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Modak S, Aktar T, Majumder D, Singha AK, Maiti D. A systematic review on leptin's role in defining cancer: special emphasis on immunomodulation, inflammation, and therapeutic interventions. Genes Immun 2025:10.1038/s41435-025-00333-7. [PMID: 40374921 DOI: 10.1038/s41435-025-00333-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2024] [Revised: 04/22/2025] [Accepted: 04/30/2025] [Indexed: 05/18/2025]
Abstract
Leptin, an adipokine related to obesity, is mainly known for its role in regulating energy homeostasis and appetite by working via the leptin receptor. Recently, different groups have demonstrated that apart from adipocytes, specific cell types associated with cancer and tumor microenvironments express leptin and leptin receptors. This tumor microenvironment-associated leptin-leptin receptor signaling contributes to the different hallmarks of cancer, ranging from inflammatory changes to metastasis. Eventually, it has also been reported that high serum level of leptin, a characteristic of obese people, is linked to enhanced tumor growth. On the other hand, leptin can influence both innate as well as adaptive immunity related to cancer. Overall, leptin's role in modulating cancer is controversial. So, in this review, we summarized the role of leptin in shaping different forms of cancer that are influenced by leptin-leptin receptor signaling with special emphasis on immunomodulation and inflammatory events and also discussed the possible therapeutic interventions to date. As this review work, with the collection of different updated knowledge, has summarized the role of leptin on cancer, it would be useful material to have on hand for both beginners as well as pioneers of these and related fields.
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Affiliation(s)
- Snehashish Modak
- Immunology Microbiology Lab, Tripura University, Suryamaninagar, Tripura, India
| | - Tamanna Aktar
- Immunology Microbiology Lab, Tripura University, Suryamaninagar, Tripura, India
| | - Debabrata Majumder
- Immunology Microbiology Lab, Tripura University, Suryamaninagar, Tripura, India
- Department of Integrative Immunobiology, Duke University Medical Center, Durham, NC, USA
| | - Ashish Kr Singha
- Immunology Microbiology Lab, Tripura University, Suryamaninagar, Tripura, India
- Department of Human Physiology, Holy Cross College, Agartala, West Tripura, India
| | - Debasish Maiti
- Immunology Microbiology Lab, Tripura University, Suryamaninagar, Tripura, India.
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De Munter S, Buhl JL, De Cock L, Van Parys A, Daneels W, Pascal E, Deseins L, Ingels J, Goetgeluk G, Jansen H, Billiet L, Pille M, Van Duyse J, Bonte S, Vandamme N, Van Dorpe J, Offner F, Leclercq G, Taghon T, Depla E, Tavernier J, Kerre T, Drost J, Vandekerckhove B. Knocking Out CD70 Rescues CD70-Specific NanoCAR T Cells from Antigen-Induced Exhaustion. Cancer Immunol Res 2024; 12:1236-1251. [PMID: 38874582 DOI: 10.1158/2326-6066.cir-23-0677] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2023] [Revised: 03/29/2024] [Accepted: 06/12/2024] [Indexed: 06/15/2024]
Abstract
CD70 is an attractive target for chimeric antigen receptor (CAR) T-cell therapy for the treatment of both solid and liquid malignancies. However, the functionality of CD70-specific CAR T cells is modest. We optimized a CD70-specific VHH-based CAR (nanoCAR). We evaluated the nanoCARs in clinically relevant models in vitro, using co-cultures of CD70-specific nanoCAR T cells with malignant rhabdoid tumor organoids, and in vivo, using a diffuse large B-cell lymphoma patient-derived xenograft (PDX) model. Although the nanoCAR T cells were highly efficient in organoid co-cultures, they showed only modest efficacy in the PDX model. We determined that fratricide was not causing this loss in efficacy but rather CD70 interaction in cis with the nanoCAR-induced exhaustion. Knocking out CD70 in nanoCAR T cells using CRISPR/Cas9 resulted in dramatically enhanced functionality in the diffuse large B-cell lymphoma PDX model. Through single-cell transcriptomics, we obtained evidence that CD70 knockout CD70-specific nanoCAR T cells were protected from antigen-induced exhaustion. In addition, we demonstrated that wild-type CD70-specific nanoCAR T cells already exhibited signs of exhaustion shortly after production. Their gene signature strongly overlapped with gene signatures of exhausted CAR T cells. Conversely, the gene signature of knockout CD70-specific nanoCAR T cells overlapped with the gene signature of CAR T-cell infusion products leading to complete responses in chronic lymphatic leukemia patients. Our data show that CARs targeting endogenous T-cell antigens negatively affect CAR T-cell functionality by inducing an exhausted state, which can be overcome by knocking out the specific target.
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MESH Headings
- Humans
- CD27 Ligand
- Animals
- Mice
- Immunotherapy, Adoptive/methods
- Xenograft Model Antitumor Assays
- Receptors, Chimeric Antigen/immunology
- Receptors, Chimeric Antigen/genetics
- T-Lymphocytes/immunology
- T-Lymphocytes/metabolism
- Lymphoma, Large B-Cell, Diffuse/immunology
- Lymphoma, Large B-Cell, Diffuse/therapy
- Lymphoma, Large B-Cell, Diffuse/genetics
- Gene Knockout Techniques
- Cell Line, Tumor
- CRISPR-Cas Systems
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Affiliation(s)
- Stijn De Munter
- Department of Diagnostic Sciences, Ghent University, Ghent, Belgium
- Cancer Research Institute Ghent (CRIG), Ghent, Belgium
| | - Juliane L Buhl
- Princess Máxima Center and Oncode Institute, Utrecht, the Netherlands
| | - Laurenz De Cock
- Cancer Research Institute Ghent (CRIG), Ghent, Belgium
- Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
| | | | - Willem Daneels
- Cancer Research Institute Ghent (CRIG), Ghent, Belgium
- Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium
- Department of Hematology, Ghent University Hospital, Ghent, Belgium
| | - Eva Pascal
- Department of Diagnostic Sciences, Ghent University, Ghent, Belgium
- Cancer Research Institute Ghent (CRIG), Ghent, Belgium
| | - Lucas Deseins
- Department of Diagnostic Sciences, Ghent University, Ghent, Belgium
| | - Joline Ingels
- Department of Diagnostic Sciences, Ghent University, Ghent, Belgium
- Cancer Research Institute Ghent (CRIG), Ghent, Belgium
| | - Glenn Goetgeluk
- Department of Diagnostic Sciences, Ghent University, Ghent, Belgium
- Cancer Research Institute Ghent (CRIG), Ghent, Belgium
| | - Hanne Jansen
- Department of Diagnostic Sciences, Ghent University, Ghent, Belgium
| | - Lore Billiet
- Department of Diagnostic Sciences, Ghent University, Ghent, Belgium
| | - Melissa Pille
- Department of Diagnostic Sciences, Ghent University, Ghent, Belgium
| | - Julie Van Duyse
- VIB Flow Core, VIB Center for Inflammation Research, Ghent, Belgium
- Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
| | - Sarah Bonte
- Cancer Research Institute Ghent (CRIG), Ghent, Belgium
- Department of Applied Mathematics, Computer Science and Statistics, Ghent University, Ghent, Belgium
| | | | - Jo Van Dorpe
- Cancer Research Institute Ghent (CRIG), Ghent, Belgium
- Department of Pathology, Ghent University Hospital, Ghent, Belgium
| | - Fritz Offner
- Cancer Research Institute Ghent (CRIG), Ghent, Belgium
- Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium
- Department of Hematology, Ghent University Hospital, Ghent, Belgium
| | - Georges Leclercq
- Department of Diagnostic Sciences, Ghent University, Ghent, Belgium
- Cancer Research Institute Ghent (CRIG), Ghent, Belgium
| | - Tom Taghon
- Department of Diagnostic Sciences, Ghent University, Ghent, Belgium
- Cancer Research Institute Ghent (CRIG), Ghent, Belgium
| | | | | | - Tessa Kerre
- Department of Diagnostic Sciences, Ghent University, Ghent, Belgium
- Cancer Research Institute Ghent (CRIG), Ghent, Belgium
- Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium
- Department of Hematology, Ghent University Hospital, Ghent, Belgium
| | - Jarno Drost
- Princess Máxima Center and Oncode Institute, Utrecht, the Netherlands
| | - Bart Vandekerckhove
- Department of Diagnostic Sciences, Ghent University, Ghent, Belgium
- Cancer Research Institute Ghent (CRIG), Ghent, Belgium
- GMP Unit cell Therapy, Ghent University Hospital, Ghent, Belgium
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Caruso A, Gelsomino L, Panza S, Accattatis FM, Naimo GD, Barone I, Giordano C, Catalano S, Andò S. Leptin: A Heavyweight Player in Obesity-Related Cancers. Biomolecules 2023; 13:1084. [PMID: 37509120 PMCID: PMC10377641 DOI: 10.3390/biom13071084] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 07/04/2023] [Accepted: 07/05/2023] [Indexed: 07/30/2023] Open
Abstract
Obesity, defined as the abnormal or excessive expansion of white adipose tissue, has reached pandemic proportions and is recognized as an important health concern since it is a common root for several comorbidities, including malignancies. Indeed, the current knowledge of the white adipose tissue, which shifts its role from an energy storage tissue to an important endocrine and metabolic organ, has opened up new avenues for the discovery of obesity's effects on tumor biology. In this review, we will report the epidemiological studies concerning the strong impact of obesity in several types of cancer and describe the mechanisms underlying the heterotypic signals between cancer cell lines and adipocytes, with particular emphasis on inflammation, the insulin/IGF-1 axis, and adipokines. Among the adipokines, we will further describe the in vitro, in vivo, and clinical data concerning the role of leptin, recognized as one of the most important mediators of obesity-associated cancers. In fact, leptin physiologically regulates energy metabolism, appetite, and reproduction, and several studies have also described the role of leptin in affecting cancer development and progression. Finally, we will summarize the newest pharmacological strategies aimed at mitigating the protumorigenic effects of leptin, underlining their mechanisms of action.
