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1.
Genes Dev ; 35(3-4): 218-233, 2021 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-33446568

RESUMEN

Pancreatic ductal adenocarcinoma is a lethal disease characterized by late diagnosis, propensity for early metastasis and resistance to chemotherapy. Little is known about the mechanisms that drive innate therapeutic resistance in pancreatic cancer. The ataxia-telangiectasia group D-associated gene (ATDC) is overexpressed in pancreatic cancer and promotes tumor growth and metastasis. Our study reveals that increased ATDC levels protect cancer cells from reactive oxygen species (ROS) via stabilization of nuclear factor erythroid 2-related factor 2 (NRF2). Mechanistically, ATDC binds to Kelch-like ECH-associated protein 1 (KEAP1), the principal regulator of NRF2 degradation, and thereby prevents degradation of NRF2 resulting in activation of a NRF2-dependent transcriptional program, reduced intracellular ROS and enhanced chemoresistance. Our findings define a novel role of ATDC in regulating redox balance and chemotherapeutic resistance by modulating NRF2 activity.


Asunto(s)
Carcinogénesis/genética , Proteínas de Unión al ADN/metabolismo , Resistencia a Antineoplásicos/genética , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Neoplasias Pancreáticas/fisiopatología , Factores de Transcripción/metabolismo , Humanos , Unión Proteica , Neoplasias Pancreáticas
2.
Nat Immunol ; 17(1): 95-103, 2016 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-26523864

RESUMEN

Aerobic glycolysis regulates T cell function. However, whether and how primary cancer alters T cell glycolytic metabolism and affects tumor immunity in cancer patients remains a question. Here we found that ovarian cancers imposed glucose restriction on T cells and dampened their function via maintaining high expression of microRNAs miR-101 and miR-26a, which constrained expression of the methyltransferase EZH2. EZH2 activated the Notch pathway by suppressing Notch repressors Numb and Fbxw7 via trimethylation of histone H3 at Lys27 and, consequently, stimulated T cell polyfunctional cytokine expression and promoted their survival via Bcl-2 signaling. Moreover, small hairpin RNA-mediated knockdown of human EZH2 in T cells elicited poor antitumor immunity. EZH2(+)CD8(+) T cells were associated with improved survival in patients. Together, these data unveil a metabolic target and mechanism of cancer immune evasion.


Asunto(s)
Regulación Neoplásica de la Expresión Génica/inmunología , MicroARNs , Neoplasias/inmunología , Complejo Represivo Polycomb 2/inmunología , Linfocitos T/inmunología , Escape del Tumor/inmunología , Animales , Separación Celular , Inmunoprecipitación de Cromatina , Proteína Potenciadora del Homólogo Zeste 2 , Femenino , Citometría de Flujo , Técnica del Anticuerpo Fluorescente , Glucólisis , Humanos , Immunoblotting , Melanoma Experimental/inmunología , Ratones Endogámicos C57BL , Neoplasias Ováricas/inmunología , Reacción en Cadena en Tiempo Real de la Polimerasa , Análisis de Matrices Tisulares , Transfección
3.
Immunity ; 40(5): 772-784, 2014 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-24816405

RESUMEN

Little is known about how the immune system impacts human colorectal cancer invasiveness and stemness. Here we detected interleukin-22 (IL-22) in patient colorectal cancer tissues that was produced predominantly by CD4(+) T cells. In a mouse model, migration of these cells into the colon cancer microenvironment required the chemokine receptor CCR6 and its ligand CCL20. IL-22 acted on cancer cells to promote activation of the transcription factor STAT3 and expression of the histone 3 lysine 79 (H3K79) methytransferase DOT1L. The DOT1L complex induced the core stem cell genes NANOG, SOX2, and Pou5F1, resulting in increased cancer stemness and tumorigenic potential. Furthermore, high DOT1L expression and H3K79me2 in colorectal cancer tissues was a predictor of poor patient survival. Thus, IL-22(+) cells promote colon cancer stemness via regulation of stemness genes that negatively affects patient outcome. Efforts to target this network might be a strategy in treating colorectal cancer patients.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Neoplasias Colorrectales/inmunología , Interleucinas/inmunología , Metiltransferasas/inmunología , Células Madre Neoplásicas/inmunología , Factor de Transcripción STAT3/inmunología , Animales , Línea Celular Tumoral , Proliferación Celular , Quimiocina CCL20/inmunología , Quimiocina CCL20/metabolismo , Neoplasias Colorrectales/mortalidad , Neoplasias Colorrectales/patología , Activación Enzimática/inmunología , Células HT29 , N-Metiltransferasa de Histona-Lisina , Proteínas de Homeodominio/inmunología , Proteínas de Homeodominio/metabolismo , Humanos , Metiltransferasas/metabolismo , Ratones , Proteína Homeótica Nanog , Trasplante de Neoplasias , Células Madre Neoplásicas/patología , Factor 3 de Transcripción de Unión a Octámeros/inmunología , Factor 3 de Transcripción de Unión a Octámeros/metabolismo , Receptores CCR6/inmunología , Receptores CCR6/metabolismo , Factores de Transcripción SOXB1/inmunología , Factores de Transcripción SOXB1/metabolismo , Factor de Transcripción STAT3/metabolismo , Interleucina-22
4.
Immunity ; 39(3): 611-21, 2013 Sep 19.
Artículo en Inglés | MEDLINE | ID: mdl-24012420

