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1
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Mondal T, Gaur H, Wamba BEN, Michalak AG, Stout C, Watson MR, Aleixo SL, Singh A, Condello S, Faller R, Leiserowitz GS, Bhatnagar S, Tushir-Singh J. Characterizing the regulatory Fas (CD95) epitope critical for agonist antibody targeting and CAR-T bystander function in ovarian cancer. Cell Death Differ 2023; 30:2408-2431. [PMID: 37838774 PMCID: PMC10657439 DOI: 10.1038/s41418-023-01229-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Revised: 09/14/2023] [Accepted: 09/28/2023] [Indexed: 10/16/2023] Open
Abstract
Receptor clustering is the most critical step to activate extrinsic apoptosis by death receptors belonging to the TNF superfamily. Although clinically unsuccessful, using agonist antibodies, the death receptors-5 remains extensively studied from a cancer therapeutics perspective. However, despite its regulatory role and elevated function in ovarian and other solid tumors, another tumor-enriched death receptor called Fas (CD95) remained undervalued in cancer immunotherapy until recently, when its role in off-target tumor killing by CAR-T therapies was imperative. By comprehensively analyzing structure studies in the context of the binding epitope of FasL and various preclinical Fas agonist antibodies, we characterize a highly significant patch of positively charged residue epitope (PPCR) in its cysteine-rich domain 2 of Fas. PPCR engagement is indispensable for superior Fas agonist signaling and CAR-T bystander function in ovarian tumor models. A single-point mutation in FasL or Fas that interferes with the PPCR engagement inhibited apoptotic signaling in tumor cells and T cells. Furthermore, considering that clinical and immunological features of the autoimmune lymphoproliferative syndrome (ALPS) are directly attributed to homozygous mutations in FasL, we reveal differential mechanistic details of FasL/Fas clustering at the PPCR interface compared to described ALPS mutations. As Fas-mediated bystander killing remains vital to the success of CAR-T therapies in tumors, our findings highlight the therapeutic analytical design for potentially effective Fas-targeting strategies using death agonism to improve cancer immunotherapy in ovarian and other solid tumors.
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Affiliation(s)
- Tanmoy Mondal
- Laboratory of Novel Biologics, University of California Davis, Davis, CA, USA
- Department of Medical Microbiology and Immunology, University of California Davis, Davis, CA, USA
| | - Himanshu Gaur
- Laboratory of Novel Biologics, University of California Davis, Davis, CA, USA
- Department of Medical Microbiology and Immunology, University of California Davis, Davis, CA, USA
| | - Brice E N Wamba
- Laboratory of Novel Biologics, University of California Davis, Davis, CA, USA
- Department of Medical Microbiology and Immunology, University of California Davis, Davis, CA, USA
| | - Abby Grace Michalak
- Laboratory of Novel Biologics, University of California Davis, Davis, CA, USA
- Department of Medical Microbiology and Immunology, University of California Davis, Davis, CA, USA
- Undergraduate Research Program Volunteers, University of California Davis, Davis, CA, USA
| | - Camryn Stout
- Laboratory of Novel Biologics, University of California Davis, Davis, CA, USA
- Department of Medical Microbiology and Immunology, University of California Davis, Davis, CA, USA
- Undergraduate Research Program Volunteers, University of California Davis, Davis, CA, USA
| | - Matthew R Watson
- Laboratory of Novel Biologics, University of California Davis, Davis, CA, USA
- Department of Medical Microbiology and Immunology, University of California Davis, Davis, CA, USA
- Undergraduate Research Program Volunteers, University of California Davis, Davis, CA, USA
| | - Sophia L Aleixo
- Laboratory of Novel Biologics, University of California Davis, Davis, CA, USA
- Department of Medical Microbiology and Immunology, University of California Davis, Davis, CA, USA
- Undergraduate Research Program Volunteers, University of California Davis, Davis, CA, USA
| | - Arjun Singh
- Department of Medical Microbiology and Immunology, University of California Davis, Davis, CA, USA
| | - Salvatore Condello
- Department of Obstetrics and Gynecology, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Roland Faller
- Department of Chemical Engineering, University of California Davis, Davis, CA, USA
| | - Gary Scott Leiserowitz
- Department of Obstetrics and Gynecology, UC Davis School of Medicine, Sacramento, CA, USA
- UC Davis Comprehensive Cancer Center, UC Davis School of Medicine, Sacramento, CA, USA
| | - Sanchita Bhatnagar
- Department of Medical Microbiology and Immunology, University of California Davis, Davis, CA, USA
- UC Davis Comprehensive Cancer Center, UC Davis School of Medicine, Sacramento, CA, USA
| | - Jogender Tushir-Singh
- Laboratory of Novel Biologics, University of California Davis, Davis, CA, USA.
- Department of Medical Microbiology and Immunology, University of California Davis, Davis, CA, USA.
- UC Davis Comprehensive Cancer Center, UC Davis School of Medicine, Sacramento, CA, USA.
- Ovarian Cancer Academy Early Career Investigator at UC Davis, Davis, CA, USA.
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Ghorani E, Swanton C, Quezada SA. Cancer cell-intrinsic mechanisms driving acquired immune tolerance. Immunity 2023; 56:2270-2295. [PMID: 37820584 DOI: 10.1016/j.immuni.2023.09.004] [Citation(s) in RCA: 35] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Revised: 09/11/2023] [Accepted: 09/11/2023] [Indexed: 10/13/2023]
Abstract
Immune evasion is a hallmark of cancer, enabling tumors to survive contact with the host immune system and evade the cycle of immune recognition and destruction. Here, we review the current understanding of the cancer cell-intrinsic factors driving immune evasion. We focus on T cells as key effectors of anti-cancer immunity and argue that cancer cells evade immune destruction by gaining control over pathways that usually serve to maintain physiological tolerance to self. Using this framework, we place recent mechanistic advances in the understanding of cancer immune evasion into broad categories of control over T cell localization, antigen recognition, and acquisition of optimal effector function. We discuss the redundancy in the pathways involved and identify knowledge gaps that must be overcome to better target immune evasion, including the need for better, routinely available tools that incorporate the growing understanding of evasion mechanisms to stratify patients for therapy and trials.
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Affiliation(s)
- Ehsan Ghorani
- Cancer Immunology and Immunotherapy Unit, Department of Surgery and Cancer, Imperial College London, London, UK; Department of Medical Oncology, Imperial College London Hospitals, London, UK.
| | - Charles Swanton
- Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK; Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK; Department of Oncology, University College London Hospitals, London, UK
| | - Sergio A Quezada
- Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK; Cancer Immunology Unit, Research Department of Hematology, University College London Cancer Institute, London, UK.
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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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Risso V, Lafont E, Le Gallo M. Therapeutic approaches targeting CD95L/CD95 signaling in cancer and autoimmune diseases. Cell Death Dis 2022; 13:248. [PMID: 35301281 PMCID: PMC8931059 DOI: 10.1038/s41419-022-04688-x] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Revised: 02/09/2022] [Accepted: 02/24/2022] [Indexed: 12/14/2022]
Abstract
Cell death plays a pivotal role in the maintenance of tissue homeostasis. Key players in the controlled induction of cell death are the Death Receptors (DR). CD95 is a prototypic DR activated by its cognate ligand CD95L triggering programmed cell death. As a consequence, alterations in the CD95/CD95L pathway have been involved in several disease conditions ranging from autoimmune diseases to inflammation and cancer. CD95L-induced cell death has multiple roles in the immune response since it constitutes one of the mechanisms by which cytotoxic lymphocytes kill their targets, but it is also involved in the process of turning off the immune response. Furthermore, beyond the canonical pro-death signals, CD95L, which can be membrane-bound or soluble, also induces non-apoptotic signaling that contributes to its tumor-promoting and pro-inflammatory roles. The intent of this review is to describe the role of CD95/CD95L in the pathophysiology of cancers, autoimmune diseases and chronic inflammation and to discuss recently patented and emerging therapeutic strategies that exploit/block the CD95/CD95L system in these diseases.
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Affiliation(s)
- Vesna Risso
- INSERM U1242, Oncogenesis Stress Signaling, University of Rennes, Rennes, France
- Centre de lutte contre le cancer Eugène Marquis, Rennes, France
| | - Elodie Lafont
- INSERM U1242, Oncogenesis Stress Signaling, University of Rennes, Rennes, France
- Centre de lutte contre le cancer Eugène Marquis, Rennes, France
| | - Matthieu Le Gallo
- INSERM U1242, Oncogenesis Stress Signaling, University of Rennes, Rennes, France.
- Centre de lutte contre le cancer Eugène Marquis, Rennes, France.
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Szulc-Kielbik I, Klink M. Polymorphonuclear Neutrophils and Tumors: Friend or Foe? EXPERIENTIA SUPPLEMENTUM (2012) 2022; 113:141-167. [PMID: 35165863 DOI: 10.1007/978-3-030-91311-3_5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
Tumor microenvironment (TME) is a dynamic network that apart from tumor cells includes also cells of the immune system, e.g., neutrophils, which are recruited from blood circulation. In TME, neutrophils are strongly implicated in the direct and indirect interactions with tumor cells or other immune cells, and they play roles in both preventing and/or facilitating tumor progression and metastasis. The dual role of neutrophils is determined by their high plasticity and heterogeneity. Analogous to the macrophages, neutrophils can express antitumoral (N1) and protumoral (N2) phenotypes which differ substantially in morphology and function. N1 phenotype characterizes with a high cytotoxic and proinflammatory activities, while N2 phenotype with immunosuppressive and prometastatic properties. The antitumoral effect of neutrophils includes for example the production of reactive oxygen species or proapoptotic molecules. The protumoral action of neutrophils relies on releasing of proangiogenic and prometastatic mediators, immunosuppressive factors, as well as on direct helping tumor cells in extravasation process. This chapter summarizes the heterogeneity of neutrophils in TME, as well as their dual role on tumor cells.
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Affiliation(s)
| | - Magdalena Klink
- Institute of Medical Biology, Polish Academy of Sciences, Lodz, Poland.
