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Zhou Y, Liu D, Li H. FGL1 Promotes Tumor Immune Escape in Stomach Adenocarcinoma via the Notch Signaling Pathway. Mol Biotechnol 2024; 66:3203-3212. [PMID: 37902887 DOI: 10.1007/s12033-023-00928-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Accepted: 10/05/2023] [Indexed: 11/01/2023]
Abstract
Immune escape is the major reason for immunotherapy failure in stomach adenocarcinoma (STAD). We tried to reveal the underlying mechanism of FGL1 influencing STAD in this study. Bioinformatics analyses were conducted to analyze the expression of FGL1, the signaling pathways affected by FGL1, and the relation between FGL1 and immune cell infiltration. Quantitative real-time PCR (qRT-PCR), cell counting kit-8 assay, colony formation assay, flow cytometry and Transwell assay were adopted to analyze FGL1 expression, cell viability, cell proliferation, cell apoptosis, and cell invasion, respectively. Enzyme-linked immunosorbent assay, lactate dehydrogenase method, qRT-PCR and Western blot were adopted to reveal proinflammatory cytokine expression, cytotoxicity and mRNA and protein expression of the Notch signaling-related genes, respectively, after co-culture of STAD cells and CD8+T cells. Nude mice experiment was conducted to validate the results obtained above. FGL1 expressed highly in STAD and could activate the Notch signaling pathway, and it was negatively correlated with CD8+T cell infiltration. Cell experiments confirmed that high expression of FGL1 facilitated proliferation and hindered apoptosis of STAD cells. Knockdown of FGL1 could facilitate expression of pro-inflammatory factors and the cytotoxicity of CD8+T cells in co-culture system of STAD and CD8+ T cells. Knockdown of FGL1 could suppress the expression of the Notch signaling pathway-related genes, and the addition of Notch inhibitor proved that FGL1 promoted immune escape via the Notch signaling pathway. This study investigated the influence of FGL1 on STAD immune escape and demonstrated that FGL1 inhibited CD8+ T cell activation by activating the Notch signaling pathway and thus promoted tumor immune escape in STAD, providing a new potential diagnostic marker and therapeutic target for the immunotherapy of STAD patients.
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Affiliation(s)
- Yani Zhou
- School of Health Management, Shangluo University, Shangluo, 726000, China
| | - Dan Liu
- Department of Rheumatology, First Affiliated Hospital of Xi'an Medical College, Xi'an, 710077, China
| | - Huirong Li
- Department of Mathematics and Computer Application, Shangluo University, No. 10, Beixin Street, Shangzhou District, Shangluo, 726000, Shaanxi Province, China.
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2
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Katifelis H, Gazouli M. RNA biomarkers in cancer therapeutics: The promise of personalized oncology. Adv Clin Chem 2024; 123:179-219. [PMID: 39181622 DOI: 10.1016/bs.acc.2024.06.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/27/2024]
Abstract
Cancer therapy is a rapidly evolving and constantly expanding field. Current approaches include surgery, conventional chemotherapy and novel biologic agents as in immunotherapy, that together compose a wide armamentarium. The plethora of choices can, however, be clinically challenging in prescribing the most suitable treatment for any given patient. Fortunately, biomarkers can greatly facilitate the most appropriate selection. In recent years, RNA-based biomarkers have proven most promising. These molecules that range from small noncoding RNAs to protein coding gene transcripts can be valuable in cancer management and especially in cancer therapeutics. Compared to their DNA counterparts which are stable throughout treatment, RNA-biomarkers are dynamic. This allows prediction of success prior to treatment start and can identify alterations in expression that could reflect response. Moreover, improved nucleic acid technology allows RNA to be extracted from practically every biofluid/matrix and evaluated with exceedingly high analytic sensitivity. In addition, samples are largely obtained by minimally invasive procedures and as such can be used serially to assess treatment response real-time. This chapter provides the reader insight on currently known RNA biomarkers, the latest research employing Artificial Intelligence in the identification of such molecules and in clinical decisions driving forward the era of personalized oncology.
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Affiliation(s)
- Hector Katifelis
- Laboratory of Biology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Maria Gazouli
- Laboratory of Biology, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
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3
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Bajgain P, Chavez AGT, Balasubramanian K, Fleckenstein L, Lulla P, Heslop HE, Vera J, Leen AM. Secreted Fas Decoys Enhance the Antitumor Activity of Engineered and Bystander T Cells in Fas Ligand-Expressing Solid Tumors. Cancer Immunol Res 2022; 10:1370-1385. [PMID: 36122411 PMCID: PMC9633434 DOI: 10.1158/2326-6066.cir-22-0115] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Revised: 07/11/2022] [Accepted: 09/16/2022] [Indexed: 11/16/2022]
Abstract
T-cell immunotherapy has demonstrated remarkable clinical outcomes in certain hematologic malignancies. However, efficacy in solid tumors has been suboptimal, partially due to the hostile tumor microenvironment composed of immune-inhibitory molecules. One such suppressive agent abundantly expressed in solid tumors is Fas ligand (FasL), which can trigger apoptosis of Fas-expressing effector cells such as T cells and natural killer (NK) cells. To alleviate this FasL-induced suppression of tumor-specific immune cells in solid tumors, we describe here the development of a Fas decoy that is secreted by engineered cells upon activation and sequesters the ligand, preventing it from engaging with Fas on the surface of effector cells. We further improved the immune-stimulatory effects of this approach by creating a Fas decoy and IL15 cytokine fusion protein, which enhanced the persistence and antitumor activity of decoy-engineered as well as bystander chimeric-antigen receptor (CAR) T cells in xenograft models of pancreatic cancer. Our data indicate that secreted Fas decoys can augment the efficacy of both adoptively transferred and endogenous tumor-specific effector cells in FasL-expressing solid tumors.
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Affiliation(s)
- Pradip Bajgain
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children’s Hospital and Houston Methodist Hospital, Houston, Texas
- Center for Cancer Research, National Cancer Institute, Frederick, MD
| | - Alejandro G. Torres Chavez
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children’s Hospital and Houston Methodist Hospital, Houston, Texas
| | - Kishore Balasubramanian
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children’s Hospital and Houston Methodist Hospital, Houston, Texas
| | - Lindsey Fleckenstein
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children’s Hospital and Houston Methodist Hospital, Houston, Texas
| | - Premal Lulla
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children’s Hospital and Houston Methodist Hospital, Houston, Texas
| | - Helen E. Heslop
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children’s Hospital and Houston Methodist Hospital, Houston, Texas
| | - Juan Vera
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children’s Hospital and Houston Methodist Hospital, Houston, Texas
- Marker Therapeutics, Inc., Houston, Texas
| | - Ann M. Leen
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children’s Hospital and Houston Methodist Hospital, Houston, Texas
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4
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Cell death affecting the progression of gastric cancer. Cell Death Dis 2022; 8:377. [PMID: 36038533 PMCID: PMC9424204 DOI: 10.1038/s41420-022-01161-8] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Revised: 08/04/2022] [Accepted: 08/08/2022] [Indexed: 12/07/2022]
Abstract
Gastric cancer is a gastrointestinal tumor with high morbidity and mortality rates. Several factors influence its progression, cell death being an important element. In this review, we summarized the effects of necrosis, apoptosis, necroptosis, pyroptosis, ferroptosis, and eight less common cell death modalities on gastric cancer cells and the tumor microenvironment, detailed the molecular mechanisms of various cell death and their major regulatory pathways in gastric cancer, explored the prevalence and complexity of cell death in gastric cancer progression and highlighted the potentials of cell death-related therapies in gastric cancer.
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5
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Shan Z, Zhao Y, Zhang J, Yan Z, Wang T, Mao F, Teng Y, Peng L, Chen W, Wang P, Cheng P, Tian W, Chen J, Chen W, Zhuang Y. FasL + PD-L2 + Identifies a Novel Immunosuppressive Neutrophil Population in Human Gastric Cancer That Promotes Disease Progression. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2022; 9:e2103543. [PMID: 34957697 PMCID: PMC8844550 DOI: 10.1002/advs.202103543] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/15/2021] [Revised: 11/28/2021] [Indexed: 05/05/2023]
Abstract
Neutrophils constitute abundant cellular components in human gastric cancer (GC) tissues, but their protumorigenic subset in pathogenesis of GC progression is unclear. Here, it is found that patients with GC show significantly higher neutrophil infiltration in tumors that is regulated by CXCL12-CXCR4 chemotaxis. These tumor-infiltrating neutrophils express high level immunosuppressive molecules FasL and PD-L2, and this FasL+ PD-L2+ neutrophil subset with a unique phenotype constitutes at least 20% of all neutrophils in advanced GC and predicts poor patient survival. Tumor induces neutrophils to express FasL and PD-L2 proteins with similar phenotype to those in GC tumors in both time-dependent and dose-dependent manners. Mechanistically, Th17 cell-derived IL-17A and tumor cell-derived G-CSF can significantly induce neutrophil FasL and PD-L2 expression via activating ERK-NF-κB and JAK-STAT3 signaling pathway, respectively. Importantly, upon over-expressing FasL and PD-L2, neutrophils acquire immunosuppressive functions on tumor-specific CD8+ T-cells and promote the growth and progression of human GC tumors in vitro and in vivo, which can be reversed by blocking FasL and PD-L2 on these neutrophils. Thus, the work identifies a novel protumorigenic FasL+ PD-L2+ neutrophil subset in GC and provides new insights for human cancer immunosuppression and anti-cancer therapies targeting these pathogenic cells.
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Affiliation(s)
- Zhi‐Guo Shan
- Department of General Surgery and Center of Minimal Invasive Gastrointestinal SurgerySouthwest HospitalThird Military Medical UniversityChongqing400038China
| | - Yong‐Liang Zhao
- Department of General Surgery and Center of Minimal Invasive Gastrointestinal SurgerySouthwest HospitalThird Military Medical UniversityChongqing400038China
| | - Jin‐Yu Zhang
- National Engineering Research Center of Immunological ProductsDepartment of Microbiology and Biochemical PharmacyCollege of Pharmacy and Laboratory MedicineThird Military Medical UniversityChongqing400038China
| | - Zong‐Bao Yan
- Department of General Surgery and Center of Minimal Invasive Gastrointestinal SurgerySouthwest HospitalThird Military Medical UniversityChongqing400038China
| | - Ting‐Ting Wang
- Chongqing Key Research Laboratory for Drug MetabolismDepartment of PharmacologyChongqing Medical UniversityChongqing400016China
| | - Fang‐Yuan Mao
- National Engineering Research Center of Immunological ProductsDepartment of Microbiology and Biochemical PharmacyCollege of Pharmacy and Laboratory MedicineThird Military Medical UniversityChongqing400038China
| | - Yong‐Sheng Teng
- National Engineering Research Center of Immunological ProductsDepartment of Microbiology and Biochemical PharmacyCollege of Pharmacy and Laboratory MedicineThird Military Medical UniversityChongqing400038China
| | - Liu‐Sheng Peng
- National Engineering Research Center of Immunological ProductsDepartment of Microbiology and Biochemical PharmacyCollege of Pharmacy and Laboratory MedicineThird Military Medical UniversityChongqing400038China
| | - Wan‐Yan Chen
- National Engineering Research Center of Immunological ProductsDepartment of Microbiology and Biochemical PharmacyCollege of Pharmacy and Laboratory MedicineThird Military Medical UniversityChongqing400038China
| | - Pan Wang
- National Engineering Research Center of Immunological ProductsDepartment of Microbiology and Biochemical PharmacyCollege of Pharmacy and Laboratory MedicineThird Military Medical UniversityChongqing400038China
| | - Ping Cheng
- National Engineering Research Center of Immunological ProductsDepartment of Microbiology and Biochemical PharmacyCollege of Pharmacy and Laboratory MedicineThird Military Medical UniversityChongqing400038China
| | - Wen‐Qing Tian
- Department of Endocrinologythe First Affiliated Hospital of Chongqing Medical UniversityChongqing400016China
| | - Jun Chen
- Department of General Surgery and Center of Minimal Invasive Gastrointestinal SurgerySouthwest HospitalThird Military Medical UniversityChongqing400038China
| | - Weisan Chen
- La Trobe Institute of Molecular ScienceLa Trobe UniversityBundooraVictoria3085Australia
| | - Yuan Zhuang
- National Engineering Research Center of Immunological ProductsDepartment of Microbiology and Biochemical PharmacyCollege of Pharmacy and Laboratory MedicineThird Military Medical UniversityChongqing400038China
- Department of Gastroenterologythe Affiliated Hospital of Southwest Medical UniversityLuzhouSichuan646000China
- Jiangsu Key Laboratory of Medical Science and Laboratory MedicineSchool of MedicineJiangsu UniversityJiangsu21013China
- Department of GastroenterologySouthwest HospitalThird Military Medical UniversityChongqing400038China
- Department of Gastroenterologythe Affiliated Hospital of Zunyi Medical UniversityZunyiGuizhou563003China
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6
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Zou JZ, Liu DS, Tong X, Zhang XP, Wang XB. RNA In Situ Hybridization of Detecting Cucumber Mosaic Virus in Shoots of Nicotiana benthamiana Plants. Methods Mol Biol 2022; 2400:283-296. [PMID: 34905211 DOI: 10.1007/978-1-0716-1835-6_27] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
RNA in situ hybridization, a histological technique derived from Southern blotting and northern blotting, has been an important approach in biology studies for many years. In the studies of virus-plant interactions, RNA in situ hybridization provides a direct visualization of viral RNA in host plants. Here, we provide a detailed protocol for viral RNA in situ hybridization that has been successfully used to detect Cucumber mosaic virus genome (CMV) RNAs in shoots of N. benthamiana plants.