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Affiliation(s)
- Amanda Caruso
- Department of Pharmacy, Health and Nutritional Sciences, Via P Bucci, University of Calabria, Arcavacata di Rende (CS), 87036 Cosenza, Italy
| | - Luca Gelsomino
- Department of Pharmacy, Health and Nutritional Sciences, Via P Bucci, University of Calabria, Arcavacata di Rende (CS), 87036 Cosenza, Italy
- Centro Sanitario, Via P. Bucci, University of Calabria, Arcavacata di Rende (CS), 87036 Cosenza, Italy
| | - Salvatore Panza
- Department of Pharmacy, Health and Nutritional Sciences, Via P Bucci, University of Calabria, Arcavacata di Rende (CS), 87036 Cosenza, Italy
| | - Felice Maria Accattatis
- Department of Pharmacy, Health and Nutritional Sciences, Via P Bucci, University of Calabria, Arcavacata di Rende (CS), 87036 Cosenza, Italy
| | - Giuseppina Daniela Naimo
- Department of Pharmacy, Health and Nutritional Sciences, Via P Bucci, University of Calabria, Arcavacata di Rende (CS), 87036 Cosenza, Italy
| | - Ines Barone
- Department of Pharmacy, Health and Nutritional Sciences, Via P Bucci, University of Calabria, Arcavacata di Rende (CS), 87036 Cosenza, Italy
- Centro Sanitario, Via P. Bucci, University of Calabria, Arcavacata di Rende (CS), 87036 Cosenza, Italy
| | - Cinzia Giordano
- Department of Pharmacy, Health and Nutritional Sciences, Via P Bucci, University of Calabria, Arcavacata di Rende (CS), 87036 Cosenza, Italy
- Centro Sanitario, Via P. Bucci, University of Calabria, Arcavacata di Rende (CS), 87036 Cosenza, Italy
| | - Stefania Catalano
- Department of Pharmacy, Health and Nutritional Sciences, Via P Bucci, University of Calabria, Arcavacata di Rende (CS), 87036 Cosenza, Italy
- Centro Sanitario, Via P. Bucci, University of Calabria, Arcavacata di Rende (CS), 87036 Cosenza, Italy
| | - Sebastiano Andò
- Department of Pharmacy, Health and Nutritional Sciences, Via P Bucci, University of Calabria, Arcavacata di Rende (CS), 87036 Cosenza, Italy
- Centro Sanitario, Via P. Bucci, University of Calabria, Arcavacata di Rende (CS), 87036 Cosenza, Italy
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Obesity and main urologic cancers: Current systematic evidence, novel biological mechanisms, perspectives and challenges. Semin Cancer Biol 2023; 91:70-98. [PMID: 36893965 DOI: 10.1016/j.semcancer.2023.03.002] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 03/06/2023] [Accepted: 03/06/2023] [Indexed: 03/09/2023]
Abstract
Urologic cancers (UC) account for 13.1% of all new cancer cases and 7.9% of all cancer-related deaths. A growing body of evidence has indicated a potential causal link between obesity and UC. The aim of the present review is to appraise in a critical and integrative manner evidence from meta-analyses and mechanistic studies on the role of obesity in four prevalent UC (kidney-KC, prostate-PC, urinary bladder-UBC, and testicular cancer-TC). Special emphasis is given on Mendelian Randomization Studies (MRS) corroborating a genetic causal association between obesity and UC, as well as on the role of classical and novel adipocytokines. Furthermore, the molecular pathways that link obesity to the development and progression of these cancers are reviewed. Available evidence indicates that obesity confers increased risk for KC, UBC, and advanced PC (20-82%, 10-19%, and 6-14%, respectively), whereas for TC adult height (5-cm increase) may increase the risk by 13%. Obese females tend to be more susceptible to UBC and KC than obese males. MRS have shown that a higher genetic-predicted BMI may be causally linked to KC and UBC but not PC and TC. Biological mechanisms that are involved in the association between excess body weight and UC include the Insulin-like Growth Factor axis, altered availability of sex hormones, chronic inflammation and oxidative stress, abnormal secretion of adipocytokines, ectopic fat deposition, dysbiosis of the gastrointestinal and urinary tract microbiomes and circadian rhythm dysregulation. Anti-hyperglycemic and non-steroidal anti-inflammatory drugs, statins, and adipokine receptor agonists/antagonists show potential as adjuvant cancer therapies. Identifying obesity as a modifiable risk factor for UC may have significant public health implications, allowing clinicians to tailor individualized prevention strategies for patients with excess body weight.
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Shoari A, Tahmasebi M, Khodabakhsh F, Cohan RA, Oghalaie A, Behdani M. Angiogenic biomolecules specific nanobodies application in cancer imaging and therapy; review and updates. Int Immunopharmacol 2022; 105:108585. [DOI: 10.1016/j.intimp.2022.108585] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Revised: 01/18/2022] [Accepted: 01/25/2022] [Indexed: 11/05/2022]
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Duquenne M, Folgueira C, Bourouh C, Millet M, Silva A, Clasadonte J, Imbernon M, Fernandois D, Martinez-Corral I, Kusumakshi S, Caron E, Rasika S, Deliglia E, Jouy N, Oishi A, Mazzone M, Trinquet E, Tavernier J, Kim YB, Ory S, Jockers R, Schwaninger M, Boehm U, Nogueiras R, Annicotte JS, Gasman S, Dam J, Prévot V. Leptin brain entry via a tanycytic LepR-EGFR shuttle controls lipid metabolism and pancreas function. Nat Metab 2021; 3:1071-1090. [PMID: 34341568 PMCID: PMC7611554 DOI: 10.1038/s42255-021-00432-5] [Citation(s) in RCA: 84] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2019] [Accepted: 06/23/2021] [Indexed: 01/14/2023]
Abstract
Metabolic health depends on the brain's ability to control food intake and nutrient use versus storage, processes that require peripheral signals such as the adipocyte-derived hormone, leptin, to cross brain barriers and mobilize regulatory circuits. We have previously shown that hypothalamic tanycytes shuttle leptin into the brain to reach target neurons. Here, using multiple complementary models, we show that tanycytes express functional leptin receptor (LepR), respond to leptin by triggering Ca2+ waves and target protein phosphorylation, and that their transcytotic transport of leptin requires the activation of a LepR-EGFR complex by leptin and EGF sequentially. Selective deletion of LepR in tanycytes blocks leptin entry into the brain, inducing not only increased food intake and lipogenesis but also glucose intolerance through attenuated insulin secretion by pancreatic β-cells, possibly via altered sympathetic nervous tone. Tanycytic LepRb-EGFR-mediated transport of leptin could thus be crucial to the pathophysiology of diabetes in addition to obesity, with therapeutic implications.
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Affiliation(s)
- Manon Duquenne
- Univ. Lille, Inserm, CHU Lille, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Lille Neuroscience & Cognition, UMR-S1172, EGID, DISTALZ, Lille, France
| | - Cintia Folgueira
- Universidade de Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, Spain
- CIBER Fisiopatología de la Obesidad y Nutrición, Santiago de Compostela, Spain
| | - Cyril Bourouh
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, CNRS, U1283-UMR 8199-EGID, Lille, France
| | - Marion Millet
- Centre National de la Recherche Scientifique, Université de Strasbourg, Institut des Neurosciences Cellulaires et Intégratives, Strasbourg, France
| | - Anisia Silva
- Institut Cochin, Inserm U1016, CNRS UMR 8104, University Paris Descartes, Sorbonne Paris Cité, Paris, France
| | - Jérôme Clasadonte
- Univ. Lille, Inserm, CHU Lille, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Lille Neuroscience & Cognition, UMR-S1172, EGID, DISTALZ, Lille, France
| | - Monica Imbernon
- Univ. Lille, Inserm, CHU Lille, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Lille Neuroscience & Cognition, UMR-S1172, EGID, DISTALZ, Lille, France
| | - Daniela Fernandois
- Univ. Lille, Inserm, CHU Lille, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Lille Neuroscience & Cognition, UMR-S1172, EGID, DISTALZ, Lille, France
| | - Ines Martinez-Corral
- Univ. Lille, Inserm, CHU Lille, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Lille Neuroscience & Cognition, UMR-S1172, EGID, DISTALZ, Lille, France
| | - Soumya Kusumakshi
- Experimental Pharmacology, Center for Molecular Signaling, Saarland University School of Medicine, Homburg, Germany
| | - Emilie Caron
- Univ. Lille, Inserm, CHU Lille, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Lille Neuroscience & Cognition, UMR-S1172, EGID, DISTALZ, Lille, France
| | - S Rasika
- Univ. Lille, Inserm, CHU Lille, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Lille Neuroscience & Cognition, UMR-S1172, EGID, DISTALZ, Lille, France
| | - Eleonora Deliglia
- Univ. Lille, Inserm, CHU Lille, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Lille Neuroscience & Cognition, UMR-S1172, EGID, DISTALZ, Lille, France
| | - Nathalie Jouy
- Univ. Lille, Inserm, CHU Lille, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Lille Neuroscience & Cognition, UMR-S1172, EGID, DISTALZ, Lille, France
- Flow Cytometry Core Facility, BioImaging Center of Lille, Hospital Campus, UMS2014-US41, Lille, France
| | - Asturo Oishi
- Institut Cochin, Inserm U1016, CNRS UMR 8104, University Paris Descartes, Sorbonne Paris Cité, Paris, France
| | - Massimiliano Mazzone
- Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, VIB, Department of Oncology, Leuven, Belgium
| | - Eric Trinquet
- Cisbio Bioassays, Parc Technologique Marcel Boiteux, Codolet, France
| | - Jan Tavernier
- VIB-UGent Center for Medical Biotechnology, Gent, Belgium
| | - Young-Bum Kim
- Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA
| | - Stéphane Ory
- Centre National de la Recherche Scientifique, Université de Strasbourg, Institut des Neurosciences Cellulaires et Intégratives, Strasbourg, France
| | - Ralf Jockers
- Institut Cochin, Inserm U1016, CNRS UMR 8104, University Paris Descartes, Sorbonne Paris Cité, Paris, France
| | - Markus Schwaninger
- Institute for Experimental and Clinical Pharmacology and Toxicology, University of Lübeck, Lübeck, Germany
| | - Ulrich Boehm
- Experimental Pharmacology, Center for Molecular Signaling, Saarland University School of Medicine, Homburg, Germany
| | - Ruben Nogueiras
- Universidade de Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, Spain
| | - Jean-Sébastien Annicotte
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, CNRS, U1283-UMR 8199-EGID, Lille, France
| | - Stéphane Gasman
- Centre National de la Recherche Scientifique, Université de Strasbourg, Institut des Neurosciences Cellulaires et Intégratives, Strasbourg, France
| | - Julie Dam
- Institut Cochin, Inserm U1016, CNRS UMR 8104, University Paris Descartes, Sorbonne Paris Cité, Paris, France
| | - Vincent Prévot
- Univ. Lille, Inserm, CHU Lille, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Lille Neuroscience & Cognition, UMR-S1172, EGID, DISTALZ, Lille, France.