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Mo G, Zhang B, Jiang Q. Role of ARK5 in cancer and other diseases (Review). Exp Ther Med 2021; 22:697. [PMID: 33986861 PMCID: PMC8112134 DOI: 10.3892/etm.2021.10129] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2019] [Accepted: 06/20/2020] [Indexed: 12/14/2022] Open
Abstract
Malignant tumors are often exposed to hypoxic and glucose-starved microenvironments. AMP-activated protein kinase (AMPK) is an energy sensor that is stimulated during energy-deficient conditions and protects cells from hypoxic injury by regulating metabolism. AMPK-related protein kinase 5 (ARK5) is a member of the catalytic sub-unit of the AMPK family and has an important role in energy regulation and hypoxia. ARK5 is regulated by Akt and liver kinase B1 and is associated with numerous tumor-related molecules to exert the negative effects of tumors. Studies have revealed ARK5 overexpression in cases of tumor invasion and metastasis and a positive association with the degree of cancer cell malignancy, which is regarded as a key element in determining cancer prognosis. Furthermore, ARK5 downregulation improves drug sensitivity through the epithelial-mesenchymal transition pathway, indicating that it may be a potential therapeutic target. In other non-cancer conditions, ARK5 has various roles in neurodegenerative diseases (Alzheimer's and Huntington's disease), renal disorders (diabetic nephropathy and renal fibrosis) and physiological processes (striated muscle generation). In the present review, the upstream and downstream molecular pathways of ARK5 in cancer and other diseases are described and potential therapeutic strategies are discussed.
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Affiliation(s)
- Guoheng Mo
- Department of Neurosurgery, Queen Mary College of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Bohan Zhang
- First Clinical Medical College, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Qunguang Jiang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
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7
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Li Z, Li X, Du X, Zhang H, Wu Z, Ren K, Han X. The Interaction Between lncRNA SNHG1 and miR-140 in Regulating Growth and Tumorigenesis via the TLR4/NF-κB Pathway in Cholangiocarcinoma. Oncol Res 2019; 27:663-672. [PMID: 30764893 PMCID: PMC7848332 DOI: 10.3727/096504018x15420741307616] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
Cholangiocarcinoma (CCA) is the second most common primary hepatobiliary carcinoma. The long noncoding RNA (lncRNA) small nucleolar RNA host gene 1 (SNHG1) has been reported to contribute to the progression of multiple cancers. Nonetheless, the functions and hidden mechanism of SNHG1 remain unclear in CCA. In this study, the SNHG1 levels were boosted in CCA cell lines, and knockdown of SNHG1 repressed CCA cell proliferation and invasion in vitro. The data also demonstrated that miR-140 could act as a target of SNHG1 in CCA and inhibited CCA cell proliferation and invasion, whereas the inhibition effects were relieved by overexpression of SNHG1. In addition, Toll-like receptor 4 (TLR4), an NF-κB-activating signal, was identified to be a target of miR-140. SNHG1, as a competing endogenous RNA (ceRNA) for miR-140, enhanced TLR4 expression and activated NF-κB signaling, thereby regulating growth and tumorigenesis in CCA. Animal experiments further confirmed this conclusion. Collectively, these findings not only uncovered a key role of SNHG1/miR-140/TLR4/NF-κB signaling axis in CCA tumorigenesis and progression but also denoted the probable utilization of SNHG1 as a therapeutic target for CCA.
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Affiliation(s)
- Zhen Li
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, P.R. China
| | - Xin Li
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, P.R. China
| | - Xiao Du
- Beijing Genecast Biotechnology Co., Beijing, P.R. China
| | - Henghui Zhang
- Beijing Genecast Biotechnology Co., Beijing, P.R. China
| | - Zhengyang Wu
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, P.R. China
| | - Kewei Ren
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, P.R. China
| | - Xinwei Han
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, P.R. China
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Boldrini L, Loggini B, Gisfredi S, Zucconi Y, Baldinotti F, Fogli A, Simi P, Cervadoro G, Barachini P, Basolo F, Pingitore R, Fontanini G. Mutations of Fas (APO-1/CD95) and p53 Genes in Nonmelanoma Skin Cancer. J Cutan Med Surg 2016. [DOI: 10.1177/120347540300700203] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Background: There is considerable evidence that apoptosis plays an important role in the pathogenesis of a wide variety of skin diseases. Apoptosis failure may ensure the survival of transformed cells prone to sustain further genetic damage and it plays an important part in the development of tumors. Genetic alterations of Fas and p53, with consequent inactivation of gene protein products, may be involved in transcriptional downregulation of Fas. Objective: We investigated Fas and its ligand expression in 30 cases of nonmelanoma skin cancer, 19 basal cell and 11 squamous cell carcinomas, and we also analyzed Fas and p53 status, in an attempt to detect putative alterations. Method: Fas and its ligand expression were evaluated by RT-PCR; the promoter and the entire coding region of Fas, and the coding exons 4–9 of p53 were investigated by polymerase chain reaction, single strand conformation polymorphism, and DNA sequencing. Results: Fas alterations were found in 3/19 (15.8%) basal cell and in 4/11 (36.4%) squamous cell carcinomas. Five out of 25 cases (3/19 basal cell and 2/11 squamous cell carcinomas) were p53-mutated, and in the majority of these cases there were concomitant mutations of the Fas gene (χ2 test; p = 0.035). Conclusion: Taken together, our findings highlight an involvement of the Fas/Fas-ligand system in the development of skin cancer, suggesting that the loss of its apoptotic function, in some cases linked to p53 alterations, may contribute to the self-maintenance of cancer cells.
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Affiliation(s)
- Laura Boldrini
- Department of Oncology, Transplants and Advanced Technologies in Medicine, University of Pisa, Pisa, Italy
| | | | - Silvia Gisfredi
- Department of Oncology, Transplants and Advanced Technologies in Medicine, University of Pisa, Pisa, Italy
| | - Ylenia Zucconi
- Department of Oncology, Transplants and Advanced Technologies in Medicine, University of Pisa, Pisa, Italy
| | - Fulvia Baldinotti
- Department of Oncology, Division of Cytogenetics and Molecular Genetics, University of Pisa, Pisa, Italy
| | - Antonella Fogli
- Department of Oncology, Division of Cytogenetics and Molecular Genetics, University of Pisa, Pisa, Italy
| | - Paolo Simi
- Department of Oncology, Division of Cytogenetics and Molecular Genetics, University of Pisa, Pisa, Italy
| | - Gregorio Cervadoro
- Department of Experimental Pathology, Division of Dermatology, University of Pisa, Pisa, Italy
| | - Paolo Barachini
- Department of Experimental Pathology, Division of Dermatology, University of Pisa, Pisa, Italy
| | - Fulvio Basolo
- Department of Oncology, Transplants and Advanced Technologies in Medicine, University of Pisa, Pisa, Italy
| | | | - Gabriella Fontanini
- Department of Oncology, Transplants and Advanced Technologies in Medicine, University of Pisa, Pisa, Italy
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Sharma G, Rani I, Bhatnagar A, Agnihotri N. Apoptosis-Mediated Chemoprevention by Different Ratios of Fish Oil in Experimental Colon Carcinogenesis. Cancer Invest 2016; 34:220-30. [PMID: 27191482 DOI: 10.1080/07357907.2016.1183023] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Apoptosis plays an important role in prevention of colon cancer. In the present study, different ratios of fish oil and corn oil increased Fas expression in both phases and a decrease in FasL expression only in post initiation phase. Treatment with fish oil activated the intrinsic apoptotic pathway by increasing Bax expression and Cyt c release and decreasing Bcl-2 levels in both phases. This suggests that intrinsic pathway is upregulated by fish oil; however, Fas-FasL activity may be involved in inhibition of reversal of immune surveillance in tumor cells.
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Affiliation(s)
- Gayatri Sharma
- a Department of Biochemistry , Panjab University , Chandigarh , India
| | - Isha Rani
- a Department of Biochemistry , Panjab University , Chandigarh , India
| | - Archana Bhatnagar
- a Department of Biochemistry , Panjab University , Chandigarh , India
| | - Navneet Agnihotri
- a Department of Biochemistry , Panjab University , Chandigarh , India
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Li Y, Xu KP, Jiang D, Zhao J, Ge JF, Zheng SY. Relationship of Fas, FasL, p53 and bcl-2 expression in human non-small cell lung carcinomas. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2015; 8:13978-13986. [PMID: 26823709 PMCID: PMC4713495] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 07/18/2015] [Accepted: 08/25/2015] [Indexed: 06/05/2023]
Abstract
OBJECTIVE Lack of surface Fas expression is a main route for apoptotic resistance which is considered an important mechanism of tumorigenesis and tumor progression. Fas and FasL expression in 110 non-small cell lung carcinomas (NSCLCs) were investigated to evaluate their roles in pulmonary carcinogenesis and to examine the clinicopathologic significance of Fas expression with its relationship with p53 and bcl-2 over- expression. METHODS Immunohistochemical analysis using tissue microarray demonstrated that a large proportion of NSCLC patients (60%) showed lack of membranous Fas expression. The Fas-negative cases revealed the significantly lower survival rate than Fas-positive ones. Also, the loss of Fas receptor expression was found more frequently in advanced stage and higher nodal status. FasL protein was increased in most NSCLCs (89%) compared to normal lungs. RESULTS p53 and bcl-2 overexpression showed no association with Fas expression. Conclusively, reduced membranous Fas expression as a mechanism of apoptotic resistance is considered to play an important part of the pulmonary carcinogenesis, which may predict poor survival and have a negative prognostic influence. CONCLUSION Increased FasL expression is thought to be a basis for the immune evasion in NSCLCs. The rare bcl-2 overexpression suggests that this anti-apoptotic protein is unlikely to play a role in the apoptotic resistance of NSCLCs.