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Affiliation(s)
- Jing-Ze Zou
- State Key Laboratory of Agro-Biotechnology, College of Biological Sciences, China Agricultural University, Beijing, China
| | - De-Shui Liu
- State Key Laboratory of Agro-Biotechnology, College of Biological Sciences, China Agricultural University, Beijing, China
| | - Xin Tong
- State Key Laboratory of Agro-Biotechnology, College of Biological Sciences, China Agricultural University, Beijing, China
| | - Xiao-Peng Zhang
- State Key Laboratory of Agro-Biotechnology, College of Biological Sciences, China Agricultural University, Beijing, China
| | - Xian-Bing Wang
- State Key Laboratory of Agro-Biotechnology, College of Biological Sciences, China Agricultural University, Beijing, China.
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7
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Smirnova OV, Sinyakov AA, Tsukanov VV. Monocyte Chemiluminescence Traits in Gastric Cancer. RUSSIAN JOURNAL OF GASTROENTEROLOGY, HEPATOLOGY, COLOPROCTOLOGY 2021; 31:34-39. [DOI: 10.22416/1382-4376-2021-31-2-34-39] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/12/2024]
Abstract
Aim. A study of monocyte chemiluminescent activity at variant stages of gastric cancer.Materials and methods. The study enrolled 90 gastric cancer patients and 70 healthy donors. Spontaneous and induced chemiluminescence in monocytes was assessed for 90 min with a “BLM 3607” 36-channel chemiluminescence analyser (Russia). Opsonized zymosan-induced chemiluminescence enhancement was measured as a ratio of the areas under the induced vs. spontaneous chemiluminescence curves, the activation index. Statistical significance was estimated with the Mann—Whitney criterion (p < 0.05).Results. The maximal spontaneous monocyte chemiluminescence intensity significantly decreased in stage IV gastric cancer patients compared to the control cohort (p = 0.035). Time to maximum in spontaneous chemiluminescence increased in all gastric cancer patients vs. control (p = 0.001), and in stage IV gastric cancer vs. stage I patients (p = 0.043). The areas under a curve in spontaneous and induced monocyte chemiluminescence increased in all gastric cancer patients vs. control (p = 0.001), and in stage IV gastric cancer vs. stage I patients (p = 0.037). The activation index was higher in all gastric cancer cases compared to control (p = 0.001).Conclusion. All patients with gastric adenocarcinoma, irrespective of the stage, revealed changes in the monocyte chemiluminescence activity, i.e. a longer time to maximum in spontaneous chemiluminescence and larger area under the curve of spontaneous and induced chemiluminescence, the activation index. Maximal monocyte spontaneous chemiluminescence intensity diminished in stage IV gastric cancer compared to the control cohort. Immune activity reflected in monocyte chemiluminescence correlates with the stage of gastric adenocarcinoma.
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Affiliation(s)
- O. V. Smirnova
- Krasnoyarsk Scientific Center of the Siberian Branch of the Russian Academy of Sciences, Research Institute of Medical Problems of the North
| | - A. A. Sinyakov
- Krasnoyarsk Scientific Center of the Siberian Branch of the Russian Academy of Sciences, Research Institute of Medical Problems of the North
| | - V. V. Tsukanov
- Krasnoyarsk Scientific Center of the Siberian Branch of the Russian Academy of Sciences, Research Institute of Medical Problems of the North
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8
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Kashyap D, Garg VK, Goel N. Intrinsic and extrinsic pathways of apoptosis: Role in cancer development and prognosis. ADVANCES IN PROTEIN CHEMISTRY AND STRUCTURAL BIOLOGY 2021; 125:73-120. [PMID: 33931145 DOI: 10.1016/bs.apcsb.2021.01.003] [Citation(s) in RCA: 177] [Impact Index Per Article: 44.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Apoptosis, also named programmed cell death, is a fundament process required for morphogenetic homeostasis during early development and in pathophysiological conditions. It is come into existence in 1972 by work of Kerr, Wyllie and Currie and later on investigated during the research on development of the C. elegans. Trigger by several stimuli, apoptosis is necessary during the embryonic development and aging as homeostatic mechanism to control the cell population and also play a key role as defense mechanism against the immune responses and elimination of damaged cells. Cancer, a genetic disease, is a growing burden on the health and economy of both developing and developed countries. Every year there is tremendously increasing in the number of new cancer cases and mortality rate. Although, there is a significant improvement have been made in biotechnological and bioinformatic fields however, the therapeutic advantages and cancer etiology is still under explored. Several studies determined the deregulation of different apoptotic components during the cancer development and progression. Apoptosis relies on activation of distinct signaling pathways that are often deregulated in cancer. Thus, exploring the single or more than one apoptotic component underlying their expression in carcinogenesis could help to track the disease progression. Current book chapter will provide the several evidences supporting the use of different apoptotic components as prognosis and prediction markers in various human cancer types.
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Affiliation(s)
- Dharambir Kashyap
- Department of Histopathology, Postgraduation Institute of Medical Education and Research (PGIMER), Chandigarh, India
| | | | - Neelam Goel
- Department of Information Technology, UIET, Panjab University, Chandigarh, India.
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9
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Zhao T, Li W, Chen J, Qin W. Genomic variants in Fas-mediated apoptosis pathway predict a poor response to Platinum-based Chemotherapy for Chinese Gastric Cancer Patients. J Cancer 2021; 12:849-859. [PMID: 33403042 PMCID: PMC7778532 DOI: 10.7150/jca.48120] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2020] [Accepted: 02/09/2020] [Indexed: 12/16/2022] Open
Abstract
Platinum-based adjuvant chemotherapy is very common for gastric cancer (GC) patients, but the chemotherapy sensitivity is very heterogeneous. The genomic variants and the gene-gene interactions involved in Fas-mediated apoptosis pathway including Fas (FAS 1377 G > A and 670 A > G), FasL (FASL 844 C > T) and caspase-8 (CASP8 -652 6N ins > del or I > D), may paly vital roles in the response to platinum-based treatment. In our investigation, 662 stage II-III postoperative GC patients were enrolled between 1998 and 2006. 261 patients accepted platinum-based regimens and the remaining 401 were not. The log rank tests, Kaplan Meier plots, Pearson chi-square tests, Student t-tests and Cox regression analyses were performed. For the chemotherapy cohort, FAS 1377 G > A or FAS 670 A > G variants alone was related with inferior survival, and a greater than additive effect was identified when patients simultaneously carrying FAS 1377 GA and FAS 670 GA genotypes. But the poor response was neutralized when patients simultaneously carrying FASL 844 C > T or CASP8 -652 6N ins > del mutations. Our study suggested that FAS 1377 G > A and FAS 670 A > G variants may serve as potential biomarkers to predict the response to platinum-based adjuvant chemotherapy, and the gene-gene interactions involved in Fas-mediated apoptosis pathway may enhance or neutralize the chemosensitivity.
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Affiliation(s)
- Tingting Zhao
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, 21000, China
| | - Wei Li
- Department of Gynecology, Zhenjiang Maternity and Childcare Hospital, Zhenjiang, 212000, China
| | - Jinfei Chen
- Cancer Center, Taikang Xianlin Drum Tower Hospital, Nanjing University School of Medicine, Nanjing, 21000, China
| | - Weisong Qin
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, 21000, China
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10
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Rommereim LM, Akhade AS, Dutta B, Hutcheon C, Lounsbury NW, Rostomily CC, Savan R, Fraser IDC, Germain RN, Subramanian N. A small sustained increase in NOD1 abundance promotes ligand-independent inflammatory and oncogene transcriptional responses. Sci Signal 2020; 13:13/661/eaba3244. [PMID: 33293463 DOI: 10.1126/scisignal.aba3244] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Small, genetically determined differences in transcription [expression quantitative trait loci (eQTLs)] are implicated in complex diseases through unknown molecular mechanisms. Here, we showed that a small, persistent increase in the abundance of the innate pathogen sensor NOD1 precipitated large changes in the transcriptional state of monocytes. A ~1.2- to 1.3-fold increase in NOD1 protein abundance resulting from loss of regulation by the microRNA cluster miR-15b/16 lowered the threshold for ligand-induced activation of the transcription factor NF-κB and the MAPK p38. An additional sustained increase in NOD1 abundance to 1.5-fold over basal amounts bypassed this low ligand concentration requirement, resulting in robust ligand-independent induction of proinflammatory genes and oncogenes. These findings reveal that tight regulation of NOD1 abundance prevents this sensor from exceeding a physiological switching checkpoint that promotes persistent inflammation and oncogene expression. Furthermore, our data provide insight into how a quantitatively small change in protein abundance can produce marked changes in cell state that can serve as the initiator of disease.
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Affiliation(s)
| | | | - Bhaskar Dutta
- Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892-0421, USA
| | | | - Nicolas W Lounsbury
- Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892-0421, USA
| | | | - Ram Savan
- Department of Immunology, University of Washington, Seattle, WA 98109, USA
| | - Iain D C Fraser
- Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892-0421, USA
| | - Ronald N Germain
- Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892-0421, USA
| | - Naeha Subramanian
- Institute for Systems Biology, Seattle, WA 98109, USA. .,Department of Immunology, University of Washington, Seattle, WA 98109, USA.,Department of Global Health, University of Washington, Seattle, WA 98109, USA
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11
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Mravec B, Horvathova L, Hunakova L. Neurobiology of Cancer: the Role of β-Adrenergic Receptor Signaling in Various Tumor Environments. Int J Mol Sci 2020; 21:ijms21217958. [PMID: 33114769 PMCID: PMC7662752 DOI: 10.3390/ijms21217958] [Citation(s) in RCA: 63] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Revised: 10/21/2020] [Accepted: 10/26/2020] [Indexed: 12/13/2022] Open
Abstract
The development and progression of cancer depends on both tumor micro- and macroenvironments. In addition, psychosocial and spiritual “environments” might also affect cancer. It has been found that the nervous system, via neural and humoral pathways, significantly modulates processes related to cancer at the level of the tumor micro- and macroenvironments. The nervous system also mediates the effects of psychosocial and noetic factors on cancer. Importantly, data accumulated in the last two decades have clearly shown that effects of the nervous system on cancer initiation, progression, and the development of metastases are mediated by the sympathoadrenal system mainly via β-adrenergic receptor signaling. Here, we provide a new complex view of the role of β-adrenergic receptor signaling within the tumor micro- and macroenvironments as well as in mediating the effects of the psychosocial and spiritual environments. In addition, we describe potential preventive and therapeutic implications.
