high power fields. Also, distribution of HMGB1 in tumor cells was detected. In lung adenocarcinomas, irrespective of subclassification, high densities of infiltrating DCs directly associated to high densities of peritumoral TILs. A 2.5-fold increase in TILs was found in specimens with high densities of infiltrating DCs compared with TILs from adenocarcinomas with low densities of infiltrating DCs. High densities of infiltrating DCs were associated with lung adenocarcinomas expressing cytoplasmic or nuclear-cytoplasmic HMGB1. Our results suggest that in adenocarcinoma patients, HMGB1 produced by tumor cells recruits DCs, which associate to an increase of TILs. Encouraging tumor-DCs-T lymphocytes interactions should improve the quality of life and survival of NSCLC patients.


Subject(s)
CD8-Positive T-Lymphocytes/pathology , Carcinoma, Non-Small-Cell Lung/diagnosis , Cell Nucleus/metabolism , Cytoplasm/metabolism , Dendritic Cells/immunology , HMGB1 Protein/metabolism , Killer Cells, Natural/pathology , Lung Neoplasms/diagnosis , Lymphocytes, Tumor-Infiltrating/pathology , Autopsy , Biopsy , CD3 Complex/metabolism , Carcinoma, Non-Small-Cell Lung/pathology , Humans , Immunohistochemistry , Lung Neoplasms/pathology , Protein Transport
6.
Clin Dev Immunol ; 2012: 741741, 2012.
Article in English | MEDLINE | ID: mdl-23118782

ABSTRACT

Lung cancer is the leading cause of cancer deaths worldwide and one of the most common types of cancers. The limited success of chemotherapy and radiotherapy regimes have highlighted the need to develop new therapies like antitumor immunotherapy. CD8+ T-cells represent a major arm of the cell-mediated anti-tumor response and a promising target for developing T-cell-based immunotherapies against lung cancer. Lung tumors, however, have been considered to possess poor immunogenicity; even so, lung tumor-specific CD8+ T-cell clones can be established that possess cytotoxicity against autologous tumor cells. This paper will focus on the alterations induced in CD8+ T-cells by lung cancer. Although memory CD8+ T-cells infiltrate lung tumors, in both tumor-infiltrating lymphocytes (TILs) and malignant pleural effusions, these cells are dysfunctional and the effector subset is reduced. We propose that chronic presence of lung tumors induces dysfunctions in CD8+ T-cells and sensitizes them to activation-induced cell death, which may be associated with the poor clinical responses observed in immunotherapeutic trials. Getting a deeper knowledge of the evasion mechanisms lung cancer induce in CD8+ T-cells should lead to further understanding of lung cancer biology, overcome tumor evasion mechanisms, and design improved immunotherapeutic treatments for lung cancer.


Subject(s)
CD8-Positive T-Lymphocytes/immunology , Lung Neoplasms/immunology , Animals , Humans , Immunotherapy/methods , Lung Neoplasms/therapy , Lymphocytes, Tumor-Infiltrating/immunology , Pleural Effusion, Malignant/immunology
7.
Cancer Immunol Immunother ; 57(3): 325-36, 2008 Mar.
Article in English | MEDLINE | ID: mdl-17668204