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Affiliation(s)
- Yin Li
- Department of Thoracic Surgery, Tumor Hospital of HenanZhengzhou 450008, Henan Province, China
| | - Ke-Ping Xu
- Department of Thoracic Surgery, Huai’an First People’s Hospital, Nanjing Madical UniversityHuaian, 223300, Jiangsu Province, China
| | - Dong Jiang
- Department of Cardio-Thoracic Surgery, First Affiliated Hospital of Soochow UniversitySuzhou 215006, Jiangsu Province, China
| | - Jun Zhao
- Department of Cardio-Thoracic Surgery, First Affiliated Hospital of Soochow UniversitySuzhou 215006, Jiangsu Province, China
| | - Jin-Feng Ge
- Department of Cardio-Thoracic Surgery, First Affiliated Hospital of Soochow UniversitySuzhou 215006, Jiangsu Province, China
| | - Shi-Ying Zheng
- Department of Cardio-Thoracic Surgery, First Affiliated Hospital of Soochow UniversitySuzhou 215006, Jiangsu Province, China
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Wu GZ, Pan CX, Jiang D, Zhang Q, Li Y, Zheng SY. Clinicopathological significance of Fas and Fas ligand expressions in esophageal cancer. Am J Cancer Res 2015; 5:2865-2871. [PMID: 26609492 PMCID: PMC4633913] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2015] [Accepted: 06/10/2015] [Indexed: 06/05/2023] Open
Abstract
Esophageal carcinomas have recently been shown to express Fas ligand (FasL) and down-regulate Fas to escape from host immune surveillance. However, the prognostic importance of Fas/FasL and their correlation with clinicopathological characteristics are yet to be delineated in this highly malignant carcinoma. Specimens from 106 esophageal squamous cell carcinoma patients were used for immuno-histochemical evaluation of Fas, FasL, and CD8 expressions. Fifty-two (49%) and 34 (32%) patients were positive for FasL and Fas, respectively. There were no associations between FasL expression and clinicopathological characteristics except lymph vessel invasion. Strong FasL expression correlated with significant (P < 0.001) decrease in tumor nest CD81 cells. However, neither FasL nor CD81 had any impact on patient survival. Strong Fas expression was correlated with depth of invasion (40.3% in pT1, T2 versus 20.5% in pT3, T4; P5 0.0308), histological differentiation (45.7% in well versus 25.4% in nonwell; P < 0.05), and lymph node metastasis (22.6% in positive versus 45.5% in negative; P < 0.01). Fas expression was one of the independent favorable prognosticators for patients' survival (risk ratio, 3.26; P < 0.01) in esophageal SCC. Fas expression was an independent prognosticator for recurrencefree survival, whereas FasL expression did not influence the survival in esophageal squamous cell carcinoma. Down-regulation of tumor Fas may be the hallmark of immune privilege for the tumor, thus causing the patients' poorer outcome. Tumor FasL may counterattack the host immune cells to such an extent that the prognosis is not affected.
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Affiliation(s)
- Guang-Zhou Wu
- Department of Cardio-Thoracic Surgery, The First People’s Hospital of YanchengYancheng 224006, Jiangsu Province, China
| | - Chun-Xia Pan
- The Third People’s Hospital of DalianDalian 116000, China
| | - Dong Jiang
- Department of Cardio-Thoracic Surgery, The First Affiliated Hospital of Soochow UniversitySuzhou 215006, Jiangsu Province, China
| | - Qiang Zhang
- Department of Cardio-Thoracic Surgery, The First Affiliated Hospital of Soochow UniversitySuzhou 215006, Jiangsu Province, China
| | - Yin Li
- Department of Thoracic Surgery, The Tumor Hospital of HenanZhengzhou 450008, Henan Province, P. R. China
| | - Shi-Ying Zheng
- Department of Cardio-Thoracic Surgery, The First Affiliated Hospital of Soochow UniversitySuzhou 215006, Jiangsu Province, China
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12
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Hariprasad G, Hariprasad R, Kumar L, Srinivasan A, Kola S, Kaushik A. Apolipoprotein A1 as a potential biomarker in the ascitic fluid for the differentiation of advanced ovarian cancers. Biomarkers 2013; 18:532-41. [PMID: 23902290 DOI: 10.3109/1354750x.2013.822561] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
CONTEXT Primary ovarian cancer and ovarian metastasis from non-ovarian cancers in advanced stage are closely mimicking conditions whose therapeutics and prognosis are different. OBJECTIVE To identify biomarkers that can differentiate the two variants of advanced ovarian cancers. METHODS Gel-based proteomics and antibody-based assays were used to study the differentially expressed proteins in the ascitic fluid of fourteen patients with advanced ovarian cancers. RESULTS Programmed Cell Death 1-Ligand 2, apolipoprotein A1, apolipoprotein A4 and anti-human fas antibody are differentially expressed proteins. CONCLUSIONS Apolipoprotein A1 with a 61.8 ng/ml cut-off is a potential biomarker with the best differentiating statistical parameters.
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Affiliation(s)
- Gururao Hariprasad
- Department of Biophysics, All India Institute of Medical Sciences , Ansari nagar, New Delhi, 110029 , India
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Prognostic value of the Fas/Fas ligand system in breast cancer. Contemp Oncol (Pozn) 2013; 17:120-2. [PMID: 23788976 PMCID: PMC3685366 DOI: 10.5114/wo.2013.34612] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2010] [Revised: 05/24/2011] [Accepted: 08/09/2011] [Indexed: 12/30/2022] Open
Abstract
Fas and its ligand (FasL) are known to play a crucial role in the genetically controlled mechanism of cell death, and their deregulation in cancer cells is involved in the immune escape of the tumor. The aim of this review is to analyze the current knowledge on the prognostic value of Fas/FasL in breast cancer patients. Both the results of other authors and our own experiences indicate that the lack of Fas ligand, and particularly Fas, is related to a significantly worse prognosis. It probably results from the resistance of Fas-deficient breast tumors to the mechanisms of apoptosis. On the other hand, some results suggest that the Fas/FasL-dependent mechanisms of tumor spread may be different for various target tissues. The expression of the Fas/Fas-ligand system has potential prognostic application in view of current knowledge, and consequently should be considered as an additional prognostic factor in breast cancer patients.
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Zitron IM, Thakur A, Norkina O, Barger GR, Lum LG, Mittal S. Targeting and killing of glioblastoma with activated T cells armed with bispecific antibodies. BMC Cancer 2013; 13:83. [PMID: 23433400 PMCID: PMC3599512 DOI: 10.1186/1471-2407-13-83] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2012] [Accepted: 02/11/2013] [Indexed: 12/29/2022] Open
Abstract
Background Since most glioblastomas express both wild-type EGFR and EGFRvIII as well as HER2/neu, they are excellent targets for activated T cells (ATC) armed with bispecific antibodies (BiAbs) that target EGFR and HER2. Methods ATC were generated from PBMC activated for 14 days with anti-CD3 monoclonal antibody in the presence of interleukin-2 and armed with chemically heteroconjugated anti-CD3×anti-HER2/neu (HER2Bi) and/or anti-CD3×anti-EGFR (EGFRBi). HER2Bi- and/or EGFRBi-armed ATC were examined for in vitro cytotoxicity using MTT and 51Cr-release assays against malignant glioma lines (U87MG, U118MG, and U251MG) and primary glioblastoma lines. Results EGFRBi-armed ATC killed up to 85% of U87, U118, and U251 targets at effector:target ratios (E:T) ranging from 1:1 to 25:1. Engagement of tumor by EGFRBi-armed ATC induced Th1 and Th2 cytokine secretion by armed ATC. HER2Bi-armed ATC exhibited comparable cytotoxicity against U118 and U251, but did not kill HER2-negative U87 cells. HER2Bi- or EGFRBi-armed ATC exhibited 50—80% cytotoxicity against four primary glioblastoma lines as well as a temozolomide (TMZ)-resistant variant of U251. Both CD133– and CD133+ subpopulations were killed by armed ATC. Targeting both HER2Bi and EGFRBi simultaneously showed enhanced efficacy than arming with a single BiAb. Armed ATC maintained effectiveness after irradiation and in the presence of TMZ at a therapeutic concentration and were capable of killing multiple targets. Conclusion High-grade gliomas are suitable for specific targeting by armed ATC. These data, together with additional animal studies, may provide the preclinical support for the use of armed ATC as a valuable addition to current treatment regimens.
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Affiliation(s)
- Ian M Zitron
- Department of Neurosurgery, Wayne State University, Karmanos Cancer Institute, Detroit, MI, USA
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15
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Lee YB, Kyung Kim E, Park HJ, Cho BK, Park YM, Kim JW, Yoo NJ, Park YG, Oh ST. Expression of Fas and Fas ligand in primary cutaneous squamous cell carcinoma in association with grade of tumor differentiation. Int J Dermatol 2012; 52:1092-7. [DOI: 10.1111/j.1365-4632.2012.05525.x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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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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17
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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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18
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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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Dittmar T, Zänker KS. Horizontal gene transfers with or without cell fusions in all categories of the living matter. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2011; 714:5-89. [PMID: 21506007 PMCID: PMC7120942 DOI: 10.1007/978-94-007-0782-5_2] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
This article reviews the history of widespread exchanges of genetic segments initiated over 3 billion years ago, to be part of their life style, by sphero-protoplastic cells, the ancestors of archaea, prokaryota, and eukaryota. These primordial cells shared a hostile anaerobic and overheated environment and competed for survival. "Coexist with, or subdue and conquer, expropriate its most useful possessions, or symbiose with it, your competitor" remain cellular life's basic rules. This author emphasizes the role of viruses, both in mediating cell fusions, such as the formation of the first eukaryotic cell(s) from a united crenarchaeon and prokaryota, and the transfer of host cell genes integrated into viral (phages) genomes. After rising above the Darwinian threshold, rigid rules of speciation and vertical inheritance in the three domains of life were established, but horizontal gene transfers with or without cell fusions were never abolished. The author proves with extensive, yet highly selective documentation, that not only unicellular microorganisms, but the most complex multicellular entities of the highest ranks resort to, and practice, cell fusions, and donate and accept horizontally (laterally) transferred genes. Cell fusions and horizontally exchanged genetic materials remain the fundamental attributes and inherent characteristics of the living matter, whether occurring accidentally or sought after intentionally. These events occur to cells stagnating for some 3 milliard years at a lower yet amazingly sophisticated level of evolution, and to cells achieving the highest degree of differentiation, and thus functioning in dependence on the support of a most advanced multicellular host, like those of the human brain. No living cell is completely exempt from gene drains or gene insertions.
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Affiliation(s)
- Thomas Dittmar
- Inst. Immunologie, Universität Witten/Herdecke, Stockumer Str. 10, Witten, 58448 Germany
| | - Kurt S. Zänker
- Institute of Immunologie, University of Witten/Herdecke, Stockumer Str. 10, Witten, 58448 Germany
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Reimers K, Radtke C, Choi CY, Allmeling C, Kall S, Kiefer P, Muehlberger T, Vogt PM. Expression of TNF-related apoptosis-inducing ligand (TRAIL) in keratinocytes mediates apoptotic cell death in allogenic T cells. ANNALS OF SURGICAL INNOVATION AND RESEARCH 2009; 3:13. [PMID: 19925644 PMCID: PMC2790448 DOI: 10.1186/1750-1164-3-13] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/25/2009] [Accepted: 11/19/2009] [Indexed: 11/10/2022]
Abstract
The objective of the present study was to evaluate the aptitude of TRAIL gene expression for inducing apoptosis in co-cultivated T-cells. This should allow preparing a strategy for the development of a durable, allogenic skin substitute based on the induction of an immune-privileged transplant. In order to counteract the significant potential of rejection in transplanted allogenic keratinocytes, we created a murine keratinocyte cell line which expressed TRAIL through stable gene transfer. The exogenic protein was localized on the cellular surface and was not found in soluble condition as sTRAIL. Contact to TRAIL expressing cells in co-culture induced cell death in sensitive Jurkat-cells, which was further intensified by lymphocyte activation. This cytotoxic effect is due to the induction of apoptosis. We therefore assume that the de-novo expression of TRAIL in keratinocytes can trigger apoptosis in activated lymphocytes and thus prevent the rejection of keratinocytes in allogenic, immune-privileged transplants.