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Affiliation(s)
- Boris Mravec
- Institute of Physiology, Faculty of Medicine, Comenius University, 813 72 Bratislava, Slovakia
- Biomedical Research Center, Institute of Experimental Endocrinology, Slovak Academy of Sciences, 814 39 Bratislava, Slovakia;
- Correspondence: ; Tel.: +421-(2)-59357527; Fax: +421-(2)-59357601
| | - Lubica Horvathova
- Biomedical Research Center, Institute of Experimental Endocrinology, Slovak Academy of Sciences, 814 39 Bratislava, Slovakia;
| | - Luba Hunakova
- Institute of Microbiology, Faculty of Medicine, Comenius University, 811 08 Bratislava, Slovakia;
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12
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He Y, Liu B, Yao P, Shao Y, Cheng Y, Zhao J, Wu J, Zhao ZW, Huang W, Christopher TA, Lopez B, Ma X, Cao Y. Adiponectin inhibits cardiac arrest/cardiopulmonary resuscitation‑induced apoptosis in brain by increasing autophagy involved in AdipoR1‑AMPK signaling. Mol Med Rep 2020; 22:870-878. [PMID: 32468051 PMCID: PMC7339636 DOI: 10.3892/mmr.2020.11181] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2019] [Accepted: 04/04/2020] [Indexed: 02/05/2023] Open
Abstract
Emerging evidence suggests that both apoptosis and autophagy contribute to global cerebral ischemia‑reperfusion (GCIR)‑induced neuronal death, which results from cardiac arrest (CA). However, the mechanism of how GCIR may affect the balance between apoptosis and autophagy resulting from CA remains to be elucidated. Additionally, the role of adiponectin (APN) in reversing the apoptosis and autophagy induced by GCIR following cardiac arrest‑cardiopulmonary resuscitation (CA‑CPR) is unclear. Thus, the aim of the present study was to investigate how GCIR affect the apoptosis and autophagy in response to CA and to clarify whether APN may alter the apoptosis and autophagy of neuronal death in GCIR‑injured brain post‑CA‑CPR. Using normal controls (Sham group) and two experimental groups [CA‑CPR‑induced GCIR injury (PCAS) group and exogenous treatment with adiponectin post‑CA‑CPR (APN group)], it was demonstrated that both apoptosis and autophagy were observed simultaneously in the brain subjected to GCIR, but apoptosis appeared to be more apparent. Exogenous administration of APN significantly reduced the formation of malondialdehyde, a marker of oxidative stress and increased the expression of superoxide dismutase, an anti‑oxidative enzyme, resulting in the stimulation of autophagy, inhibition of apoptosis and reduced brain tissue injury (P<0.05 vs. PCAS). APN treatment increased the expression of APN receptor 1 (AdipR1) and the phosphorylation of AMP‑activated protein kinase (AMPK; Ser182) in brain tissues. In conclusion, GCIR induced apoptosis and inhibited autophagy, contributing to brain injury in CA‑CPR. By contrast, APN reduced the brain injury by reversing the changes of neuronal autophagy and apoptosis induced by GCIR. The possible mechanism might owe to its effects on the activation of AMPK after combining with AdipR1 on neurons, which suggests a novel intervention against GCIR injury in CA‑CPR conditions.
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Affiliation(s)
- Yarong He
- Emergency Medicine Department, West China Hospital, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Bofu Liu
- Emergency Medicine Department, West China Hospital, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Peng Yao
- Emergency Medicine Department, West China Hospital, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Yuming Shao
- Emergency Medicine Department, West China Hospital, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Yanwei Cheng
- Emergency Medicine Department, West China Hospital, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Jie Zhao
- Emergency Medicine Department, West China Hospital, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Jiang Wu
- West China Clinical Medical School, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Zhi Wei Zhao
- West China School of Preclinical and Forensic Medicine, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Wen Huang
- Laboratory of Ethnopharmacology, Regenerative Medicine Research Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Theodore A Christopher
- Emergency Medicine Department, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Bernard Lopez
- Emergency Medicine Department, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Xinliang Ma
- Emergency Medicine Department, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Yu Cao
- Emergency Medicine Department, West China Hospital, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
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13
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The Gastrointestinal Tumor Microenvironment: An Updated Biological and Clinical Perspective. JOURNAL OF ONCOLOGY 2019; 2019:6240505. [PMID: 31885581 PMCID: PMC6893275 DOI: 10.1155/2019/6240505] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 05/31/2019] [Accepted: 10/30/2019] [Indexed: 12/24/2022]
Abstract
Gastrointestinal cancers are still responsible for high numbers of cancer-related deaths despite advances in therapy. Tumor-associated cells play a key role in tumor biology, by supporting or halting tumor development through the production of extracellular matrix, growth factors, cytokines, and extracellular vesicles. Here, we review the roles of these tumor-associated cells in the initiation, angiogenesis, immune modulation, and resistance to therapy of gastrointestinal cancers. We also discuss novel diagnostic and therapeutic strategies directed at tumor-associated cells and their potential benefits for the survival of these patients.
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14
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Nandi B, Talluri S, Kumar S, Yenumula C, Gold JS, Prabhala R, Munshi NC, Shammas MA. The roles of homologous recombination and the immune system in the genomic evolution of cancer. ACTA ACUST UNITED AC 2018; 5. [PMID: 30873294 PMCID: PMC6411307 DOI: 10.15761/jts.1000282] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
A variety of factors, whether extracellular (mutagens/carcinogens and viruses in the environment, chronic inflammation and radiation associated with the environment and/or electronic devices/machines) and/or intracellular (oxidative metabolites of food, oxidative stress due to inflammation, acid production, replication stress, DNA replication/repair errors, and certain hormones, cytokines, growth factors), pose a constant threat to the genomic integrity of a living cell. However, in the normal cellular environment multiple biological pathways including DNA repair, cell cycle, apoptosis and the immune system work in a precise, regulated (tightly controlled), timely and concerted manner to ensure genomic integrity, stability and proper functioning of a cell. If damage to DNA takes place, it is efficiently and accurately repaired by the DNA repair systems. Homologous recombination (HR) which utilizes either a homologous chromosome (in G1 phase) or a sister chromatid (in G2) as a template to repair the damage, is known to be the most precise repair system. HR in G2 which utilizes a sister chromatid as a template is also called an error free repair system. If DNA damage in a cell is so extensive that it overwhelms the repair system/s, the cell is eliminated by apoptosis. Thus, multiple pathways ensure that genome of a cell is intact and stable. However, constant exposure to DNA damage and/or dysregulation of DNA repair mechanism/s poses a risk of mutation and cancer. Oncogenesis, which seems to be a multistep process, is associated with acquisition of a number of genomic changes that enable a normal cell to progress from benign to malignant transformation. Transformed/cancer cells are recognized and killed by the immune system. However, the ongoing acquisition of new genomic changes enables cancer cells to survive/escape immune attack, evolve into a more aggressive phenotype, and eventually develop resistance to therapy. Although DNA repair (especially the HR) and the immune system play unique roles in preserving genomic integrity of a cell, they can also contribute to DNA damage, genomic instability and oncogenesis. The purpose of this article is to highlight the roles of DNA repair (especially HR) and the immune system in genomic evolution, with special focus on gastrointestinal cancer.
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Affiliation(s)
- B Nandi
- Harvard Medical School and Brigham and Women's Hospital, USA.,Researh Services, VA Healthcare System, West Roxbury, MA, USA
| | - S Talluri
- Harvard (Dana Farber) Cancer Institute, Boston, MA, USA.,Researh Services, VA Healthcare System, West Roxbury, MA, USA
| | - S Kumar
- Harvard (Dana Farber) Cancer Institute, Boston, MA, USA.,Harvard Medical School and Brigham and Women's Hospital, USA
| | - C Yenumula
- Harvard Medical School and Brigham and Women's Hospital, USA.,Researh Services, VA Healthcare System, West Roxbury, MA, USA
| | - J S Gold
- Harvard Medical School and Brigham and Women's Hospital, USA.,Surgery Services, VA Healthcare System, West Roxbury, MA, USA
| | - R Prabhala
- Harvard (Dana Farber) Cancer Institute, Boston, MA, USA.,Researh Services, VA Healthcare System, West Roxbury, MA, USA
| | - N C Munshi
- Harvard (Dana Farber) Cancer Institute, Boston, MA, USA.,Harvard Medical School and Brigham and Women's Hospital, USA.,Researh Services, VA Healthcare System, West Roxbury, MA, USA
| | - M A Shammas
- Harvard (Dana Farber) Cancer Institute, Boston, MA, USA.,Researh Services, VA Healthcare System, West Roxbury, MA, USA
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15
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Tada H, Kishida T, Fujiwara H, Kosuga T, Konishi H, Komatsu S, Shiozaki A, Ichikawa D, Okamoto K, Otsuji E, Mazda O. Reprogrammed chondrocytes engineered to produce IL-12 provide novel ex vivo immune-gene therapy for cancer. Immunotherapy 2017; 9:239-248. [PMID: 28231722 DOI: 10.2217/imt-2016-0004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
AIM The somatic cell reprogramming technology was applied to a novel and promising ex vivo immune-gene therapy strategy for cancer. To establish a novel ex vivo cytokine gene therapy of cancer using the somatic cell reprogramming procedures. METHODS Mouse fibroblasts were converted into chondrocytes and subsequently transduced with IL-12 gene. The resultant IL-12 induced chondrogenic cells were irradiated with x-ray and inoculated into mice bearing CT26 colon cancer. RESULTS The irradiation at 20 Gy or higher totally eliminated the proliferative potential of the cells, while less significantly influencing the IL-12 production from the cells. An inoculation of the irradiated IL-12 induced chondrogenic cells significantly suppressed tumor by inducing tumor-specific cytotoxic T lymphocytes, enhancing natural killer tumoricidal activity and inhibiting tumor neoangiogenesis in the mice. CONCLUSION The somatic cell reprogramming procedures may provide a novel and effective means to treat malignancies.
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Affiliation(s)
- Hiroyuki Tada
- Department of Immunology, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan.,Division of Digestive Surgery, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Tsunao Kishida
- Department of Immunology, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Hitoshi Fujiwara
- Division of Digestive Surgery, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Toshiyuki Kosuga
- Division of Digestive Surgery, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Hirotaka Konishi
- Division of Digestive Surgery, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Shuhei Komatsu
- Division of Digestive Surgery, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Atsushi Shiozaki
- Division of Digestive Surgery, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Daisuke Ichikawa
- Division of Digestive Surgery, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Kazuma Okamoto
- Division of Digestive Surgery, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Eigo Otsuji
- Division of Digestive Surgery, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Osam Mazda
- Department of Immunology, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
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16
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Abstract
Gastrointestinal (GI) cancers such as gastric, esophageal, pancreas, hepatobiliary, colorectal and anal cancers are a major cause of cancer related mortality worldwide. Traditional treatment options such as chemotherapy, surgery, radiation therapy, monoclonal antibodies and anti-angiogenic agents have been the backbone of treatment of GI cancers in various stages. Current cancer research is moving forward to incorporate immunotherapies in the treatment of GI cancers either as single agent or in combination with current available treatment modalities. This review summarizes the existing and ongoing immunotherapies in the treatment of GI cancers.
