42 results on '"Jarahian M"'
Search Results
2. Activation of AMP-activated protein kinase sensitizes lung cancer cells and H1299 xenografts to erlotinib
- Author
-
Huelsmann, H.J., Rolff, J., Bender, C., Jarahian, M., Korf, U., Herwig, R., Froehlich, H., Thomas, M., Merk, J., Fichtner, I., Sueltmann, H., Kuner, R., and MDC Library
- Subjects
610 Medical Sciences, Medicine ,AMPK ,Cancer Research ,Erlotinib ,EGFR ,Lung Cancer ,570 Life Sciences ,Xenograft Models ,respiratory tract diseases - Abstract
OBJECTIVES: The therapeutic scheme for non-small cell lung cancer (NSCLC) patients can be improved if adapted to the individual response. For example, 60-70% of adenocarcinoma patients show response to EGFR-tyrosine kinase inhibitors in the presence of mutated EGFR. We searched for additional target molecules involved in the action of the EGFR-tyrosine kinase inhibitor erlotinib in the absence of EGFR mutations, which might be suitable for combinatorial therapy approaches. MATERIALS AND METHODS: Erlotinib-response associated proteins were investigated in patient-derived NSCLC mouse xenografts by reverse-phase protein array technology (RPPA) and Western blotting. A combinatorial treatment approach was carried out in NSCLC cell lines and H1299 mouse xenografts, and subsequently analyzed for consequences in cell growth and signal transduction. RESULTS: AMP-activated protein kinase (AMPK) expression was increased in erlotinib responders before and after treatment. In a combinatorial approach, activation of AMPK by A-769662 and erlotinib treatment showed a synergistic effect in cell growth reduction and apoptosis activation in H1299 cells compared to the single drugs. AMPK pathway analyses revealed an effective inhibition of mTOR signaling by drug combination. In H1299 xenografts, the tumor size was significantly decreased after combinatorial treatment. CONCLUSION: Our results suggest that AMPK activation status affects response to erlotinib in distinct lung tumor models.
- Published
- 2014
3. The AP-1 transcription factor JunB is essential for multiple myeloma cell proliferation and drug resistance in the bone marrow microenvironment
- Author
-
Fan, F, primary, Bashari, M H, additional, Morelli, E, additional, Tonon, G, additional, Malvestiti, S, additional, Vallet, S, additional, Jarahian, M, additional, Seckinger, A, additional, Hose, D, additional, Bakiri, L, additional, Sun, C, additional, Hu, Y, additional, Ball, C R, additional, Glimm, H, additional, Sattler, M, additional, Goldschmidt, H, additional, Wagner, E F, additional, Tassone, P, additional, Jaeger, D, additional, and Podar, K, additional
- Published
- 2016
- Full Text
- View/download PDF
4. The AP-1 Transcription Factor JunB Promotes Multiple Myeloma (MM) Cell Proliferation, Survival and Drug Resistance in the Bone Marrow Microenvironment
- Author
-
Fan, F., primary, Vallet, S., additional, Sattler, M., additional, Tonon, G., additional, Bashari, M.H., additional, Bakiri, L., additional, Jarahian, M., additional, Roccaro, A., additional, Ghobrial, I., additional, Ball, C., additional, Glimm, H., additional, Anderson, K.C., additional, Goldschmidt, H., additional, Wagner, E.F., additional, Jaeger, D., additional, and Podar, K., additional
- Published
- 2015
- Full Text
- View/download PDF
5. The AP-1 transcription factor JunB is essential for multiple myeloma cell proliferation and drug resistance in the bone marrow microenvironment
- Author
-
Sonia Vallet, Giovanni Tonon, M. Jarahian, Anja Seckinger, Dirk Jaeger, Fengjuan Fan, Erwin F. Wagner, Latifa Bakiri, Martin Sattler, Claudia R. Ball, Chunyan Sun, Stefano Malvestiti, H. Goldschmidt, Eugenio Morelli, Pierfrancesco Tassone, Yu Hu, Hanno Glimm, Klaus Podar, Muhammad Hasan Bashari, Dirk Hose, Fan, F, Bashari, Mh, Morelli, E, Tonon, G, Malvestiti, S, Vallet, S, Jarahian, M, Seckinger, A, Hose, D, Bakiri, L, Sun, C, Hu, Y, Ball, Cr, Glimm, H, Sattler, M, Goldschmidt, H, Wagner, Ef, Tassone, P, Jaeger, D, and Podar, K
- Subjects
0301 basic medicine ,Cancer Research ,Stromal cell ,JUNB ,Biology ,Dexamethasone ,Bortezomib ,03 medical and health sciences ,Mice ,Bone Marrow ,hemic and lymphatic diseases ,medicine ,Tumor Microenvironment ,Animals ,Humans ,Transcription factor ,Cell Proliferation ,Tumor microenvironment ,Cell growth ,NF-kappa B ,Hematology ,AP-1 transcription factor ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,Drug Resistance, Neoplasm ,Cancer research ,Female ,Bone marrow ,Stem cell ,Multiple Myeloma ,Transcription Factors - Abstract
Despite therapeutic advances, multiple myeloma (MM) remains an incurable disease, predominantly because of the development of drug resistance. The activator protein-1 (AP-1) transcription factor family has been implicated in a multitude of physiologic processes and tumorigenesis; however, its role in MM is largely unknown. Here we demonstrate specific and rapid induction of the AP-1 family member JunB in MM cells when co-cultured with bone marrow stromal cells. Supporting a functional key role of JunB in MM pathogenesis, knockdown of JUNB significantly inhibited in vitro MM cell proliferation and survival. Consistently, induced silencing of JUNB markedly decreased tumor growth in a murine MM model of the microenvironment. Subsequent gene expression profiling revealed a role for genes associated with apoptosis, DNA replication and metabolism in driving the JunB-mediated phenotype in MM cells. Importantly, knockdown of JUNB restored the response to dexamethasone in dexamethasone-resistant MM cells. Moreover, 4-hydroxytamoxifen-induced activation of a JunB-ER fusion protein protected dexamethasone-sensitive MM cells against dexamethasone- and bortezomib-induced cytotoxicity. In summary, our results demonstrate for the first time a specific role for AP-1/JunB in MM cell proliferation, survival and drug resistance, thereby strongly supporting that this transcription factor is a promising new therapeutic target in MM.
- Published
- 2016
6. Corrigendum to "Cloning and Embryo Splitting in Mammalians: Brief History, Methods, and Achievements".
- Author
-
Rahbaran M, Razeghian E, Maashi MS, Jalil AT, Widjaja G, Thangavelu L, Kuznetsova MY, Nasirmoghadas P, Heidari F, Marofi F, and Jarahian M
- Abstract
[This corrects the article DOI: 10.1155/2021/2347506.]., (Copyright © 2024 Mohaddeseh Rahbaran et al.)
- Published
- 2024
- Full Text
- View/download PDF
7. Retraction Note: Mesenchymal stem/stromal cells as a valuable source for the treatment of immune-mediated disorders.
- Author
-
Markov A, Thangavelu L, Aravindhan S, Zekiy AO, Jarahian M, Chartrand MS, Pathak Y, Marofi F, Shamlou S, and Hassanzadeh A
- Published
- 2024
- Full Text
- View/download PDF
8. Nicaraven-loaded electrospun wound dressings promote diabetic wound healing via proangiogenic and immunomodulatory functions: a preclinical investigation.
- Author
-
Suliman Maashi M, Felemban SG, Almasmoum HA, and Jarahian M
- Subjects
- Animals, Rats, Drug Compounding, Collagen, Diabetes Mellitus
- Abstract
The current study developed a biopolymer-based wound dressing by electrospinning of Nicaraven-loaded collagen solution. Firstly, collagen was dissolved in acetic acid, and then Nicaraven was added to the polymeric solution at three different concentrations of 2 w/w%, 4 w/w%, and 6 w/w%. The resulting solution was then electrospun. Various experiments were performed to characterize the produced wound dressings. In vitro studies showed that Nicaraven-loaded scaffolds were not toxic against L929 fibroblast cells and protected them against oxidative stress. Wound healing potential of different formulations of Nicaraven-loaded collagen wound dressings was studied in a rat model of the excisional diabetic wound. The study showed that the collagen/4% Nicaraven and collagen/6% Nicaraven wound dressings exhibited a significantly higher percentage of wound closure, the thickness of the epithelium, and collagen deposition compared with collagen/2% Nicaraven, collagen-only, and sterile gauze groups. Gene expression study showed that the developed wound dressings reduced the tissue expression levels of glutathione peroxidase, NFKβ, and matrix metalloproteinase 9 (MMP9) genes. In addition, in the wounds treated with collagen/4% Nicaraven and collagen/6% Nicaraven scaffolds, wound healing was associated with a higher tissue expression level of b-FGF, VEGF, and collagen type I genes. Overall, wound healing activity of collagen/4% Nicaraven and collagen/6% Nicaraven wound dressings was not significantly different. This study implies that collagen wound dressings incorporated with 4% and 6% Nicaraven can be considered a potential candidate to treat diabetic wounds in the clinic., (© 2022. Controlled Release Society.)
- Published
- 2023
- Full Text
- View/download PDF
9. Dysregulation of Survivin-Targeting microRNAs in Autoimmune Diseases: New Perspectives for Novel Therapies.
- Author
-
Shomali N, Suliman Maashi M, Baradaran B, Daei Sorkhabi A, Sarkesh A, Mohammadi H, Hemmatzadeh M, Marofi F, Sandoghchian Shotorbani S, and Jarahian M
- Subjects
- Autoimmunity genetics, Humans, Survivin genetics, Autoimmune Diseases genetics, Autoimmune Diseases therapy, MicroRNAs genetics
- Abstract
It has been well established that the etiopathogenesis of diverse autoimmune diseases is rooted in the autoreactive immune cells' excessively proliferative state and impaired apoptotic machinery. Survivin is an anti-apoptotic and mitotic factor that has sparked a considerable research interest in this field. Survivin overexpression has been shown to contribute significantly to the development of autoimmune diseases via autoreactive immune cell overproliferation and apoptotic dysregulation. Several microRNAs (miRNAs/miRs) have been discovered to be involved in survivin regulation, rendering the survivin-miRNA axis a perspective target for autoimmune disease therapy. In this review, we discuss the role of survivin as an immune regulator and a highly implicated protein in the pathogenesis of autoimmune diseases, the significance of survivin-targeting miRNAs in autoimmunity, and the feasibility of targeting the survivin-miRNA axis as a promising therapeutic option for autoimmune diseases., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Shomali, Suliman Maashi, Baradaran, Daei Sorkhabi, Sarkesh, Mohammadi, Hemmatzadeh, Marofi, Sandoghchian Shotorbani and Jarahian.)