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Affiliation(s)
- Kerstin Reimers
- Department of Plastic, Hand and Reconstructive Surgery, Medical School Hannover Podbielskistraße 380, 30659 Hannover, Germany
| | - Christine Radtke
- Department of Plastic, Hand and Reconstructive Surgery, Medical School Hannover Podbielskistraße 380, 30659 Hannover, Germany
| | - Claudia Y Choi
- Department of Plastic, Hand and Reconstructive Surgery, Medical School Hannover Podbielskistraße 380, 30659 Hannover, Germany
| | - Christina Allmeling
- Department of Plastic, Hand and Reconstructive Surgery, Medical School Hannover Podbielskistraße 380, 30659 Hannover, Germany
| | - Susanne Kall
- Department of Plastic, Hand and Reconstructive Surgery, Medical School Hannover Podbielskistraße 380, 30659 Hannover, Germany
| | - Paul Kiefer
- University Duesseldorf, Moorenstrasse 5, 40225 Duesseldorf, Germany
| | - Thomas Muehlberger
- Department of Plastic, Hand and Reconstructive Surgery, Medical School Hannover Podbielskistraße 380, 30659 Hannover, Germany
| | - Peter M Vogt
- Department of Plastic, Hand and Reconstructive Surgery, Medical School Hannover Podbielskistraße 380, 30659 Hannover, Germany
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Tokushige K, Hashimoto E, Noto H, Yatsuji S, Tobari M, Torii N, Taniai M, Shiratori K, Murayama H. Clinical significance of serum ornithine carbamoyltransferase in patients with non-alcoholic steatohepatitis. Hepatol Res 2009; 39:939-43. [PMID: 19712272 DOI: 10.1111/j.1872-034x.2009.00530.x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
AIM Ornithine carbamoyltransferase (OCT) is reported to be a liver-specific marker for the evaluation of hapatocellular damage. In this study, we investigated its clinical significance in non-alcoholic steatohepatitis (NASH). METHODS Serum OCT levels were measured by the ELISA (enzyme-linked immunosorbent assay) method. One hundred and twenty patients with NASH (18 liver cirrhosis induced by NASH and 9 NASH combined with hepatocellular carcinoma) were measured. RESULTS The serum levels of OCT and the ratios of OCT : alanine amino transferase (ALT) and OCT : aspartate amino transferase (AST) were increased in parallel with the progression of NASH. Especially, OCT and both ratios were markedly increased in hepatocellular carcinoma. As for the relationship between fibrosis grade and OCT, the serum OCT levels and the ratio of OCT : ALT levels were increased in parallel with liver fibrosis. In NASH patients with ALT within normal range, about 30% showed elevation of OCT. CONCLUSION Serum OCT levels and the ratios of OCT : ALT and OCT : AST increase in parallel with the progression of NASH. It was suggested that OCT is a useful marker in the progression of NASH.
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Affiliation(s)
- Katsutoshi Tokushige
- Tokyo Women's Medical University, Department of Medicine and Gastroenterology, Tokyo, Japan
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22
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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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Fas expression in primary breast cancer is related to neoplastic infiltration of perilymphatic fat. Adv Med Sci 2008; 53:49-53. [PMID: 18614439 DOI: 10.2478/v10039-008-0015-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
PURPOSE Various studies have revealed that both Fas and its ligand play an important role in cancer biology. The aim of our study was to determine if there is a relationship between the expression of Fas or Fas-ligand in breast cancer and the presence of malignant cells in perilymphatic fat. MATERIAL/METHODS Tumor samples from 147 consecutive breast cancer patients, aged 35-81 (median, 59), were subjected to analysis. The expressions of Fas and Fas-ligand were determined immunohistochemically. RESULTS The expression of Fas, but not Fas-ligand, was significantly less frequent in breast cancer patients in whom malignant cells infiltrated through the perilymphatic fat (p=0.042). The infiltration of paranodal fatty tissue occurred more often in cases of ductal carcinomas (p=0.008), larger primary tumors (pT>or=2, p=0.030) and regional lymph node involvement (pN>or=1, p=0.021). Univariate analysis revealed that perilymphatic fat infiltration shortened overall survivals in breast cancer patients (p=0.05), similarly to postmenopausal status (p=0.034), age >60 years (p=0.05) and regional lymph node involvement (p=0.05). None of the aforementioned factors, however, was revealed as an independent predictor of survival in multivariate analysis. CONCLUSIONS The study showed that lack of Fas in primary breast cancer is associated with perilymphatic fat infiltration. Consequently, both the absence of Fas in the primary tumor and the occurrence of neoplatic cells in paranodal fatty tissue should be considered in the prognosis, complementing existing conventional factors.
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Dallas A, Balatskaya SV, Kuo TC, Ilves H, Vlassov AV, Kaspar RL, Kisich KO, Kazakov SA, Johnston BH. Hairpin ribozyme-antisense RNA constructs can act as molecular Lassos. Nucleic Acids Res 2008; 36:6752-66. [PMID: 18953032 PMCID: PMC2588507 DOI: 10.1093/nar/gkn637] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
We have developed a novel class of antisense agents, RNA Lassos, which are capable of binding to and circularizing around complementary target RNAs. The RNA Lasso consists of a fixed sequence derived from the hairpin ribozyme and an antisense segment whose size and sequence can be varied to base pair with accessible sites in the target RNA. The ribozyme catalyzes self-processing of the 5′- and 3′-ends of a transcribed Lasso precursor and ligates the processed ends to produce a circular RNA. The circular and linear forms of the self-processed Lasso coexist in an equilibrium that is dependent on both the Lasso sequence and the solution conditions. Lassos form strong, noncovalent complexes with linear target RNAs and form true topological linkages with circular targets. Lasso complexes with linear RNA targets were detected by denaturing gel electrophoresis and were found to be more stable than ordinary RNA duplexes. We show that expression of a fusion mRNA consisting of a sequence from the murine tumor necrosis factor-α (TNF-α) gene linked to luciferase reporter can be specifically and efficiently blocked by an anti-TNF Lasso. We also show in cell culture experiments that Lassos directed against Fas pre-mRNA were able to induce a change in alternative splicing patterns.
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25
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Genetic association of cytokine DNA polymorphisms with head and neck cancer. Oral Oncol 2008; 44:1093-9. [PMID: 18486534 DOI: 10.1016/j.oraloncology.2008.02.012] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2008] [Revised: 02/03/2008] [Accepted: 02/25/2008] [Indexed: 12/22/2022]
Abstract
Mutations in oncogenes or tumor suppressor genes, as well as environmental factors such as tobacco chewing or smoking, poor oral hygiene, ill-fitting dental appliances, infection by certain HPV types, or alcohol abuse, seem to be involved in the multifactorial process of carcinogenesis in head and neck. Recently, several genetic association studies have indicated that common DNA polymorphisms in low penetrance genes may affect the susceptibility of an individual to malignancy. Cytokines are an important group of proteins that regulate and mediate inflammation and angiogenesis. Tumor growth, invasion and metastasis are facilitated when there is a deregulation in their production. Cytokines include interleukins (ILs), tumor necrosis factors (TNFs) and certain growth factors (GFs). A number of genetic association studies have recently investigated the putative correlation between functional DNA polymorphisms in cytokine genes and head and neck carcinomas. This review discusses the findings of such studies in oral, nasopharyngeal and esophageal squamous cell carcinomas. Extensive research has indicated that functional polymorphisms affecting gene expression of IL-4,-6,-8,-10 as well as TNF-alpha are strongly associated with increased risk for oral cancer. Gene expression of TNF-alpha seems to be associated also with esophageal carcinomas, while for nasopharyngeal cancer the picture is yet unclear. It is generally believed that such genetic association studies will gradually increase our knowledge regarding the predisposed manifestation and advancement of these malignancies in the head and neck region.
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Bowlus CL. Tumor Immunology. LIVER IMMUNOLOGY 2008:137-149. [DOI: 10.1007/978-1-59745-518-3_12] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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Su CC, Lin YP, Cheng YJ, Huang JY, Chuang WJ, Shan YS, Yang BC. Phosphatidylinositol 3-Kinase/Akt Activation by Integrin-Tumor Matrix Interaction Suppresses Fas-Mediated Apoptosis in T Cells. THE JOURNAL OF IMMUNOLOGY 2007; 179:4589-97. [PMID: 17878356 DOI: 10.4049/jimmunol.179.7.4589] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
It has recently become apparent that the microenvironment made up of the extracellular matrix may affect cell signaling. In this study, we evaluated Fas-triggered apoptosis in T cells in contact with tumor cells, which resembles the cell-to-cell interactions found in tumor regions. Jurkat cells were less susceptible to the Fas-mediated apoptosis when cocultured with U118, HeLa, A549, and Huh-7 tumor cells. This was indicated by less plasma membrane alteration, an amelioration of the loss of mitochondria membrane potential, a decrease in caspase-8 and caspase-3 activation, a decrease in DNA fragmentation factor-45/35 cleavage, and a reduction in the breakage of DNA when compared with Jurkat cells cultured alone. In contrast, the tumor cell lines MCF-7 and HepG2 produced no such protective effect. This protective event was independent of the expression of Fas ligand on the tumor cells. Interrupting the beta integrins-matrix interaction diminished the coculture effect. In Jurkat cells, cell matrix contact reduced the assembly of the Fas death-inducing signaling complex and Bcl-x(L) cleavage, but enhanced the phosphorylation of ERK1/2, p38 MAPK, and Akt. Only PI3K inhibitor, but not kinase inhibitors for MEK, ERK1/2, p38 MAPK, JNK, protein kinase C, and protein kinase A, completely abolished this tumor cell contact-associated protection and in parallel restored Fas-induced Bcl-x(L) cleavage as well as decreasing the phosphorylation of Bad at serine 136. Together, our results indicate that stimulation of the beta integrin signal of T cells by contact with tumor cells may trigger a novel protective signaling through the PI3K/Akt pathway of T cells against Fas-mediated apoptosis.