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Affiliation(s)
- Patrick Grierson
- Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, Saint Louis, MO, USA
| | - Kian-Huat Lim
- Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, Saint Louis, MO, USA
| | - Manik Amin
- Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, Saint Louis, MO, USA
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17
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Frey AB. Suppression of T cell responses in the tumor microenvironment. Vaccine 2015; 33:7393-7400. [PMID: 26403368 DOI: 10.1016/j.vaccine.2015.08.096] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2015] [Revised: 07/06/2015] [Accepted: 08/05/2015] [Indexed: 12/29/2022]
Abstract
The immune system recognizes protein antigens expressed in transformed cells evidenced by accumulation of antigen-specific T cells in tumor and tumor draining lymph nodes. However, despite demonstrable immune response, cancers grow progressively suggesting that priming of antitumor immunity is insufficiently vigorous or that antitumor immunity is suppressed, or both. Compared to virus infection, antitumor T cells are low abundance that likely contributes to tumor escape and enhancement of priming is a long-sought goal of experimental vaccination therapy. Furthermore, patient treatment with antigen-specific T cells can in some cases overcome deficient priming and cause tumor regression supporting the notion that low numbers of T cells permits tumor outgrowth. However, tumor-induced suppression of antitumor immune response is now recognized as a significant factor contributing to cancer growth and reversal of the inhibitory influences within the tumor microenvironment is a major research objective. Multiple cell types and factors can inhibit T cell functions in tumors and may be grouped in two general classes: T cell intrinsic and T cell extrinsic. T cell intrinsic factors are exemplified by T cell expression of cell surface inhibitory signaling receptors that, after contact with cells expressing a cognate ligand, inactivate proximal T Cell Receptor-mediated signal transduction therein rendering T cells dysfunctional. T cell extrinsic factors are more diverse in nature and are produced by tumors and various non-tumor cells in the tumor microenvironment. These include proteins secreted by tumor or stromal cells, highly reactive soluble oxygen and nitrogen species, cytokines, chemokines, gangliosides, and toxic metabolites. These factors may restrict T cell entrance into the tumor parenchyma, cause inactivation of effector phase T cell functions, or induce T cell apoptosis ultimately causing diminished cancer elimination. Here, we review the contributions of inhibitory factors to tumor T cell dysfunction leading to tumor escape.
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Affiliation(s)
- Alan B Frey
- Department of Cell Biology, Perlmutter Cancer Center, New York University Langone School of Medicine, 550 First Avenue, New York, NY 10016, USA.
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18
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Li Y, Xu DF, Jiang D, Zhao J, Ge JF, Zheng SY. Significance of Fas and FasL protein expression in cardiac carcinoma and local lymph node tissues. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2015; 8:11915-11920. [PMID: 26617948 PMCID: PMC4637764] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 07/15/2015] [Accepted: 08/25/2015] [Indexed: 06/05/2023]
Abstract
OBJECTIVE To investigate the relation of Fas and Fas ligand (FasL) protein expression with carcinogenesis and metastasis of cardiac carcinoma. METHODS Immunohistochemistry was used to detect Fas and FasL protein expression in 64 cardiac carcinoma tissue samples and 20 normal gastric tissue samples. Relation between FasL and Fas expression, age and gender of gastric cancer patients, and pathological subtype and lymph node metastasis of gastric cancer was analyzed. RESULTS The Fas expression level was significantly higher in normal gastric tissue samples than in cardiac carcinoma tissue samples (85.0% vs. 25.0%, P<0.001), while the FasL expression level was significantly lower in normal gastric tissue samples than in cardiac carcinoma tissue samples (30.0% vs. 81.3%, P<0.001). The Fas expression level was significantly higher in invasive lymph nodes than in non-invasive lymph nodes (82.9% vs. 56.5%, P<0.003) and in well-differentiated gastric carcinoma tissue samples than in poorly-differentiated cardiac carcinoma tissue samples (50.0% vs. 18.0%, P=0.015). The FasL expression level was significantly lower in well-differentiated cardiac carcinoma tissue samples than in poorly- differentiated cardiac carcinoma tissue samples (42.9% vs. 84.0%, P=0.021). The Fas and FasL expression levels (25.0% and 81.3%) were significantly different in cardiac carcinoma tissue samples (P<0.001), but had a non-linear correlation (P=0.575). CONCLUSION Abnormal Fas and FasL expressions in cardiac carcinoma and lymph node tissues are involved in carcinogenesis and metastasis of gastric cancer.
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Affiliation(s)
- Yin Li
- Department of Thoracic Surgery, The Tumor Hospital of HenanZhengzhou 450008, Henan Province, P. R. China
| | - Da-Fu Xu
- Department of Cardio-Thoracic Surgery, The First Affiliated Hospital of Soochow UniversitySuzhou 215006, Jiangsu Province, China
- Huai’an First People’s Hospital, Nanjing Madical UniversityHuaian 223300, Jiangsu Province, China
| | - Dong Jiang
- Department of Cardio-Thoracic Surgery, The First Affiliated Hospital of Soochow UniversitySuzhou 215006, Jiangsu Province, China
| | - Jun Zhao
- Department of Cardio-Thoracic Surgery, The First Affiliated Hospital of Soochow UniversitySuzhou 215006, Jiangsu Province, China
| | - Jin-Feng Ge
- Department of Cardio-Thoracic Surgery, The First Affiliated Hospital of Soochow UniversitySuzhou 215006, Jiangsu Province, China
| | - Shi-Ying Zheng
- Department of Cardio-Thoracic Surgery, The First Affiliated Hospital of Soochow UniversitySuzhou 215006, Jiangsu Province, China
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FasL -844T/C and Fas -1377G/A: mutations of pulmonary adenocarcinoma in South China and their clinical significances. Tumour Biol 2015; 36:4319-26. [PMID: 25596086 PMCID: PMC4529455 DOI: 10.1007/s13277-015-3071-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2014] [Accepted: 01/08/2015] [Indexed: 11/22/2022] Open
Abstract
Apoptosis is an important mechanism of malignant tumor formation and progression. Single nucleotide polymorphisms (SNPs) located within cell death genes may influence cancer risk. We explored the relationship between FasL −844T/C and/or Fas −1377G/A SNPs and pulmonary adenocarcinoma (AD). Two hundred seventy-five patients with pulmonary AD of South China admitted into Zhejiang Cancer Hospital from July 2007 to October 2011 were randomly selected, and their clinicopathological data were collected at the same time. Two hundred ninety-seven cases of healthy individuals were selected as control. FasL −844T/C and Fas −1377G/A SNPs were detected by PCR-RFLP technique to evaluate the relationships between these two SNPs and pulmonary AD. Age, FasL −844 and Fas −1377 SNPs were associated with increased risk of pulmonary AD susceptibility in main effect analysis. FasL −844CC and Fas −1377 AA were associated with an increased risk for the development of pulmonary AD only in age <60 years people, but not in those ≥60 years. FasL −844CC genotype was associated with an increased risk for pulmonary AD (adjusted OR = 2.010, 95 % CI 1.196–3.379, P = 0.008) compared with TT genotype. However, Fas −1377 AA was a risk factor only when FasL −844 genotype was CC. Fas −1377 genotypes showed significant effect modification of pulmonary AD risk by FasL −844 genotype with test of the interaction term adjusting for age, gender, and FasL −844 SNP. Fas −1377G/A was not associated with the clinicopathological factors, while FasL −844C/T was associated with tumor stage and lymph node metastasis in age ≥60 years people and tumor stage in those <60 years. In conclusion, FasL −844 SNP is associated with the susceptibility of pulmonary AD in age <60 years people. Fas −1377 SNP may modify the association of FasL −844 SNP with the risk of pulmonary AD. FasL −844 genotype plays an important role in the occurrence and progression of pulmonary AD.
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20
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Dong B, Dai G, Xu L, Zhang Y, Ling L, Sun L, Lv J. Tumor cell lysate induces the immunosuppression and apoptosis of mouse immunocytes. Mol Med Rep 2014; 10:2827-34. [PMID: 25310154 PMCID: PMC4227419 DOI: 10.3892/mmr.2014.2606] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2014] [Accepted: 06/10/2014] [Indexed: 11/05/2022] Open
Abstract
Although tumor cell lysate (TCL) is a type of immunocyte stimulator, its immunosuppressive function must not be ignored. The present study reported that TCL prepared from a Lewis lung cancer cell was able to induce the development of immunosuppressive macrophages (MΦ) and tolerogenic dendritic cells. In addition, TCL upregulated the expression of CD69 in mouse splenocytes, and cell apoptosis and the percentage of regulatory T cells in mouse splenocytes simultaneously increased. Furthermore, the present study found that the immunosuppressive factor, hyaluronan, and the apoptosis inducers, Fas ligand and transforming growth factor-β, are present in TCL. These components may be associated with the emergence of immunosuppressive cells or splenocyte apoptosis. Thus, the present study has enriched our understanding of the composition of TCL and its negative regulatory effect on immunocytes.
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Affiliation(s)
- Bohan Dong
- Department of Biochemistry, Wannan Medical College, Wuhu, Anhui 241002, P.R. China
| | - Guangli Dai
- Department of Gynaecology and Obstetrics, Traditional Chinese Medical Hospital of Wuhu, Wuhu, Anhui 241000, P.R. China
| | - Lei Xu
- Department of Biochemistry, Wannan Medical College, Wuhu, Anhui 241002, P.R. China
| | - Yao Zhang
- Department of Biochemistry, Wannan Medical College, Wuhu, Anhui 241002, P.R. China
| | - Liefeng Ling
- Department of Biochemistry, Wannan Medical College, Wuhu, Anhui 241002, P.R. China
| | - Lingling Sun
- Department of Biochemistry, Wannan Medical College, Wuhu, Anhui 241002, P.R. China
| | - Jun Lv
- Department of Biochemistry, Wannan Medical College, Wuhu, Anhui 241002, P.R. China
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21
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Gryko M, Guzińska-Ustymowicz K, Kiśluk J, Cepowicz D, Kemona A, Kędra B. High Fas expression in gastric carcinoma cells as a factor correlating with the occurrence of metastases to regional lymph nodes. Adv Med Sci 2014; 59:47-51. [PMID: 24797974 DOI: 10.1016/j.advms.2013.07.005] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2012] [Accepted: 07/23/2013] [Indexed: 02/06/2023]
Abstract
PURPOSE The aim of this study was to evaluate the correlation of the expression of Fas and Fas-L proteins in gastric carcinoma cells on the occurrence of metastases to regional lymph nodes. MATERIAL/METHODS The study included 89 patients treated surgically for gastric carcinoma. The evaluated clinicomorphological parameters were verified based on both histopathological material collected at surgery and intraoperative image. Fas and Fas-L expression was evaluated immunohistochemically in the neoplastic tissue of the removed gastric tumors. RESULTS A statistically significant positive correlation between Fas expression in gastric carcinoma cells and the number of regional lymph nodes affected by metastases was observed (p<0.05). No such correlation was noticed with respect to Fas-L. A statistically significant correlation between the depth of neoplastic infiltration of the stomach wall (T feature) and the number of affected lymph nodes was observed (p<0.05). No statistically significant correlations in the other examined clinicomorphological features and the number of metastatic lymph nodes was observed. CONCLUSION A positive Fas expression correlates with more frequent occurrence of metastases to regional lymph nodes. Determination of this protein expression in cancer cells prior to surgery may be helpful for planning the surgical procedure, especially with respect to the extent of lymph node excision.
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Affiliation(s)
- Mariusz Gryko
- 2nd Department of General and Gastroenterological Surgery, Medical University of Bialystok, Bialystok, Poland
| | | | - Joanna Kiśluk
- Department of General Pathomorphology, Medical University of Bialystok, Bialystok, Poland
| | - Dariusz Cepowicz
- 2nd Department of General and Gastroenterological Surgery, Medical University of Bialystok, Bialystok, Poland
| | - Andrzej Kemona
- Department of General Pathomorphology, Medical University of Bialystok, Bialystok, Poland
| | - Bogusław Kędra
- 2nd Department of General and Gastroenterological Surgery, Medical University of Bialystok, Bialystok, Poland
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22
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FasL gene -844T/C mutation of esophageal cancer in South China and its clinical significance. Sci Rep 2014; 4:3866. [PMID: 24473454 PMCID: PMC5379236 DOI: 10.1038/srep03866] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2013] [Accepted: 01/07/2014] [Indexed: 01/22/2023] Open
Abstract
In this study, we investigated the association between the FasL -844T/C polymorphism and the risk of developing esophageal squamous cell carcinoma (ESCC) in South China. For the investigation, we randomly selected 248 patients suffering from ESCC from Southern China along with 297 healthy individuals as the control group. The relationship between the FasL gene -844T/C SNP and ESCC was studied using PCR-RFLP and immunohistochemistry. The Fas -1377G/A SNP was also selected for investigation to detect whether it interferes with the functional effect of the FasL -844C/T polymorphism in ESCC development. A significant difference in the FasL -844T/C genotypes between the patients and the control group was observed (P<0.05), with those expressing the C allele having a significantly reduced risk of developing ESCC, however younger patients (<60 years) exhibited a more
malignant pathological T grade if they were homozygous for the C allele. FasL -844 CC combined with the Fas -1377 G allele is a protective factor against ESCC. Having said this, even though the C allele has a protective effect prior to development of ESCC, once the host does develop the condition the tumour will develop faster and have a higher degree of malignancy than T carriers.