- Published
- 2022
- Full Text
- View/download PDF
10. Activating Natural Killer Cell Receptors, Selectins, and Inhibitory Siglecs Recognize Ebolavirus Glycoprotein.
- Author
-
Jarahian M, Marstaller K, Banna N, Ahani R, Etemadzadeh MH, Boller LK, Azadmanesh K, Cid-Arregui A, Khezri A, Berger MR, Momburg F, and Watzl C
- Subjects
- Glycoproteins metabolism, Receptors, Natural Killer Cell metabolism, Selectins metabolism, Sialic Acid Binding Immunoglobulin-like Lectins metabolism, Viral Envelope Proteins metabolism, Ebolavirus physiology
- Abstract
Expression of the extensively glycosylated Ebolavirus glycoprotein (EBOV-GP) induces physical alterations of surface molecules and plays a crucial role in viral pathogenicity. Here we investigate the interactions of EBOV-GP with host surface molecules using purified EBOV-GP, EBOV-GP-transfected cell lines, and EBOV-GP-pseudotyped lentiviral particles. Subsequently, we wanted to examine which receptors are involved in this recognition by binding studies to cells transfected with the EBOV-GP as well as to recombinant soluble EBOV-GP. As the viral components can also bind to inhibitory receptors of immune cells (e.g., Siglecs, TIM-1), they can even suppress the activity of immune effector cells. Our data show that natural killer (NK) cell receptors NKp44 and NKp46, selectins (CD62E/P/L), the host factors DC-SIGNR/DC-SIGN, and inhibitory Siglecs function as receptors for EBOV-GP. Our results show also moderate to strong avidity of homing receptors (P-, L-, and E-selectin) and DC-SIGNR/DC-SIGN to purified EBOV-GP, to cells transfected with EBOV-GP, as well as to the envelope of a pseudotyped lentiviral vector carrying the EBOV-GP. The concomitant activation and inhibition of the immune system exemplifies the evolutionary antagonism between the immune system and pathogens. Altogether these interactions with activating and inhibitory receptors result in a reduced NK cell-mediated lysis of EBOV-GP-expressing cells. Modulation of these interactions may provide new strategies for treating infections caused by this virus., (© 2021 The Author(s) Published by S. Karger AG, Basel.)
- Published
- 2022
- Full Text
- View/download PDF
11. The Role of Janus Kinase/STAT3 Pathway in Hematologic Malignancies With an Emphasis on Epigenetics.
- Author
-
Zeinalzadeh E, Valerievich Yumashev A, Rahman HS, Marofi F, Shomali N, Kafil HS, Solali S, Sajjadi-Dokht M, Vakili-Samiani S, Jarahian M, and Hagh MF
- Abstract
The Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway has been known to be involved in cell growth, cellular differentiation processes development, immune cell survival, and hematopoietic system development. As an important member of the STAT family, STAT3 participates as a major regulator of cellular development and differentiation-associated genes. Prolonged and persistent STAT3 activation has been reported to be associated with tumor cell survival, proliferation, and invasion. Therefore, the JAK-STAT pathway can be a potential target for drug development to treat human cancers, e.g., hematological malignancies. Although STAT3 upregulation has been reported in hematopoietic cancers, protein-level STAT3 mutations have also been reported in invasive leukemias/lymphomas. The principal role of STAT3 in tumor cell growth clarifies the importance of approaches that downregulate this molecule. Epigenetic modifications are a major regulatory mechanism controlling the activity and function of STAT3. So far, several compounds have been developed to target epigenetic regulatory enzymes in blood malignancies. Here, we discuss the current knowledge about STAT3 abnormalities and carcinogenic functions in hematopoietic cancers, novel STAT3 inhibitors, the role of epigenetic mechanisms in STAT3 regulation, and targeted therapies, by focusing on STAT3-related epigenetic modifications., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Zeinalzadeh, Valerievich Yumashev, Rahman, Marofi, Shomali, Kafil, Solali, Sajjadi-Dokht, Vakili-Samiani, Jarahian and Hagh.)
- Published
- 2021
- Full Text
- View/download PDF
12. MicroRNAs and JAK/STAT3 signaling: A new promising therapeutic axis in blood cancers.
- Author
-
Sajjadi-Dokht M, Merza Mohamad TA, Sulaiman Rahman H, Suliman Maashi M, Danshina S, Shomali N, Solali S, Marofi F, Zeinalzadeh E, Akbari M, Adili A, Aslaminabad R, Farshdousti Hagh M, and Jarahian M
- Abstract
Blood disorders include a wide spectrum of blood-associated malignancies resulting from inherited or acquired defects. The ineffectiveness of existing therapies against blood disorders arises from different reasons, one of which is drug resistance, so different types of leukemia may show different responses to treatment. Leukemia occurs for a variety of genetic and acquired reasons, leading to uncontrolled proliferation in one or more cell lines. Regarding the genetic defects, oncogene signal transducer and activator of transcription (STAT) family transcription factor, especially STAT3, play an essential role in hematological disorders onset and progress upon mutations, dysfunction, or hyperactivity. Besides, microRNAs, as biological molecules, has been shown to play a dual role in either tumorigenesis and tumor suppression in various cancers. Besides, a strong association between STAT3 and miRNA has been reported. For example, miRNAs can regulate STAT3 via targeting its upstream mediators such as IL6, IL9, and JAKs or directly binding to the STAT3 gene. On the other hand, STAT3 can regulate miRNAs. In this review study, we aimed to determine the role of either microRNAs and STAT3 along with their effect on one another's activity and function in hematological malignancies., Competing Interests: Authors declare no conflict of interests., (© 2021 Chongqing Medical University. Production and hosting by Elsevier B.V.)
- Published
- 2021
- Full Text
- View/download PDF
13. Cloning and Embryo Splitting in Mammalians: Brief History, Methods, and Achievements.
- Author
-
Rahbaran M, Razeghian E, Maashi MS, Jalil AT, Widjaja G, Thangavelu L, Kuznetsova MY, Nasirmoghadas P, Heidari F, Marofi F, and Jarahian M
- Abstract
Embryo splitting is one of the newest developed methods in reproductive biotechnology. In this method, after splitting embryos in 2-, 4-, and even 8-cell stages, every single blastomere can be developed separately, but the embryos are genetically identical. Embryo splitting, as an approach in reproductive cloning, is extensively employed in reproductive medicine studies, such as investigating human diseases, treating sterility, embryo donation, and gene therapy. In the present study, cloning in mammalians and cloning approaches are briefly reviewed. In addition, embryo splitting and the methods commonly used in embryo splitting and recent achievements in this field, as well as the applications of embryo splitting into livestock species, primate animals, and humans, are outlined. Finally, a perspective of embryo splitting is provided as the conclusion., Competing Interests: The authors declare that they have no conflict of interests., (Copyright © 2021 Mohaddeseh Rahbaran et al.)
- Published
- 2021
- Full Text
- View/download PDF
14. Optimizing sgRNA to Improve CRISPR/Cas9 Knockout Efficiency: Special Focus on Human and Animal Cell.
- Author
-
Shojaei Baghini S, Gardanova ZR, Zekiy AO, Shomali N, Tosan F, and Jarahian M
- Abstract
During recent years, clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated protein 9 (Cas9) technologies have been noticed as a rapidly evolving tool to deliver a possibility for modifying target sequence expression and function. The CRISPR/Cas9 tool is currently being used to treat a myriad of human disorders, ranging from genetic diseases and infections to cancers. Preliminary reports have shown that CRISPR technology could result in valued consequences for the treatment of Duchenne muscular dystrophy (DMD), cystic fibrosis (CF), β-thalassemia, Huntington's diseases (HD), etc. Nonetheless, high rates of off-target effects may hinder its application in clinics. Thereby, recent studies have focused on the finding of the novel strategies to ameliorate these off-target effects and thereby lead to a high rate of fidelity and accuracy in human, animals, prokaryotes, and also plants. Meanwhile, there is clear evidence indicating that the design of the specific sgRNA with high efficiency is of paramount importance. Correspondingly, elucidation of the principal parameters that contributed to determining the sgRNA efficiencies is a prerequisite. Herein, we will deliver an overview regarding the therapeutic application of CRISPR technology to treat human disorders. More importantly, we will discuss the potent influential parameters (e.g., sgRNA structure and feature) implicated in affecting the sgRNA efficacy in CRISPR/Cas9 technology, with special concentration on human and animal studies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Shojaei Baghini, Gardanova, Zekiy, Shomali, Tosan and Jarahian.)
- Published
- 2021
- Full Text
- View/download PDF
15. Re-Expression of Poly/Oligo-Sialylated Adhesion Molecules on the Surface of Tumor Cells Disrupts Their Interaction with Immune-Effector Cells and Contributes to Pathophysiological Immune Escape.
- Author
-
Jarahian M, Marofi F, Maashi MS, Ghaebi M, Khezri A, and Berger MR
- Abstract
Glycans linked to surface proteins are the most complex biological macromolecules that play an active role in various cellular mechanisms. This diversity is the basis of cell-cell interaction and communication, cell growth, cell migration, as well as co-stimulatory or inhibitory signaling. Our review describes the importance of neuraminic acid and its derivatives as recognition elements, which are located at the outermost positions of carbohydrate chains linked to specific glycoproteins or glycolipids. Tumor cells, especially from solid tumors, mask themselves by re-expression of hypersialylated neural cell adhesion molecule (NCAM), neuropilin-2 (NRP-2), or synaptic cell adhesion molecule 1 (SynCAM 1) in order to protect themselves against the cytotoxic attack of the also highly sialylated immune effector cells. More particularly, we focus on α-2,8-linked polysialic acid chains, which characterize carrier glycoproteins such as NCAM, NRP-2, or SynCam-1. This characteristic property correlates with an aggressive clinical phenotype and endows them with multiple roles in biological processes that underlie all steps of cancer progression, including regulation of cell-cell and/or cell-extracellular matrix interactions, as well as increased proliferation, migration, reduced apoptosis rate of tumor cells, angiogenesis, and metastasis. Specifically, re-expression of poly/oligo-sialylated adhesion molecules on the surface of tumor cells disrupts their interaction with immune-effector cells and contributes to pathophysiological immune escape. Further, sialylated glycoproteins induce immunoregulatory cytokines and growth factors through interactions with sialic acid-binding immunoglobulin-like lectins. We describe the processes, which modulate the interaction between sialylated carrier glycoproteins and their ligands, and illustrate that sialic acids could be targets of novel therapeutic strategies for treatment of cancer and immune diseases.