ABSTRACT

BACKGROUND: Non-small cell lung carcinoma (NSCLC) patients have impaired cellular immune responses. It has been hypothesized that tumor cells expressing Fas Ligand (FasL) induce in T lymphocytes: (a) apoptosis (tumor counterattack) and (b) down-regulation of CD3zeta expression. However, the hypothesis of tumor counterattack is still controversial. METHODS: We analyzed FasL expression on NSCLC cell lines and on tumor cells from lung adenocarcinoma patients by flow cytometry and immunocytochemistry. FasL mRNA expression was detected in NSCLC cell lines using RT-PCR, and functional FasL was evaluated on Fas-expressing Jurkat T-cells by annexin-V-FITC staining and by SubG(1) peak detection. Also, the proapoptotic effect of microvesicles released from NSCLC cell lines in Jurkat T-cells was studied. Alterations in the expression levels of CD3zeta, CD3epsilon, and CD28 [measured as mean fluorescence intensity (MFI)] were determined in Jurkat T-cells after co-culture with NSCLC cell lines or tumor-derived microvesicles. Furthermore, the expression levels of CD3zeta and CD3epsilon in CD4+T and CD8+T lymphocytes from lung adenocarcinoma patients was studied. RESULTS: Our results indicate that NSCLC cells neither FasL expressed nor induced apoptosis in Jurkat T-cells. Tumor-derived microvesicles did not induce apoptosis in Jurkat T-cells. In contrast, NSCLC cell lines down-regulated CD3epsilon but not CD3zeta chain expression in Jurkat T-cells; this effect was induced by soluble factors but not by microvesicles. In lung adenocarcinoma patients, significant decreases of MFI values for CD3epsilon, but not CD3zeta, were found in CD4+T and CD8+T cells from pleural effusion compared to peripheral blood and in peripheral blood of patients compared to healthy donors. CONCLUSIONS: Our data do not support the tumor counterattack hypothesis for NSCLC. Nonetheless, down-regulation of CD3epsilon in T-cells induced by NSCLC cells might lead to T-cell dysfunction.


Subject(s)
Apoptosis/immunology , CD3 Complex/metabolism , Carcinoma, Non-Small-Cell Lung/immunology , Down-Regulation/immunology , Lung Neoplasms/immunology , T-Lymphocytes/immunology , Adult , Aged , CD28 Antigens/genetics , CD28 Antigens/metabolism , CD3 Complex/genetics , Cell Line, Tumor , Coculture Techniques , Down-Regulation/genetics , Fas Ligand Protein/analysis , Fas Ligand Protein/biosynthesis , Flow Cytometry , Humans , Immunohistochemistry , Jurkat Cells , Middle Aged , RNA, Messenger/biosynthesis , RNA, Messenger/genetics , RNA, Messenger/immunology , Reverse Transcriptase Polymerase Chain Reaction , Signal Transduction/immunology
8.
Clin Immunol ; 122(3): 323-9, 2007 Mar.
Article in English | MEDLINE | ID: mdl-17175197

ABSTRACT

The role that inflammation plays in cancer is puzzling. In peripheral blood, TNF-alpha-producing monocytes (CD14+ cells) were compared among patients with lung cancer, patients with tuberculosis and healthy donors; also, in pleural effusion TNF-alpha-producing CD14+ cells were compared between tuberculous patients and lung cancer patients. To analyze the level of the cellular alteration in TNF-alpha production, an experimental model was set up. TNF-alpha-producing CD14+ cells in peripheral blood from lung cancer patients were significantly lower than those from healthy donors. In pleural effusion, TNF-alpha-producing CD14+ cells were significantly lower in lung cancer patients than in tuberculous patients. Based on the results obtained from an experimental model, we suggest that this phenomenon was attributed to a reduced expression of TNF-alpha transcript. These findings provide evidence that lung carcinomas reduce TNF-alpha production by macrophages, possibly by inducing in these cells an M2 phenotype, which favor tumor progression.


Subject(s)
Adenocarcinoma/immunology , Carcinoma, Squamous Cell/immunology , Lipopolysaccharide Receptors/biosynthesis , Lung Neoplasms/immunology , Lung Neoplasms/pathology , Macrophages/pathology , Tumor Necrosis Factor-alpha/biosynthesis , Adenocarcinoma/metabolism , Adenocarcinoma/pathology , Adult , Aged , Aged, 80 and over , Carcinoma, Squamous Cell/metabolism , Carcinoma, Squamous Cell/pathology , Cell Communication/immunology , Cell Count , Coculture Techniques , Female , Humans , Immunophenotyping , Lung Neoplasms/metabolism , Macrophages/immunology , Macrophages/metabolism , Male , Middle Aged , U937 Cells
9.
Rev. Inst. Nac. Enfermedades Respir ; 14(2): 79-84, abr.-jun. 2001. ilus, graf, CD-ROM
Article in Spanish | LILACS | ID: lil-306529