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Yuan YL, Liu AQ, Feng J, Chen JW, Ge LY. Effects of FAF1 overexpression on proliferation and apoptosis of gastric carcinoma HGC-27 cells. Shijie Huaren Xiaohua Zazhi 2014; 22:17-23. [DOI: 10.11569/wcjd.v22.i1.17] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the influence of the overexpression of Fas-associated factor 1 (FAF1) on cell proliferation and apoptosis in human gastric cancer cell line HGC-27 to explore the relationship between FAF1 and gastric cancer.
METHODS: HGC-27 cells were divided into three groups: a negative control group, an empty vector transfection group (those transfected with empty vector particles 1.0 × 108 TU/mL), and a FAF1 overexpression group (those transfected with recombinant FAF1 lentiviral particles 1.0 × 108 TU/mL). Transfection efficiency was detected by laser scanning confocal microscopy. Protein expression level of FAF1 was detected by Western blot. Changes of cell ultrastructure were detected by transmission electron microscopy. Cell cycle distribution and apoptosis were observed by flow cytometry. Cell proliferation was detected by MTT assay.
RESULTS: The transfection efficiency was greater than 95% according to the green fluorescence. The expression of FAF1 protein was significantly higher in the FAF1 overexpression group than in the two control groups. The cell ultrastructure was normal in the two control groups; however, in the FAF1 overexpression group, cell nuclei split into pieces and apoptotic bodies and vacuoles formed. Overexpression of FAF1 inhibited HGC-27 cell growth, induced cell apoptosis, and changed the cell cycle progression. Compared to the negative control group and empty vector transfection group, cell doubling time was significantly extended, cell apoptosis was significantly increased (84.66% ± 5.92% vs 4.60% ± 3.80%, 7.32% ± 3.82%, both P < 0.05), the percentage of cells in G0/G1 phase was significantly decreased (46.43% ± 2.43% vs 54.93% ± 3.5%, 54% ± 0.3%, both P < 0.05), and the percentage of cells in G2/M phase was significantly increased (29.78% ± 3.91% vs 19.33% ± 3.82%, 20.93% ± 2.46%, both P < 0.05) in the FAF1 overexpression group.
CONCLUSION: FAF1 overexpression could inhibit cell growth, induce cell apoptosis, and change cell cycle progression.
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24
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Cheng B. Association between up-regulation of Fas ligand expression and apoptosis of tumor-infiltrating lymphocytes in human breast cancer. ACTA ACUST UNITED AC 2013; 26:573-5. [PMID: 17219972 DOI: 10.1007/s11596-006-0524-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
In order to study the significance of FasL expression in immune escape of breast cancer, FasL protein expression and the number of tumor-infiltrating lymphocytes (TILs) in 40 specimens of breast cancer were detected by immunohistochemitry. The expression of FasL mRNA was measured by in situ hybridization in the consecutive tissue slices of 40 breast cancers respectively. By using terminal deoxynucleotidyl transferase-mediaed dUTP nick end labeling (TUNEL), apoptotic cells were detected in 40 specimens of breast cancer. The expression of FasL was detected in all 40 specimens to varying degrees. In the consecutive tissue slices, the location of expression of FasL protein corresponded with that of FasL mRNA. In those with FasL extensive expression, the number of TILs was less (P<0.05), the apoptotic index (AI) of TILs was higher and the AI of tumor cells was lower (P<0.01) than those with FasL weak expression respectively. The AI of TILs was correlated with that of tumor cells (r= -0.629, P<0.01). In conclusion, breast cancer cells can induce the apoptosis of TILs through the expression of FasL, which can counterattack the immune system. This may be a mechanism of immune evasion in breast cancer.
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Affiliation(s)
- Bo Cheng
- Department of General Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
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25
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Cao A, Li Q, Yin P, Dong Y, Shi H, Wang L, Ji G, Xie J, Wu D. Curcumin induces apoptosis in human gastric carcinoma AGS cells and colon carcinoma HT-29 cells through mitochondrial dysfunction and endoplasmic reticulum stress. Apoptosis 2013; 18:1391-1402. [PMID: 23881281 DOI: 10.1007/s10495-013-0871-1] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
In the present study, we investigate the effect of curcumin, a major active component isolated from rhizomes of Curcuma longa, on the cytotoxicity of three human carcinoma cell lines (AGS, HT-29 and MGC803) in gastrointestinal tract and a normal gastric epithelial cell line GES-1, and the mechanism of curcumin-induced apoptosis. The results indicated that curcumin inhibited the gastrointestinal carcinoma cell growth in a dose-dependent manner and cytotoxicity was more towards the gastric carcinoma cell AGS and colon carcinoma cell HT-29 compared to normal gastric cell GES-1, and increased externalization of phosphatidylserine residue was observed by Annexin V/PI staining in the two cell lines. Treatment of AGS and HT-29 cells with curcumin enhanced the cleavage of procaspase-3, -7, -8 and -9. Meanwhile, curcumin induced endoplasmic reticulum (ER) stress and mitochondrial dysfunction as evidenced by up-regulation of CCAAT/enhancer binding protein homologous protein (CHOP), phosphorylation of JNK and down-regulation of SERCA2ATPase, release of cytochrome c, decrease of Bcl-2 and reduction of mitochondrial membrane potential in both AGS and HT-29 cells. Overexpression of bax, total JNK, phospho-FADD and total FADD were also observed in curcumin-treated HT-29 cells. Moreover, curcumin decreased cytosolic and ER Ca(2+), but increased mitochondrial Ca(2+) in the two cell lines. 2-Aminoethoxydiphenyl borate, an antagonist of inositol 1, 4, 5-triphosphate receptor, partly blocked curcumin-induced cytosolic Ca(2+) decrease in AGS and HT-29 cells. Additionally, carbonyl cyanide m-chlorophenylhydrazone, an inhibitor of mitochondrial Ca(2+) uptake, reversed curcumin-triggered AGS and HT-29 cells growth inhibition. siRNA to CHOP markedly reduced curcumin-induced apoptosis. These results suggest that curcumin can impact on ER stress and mitochondria functional pathways in AGS and HT-29 cells, death receptor pathway was also involved in curcumin-treated HT-29 cells, thus identifying specific well-defined molecular mechanisms that may be targeted by therapeutic strategies.
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Affiliation(s)
- Aili Cao
- Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Qi Li
- Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200062, China
| | - Peihao Yin
- Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200062, China
| | - Yang Dong
- Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Hailian Shi
- Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Li Wang
- Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200062, China
| | - Guang Ji
- Institute of Digestive Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China
| | - Jianqun Xie
- Institute of Digestive Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China.
| | - Dazheng Wu
- Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
- Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200062, China.
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Jin Y, Da W. Screening of key genes in gastric cancer with DNA microarray analysis. Eur J Med Res 2013; 18:37. [PMID: 24093889 PMCID: PMC3852022 DOI: 10.1186/2047-783x-18-37] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2013] [Accepted: 09/05/2013] [Indexed: 12/23/2022] Open
Abstract
Background The aim of this study was to identify key genes and novel potential therapeutic targets related to gastric cancer (GC) by comparing cancer tissue samples and healthy control samples using DNA microarray analysis. Methods Microarray data set GSE19804 was downloaded from Gene Expression Omnibus. Preprocessing and differential analysis were conducted with of R statistical software packages, and a number of differentially expressed genes (DEGs) were obtained. Cluster analysis was also done with gene expression values. Functional enrichment analysis was performed for all the DEGs with DAVID tools. The significantly up- and downregulated genes were selected out and their interactors were retrieved with STRING and HitPredict, followed by construction of networks. For all the genes in the two networks, GeneCodis was chosen for gene function annotation. Results A total of 638 DEGs were identified, and we found that SPP1 and FABP4 were the markedly up- and downregulated genes, respectively. Cell cycle and regulation of proliferation were the most significantly overrepresented functional terms in up- and downregulated genes. In addition, extracellular matrix–receptor interaction was found to be significant in the SPP1-included interaction network. Conclusions A range of DEGs were obtained for GC. These genes not only provided insights into the pathogenesis of GC but also could develop into biomarkers for diagnosis or treatment.
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Affiliation(s)
- Yong Jin
- Department of gastroenterology, The 6th People's Hospital affiliated to Shanghai Jiaotong University, No, 600 Yishan Road, Shanghai 200233, China.
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Man YG, Stojadinovic A, Mason J, Avital I, Bilchik A, Bruecher B, Protic M, Nissan A, Izadjoo M, Zhang X, Jewett A. Tumor-infiltrating immune cells promoting tumor invasion and metastasis: existing theories. J Cancer 2013; 4:84-95. [PMID: 23386907 PMCID: PMC3564249 DOI: 10.7150/jca.5482] [Citation(s) in RCA: 144] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2012] [Accepted: 12/20/2012] [Indexed: 12/12/2022] Open
Abstract
It is a commonly held belief that infiltration of immune cells into tumor tissues and direct physical contact between tumor cells and infiltrated immune cells is associated with physical destructions of the tumor cells, reduction of the tumor burden, and improved clinical prognosis. An increasing number of studies, however, have suggested that aberrant infiltration of immune cells into tumor or normal tissues may promote tumor progression, invasion, and metastasis. Neither the primary reason for these contradictory observations, nor the mechanism for the reported diverse impact of tumor-infiltrating immune cells has been elucidated, making it difficult to judge the clinical implications of infiltration of immune cells within tumor tissues. This mini-review presents several existing hypotheses and models that favor the promoting impact of tumor-infiltrating immune cells on tumor invasion and metastasis, and also analyzes their strength and weakness.
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Affiliation(s)
- Yan-gao Man
- 1. Diagnostic and Translational Research Center, Henry Jackson Foundation, Gaithersburg, MD, USA
- 2. College of Animal Science and Veterinary Medicine, Jilin University, Changchun, Jilin, China
| | - Alexander Stojadinovic
- 3. Surgical Oncology, Walter Reed National Military Medical Center, and Uniformed Services University of the Health Sciences, Bethesda, MD, USA
| | - Jeffrey Mason
- 4. Veterans Affair Medical Center, Washington, DC, USA
| | - Itzhak Avital
- 5. Bon Secours National Cancer Institute (BSNCI), Richmond VA, USA
| | - Anton Bilchik
- 6. John Wayne Cancer Institute; California Oncology Research Institute; and, David Geffen School of Medicine, University of California, Los Angeles, USA
| | | | - Mladjan Protic
- 8. Clinic of Abdominal, Endocrine, and Transplantation Surgery, Clinical Center of Vojvodina, University of Novi Sad - Medical Faculty, Novi Sad, Serbia
| | - Aviram Nissan
- 9. The Surgical Oncology Laboratory, Department of Surgery, Hadassah-Hebrew University Medical Center, Mount Scopus, Jerusalem, Israel
| | - Mina Izadjoo
- 1. Diagnostic and Translational Research Center, Henry Jackson Foundation, Gaithersburg, MD, USA
| | - Xichen Zhang
- 2. College of Animal Science and Veterinary Medicine, Jilin University, Changchun, Jilin, China
| | - Anahid Jewett
- 10. Division of Oral Biology and Medicine, Jonsson Comprehensive Cancer Center, UCLA School of Dentistry, Los Angeles, CA, USA
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Attack the Tumor Counterattack-C-Flip Expression in Jurkat-T-Cells Protects Against Apoptosis Induced by Coculture with SW620 Colorectal Adenocarcinoma Cells. J Surg Res 2012; 176:133-40. [DOI: 10.1016/j.jss.2011.06.023] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2011] [Revised: 06/01/2011] [Accepted: 06/10/2011] [Indexed: 11/22/2022]
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Wu J, Richards MH, Huang J, Al-Harthi L, Xu X, Lin R, Xie F, Gibson AW, Edberg JC, Kimberly RP. Human FasL gene is a target of β-catenin/T-cell factor pathway and complex FasL haplotypes alter promoter functions. PLoS One 2011; 6:e26143. [PMID: 22022540 PMCID: PMC3191176 DOI: 10.1371/journal.pone.0026143] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2011] [Accepted: 09/20/2011] [Indexed: 01/01/2023] Open
Abstract
FasL expression on human immune cells and cancer cells plays important roles in immune homeostasis and in cancer development. Our previous study suggests that polymorphisms in the FasL promoter can significantly affect the gene expression in human cells. In addition to the functional FasL SNP -844C>T (rs763110), three other SNPs (SNP -756A>G or rs2021837, SNP -478A>T or rs41309790, and SNP -205 C>G or rs74124371) exist in the proximal FasL promoter. In the current study, we established three major FasL hyplotypes in humans. Interestingly, a transcription motif search revealed that the FasL promoter possessed two consensus T-cell factor (TCF/LEF1) binding elements (TBEs), which is either polymorphic (SNP -205C>G) or close to the functional SNP -844C>T. Subsequently, we demonstrate that both FasL TBEs formed complexes with the TCF-4 and β-catenin transcription factors in vitro and in vivo. Co-transfection of LEF-1 and β-catenin transcription factors significantly increased FasL promoter activities, suggesting that FasL is a target gene of the β-catenin/T-cell factor pathway. More importantly, we found that the rare allele (-205G) of the polymorphic FasL TBE (SNP -205C>G) failed to bind the TCF-4 transcription factor and that SNP -205 C>G significantly affected the promoter activity. Furthermore, promoter reporter assays revealed that FasL SNP haplotypes influenced promoter activities in human colon cancer cells and in human T cells. Finally, β-catenin knockdown significantly decreased the FasL expression in human SW480 colon cancer cells. Collectively, our data suggest that β-catenin may be involved in FasL gene regulation and that FasL expression is influenced by FasL SNP haplotypes, which may have significant implications in immune response and tumorigenesis.