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Leptin-Activity Modulators and Their Potential Pharmaceutical Applications. Biomolecules 2021; 11:biom11071045. [PMID: 34356668 PMCID: PMC8301849 DOI: 10.3390/biom11071045] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Revised: 07/08/2021] [Accepted: 07/13/2021] [Indexed: 12/12/2022] Open
Abstract
Leptin, a multifunctional hormone primarily, but not exclusively, secreted in adipose tissue, is implicated in a wide range of biological functions that control different processes, such as the regulation of body weight and energy expenditure, reproductive function, immune response, and bone metabolism. In addition, leptin can exert angiogenic and mitogenic actions in peripheral organs. Leptin biological activities are greatly related to its interaction with the leptin receptor. Both leptin excess and leptin deficiency, as well as leptin resistance, are correlated with different human pathologies, such as autoimmune diseases and cancers, making leptin and leptin receptor important drug targets. The development of leptin signaling modulators represents a promising strategy for the treatment of cancers and other leptin-related diseases. In the present manuscript, we provide an update review about leptin-activity modulators, comprising leptin mutants, peptide-based leptin modulators, as well as leptin and leptin receptor specific monoclonal antibodies and nanobodies.
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Cecon E, Lhomme T, Maurice T, Luka M, Chen M, Silva A, Wauman J, Zabeau L, Tavernier J, Prévot V, Dam J, Jockers R. Amyloid Beta Peptide Is an Endogenous Negative Allosteric Modulator of Leptin Receptor. Neuroendocrinology 2021; 111:370-387. [PMID: 32335558 DOI: 10.1159/000508105] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Accepted: 04/23/2020] [Indexed: 11/19/2022]
Abstract
INTRODUCTION Metabolic dysfunction is now recognized as a pivotal component of Alzheimer's disease (AD), the most common dementia worldwide. However, the precise molecular mechanisms linking metabolic dysfunction to AD remain elusive. OBJECTIVE Here, we investigated the direct impact of soluble oligomeric amyloid beta (Aβ) peptides, the main molecular hallmark of AD, on the leptin system, a major component of central energy metabolism regulation. METHODS We developed a new time-resolved fluorescence resonance energy transfer-based Aβ binding assay for the leptin receptor (LepR) and studied the effect of Aβ on LepR function in several in vitro assays. The in vivo effect of Aβ on LepR function was studied in an Aβ-specific AD mouse model and in pro-opiomelanocortin (POMC) neurons of the hypothalamic arcuate nucleus. RESULTS We revealed specific and high-affinity (Ki = 0.1 nM) binding of Aβ to LepR. Pharmacological characterization of this interaction showed that Aβ binds allosterically to the extracellular domain of LepR and negatively affects receptor function. Negative allosteric modulation of LepR by Aβ was detected at the level of signaling pathways (STAT-3, AKT, and ERK) in vitroand in vivo. Importantly, the leptin-induced response of POMC neurons, key players in the regulation of metabolic function, was completely abolished in the presence of Aβ. CONCLUSION Our data indicate that Aβ is a negative allosteric modulator of LepR, resulting in impaired leptin action, and qualify LepR as a new and direct target of Aβ oligomers. Preventing the interaction of Aβ with LepR might improve both the metabolic and cognitive dysfunctions in AD condition.
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Affiliation(s)
- Erika Cecon
- Institut Cochin, Université de Paris, CNRS, INSERM, Paris, France
| | - Tori Lhomme
- Univ. Lille, Inserm, CHU Lille, Laboratory of Development and Plasticity of the Neuroendocrine Brain, EGID, DistAlz, Lille Neuroscience & Cognition, UMR-S 1172, Lille, France
| | - Tangui Maurice
- MMDN, University of Montpellier, EPHE, INSERM, UMR_S1198, Montpellier, France
| | - Marine Luka
- Institut Cochin, Université de Paris, CNRS, INSERM, Paris, France
| | - Min Chen
- Institut Cochin, Université de Paris, CNRS, INSERM, Paris, France
| | - Anisia Silva
- Institut Cochin, Université de Paris, CNRS, INSERM, Paris, France
| | - Joris Wauman
- VIB Center for Medical Biotechnology, Department of Biomolecular Medicine, University of Ghent, Ghent, Belgium
| | - Lennart Zabeau
- VIB Center for Medical Biotechnology, Department of Biomolecular Medicine, University of Ghent, Ghent, Belgium
| | - Jan Tavernier
- VIB Center for Medical Biotechnology, Department of Biomolecular Medicine, University of Ghent, Ghent, Belgium
| | - Vincent Prévot
- Univ. Lille, Inserm, CHU Lille, Laboratory of Development and Plasticity of the Neuroendocrine Brain, EGID, DistAlz, Lille Neuroscience & Cognition, UMR-S 1172, Lille, France
| | - Julie Dam
- Institut Cochin, Université de Paris, CNRS, INSERM, Paris, France
| | - Ralf Jockers
- Institut Cochin, Université de Paris, CNRS, INSERM, Paris, France,
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Pardridge WM. Brain Delivery of Nanomedicines: Trojan Horse Liposomes for Plasmid DNA Gene Therapy of the Brain. FRONTIERS IN MEDICAL TECHNOLOGY 2020; 2:602236. [PMID: 35047884 PMCID: PMC8757841 DOI: 10.3389/fmedt.2020.602236] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Accepted: 10/06/2020] [Indexed: 12/14/2022] Open
Abstract
Non-viral gene therapy of the brain is enabled by the development of plasmid DNA brain delivery technology, which requires the engineering and manufacturing of nanomedicines that cross the blood-brain barrier (BBB). The development of such nanomedicines is a multi-faceted problem that requires progress at multiple levels. First, the type of nanocontainer, e.g., nanoparticle or liposome, which encapsulates the plasmid DNA, must be developed. Second, the type of molecular Trojan horse, e.g., peptide or receptor-specific monoclonal antibody (MAb), must be selected for incorporation on the surface of the nanomedicine, as this Trojan horse engages specific receptors expressed on the BBB, and the brain cell membrane, to trigger transport of the nanomedicine from blood into brain cells beyond the BBB. Third, the plasmid DNA must be engineered without bacterial elements, such as antibiotic resistance genes, to enable administration to humans; the plasmid DNA must also be engineered with tissue-specific gene promoters upstream of the therapeutic gene, to insure gene expression in the target organ with minimal off-target expression. Fourth, upstream manufacturing of the nanomedicine must be developed and scalable so as to meet market demand for the target disease, e.g., annual long-term treatment of 1,000 patients with an orphan disease, short term treatment of 10,000 patients with malignant glioma, or 100,000 patients with new onset Parkinson's disease. Fifth, downstream manufacturing problems, such as nanomedicine lyophilization, must be solved to ensure the nanomedicine has a commercially viable shelf-life for treatment of CNS disease in humans.
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Affiliation(s)
- William M Pardridge
- Department of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
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10
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Onogi Y, Khalil AEMM, Ussar S. Identification and characterization of adipose surface epitopes. Biochem J 2020; 477:2509-2541. [PMID: 32648930 PMCID: PMC7360119 DOI: 10.1042/bcj20190462] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2020] [Revised: 06/11/2020] [Accepted: 06/12/2020] [Indexed: 12/14/2022]
Abstract
Adipose tissue is a central regulator of metabolism and an important pharmacological target to treat the metabolic consequences of obesity, such as insulin resistance and dyslipidemia. Among the various cellular compartments, the adipocyte cell surface is especially appealing as a drug target as it contains various proteins that when activated or inhibited promote adipocyte health, change its endocrine function and eventually maintain or restore whole-body insulin sensitivity. In addition, cell surface proteins are readily accessible by various drug classes. However, targeting individual cell surface proteins in adipocytes has been difficult due to important functions of these proteins outside adipose tissue, raising various safety concerns. Thus, one of the biggest challenges is the lack of adipose selective surface proteins and/or targeting reagents. Here, we discuss several receptor families with an important function in adipogenesis and mature adipocytes to highlight the complexity at the cell surface and illustrate the problems with identifying adipose selective proteins. We then discuss that, while no unique adipocyte surface protein might exist, how splicing, posttranslational modifications as well as protein/protein interactions can create enormous diversity at the cell surface that vastly expands the space of potentially unique epitopes and how these selective epitopes can be identified and targeted.
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Affiliation(s)
- Yasuhiro Onogi
- RG Adipocytes and Metabolism, Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, 85764 Neuherberg, Germany
- German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany
| | - Ahmed Elagamy Mohamed Mahmoud Khalil
- RG Adipocytes and Metabolism, Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, 85764 Neuherberg, Germany
- German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany
| | - Siegfried Ussar
- RG Adipocytes and Metabolism, Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, 85764 Neuherberg, Germany
- German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany
- Department of Medicine, Technische Universität München, Munich, Germany
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11
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De Munter S, Van Parys A, Bral L, Ingels J, Goetgeluk G, Bonte S, Pille M, Billiet L, Weening K, Verhee A, Van der Heyden J, Taghon T, Leclercq G, Kerre T, Tavernier J, Vandekerckhove B. Rapid and Effective Generation of Nanobody Based CARs using PCR and Gibson Assembly. Int J Mol Sci 2020; 21:E883. [PMID: 32019116 PMCID: PMC7037261 DOI: 10.3390/ijms21030883] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2019] [Revised: 01/20/2020] [Accepted: 01/28/2020] [Indexed: 12/25/2022] Open
Abstract
Recent approval of chimeric antigen receptor (CAR) T cell therapy by the European Medicines Agency (EMA)/Federal and Drug Administration (FDA) and the remarkable results of CAR T clinical trials illustrate the curative potential of this therapy. While CARs against a multitude of different antigens are being developed and tested (pre)clinically, there is still a need for optimization. The use of single-chain variable fragments (scFvs) as targeting moieties hampers the quick generation of functional CARs and could potentially limit the efficacy. Instead, nanobodies may largely circumvent these difficulties. We used an available nanobody library generated after immunization of llamas against Cluster of Differentiation (CD) 20 through DNA vaccination or against the ectodomain of CD33 using soluble protein. The nanobody specific sequences were amplified by PCR and cloned by Gibson Assembly into a retroviral vector containing two different second-generation CAR constructs. After transduction in T cells, we observed high cell membrane nanoCAR expression in all cases. Following stimulation of nanoCAR-expressing T cells with antigen-positive cell lines, robust T cell activation, cytokine production and tumor cell lysis both in vitro and in vivo was observed. The use of nanobody technology in combination with PCR and Gibson Assembly allows for the rapid and effective generation of compact CARs.