- Published
- 2021
- Full Text
- View/download PDF
16. Liposomes: Structure, Biomedical Applications, and Stability Parameters With Emphasis on Cholesterol.
- Author
-
Nakhaei P, Margiana R, Bokov DO, Abdelbasset WK, Jadidi Kouhbanani MA, Varma RS, Marofi F, Jarahian M, and Beheshtkhoo N
- Abstract
Liposomes are essentially a subtype of nanoparticles comprising a hydrophobic tail and a hydrophilic head constituting a phospholipid membrane. The spherical or multilayered spherical structures of liposomes are highly rich in lipid contents with numerous criteria for their classification, including structural features, structural parameters, and size, synthesis methods, preparation, and drug loading. Despite various liposomal applications, such as drug, vaccine/gene delivery, biosensors fabrication, diagnosis, and food products applications, their use encounters many limitations due to physico-chemical instability as their stability is vigorously affected by the constituting ingredients wherein cholesterol performs a vital role in the stability of the liposomal membrane. It has well established that cholesterol exerts its impact by controlling fluidity, permeability, membrane strength, elasticity and stiffness, transition temperature (Tm), drug retention, phospholipid packing, and plasma stability. Although the undetermined optimum amount of cholesterol for preparing a stable and controlled release vehicle has been the downside, but researchers are still focused on cholesterol as a promising material for the stability of liposomes necessitating explanation for the stability promotion of liposomes. Herein, the prior art pertaining to the liposomal appliances, especially for drug delivery in cancer therapy, and their stability emphasizing the roles of cholesterol., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Nakhaei, Margiana, Bokov, Abdelbasset, Jadidi Kouhbanani, Varma, Marofi, Jarahian and Beheshtkhoo.)
- Published
- 2021
- Full Text
- View/download PDF
17. CAR-NK cell in cancer immunotherapy; A promising frontier.
- Author
-
Marofi F, Abdul-Rasheed OF, Rahman HS, Budi HS, Jalil AT, Yumashev AV, Hassanzadeh A, Yazdanifar M, Motavalli R, Chartrand MS, Ahmadi M, Cid-Arreguid A, and Jarahian M
- Subjects
- Animals, Antigens, Neoplasm immunology, Genetic Engineering methods, Genetic Vectors, Humans, Mice, Receptors, Chimeric Antigen genetics, Treatment Outcome, Tumor Microenvironment, Xenograft Model Antitumor Assays, Cell- and Tissue-Based Therapy methods, Hematologic Neoplasms therapy, Immunotherapy, Adoptive methods, Killer Cells, Natural immunology, Receptors, Chimeric Antigen immunology
- Abstract
Chimeric antigen receptors (CARs) have a unique facet of synthetic biology and offer a paradigm shift in personalized medicine as they can use and redirect the patient's immune cells to attack cancer cells. CAR-natural killer (NK) cells combine the targeted specificity of antigens with the subsequent intracellular signaling ability of the receptors to increase their anti-cancer functions. Importantly, CAR-NK cells can be utilized as universal cell-based therapy without requiring human leukocyte antigen (HLA) matching or earlier contact with tumor-associated antigens (TAAs). Indeed, CAR-NK cells can be adapted to recognize various antigens, hold higher proliferation capacity, and in vivo persistence, show improved infiltration into the tumors, and the ability to overcome the resistant tumor microenvironment leading to sustained cytotoxicity against tumors. Accumulating evidence from recent in vivo studies rendering CAR-NK cell anti-cancer competencies renewed the attention in the context of cancer immunotherapy, as these redirected effector cells can be used in the development of the "off-the-shelf" anti-cancer immunotherapeutic products. In the current review, we focus on the therapeutic efficacy of CAR-NK cell therapies for treating various human malignancies, including hematological malignancies and solid tumors, and will discuss the recent findings in this regard, with a special focus on animal studies., (© 2021 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)
- Published
- 2021
- Full Text
- View/download PDF
18. Mesenchymal Stem/Stromal Cells as a Vehicle for Cytokine Delivery: An Emerging Approach for Tumor Immunotherapy.
- Author
-
Razeghian E, Margiana R, Chupradit S, Bokov DO, Abdelbasset WK, Marofi F, Shariatzadeh S, Tosan F, and Jarahian M
- Abstract
Pro-inflammatory cytokines can effectively be used for tumor immunotherapy, affecting every step of the tumor immunity cycle. Thereby, they can restore antigen priming, improve the effector immune cell frequencies in the tumor microenvironment (TME), and eventually strengthen their cytolytic function. A renewed interest in the anticancer competencies of cytokines has resulted in a substantial promotion in the number of trials to address the safety and efficacy of cytokine-based therapeutic options. However, low response rate along with the high toxicity associated with high-dose cytokine for reaching desired therapeutic outcomes negatively affect their clinical utility. Recently, mesenchymal stem/stromal cells (MSCs) due to their pronounced tropism to tumors and also lower immunogenicity have become a promising vehicle for cytokine delivery for human malignancies. MSC-based delivery of the cytokine can lead to the more effective immune cell-induced antitumor response and provide sustained release of target cytokines, as widely evidenced in a myriad of xenograft models. In the current review, we offer a summary of the novel trends in cytokine immunotherapy using MSCs as a potent and encouraging carrier for antitumor cytokines, focusing on the last two decades' animal reports., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Razeghian, Margiana, Chupradit, Bokov, Abdelbasset, Marofi, Shariatzadeh, Tosan and Jarahian.)
- Published
- 2021
- Full Text
- View/download PDF
19. Novel CAR T therapy is a ray of hope in the treatment of seriously ill AML patients.
- Author
-
Marofi F, Rahman HS, Al-Obaidi ZMJ, Jalil AT, Abdelbasset WK, Suksatan W, Dorofeev AE, Shomali N, Chartrand MS, Pathak Y, Hassanzadeh A, Baradaran B, Ahmadi M, Saeedi H, Tahmasebi S, and Jarahian M
- Subjects
- Humans, Immunotherapy, Immunotherapy, Adoptive, T-Lymphocytes, Leukemia, Myeloid, Acute therapy, Receptors, Chimeric Antigen genetics
- Abstract
Acute myeloid leukemia (AML) is a serious, life-threatening, and hardly curable hematological malignancy that affects the myeloid cell progenies and challenges patients of all ages but mostly occurs in adults. Although several therapies are available including chemotherapy, allogeneic hematopoietic stem cell transplantation (alloHSCT), and receptor-antagonist drugs, the 5-year survival of patients is quietly disappointing, less than 30%. alloHSCT is the major curative approach for AML with promising results but the treatment has severe adverse effects such as graft-versus-host disease (GVHD). Therefore, as an alternative, more efficient and less harmful immunotherapy-based approaches such as the adoptive transferring T cell therapy are in development for the treatment of AML. As such, chimeric antigen receptor (CAR) T cells are engineered T cells which have been developed in recent years as a breakthrough in cancer therapy. Interestingly, CAR T cells are effective against both solid tumors and hematological cancers such as AML. Gradually, CAR T cell therapy found its way into cancer therapy and was widely used for the treatment of hematologic malignancies with successful results particularly with somewhat better results in hematological cancer in comparison to solid tumors. The AML is generally fatal, therapy-resistant, and sometimes refractory disease with a disappointing low survival rate and weak prognosis. The 5-year survival rate for AML is only about 30%. However, the survival rate seems to be age-dependent. Novel CAR T cell therapy is a light at the end of the tunnel. The CD19 is an important target antigen in AML and lymphoma and the CAR T cells are engineered to target the CD19. In addition, a lot of research goes on the discovery of novel target antigens with therapeutic efficacy and utilizable for generating CAR T cells against various types of cancers. In recent years, many pieces of research on screening and identification of novel AML antigen targets with the goal of generation of effective anti-cancer CAR T cells have led to new therapies with strong cytotoxicity against cancerous cells and impressive clinical outcomes. Also, more recently, an improved version of CAR T cells which were called modified or smartly reprogrammed CAR T cells has been designed with less unwelcome effects, less toxicity against normal cells, more safety, more specificity, longer persistence, and proliferation capability. The purpose of this review is to discuss and explain the most recent advances in CAR T cell-based therapies targeting AML antigens and review the results of preclinical and clinical trials. Moreover, we will criticize the clinical challenges, side effects, and the different strategies for CAR T cell therapy., (© 2021. The Author(s).)
- Published
- 2021
- Full Text
- View/download PDF
20. Harnessing TRAIL-Induced Apoptosis Pathway for Cancer Immunotherapy and Associated Challenges.
- Author
-
Razeghian E, Suksatan W, Sulaiman Rahman H, Bokov DO, Abdelbasset WK, Hassanzadeh A, Marofi F, Yazdanifar M, and Jarahian M
- Subjects
- Animals, Humans, Neoplasms immunology, Apoptosis physiology, Immunotherapy methods, Neoplasms diet therapy, TNF-Related Apoptosis-Inducing Ligand
- Abstract
The immune cytokine tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has attracted rapidly evolving attention as a cancer treatment modality because of its competence to selectively eliminate tumor cells without instigating toxicity in vivo . TRAIL has revealed encouraging promise in preclinical reports in animal models as a cancer treatment option; however, the foremost constraint of the TRAIL therapy is the advancement of TRAIL resistance through a myriad of mechanisms in tumor cells. Investigations have documented that improvement of the expression of anti-apoptotic proteins and survival or proliferation involved signaling pathways concurrently suppressing the expression of pro-apoptotic proteins along with down-regulation of expression of TRAILR1 and TRAILR2, also known as death receptor 4 and 5 (DR4/5) are reliable for tumor cells resistance to TRAIL. Therefore, it seems that the development of a therapeutic approach for overcoming TRAIL resistance is of paramount importance. Studies currently have shown that combined treatment with anti-tumor agents, ranging from synthetic agents to natural products, and TRAIL could result in induction of apoptosis in TRAIL-resistant cells. Also, human mesenchymal stem/stromal cells (MSCs) engineered to generate and deliver TRAIL can provide both targeted and continued delivery of this apoptosis-inducing cytokine. Similarly, nanoparticle (NPs)-based TRAIL delivery offers novel platforms to defeat barricades to TRAIL therapeutic delivery. In the current review, we will focus on underlying mechanisms contributed to inducing resistance to TRAIL in tumor cells, and also discuss recent findings concerning the therapeutic efficacy of combined treatment of TRAIL with other antitumor compounds, and also TRAIL-delivery using human MSCs and NPs to overcome tumor cells resistance to TRAIL., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Razeghian, Suksatan, Sulaiman Rahman, Bokov, Abdelbasset, Hassanzadeh, Marofi, Yazdanifar and Jarahian.)