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Affiliation(s)
- Jianming Wu
- Department of Veterinary and Biomedical Sciences, University of Minnesota, St. Paul, Minnesota, United States of America.
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Sung WW, Wang YC, Cheng YW, Lee MC, Yeh KT, Wang L, Wang J, Chen CY, Lee H. A polymorphic -844T/C in FasL promoter predicts survival and relapse in non-small cell lung cancer. Clin Cancer Res 2011; 17:5991-5999. [PMID: 21807637 DOI: 10.1158/1078-0432.ccr-11-0227] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PURPOSE Fas ligand (FasL) -844T/C polymorphism (rs763110) has a demonstrated association with lung cancer risk. FasL -844CC with higher FasL expression has been suggested to contribute to tumor progression via immune escape. However, the impact of FasL -844T/C polymorphism on the clinical outcome of non-small cell lung cancer (NSCLC) remains to be identified. EXPERIMENTAL DESIGN A total of 385 adjacent normal lung tissues from patients with NSCLC were collected to determine FasL -844T/C polymorphism by PCR-based restriction fragment length polymorphism. FasL mRNA and protein expression in lung tumors were evaluated by real-time PCR and immunohistochemistry. The prognostic value of FasL -844T/C polymorphism on survival and relapse was determined by Kaplan-Meier analysis and Cox proportional hazards models. RESULTS The FasL -844CC genotype had higher prevalence in those with advanced tumors than in those with early tumors (P = 0.008). In addition, patients with the FasL -844CC genotype were more prone to tumor relapse than those with the FasL -844TT+TC genotype (62.1% vs. 37.9%, P = 0.001). Multivariate Cox regression analysis showed that patients with the FasL -844CC genotype had poorer survival in terms of overall survival (OS) and relapse-free survival (RFS) than those with the FasL -844TT+TC genotype (24.1 vs. 42.8 months for OS, HR = 1.455, P = 0.004; 15.4 vs. 31.4 months for RFS, HR = 1.710, P < 0.001). CONCLUSIONS FasL -844T/C polymorphism may predict survival and relapse in NSCLC. We suggest that FasL may be a molecular target for immunotherapeutic interventions to improve the clinical outcome of patients with NSCLC. This finding should be validated by another investigative group.
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Affiliation(s)
- Wen-Wei Sung
- Institute of Medical & Molecular Toxicology, School of Medicine, Institute of Medicine, and School of Public Health, Chung Shan Medical University, Changhua, Taiwan, ROC
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Du C, Wang Y. The immunoregulatory mechanisms of carcinoma for its survival and development. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2011; 30:12. [PMID: 21255410 PMCID: PMC3031251 DOI: 10.1186/1756-9966-30-12] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/15/2010] [Accepted: 01/21/2011] [Indexed: 12/24/2022]
Abstract
The immune system in patients detects and eliminates tumor cells, but tumors still progress persistently. The mechanisms by which tumor cells survive under the pressure of immune surveillance are not fully understood. This review is to present the evidence from clinical studies, showing a significant correlation of clinicopathological features of carcinoma with: (1) the loss of classical human leukocyte antigen class I, (2) the up-regulation of non-classical human leukocyte antigen class I, pro-apoptotic Fas ligand and receptor-binding cancer antigen expressed on SiSo cells I, and (3) the formation of immunosuppressive microenvironment by up-regulation of transforming growth factor-beta, Galectin-1, inhibitory ligand B7s, indoleamine 2,3-dioxygenase and arginase, as well as by recruitment of tumor-induced myeloid-derived suppressor cells and regulatory T cells. All of these factors may together protect carcinoma cells from the immune-cytotoxicity.
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Affiliation(s)
- Caigan Du
- Department of Urologic Sciences, University of British Columbia, Vancouver, Canada.
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Bourke MG, Salwa S, Harrington KJ, Kucharczyk MJ, Forde PF, de Kruijf M, Soden D, Tangney M, Collins JK, O'Sullivan GC. The emerging role of viruses in the treatment of solid tumours. Cancer Treat Rev 2011; 37:618-32. [PMID: 21232872 DOI: 10.1016/j.ctrv.2010.12.003] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2010] [Revised: 12/04/2010] [Accepted: 12/07/2010] [Indexed: 12/13/2022]
Abstract
There is increasing optimism for the use of non-pathogenic viruses in the treatment of many cancers. Initial interest in oncolytic virotherapy was based on the observation of an occasional clinical resolution of a lymphoma after a systemic viral infection. In many cancers, by comparison with normal tissues, the competency of the cellular anti-viral mechanism is impaired, thus creating an exploitable difference between the tumour and normal cells, as an unimpeded viral proliferation in cancer cells is eventually cytocidal. In addition to their oncolytic capability, these particular viruses may be engineered to facilitate gene delivery to tumour cells to produce therapeutic effects such as cytokine secretion and anti -tumour immune responses prior to the eventual cytolysis. There is now promising clinical experience with these viral strategies, particularly as part of multimodal studies, and already several clinical trials are in progress. The limitations of standard cancer chemotherapies, including their lack of specificity with consequent collateral toxicity and the development of cross-resistance, do not appear to apply to viral-based therapies. Furthermore, virotherapy frequently restores chemoradiosensitivity to resistant tumours and has also demonstrated efficacy against cancers that historically have a dismal prognosis. While there is cause for optimism, through continued improvements in the efficiency and safety of systemic delivery, through the emergence of alternative viral agents and through favourable clinical experiences, clinical trials as part of multimodal protocols will be necessary to define clinical utility. Significant progress has been made and this is now a major research area with an increasing annual bibliography.
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Affiliation(s)
- M G Bourke
- Cork Cancer Research Centre, Leslie C. Quick Jnr. Laboratory, Biosciences Institute, University College Cork, Ireland.
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Nobakht M, Hoseini SM, Mortazavi P, Sohrabi I, Esmailzade B, Roosh NR, Omidzahir S. Neuropathological changes in brain cortex and hippocampus in a rat model of Alzheimer's disease. IRANIAN BIOMEDICAL JOURNAL 2011; 15:51-58. [PMID: 21725500 PMCID: PMC3639737] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 09/05/2010] [Revised: 01/08/2011] [Accepted: 01/15/2011] [Indexed: 05/31/2023]
Abstract
BACKGROUND Alzheimer's disease (AD) is a neurodegenerative disorder with progressive loss of cognitive abilities and memory loss. The aim of this study was to compare neuropathological changes in hippocampus and brain cortex in a rat model of AD. METHODS Adult male Albino Wistar rats (weighing 250-300 g) were used for behavioral and histopathological studies. The rats were randomly assigned to three groups: control, sham and Beta amyloid (ABeta) injection. For behavioral analysis, Y-maze and shuttle box were used, respectively at 14 and 16 days post-lesion. For histological studies, Nissl, modified Bielschowsky and modified Congo red staining were performed. The lesion was induced by injection of 4 muL of ABeta (1-40) into the hippocampal fissure. RESULTS In the present study, ABeta (1-40) injection into hippocampus could decrease the behavioral indexes and the number of CA1 neurons in hippocampus. ABeta injection CA1 caused ABeta deposition in the hippocampus and less than in cortex. We observed the loss of neurons in the hippocampus and cerebral cortex and certain subcortical regions. Y-maze test and single-trial passive avoidance test showed reduced memory retention in AD group. CONCLUSION We found a significant decreased acquisition of passive avoidance and alternation behavior responses in AD group compared to control and sham group (P<0.0001). Compacted amyloid cores were present in the cerebral cortex, hippocampus and white matter, whereas, scattered amyloid cores were seen in cortex and hippocampus of AD group. Also, reduced neuronal density was indicated in AD group.
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Affiliation(s)
- Maliheh Nobakht
- Dept. of Pathology, Faculty of Specialized Veterinary Science, Science and Research Branch Islamic Azad University, Tehran;
- Dept. of Histology and Neuroscience, School of Medicine, Iran University of Medical Sciences, Tehram;
- Anti-Microbial Resistance Research Center, Iran University of Medical Sciences, Tehran;
- Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran;
| | - Seyed Mohammad Hoseini
- Dept. of Pathology, Faculty of Specialized Veterinary Science, Science and Research Branch Islamic Azad University, Tehran;
| | - Pejman Mortazavi
- Dept. of Pathology, Faculty of Specialized Veterinary Science, Science and Research Branch Islamic Azad University, Tehran;
| | - Iraj Sohrabi
- Dept. of Pathology, Faculty of Specialized Veterinary Science, Science and Research Branch Islamic Azad University, Tehran;
| | - Banafshe Esmailzade
- Dept. of Anatomy, School of Medicine, Iran University of Medical Sciences, Tehran;
| | - Nahid Rahbar Roosh
- Dept. of Pathology, Faculty of Specialized Veterinary Science, Science and Research Branch Islamic Azad University, Tehran;
| | - Shila Omidzahir
- Veterinary Medicine, Faculty of Specialized Veterinary Science, Tehran University of Veterinary Sciences, Tehran, Iran
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Drescher KM, Sharma P, Lynch HT. Current hypotheses on how microsatellite instability leads to enhanced survival of Lynch Syndrome patients. Clin Dev Immunol 2010; 2010:170432. [PMID: 20631828 PMCID: PMC2901607 DOI: 10.1155/2010/170432] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2010] [Accepted: 04/13/2010] [Indexed: 01/20/2023]
Abstract
High levels of microsatellite instability (MSI-high) are a cardinal feature of colorectal tumors from patients with Lynch Syndrome. Other key characteristics of Lynch Syndrome are that these patients experience fewer metastases and have enhanced survival when compared to patients diagnosed with microsatellite stable (MSS) colorectal cancer. Many of the characteristics associated with Lynch Syndrome including enhanced survival are also observed in patients with sporadic MSI-high colorectal cancer. In this review we will present the current state of knowledge regarding the mechanisms that are utilized by the host to control colorectal cancer in Lynch Syndrome and why these same mechanisms fail in MSS colorectal cancers.
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Affiliation(s)
- Kristen M Drescher
- Department of Medical Microbiology and Immunology, Creighton University School of Medicine, Omaha, NE 68178, USA.