RESUMEN

Myeloid-derived suppressor cells (MDSCs) and cancer stem cells (CSCs) are important cellular components in the cancer microenvironment and may affect cancer phenotype and patient outcome. The nature of MDSCs and their interaction with CSCs in ovarian carcinoma are unclear. We examined the interaction between MDSCs and CSCs in patients with ovarian carcinoma and showed that MDSCs inhibited T cell activation and enhanced CSC gene expression, sphere formation, and cancer metastasis. MDSCs triggered miRNA101 expression in cancer cells. miRNA101 subsequently repressesed the corepressor gene C-terminal binding protein-2 (CtBP2), and CtBP2 directly targeted stem cell core genes resulting in increased cancer cell stemness and increasing metastatic and tumorigenic potential. Increased MDSC density and tumor microRNA101 expression predict poor survival, as does decreased tumor CtBP2 expression, independent of each other. Collectively, our work identifies an immune-associated cellular, molecular, and clinical network involving MDSCs-microRNA101-CtBP2-stem cell core genes, which extrinsically controls cancer stemness and impacts patient outcome.


Asunto(s)
Oxidorreductasas de Alcohol/metabolismo , MicroARNs/metabolismo , Células Mieloides/metabolismo , Células Madre Neoplásicas/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Neoplasias Ováricas/inmunología , Oxidorreductasas de Alcohol/antagonistas & inhibidores , Oxidorreductasas de Alcohol/genética , Comunicación Celular , Proteínas Co-Represoras , Femenino , Humanos , Activación de Linfocitos , MicroARNs/genética , Células Mieloides/citología , Células Mieloides/inmunología , Metástasis de la Neoplasia , Células Madre Neoplásicas/inmunología , Proteínas del Tejido Nervioso/antagonistas & inhibidores , Proteínas del Tejido Nervioso/genética , Neoplasias Ováricas/metabolismo , Interferencia de ARN , ARN Interferente Pequeño , Linfocitos T/inmunología
5.
Gastric Cancer ; 25(3): 527-541, 2022 05.
Artículo en Inglés | MEDLINE | ID: mdl-35094168

RESUMEN

BACKGROUND: Increasing evidence indicates that leucine-rich-alpha-2-glycoprotein 1 (LRG1) is associated with multiple malignancies, but whether it participates in gastric cancer (GC) angiogenesis remains unclear. METHODS: The expression levels of LRG1 were assessed in GC samples. Endothelial tube formation analysis, HUVEC migration assay, chorioallantoic membrane assay (CAM), and xenograft tumor model were used to investigate the effect of LRG1 on angiogenesis in gastric cancer. The involvement of activating transcription factor 3 (ATF3) was analyzed by chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assay. Western blot and enzyme-linked immunosorbent assay were performed to measure the SRC/STAT3/VEGFA pathway. RESULTS: LRG1 was overexpressed in GC tissues and associated with cancer angiogenesis. In addition, LRG1 markedly promoted GC cell proliferation in vitro and in vivo. Moreover, overexpression of LRG1 could stimulate GC angiogenesis in vitro and in vivo. Then, we identified ATF3 promotes the transcription of LRG1 and is a positive regulator of angiogenesis. Additionally, LRG1 could activate VEGFA expression via the SRC/STAT3/ VEGFA pathway in GC cells, thus contributing to the angiogenesis of GC. CONCLUSIONS: The present study suggests LRG1 plays a crucial role in the regulation of angiogenesis in GC and could be a potential therapeutic target for GC.