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Affiliation(s)
- Stijn De Munter
- Department of Diagnostic Sciences, Ghent University, 9000 Ghent, Belgium
| | - Alexander Van Parys
- Cytokine Receptor Laboratory, Flanders Institute of Biotechnology, VIB-UGent Center for Medical Biotechnology, Faculty of Medicine and Health Sciences, Ghent University, 9000 Ghent, Belgium
| | - Layla Bral
- Department of Diagnostic Sciences, Ghent University, 9000 Ghent, Belgium
| | - Joline Ingels
- Department of Diagnostic Sciences, Ghent University, 9000 Ghent, Belgium
| | - Glenn Goetgeluk
- Department of Diagnostic Sciences, Ghent University, 9000 Ghent, Belgium
| | - Sarah Bonte
- Department of Internal Medicine and Pediatrics, Ghent University, 9000 Ghent, Belgium
| | - Melissa Pille
- Department of Diagnostic Sciences, Ghent University, 9000 Ghent, Belgium
| | - Lore Billiet
- Department of Diagnostic Sciences, Ghent University, 9000 Ghent, Belgium
| | - Karin Weening
- Department of Diagnostic Sciences, Ghent University, 9000 Ghent, Belgium
| | - Annick Verhee
- Cytokine Receptor Laboratory, Flanders Institute of Biotechnology, VIB-UGent Center for Medical Biotechnology, Faculty of Medicine and Health Sciences, Ghent University, 9000 Ghent, Belgium
| | - Jose Van der Heyden
- Cytokine Receptor Laboratory, Flanders Institute of Biotechnology, VIB-UGent Center for Medical Biotechnology, Faculty of Medicine and Health Sciences, Ghent University, 9000 Ghent, Belgium
| | - Tom Taghon
- Department of Diagnostic Sciences, Ghent University, 9000 Ghent, Belgium
| | - Georges Leclercq
- Department of Diagnostic Sciences, Ghent University, 9000 Ghent, Belgium
| | - Tessa Kerre
- Department of Diagnostic Sciences, Ghent University, 9000 Ghent, Belgium
- Department of Internal Medicine and Pediatrics, Ghent University, 9000 Ghent, Belgium
| | - Jan Tavernier
- Cytokine Receptor Laboratory, Flanders Institute of Biotechnology, VIB-UGent Center for Medical Biotechnology, Faculty of Medicine and Health Sciences, Ghent University, 9000 Ghent, Belgium
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12
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Ghasemi A, Saeidi J, Azimi-Nejad M, Hashemy SI. Leptin-induced signaling pathways in cancer cell migration and invasion. Cell Oncol (Dordr) 2019; 42:243-260. [PMID: 30877623 DOI: 10.1007/s13402-019-00428-0] [Citation(s) in RCA: 54] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/06/2019] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Increasing evidence indicates that obesity is associated with tumor development and progression. Leptin is an adipocyte-related hormone with a key role in energy metabolism and whose circulating levels are elevated in obesity. The effect of leptin on cancer progression and metastasis and its underlying mechanisms are still unclear. Leptin can impact various steps in tumor metastasis, including epithelial-mesenchymal transition, cell adhesion to the extracellular matrix (ECM), and proteolysis of ECM components. To do so, leptin binds to its receptor (OB-Rb) to activate signaling pathways and downstream effectors that participate in tumor cell invasion as well as distant metastasis. CONCLUSIONS In this review, we describe metastasis steps in detail and characterize metastasis-related molecules activated by leptin, which may help to develop a roadmap that guides future work. In addition, we conclude that a profound understanding of the fundamental molecular processes that contribute to leptin-induced metastasis may pave the way for the development of new prognostic molecules and appropriate approaches to the treatment of obesity-related cancers.
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Affiliation(s)
- Ahmad Ghasemi
- Department of Basic Medical Sciences, Neyshabur University of Medical Sciences, Neyshabur, Iran
- Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Jafar Saeidi
- Department of Physiology, School of Basic Science, Neyshabur Branch, Islamic Azad University, Neyshabur, Iran
| | - Mohsen Azimi-Nejad
- Department of Basic Medical Sciences, Neyshabur University of Medical Sciences, Neyshabur, Iran
- Department of Genetic, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Seyed Isaac Hashemy
- Surgical Oncology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
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13
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Zabeau L, Wauman J, Dam J, Van Lint S, Burg E, De Geest J, Rogge E, Silva A, Jockers R, Tavernier J. A novel leptin receptor antagonist uncouples leptin's metabolic and immune functions. Cell Mol Life Sci 2019; 76:1201-1214. [PMID: 30659329 PMCID: PMC11105424 DOI: 10.1007/s00018-019-03004-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2018] [Revised: 12/28/2018] [Accepted: 01/02/2019] [Indexed: 12/19/2022]
Abstract
Leptin links body energy stores to high energy demanding processes like reproduction and immunity. Based on leptin's role in autoimmune diseases and cancer, several leptin and leptin receptor (LR) antagonists have been developed, but these intrinsically lead to unwanted weight gain. Here, we report on the uncoupling of leptin's metabolic and immune functions based on the cross talk with the epidermal growth factor receptor (EGFR). We show that both receptors spontaneously interact and, remarkably, that this complex can partially overrule the lack of LR activation by a leptin antagonistic mutein. Moreover, this leptin mutant induces EGFR phosphorylation comparable to wild-type leptin. Exploiting this non-canonical leptin signalling pathway, we identified a camelid single-domain antibody that selectively inhibits this LR-EGFR cross talk without interfering with homotypic LR signalling. Administration in vivo showed that this single-domain antibody did not interfere with leptin's metabolic functions, but could reverse the leptin-driven protection against starvation-induced thymic and splenic atrophy. These findings offer new opportunities for the design and clinical application of selective leptin and LR antagonists that avoid unwanted metabolic side effects.
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Affiliation(s)
- Lennart Zabeau
- Faculty of Medicine and Health Sciences, VIB-UGent Center for Medical Biotechnology, Flanders Institute for Biotechnology, Ghent University, A. Baertsoenkaai 3, 9000, Ghent, Belgium
| | - Joris Wauman
- Faculty of Medicine and Health Sciences, VIB-UGent Center for Medical Biotechnology, Flanders Institute for Biotechnology, Ghent University, A. Baertsoenkaai 3, 9000, Ghent, Belgium
| | - Julie Dam
- Inserm U1016, CNRS UMR 8104, Univ. Paris Descartes, Sorbonne Paris Cité, Institut Cochin, 22 rue Méchain, 75014, Paris, France
| | - Sandra Van Lint
- Faculty of Medicine and Health Sciences, VIB-UGent Center for Medical Biotechnology, Flanders Institute for Biotechnology, Ghent University, A. Baertsoenkaai 3, 9000, Ghent, Belgium
| | - Elianne Burg
- Faculty of Medicine and Health Sciences, VIB-UGent Center for Medical Biotechnology, Flanders Institute for Biotechnology, Ghent University, A. Baertsoenkaai 3, 9000, Ghent, Belgium
| | - Jennifer De Geest
- Faculty of Medicine and Health Sciences, VIB-UGent Center for Medical Biotechnology, Flanders Institute for Biotechnology, Ghent University, A. Baertsoenkaai 3, 9000, Ghent, Belgium
| | - Elke Rogge
- Faculty of Medicine and Health Sciences, VIB-UGent Center for Medical Biotechnology, Flanders Institute for Biotechnology, Ghent University, A. Baertsoenkaai 3, 9000, Ghent, Belgium
| | - Anisia Silva
- Inserm U1016, CNRS UMR 8104, Univ. Paris Descartes, Sorbonne Paris Cité, Institut Cochin, 22 rue Méchain, 75014, Paris, France
| | - Ralf Jockers
- Inserm U1016, CNRS UMR 8104, Univ. Paris Descartes, Sorbonne Paris Cité, Institut Cochin, 22 rue Méchain, 75014, Paris, France
| | - Jan Tavernier
- Faculty of Medicine and Health Sciences, VIB-UGent Center for Medical Biotechnology, Flanders Institute for Biotechnology, Ghent University, A. Baertsoenkaai 3, 9000, Ghent, Belgium.
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14
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Nikolaou S, Qiu S, Fiorentino F, Rasheed S, Tekkis P, Kontovounisios C. The prognostic and therapeutic role of hormones in colorectal cancer: a review. Mol Biol Rep 2018; 46:1477-1486. [PMID: 30535551 DOI: 10.1007/s11033-018-4528-6] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2018] [Accepted: 11/23/2018] [Indexed: 02/06/2023]
Abstract
Colorectal cancer (CRC) is one of the commonest cancers in Western society with a poor prognosis in patients with advanced disease. Targeted therapy is of increasing interest and already, targeted hormone treatment for breast and prostate cancer has improved survival. The aim of this literature review is to summarise the role of hormones in CRC prognosis and treatment. A literature review of all human and animal in vivo and in vitro studies in the last 20 years, which assessed the role of hormones in CRC treatment or prognosis, was carried out. The hormones described in this review have been subdivided according to their secretion origin. Most of the studies are based on in vitro or animal models. The main findings point to adipokines, insulin and the insulin growth factor axis as key players in the link between obesity, type 2 diabetes mellitus and a subset of CRC. Gut-derived hormones, especially uroguanylin and guanylin are being increasingly investigated as therapeutic targets, with promising results. Using hormones as prognostic and therapeutic markers in CRC is still in the preliminary stages for only a fraction of the hormones affecting the GIT. In light of the increasing interest in tailoring treatment strategies, hormones are an important area of focus in the future of CRC management.