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Affiliation(s)
- Chung-Chen Su
- Institute of Basic Medical Sciences, National Cheng Kung University, Tainan, Taiwan, Republic of China
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Lu R, Wang X, Chen ZF, Sun DF, Tian XQ, Fang JY. Inhibition of the extracellular signal-regulated kinase/mitogen-activated protein kinase pathway decreases DNA methylation in colon cancer cells. J Biol Chem 2007; 282:12249-59. [PMID: 17307743 DOI: 10.1074/jbc.m608525200] [Citation(s) in RCA: 88] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
The extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK-MAPK) pathway is a critical intermediary for cell proliferation, differentiation, and survival. In the human colon cancer cell line SW1116, treatment with the DNA methyltransferase 1 (DNMT1) inhibitor 5-aza-2'-deoxycytidine (5-aza-dC) or the ERK-MAPK inhibitors PD98059 or rottlerin, or transient transfection with the MAP/ERK kinase (MEK)1/2 small interfering RNA down-regulates DNMT1 and proliferating cell nuclear antigen levels. In this report, we found that drug treatment or small interfering RNA transfection of SW1116 cells induced promoter demethylation of the p16(INK4A) and p21(WAF1) genes, which up-regulated their mRNA and protein expression levels. Flow cytometry revealed that rottlerin treatment induced cell cycle arrest at phase G(1) (p < 0.05). Thus, the ERK-MAPK inhibitor treatment or siRNA-mediated knockdown of ERK-MAPK decreases DNA methylation via down-regulating DNMT1 expression and other unknown mediator(s) in SW1116 colon cancer cells.
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Affiliation(s)
- Rong Lu
- Shanghai Jiaotong University School of Medicine, Renji Hospital, Shanghai Institute of Digestive Disease, Shanghai 200001, China
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Tohnosu N, Narushima K, Sunouchi K, Saito T, Shimizu T, Tanaka H, Maruyama T, Watanabe Y, Kato T, Shimizu S, Uehara T, Ishii S. A case of breast cancer metastatic to the tail of the pancreas. Breast Cancer 2006; 13:225-9. [PMID: 16755123 DOI: 10.2325/jbcs.13.225] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
Breast cancer metastasis to pancreas is rarely seen. There have been only 6 cases described in the literature. We present the seventh case of a 54-year-old woman with breast cancer that metastasized to the tail of the pancreas 4 years and 4 months after radical mastectomy. Although the serum levels of CA15-3 and TPA had gradually increased without symptoms, it was difficult to establish the diagnosis before contrast-enhanced abdominal CT scan was performed. Immunohistochemical staining using E-cadherin was positive, proving that the breast cancer was ductal rather than lobular in origin. CA15-3 immunohistochemically stained positive in the resected pancreas lesion. Positive monoclonal staining by GCDFP-15 (gross cystic disease fluid protein-15) in the pancreas tumor also confirmed it breast cancer origin. Investigation of chemokine/chemokine receptors may clarify a new mechanism of metastasis to the pancreas from breast cancer.
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Affiliation(s)
- Noriyuki Tohnosu
- Department of Surgery, Funabashi Municipal Medical Center, Chiba, Japan
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McKechnie NM, King BCR, Fletcher E, Braun G. Fas-ligand is stored in secretory lysosomes of ocular barrier epithelia and released with microvesicles. Exp Eye Res 2006; 83:304-14. [PMID: 16563377 DOI: 10.1016/j.exer.2005.11.028] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2004] [Revised: 08/01/2005] [Accepted: 11/29/2005] [Indexed: 01/07/2023]
Abstract
Previously we described the release of hr44 from the ciliary epithelium to coincide with the loss of the late endosomal/lysosomal marker protein CD63 in mildly inflamed rat eyes. We showed that both proteins are released with microvesicles into the supernatant of cultured retinal pigmented epithelial cells (ARPE-19). Here we wish to determine whether there is a concomitant loss of fas-ligand (FasL) in vivo and whether ocular epithelial cells have secretory lysosomes similar to T cells, from where FasL and hr44 could derive. FasL plays an important role in immunity, immune cell homeostasis and in the maintenance of immune privilege in the eye. However the mode of release of FasL from ocular epithelial cells or its activity in the eye is not fully understood. In normal rat eyes, FasL was detected in the epithelia of the iris and ciliary body and in the anterior region of the retinal pigmented epithelium. FasL is expressed constitutively and is associated with vesicular structures in the normal ciliary epithelium but is not detectable in the ciliary epithelium of inflamed eyes. In contrast, the posterior RPE, which under normal conditions is negative for FasL and hr44 showed strong staining for both molecules in areas adjacent to sub-retinal inflammatory infiltrates. Immunofluorescence and Western blot analysis indicated that cultured ARPE-19 cells express both the soluble and membrane form of FasL. The intracellular concentration of FasL was significantly increased in cells grown in presence of interferon (INF)-gamma. The microvesicles released by cultured ARPE-19 cells and previously shown to be positive for hr44 and CD63 are also positive for membrane FasL. Expression of a recombinant fluorescent construct of FasL together with immuno-staining for CD63 demonstrated that FasL localises to the endocytic compartment of ARPE-19 cells and of melanoma cells (positive control). In cells with lysosomes devoid of specialised secretory functions (e g. HeLa cells) recombinant FasL localised to the cell membrane, demonstrating that RPE cells have secretory lysosomes. We suggest that ocular epithelial cells release soluble FasL and the membrane form of FasL with vesicles. Both forms may contribute in different ways to the effectiveness of the ocular immune response and immune privilege.
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Affiliation(s)
- Nicol M McKechnie
- Department of Pathology and Microbiology, School of Medical Sciences, University of Bristol, University Walk, Bristol BS8 1TD, UK
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Grandics P. The cancer stem cell: evidence for its origin as an injured autoreactive T cell. Mol Cancer 2006; 5:6. [PMID: 16478542 PMCID: PMC1386699 DOI: 10.1186/1476-4598-5-6] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2006] [Accepted: 02/14/2006] [Indexed: 02/06/2023] Open
Abstract
This review explores similarities between lymphocytes and cancer cells, and proposes a new model for the genesis of human cancer. We suggest that the development of cancer requires infection(s) during which antigenic determinants from pathogens mimicking self-antigens are co-presented to the immune system, leading to breaking T cell tolerance. Some level of autoimmunity is normal and necessary for effective pathogen eradication. However, autoreactive T cells must be eliminated by apoptosis when the immune response is terminated. Apoptosis can be deficient in the event of a weakened immune system, the causes of which are multifactorial. Some autoreactive T cells suffer genomic damage in this process, but manage to survive. The resulting cancer stem cell still retains some functions of an inflammatory T cell, so it seeks out sites of inflammation inside the body. Due to its defective constitutive production of inflammatory cytokines and other growth factors, a stroma is built at the site of inflammation similar to the temporary stroma built during wound healing. The cancer cells grow inside this stroma, forming a tumor that provides their vascular supply and protects them from cellular immune response. As cancer stem cells have plasticity comparable to normal stem cells, interactions with surrounding normal tissues cause them to give rise to all the various types of cancers, resembling differentiated tissue types. Metastases form at an advanced stage of the disease, with the proliferation of sites of inflammation inside the body following a similar mechanism. Immunosuppressive cancer therapies inadvertently re-invigorate pathogenic microorganisms and parasitic infections common to cancer, leading to a vicious circle of infection, autoimmunity and malignancy that ultimately dooms cancer patients. Based on this new understanding, we recommend a systemic approach to the development of cancer therapies that supports rather than antagonizes the immune system.
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Wang WS, Chen PM, Wang HS, Liang WY, Su Y. Matrix metalloproteinase-7 increases resistance to Fas-mediated apoptosis and is a poor prognostic factor of patients with colorectal carcinoma. Carcinogenesis 2006; 27:1113-20. [PMID: 16474169 DOI: 10.1093/carcin/bgi351] [Citation(s) in RCA: 67] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
The ability of tumor cells to resist apoptosis triggered by immune cells results in their escape from immune surveillance of the host. A critical effector of apoptosis is the Fas/Fas ligand (FasL) system that mediates the tumoricidal effects of cytotoxic T cells. Recently, in vitro cleavage of Fas expressed in various tumor cells by matrix metalloproteinase-7 (MMP-7) was demonstrated. In the present study, we first analyzed the influence of this metalloproteinase on Fas signaling in SW480, HCT-15 and HT-29 colorectal carcinoma (CRC) cells by assessing their responses to either an agonistic Fas antibody (CH11) or the FasL-bearing Jurkat cells after they were pretreated with MMP-7. Interestingly, both antibody- and Jurkat cell-induced apoptosis in three different CRC lines were significantly reduced by MMP-7 pretreatment. Additionally, immunohistochemical (IHC) staining was used to examine the expression levels of MMP-7 and Fas in tumor samples of 54 CRC patients. In agreement with our in vitro observation, the expression of MMP-7 in tumor tissues was inversely correlated with those of Fas (P < 0.001; chi2-test). Moreover, shortened survival was found in patients with a higher MMP-7 and a lower Fas expression, respectively, in their tumor tissues (P < 0.0001). Finally, by multivariate analysis, we discovered that MMP-7 (P = 0.001) and Fas levels (P = 0.036) were independent prognostic factors for CRC patients. These results suggest that Fas downregulation and a consequential increased resistance to FasL-triggered apoptosis resulting from upregulated MMP-7 in colorectal cancer cells could be a key mechanism for their escape from the immune surveillance, thereby predicting a poor survival in CRC patients.
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Affiliation(s)
- Wei-Shu Wang
- Division of Medical Oncology, Department of Medicine. Division of Colorectal Surgery, Taipei Veterans General Hospital, Taipei, Taiwan, Republic of China
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Ibrahim R, Frederickson H, Parr A, Ward Y, Moncur J, Khleif SN. Expression of FasL in squamous cell carcinomas of the cervix and cervical intraepithelial neoplasia and its role in tumor escape mechanism. Cancer 2006; 106:1065-77. [PMID: 16456813 DOI: 10.1002/cncr.21697] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
BACKGROUND To date, several mechanisms have been described by which malignant cells escape from the immune system. One of these is through the expression of FasL. The authors hypothesized that the Fas/FasL interaction enables cervical carcinoma cells to induce apoptosis of the cells of the immune system and thereby escape from them. METHODS The authors tested the expression of FASL on the surface of cervical carcinoma tissues. Next, they stained the same cervical tissues with anti-human leukocyte common antigen and TUNEL to identify apoptotic cells. An in vitro functional assay was then done to test if the FASL expressed on the surface of cervical carcinoma cell lines was or was not responsible for inducing apoptosis in T-cells. Finally, they compared the expression of FASL on normal and dysplastic cervical tissues. RESULTS Ninety-four percent of the cervical carcinoma tissues the authors tested expressed FasL and the majority of the apoptotic cells in the specimens were leukocytes with very few tumor cells. In the in vitro functional assay, only the Fasl expressing cell line and not the Fasl negative cell line was able to induce apoptosis of the Fas-expressing Jurkat cells. On examining the normal cervical tissues, the authors found that the expression of Fasl was confined to the basal cell layer with loss of expression observed in the suprabasal layers, which made it an immune privileged site. Conversely, there was persistent expression of FasL in the dysplastic layers in cervical dysplasia and squamous cell carcinoma specimens. CONCLUSIONS The findings of the current study support the authors' hypothesis that persistent expression of FasL plays a role in the ability of cervical carcinoma cells to escape from the immune system.