Asunto(s)
Factor de Transcripción Activador 3 , Neoplasias Gástricas , Factor de Transcripción Activador 3/metabolismo , Proliferación Celular , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Regulación Neoplásica de la Expresión Génica , Glicoproteínas/genética , Glicoproteínas/metabolismo , Humanos , Neovascularización Patológica/genética , Factor de Transcripción STAT3/metabolismo , Neoplasias Gástricas/patología , Factor A de Crecimiento Endotelial Vascular/genética , Factor A de Crecimiento Endotelial Vascular/metabolismo
6.
Nature ; 527(7577): 249-53, 2015 Nov 12.
Artículo en Inglés | MEDLINE | ID: mdl-26503055

RESUMEN

Epigenetic silencing including histone modifications and DNA methylation is an important tumorigenic mechanism. However, its role in cancer immunopathology and immunotherapy is poorly understood. Using human ovarian cancers as our model, here we show that enhancer of zeste homologue 2 (EZH2)-mediated histone H3 lysine 27 trimethylation (H3K27me3) and DNA methyltransferase 1 (DNMT1)-mediated DNA methylation repress the tumour production of T helper 1 (TH1)-type chemokines CXCL9 and CXCL10, and subsequently determine effector T-cell trafficking to the tumour microenvironment. Treatment with epigenetic modulators removes the repression and increases effector T-cell tumour infiltration, slows down tumour progression, and improves the therapeutic efficacy of programmed death-ligand 1 (PD-L1; also known as B7-H1) checkpoint blockade and adoptive T-cell transfusion in tumour-bearing mice. Moreover, tumour EZH2 and DNMT1 are negatively associated with tumour-infiltrating CD8(+) T cells and patient outcome. Thus, epigenetic silencing of TH1-type chemokines is a novel immune-evasion mechanism of tumours. Selective epigenetic reprogramming alters the T-cell landscape in cancer and may enhance the clinical efficacy of cancer therapy.


Asunto(s)
Quimiocinas/genética , Epigénesis Genética , Silenciador del Gen , Inmunoterapia , Neoplasias Ováricas/inmunología , Neoplasias Ováricas/terapia , Células TH1/metabolismo , Animales , Antígeno B7-H1/metabolismo , Linfocitos T CD8-positivos/citología , Linfocitos T CD8-positivos/inmunología , Quimiocina CXCL10/biosíntesis , Quimiocina CXCL10/genética , Quimiocina CXCL10/inmunología , Quimiocina CXCL9/biosíntesis , Quimiocina CXCL9/genética , Quimiocina CXCL9/inmunología , Quimiocinas/biosíntesis , Quimiocinas/inmunología , ADN (Citosina-5-)-Metiltransferasa 1 , ADN (Citosina-5-)-Metiltransferasas/antagonistas & inhibidores , ADN (Citosina-5-)-Metiltransferasas/metabolismo , Metilación de ADN/efectos de los fármacos , Proteína Potenciadora del Homólogo Zeste 2 , Epigénesis Genética/efectos de los fármacos , Femenino , Histonas/química , Histonas/metabolismo , Humanos , Inmunoterapia/métodos , Linfocitos Infiltrantes de Tumor/inmunología , Lisina/metabolismo , Ratones , Neoplasias Ováricas/enzimología , Neoplasias Ováricas/patología , Complejo Represivo Polycomb 2/antagonistas & inhibidores , Complejo Represivo Polycomb 2/metabolismo , Pronóstico , Células TH1/inmunología , Células Tumorales Cultivadas , Escape del Tumor/inmunología , Ensayos Antitumor por Modelo de Xenoinjerto
7.
Cell Physiol Biochem ; 46(2): 860-872, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-29627827

RESUMEN

BACKGROUND/AIMS: Although EpCAM+CD44+ cells exhibit more stem-like properties than did EpCAM-CD44- cells, the specificity of EpCAM combined with CD44 in defining CSCs needs further improvement. Lgr5 is used as a biomarker to isolate cancer stem cells (CSCs) in colorectal cancer. However, it remains unclear whether Lgr5, along with EpCAM and CD44, can further identify and define CSCs in colorectal cancer. METHODS: Lgr5+CD44+EpCAM+, Lgr5+CD44+EpCAM-, Lgr5+CD44-EpCAM+, Lgr5-CD44+EpCAM+, and Lgr5-CD44-EpCAM-cells were separately isolated using fluorescence-activated cell sorting (FACS). Colony formation, self-renewal, differentiation, and tumorigenic properties of these cells were investigated through in vitro experiments and in vivo tumor xenograft models. The expression of stemness genes and CSC- and epithelial-mesenchymal transition (EMT)-related genes, such as KLF4, Oct4, Sox2, Nanog, CD133, CD44, CD166, ALDH1, Lgr5, E-cadherin, ZO-1, Vimentin, Snail, Slug, and Twist, was examined using real-time PCR. RESULTS: Lgr5-positive subpopulations exhibited higher capacities for colony formation, self-renewal, differentiation, and tumorigenicity as well as higher expression of stemness genes and mesenchymal genes and lower expression of epithelial genes than did Lgr5-negative subpopulations. CONCLUSION: Our data revealed that tumorigenic cells were highly restricted to Lgr5-positive subpopulations. Most importantly, Lgr5+CD44+EpCAM+ cells exhibited more pronounced CSC-like traits than did any other subpopulation, indicating that Lgr5 combined with CD44 and EpCAM can further improve the stem-like traits of CSCs in colorectal cancer.