ABSTRACT

Introducción: La importancia de las nucleasas en la regulación del crecimiento celular (a través de la apoptosis) hace relevante investigar su utilidad para controlar el crecimiento tumoral.Objetivo: Valorar el efecto que una desoxirribo-nucleasa tuvo sobre células del melanoma murino B16-F10. Material y métodos: Las células fueron incubadas a diferentes tiempos y concentraciones de la DNasa, después de lo cual se evaluó su viabilidad, crecimiento y daño al DNA.Resultados: Se encontró que la viabilidad y actividad mitocondrial medida por medio de la técnica de exclusión con azul de tripán o, bien, por el colorante MTT no mostró ningún cambio significativo, sin embargo, la capacidad de crecimiento celular (número total de células) sí se vio modificada de una manera dosis dependiente. Con respecto del daño al DNA, nuestros resultados indican un efecto a las 24 horas de incubación de la nucleasa con las células, bandas de 400 y 200pb se encontraron en el corrimiento electroforético.Conclusión: la DNasa utilizada en este trabajo no tuvo ningún efecto significativo sobre la viabilidad, pero sí en el crecimiento celular, así como sobre la estructura del DNA por un mecanismo aún no determinado.


Subject(s)
Apoptosis , Deoxyribonuclease I , In Vitro Techniques , Melanoma, Experimental , Neoplasms , Research
10.
Rev. Inst. Nac. Enfermedades Respir ; 12(1): 6-12, ene.-mar. 1999. ilus, graf, tab
Article in Spanish | LILACS | ID: lil-254645

ABSTRACT

Introducción: Trabajos previos mostraron la capacidad antiviral in vitro, así como la utilidad como inductor de interferón natural (IFN-n) in vivo de un RNA de transferencia (tRNA) de origen fúngico, por este motivo se sigue estudiando esta molécula como una alternativa para el tratamiento antiviral. Objetivos: Estudiar el efecto del tRNA fúngico en la viabilidad, síntesis de DNA y en la multiplicación del adenovirus tipo 6 (AV-6) en células HEp-2, comparado su efecto con el producido por el polyl:polyC o por IFN-Ó. Valorar su capacidad como unductor a largo plazo de la síntesis de IFN-n in vivo. Material y métodos: Células HEp-2 se incubaron con diferentes concentraciones de las moléculas mencionadas durante 24 horas, y se determinó la viabilidad y la síntesis de DNA celular; adicionalmente cultivos tratados en las mismas condiciones se infectaron con 200 unidades formadoras de placas (ufp) del AV-6, se incubaron cinco días adicionales, y se valoró el grado de protección. In vivo a siete voluntarios clínicamente sanos se les administró intramuscularmente una dosis única de 100 mg del tRNA, y se determinó mediante la técnica de inhibición del efecto citopático (ECP) el nivel sérico de IFN-n, cinco días después de la inoculación. Resultados. El tRNA protegió a las células HEp-2 contra la infección por AV-6, mejor que el polyl:polyC y de forma similar al IFN-Ó. Ninguna de las tres sustancias afectó significativamente la viabilidad celular. En cambio, la síntesis de DNA sí disminuyó de manera directa en relación con la concentración de los inductores, no así con el IFN-Ó. En los plasmas de los sujetos tratados con el tRNA fúngico se encontró un aumento en la concentración de IFN-n (de 84.2 ñ 107.6 a 171.42 ñ 129.5 UI/mL) a los cinco días, aunque la diferencia no fue estadísticamente significativa. Conclusión. El tRNA fúngico mostró actividad antiviral contra el AV-6, no afectó la viabilidad pero sí la síntesis celular de DNA, y con una capacidad de mantener elevada hasta por cinco días la concentración plasmática de IFN-n en humanos


Subject(s)
Humans , Adenoviruses, Human , Antiviral Agents , Cells, Cultured , Cytopathogenic Effect, Viral , Interferon Inducers/analysis , Interferon Inducers/blood , RNA, Transfer , Data Interpretation, Statistical
11.
Rev. Inst. Nac. Enfermedades Respir ; 9(1): 31-4, ene.-mar. 1996. tab, ilus
Article in Spanish | LILACS | ID: lil-180601