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Affiliation(s)
- Stella Nikolaou
- Department of Colorectal Surgery, Chelsea & Westminster Hospital, London, UK. .,Department of Colorectal Surgery, Royal Marsden Hospital, London, UK. .,Department of Surgery and Cancer, Imperial College, London, UK. .,Department of Surgery and Cancer, Imperial College London, Royal Marsden Hospital, Fulham Road & Chelsea and Westminster Campus, 369 Fulham Road, London, SW10 9NH, UK.
| | - Shengyang Qiu
- Department of Colorectal Surgery, Chelsea & Westminster Hospital, London, UK.,Department of Surgery and Cancer, Imperial College, London, UK
| | | | - Shahnawaz Rasheed
- Department of Colorectal Surgery, Chelsea & Westminster Hospital, London, UK.,Department of Colorectal Surgery, Royal Marsden Hospital, London, UK.,Department of Surgery and Cancer, Imperial College, London, UK
| | - Paris Tekkis
- Department of Colorectal Surgery, Chelsea & Westminster Hospital, London, UK.,Department of Colorectal Surgery, Royal Marsden Hospital, London, UK.,Department of Surgery and Cancer, Imperial College, London, UK
| | - Christos Kontovounisios
- Department of Colorectal Surgery, Chelsea & Westminster Hospital, London, UK.,Department of Colorectal Surgery, Royal Marsden Hospital, London, UK.,Department of Surgery and Cancer, Imperial College, London, UK
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15
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Favreau M, Menu E, Gaublomme D, Vanderkerken K, Faict S, Maes K, De Bruyne E, Govindarajan S, Drennan M, Van Calenbergh S, Leleu X, Zabeau L, Tavernier J, Venken K, Elewaut D. Leptin receptor antagonism of iNKT cell function: a novel strategy to combat multiple myeloma. Leukemia 2017; 31:2678-2685. [PMID: 28490813 DOI: 10.1038/leu.2017.146] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2017] [Revised: 04/27/2017] [Accepted: 05/03/2017] [Indexed: 12/28/2022]
Abstract
A hallmark of bone marrow changes with aging is the increase in adipocyte composition, but how this impacts development of multiple myeloma (MM) is unknown. Here, we report the role of the adipokine leptin as master regulator of anti-myeloma tumor immunity by modulating the invariant natural killer T (iNKT) cell function. A marked increase in serum leptin levels and leptin receptor (LR) expression on iNKT cells in MM patients and the 5T33 murine MM model was observed. MM cells and leptin synergistically counteracted anti-tumor functionality of both murine and human iNKT cells. In vivo blockade of LR signaling combined with iNKT stimulation resulted in superior anti-tumor protection. This was linked to persistent IFN-γ secretion upon repeated iNKT cell stimulation and a restoration of the dynamic antigen-induced motility arrest as observed by intravital microscopy, thereby showing alleviation of iNKT cell anergy. Overall our data reveal the LR axis as novel therapeutic target for checkpoint inhibition to treat MM.
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Affiliation(s)
- M Favreau
- Department of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel, Brussels, Belgium.,Department of Rheumatology, Ghent University Hospital, Ghent, Belgium.,Unit for Molecular Immunology and Inflammation, VIB Inflammation Research Center, Ghent University, Ghent, Belgium
| | - E Menu
- Department of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel, Brussels, Belgium
| | - D Gaublomme
- Department of Rheumatology, Ghent University Hospital, Ghent, Belgium.,Unit for Molecular Immunology and Inflammation, VIB Inflammation Research Center, Ghent University, Ghent, Belgium
| | - K Vanderkerken
- Department of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel, Brussels, Belgium
| | - S Faict
- Department of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel, Brussels, Belgium
| | - K Maes
- Department of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel, Brussels, Belgium
| | - E De Bruyne
- Department of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel, Brussels, Belgium
| | - S Govindarajan
- Department of Rheumatology, Ghent University Hospital, Ghent, Belgium.,Unit for Molecular Immunology and Inflammation, VIB Inflammation Research Center, Ghent University, Ghent, Belgium
| | - M Drennan
- Department of Rheumatology, Ghent University Hospital, Ghent, Belgium.,Unit for Molecular Immunology and Inflammation, VIB Inflammation Research Center, Ghent University, Ghent, Belgium
| | - S Van Calenbergh
- Laboratory for Medicinal Chemistry, Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Ghent University, Ghent, Belgium
| | - X Leleu
- Service d'Hématologie et Thérapie Cellulaire, Pôle Régional de Cancérologie, Hospital de la Miléterie, Poitiers, France
| | - L Zabeau
- Department of Biochemistry, VIB Medical Biotechnology Center, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium
| | - J Tavernier
- Department of Biochemistry, VIB Medical Biotechnology Center, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium
| | - K Venken
- Department of Rheumatology, Ghent University Hospital, Ghent, Belgium.,Unit for Molecular Immunology and Inflammation, VIB Inflammation Research Center, Ghent University, Ghent, Belgium
| | - D Elewaut
- Department of Rheumatology, Ghent University Hospital, Ghent, Belgium.,Unit for Molecular Immunology and Inflammation, VIB Inflammation Research Center, Ghent University, Ghent, Belgium
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16
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Steeland S, Vandenbroucke RE, Libert C. Nanobodies as therapeutics: big opportunities for small antibodies. Drug Discov Today 2016; 21:1076-113. [DOI: 10.1016/j.drudis.2016.04.003] [Citation(s) in RCA: 196] [Impact Index Per Article: 21.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2015] [Revised: 02/26/2016] [Accepted: 04/04/2016] [Indexed: 12/28/2022]
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17
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Shpakov AO. The brain leptin signaling system and its functional state in metabolic syndrome and type 2 diabetes mellitus. J EVOL BIOCHEM PHYS+ 2016; 52:177-195. [DOI: 10.1134/s0022093016030017] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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18
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High efficiency cell-specific targeting of cytokine activity. Nat Commun 2015; 5:3016. [PMID: 24398568 DOI: 10.1038/ncomms4016] [Citation(s) in RCA: 62] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2013] [Accepted: 11/26/2013] [Indexed: 11/09/2022] Open
Abstract
Systemic toxicity currently prevents exploiting the huge potential of many cytokines for medical applications. Here we present a novel strategy to engineer immunocytokines with very high targeting efficacies. The method lies in the use of mutants of toxic cytokines that markedly reduce their receptor-binding affinities, and that are thus rendered essentially inactive. Upon fusion to nanobodies specifically binding to marker proteins, activity of these cytokines is selectively restored for cell populations expressing this marker. This 'activity-by-targeting' concept was validated for type I interferons and leptin. In the case of interferon, activity can be directed to target cells in vitro and to selected cell populations in mice, with up to 1,000-fold increased specific activity. This targeting strategy holds promise to revitalize the clinical potential of many cytokines.
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19
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Wolfson B, Eades G, Zhou Q. Adipocyte activation of cancer stem cell signaling in breast cancer. World J Biol Chem 2015; 6:39-47. [PMID: 26009703 PMCID: PMC4436905 DOI: 10.4331/wjbc.v6.i2.39] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2015] [Revised: 03/18/2015] [Accepted: 04/20/2015] [Indexed: 02/05/2023] Open
Abstract
Signaling within the tumor microenvironment has a critical role in cancer initiation and progression. Adipocytes, one of the major components of the breast microenvironment, have been shown to provide pro-tumorigenic signals that promote cancer cell proliferation and invasiveness in vitro and tumorigenicity in vivo. Adipocyte secreted factors such as leptin and interleukin-6 (IL-6) have a paracrine effect on breast cancer cells. In adipocyte-adjacent breast cancer cells, the leptin and IL-6 signaling pathways activate janus kinase 2/signal transducer and activator of transcription 5, promoting the epithelial-mesenchymal transition, and upregulating stemness regulators such as Notch, Wnt and the Sex determining region Y-box 2/octamer binding transcription factor 4/Nanog signaling axis. In this review we will summarize the major signaling pathways that regulate cancer stem cells in breast cancer and describe the effects that adipocyte secreted IL-6 and leptin have on breast cancer stem cell signaling. Finally we will introduce a new potential treatment paradigm of inhibiting the adipocyte-breast cancer cell signaling via targeting the IL-6 or leptin pathways.
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20
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Leptin: From structural insights to the design of antagonists. Life Sci 2015; 140:49-56. [PMID: 25998027 DOI: 10.1016/j.lfs.2015.04.015] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2015] [Revised: 04/28/2015] [Accepted: 04/29/2015] [Indexed: 12/20/2022]
Abstract
After its discovery in 1994, it soon became clear that leptin acts as an adipocyte-derived hormone with a central role in the control of body weight and energy homeostasis. However, a growing body of evidence has revealed that leptin is a pleiotropic cytokine with activities on many peripheral cell types. Inappropriate leptin signaling can promote autoimmunity, certain cardiovascular diseases, elevated blood pressure and cancer, which makes leptin and the leptin receptor interesting targets for antagonism. Profound insights in the leptin receptor (LR) activation mechanisms are a prerequisite for the rational design of these antagonists. In this review, we focus on the molecular mechanisms underlying leptin receptor activation and signaling. We also discuss the current strategies to interfere with leptin signaling and their therapeutic potential.
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21
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Jiang N, Sun R, Sun Q. Leptin signaling molecular actions and drug target in hepatocellular carcinoma. DRUG DESIGN DEVELOPMENT AND THERAPY 2014; 8:2295-302. [PMID: 25484575 PMCID: PMC4238752 DOI: 10.2147/dddt.s69004] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Previous reports indicate that over 13 different tumors, including hepatocellular carcinoma (HCC), are related to obesity. Obesity-associated inflammatory, metabolic, and endocrine mediators, as well as the functioning of the gut microbiota, are suspected to contribute to tumorigenesis. In obese people, proinflammatory cytokines/chemokines including tumor necrosis factor-alpha, interleukin (IL)-1 and IL-6, insulin and insulin-like growth factors, adipokines, plasminogen activator inhibitor-1, adiponectin, and leptin are found to play crucial roles in the initiation and development of cancer. The cytokines induced by leptin in adipose tissue or tumor cells have been intensely studied. Leptin-induced signaling pathways are critical for biological functions such as adiposity, energy balance, endocrine function, immune reaction, and angiogenesis as well as oncogenesis. Leptin is an activator of cell proliferation and anti-apoptosis in several cell types, and an inducer of cancer stem cells; its critical roles in tumorigenesis are based on its oncogenic, mitogenic, proinflammatory, and pro-angiogenic actions. This review provides an update of the pathological effects of leptin signaling with special emphasis on potential molecular mechanisms and therapeutic targeting, which could potentially be used in future clinical settings. In addition, leptin-induced angiogenic ability and molecular mechanisms in HCC are discussed. The stringent binding affinity of leptin and its receptor Ob-R, as well as the highly upregulated expression of both leptin and Ob-R in cancer cells compared to normal cells, makes leptin an ideal drug target for the prevention and treatment of HCC, especially in obese patients.