Asunto(s)
Neoplasias Colorrectales/patología , Molécula de Adhesión Celular Epitelial/metabolismo , Receptores de Hialuranos/metabolismo , Células Madre Neoplásicas/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Animales , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Cadherinas/genética , Cadherinas/metabolismo , Diferenciación Celular , Línea Celular Tumoral , Autorrenovación de las Células , Neoplasias Colorrectales/metabolismo , Molécula de Adhesión Celular Epitelial/genética , Transición Epitelial-Mesenquimal/genética , Femenino , Humanos , Receptores de Hialuranos/genética , Factor 4 Similar a Kruppel , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Microscopía Confocal , Microscopía Fluorescente , Células Madre Neoplásicas/citología , Receptores Acoplados a Proteínas G/genética , Trasplante Heterólogo , Proteína de la Zonula Occludens-1/genética , Proteína de la Zonula Occludens-1/metabolismo
8.
Gastroenterology ; 147(6): 1393-404, 2014 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-25181692

RESUMEN

BACKGROUND & AIMS: Cancer stem cells (CSCs) can contribute to hepatocellular carcinoma (HCC) progression and recurrence after therapy. The presence of tumor-associated macrophages (TAMs) in patients with HCC is associated with poor outcomes. It is not clear whether TAMs interact with CSCs during HCC development. We investigated whether TAMs affect the activities of CSCs in the microenvironment of human HCCs. METHODS: HCCs were collected from 17 patients during surgical resection and single-cell suspensions were analyzed by flow cytometry. CD14(+) TAMs were isolated from the HCC cell suspensions and placed into co-culture with HepG2 or Hep3B cells, and CSC functions were measured. The interleukin 6 (IL6) receptor was blocked with a monoclonal antibody (tocilizumab), and signal transducer and activator of transcription 3 was knocked down with small hairpin RNAs in HepG2 cells. Xenograft tumors were grown in NOD-SCID/Il2Rg(null) mice from human primary HCC cells or HepG2 cells. RESULTS: CD44(+) cells from human HCCs and cell lines formed more spheres in culture and more xenograft tumors in mice than CD44(-) cells, indicating that CD44(+) cells are CSCs. Incubation of the CD44(+) cells with TAMs promoted expansion of CD44(+) cells, and increased their sphere formation in culture and formation of xenograft tumors in mice. In human HCC samples, the numbers of TAMs correlated with the numbers of CD44(+) cells. Of all cytokines expressed by TAMs, IL6 was increased at the highest level in human HCC co-cultures, compared with TAMs not undergoing co-culture. IL6 was detected in the microenvironment of HCC samples and induced expansion of CD44(+) cells in culture. Levels of IL6 correlated with stages of human HCCs and detection of CSC markers. Incubation of HCC cell lines with tocilizumab or knockdown of signal transducer and activator of transcription 3 in HCC cells reduced the ability of TAMs to promote sphere formation by CD44+ cells in culture and growth of xenograft tumors in mice. CONCLUSIONS: CD44(+) cells isolated from human HCC tissues and cell lines have CSC activities in vitro and form a larger number of xenograft tumors in mice than CD44(-) cells. TAMs produce IL6, which promotes expansion of these CSCs and tumorigenesis. Levels of IL6 in human HCC samples correlate with tumor stage and markers of CSCs. Blockade of IL6 signaling with tocilizumab, a drug approved by the Food and Drug Administration for treatment of rheumatoid arthritis, inhibits TAM-stimulated activity of CD44(+) cells. This drug might be used to treat patients with HCC.


Asunto(s)
Carcinoma Hepatocelular/inmunología , Interleucina-6/inmunología , Neoplasias Hepáticas/inmunología , Macrófagos/inmunología , Células Madre Neoplásicas/inmunología , Factor de Transcripción STAT3/inmunología , Animales , Anticuerpos Monoclonales Humanizados/farmacología , Biomarcadores de Tumor/metabolismo , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Técnicas de Cocultivo , Células Hep G2 , Humanos , Receptores de Hialuranos/metabolismo , Interleucina-6/metabolismo , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Macrófagos/citología , Macrófagos/metabolismo , Ratones Endogámicos NOD , Ratones SCID , Células Madre Neoplásicas/citología , Células Madre Neoplásicas/metabolismo , Factor de Transcripción STAT3/metabolismo , Transducción de Señal/efectos de los fármacos , Transducción de Señal/inmunología , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto
9.
Wound Repair Regen ; 22(5): 631-9, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-24898474