- Published
- 2021
- Full Text
- View/download PDF
21. Correction to: Any closer to successful therapy of multiple myeloma? CAR-T cell is a good reason for optimism.
- Author
-
Marofi F, Tahmasebi S, Rahman HS, Kaigorodov D, Markov A, Yumashev AV, Shomali N, Chartrand MS, Pathak Y, Mohammed RN, Jarahian M, Motavalli R, and Khiavi FM
- Published
- 2021
- Full Text
- View/download PDF
22. The lethal internal face of the coronaviruses: Kidney tropism of the SARS, MERS, and COVID19 viruses.
- Author
-
Motavalli R, Abdelbasset WK, Rahman HS, Achmad MH, Sergeevna NK, Zekiy AO, Adili A, Khiavi FM, Marofi F, Yousefi M, Ghoreishizadeh S, Shomali N, Etemadi J, and Jarahian M
- Subjects
- Angiotensin-Converting Enzyme 2 genetics, Angiotensin-Converting Enzyme 2 metabolism, COVID-19 genetics, COVID-19 pathology, COVID-19 virology, Coronavirus Infections genetics, Coronavirus Infections pathology, Coronavirus Infections virology, Dipeptidyl Peptidase 4 genetics, Dipeptidyl Peptidase 4 metabolism, Gene Expression Regulation, Humans, Kidney metabolism, Kidney pathology, Kidney virology, Middle East Respiratory Syndrome Coronavirus genetics, Middle East Respiratory Syndrome Coronavirus metabolism, Protein Binding, Receptors, Virus genetics, Receptors, Virus metabolism, Severe acute respiratory syndrome-related coronavirus genetics, Severe acute respiratory syndrome-related coronavirus metabolism, SARS-CoV-2 genetics, SARS-CoV-2 metabolism, Severe Acute Respiratory Syndrome genetics, Severe Acute Respiratory Syndrome pathology, Severe Acute Respiratory Syndrome virology, Severity of Illness Index, Spike Glycoprotein, Coronavirus genetics, Spike Glycoprotein, Coronavirus metabolism, Survival Analysis, COVID-19 mortality, Coronavirus Infections mortality, Middle East Respiratory Syndrome Coronavirus pathogenicity, Severe acute respiratory syndrome-related coronavirus pathogenicity, SARS-CoV-2 pathogenicity, Severe Acute Respiratory Syndrome mortality, Viral Tropism genetics
- Abstract
The kidney is one of the main targets attacked by viruses in patients with a coronavirus infection. Until now, SARS-CoV-2 has been identified as the seventh member of the coronavirus family capable of infecting humans. In the past two decades, humankind has experienced outbreaks triggered by two other extremely infective members of the coronavirus family; the MERS-CoV and the SARS-CoV. According to several investigations, SARS-CoV causes proteinuria and renal impairment or failure. The SARS-CoV was identified in the distal convoluted tubules of the kidney of infected patients. Also, renal dysfunction was observed in numerous cases of MERS-CoV infection. And recently, during the 2019-nCoV pandemic, it was found that the novel coronavirus not only induces acute respiratory distress syndrome (ARDS) but also can induce damages in various organs including the liver, heart, and kidney. The kidney tissue and its cells are targeted massively by the coronaviruses due to the abundant presence of ACE2 and Dpp4 receptors on kidney cells. These receptors are characterized as the main route of coronavirus entry to the victim cells. Renal failure due to massive viral invasion can lead to undesirable complications and enhanced mortality rate, thus more attention should be paid to the pathology of coronaviruses in the kidney. Here, we have provided the most recent knowledge on the coronaviruses (SARS, MERS, and COVID19) pathology and the mechanisms of their impact on the kidney tissue and functions., (© 2021 International Union of Biochemistry and Molecular Biology.)
- Published
- 2021
- Full Text
- View/download PDF
23. A paradigm shift in cell-free approach: the emerging role of MSCs-derived exosomes in regenerative medicine.
- Author
-
Moghadasi S, Elveny M, Rahman HS, Suksatan W, Jalil AT, Abdelbasset WK, Yumashev AV, Shariatzadeh S, Motavalli R, Behzad F, Marofi F, Hassanzadeh A, Pathak Y, and Jarahian M
- Subjects
- Cell Differentiation, Humans, Regenerative Medicine, Exosomes, Mesenchymal Stem Cells, MicroRNAs
- Abstract
Recently, mesenchymal stem/stromal cells (MSCs) due to their pro-angiogenic, anti-apoptotic, and immunoregulatory competencies along with fewer ethical issues are presented as a rational strategy for regenerative medicine. Current reports have signified that the pleiotropic effects of MSCs are not related to their differentiation potentials, but rather are exerted through the release of soluble paracrine molecules. Being nano-sized, non-toxic, biocompatible, barely immunogenic, and owning targeting capability and organotropism, exosomes are considered nanocarriers for their possible use in diagnosis and therapy. Exosomes convey functional molecules such as long non-coding RNAs (lncRNAs) and micro-RNAs (miRNAs), proteins (e.g., chemokine and cytokine), and lipids from MSCs to the target cells. They participate in intercellular interaction procedures and enable the repair of damaged or diseased tissues and organs. Findings have evidenced that exosomes alone are liable for the beneficial influences of MSCs in a myriad of experimental models, suggesting that MSC- exosomes can be utilized to establish a novel cell-free therapeutic strategy for the treatment of varied human disorders, encompassing myocardial infarction (MI), CNS-related disorders, musculoskeletal disorders (e.g. arthritis), kidney diseases, liver diseases, lung diseases, as well as cutaneous wounds. Importantly, compared with MSCs, MSC- exosomes serve more steady entities and reduced safety risks concerning the injection of live cells, such as microvasculature occlusion risk. In the current review, we will discuss the therapeutic potential of MSC- exosomes as an innovative approach in the context of regenerative medicine and highlight the recent knowledge on MSC- exosomes in translational medicine, focusing on in vivo researches., (© 2021. The Author(s).)
- Published
- 2021
- Full Text
- View/download PDF
24. Mesenchymal Stem/Stromal Cell-Based Delivery: A Rapidly Evolving Strategy for Cancer Therapy.
- Author
-
Hassanzadeh A, Altajer AH, Rahman HS, Saleh MM, Bokov DO, Abdelbasset WK, Marofi F, Zamani M, Yaghoubi Y, Yazdanifar M, Pathak Y, Chartrand MS, and Jarahian M
- Abstract
Mesenchymal stem/stromal cell (MSC)-based therapy has become an attractive and advanced scientific research area in the context of cancer therapy. This interest is closely linked to the MSC-marked tropism for tumors, suggesting them as a rational and effective vehicle for drug delivery for both hematological and solid malignancies. Nonetheless, the therapeutic application of the MSCs in human tumors is still controversial because of the induction of several signaling pathways largely contributing to tumor progression and metastasis. In spite of some evidence supporting that MSCs may sustain cancer pathogenesis, increasing proofs have indicated the suppressive influences of MSCs on tumor cells. During the last years, a myriad of preclinical and some clinical studies have been carried out or are ongoing to address the safety and efficacy of the MSC-based delivery of therapeutic agents in diverse types of malignancies. A large number of studies have focused on the MSC application as delivery vehicles for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), chemotherapeutic drug such as gemcitabine (GCB), paclitaxel (PTX), and doxorubicin (DOX), prodrugs such as 5-fluorocytosine (5-FC) and ganciclovir (GCV), and immune cell-activating cytokines along with oncolytic virus. In the current review, we evaluate the latest findings rendering the potential of MSCs to be employed as potent gene/drug delivery vehicle for inducing tumor regression with a special focus on the in vivo reports performed during the last two decades., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Hassanzadeh, Altajer, Rahman, Saleh, Bokov, Abdelbasset, Marofi, Zamani, Yaghoubi, Yazdanifar, Pathak, Chartrand and Jarahian.)
- Published
- 2021
- Full Text
- View/download PDF
25. Up-regulation of KISS1 as a novel target of Let-7i in melanoma serves as a potential suppressor of migration and proliferation in vitro.
- Author
-
Alkafaji HA, Raji A, Rahman HS, Zekiy AO, Adili A, Jalili M, Hojjatipour T, Cid-Arregui A, Shomali N, Tarzi S, Tamjidifar R, Heshmati R, Marofi F, Akbari M, Hasanzadeh A, Deljavanghodrati M, Jarahian M, and Sandoghchian Shotorbani S
- Subjects
- Apoptosis, Cell Line, Tumor, Cell Movement, Cell Proliferation, Female, Humans, Kisspeptins genetics, Male, Melanoma genetics, Melanoma pathology, MicroRNAs genetics, Middle Aged, Skin Neoplasms genetics, Skin Neoplasms pathology, Up-Regulation, Kisspeptins metabolism, Melanoma metabolism, MicroRNAs metabolism, Skin Neoplasms metabolism
- Abstract
Melanoma is a kind of skin cancer that is begun by the alteration of melanocytes. miRNAs are small non-coding RNA molecules that regulate a variety of biological processes. KISS1, the metastasis-suppressor gene, encodes kisspeptins which inhibits migration and proliferation of cancers. This study was aimed to determine the role of Let-7i and KISS1 in melanoma cell migration and proliferation. At first, the expression of Let-7i and KISS1 was determined in patients with melanoma. In the in vitro part of the study, Let-7i mimics were transfected and the impact of its restoration on target gene expression, proliferation, migration and apoptosis of SK-MEL-3 melanoma cell line was assessed by real-time PCR and Western blotting, MTT assay, wound-healing assay and flow cytometry, respectively. Besides, KISS1 inhibitor siRNA alone and along with Let-7i was transfected to determine their probable correlation. The results revealed that either Let-7i or KISS1 were down-regulated in patients with melanoma. The results obtained from the in vitro part of the study revealed that restoration of Let-7i reduced the expression of metastasis- and proliferation-related target genes. Moreover, it was revealed that up-regulation of Let-7i attenuated migration and proliferation capability of SK-MEL-3 cells. Besides, it was demonstrated that Let-7i restoration induced apoptosis in melanoma cells. More importantly, the KISS1 inhibitor caused a prominent cell migration and proliferation, attenuated by Let-7i re-expression. To sum up, the present study revealed the impressive role of Let-7i restoration along with its correlation with KISS1 on melanoma carcinogenicity which may be applicable in future in vivo studies., (© 2021 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)
- Published
- 2021
- Full Text
- View/download PDF
26. Bi/tri-specific antibodies (HN-Fc-CD16 and HN-Fc-IL-15-CD16) cross-linking natural killer (NK)-CD16 and Newcastle Disease Virus (NDV)-HN, enhanced NK activation for cancer immunotherapy.