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Soluble Fas might serve as a diagnostic tool for gastric adenocarcinoma. BMC Cancer 2010; 10:275. [PMID: 20534173 PMCID: PMC2906478 DOI: 10.1186/1471-2407-10-275] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2009] [Accepted: 06/10/2010] [Indexed: 01/10/2023] Open
Abstract
BACKGROUND Fas (Apo-1/CD95) and its specific ligand (FasL) are key elements in apoptosis. They have been studied in different malignancies but there are few published studies about the soluble forms of these markers (i.e. sFas/sFasL) in gastric cancer. We have compared the serum levels of sFas/sFasL in gastric adenocarcinoma patients and cases with pre-neoplastic lesions as potential markers for early diagnosis, and investigated their relation with clinicopathological characteristics. METHODS Fifty-nine newly-diagnosed cases of gastric adenocarcinoma who had undergone gastrectomy, along with 62 endoscopically- and histologically-confirmed non-cancer individuals were enrolled in this study. sFas/sFasL serum levels were detected by Enzyme Linked Immunosurbent Assay. RESULTS Mean serum sFas level was significantly higher in gastric cancer patients than in control group (305.97 +/- 63.71 (pg/ml) vs. 92.98 +/- 4.95 (pg/ml), P < 0.001); while the mean serum level of sFasL was lower in patients with gastric adenocarcinoma (0.138 +/- 0.04 (pg/ml) vs. 0.150 +/- 0.02 (pg/ml), P < 0.001). Mean serum levels of sFas/sFasL were significantly different in both intestinal/diffuse and cardiac/non-cardiac subtypes when compared to the control group (P < 0.001). There was an increase in the serum level of sFas from the first steps of pre-neoplastic lesions to gastric adenocarcinoma (P < 0.001). Patients who had no lymph node involvement (N0) showed significantly higher serum levels of sFas compared to others (P = 0.044). CONCLUSIONS Production of sFas may play a critical role in the carcinogenesis of intestinal-type gastric cancer. sFas serum level may serve as a non-invasive tool for early diagnosis of gastric cancer.
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Li Q, Peng J, Li XH, Liu T, Liang QC, Zhang GY. Clinical significance of Fas and FasL protein expression in gastric carcinoma and local lymph node tissues. World J Gastroenterol 2010; 16:1274-8. [PMID: 20222173 PMCID: PMC2839182 DOI: 10.3748/wjg.v16.i10.1274] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the relation of Fas and Fas ligand (FasL) protein expression with carcinogenesis and metastasis of gastric carcinoma.
METHODS: Immunohistochemistry was used to detect Fas and FasL protein expression in 64 gastric carcinoma tissue samples and 20 normal gastric tissue samples. Relation between FasL and Fas expression, age and gender of gastric cancer patients, and pathological subtype and lymph node metastasis of gastric cancer was analyzed.
RESULTS: The Fas expression level was significantly higher in normal gastric tissue samples than in gastric carcinoma tissue samples (85.0% vs 25.0%, P < 0.001), while the FasL expression level was significantly lower in normal gastric tissue samples than in gastric carcinoma tissue samples (30.0% vs 81.3%, P < 0.001). The Fas expression level was significantly higher in invasive lymph nodes than in non-invasive lymph nodes (82.9% vs 56.5%, P < 0.003) and in well-differentiated gastric carcinoma tissue samples than in poorly-differentiated gastric carcinoma tissue samples (50.0% vs 18.0%, P = 0.015). The FasL expression level was significantly lower in well-differentiated gastric carcinoma tissue samples than in poorly- differentiated gastric carcinoma tissue samples (42.9% vs 84.0%, P = 0.021). The Fas and FasL expression levels (25.0% and 81.3%) were significantly different in gastric carcinoma tissue samples (P < 0.001), but had a non-linear correlation (P = 0.575).
CONCLUSION: Abnormal Fas and FasL expressions in gastric carcinoma and lymph node tissues are involved in carcinogenesis and metastasis of gastric cancer.
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The distribution and intracellular location of Fas and Fas Ligand following gastric carcinogenesis: Fas Ligand expressing gastric carcinoma cells can inhibit local immune response. Mol Cell Biochem 2009; 331:181-6. [DOI: 10.1007/s11010-009-0156-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2009] [Accepted: 04/29/2009] [Indexed: 10/20/2022]
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Drescher KM, Sharma P, Watson P, Gatalica Z, Thibodeau SN, Lynch HT. Lymphocyte recruitment into the tumor site is altered in patients with MSI-H colon cancer. Fam Cancer 2009; 8:231-9. [PMID: 19165625 DOI: 10.1007/s10689-009-9233-0] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2008] [Accepted: 01/07/2009] [Indexed: 12/28/2022]
Abstract
The ability of the host to mount an appropriate immune response to aberrant cells is one factor that determines prognosis in cancer patients. Naturally occurring regulatory T cells (T regs; CD4+ CD25+ cells) are key regulators of peripheral tolerance. It has been suggested that high levels of T regs are detrimental to the patient in some forms of cancer, but the role of these antigen-specific cells in individuals with colorectal cancers with high levels of microsatellite instability is unknown. Herein, we examined the ability of individuals with MSI-H or microsatellite stable colon cancer to recruit lymphocytes to the tumor site. Immunohistochemical staining was performed on archived paraffin-embedded specimens from a total of 38 individuals with MSI-H (n = 25) or MSS (n = 13) colon cancers to determine the proportion of CD3+, CD8+ and CD25+ cells infiltrating the tumor site. Patients with MSI-H colon cancers had increased percentages of CD8+ TILs (cytotoxic T cells) as compared to individuals with MSS colon cancer (47.3 vs. 24.04% of the infiltrate CD8+, respectively). No differences in the levels of CD25+ T cells were observed between individuals with MSI-H colon cancers and MSS colon cancers (0.53 vs. 0.54% CD25+, respectively). Together, these data suggest that the survival advantage enjoyed by patients with MSI-H colorectal cancer may, in part, be attributed to the increased cytolytic response, but not to an antigen-specific immunosuppressive response in MSS patients.
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Affiliation(s)
- Kristen M Drescher
- Department of Medical Microbiology and Immunology, Creighton University School of Medicine, Omaha, NE 68178, USA.
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Sugasawa H, Ichikura T, Kinoshita M, Ono S, Majima T, Tsujimoto H, Chochi K, Hiroi S, Takayama E, Saitoh D, Seki S, Mochizuki H. Gastric cancer cells exploit CD4+ cell-derived CCL5 for their growth and prevention of CD8+ cell-involved tumor elimination. Int J Cancer 2008; 122:2535-41. [PMID: 18246596 DOI: 10.1002/ijc.23401] [Citation(s) in RCA: 63] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
The level of serum CCL5, a C-C chemokine, is reportedly correlated with tumor progression in several cancers. We herein investigated the mechanisms by which CCL5 might contribute to tumor progression in gastric cancer. Serum CCL5 levels significantly correlated with tumor progression and prognosis in patients with gastric cancer. Immunohistochemistry showed that tumor-infiltrating lymphocytes expressed CCL5, while the tumor cells expressed the CCL5 receptors. Fluorescent double staining showed that tumor-infiltrating CD4+ cells rather than CD8+ cells preferentially expressed CCL5. Using gastric cancer cell lines (MKN45, KATO III), we examined CCL5 production by coculturing whole peripheral blood mononuclear cells (PBMCs), CD4+ cells, or CD8+ cells, with tumor cells. CD4+ cells cocultured with tumor cells remarkably enhanced CCL5 production in a direct cell-cell contact manner over other cocultured PBMCs, including CD8+ cells. Gastric cancer cell lines expressed CCL5 receptors and augmented their proliferation in response to CCL5 stimulation. Furthermore, we examined the effect of CCL5-treated cancer cells on the cocultured PBMCs, focusing on the CD4+/CD8+ proportion and apoptosis. Coculture of CCL5-treated gastric cancer cells with PBMCs resulted in a significant decrease in the proportion of CD8+ cells but not CD4+ cells, suggesting Fas-FasL-mediated apoptosis in CD8+ cells. In immunodeficient mice coinjected with KATO III and PBMCs, neutralization of CCL5 significantly suppressed tumor progression, resulting in a favorable outcome. In conclusion, gastric cancer cells might thus induce CD4+ T cells to secrete CCL5 and exploit it for their progression, as well as to aid in the prevention of CD8+ T cell-involved tumor elimination.
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Affiliation(s)
- Hidekazu Sugasawa
- Department of Surgery, National Defense Medical College, Tokorozawa, Japan.
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Shi Y, Guan JM, Han D. Progress in studies on the Fas/FasL expression system and colon carcinoma. Shijie Huaren Xiaohua Zazhi 2007; 15:3830-3835. [DOI: 10.11569/wcjd.v15.i36.3830] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Cell apoptosis or programmed cell death is the term used to describe active cell death to maintain stability under physiological and pathological conditions. Interaction of the death receptor and death ligand is one of the main ways to induce apoptosis, of which, the Fas/FasL system is considered as the major signal transduction pathway to mediate apoptosis. Colon carcinoma is one of the common malignant tumors that are a threat to human health. The occurrence and development of colon carcinoma is related to the regulation imbalance of cell apoptosis. This article reviews the relationship between the Fas/FasL expression system and the occurrence and development of colon carcinoma.
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Omoteyama K, Inoue S. The variation in Fas localization and the changes in Fas expression level upon stimulation with growth factors. Biochem Biophys Res Commun 2006; 353:159-63. [PMID: 17174268 DOI: 10.1016/j.bbrc.2006.11.145] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2006] [Accepted: 11/30/2006] [Indexed: 11/26/2022]
Abstract
Although Fas (APO-1/CD95) is well known as a death receptor, its stimulation occasionally fails to induce apoptosis in malignant cells. On the contrary, Fas is reported to advance the cell cycle in cancer cells. Therefore, we investigated roles of Fas in cell growth and apoptosis using human lung cancer cell lines. Fas was localized in the cytoplasm in exponentially growing cells, whereas only confluent cells expressed Fas on the cell membrane. A stimulation of confluent cells by either of EGF, IGF-I or VEGF induced once a decrease in Fas expression level and its sequential recovery. Fas expression levels in confluent cells were negatively correlated with cell doubling times (r=0.757, p=0.0088). Fas remained on the cell membrane of IgM-treated cells even after the growth factor stimulation, leading to apoptosis with abnormal mitosis, whereas the same stimulation induced Fas internalization in IgG(1)-treated cells. From these results, we suggest that Fas remaining on the cell membrane amplifies to induce apoptosis. Conversely, Fas internalization may enable cancer cells to escape from apoptosis. Our results suggest that growth factor may contribute to the resistance of cancer cells to Fas-mediated apoptosis in an autocrine or paracrine fashion.
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Affiliation(s)
- Kazuki Omoteyama
- Department of Anatomy, Nihon University School of Dentistry, 1-8-13 Kanda-Surugadai, Tokyo 101-8310, Japan.
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Tong Q, Liu K, Wang G. FasL expression in colorectal carcinoma and its significance in immune escape of cancer. ACTA ACUST UNITED AC 2006; 26:79-81. [PMID: 16711013 DOI: 10.1007/bf02828044] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
To study the significance of FasL expression in immune escape of colorectal carcinoma, FasL protein expression and the number of tumor infiltrating lymphocytes (TILs) in 80 specimens of colorectal carcinoma were detected by immunohistochemitry. The mRNA of FasL was measured by in situ hybridization in the consecutive tissue slices of 80 colorectal carcinomas respectively. Using terminal deoxynucleotidyl transferase-mediaed dUTP nick end labeling (TUNEL), apoptotic cells were detected in 80 specimens of colorectal carcinoma. The expression of FasL was detected in all 80 specimens, but it was not even in the same or among different tissues. In the consecutive tissue slices, the location of expression of FasL protein corresponded with that of FasL mRNA. In those with FasL extensive expression, the number of TILs was less than that of FasL weak expression (P < 0.05), and the apoptotic index (AI) of TILs was higher and that of tumor cells was lower than that of FasL with weak expression respectively (P < 0.01). The Al of TILs was correlated with that of tumor cells (r = -0.631, P < 0.01). It was suggested that colorectal carcinoma cells can induce the apoptosis of TILs through the expression of FasL, which can counterattack the immune system. This may be one of the mechanisms of immune evasion in colorectal carcinoma.