RESUMEN

Peritoneal adhesions are fibrous tissues formed after surgery. Both cytokines and transforming growth factors (TGFs) are involved in this process. The objective of this study was to investigate the cross talk between these entities. Peritoneal drainage fluid after surgery from patients and rodent models was examined by enzyme-linked immunosorbent assay and fluorescence-activated cell sorter. Data showed that the concentrations of interferon (IFN)-γ and interleukin (IL)-17 reached their peaks 6-12 hours after surgery, whereas TGF-ß1 concentrations showed two postoperative peak time points at 2 and 72-96 hours. By neutralizing IFN-γ, IL-17 6-12 hours, and TGF-ß1 72-96 hours after surgery, the degree of adhesion reduced significantly. However, neutralizing TGF-ß1 2 hours after surgery did not affect adhesion formation. Furthermore, in vitro studies showed that compared with the fibroblasts that were directly stimulated with TGF-ß1, the prestimulation of IL-17 promoted plasminogen activator inhibitor-1 production while inhibiting tissue-type plasminogen activator production. Moreover, additional stimulation with IFN-γ enhanced this effect. Together, these data indicate that IL-17 may promote adhesion formation by increasing the reaction of fibroblasts against TGF-ß1. Blocking IL-17 might have a therapeutic potential in preventing adhesion formation after surgery.


Asunto(s)
Interferón gamma/inmunología , Interleucina-17/inmunología , Enfermedades Peritoneales/inmunología , Linfocitos T/inmunología , Factor de Crecimiento Transformador beta1/inmunología , Adulto , Anciano , Animales , Colectomía/efectos adversos , Femenino , Fibroblastos/metabolismo , Humanos , Masculino , Ratones , Persona de Mediana Edad , Células 3T3 NIH , Enfermedades Peritoneales/etiología , Serpina E2/metabolismo , Transducción de Señal/inmunología , Adherencias Tisulares/etiología , Adherencias Tisulares/inmunología , Activador de Tejido Plasminógeno/metabolismo
10.
Nat Cancer ; 5(1): 85-99, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-37814010

RESUMEN

Pancreatic ductal adenocarcinoma (PDAC) cells use glutamine (Gln) to support proliferation and redox balance. Early attempts to inhibit Gln metabolism using glutaminase inhibitors resulted in rapid metabolic reprogramming and therapeutic resistance. Here, we demonstrated that treating PDAC cells with a Gln antagonist, 6-diazo-5-oxo-L-norleucine (DON), led to a metabolic crisis in vitro. In addition, we observed a profound decrease in tumor growth in several in vivo models using sirpiglenastat (DRP-104), a pro-drug version of DON that was designed to circumvent DON-associated toxicity. We found that extracellular signal-regulated kinase (ERK) signaling is increased as a compensatory mechanism. Combinatorial treatment with DRP-104 and trametinib led to a significant increase in survival in a syngeneic model of PDAC. These proof-of-concept studies suggested that broadly targeting Gln metabolism could provide a therapeutic avenue for PDAC. The combination with an ERK signaling pathway inhibitor could further improve the therapeutic outcome.


Asunto(s)
Antineoplásicos , Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Glutamina/metabolismo , Línea Celular Tumoral , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/metabolismo , Antineoplásicos/farmacología , Carcinoma Ductal Pancreático/tratamiento farmacológico , Carcinoma Ductal Pancreático/metabolismo , Inhibidores Enzimáticos/farmacología
11.
Biochem Biophys Res Commun ; 436(2): 156-61, 2013 Jun 28.
Artículo en Inglés | MEDLINE | ID: mdl-23707808

RESUMEN

Peritoneal metastasis of colorectal cancer is a major clinical issue and results in poor prognosis for patients after surgical resection. Here, we found that abdominal surgery trauma induced high release of high-mobility group box 1 (HMGB1) in the peritoneal cavity of mice. Recombinant HMGB1 injected in the peritoneal cavity recruited abundant myeloid derived suppressor cells (MDSCs) after the surgical trauma. HMGB1 Box-A and gemcitabine reduced the recruitment of MDSCs in the peritoneal cavity after the operation and ameliorated the peritoneal metastasis burden of colon cancer in mouse model. These results showed that abdominal surgery trauma leads to a large amount of HMGB1 released in the peritoneal cavity which recruits numerous MDSCs to promote peritoneal metastasis of colon cancer after curative surgery.