- Author
-
Bahrololoumi Shapourabadi M, Momburg F, Roohvand F, Jarahian M, Mohajel N, Arashkia A, Hajari Taheri F, Abbasalipour M, and Azadmanesh K
- Subjects
- Antibodies, Bispecific chemistry, Antibodies, Bispecific immunology, Antineoplastic Agents, Immunological chemistry, Antineoplastic Agents, Immunological immunology, Binding Sites, Cytotoxicity Tests, Immunologic, HEK293 Cells, HeLa Cells, Humans, Immunoglobulin Fc Fragments immunology, Immunotherapy methods, Interferon-gamma metabolism, Killer Cells, Natural immunology, Ligands, Models, Molecular, Neoplasms immunology, Antibodies, Bispecific biosynthesis, Antibodies, Bispecific pharmacology, Antineoplastic Agents, Immunological pharmacology, HN Protein immunology, Neoplasms therapy, Newcastle disease virus immunology, Receptors, IgG immunology
- Abstract
Cancer/tumor cells infected with the "avian paramyxovirus Newcastle Disease Virus (TC-NDV)" express the viral hemagglutinin-neuraminidase (HN) on the cell surface that is used as both the danger signal and anchor for bi/tri-specific antibodies (bs/tsAbs).We constructed a bs-Ab (HN-Fc-CD16) that bindsto HN and natural killer (NK)-CD16 receptor (FcgRIII)and a ts-Ab (HN-Fc-IL15-CD16) harbouring NK-activating cytokine "IL-15" within the bs-Ab.In silicoand computational predictions indicated proper exposure of both Abs in bs/tsAbs.Properbinding of thebi/tsAbstoHN on surface of TC-NDVandCD16
+ -cells was demonstrated by flow cytometry.The bi/tsAbstriggeredspecificcytotoxicity of NK cells againstTC-NDVand elicited substantial IFN-γproduction by activated NK cells(higher for ts-Ab) that sound promising for cancer immunotherapy purposes., (Copyright © 2021 Elsevier B.V. All rights reserved.)- Published
- 2021
- Full Text
- View/download PDF
27. A Deep Insight Into CAR-T Cell Therapy in Non-Hodgkin Lymphoma: Application, Opportunities, and Future Directions.
- Author
-
Marofi F, Rahman HS, Achmad MH, Sergeevna KN, Suksatan W, Abdelbasset WK, Mikhailova MV, Shomali N, Yazdanifar M, Hassanzadeh A, Ahmadi M, Motavalli R, Pathak Y, Izadi S, and Jarahian M
- Subjects
- Animals, Antigens, Neoplasm immunology, Combined Modality Therapy, Disease Management, Disease Susceptibility, Genetic Engineering, Humans, Immunotherapy, Adoptive adverse effects, Immunotherapy, Adoptive trends, Treatment Outcome, Immunotherapy, Adoptive methods, Lymphoma, Non-Hodgkin immunology, Lymphoma, Non-Hodgkin therapy, Receptors, Chimeric Antigen immunology, T-Lymphocytes immunology, T-Lymphocytes metabolism
- Abstract
Non-Hodgkin's lymphoma (NHL) is a cancer that starts in the lymphatic system. In NHL, the important part of the immune system, a type of white blood cells called lymphocytes become cancerous. NHL subtypes include marginal zone lymphoma, small lymphocytic lymphoma, follicular lymphoma (FL), and lymphoplasmacytic lymphoma. The disease can emerge in either aggressive or indolent form. 5-year survival duration after diagnosis is poor among patients with aggressive/relapsing form of NHL. Therefore, it is necessary to understand the molecular mechanisms of pathogenesis involved in NHL establishment and progression. In the next step, we can develop innovative therapies for NHL based on our knowledge in signaling pathways, surface antigens, and tumor milieu of NHL. In the recent few decades, several treatment solutions of NHL mainly based on targeted/directed therapies have been evaluated. These approaches include B-cell receptor (BCR) signaling inhibitors, immunomodulatory agents, monoclonal antibodies (mAbs), epigenetic modulators, Bcl-2 inhibitors, checkpoint inhibitors, and T-cell therapy. In recent years, methods based on T cell immunotherapy have been considered as a novel promising anti-cancer strategy in the treatment of various types of cancers, and particularly in blood cancers. These methods could significantly increase the capacity of the immune system to induce durable anti-cancer responses in patients with chemotherapy-resistant lymphoma. One of the promising therapy methods involved in the triumph of immunotherapy is the chimeric antigen receptor (CAR) T cells with dramatically improved killing activity against tumor cells. The CAR-T cell-based anti-cancer therapy targeting a pan-B-cell marker, CD19 is recently approved by the US Food and Drug Administration (FDA) for the treatment of chemotherapy-resistant B-cell NHL. In this review, we will discuss the structure, molecular mechanisms, results of clinical trials, and the toxicity of CAR-T cell-based therapies. Also, we will criticize the clinical aspects, the treatment considerations, and the challenges and possible drawbacks of the application of CAR-T cells in the treatment of NHL., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Marofi, Rahman, Achmad, Sergeevna, Suksatan, Abdelbasset, Mikhailova, Shomali, Yazdanifar, Hassanzadeh, Ahmadi, Motavalli, Pathak, Izadi and Jarahian.)
- Published
- 2021
- Full Text
- View/download PDF
28. CAR-NK Cell: A New Paradigm in Tumor Immunotherapy.
- Author
-
Marofi F, Al-Awad AS, Sulaiman Rahman H, Markov A, Abdelbasset WK, Ivanovna Enina Y, Mahmoodi M, Hassanzadeh A, Yazdanifar M, Stanley Chartrand M, and Jarahian M
- Abstract
The tumor microenvironment (TME) is greatly multifaceted and immune escape is an imperative attribute of tumors fostering tumor progression and metastasis. Based on reports, the restricted achievement attained by T cell immunotherapy reflects the prominence of emerging other innovative immunotherapeutics, in particular, natural killer (NK) cells-based treatments. Human NK cells act as the foremost innate immune effector cells against tumors and are vastly heterogeneous in the TME. Currently, there exists a rapidly evolving interest in the progress of chimeric antigen receptor (CAR)-engineered NK cells for tumor immunotherapy. CAR-NK cells superiorities over CAR-T cells in terms of better safety (e.g., absence or minimal cytokine release syndrome (CRS) and graft-versus-host disease (GVHD), engaging various mechanisms for stimulating cytotoxic function, and high feasibility for 'off-the-shelf' manufacturing. These effector cells could be modified to target various antigens, improve proliferation and persistence in vivo , upturn infiltration into tumors, and defeat resistant TME, which in turn, result in a desired anti-tumor response. More importantly, CAR-NK cells represent antigen receptors against tumor-associated antigens (TAAs), thereby redirecting the effector NK cells and supporting tumor-related immunosurveillance. In the current review, we focus on recent progress in the therapeutic competence of CAR-NK cells in solid tumors and offer a concise summary of the present hurdles affecting therapeutic outcomes of CAR-NK cell-based tumor immunotherapies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Marofi, Al-Awad, Sulaiman Rahman, Markov, Abdelbasset, Ivanovna Enina, Mahmoodi, Hassanzadeh, Yazdanifar, Stanley Chartrand and Jarahian.)
- Published
- 2021
- Full Text
- View/download PDF
29. Mesenchymal stem/stromal cell-derived exosomes in regenerative medicine and cancer; overview of development, challenges, and opportunities.
- Author
-
Hassanzadeh A, Rahman HS, Markov A, Endjun JJ, Zekiy AO, Chartrand MS, Beheshtkhoo N, Kouhbanani MAJ, Marofi F, Nikoo M, and Jarahian M
- Subjects
- Humans, Regenerative Medicine, Exosomes, Mesenchymal Stem Cells, MicroRNAs genetics, Neoplasms therapy
- Abstract
Recently, mesenchymal stem/stromal cells (MSCs) and their widespread biomedical applications have attracted great consideration from the scientific community around the world. However, reports have shown that the main populations of the transplanted MSCs are trapped in the liver, spleen, and lung upon administration, highlighting the importance of the development of cell-free therapies. Concerning rising evidence suggesting that the beneficial effects of MSC therapy are closely linked to MSC-released components, predominantly MSC-derived exosomes, the development of an MSC-based cell-free approach is of paramount importance. The exosomes are nano-sized (30-100 nm) lipid bilayer membrane vesicles, which are typically released by MSCs and are found in different body fluids. They include various bioactive molecules, such as messenger RNA (mRNA), microRNAs, proteins, and bioactive lipids, thus showing pronounced therapeutic competence for tissues recovery through the maintenance of their endogenous stem cells, the enhancement of regenerative phenotypic traits, inhibition of apoptosis concomitant with immune modulation, and stimulation of the angiogenesis. Conversely, the specific roles of MSC exosomes in the treatment of various tumors remain challenging. The development and clinical application of novel MSC-based cell-free strategies can be supported by better understanding their mechanisms, classifying the subpopulation of exosomes, enhancing the conditions of cell culture and isolation, and increasing the production of exosomes along with engineering exosomes to deliver drugs and therapeutic molecules to the target sites. In the current review, we deliver a brief overview of MSC-derived exosome biogenesis, composition, and isolation methods and discuss recent investigation regarding the therapeutic potential of MSC exosomes in regenerative medicine accompanied by their double-edged sword role in cancer.