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Affiliation(s)
- Ramy Ibrahim
- Cancer Vaccine Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20889, USA
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Hsiao HL, Wang WS, Chen PM, Su Y. Overexpression of thymosin β-4 renders SW480 colon carcinoma cells more resistant to apoptosis triggered by FasL and two topoisomerase II inhibitors via downregulating Fas and upregulating Survivin expression, respectively. Carcinogenesis 2005; 27:936-44. [PMID: 16364925 DOI: 10.1093/carcin/bgi316] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
The present work was conducted to further examine the effects of thymosin beta-4 (Tbeta4) upregulation on the apoptosis of SW480 colon cancer cells induced by T cells and various chemotherapeutic agents because reduced susceptibility to the cytotoxicity of an anti-Fas IgM (CH-11) in Tbeta4-overexpressing cells has previously been reported by us. As expected, Tbeta4 overexpressers were also more resistant to the killing effect of FasL-bearing Jurkat T cells. On the other hand, pretreating these cells with an MMP inhibitor restored not only their Fas levels but also their sensitivity to CH-11, suggesting a pivotal role of MMP in downregulating Fas in Tbeta4 overexpressers. Interestingly, while the susceptibilities of Tbeta4 overexpressers to 5-FU and irinotecan remained unchanged, they were more resistant to doxorubicin and etoposide which triggered apoptosis via a mitochondrial pathway. Concordantly, activation of both caspases 9 and 3 in Tbeta4 overexpressers by the two aforementioned topoisomerase II inhibitors was dramatically abrogated which could be accounted mainly by an increased expression of Survivin, a critical anti-apoptotic factor. Finally, poor survival was found in stage III colon cancer patients whose tumors were stained positively by the anti-Survivin antibody. Thus, advantages such as immune evasion and resistance to anticancer drug-induced apoptosis acquired by colon cancer cells through Tbeta4 overexpression might facilitate their survival during metastasis and chemotherapy.
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Affiliation(s)
- Hung-Liang Hsiao
- Institute of Pharmacology, College of Medicine, National Yang-Ming University, Shih-Pai, Taipei 11221, Taiwan, R.O. China
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Saitou Y, Shiraki K, Fuke H, Inoue T, Miyashita K, Yamanaka Y, Yamaguchi Y, Yamamoto N, Ito K, Sugimoto K, Nakano T. Involvement of tumor necrosis factor-related apoptosis-inducing ligand and tumor necrosis factor-related apoptosis-inducing ligand receptors in viral hepatic diseases. Hum Pathol 2005; 36:1066-73. [PMID: 16226105 DOI: 10.1016/j.humpath.2005.07.019] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2005] [Accepted: 07/21/2005] [Indexed: 12/12/2022]
Abstract
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in tumor cells, but not in most normal cells. The role of TRAIL in hepatic cell death and hepatic diseases is not well understood. The present study investigated the expression of TRAIL and TRAIL receptors (TRAIL-Rs) in patients with hepatitis C virus infection using immunohistochemistry and examined physiological roles under viral infection in the HepG2 cell line. Staining of TRAIL or TRAIL-Rs was prominent in the cytoplasm and membrane of hepatocytes in the periportal area. Some liver-infiltrating lymphocytes also displayed positive staining for TRAIL. Staining intensity was significantly increased with disease progression, particularly in the periportal area. AdCMVLacZ (Q-BIOgene, Carisbad, Calif) infection was also found to induce apoptosis in HepG2 cells and significantly augment TRAIL-induced apoptosis. Anti-TRAIL antibody significantly inhibited apoptosis induced by AdCMVLacZ infection. Flow cytometry analysis revealed that both TRAIL-R2 and TRAIL were up-regulated on the cell surface of HepG2 cells with AdCMVLacZ infection. Transforming growth factor-beta1 also enhanced TRAIL expression in HepG2 cells. These results indicate that TRAIL/TRAIL-R apoptotic pathways play important roles in the hepatic cell death during viral infection.
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Affiliation(s)
- Yukiko Saitou
- First Department of Internal Medicine, Mie University School of Medicine, Tsu, Mie 514-8507, Japan
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Saitou Y, Shiraki K, Yamanaka T, Miyashita K, Inoue T, Yamanaka Y, Yamaguchi Y, Enokimura N, Yamamoto N, Itou K, Sugimoto K, Nakano T. Augmentation of tumor necrosis factor family-induced apoptosis by E3330 in human hepatocellular carcinoma cell lines via inhibition of NFκB. World J Gastroenterol 2005; 11:6258-61. [PMID: 16419152 PMCID: PMC4320327 DOI: 10.3748/wjg.v11.i40.6258] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the reduction of cell viability in human hepatocellular carcinoma (HCC) cell lines induced by inhibition of nuclear factor κB (NFκB).
METHODS: HLE, SKHep1, and HepG2 were incubated and E3330 was used to compare the stimulation of some chemotherapeutic drugs with that of TNF family, Fas ligand, TNFα and TNF-related apoptosis-inducing ligand (TRAIL) at the point of the reduction of cell viability by inhibiting NFκB.
RESULTS: E3330 decreased NFκB levels in HLE cells stimulated by TNF and TRAIL. The cytotoxicity of the combination of TRAIL, TNFα, Fas ligand, and E3330 increased synergistically in a dose-dependent manner compared to either E3330 alone in all HCC cell lines by MTT assay. However, the combination of some chemotherapeutic drugs and E3330 did not decrease the cell viability.
CONCLUSION: Inhibition of NFκB sensitizes human HCC cell lines to TNF-mediated apoptosis including TRAIL, and TRAIL-based tumor therapy might be a powerful potential therapeutic tool in the treatment of human HCC.
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Affiliation(s)
- Yukiko Saitou
- First Department of Internal Medicine, Mie University School of Medicine, Tsu, Mie 514-8507, Japan
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Reipert BM, Tanneberger S, Pannetta A, Bedosti M, Poell M, Zimmermann K, Stellamor MT. Increase in autoantibodies against Fas (CD95) during carcinogenesis in the human colon: a hope for the immunoprevention of cancer? Cancer Immunol Immunother 2005; 54:1038-42. [PMID: 15864586 PMCID: PMC11032757 DOI: 10.1007/s00262-005-0679-0] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2004] [Accepted: 01/14/2005] [Indexed: 12/31/2022]
Abstract
A thorough understanding of the naturally occurring events in the immune system in response to carcinogenesis will facilitate the development of strategies for the immunoprevention of cancer. The adenoma-carcinoma sequence in the human colon is a well-established clinical example of multi-step carcinogenesis and can be used for immunological studies. Based on previous observations that both apoptosis and the expression of Fas (Apo-1, CD95) are altered during carcinogenesis in the human colon, we asked the question whether serum titers of autoantibodies against Fas show any modification during the adenoma-carcinoma sequence. Healthy controls (38), patients with colorectal adenomas (38) and patients with colorectal adenocarcinomas (21) were investigated. Anti-Fas antibody titers were found to be significantly higher in patients with colorectal adenomas than in healthy controls and higher still in patients with colorectal adenocarcinomas. This increase in anti-Fas autoantibody titers during carcinogenesis might reflect the activation of natural defense mechanisms by the immune system.
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Affiliation(s)
- B M Reipert
- Biomolecular Therapeutics (BMT)-Research Center, Industriestrasse 72, 1220 Vienna, Austria.
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Myong NH. Tissue microarray analysis of Fas and FasL expressions in human non-small cell lung carcinomas; with reference to the p53 and bcl-2 overexpressions. J Korean Med Sci 2005; 20:770-6. [PMID: 16224150 PMCID: PMC2779273 DOI: 10.3346/jkms.2005.20.5.770] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
Lack of surface Fas expression is a main route for apoptotic resistance which is considered an important mechanism of tumorigenesis and tumor progression. Fas and FasL expressions in 110 non-small cell lung carcinomas (NSCLCs) were investigated to evaluate their roles in pulmonary carcinogenesis and to examine the clinicopathologic significance of Fas expression with its relationship with p53 and bcl-2 overexpressions. Immunohistochemical analysis using tissue microarray demonstrated that a large proportion of NSCLC patients (60%) showed lack of membranous Fas expression. The Fas-negative cases revealed the significantly lower survival rate than Fas-positive ones. Also, the loss of Fas receptor expression was found more frequently in advanced stage and higher nodal status. FasL protein was increased in most NSCLCs (89%) compared to normal lungs. p53 and bcl-2 overexpressions showed no association with Fas expression. Conclusively, reduced membranous Fas expression as a mechanism of apoptotic resistance is considered to play an important part of the pulmonary carcinogenesis, which may predict poor survival and have a bad prognostic influence. Increased FasL expression is thought to be a basis for the immune evasion in NSCLCs. The rare bcl-2 overexpression suggests that this anti-apoptotic protein is unlikely to play a role in the apoptotic resistance of NSCLCs.
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Affiliation(s)
- Na-Hye Myong
- Department of Pathology, Dankook University College of Medicine, Cheonan, Korea.