Asunto(s)
Neoplasias del Colon/metabolismo , Proteína HMGB1/metabolismo , Células Mieloides/metabolismo , Neoplasias Peritoneales/metabolismo , Animales , Antimetabolitos Antineoplásicos/farmacología , Líquido Ascítico/metabolismo , Línea Celular Tumoral , Neoplasias del Colon/patología , Neoplasias del Colon/cirugía , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacología , Ensayo de Inmunoadsorción Enzimática , Citometría de Flujo , Proteína HMGB1/genética , Proteína HMGB1/farmacología , Ratones , Ratones Endogámicos BALB C , Células Mieloides/efectos de los fármacos , Neoplasias Peritoneales/secundario , Proteínas Recombinantes/farmacología , Gemcitabina
12.
J Immunol ; 186(7): 4388-95, 2011 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-21357259

RESUMEN

Foxp3(+)CD4(+) regulatory T (Treg) cells inhibit immune responses and temper inflammation. IL-17(+)CD4(+) T (Th17) cells mediate inflammation of autoimmune diseases. A small population of IL-17(+)Foxp3(+)CD4(+) T cells has been observed in peripheral blood in healthy human beings. However, the biology of IL-17(+)Foxp3(+)CD4(+) T cells remains poorly understood in humans. We investigated their phenotype, cytokine profile, generation, and pathological relevance in patients with ulcerative colitis. We observed that high levels of IL-17(+)Foxp3(+)CD4(+) T cells were selectively accumulated in the colitic microenvironment and associated colon carcinoma. The phenotype and cytokine profile of IL-17(+)Foxp3(+)CD4(+) T cells was overlapping with Th17 and Treg cells. Myeloid APCs, IL-2, and TGF-ß are essential for their induction from memory CCR6(+) T cells or Treg cells. IL-17(+)Foxp3(+)CD4(+) T cells functionally suppressed T cell activation and stimulated inflammatory cytokine production in the colitic tissues. Our data indicate that IL-17(+)Foxp3(+) cells may be "inflammatory" Treg cells in the pathological microenvironments. These cells may contribute to the pathogenesis of ulcerative colitis through inducing inflammatory cytokines and inhibiting local T cell immunity, and in turn may mechanistically link human chronic inflammation to tumor development. Our data therefore challenge commonly held beliefs of the anti-inflammatory role of Treg cells and suggest a more complex Treg cell biology, at least in the context of human chronic inflammation and associated carcinoma.


Asunto(s)
Mediadores de Inflamación/fisiología , Interleucina-17/fisiología , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/patología , Carcinoma de Células Renales/inmunología , Carcinoma de Células Renales/metabolismo , Carcinoma de Células Renales/patología , Células Cultivadas , Enfermedad Crónica , Técnicas de Cocultivo , Colitis Ulcerosa/inmunología , Colitis Ulcerosa/metabolismo , Colitis Ulcerosa/patología , Neoplasias del Colon/inmunología , Neoplasias del Colon/metabolismo , Neoplasias del Colon/patología , Citocinas/biosíntesis , Femenino , Factores de Transcripción Forkhead/biosíntesis , Factores de Transcripción Forkhead/fisiología , Inhibidores de Crecimiento/biosíntesis , Inhibidores de Crecimiento/fisiología , Humanos , Tolerancia Inmunológica/inmunología , Mediadores de Inflamación/metabolismo , Interleucina-17/biosíntesis , Neoplasias Renales/inmunología , Neoplasias Renales/metabolismo , Neoplasias Renales/patología , Melanoma/inmunología , Melanoma/metabolismo , Melanoma/patología , Neoplasias Ováricas/inmunología , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/patología , Linfocitos T Reguladores/metabolismo
13.
Front Immunol ; 14: 1067352, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-36798126

RESUMEN

Hepato-pancreatico-biliary (HPB) malignancies are difficult-to-treat and continue to to have a high mortality and significant therapeutic resistance to standard therapies. Immune oncology (IO) therapies have demonstrated efficacy in several solid malignancies when combined with chemotherapy, whereas response rates in pancreatic ductal adenocarcinoma (PDA) are poor. While promising in hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), there remains an unmet need to fully leverage IO therapies to treat HPB tumors. We therefore defined T cell subsets in the tumor microenvironment of HPB patients utilizing a novel, multiparameter flow cytometry and bioinformatics analysis. Our findings quantify the T cell phenotypic states in relation to checkpoint receptor expression. We demonstrate the presence of CD103+ tissue resident memory T cells (TRM), CCR7+ central memory T cells, and CD57+ terminally differentiated effector cells across all HPB cancers, while the anti-tumor function was dampened by expression of multiple co-inhibitory checkpoint receptors. Terminally exhausted T cells lacking co-stimulatory receptors were more prevalent in PDA, whereas partially exhausted T cells expressing both co-inhibitory and co-stimulatory receptors were most prevalent in HCC, especially in early stage. HCC patients had significantly higher TRM with a phenotype that could confer restored activation in response to immune checkpoint therapies. Further, we found a lack of robust alteration in T cell activation state or checkpoint expression in response to chemotherapy in PDA patients. These results support that HCC patients might benefit most from combined checkpoint therapies, whereas efforts other than cytotoxic chemotherapy will likely be necessary to increase overall T cell activation in CCA and PDA for future clinical development.