- Published
- 2021
- Full Text
- View/download PDF
30. Any closer to successful therapy of multiple myeloma? CAR-T cell is a good reason for optimism.
- Author
-
Marofi F, Tahmasebi S, Rahman HS, Kaigorodov D, Markov A, Yumashev AV, Shomali N, Chartrand MS, Pathak Y, Mohammed RN, Jarahian M, Motavalli R, and Motavalli Khiavi F
- Subjects
- Humans, Immunotherapy, Immunotherapy, Adoptive, Receptors, Antigen, T-Cell genetics, T-Lymphocytes, Multiple Myeloma therapy, Receptors, Chimeric Antigen genetics
- Abstract
Despite many recent advances on cancer novel therapies, researchers have yet a long way to cure cancer. They have to deal with tough challenges before they can reach success. Nonetheless, it seems that recently developed immunotherapy-based therapy approaches such as adoptive cell transfer (ACT) have emerged as a promising therapeutic strategy against various kinds of tumors even the cancers in the blood (liquid cancers). The hematological (liquid) cancers are hard to be targeted by usual cancer therapies, for they do not form localized solid tumors. Until recently, two types of ACTs have been developed and introduced; tumor-infiltrating lymphocytes (TILs) and chimeric antigen receptor (CAR)-T cells which the latter is the subject of our discussion. It is interesting about engineered CAR-T cells that they are genetically endowed with unique cancer-specific characteristics, so they can use the potency of the host immune system to fight against either solid or liquid cancers. Multiple myeloma (MM) or simply referred to as myeloma is a type of hematological malignancy that affects the plasma cells. The cancerous plasma cells produce immunoglobulins (antibodies) uncontrollably which consequently damage the tissues and organs and break the immune system function. Although the last few years have seen significant progressions in the treatment of MM, still a complete remission remains unconvincing. MM is a medically challenging and stubborn disease with a disappointingly low rate of survival rate. When comparing the three most occurring blood cancers (i.e., lymphoma, leukemia, and myeloma), myeloma has the lowest 5-year survival rate (around 40%). A low survival rate indicates a high mortality rate with difficulty in treatment. Therefore, novel CAR-T cell-based therapies or combination therapies along with CAT-T cells may bring new hope for multiple myeloma patients. CAR-T cell therapy has a high potential to improve the remission success rate in patients with MM. To date, many preclinical and clinical trial studies have been conducted to investigate the ability and capacity of CAR T cells in targeting the antigens on myeloma cells. Despite the problems and obstacles, CAR-T cell experiments in MM patients revealed a robust therapeutic potential. However, several factors might be considered during CAR-T cell therapy for better response and reduced side effects. Also, incorporating the CAT-T cell method into a combinational treatment schedule may be a promising approach. In this paper, with a greater emphasis on CAR-T cell application in the treatment of MM, we will discuss and introduce CAR-T cell's history and functions, their limitations, and the solutions to defeat the limitations and different types of modifications on CAR-T cells.
- Published
- 2021
- Full Text
- View/download PDF
31. Renaissance of armored immune effector cells, CAR-NK cells, brings the higher hope for successful cancer therapy.
- Author
-
Marofi F, Rahman HS, Thangavelu L, Dorofeev A, Bayas-Morejón F, Shirafkan N, Shomali N, Chartrand MS, Jarahian M, Vahedi G, Mohammed RN, Shahrokh S, Akbari M, and Khiavi FM
- Subjects
- Immunotherapy, Immunotherapy, Adoptive, Killer Cells, Natural, T-Lymphocytes, Neoplasms therapy, Receptors, Chimeric Antigen genetics
- Abstract
In recent decades, a new method of cellular immunotherapy was introduced based on engineering and empowering the immune effector cells. In this type of immunotherapy, the immune effector cells are equipped with chimeric antigen receptor (CAR) to specifically target cancer cells. In much of the trials and experiments, CAR-modified T cell immunotherapy has achieved very promising therapeutic results in the treatment of some types of cancers and infectious diseases. However, there are also some considerable drawbacks in the clinical application of CAR-T cells although much effort is in progress to rectify the issues. In some conditions, CAR-T cells initiate over-activated and strong immune responses, therefore, causing unexpected side-effects such as systemic cytokine toxicity (i.e., cytokine release syndrome), neurotoxicity, on-target, off-tumor toxicity, and graft-versus-host disease (GvHD). To overcome these limitations in CAR-T cell immunotherapy, NK cells as an alternative source of immune effector cells have been utilized for CAR-engineering. Natural killer cells are key players of the innate immune system that can destroy virus-infected cells, tumor cells, or other aberrant cells with their efficient recognizing capability. Compared to T cells, CAR-transduced NK cells (CAR-NK) have several advantages, such as safety in clinical use, non-MHC-restricted recognition of tumor cells, and renewable and easy cell sources for their preparation. In this review, we will discuss the recent preclinical and clinical studies, different sources of NK cells, transduction methods, possible limitations and challenges, and clinical considerations.
- Published
- 2021
- Full Text
- View/download PDF
32. Mesenchymal stem/stromal cells as a valuable source for the treatment of immune-mediated disorders.
- Author
-
Markov A, Thangavelu L, Aravindhan S, Zekiy AO, Jarahian M, Chartrand MS, Pathak Y, Marofi F, Shamlou S, and Hassanzadeh A
- Subjects
- Humans, COVID-19 immunology, COVID-19 therapy, Immunomodulation, Mesenchymal Stem Cell Transplantation, Mesenchymal Stem Cells immunology, SARS-CoV-2 immunology
- Abstract
Over recent years, mesenchymal stem/stromal cells (MSCs) and their potential biomedical applications have received much attention from the global scientific community in an increasing manner. Firstly, MSCs were successfully isolated from human bone marrow (BM), but in the next steps, they were also extracted from other sources, mostly from the umbilical cord (UC) and adipose tissue (AT). The International Society for Cellular Therapy (ISCT) has suggested minimum criteria to identify and characterize MSCs as follows: plastic adherence, surface expression of CD73, D90, CD105 in the lack of expression of CD14, CD34, CD45, and human leucocyte antigen-DR (HLA-DR), and also the capability to differentiate to multiple cell types including adipocyte, chondrocyte, or osteoblast in vitro depends on culture conditions. However, these distinct properties, including self-renewability, multipotency, and easy accessibility are just one side of the coin; another side is their huge secretome which is comprised of hundreds of mediators, cytokines, and signaling molecules and can effectively modulate the inflammatory responses and control the infiltration process that finally leads to a regulated tissue repair/healing or regeneration process. MSC-mediated immunomodulation is a direct result of a harmonic synergy of MSC-released signaling molecules (i.e., mediators, cytokines, and chemokines), the reaction of immune cells and other target cells to those molecules, and also feedback in the MSC-molecule-target cell axis. These features make MSCs a respectable and eligible therapeutic candidate to be evaluated in immune-mediated disorders, such as graft versus host diseases (GVHD), multiple sclerosis (MS), Crohn's disease (CD), and osteoarthritis (OA), and even in immune-dysregulating infectious diseases such as the novel coronavirus disease 2019 (COVID-19). This paper discussed the therapeutic applications of MSC secretome and its biomedical aspects related to immune-mediated conditions. Sources for MSC extraction, their migration and homing properties, therapeutic molecules released by MSCs, and the pathways and molecular mechanisms possibly involved in the exceptional immunoregulatory competence of MSCs were discussed. Besides, the novel discoveries and recent findings on immunomodulatory plasticity of MSCs, clinical applications, and the methods required for their use as an effective therapeutic option in patients with immune-mediated/immune-dysregulating diseases were highlighted.
- Published
- 2021
- Full Text
- View/download PDF
33. CAR T cells in solid tumors: challenges and opportunities.
- Author
-
Marofi F, Motavalli R, Safonov VA, Thangavelu L, Yumashev AV, Alexander M, Shomali N, Chartrand MS, Pathak Y, Jarahian M, Izadi S, Hassanzadeh A, Shirafkan N, Tahmasebi S, and Khiavi FM
- Subjects
- Humans, Immunotherapy, Adoptive, T-Lymphocytes, Tumor Microenvironment, Neoplasms therapy, Receptors, Chimeric Antigen genetics
- Abstract
Background: CARs are simulated receptors containing an extracellular single-chain variable fragment (scFv), a transmembrane domain, as well as an intracellular region of immunoreceptor tyrosine-based activation motifs (ITAMs) in association with a co-stimulatory signal., Main Body: Chimeric antigen receptor (CAR) T cells are genetically engineered T cells to express a receptor for the recognition of the particular surface marker that has given rise to advances in the treatment of blood disorders. The CAR T cells obtain supra-physiological properties and conduct as "living drugs" presenting both immediate and steady effects after expression in T cells surface. But, their efficacy in solid tumor treatment has not yet been supported. The pivotal challenges in the field of solid tumor CAR T cell therapy can be summarized in three major parts: recognition, trafficking, and surviving in the tumor. On the other hand, the immunosuppressive tumor microenvironment (TME) interferes with T cell activity in terms of differentiation and exhaustion, and as a result of the combined use of CARs and checkpoint blockade, as well as the suppression of other inhibitor factors in the microenvironment, very promising results were obtained from the reduction of T cell exhaustion., Conclusion: Nowadays, identifying and defeating the mechanisms associated with CAR T cell dysfunction is crucial to establish CAR T cells that can proliferate and lyse tumor cells severely. In this review, we discuss the CAR signaling and efficacy T in solid tumors and evaluate the most significant barriers in this process and describe the most novel therapeutic methods aiming to the acquirement of the promising therapeutic outcome in non-hematologic malignancies.
- Published
- 2021
- Full Text
- View/download PDF
34. The CCR5 antagonist maraviroc causes remission of pancreatic cancer liver metastasis in nude rats based on cell cycle inhibition and apoptosis induction.