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Affiliation(s)
- Qiang Tong
- Department of General Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
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Sun Y, Chen XY, Liu J, Cheng XX, Wang XW, Kong QY, Li H. Differential caspase-3 expression in noncancerous, premalignant and cancer tissues of stomach and its clinical implication. ACTA ACUST UNITED AC 2006; 30:168-73. [PMID: 16697119 DOI: 10.1016/j.cdp.2006.02.004] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/28/2006] [Indexed: 01/28/2023]
Abstract
BACKGROUND Caspase-3 is a critical apoptosis-promoting element but its status during stepwise gastrocarcinogenesis needs to be further clarified. MATERIALS AND METHODS By the use of frozen tissue microarrays constructed with the tissue spots cored from defined histological regions in tissue blocks, the pattern of caspase-3 expression in noncancerous, premalignant (atrophic gastritis and intestinal metaplasia) tissue and cancer spots were analyzed under the same experimental conditions by the methods of immunohistochemistry and mRNA-in situ hybridization. RESULTS Caspase-3 was expressed in all 34 of the noncancerous mucosa (100%), in 16 of the 17 premalignant tissues (94.1%) and in 15 of the 48 gastric cancers (31.3%). The incidences of caspase-3 detection were significantly different (p<0.01) between noncancerous mucosa and intestinal as well as diffuse gastric cancers. CONCLUSION Down-regulated caspase-3 is closely correlated with gastric cancer formation and would be a potential indicator of tumor formation and progression. Helicobacter pylori (H. pylori; Hp) infection is but not the only one element responsible to the enhanced caspase-3 expression in gastric epithelia.
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Affiliation(s)
- Yuan Sun
- Cancer Institute, Liaoning Lab of Cancer Genomics, College of Basic Medical Sciences, Dalian Medical University, Dalian 116027, PR China
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Kojima Y, Tsurumi H, Goto N, Shimizu M, Kasahara S, Yamada T, Kanemura N, Hara T, Sawada M, Saio M, Yamada T, Takahashi T, Tomita E, Takami T, Moriwaki H. Fas and Fas ligand expression on germinal center type-diffuse large B-cell lymphoma is associated with the clinical outcome. Eur J Haematol 2006; 76:465-72. [PMID: 16494623 DOI: 10.1111/j.1600-0609.2006.00631.x] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
In recent years, diffuse large B-cell lymphoma (DLBCL) has been classified by DNA microarray analysis into the germinal center B-cell-like (GC) type, the activated B-cell-like (ABC) type and type 3. The latter two types can be collectively categorized as the non-GC (NGC) type. From the prognostic perspective, the GC type has a favorable clinical outcome when compared with the NGC type. The protein Fas induces apoptosis of lymphocytes by binding with the Fas ligand (FasL), and escape from such apoptosis is considered to lead to malignant transformation of the cells and unrestricted growth of lymphoma. We proposed a hypothesis that Fas/FasL expression could be possibly related with a better survival of GC type DLBCL and evaluated 69 DLBCL cases immunohistochemically with CD10, Bcl-6, MUM1, Fas and FasL. These lymphomas were classified as GC type (positive for CD10 or Bcl-6 and negative for MUM1) or NGC type. The GC type had a better overall survival rate than the NGC type (P = 0.0723). Among markers as given above, positive CD10 was the most significant prognostic factor for overall survival in total DLBCL (P < 0.05). In the GC type, Fas and FasL expressions were significantly associated with a favorable overall survival (Fas: P < 0.005; FasL: P < 0.05). Hence, Fas or FasL expression might contribute to a better prognosis of this type of DLBCL.
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MESH Headings
- Adult
- Aged
- Aged, 80 and over
- Antineoplastic Combined Chemotherapy Protocols/administration & dosage
- Antineoplastic Combined Chemotherapy Protocols/therapeutic use
- Apoptosis/physiology
- B-Lymphocytes/metabolism
- B-Lymphocytes/pathology
- Biomarkers, Tumor/blood
- Cyclophosphamide/administration & dosage
- DNA-Binding Proteins/analysis
- Doxorubicin/administration & dosage
- Doxorubicin/analogs & derivatives
- Embryonal Carcinoma Stem Cells
- Fas Ligand Protein
- Female
- Follow-Up Studies
- Germinal Center/pathology
- Humans
- Interferon Regulatory Factors/analysis
- L-Lactate Dehydrogenase/blood
- Life Tables
- Lymphoma, Large B-Cell, Diffuse/classification
- Lymphoma, Large B-Cell, Diffuse/drug therapy
- Lymphoma, Large B-Cell, Diffuse/genetics
- Lymphoma, Large B-Cell, Diffuse/metabolism
- Lymphoma, Large B-Cell, Diffuse/mortality
- Lymphoma, Large B-Cell, Diffuse/pathology
- Male
- Membrane Glycoproteins/biosynthesis
- Membrane Glycoproteins/genetics
- Middle Aged
- Neoplasm Proteins/biosynthesis
- Neoplasm Proteins/genetics
- Neoplastic Stem Cells/metabolism
- Neoplastic Stem Cells/pathology
- Prednisolone/administration & dosage
- Prognosis
- Proportional Hazards Models
- Proto-Oncogene Proteins c-bcl-6
- Survival Analysis
- Treatment Outcome
- Tumor Necrosis Factors/biosynthesis
- Tumor Necrosis Factors/genetics
- Vincristine/administration & dosage
- fas Receptor/biosynthesis
- fas Receptor/genetics
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Affiliation(s)
- Yasushi Kojima
- First Department of Internal Medicine, Gifu University Graduate School of Medicine, Gifu, Japan
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Igney FH, Krammer PH. Tumor counterattack: fact or fiction? Cancer Immunol Immunother 2005; 54:1127-36. [PMID: 15889255 PMCID: PMC11034178 DOI: 10.1007/s00262-005-0680-7] [Citation(s) in RCA: 59] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2004] [Accepted: 01/24/2005] [Indexed: 12/30/2022]
Abstract
Cancer development relies on a variety of mechanisms that facilitate tumor growth despite the presence of a functioning immune system. Understanding these mechanisms may foster novel therapeutic approaches for oncology and organ transplantation. By expression of the apoptosis-inducing protein CD95L (FasL, APO-1L, CD178), tumors may eliminate tumor-infiltrating lymphocytes and suppress anti-tumor immune responses, a phenomenon called "tumor counterattack". On the one hand, preliminary evidence of tumor counterattack in human tumors exists, and CD95L expression can prevent T-cell responses in vitro. On the other hand, CD95L-expressing tumors are rapidly rejected and induce inflammation in mice. Here, we summarize and discuss the consequences of CD95L expression of tumor cells and its contribution to immune escape.
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Affiliation(s)
- Frederik H Igney
- Tumor Immunology Program, German Cancer Research Center (DKFZ), Heidelberg, Germany.
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O'Brien DI, Nally K, Kelly RG, O'Connor TM, Shanahan F, O'Connell J. Targeting the Fas/Fas ligand pathway in cancer. Expert Opin Ther Targets 2005; 9:1031-44. [PMID: 16185156 DOI: 10.1517/14728222.9.5.1031] [Citation(s) in RCA: 37] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Fas is a transmembrane receptor that can induce apoptosis after cross-linking with either agonistic antibodies or with Fas ligand (FasL). Although originally described as an important regulator of peripheral immune homeostasis, accumulating evidence suggests that the Fas/FasL system plays an important role in tumour development. In addition to its proapoptotic functions, accumulating evidence demonstrates that Fas can activate numerous nonapoptotic signalling pathways, and that activation of these pathways can result in increased tumourigenicity and metastasis. This review summarises the current understanding of the Fas/FasL system in tumorigenesis and discusses attempts to utilise the Fas/FasL system in the treatment of cancer.
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Affiliation(s)
- Darren I O'Brien
- Department of Medicine, NUIC, Clinical Sciences Building, University Hospital, Cork, Ireland
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Chui SY, Clay TM, Lyerly HK, Morse MA. The Development of Therapeutic and Preventive Vaccines for Gastric Cancer and Helicobacter pylori. Cancer Epidemiol Biomarkers Prev 2005; 14:1883-9. [PMID: 16103431 DOI: 10.1158/1055-9965.epi-04-0775] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Gastric cancer is one of the most important worldwide public health problems. Convincing epidemiologic and etiologic associations have been made between the development of gastric cancer and infection with Helicobacter pylori. H. pylori not only has adapted to survive within the harsh environment of the stomach but also is able to modulate and avoid endogenous immune responses. The design and creation of efficacious vaccine strategies against H. pylori requires an understanding of the complex interactions that make up mucosal immunity. An effective vaccine strategy against H. pylori has the potential to affect significantly on population health worldwide.
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Affiliation(s)
- Stephen Y Chui
- Duke University Medical Center, Box 2606, Durham, NC 27710, USA
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Stoicov C, Saffari R, Cai X, Hasyagar C, Houghton J. Molecular biology of gastric cancer: Helicobacter infection and gastric adenocarcinoma: bacterial and host factors responsible for altered growth signaling. Gene 2005; 341:1-17. [PMID: 15474284 DOI: 10.1016/j.gene.2004.07.023] [Citation(s) in RCA: 71] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2004] [Revised: 07/06/2004] [Accepted: 07/26/2004] [Indexed: 02/07/2023]
Abstract
Gastric cancer remains the second most common cause of cancer-related mortality worldwide. The single most common cause of gastric cancer is chronic infection with the gram-negative microaerophilic spiral bacterium: Helicobacter pylori. Recent advances in this field have identified host factors which predispose to gastric cancer formation via modulation of the host immune response. In addition, recent work has explored bacterial virulence factors which may directly cause tissue damage, and lead to gastric carcinogenesis, as well as factors responsible for enhanced immune response. Environmental factors, long associated with a predilection for gastric cancer, are recognized as modifiers of key growth signalling pathways within the gastric mucosa and as such lead to growth alterations. This review focuses on exploring new advances in our understanding of bacterial factors, host genetic polymorphisms and the interaction between the bacterium and host at the level of the immune response and the regulation of proliferative and apoptotic signal transduction cascades. Modulation of the pivotal balance between cell growth and cell death leads to the formation of gastric adenocarcinoma.
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Affiliation(s)
- Calin Stoicov
- Department of Medicine, University of Massachusetts Medical Center, 364 Plantation Street, Lazare Research Building Room, 2nd floor, Room 209, Worcester, MA 01605, USA
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Igney FH, Behrens CK, Krammer PH. CD95L mediates tumor counterattack in vitro but induces neutrophil-independent tumor rejection in vivo. Int J Cancer 2004; 113:78-87. [PMID: 15386427 DOI: 10.1002/ijc.20538] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Many tumors express CD95L (CD178, FasL, APO-1L) and may thus kill tumor-infiltrating lymphocytes, a phenomenon called tumor counterattack. However, presently it is not clear whether tumor counterattack is a relevant immune escape mechanism. To characterize the effect of CD95L expression of tumor cells on tumor-specific T cells, we established an in vitro system with TCR tg T cells and a model tumor antigen. Preactivated antitumor T cells were able to kill CD95L(-) and CD95L(+) tumor cells. CD95L(+) tumor cells killed activated T cells in vitro and inhibited the expansion of cytotoxic antitumor T cells in mixed lymphocyte tumor reactions. In vivo CD95L expression led to delayed tumor growth or complete tumor rejection. Neutrophils were not responsible for the delayed growth of the CD95L(+) tumors tested. In mice with neutrophils deficient for important cytotoxicity mechanisms (p47phox(-/-) or iNOS(-/-) mice), CD95L(+) tumors grew similarly as in wild-type mice. Incidence and growth rate of CD95L(+) tumors in mice injected with a neutrophil-depleting or an isotype control antibody was the same. In CD95-deficient lpr mice, tumor growth was not altered as compared to wild-type mice. Taken together, CD95L mediated tumor counterattack in vitro, but led to neutrophil-independent tumor rejection in vivo.
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Affiliation(s)
- Frederik H Igney
- Tumor Immunology Program, German Cancer Research Center, Heidelberg, Germany
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