Asunto(s)
Neoplasias de los Conductos Biliares , Neoplasias del Sistema Biliar , Carcinoma Hepatocelular , Carcinoma Ductal Pancreático , Neoplasias Hepáticas , Neoplasias Pancreáticas , Humanos , Carcinoma Ductal Pancreático/tratamiento farmacológico , Carcinoma Ductal Pancreático/patología , Conductos Biliares Intrahepáticos/metabolismo , Microambiente Tumoral , Neoplasias Pancreáticas
15.
J Clin Invest ; 133(11)2023 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-36976649

RESUMEN

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy that harbors mutations in homologous recombination-repair (HR-repair) proteins in 20%-25% of cases. Defects in HR impart a specific vulnerability to poly ADP ribose polymerase inhibitors and platinum-containing chemotherapy in tumor cells. However, not all patients who receive these therapies respond, and many who initially respond ultimately develop resistance. Inactivation of the HR pathway is associated with the overexpression of polymerase theta (Polθ, or POLQ). This key enzyme regulates the microhomology-mediated end-joining (MMEJ) pathway of double-strand break (DSB) repair. Using human and murine HR-deficient PDAC models, we found that POLQ knockdown is synthetically lethal in combination with mutations in HR genes such as BRCA1 and BRCA2 and the DNA damage repair gene ATM. Further, POLQ knockdown enhances cytosolic micronuclei formation and activates signaling of cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING), leading to enhanced infiltration of activated CD8+ T cells in BRCA2-deficient PDAC tumors in vivo. Overall, POLQ, a key mediator in the MMEJ pathway, is critical for DSB repair in BRCA2-deficient PDAC. Its inhibition represents a synthetic lethal approach to blocking tumor growth while concurrently activating the cGAS-STING signaling pathway to enhance tumor immune infiltration, highlighting what we believe to be a new role for POLQ in the tumor immune environment.


Asunto(s)
Adenocarcinoma , Neoplasias Pancreáticas , Humanos , Animales , Ratones , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/genética , Roturas del ADN de Doble Cadena , Línea Celular Tumoral , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/genética , Nucleotidiltransferasas/genética , Nucleotidiltransferasas/metabolismo , Recombinación Homóloga , Transducción de Señal , Inmunidad , Neoplasias Pancreáticas
16.
Nat Commun ; 14(1): 797, 2023 02 13.
Artículo en Inglés | MEDLINE | ID: mdl-36781852

RESUMEN

The tumor microenvironment (TME) in pancreatic ductal adenocarcinoma (PDAC) is a complex ecosystem that drives tumor progression; however, in-depth single cell characterization of the PDAC TME and its role in response to therapy is lacking. Here, we perform single-cell RNA sequencing on freshly collected human PDAC samples either before or after chemotherapy. Overall, we find a heterogeneous mixture of basal and classical cancer cell subtypes, along with distinct cancer-associated fibroblast and macrophage subpopulations. Strikingly, classical and basal-like cancer cells exhibit similar transcriptional responses to chemotherapy and do not demonstrate a shift towards a basal-like transcriptional program among treated samples. We observe decreased ligand-receptor interactions in treated samples, particularly between TIGIT on CD8 + T cells and its receptor on cancer cells, and identify TIGIT as the major inhibitory checkpoint molecule of CD8 + T cells. Our results suggest that chemotherapy profoundly impacts the PDAC TME and may promote resistance to immunotherapy.


Asunto(s)
Adenocarcinoma , Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/genética , Adenocarcinoma/patología , Microambiente Tumoral/genética , Ecosistema , Carcinoma Ductal Pancreático/tratamiento farmacológico , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patología , Análisis de Secuencia de ARN , Neoplasias Pancreáticas
17.
Cell Death Dis ; 13(9): 800, 2022 09 19.
Artículo en Inglés | MEDLINE | ID: mdl-36123344

RESUMEN

Long noncoding RNAs (lncRNAs) play crucial regulatory roles in the progression of various cancers. However, the functional roles of lncRNAs in breast cancer remain unclear. In this study, we investigated the functional role of a novel long noncoding RNA SEMA3B-AS1 (lncRNA SEAS1) in breast cancer progression and the underlying mechanisms. SEAS1 was downregulated in the triple-negative breast cancer (TNBC) tissues compared with the para-carcinoma tissues, which was associated with poor prognosis of TNBC patients. We demonstrated that SEAS1 knockdown significantly increased the proliferation, migration, and invasion of TNBC cell lines, whereas SEAS1 overexpression reversed these effects. Bioinformatics analysis demonstrated that microRNA (miR)-3940-3p was a potential target of SEAS1. Mechanistically, RNA immunoprecipitation (RIP) and luciferase reporter assays confirmed that lncRNA SEMA3B-AS1 acted as sponge for miR-3940-3p, preventing the degradation of its target gene KLLN, which acts as a tumor-inhibiter in TNBC. Moreover, RNA pulldown, mass spectrometry, ChIP, and luciferase reporter assays confirmed that SMAD3 directly interacted with the promoter of SEAS1 and suppressed its transcription, thereby promoting TNBC progression. The clinical samples of TNBC confirmed SEAS1 was correlated inversely with lymphatic and distant metastasis. In conclusion, our findings reveal a novel pathway for TNBC progression via SMAD3/lncRNA SEAS1/miR-3940-3p/KLLN axis, and suggest that SEAS1 may serve as a potential biomarker and therapeutic target for TNBC.