- Author
-
Huang H, Zepp M, Georges RB, Jarahian M, Kazemi M, Eyol E, and Berger MR
- Subjects
- Animals, CCR5 Receptor Antagonists pharmacology, Carcinoma, Pancreatic Ductal metabolism, Carcinoma, Pancreatic Ductal pathology, Cell Movement, Cell Proliferation, Humans, Liver Neoplasms metabolism, Liver Neoplasms secondary, Male, Pancreatic Neoplasms metabolism, Pancreatic Neoplasms pathology, Rats, Rats, Nude, Receptors, CCR5 metabolism, Tumor Cells, Cultured, Xenograft Model Antitumor Assays, Apoptosis, Carcinoma, Pancreatic Ductal drug therapy, Cell Cycle, Liver Neoplasms drug therapy, Maraviroc pharmacology, Pancreatic Neoplasms drug therapy, Receptors, CCR5 chemistry
- Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease, and novel therapeutic strategies are urgently needed. Recently, expression of the C-C chemokine receptor 5 (CCR5) and its ligands has been found to play an important role in cancer progression and metastasis. In this study, we blocked the CCR5 receptor by the FDA approved antagonist maraviroc (MVC) in Suit2-007 and MIA-PaCa-2 human PDAC cells. The treatment significantly inhibited their proliferation and induced apoptosis of exposed cells as evidenced by caspases activation and increased Bax levels. Moreover, MVC inhibited the cell cycle by down regulating the proteins of the complexes of cyclin dependent kinase (CDK) 4/6 - Cyclin D and CDK2 - Cyclin E, as well as by increasing the protein levels of CDK inhibitors p18, p21 and p27. In line with this, MVC caused significant retardation of Suit2-007 cells growing in a PDAC liver metastasis xenograft model (p < 0.05). These results suggest that maraviroc could be a promising treatment strategy for PDAC patients with liver metastases., Competing Interests: Declaration of competing interest None of the authors has a conflict of interest to disclose regarding the publication of the present manuscript., (Copyright © 2020 Elsevier B.V. All rights reserved.)
- Published
- 2020
- Full Text
- View/download PDF
35. Expression and Purification of a Bispecific Antibody against CD16 and Hemagglutinin Neuraminidase (HN) in E. Coli for Cancer Immunotherapy.
- Author
-
Bahrololoumi Shapourabadi M, Roohvand F, Arashkia A, Mohajel N, Abdoli S, Shahosseini Z, Momburg F, Jarahian M, Abolhassani M, and Azadmanesh K
- Abstract
Background: : Immunotherapy of cancer by bispecific antibodies (bsAb) is an attractive approach for retargeting immune effector cells including natural killer (NK) cells to the tumor if the proper expression and purification of the bsAb for such applications could be addressed. Herein, we describe E. coli expression of a recombinant bsAb (bsHN-CD16) recognizing NK-CD16 and hemagglutinin neuraminidase (HN) of Newcastle Disease Virus (NDV). This bsAb might be efficient for ex vivo stimulation of NK cells via coupling to HN on the surface of the NDV-infected tumor cells., Methods: A bsAb-encoding pcDNA3.1 vector (anti-HN scFv-Fc-anti-CD16 scFv) was used as a template, and the scFv segments (after enzymatic digestion and cutting of the Fc part) were rejoined to construct the Fc-deprived bsAb (anti-HN scFv-anti-CD16 scFv; bsHN-CD16). The constructed bsHN-CD16 was inserted into the HindIII and BamHI site of the T7 promoter-based pET28a plasmid. Following restriction analyses and DNA sequencing to confirm the cloning steps, bsHN-CD16 encoding pET28a was transformed into the E. coli (Rosetta DE3 strain), induced for protein expression by IPTG, and the protein was purified under native condition by Ni/NTA column using imidazole., Results: Analyses by SDS-PAGE and Western Blotting using Rabbit anti-human whole IgG-HRP conjugate, confirmed the expression and purification of the bsAb with the expected full size of 55 kDa and yields around 8% of the total protein., Conclusion: Results showed efficient production of the bsAb in E. coli for future large-scale purification.
- Published
- 2020
- Full Text
- View/download PDF
36. Brain tumour cells interconnect to a functional and resistant network.
- Author
-
Osswald M, Jung E, Sahm F, Solecki G, Venkataramani V, Blaes J, Weil S, Horstmann H, Wiestler B, Syed M, Huang L, Ratliff M, Karimian Jazi K, Kurz FT, Schmenger T, Lemke D, Gömmel M, Pauli M, Liao Y, Häring P, Pusch S, Herl V, Steinhäuser C, Krunic D, Jarahian M, Miletic H, Berghoff AS, Griesbeck O, Kalamakis G, Garaschuk O, Preusser M, Weiss S, Liu H, Heiland S, Platten M, Huber PE, Kuner T, von Deimling A, Wick W, and Winkler F
- Subjects
- Animals, Astrocytoma metabolism, Astrocytoma radiotherapy, Brain Neoplasms metabolism, Brain Neoplasms radiotherapy, Cell Communication radiation effects, Cell Death radiation effects, Cell Proliferation radiation effects, Cell Surface Extensions metabolism, Cell Surface Extensions radiation effects, Cell Survival radiation effects, Connexin 43 metabolism, Disease Progression, GAP-43 Protein metabolism, Gap Junctions radiation effects, Glioma metabolism, Glioma pathology, Glioma radiotherapy, Humans, Male, Mice, Mice, Nude, Neoplasm Invasiveness, Radiation Tolerance drug effects, Astrocytoma pathology, Brain Neoplasms pathology, Gap Junctions metabolism
- Abstract
Astrocytic brain tumours, including glioblastomas, are incurable neoplasms characterized by diffusely infiltrative growth. Here we show that many tumour cells in astrocytomas extend ultra-long membrane protrusions, and use these distinct tumour microtubes as routes for brain invasion, proliferation, and to interconnect over long distances. The resulting network allows multicellular communication through microtube-associated gap junctions. When damage to the network occurred, tumour microtubes were used for repair. Moreover, the microtube-connected astrocytoma cells, but not those remaining unconnected throughout tumour progression, were protected from cell death inflicted by radiotherapy. The neuronal growth-associated protein 43 was important for microtube formation and function, and drove microtube-dependent tumour cell invasion, proliferation, interconnection, and radioresistance. Oligodendroglial brain tumours were deficient in this mechanism. In summary, astrocytomas can develop functional multicellular network structures. Disconnection of astrocytoma cells by targeting their tumour microtubes emerges as a new principle to reduce the treatment resistance of this disease.
- Published
- 2015
- Full Text
- View/download PDF
37. Activation of AMP-activated protein kinase sensitizes lung cancer cells and H1299 xenografts to erlotinib.
- Author
-
Hülsmann HJ, Rolff J, Bender C, Jarahian M, Korf U, Herwig R, Fröhlich H, Thomas M, Merk J, Fichtner I, Sültmann H, and Kuner R
- Subjects
- Animals, Apoptosis drug effects, Biphenyl Compounds, Cell Line, Tumor, Cell Proliferation drug effects, Cell Survival drug effects, Disease Models, Animal, Enzyme Activation drug effects, Erlotinib Hydrochloride, Female, Humans, Lung Neoplasms drug therapy, Lung Neoplasms pathology, Mice, Pyrones pharmacology, Signal Transduction drug effects, TOR Serine-Threonine Kinases metabolism, Thiophenes pharmacology, Tumor Burden drug effects, Xenograft Model Antitumor Assays, AMP-Activated Protein Kinases metabolism, Antineoplastic Agents pharmacology, Drug Resistance, Neoplasm, Lung Neoplasms metabolism, Protein Kinase Inhibitors pharmacology, Quinazolines pharmacology
- Abstract
Objectives: The therapeutic scheme for non-small cell lung cancer (NSCLC) patients can be improved if adapted to the individual response. For example, 60-70% of adenocarcinoma patients show response to EGFR-tyrosine kinase inhibitors in the presence of mutated EGFR. We searched for additional target molecules involved in the action of the EGFR-tyrosine kinase inhibitor erlotinib in the absence of EGFR mutations, which might be suitable for combinatorial therapy approaches., Materials and Methods: Erlotinib-response associated proteins were investigated in patient-derived NSCLC mouse xenografts by reverse-phase protein array technology (RPPA) and Western blotting. A combinatorial treatment approach was carried out in NSCLC cell lines and H1299 mouse xenografts, and subsequently analyzed for consequences in cell growth and signal transduction., Results: AMP-activated protein kinase (AMPK) expression was increased in erlotinib responders before and after treatment. In a combinatorial approach, activation of AMPK by A-769662 and erlotinib treatment showed a synergistic effect in cell growth reduction and apoptosis activation in H1299 cells compared to the single drugs. AMPK pathway analyses revealed an effective inhibition of mTOR signaling by drug combination. In H1299 xenografts, the tumor size was significantly decreased after combinatorial treatment., Conclusion: Our results suggest that AMPK activation status affects response to erlotinib in distinct lung tumor models., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)
- Published
- 2014
- Full Text
- View/download PDF
38. Modulation of NKp30- and NKp46-mediated natural killer cell responses by poxviral hemagglutinin.
- Author
-
Jarahian M, Fiedler M, Cohnen A, Djandji D, Hämmerling GJ, Gati C, Cerwenka A, Turner PC, Moyer RW, Watzl C, Hengel H, and Momburg F
- Subjects
- Animals, Cell Line, Gene Expression Regulation, Viral, Humans, Killer Cells, Natural metabolism, Mice, Natural Cytotoxicity Triggering Receptor 1 genetics, Natural Cytotoxicity Triggering Receptor 3 genetics, Plasmids, RNA, Small Interfering, Recombinant Fusion Proteins genetics, Recombinant Fusion Proteins metabolism, Up-Regulation, Ectromelia virus immunology, Hemagglutinins metabolism, Killer Cells, Natural immunology, Natural Cytotoxicity Triggering Receptor 1 metabolism, Natural Cytotoxicity Triggering Receptor 3 metabolism, Vaccinia virus immunology
- Abstract
Natural killer (NK) cells are an important element in the immune defense against the orthopox family members vaccinia virus (VV) and ectromelia virus (ECTV). NK cells are regulated through inhibitory and activating signaling receptors, the latter involving NKG2D and the natural cytotoxicity receptors (NCR), NKp46, NKp44 and NKp30. Here we report that VV infection results in an upregulation of ligand structures for NKp30 and NKp46 on infected cells, whereas the binding of NKp44 and NKG2D was not significantly affected. Likewise, infection with ectromelia virus (ECTV), the mousepox agent, enhanced binding of NKp30 and, to a lesser extent, NKp46. The hemagglutinin (HA) molecules from VV and ECTV, which are known virulence factors, were identified as novel ligands for NKp30 and NKp46. Using NK cells with selectively silenced NCR expression and NCR-CD3ζ reporter cells, we observed that HA present on the surface of VV-infected cells, or in the form of recombinant soluble protein, was able to block NKp30-triggered activation, whereas it stimulated the activation through NKp46. The net effect of this complex influence on NK cell activity resulted in a decreased NK lysis susceptibility of infected cells at late time points of VV infection when HA was expression was pronounced. We conclude that poxviral HA represents a conserved ligand of NCR, exerting a novel immune escape mechanism through its blocking effect on NKp30-mediated activation at a late stage of infection.