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Affiliation(s)
- Nan Jiang
- Shandong University School of Medicine, Jinan, Shandong Province, People's Republic of China
| | - Rongtong Sun
- Weihai Municipal Hospital, Weihai, Shandong Province, People's Republic of China
| | - Qing Sun
- Department of Pathology, QianFoShan Hospital Affiliated to Shandong University, Jinan, Shandong Province, People's Republic of China
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22
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Peelman F, Zabeau L, Moharana K, Savvides SN, Tavernier J. 20 years of leptin: insights into signaling assemblies of the leptin receptor. J Endocrinol 2014; 223:T9-23. [PMID: 25063754 DOI: 10.1530/joe-14-0264] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Leptin plays a central role in the control of body weight and energy homeostasis, but is a pleiotropic cytokine with activities on many peripheral cell types. In this review, we discuss the interaction of leptin with its receptor, and focus on the structural and mechanistic aspects of the extracellular aspects of leptin receptor (LR) activation. We provide an extensive overview of all structural information that has been obtained for leptin and its receptor via X-ray crystallography, electron microscopy, small-angle X-ray scattering, homology modeling, and mutagenesis studies. The available knowledge is integrated into putative models toward a recapitulation of the LR activation mechanism.
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Affiliation(s)
- Frank Peelman
- Department of Medical Protein ResearchFaculty of Medicine and Health Sciences, Flanders Institute for Biotechnology (VIB), Ghent University, A. Baertsoenkaai 3, 9000 Ghent, BelgiumUnit for Structural BiologyLaboratory for Protein Biochemistry and Biomolecular Engineering (L-ProBE), Ghent University, K.L. Ledeganckstraat 35, 9000 Ghent, Belgium
| | - Lennart Zabeau
- Department of Medical Protein ResearchFaculty of Medicine and Health Sciences, Flanders Institute for Biotechnology (VIB), Ghent University, A. Baertsoenkaai 3, 9000 Ghent, BelgiumUnit for Structural BiologyLaboratory for Protein Biochemistry and Biomolecular Engineering (L-ProBE), Ghent University, K.L. Ledeganckstraat 35, 9000 Ghent, Belgium
| | - Kedar Moharana
- Department of Medical Protein ResearchFaculty of Medicine and Health Sciences, Flanders Institute for Biotechnology (VIB), Ghent University, A. Baertsoenkaai 3, 9000 Ghent, BelgiumUnit for Structural BiologyLaboratory for Protein Biochemistry and Biomolecular Engineering (L-ProBE), Ghent University, K.L. Ledeganckstraat 35, 9000 Ghent, Belgium
| | - Savvas N Savvides
- Department of Medical Protein ResearchFaculty of Medicine and Health Sciences, Flanders Institute for Biotechnology (VIB), Ghent University, A. Baertsoenkaai 3, 9000 Ghent, BelgiumUnit for Structural BiologyLaboratory for Protein Biochemistry and Biomolecular Engineering (L-ProBE), Ghent University, K.L. Ledeganckstraat 35, 9000 Ghent, Belgium
| | - Jan Tavernier
- Department of Medical Protein ResearchFaculty of Medicine and Health Sciences, Flanders Institute for Biotechnology (VIB), Ghent University, A. Baertsoenkaai 3, 9000 Ghent, BelgiumUnit for Structural BiologyLaboratory for Protein Biochemistry and Biomolecular Engineering (L-ProBE), Ghent University, K.L. Ledeganckstraat 35, 9000 Ghent, Belgium
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Molek P, Vodnik M, Strukelj B, Bratkovič T. Screening of synthetic phage display scFv libraries yields competitive ligands of human leptin receptor. Biochem Biophys Res Commun 2014; 452:479-83. [PMID: 25159846 DOI: 10.1016/j.bbrc.2014.08.087] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2014] [Accepted: 08/19/2014] [Indexed: 12/20/2022]
Abstract
Initially considered the main endogenous anorexigenic factor, fat-derived leptin turned out to be a markedly pleiotropic hormone, influencing diverse physiological processes. Moreover, hyperleptinemia in obese individuals has been linked to the onset or progression of serious disorders, such as cancer, autoimmune diseases, and atherosclerosis, and antagonizing peripheral leptin's signalization has been shown to improve these conditions. To develop an antibody-based leptin antagonist we have devised a tailored panning procedure and screened two phage display libraries of single chain variable antibody fragments (scFvs) against recombinant leptin receptor. One of the scFvs was expressed in Escherichia coli and its interaction with leptin receptor was characterized in more detail. It was found to recognize a discontinuous epitope and to compete with leptin for receptor binding with IC50 and Kd values in the nanomolar range. The reported scFv represents a lead for development of leptin antagonists that may ultimately find use in therapy of various hyperleptinemia-related disorders.
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Affiliation(s)
- Peter Molek
- University of Ljubljana, Faculty of Pharmacy, Department of Pharmaceutical Biology, Aškerčeva 7, SI-1000 Ljubljana, Slovenia.
| | - Miha Vodnik
- University of Ljubljana, Faculty of Pharmacy, Department of Pharmaceutical Biology, Aškerčeva 7, SI-1000 Ljubljana, Slovenia.
| | - Borut Strukelj
- University of Ljubljana, Faculty of Pharmacy, Department of Pharmaceutical Biology, Aškerčeva 7, SI-1000 Ljubljana, Slovenia; Jožef Stefan Institute, Department of Biotechnology, Jamova 39, SI-1000 Ljubljana, Slovenia.
| | - Tomaž Bratkovič
- University of Ljubljana, Faculty of Pharmacy, Department of Pharmaceutical Biology, Aškerčeva 7, SI-1000 Ljubljana, Slovenia.
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Zabeau L, Jensen CJ, Seeuws S, Venken K, Verhee A, Catteeuw D, van Loo G, Chen H, Walder K, Hollis J, Foote S, Morris MJ, Van der Heyden J, Peelman F, Oldfield BJ, Rubio JP, Elewaut D, Tavernier J. Leptin's metabolic and immune functions can be uncoupled at the ligand/receptor interaction level. Cell Mol Life Sci 2014; 72:629-644. [PMID: 25098352 PMCID: PMC4293488 DOI: 10.1007/s00018-014-1697-x] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2014] [Revised: 07/17/2014] [Accepted: 07/28/2014] [Indexed: 01/21/2023]
Abstract
The adipocyte-derived cytokine leptin acts as a metabolic switch, connecting the body's metabolism to high-energy consuming processes such as reproduction and immune responses. We here provide genetic and biochemical evidence that the metabolic and immune functions of leptin can be uncoupled at the receptor level. First, homozygous mutant fatt/fatt mice carry a spontaneous splice mutation causing deletion of the leptin receptor (LR) immunoglobulin-like domain (IGD) in all LR isoforms. These mice are hyperphagic and morbidly obese, but display only minimal changes in size and cellularity of the thymus, and cellular immune responses are unaffected. These animals also displayed liver damage in response to concavalin A comparable to wild-type and heterozygous littermates. Second, treatment of healthy mice with a neutralizing nanobody targeting IGD induced weight gain and hyperinsulinaemia, but completely failed to block development of experimentally induced autoimmune diseases. These data indicate that leptin receptor deficiency or antagonism profoundly affects metabolism, with little concomitant effects on immune functions.
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Affiliation(s)
- Lennart Zabeau
- Department of Medical Protein Research, Faculty of Medicine and Health Sciences, Flanders Institute for Biotechnology, Ghent University, A. Baertsoenkaai 3, 9000, Ghent, Belgium
| | - Cathy J Jensen
- Neurogenetics Laboratory, Howard Florey Institute, Melbourne, Australia.,Department of Physiology, Monash University, Melbourne, Australia
| | - Sylvie Seeuws
- Laboratory for Molecular Immunology and Inflammation, Department of Rheumatology, Ghent University Hospital, Ghent University, De Pintelaan 185, 9000, Ghent, Belgium
| | - Koen Venken
- Laboratory for Molecular Immunology and Inflammation, Department of Rheumatology, Ghent University Hospital, Ghent University, De Pintelaan 185, 9000, Ghent, Belgium
| | - Annick Verhee
- Department of Medical Protein Research, Faculty of Medicine and Health Sciences, Flanders Institute for Biotechnology, Ghent University, A. Baertsoenkaai 3, 9000, Ghent, Belgium
| | - Dominiek Catteeuw
- Department of Medical Protein Research, Faculty of Medicine and Health Sciences, Flanders Institute for Biotechnology, Ghent University, A. Baertsoenkaai 3, 9000, Ghent, Belgium
| | - Geert van Loo
- Inflammation Research Center, Unit of Molecular Signal Transduction in Inflammation, Faculty of Sciences, Flanders Institute for Biotechnology, Ghent University, Ghent, Belgium
| | - Hui Chen
- Department of Pharmacology, University of Melbourne, Melbourne, Australia
| | - Ken Walder
- Metabolic Research Unit, School of Medicine, Deakin University, Geelong, Australia
| | - Jacob Hollis
- Department of Physiology, Monash University, Melbourne, Australia
| | - Simon Foote
- Menzies Research Institute, Hobart, Australia
| | - Margaret J Morris
- Department of Pharmacology, University of Melbourne, Melbourne, Australia
| | - José Van der Heyden
- Department of Medical Protein Research, Faculty of Medicine and Health Sciences, Flanders Institute for Biotechnology, Ghent University, A. Baertsoenkaai 3, 9000, Ghent, Belgium
| | - Frank Peelman
- Department of Medical Protein Research, Faculty of Medicine and Health Sciences, Flanders Institute for Biotechnology, Ghent University, A. Baertsoenkaai 3, 9000, Ghent, Belgium
| | - Brian J Oldfield
- Department of Physiology, Monash University, Melbourne, Australia
| | - Justin P Rubio
- Neurogenetics Laboratory, Howard Florey Institute, Melbourne, Australia
| | - Dirk Elewaut
- Laboratory for Molecular Immunology and Inflammation, Department of Rheumatology, Ghent University Hospital, Ghent University, De Pintelaan 185, 9000, Ghent, Belgium
| | - Jan Tavernier
- Department of Medical Protein Research, Faculty of Medicine and Health Sciences, Flanders Institute for Biotechnology, Ghent University, A. Baertsoenkaai 3, 9000, Ghent, Belgium.