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Expression of FLIP in human colon carcinomas: A new mechanism of immune evasion. Chin J Cancer Res 2005. [DOI: 10.1007/s11670-005-0039-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022] Open
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Chiou SH, Sheu BC, Chang WC, Huang SC, Hong-Nerng H. Current concepts of tumor-infiltrating lymphocytes in human malignancies. J Reprod Immunol 2005; 67:35-50. [PMID: 16111767 DOI: 10.1016/j.jri.2005.06.002] [Citation(s) in RCA: 65] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Tumor-infiltrating lymphocytes (TILs) develop as manifestations of the recognition and defense against malignant cells by the host immune system. TILs were literally defined as "tumor-infiltrating lymphocytes", which a posteriori locate within the tumor tissues. Although such cells can be found, they fail to control the growth of tumor. Many have proposed diverse mechanisms for dysfunction of TILs with regard to the roles of immunosurveillance against cancer. However, only a few cancer types, e.g. melanoma, have seen the benefits brought by activating these cells for immunotherapy. Functional defects of TILs have been linked to abnormalities of signaling molecules; however, there is conflicting data. The death of TILs was attributed to expression of cancer-derived FasL, PD-1 and RCAS1, and cancer-induced activation-induced cell death (AICD). Confirmed by studies using TILs and animal models, the compromise of tumor-specific immune responses was thought to result from not only mechanisms of clonal anergy but also exhaustion and/or deletion. Furthermore, functional cytotoxic CD8(+) TILs might be rendered incompetent by cancer-induced up-regulation of inhibitory NK receptors or proximal signaling abnormalities. Additionally, immune privilege was partly attributed to recruitment of regulatory T cells to the tumor sites. The failure of IL-2 signaling, which stands at the center of T cell functionalities, had been linked to the enzymatic activity of cancer-derived matrix metalloproteinases (MMPs). Finally, the exploitation of IDO expression, an important enzyme in pregnancy-related immunosuppression, by cancer cells might play a role in tumor immunity. The disparity of cancer types, origin, developmental stages and individual genetic backgrounds likely account for differences, or even contradictions, which might be the reason why immunotherapy works only on a few cancer types. Delineating the mechanisms behind functional defects of TILs can help not only boost chances of the development of a successful cure but understand the not fully identified roles played by immune system in the face of malignancies.
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Affiliation(s)
- Shin-Heng Chiou
- Department of Obstetrics and Gynecology, National Taiwan University Hospital, 7 Chung-Shan South Road, Taipei 100, Taiwan
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Okano H, Shiraki K, Yamanaka Y, Inoue H, Kawakita T, Saitou Y, Yamaguchi Y, Enokimura N, Ito K, Yamamoto N, Sugimoto K, Murata K, Nakano T. Functional expression of a proliferation-related ligand in hepatocellular carcinoma and its implications for neovascularization. World J Gastroenterol 2005; 11:4650-4. [PMID: 16094704 PMCID: PMC4615405 DOI: 10.3748/wjg.v11.i30.4650] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To detect the expression of a proliferation-related ligand on human hepatocellular carcinoma (HCC) cell lines (SK-Hep1, HLE and HepG2) and in culture medium.
METHODS: APRIL expression was analyzed by Western blotting in HCC cell lines. Effects of APRIL to cell count and angiogenesis were analyzed, too.
RESULTS: Recombinant human APRIL (rhAPRIL) increased cell viability of HepG2 cells and, in HUVEC, rhAPRIL provided slight tolerance to cell death from serum starvation. Soluble APRIL (sAPRIL) from HLE cells increased after serum starvation, but did not change in SK-Hep1 or HepG2 cells. These cells showed down-regulation of VEGF after incubation with anti-APRIL antibody. Furthermore, culture medium from the HCC cells treated with anti-APRIL antibody treatment inhibited tube formation of HUVECs.
CONCLUSION: Functional expression of APRIL might contribute to neovascularization via an upregulation of VEGF in HCC.
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Affiliation(s)
- Hiroshi Okano
- First Department of Internal Medicine, Mie University School of Medicine, Tsu, Mie 514-8507, Japan
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Somma P, Lo Muzio L, Mansueto G, Delfino M, Fabbrocini G, Mascolo M, Mignogna C, Di Benedetto M, Carinci F, De Lillo A, Pastore L, Serpico R, De Rosa G, Staibano S. Squamous cell carcinoma of the lower lip: FAS/FASL expression, lymphocyte subtypes and outcome. Int J Immunopathol Pharmacol 2005; 18:59-64. [PMID: 15698511 DOI: 10.1177/039463200501800107] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Squamous cell carcinoma (SCC) of the lip is a relatively common malignancy of the head and neck region. Tumour thickness, grading and perineural invasion are significant prognostic indicators. However, there is still the need of new reliable biological markers able to predict the prognosis of the single cases with an unfavourable biological behaviour unpredictable by the classic clinical-pathological parameters. 32 cases of (SCC) of the lower lip were analysed for their clincopathologic features, and immunohistochemical expression of Fas/FasL in neoplastic cells and in inflammatory infiltrate. Moreover the density and phenotype of tumour-infiltrating lymphocytes (TIL) were analysed. The results were related with the follow-up of the patients ranging from 2 to 6 years. The cases with over-expression of Fas/FasL in neoplastic cells and Fas+ in T cells preferentially showed a more aggressive clinical behaviour (P<0.01). Moreover we found an alteration of the normal expression of CD4 and CD8 lymphocyte types in ten cases. This data suggest that the Fas/FasL pathway is involved in the close relation between neoplastic cells and T cells and so in the biological behaviour of these tumours.
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Affiliation(s)
- P Somma
- Department of Biomorphologic and Functional Sciences, Section of Pathology. University of Naples Federico II, Naples, Italy
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Xu T, Sun BC, Li Q, Hao XS. Role of cytokines in promoting immune escape of FasL-expressing human colon cancer cells. World J Gastroenterol 2005; 11:3915-9. [PMID: 15991293 PMCID: PMC4504896 DOI: 10.3748/wjg.v11.i25.3915] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the potential role of cytokines in promoting Fas ligand (FasL)-expressing colon cancer cells.
METHODS: Immunohistochemical SABC method was used to observe the expression of Fas receptor and ligand in SW620 colon cancer cell line and Jurkat T cells in order to provide the morphological evidence for the functions of Fas receptor and ligand. To examine the cytotoxicity of effector cells, CytoTox96 non-radioactive cytotoxicity assay was adopted to measure the lactate dehydrogenase-releasing value after SW620 cells were co-cultured with Jurkat T lymphocytes.
RESULTS: The FasL of colon cancer SW620 cells was positive. The positive substances were distributed in the cell membrane and cytoplasm. The Fas receptor of colon cancer SW620 cells was negative. The Fas receptor and ligand of Jurkat T lymphocytes turned out to be positive. The positive substances were distributed in the cell membrane. After phytohemagglutinin (PHA)-stimulated Jurkat T lymp-hocytes were co-cultured with phorbol 12-myristate 13-acetate (PMA)-plus-ionomycin-stimulated (for 48 h) SW620 cells or tumor necrosis factor-alpha (TNF-α)-stimulated (for 48 h) SW620 cells or unstimulated SW620 cells for 4 h, the cytotoxicity of SW620 cells to PHA-stimulated Jurkat cells at effector-to-target ratios of 10:1, 5:1, 2.5:1, and 1.25:1 was 74.6%, 40.8%, 32.4%, and 10.9% (F = 8.19, P < 0.05); or 54.9%, 35.3%, 22.0%, and 10.3% (F = 11.12, P < 0.05); or 14.9%, 10.5%, 6.9%, and 5.8% (F = 3.45, P < 0.05). After PHA-stimulated Jurkat T lymphocytes were co-cultured with unstimulated SW620 cells for 8 h, the cytotoxicity of SW620 cells to PHA-stimulated Jurkat cells at effector-to-target ratios of 5:1, 2.5:1, and 1.25:1 from the experiment was 83.9%, 74.1%, and 28.5% (F = 137.04, P < 0.05) respectively. Non-radioactive cytotoxicity assay showed that the apoptotic rate of Jurkat cells remarkably increased with the increase of planting concentration of SW620 cells and co-culture time after the SW620 cells were co-cultured with the Jurkat T lymphocytes. The cytotoxicity was significantly enhanced by PMA+ionomycin or TNF-α.
CONCLUSION: The FasL expressed in human colon cancer cells may be regulated by endogenous factors in the microenvironment of the host and facilitate the escape of tumor cells from the host immune system.
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Affiliation(s)
- Tong Xu
- Department of Abdominal Surgery, Cancer Hospital Affiliated to Tianjin Medical University, Tianjin 300060, China.
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Zhang W, Ding EX, Wang Q, Zhu DQ, He J, Li YL, Wang YH. Fas ligand expression in colon cancer: A possible mechanism of tumor immune privilege. World J Gastroenterol 2005; 11:3632-5. [PMID: 15962391 PMCID: PMC4315977 DOI: 10.3748/wjg.v11.i23.3632] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To detect the expression of Fas ligand (FasL) in colon cancer tissues and cell lines and analyze the function of FasL-expressing colon cancer cells in inducing Fas-sensitive T lymphocyte apoptosis.
METHODS: Ninety surgically resected colon cancer tissues and 15 hepatic metastasis specimens were investigated by immunohistochemical method with normal colon mucosa and colon adenoma as control. The relationship between FasL expression and pathologic features was also analyzed. FasL expression of 4 colon cancer cell lines, SW620, Lovo, LS-174T and SW1116, were detected by Western blotting assay. The function of FasL expressed on colon cancer cells was determined by coculture assay with Jurkat T lymphocytes, the apoptotic rate of which was detected by flow cytometry assay.
RESULTS: Fifty-six (62.22%) cases of all the 90 colon cancer tissues and all (100%) the liver metastasis specimens expressed FasL, significantly higher than normal colon mucosa and colonic adenoma. Higher expression of FasL was found in more advanced stage of colon cancer and in cancer tissues with lymphatic or hepatic metastasis. All the colon cancer cell lines were found to express FasL. After coculture with the SW1116 cells for 24 h with an effector: target ratio 10:1, the rate of apoptosis of Jurkat cells rose from 1.9% to 21.0%.
CONCLUSION: The expression of FasL is upregulated in colon cancer and the functionally expressed FasL can induce apoptosis of Fas-expressing T lymphocytes.
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Affiliation(s)
- Wei Zhang
- Department of General Surgery, Changzheng Hospital, Second Military Medical University, Shanghai 20003, China.
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Endoh T, Tsuji N, Asanuma K, Yagihashi A, Watanabe N. Survivin enhances telomerase activity via up-regulation of specificity protein 1- and c-Myc-mediated human telomerase reverse transcriptase gene transcription. Exp Cell Res 2005; 305:300-11. [PMID: 15817155 DOI: 10.1016/j.yexcr.2004.12.014] [Citation(s) in RCA: 54] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2004] [Revised: 12/16/2004] [Accepted: 12/20/2004] [Indexed: 01/01/2023]
Abstract
Suppression of apoptosis is thought to contribute to carcinogenesis. Survivin, a member of the inhibitor-of-apoptosis family, blocks apoptotic signaling activated by various cellular stresses. Since elevated expression of survivin observed in human cancers of varied origin was associated with poor patient survival, survivin has attracted growing attention as a potential target for cancer treatment. Immortalization of cells also is required for carcinogenesis; telomere length maintenance by telomerase is required for cancer cells to proliferate indefinitely. Yet how cancer cells activate telomerase remains unclear. We therefore examined possible interrelationships between survivin expression and telomerase activity. Correlation between survivin and human telomerase reverse transcriptase (hTERT) expression was observed in colon cancer tissues, and overexpression of survivin enhanced telomerase activity by up-regulation of hTERT expression in LS180 human colon cancer cells. DNA-binding activities of specificity protein 1 (Sp1) and c-Myc to the hTERT core promoter were increased in survivin gene transfectant cells. Phosphorylation of Sp1 and c-Myc at serine and threonine residues was enhanced by survivin, while total amounts of these proteins were unchanged. Further, "knockdown" of survivin by a small inhibitory RNA decreased Sp1 and c-Myc phosphorylation. Thus survivin participates not only in inhibition of apoptosis, but also in prolonging cellular lifespan.