ABSTRACT

Existe poca información acerca de los problemas que puede causar la exposición al ozono sobre el aprendizaje del ser vivo en general; por tal motivo, se realizó la presente investigación para medir cambios o modificaciones en el aprendizaje en ratas expuesta 30 min durante tres semanas a 0.5 ppm de ozono. Se utilizaron 20 ratas Wistar machos; 10 de ellas conformaron el grupo control (grupo 1) y las 10 restantes el grupo experimental (grupo 2). Se realizaron un total de 32 sesiones. Las primeras 16 sesiones fueron consideraras el periodo de aprendizaje, es decir, no hubo exposición a ozono, observándose exclusivamente el comportamiento de las ratas. De la sesión 17 a la 32, se llevó a cabo la etapa de exposición a dicho contaminante. Para la medición del aprendizaje, es decir, no hubo exposición a ozono, observándose exclusivamente el comportamiento de las ratas. De la sesión 17 a la 32, se llevó a cabo la etapa de exposición a dicho contaminante. Para la medición del aprendizaje, se utilizó un laberinto múltiple y una cámara de exposición al ozono, con un generador


Subject(s)
Rats , Animals , Learning , Ozone/adverse effects , Rats, Wistar
12.
Rev. Inst. Nac. Enfermedades Respir ; 8(3): 192-5, jul.-sept. 1995. tab
Article in Spanish | LILACS | ID: lil-162075

ABSTRACT

Se investigó la relación entre concentraciones de ozono atmosférico, temperatura máxima, humedad relativa y viabilidad de la población microbiana aérea, al suroeste de la ciudad de México, zona conocida como la máxima contaminación por ozono. Se tomaron un total de 35 muestras, en el periodo comprendido entre septiembre de 1992 y abril de 1993, analizadas por duplicado con cuatro medios de cultivo selectivos para el conteo total, así como el aislamiento de bacterias Gram negativas, positivas y hongos. Se encontró que para la cuenta total de microorganismos, éstos sí son afectados en su viabilidad por concentraciones elevadas de ozono, no así los parámetros climáticos de temperatura máxima y humedad relativa. El análisis de correlación entre especies y concentración de ozono, mostró que únicamente las bacterias Gram positivas y Gram negativas, no así los hongos, son afectados en número y viabilidad por concentraciones elevadas de ozono; en estecaso, tampoco son afectadas por temperatura máxima y humedad relativa. Las especies más frecuentemente identificadas fueron Micrococcus sp., Staphylococcus aureus y Penicillium sp


Subject(s)
Air Analysis , Air Samples , Colony Count, Microbial , Environmental Pollution/analysis , Environmental Pollution/adverse effects , Fungi/isolation & purification , Humidity , Micrococcus/isolation & purification , Ozone/analysis , Penicillium/isolation & purification , Soil Microbiology , Staphylococcus aureus/isolation & purification
13.
Rev. Inst. Nac. Enfermedades Respir ; 8(2): 124-7, abr.-jun. 1995. tab
Article in Spanish | LILACS | ID: lil-158949

ABSTRACT

El tabaquismo es un problema de salud que ha despertado gran interés, debido a la importancia de las enfermedades que se relacionan con el hábito tabáquico. La mayoría de las investigaciones que al respecto se han realizado están enfocadas desde un punto de vista somático y son menos numerosas las que abordan el aspecto psicológico. La presente investigación tuvo como objetivo medir la memoria a corto plazo en un grupo de estudiantes del nivel medio de educación, empleando la prueba de David Wechsler modificada. La población estuvo integrada por 119 no fumadores y 89 fumadores. La prueba estadística chi cuadrada no mostró diferencias significativas en la memoria a corto plazo entre los grupos de fumadores y no fumadores


Subject(s)
Adolescent , Humans , Male , Female , Memory, Short-Term/drug effects , Smoking/psychology , Verbal Learning/drug effects
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