- Published
- 2011
- Full Text
- View/download PDF
39. Activation of natural killer cells by newcastle disease virus hemagglutinin-neuraminidase.
- Author
-
Jarahian M, Watzl C, Fournier P, Arnold A, Djandji D, Zahedi S, Cerwenka A, Paschen A, Schirrmacher V, and Momburg F
- Subjects
- Avulavirus Infections virology, Cell Line, Tumor, HN Protein genetics, Humans, Natural Cytotoxicity Triggering Receptor 1 genetics, Natural Cytotoxicity Triggering Receptor 1 immunology, Natural Cytotoxicity Triggering Receptor 2 genetics, Natural Cytotoxicity Triggering Receptor 2 immunology, Newcastle disease virus genetics, Newcastle disease virus immunology, Avulavirus Infections immunology, HN Protein immunology, Killer Cells, Natural immunology, Newcastle disease virus enzymology
- Abstract
The avian paramyxovirus Newcastle disease virus (NDV) selectively replicates in tumor cells and is known to stimulate T-cell-, macrophage-, and NK cell-mediated responses. The mechanisms of NK cell activation by NDV are poorly understood so far. We studied the expression of ligand structures for activating NK cell receptors on NDV-infected tumor cells. Upon infection with the nonlytic NDV strain Ulster and the lytic strain MTH-68/H, human carcinoma and melanoma cells showed enhanced expression of ligands for the natural cytotoxicity receptors NKp44 and NKp46, but not NKp30. Ligands for the activating receptor NKG2D were partially downregulated. Soluble NKp44-Fc and NKp46-Fc, but not NKp30-Fc, chimeric proteins bound specifically to NDV-infected tumor cells and to NDV particle-coated plates. Hemagglutinin-neuraminidase (HN) of the virus serves as a ligand structure for NKp44 and NKp46, as indicated by the blockade of binding to NDV-infected cells and viral particles in the presence of anti-HN antibodies and by binding to cells transfected with HN cDNA. Consistent with the recognition of sialic acid moieties by the viral lectin HN, the binding of NKp44-Fc and NKp46-Fc was lost after desialylation. NKp44- and NKp46-CD3zeta lacZ-inducible reporter cells were activated by NDV-infected cells. NDV-infected tumor cells stimulated NK cells to produce increased amounts of the effector lymphokines gamma interferon and tumor necrosis factor alpha. Primary NK cells and the NK line NK-92 lysed NDV-infected tumor cells with enhanced efficiency, an effect that was eliminated by the treatment of target cells with the neuraminidase inhibitor Neu5Ac2en. These results suggest that direct activation of NK cells contributes to the antitumor effects of NDV.
- Published
- 2009
- Full Text
- View/download PDF
40. Altered glycosylation of recombinant NKp30 hampers binding to heparan sulfate: a lesson for the use of recombinant immunoreceptors as an immunological tool.
- Author
-
Hershkovitz O, Jarahian M, Zilka A, Bar-Ilan A, Landau G, Jivov S, Tekoah Y, Glicklis R, Gallagher JT, Hoffmann SC, Zer H, Mandelboim O, Watzl C, Momburg F, and Porgador A
- Subjects
- Animals, Binding Sites, CHO Cells, Cell Line, Tumor, Cricetinae, Cricetulus, Glycosylation, HeLa Cells, Humans, Natural Cytotoxicity Triggering Receptor 3, Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase metabolism, Polysaccharides analysis, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Heparitin Sulfate metabolism, Receptors, Immunologic genetics, Receptors, Immunologic metabolism, Recombinant Proteins metabolism
- Abstract
NKp30 is a natural cytotoxicity receptor expressed by human NK cells and involved in NK lytic activity. We previously published that membranal heparan sulfate serves as a coligand for human NKp30. In the present study, we complement our results by showing direct binding of recombinant NKp30 to immobilized heparin. The heparan sulfate epitope(s) on target tumor cells and the heparin epitope(s) recognized by NKp30 share similar characteristics. Warren and colleagues (Warren HS, Jones AL, Freeman C, Bettadapura J, Parish CR. 2005. Evidence that the cellular ligand for the human NK cell activation receptor NKp30 is not a heparan sulfate glycosaminoglycan. J Immunol. 175:207-212) published that NKp30 does not bind to membranal heparan sulfate on target cells and that heparan sulfate is not involved in NKp30-mediated lysis. In the current study, we examine the binding of six different recombinant NKp30s to membranal heparan sulfate and conclude that NKp30 does interact with membranal heparan sulfate. Yet, two of the six recombinant NKp30s, including the commercially available recombinant NKp30 (employed by Warren et al.) did not show heparan sulfate-dependent binding. We demonstrate that this is due to an altered glycosylation of these two recombinant NKp30s. Upon removal of its N-linked glycans, heparan sulfate-dependent binding to tumor cells and direct binding to heparin were restored. Overall, our results emphasize the importance of proper glycosylation for analysis of NKp30 binding to its ligand and that membranal heparan sulfate could serve as a coligand for NKp30. At the cellular level, soluble heparan sulfate enhanced the secretion of IFNgamma by NK-92 natural killer cells activated with anti-NKp30 monoclonal antibody. We discuss the involvement of heparan sulfate binding to NKp30 in NKp30-mediated activation of NK cells.
- Published
- 2008
- Full Text
- View/download PDF
41. Expression analysis of the ligands for the Natural Killer cell receptors NKp30 and NKp44.
- Author
-
Byrd A, Hoffmann SC, Jarahian M, Momburg F, and Watzl C
- Subjects
- Cell Line, Transformed, Humans, Ligands, Natural Cytotoxicity Triggering Receptor 2, Natural Cytotoxicity Triggering Receptor 3, Receptors, Immunologic genetics, Killer Cells, Natural metabolism, Receptors, Immunologic metabolism
- Abstract
Background: The natural cytotoxicity receptors (NCR) are important to stimulate the activity of Natural Killer (NK) cells against transformed cells. Identification of NCR ligands and their level of expression on normal and neoplastic cells has important implications for the rational design of immunotherapy strategies for cancer., Methodology/principal Findings: Here we analyze the expression of NKp30 ligand and NKp44 ligand on 30 transformed or non-transformed cell lines of different origin. We find intracellular and surface expression of these two ligands on almost all cell lines tested. Expression of NKp30 and NKp44 ligands was variable and did not correlate with the origin of the cell line. Expression of NKp30 and NKp44 ligand correlated with NKp30 and NKp44-mediated NK cell lysis of tumor cells, respectively. The surface expression of NKp30 ligand and NKp44 ligand was sensitive to trypsin treatment and was reduced in cells arrested in G(2)/M phase., Conclusion/significance: These data demonstrate the ubiquitous expression of the ligands for NKp30 and NKp44 and give an important insight into the regulation of these ligands.
- Published
- 2007
- Full Text
- View/download PDF
42. Blockade of natural killer cell-mediated lysis by NCAM140 expressed on tumor cells.
- Author
-
Jarahian M, Watzl C, Issa Y, Altevogt P, and Momburg F
- Subjects
- Animals, Antibodies, Monoclonal immunology, Antibodies, Monoclonal pharmacology, CHO Cells, Cell Adhesion Molecules, Neuronal genetics, Cell Line, Cell Line, Tumor, Clone Cells, Cricetinae, Cricetulus, Cytotoxicity Tests, Immunologic, Cytotoxicity, Immunologic drug effects, Dose-Response Relationship, Drug, Gene Expression, HeLa Cells, Humans, Intercellular Adhesion Molecule-1 genetics, Intercellular Adhesion Molecule-1 immunology, Killer Cells, Natural metabolism, Neoplasms genetics, Neoplasms immunology, Neoplasms pathology, RNA, Messenger genetics, RNA, Messenger metabolism, Reverse Transcriptase Polymerase Chain Reaction, Transfection, Cell Adhesion Molecules, Neuronal immunology, Cytotoxicity, Immunologic immunology, Killer Cells, Natural immunology
- Abstract
Expression of the neural cell adhesion molecule (NCAM) on malignant cells of neuroendocrine, epithelial and hematopoeitic origin has been reported, but its role for tumor cell recognition by the immune system remained uncertain so far. We have studied the cytotoxicity of the natural killer (NK) cell line NK92 and polyclonal NK cells from different donors, against NCAM-deficient and NCAM-transfected tumors. While the pancreatic carcinoma PANC-1 and the glioblastoma T98G showed no enhanced susceptibility to NK lysis after NCAM transfection, de novo NCAM expression in HeLa cervical carcinoma, SHEP neuroblastoma and the multiple myeloma lines RPMI-8226 and LP-1 was associated with significantly decreased lysis by NK cells. Binding of an NCAM-specific monoclonal antibody to NCAM-positive target cells was able to reverse the reduced lysis susceptibility. Conjugate formation of NCAM-expressing tumor cells with NK cells was blocked and could be restored by anti-NCAM. NK cell-expressed NCAM molecules which might engage in homotypic cis- or trans-interactions had no apparent inhibitory function. The known cis-ligands of NCAM, heparan sulfate proteoglycan and L1-CAM, were also not directly involved in NK inhibition. ICAM-1 mRNA and cell surface expression was downmodulated in NCAM-transfected HeLa cells. ICAM-1 is involved in killer cell immune synapse formation. Its downmodulation may therefore contribute to the reduced lysis of NCAM-expressing target cells. We conclude that aberrant expression of NCAM on tumor cells of different histogenetic origin can lead to inhibition of target cell recognition and lysis by NK cells.
- Published
- 2007
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.