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Affiliation(s)
- Teruo Endoh
- Department of Clinical Laboratory Medicine, Sapporo Medical University, School of Medicine, South-1, West-16, Sapporo 060-8543, Japan
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Abstract
Tle liver has a number of important functions in innate and adaptive immunity. Contributions to the innate (nonspecific) immune system include production of acute phase proteins, nonspecific phagocytosis of particles, nonspecific pinocytosis of molecules, and nonspecific cell killing. Hepatic involvement in innate immunity contributes to the systemic response to local inflammation, clearance of particles and soluble molecules from the circulation, and killing of invading cells such as neoplastic cells. Liver involvement in the adaptive (specific) immune system includes deletion of activated T cells, induction of tolerance to ingested and self-antigens, extrathymic proliferation of T cells, and deletion of many of the signaling and effector molecules. Hepatic involvement in adaptive immunity allows clearance of activated T cells and signaling molecules following inflammatory reactions, and promotes immunologic tolerance toward potentially antigenic proteins that are absorbed from the intestinal tract. The liver is a major site of extrathymic T cell development, which assumes increasing significance with aging in mammals. Perturbations in hepatic structure or function can result in significant ramifications in both the innate and adaptive immune systems.
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Huber V, Fais S, Iero M, Lugini L, Canese P, Squarcina P, Zaccheddu A, Colone M, Arancia G, Gentile M, Seregni E, Valenti R, Ballabio G, Belli F, Leo E, Parmiani G, Rivoltini L. Human colorectal cancer cells induce T-cell death through release of proapoptotic microvesicles: role in immune escape. Gastroenterology 2005; 128:1796-804. [PMID: 15940614 DOI: 10.1053/j.gastro.2005.03.045] [Citation(s) in RCA: 410] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
BACKGROUND & AIMS Normal and neoplastic cells release microvesicles, whose effects on the immune system still need to be elucidated. Because human colorectal cancer cells are hypothesized to escape immune recognition by expressing proapoptotic molecules, we investigated whether microvesicles bearing Fas ligand and tumor necrosis factor-related apoptosis-inducing ligand and inducing apoptosis of activated T cells are secreted by colorectal cancer cells both in vitro and in affected patients. METHODS Fas ligand and tumor necrosis factor-related apoptosis-inducing ligand expression were analyzed in colorectal cancer cells and purified microvesicles by flow cytometry, Western blotting, and immunoelectron microscopy. Microvesicle tumor origin was assessed through simultaneous detection of lysosomal (CD63) and adenocarcinoma (carcinoembryonic antigen) markers. Proapoptotic activity of microvesicles was evaluated by annexin V/propidium iodide staining and caspase activation in T cells, including CD8+ T lymphocytes from colorectal cancer patients. RESULTS Colorectal cancer cells showed a granular pattern of tumor necrosis factor-related apoptosis-inducing ligand and Fas ligand expression, suggesting a secretory behavior. These proapoptotic molecules were detected on isolated microvesicles, together with class I HLA, CD63, and carcinoembryonic antigen. Microvesicles induced Fas ligand-mediated and tumor necrosis factor-related apoptosis-inducing ligand-mediated apoptosis of activated CD8+ T cells generated from colorectal cancer patients. Microvesicles with comparable phenotypes and functions were found in plasma from patients with advanced disease, whereas vesicular structures expressing Fas ligand and tumor necrosis factor-related apoptosis-inducing ligand were also detected in colorectal cancer specimens. CONCLUSIONS These data show that colorectal cancer induces T-cell apoptosis through the release of Fas ligand-bearing and tumor necrosis factor-related apoptosis-inducing ligand-bearing microvesicles both in vitro and in vivo. This mechanism of immune escape has potential implications as a prognostic factor and could be targeted for the development of new antitumor therapies in colorectal cancer patients.
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Affiliation(s)
- Veronica Huber
- Unit of Immunotherapy of Human Tumors, Istituto Nazionale Tumori, Milan, Italy
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Ioachim HL, Decuseara R, Giancotti F, Dorsett BH. FAS and FAS-L expression by tumor cells and lymphocytes in breast carcinomas and their lymph node metastases. Pathol Res Pract 2005; 200:743-51. [PMID: 15792116 DOI: 10.1016/j.prp.2004.09.006] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
FAS receptor (FAS, CD95) and FAS ligand (FAS-L, CD95-L) are complementary members of a particular apoptotic pathway that plays a major role in immune regulation. The activation of FAS-L may trigger cytotoxic mechanisms leading to the death of FAS-expressing cells. Tumor cells and tumor-infiltrating lymphocytes (TIL) may express FAS and FAS-L in various proportions, and their interplay may affect tumor behavior. In the present study, we explored the expression of FAS and FAS-L in 28 mammary carcinomas (19 ductal and 9 lobular) and in their lymph node metastases. The expression of these mediators in immunostained sections was graded and evaluated comparatively between normal and neoplastic mammary epithelium, between tumor cells and TILs, and between mammary carcinoma cells and their lymph node metastases. We demonstrated the coexpression of FAS and FAS-L by breast carcinoma cells and TIL, with FAS expressed more strongly by normal epithelial cells and TIL than tumor cells. FAS-L was better stained on tumor cells than on TIL. There was equal or greater expression of FAS and FAS-L in the primary tumors and their TIL than in the metastatic counterparts. Comparing the expression of FAS with that of FAS-L, we recorded FAS equal or stronger than FAS-L in the primary mammary tumors and the reversal of their expression, FAS-L greater than FAS in the lymph node metastases. These results are consistent with reports of studies with other tumors, suggesting that the upregulated FAS-L indicates an increased ability of tumor cells to induce apoptosis in TIL and in the normal tissues invaded. However, it is understood that the FAS/FAS-L system, although essential for apoptosis, is only a contributing factor to the complex process of tumor invasion and antitumor defense.
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MESH Headings
- Adult
- Aged
- Apoptosis/physiology
- Biomarkers, Tumor/metabolism
- Breast Neoplasms/metabolism
- Breast Neoplasms/pathology
- Carcinoma, Ductal, Breast/metabolism
- Carcinoma, Ductal, Breast/secondary
- Carcinoma, Lobular/metabolism
- Carcinoma, Lobular/secondary
- Fas Ligand Protein
- Female
- Humans
- Immunoenzyme Techniques
- Lymph Nodes/metabolism
- Lymph Nodes/pathology
- Lymphatic Metastasis
- Lymphocytes, Tumor-Infiltrating/metabolism
- Lymphocytes, Tumor-Infiltrating/pathology
- Membrane Glycoproteins/metabolism
- Middle Aged
- Receptors, Tumor Necrosis Factor/metabolism
- fas Receptor
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Affiliation(s)
- Harry L Ioachim
- Department of Pathology, Lenox Hill Hospital, New York University, New York, NY 10021, USA.
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Abstract
Colon cancer is the third most common cancer globally. The risk of developing colon cancer is influenced by a number of factors that include age and diet, but is primarily a genetic disease, resulting from oncogene over-expression and tumour suppressor gene inactivation. The induction and progression of the disease is briefly outlined, as are the cellular changes that occur in its progression. While colon cancer is uniformly amenable to surgery if detected at the early stages, advanced carcinomas are usually lethal, with metastases to the liver being the most common cause of death. Oncogenes and genetic mutations that occur in colon cancer are featured. The molecules and signals that act to eradicate or initiate the apoptosis cascade in cancer cells, are elucidated, and these include caspases, Fas, Bax, Bid, APC, antisense hTERT, PUMA, 15-LOX-1, ceramide, butyrate, tributyrin and PPARgamma, whereas the molecules which promote colon cancer cell survival are p53 mutants, Bcl-2, Neu3 and COX-2. Cancer therapies aimed at controlling colon cancer are reviewed briefly.
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Affiliation(s)
- Charleen Rupnarain
- School of Molecular and Cell Biology, University of the Witwatersrand, Private Bag 3, Johannesburg 2050, South Africa
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Fang JY, Chen YX, Lu J, Lu R, Yang L, Zhu HY, Gu WQ, Lu LG. Epigenetic modification regulates both expression of tumor-associated genes and cell cycle progressing in human colon cancer cell lines: Colo-320 and SW1116. Cell Res 2005; 14:217-26. [PMID: 15225415 DOI: 10.1038/sj.cr.7290222] [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: 01/31/2023] Open
Abstract
The aim of this study is to assess the effects of DNA methylation and histone acetylation, alone or in combination, on the expression of several tumor-associated genes and cell cycle progression in two established human colon cancer cell lines: Colo-320 and SW1116. Treatments with 5-aza-2-deoxycytidine (5-aza-dC) and trichostatin A, alone or in combination, were applied respectively. The methylation status of the CDKN2A promoter was determined by methylation-specific PCR, and the acetylated status of the histones associated with the p21WAF1 and CDKN2A genes was examined by chromatin immunoprecipitation. The expression of the CDKN2A, p21WAF1, p53, p73, APC, c-myc, c-Ki-ras and survivin genes was detected by real-time RT-PCR and RT-PCR. The cell cycle profile was established by flow cytometry. We found that along with the demethylation of the CDKN2A gene promoter in both cell lines induced by 5-aza-dC alone or in combination with TSA, the expression of both CDKN2A and APC genes increased. The treatment of TSA or sodium butyrate up-regulated the transcription of p21WAF1 significantly by inducing the acetylation of histones H4 and H3, but failed to alter the acetylation level of CDKN2A-associated histones. No changes in transcription of p53, p73, c-myc, c-Ki-ras and survivin genes were observed. In addition, TSA or sodium butyrate was shown to arrest cells at the G1 phase. However, 5-aza-dC was not able to affect the cell cycle progression. In conclusion, regulation by epigenetic modification of the transcription of tumor-associated genes and the cell cycle progression in both human colon cancer cell lines Colo-320 and SW1116 is gene-specific.
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Affiliation(s)
- Jing Yuan Fang
- Shanghai Institute of Digestive Disease, Renji Hospital Shanghai Second Medical University, Shanghai 200001, China.
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