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25
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Deng ZH, Liao J, Zhang JY, Liang C, Song CH, Han M, Wang LH, Xue H, Zhang K, Zabeau L, Tavernier J, Yan GT. Inhibition of the connexin 43 elevation may be involved in the neuroprotective activity of leptin against brain ischemic injury. Cell Mol Neurobiol 2014; 34:871-9. [PMID: 24794794 PMCID: PMC11488862 DOI: 10.1007/s10571-014-0066-5] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2013] [Accepted: 04/17/2014] [Indexed: 02/08/2023]
Abstract
Leptin is a multifunctional hormone produced by the ob gene and is secreted by adipocytes that regulate food intake and energy metabolism. Numerous studies demonstrated that leptin is a novel neuroprotective effector, however, the mechanisms are largely unknown. Herein, we demonstrate the protective activities of leptin after ischemic stroke and provide the first evidence for the involvement of the connexin 43 (Cx43) in leptin-mediated neuroprotection. We found that leptin treatment reduces the infarct volume, improves animal behavioral parameters, and inhibits the elevation of Cx43 expression in vivo. In vitro, leptin reverses ischemia-induced SY5Y and U87 cells Cx43 elevation, secreted glutamate levels in medium and SY5Y cell death, these roles could be abolished by leptin receptor blocker. Additionally, leptin administration upregulated the extracellular signal-regulated kinase1/2 (ERK1/2) phosphorylation. Moreover, ERK1/2 inhibitors pretreatment reversed the effects of leptin on Cx43 expression, glutamate levels and cell apoptosis. In conclusion, the present study demonstrated that leptin can reduce the Cx43 expression and cell death both in vivo and in vitro via ERK1/2 signaling pathway. This result provides a novel regulatory signaling pathway of the neuroprotective effects of leptin and may contribute to ischemic brain injury prevention and therapy.
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Affiliation(s)
- Zi-Hui Deng
- Research Laboratory of Biochemistry, Basic Medical Institute, General Hospital of PLA, 28 Fuxing Road, Beijing, 100853, People's Republic of China,
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26
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Zhou W, Tian Y, Gong H, Guo S, Luo C. Oncogenic role and therapeutic target of leptin signaling in colorectal cancer. Expert Opin Ther Targets 2014; 18:961-71. [PMID: 24946986 DOI: 10.1517/14728222.2014.926889] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
INTRODUCTION Obesity is characterized by high secretion of several cytokines from adipose tissue and is a recognized risk factor for many cancers. Among these cytokines, leptin mainly produced by adipose tissue and cancer cells is the most studied adipokine. Leptin is an activator of cell proliferation, an antiapoptotic molecule and inducer of cancer stem cells in many cell types, and its critical roles in obesity-related tumorigenesis are based on its oncogenic, mitogenic, pro-inflammatory and pro-angiogenic actions. AREAS COVERED These leptin-induced signals and action are critical for their biological effects on energy balance, adiposity, endocrine systems, immunity, angiogenesis as well as oncogenesis. This review focuses on the up-to-date knowledge on the oncogenic role of leptin signaling, clinical significance and specific drug target development in colorectal cancer (CRC). Additionally, leptin-induced angiogenic ability and molecular mechanisms in CRC cells are discussed. EXPERT OPINION Stringent binding affinity of leptin/Ob-R and overexpression of leptin/Ob-R and their targets in cancer cells make it a unique drug target for prevention and treatment of CRC, particularly in obesity colorectal patients.
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Affiliation(s)
- Weiqiang Zhou
- Shenyang Medical College, Key Laboratory of Environmental Pollution and Microecology of Liaoning Province , No.146 North Huanghe St, Huanggu Dis, Shenyang City, Liaoning Pro 110034 , PR China
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27
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Molecular dynamics, dynamic site mapping, and highthroughput virtual screening on leptin and the Ob receptor as anti-obesity target. J Mol Model 2014; 20:2247. [DOI: 10.1007/s00894-014-2247-z] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2014] [Accepted: 04/09/2014] [Indexed: 10/25/2022]
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28
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Leggio A, Catalano S, De Marco R, Barone I, Andò S, Liguori A. Therapeutic potential of leptin receptor modulators. Eur J Med Chem 2014; 78:97-105. [DOI: 10.1016/j.ejmech.2014.03.048] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2013] [Revised: 12/19/2013] [Accepted: 03/15/2014] [Indexed: 01/13/2023]
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McMurphy T, Xiao R, Magee D, Slater A, Zabeau L, Tavernier J, Cao L. The anti-tumor activity of a neutralizing nanobody targeting leptin receptor in a mouse model of melanoma. PLoS One 2014; 9:e89895. [PMID: 24587106 PMCID: PMC3938505 DOI: 10.1371/journal.pone.0089895] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2013] [Accepted: 01/23/2014] [Indexed: 12/18/2022] Open
Abstract
Environmental and genetic activation of a brain-adipocyte axis inhibits cancer progression. Leptin is the primary peripheral mediator of this anticancer effect in a mouse model of melanoma. In this study we assessed the effect of a leptin receptor antagonist on melanoma progression. Local administration of a neutralizing nanobody targeting the leptin receptor at low dose adjacent to tumor decreased tumor mass with no effects on body weight or food intake. In contrast, systemic administration of the nanobody failed to suppress tumor growth. Daily intraperitoneal injection of high-dose nanobody led to weight gain, hyperphagia, increased adiposity, hyperleptinemia, and hyperinsulinemia, and central effects mimicking leptin deficiency. The blockade of central actions of leptin by systemic delivery of nanobody may compromise its anticancer effect, underscoring the need to develop peripherally acting leptin antagonists coupled with efficient cancer-targeting delivery.
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Affiliation(s)
- Travis McMurphy
- Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, Ohio, United States of America
- The Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, United States of America
| | - Run Xiao
- Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, Ohio, United States of America
- The Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, United States of America
| | - Daniel Magee
- Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, Ohio, United States of America
- The Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, United States of America
| | - Andrew Slater
- Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, Ohio, United States of America
- The Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, United States of America
| | - Lennart Zabeau
- Flanders Institute for Biotechnology, Department of Medical Protein Research, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium
| | - Jan Tavernier
- Flanders Institute for Biotechnology, Department of Medical Protein Research, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium
| | - Lei Cao
- Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, Ohio, United States of America
- The Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, United States of America
- * E-mail:
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Roujeau C, Jockers R, Dam J. New pharmacological perspectives for the leptin receptor in the treatment of obesity. Front Endocrinol (Lausanne) 2014; 5:167. [PMID: 25352831 PMCID: PMC4195360 DOI: 10.3389/fendo.2014.00167] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2014] [Accepted: 09/26/2014] [Indexed: 12/24/2022] Open
Abstract
After its discovery in 1994, leptin became the great hope as an anti-obesity treatment based on its ability to reduce food intake and increase energy expenditure. However, treating obese people with exogenous leptin was unsuccessful in most cases since most of them present already high circulating leptin levels to which they do not respond anymore defining the so-called state of "leptin resistance." Indeed, leptin therapy is unsuccessful to lower body weight in commonly obese people but effective in people with rare single gene mutations of the leptin gene. Consequently, treatment of obese people with leptin was given less attention and the focus of obesity research shifted toward the prevention and reversal of the state of leptin resistance. Many of these new promising approaches aim to restore or sensitize the impaired function of the leptin receptor by pharmacological means. The current review will focus on the different emerging therapeutic strategies in obesity research that are related to leptin and its receptor.
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Affiliation(s)
- Clara Roujeau
- INSERM, U1016, Institut Cochin, Paris, France
- CNRS UMR 8104, Paris, France
- University of Paris Descartes, Sorbonne Paris Cité, Paris, France
| | - Ralf Jockers
- INSERM, U1016, Institut Cochin, Paris, France
- CNRS UMR 8104, Paris, France
- University of Paris Descartes, Sorbonne Paris Cité, Paris, France
| | - Julie Dam
- INSERM, U1016, Institut Cochin, Paris, France
- CNRS UMR 8104, Paris, France
- University of Paris Descartes, Sorbonne Paris Cité, Paris, France
- *Correspondence: Julie Dam, Institut Cochin, 22 rue Méchain, 75014, Paris, France e-mail:
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Venken K, Seeuws S, Zabeau L, Jacques P, Decruy T, Coudenys J, Verheugen E, Windels F, Catteeuw D, Drennan M, Van Calenbergh S, Lambrecht BN, Yoshimura A, Tavernier J, Elewaut D. A bidirectional crosstalk between iNKT cells and adipocytes mediated by leptin modulates susceptibility for T cell mediated hepatitis. J Hepatol 2014; 60:175-82. [PMID: 23973929 DOI: 10.1016/j.jhep.2013.08.008] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2013] [Revised: 07/26/2013] [Accepted: 08/05/2013] [Indexed: 12/31/2022]
Abstract
BACKGROUND & AIMS Immunometabolism is an emerging field of clinical investigation due to the obesity epidemic worldwide. A reciprocal involvement of immune mediators in the body energy metabolism has been recognized for years, but is only partially understood. We hypothesized that the adipokine leptin could provide an important modulator of iNKT cells. METHODS The expression of leptin receptor (LR) on resting and activated iNKT cells was measured by flow cytometry. FACS-sorted hepatic iNKT cells were stimulated with anti-CD3/CD28Ab coated beads in the absence or presence of a neutralizing anti-leptin Ab. Furthermore, we evaluated the outcome of LR blocking nanobody treatment in ConA induced hepatitis and towards metabolic parameters in WT and iNKT cell deficient mice. RESULTS The LR is expressed on iNKT cells and leptin suppresses iNKT cell proliferation and cytokine production in vitro. LR deficient iNKT cells are hyper-responsive further enforcing the role of leptin as an important inhibitor of iNKT cell function. Consistently, in vivo blockade of LR signaling exacerbated ConA hepatitis in wild-type but not in iNKT cell deficient mice, through both Janus kinase (JAK)2 and mitogen-activated protein kinase (MAPK) dependent mechanisms. Moreover, LR inhibition altered fat pad features and was accompanied by insulin resistance, only in wild-type mice. Curiously, this interaction was strictly dependent on MAPK mediated LR signaling in iNKT cells and uncoupled from the more central effects of leptin. CONCLUSIONS Our data support a new concept of immune regulation by which leptin protects towards T cell mediated hepatitis via modulation of iNKT cells.