Asunto(s)
MicroARNs , ARN Largo no Codificante , Semaforinas , Neoplasias de la Mama Triple Negativas , Movimiento Celular/genética , Proliferación Celular/genética , Progresión de la Enfermedad , Regulación Neoplásica de la Expresión Génica , Humanos , Glicoproteínas de Membrana/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Semaforinas/genética , Semaforinas/metabolismo , Neoplasias de la Mama Triple Negativas/patología
18.
Carcinogenesis ; 32(5): 643-9, 2011 May.
Artículo en Inglés | MEDLINE | ID: mdl-21304053

RESUMEN

The role of CD4+ T helper (Th) 17 cells in malignancy is currently under debate. However, upon closer scrutiny, it becomes apparent that this discussion includes not only evaluations of Th17 cells but also IL-17+ cells from other immune populations, the cytokine interleukin (IL)-17 itself (both endogenous and exogenous) and IL-23. Further complicating the matter are occasionally conflicting results of studies in humans versus those in mice and contradictory data from immunocompetent versus immunodeficient mice. To better understand the role of Th17 cells in the tumor-bearing host, we focus first upon those studies investigating Th17 cells in patients and then those in mice, all the while keeping in mind that variables such as tumor-initiating agents, a pre-existing inflammatory environment and the immune competence of the host may have direct effects upon this T-cell subset. In this review, we will describe the phenotype of tumor-associated Th17 cells, review those studies that have examined the population directly, and finally, briefly discuss the studies involving Th17-associated signature cytokines.


Asunto(s)
Neoplasias/inmunología , Células Th17/fisiología , Animales , Citocinas/metabolismo , Humanos , Ratones , Neoplasias/patología
19.
Cell Rep ; 36(4): 109429, 2021 07 27.
Artículo en Inglés | MEDLINE | ID: mdl-34320344

RESUMEN

Patient-derived tumor organoids (TOs) are emerging as high-fidelity models to study cancer biology and develop novel precision medicine therapeutics. However, utilizing TOs for systems-biology-based approaches has been limited by a lack of scalable and reproducible methods to develop and profile these models. We describe a robust pan-cancer TO platform with chemically defined media optimized on cultures acquired from over 1,000 patients. Crucially, we demonstrate tumor genetic and transcriptomic concordance utilizing this approach and further optimize defined minimal media for organoid initiation and propagation. Additionally, we demonstrate a neural-network-based high-throughput approach for label-free, light-microscopy-based drug assays capable of predicting patient-specific heterogeneity in drug responses with applicability across solid cancers. The pan-cancer platform, molecular data, and neural-network-based drug assay serve as resources to accelerate the broad implementation of organoid models in precision medicine research and personalized therapeutic profiling programs.


Asunto(s)
Neoplasias/patología , Organoides/patología , Medicina de Precisión , Proliferación Celular , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Fluorescencia , Genómica , Antígenos HLA/genética , Humanos , Pérdida de Heterocigocidad , Masculino , Persona de Mediana Edad , Modelos Biológicos , Neoplasias/genética , Redes Neurales de la Computación , Transcriptoma/genética
20.
Int J Cancer ; 127(4): 748-58, 2010 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-20473951

RESUMEN

Since entering the immunological stage several decades ago, regulatory T cell biology has been realized as fundamentally important in the prevention of autoimmune conditions, induction of transplant tolerance and the immune response to cancer. The role of regulatory T cells in tumor immunobiology is still being elucidated. Currently, regulatory T cells are implicated in the dampening of antitumor T-cell responses both through direct and indirect means. A number of investigators have demonstrated that regulatory T cell density and location may serve as independent prognostic factors in several types of cancer and are alternately detrimental or beneficial to patient survival. In this article, we will review the characteristics and functional phenotype of classical regulatory T cells, describe their distribution and quantification in tumor-bearing hosts and summarize recent studies investigating the prognostic significance of regulatory T cell number and locality in various cancers.


Asunto(s)
Neoplasias/inmunología , Linfocitos T Reguladores/fisiología , Animales , Humanos , Pronóstico
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