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Affiliation(s)
- Koen Venken
- Laboratory for Molecular Immunology and Inflammation, Department of Rheumatology, Faculty of Medicine and Health Sciences, Ghent University, De Pintelaan 185, 9000 Ghent, Belgium
| | - Sylvie Seeuws
- Laboratory for Molecular Immunology and Inflammation, Department of Rheumatology, Faculty of Medicine and Health Sciences, Ghent University, De Pintelaan 185, 9000 Ghent, Belgium
| | - Lennart Zabeau
- Flanders Institute for Biotechnology, Department of Medical Protein Research, Faculty of Medicine and Health Sciences, Ghent University, A. Baertsoenkaai 3, 9000 Ghent, Belgium
| | - Peggy Jacques
- Laboratory for Molecular Immunology and Inflammation, Department of Rheumatology, Faculty of Medicine and Health Sciences, Ghent University, De Pintelaan 185, 9000 Ghent, Belgium
| | - Tine Decruy
- Laboratory for Molecular Immunology and Inflammation, Department of Rheumatology, Faculty of Medicine and Health Sciences, Ghent University, De Pintelaan 185, 9000 Ghent, Belgium
| | - Julie Coudenys
- Laboratory for Molecular Immunology and Inflammation, Department of Rheumatology, Faculty of Medicine and Health Sciences, Ghent University, De Pintelaan 185, 9000 Ghent, Belgium
| | - Eveline Verheugen
- Laboratory for Molecular Immunology and Inflammation, Department of Rheumatology, Faculty of Medicine and Health Sciences, Ghent University, De Pintelaan 185, 9000 Ghent, Belgium
| | - Fien Windels
- Laboratory for Molecular Immunology and Inflammation, Department of Rheumatology, Faculty of Medicine and Health Sciences, Ghent University, De Pintelaan 185, 9000 Ghent, Belgium
| | - Dominiek Catteeuw
- Flanders Institute for Biotechnology, Department of Medical Protein Research, Faculty of Medicine and Health Sciences, Ghent University, A. Baertsoenkaai 3, 9000 Ghent, Belgium
| | - Michael Drennan
- Laboratory for Molecular Immunology and Inflammation, Department of Rheumatology, Faculty of Medicine and Health Sciences, Ghent University, De Pintelaan 185, 9000 Ghent, Belgium
| | - Serge Van Calenbergh
- Laboratory for Medicinal Chemistry, Faculty of Pharmaceutical Sciences (FFW), Ghent University, Harelbekestraat 72, 9000 Ghent, Belgium
| | - Bart N Lambrecht
- Laboratory of Immunoregulation and Mucosal Immunology, Department of Molecular Biomedical Research, VIB and Ghent University, De Pintelaan 185, 9000 Ghent, Belgium
| | - Akihiko Yoshimura
- Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo 160-8582, Japan; Japan Science and Technology Agency, CREST, Tokyo 102-0075, Japan
| | - Jan Tavernier
- Flanders Institute for Biotechnology, Department of Medical Protein Research, Faculty of Medicine and Health Sciences, Ghent University, A. Baertsoenkaai 3, 9000 Ghent, Belgium
| | - Dirk Elewaut
- Laboratory for Molecular Immunology and Inflammation, Department of Rheumatology, Faculty of Medicine and Health Sciences, Ghent University, De Pintelaan 185, 9000 Ghent, Belgium.
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Gertler A, Solomon G. Leptin-activity blockers: development and potential use in experimental biology and medicine. Can J Physiol Pharmacol 2013; 91:873-82. [PMID: 24117254 DOI: 10.1139/cjpp-2013-0012] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
The first adipokine, leptin, discovered almost 20 years ago, is secreted into circulation mainly from adipose tissue and acts both centrally and peripherally. Leptin regulates energy metabolism, reproductive function, bone metabolism, and immune response. However in some physiological or pathological situations such as enhancement of undesired immune responses in autoimmune diseases, tumorigenesis, elevated blood pressure, and certain cardiovascular pathologies, leptin activity may be harmful. In this review we screen different approaches to blocking leptin action, in vitro and in vivo. The recent development of superactive leptin muteins exhibiting antagonistic properties, and other leptin-action-blocking peptides, proteins, monoclonal antibodies, and nanobodies, opens new perspectives for their use in research, and eventually, therapy for cachexia, autoimmune disease, cancer, and other pathologies.
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Affiliation(s)
- Arieh Gertler
- The Institute of Biochemistry, Food Science, and Nutrition, The Hebrew University of Jerusalem, P.O. Box 12, Rehovot 76100, Israel
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Leptin attenuates lipopolysaccharide-induced apoptosis of thymocytes partially via down-regulation of cPLA2 and p38 MAPK activation. Int Immunopharmacol 2013; 15:620-7. [PMID: 23376443 DOI: 10.1016/j.intimp.2013.01.014] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2012] [Revised: 01/14/2013] [Accepted: 01/17/2013] [Indexed: 01/11/2023]
Abstract
Leptin, a 16-kDa protein that is mainly secreted by adipocytes, plays a protective role in many cell types. It has been shown that leptin acts in the central and peripheral immune system to protect thymocytes. Cytosolic phospholipase A(2) (cPLA(2)) is an enzyme that can specifically initiate the release of arachidonic acid (AA) to produce eicosanoids, which regulate inflammation and immune responses. Our previous work has shown that leptin is important to prevent apoptosis of thymocytes. However, the role of cPLA(2) is still unclear, and the precise mechanism also remains to be elucidated. In this work, we demonstrated that leptin inhibited the LPS-induced toxicity and apoptosis of thymocytes. Western blot and RT-PCR showed that leptin led to a reduction of cPLA(2) activity and mRNA level, as well as caspase-3 cleavage. Moreover, we found that leptin could decrease the activation of p38 MAPK. Accordingly, we pre-treated apoptotic thymocytes with the p38 MAPK inhibitor, SB203580 and observed an effect similar to the leptin alone treated group. SB203580 also suppressed expression of cPLA(2) and cleavage of caspase-3. Based on these results, we suggest that leptin could attenuate LPS-induced apoptotic injury in mouse thymocyte cells, mainly through the p38/cPLA(2) signalling pathway. The study of the regulatory role of leptin in LPS-induced thymocyte apoptosis can help to explain the role of leptin in the immune system and may provide a novel treatment option in cases of severe trauma, infection, shock, organ failure and autoimmune disease caused by thymic atrophy.
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Vauthier V, Derviaux C, Douayry N, Roux T, Trinquet E, Jockers R, Dam J. Design and validation of a homogeneous time-resolved fluorescence-based leptin receptor binding assay. Anal Biochem 2013; 436:1-9. [PMID: 23333588 DOI: 10.1016/j.ab.2012.12.013] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2012] [Revised: 12/11/2012] [Accepted: 12/13/2012] [Indexed: 12/15/2022]
Abstract
The pleiotropic cytokine hormone leptin, by activating its receptor OB-R, plays a major role in many biological processes, including energy homeostasis, immune function, and cell survival and proliferation. Abnormal leptin action is associated with obesity, autoimmune diseases, and cancer. The pharmacological characterization of OB-R and the development of synthetic OB-R ligands are still in their infancy because currently available binding assays are not compatible with ligand saturation binding experiments and high-throughput screening (HTS) approaches. We have developed here a novel homogeneous time-resolved fluorescence-based binding assay that overcomes these limitations. In this assay, fluorescently labeled leptin or leptin antagonist binds to the SNAP-tagged OB-R covalently labeled with terbium cryptate (Tb). Successful binding is monitored by measuring the energy transfer between the Tb energy donor and the fluorescently labeled leptin energy acceptor. Ligand binding saturation experiments revealed high-affinity dissociation constants in the subnanomolar range with an excellent signal-to-noise ratio. The assay performed in a 384-well format shows high specificity and reproducibility, making it perfectly compatible with HTS applications to identify new OB-R agonists or antagonists. In addition, fluorescently labeled leptin and SNAP-tagged OB-R will be valuable tools for monitoring leptin and OB-R trafficking in cells and tissues.
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Affiliation(s)
- Virginie Vauthier
- Institut National de la Santé et de la Recherche Médicale (INSERM), U1016, Institut Cochin, 75014 Paris, France
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El-Wakkad A, Hassan NEM, Sibaii H, El-Zayat SR. Proinflammatory, anti-inflammatory cytokines and adiponkines in students with central obesity. Cytokine 2013; 61:682-7. [PMID: 23306429 DOI: 10.1016/j.cyto.2012.11.010] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2012] [Revised: 11/09/2012] [Accepted: 11/16/2012] [Indexed: 12/17/2022]
Abstract
Several studies have investigated the correlation between central obesity and inflammatory cytokines and the anti-inflammatory cytokine adiponectin. But, the correlation between central obesity and the anti-inflammatory cytokines IL-4, IL-5 has not been studied yet. Thus, we aimed to study the IL-4 and IL-5 correlation to central obesity in adolescent Egyptian girls among proinflammatory and anti-inflammatory cytokines. The study was carried out on 86 obese adolescent girls (BMI>95 percentile) divided into two groups according to central obesity. The group I with waist to hip ratio <0.8 as a control and group II with waist to hip ratio >0.8 (central obesity). There was a significant increase in TNF-alpha (p<0.0001), and IL-1β (p<0.0001), as proinflammatory cytokines in group II, as compared to their corresponding group I. Group II showed a significant increase in the anti-inflammatory cytokines IL-4 and IL-5 than group I at (p<0.0001) and (p<0.0005) respectively. In addition there was a significant decrease in the anti-inflammatory adiponectin and an increase in the inflammatory leptin levels in group II at (p<0.0001) and (p<0.0001) respectively in comparison to group I. A high positive correlation has been observed between waist to hip ratio, leptin, TNF-α, IL-1-β, IL-4 and IL-5 at (r=0.331, p<0.03), (r=0.559, p<0.001), (r=0.435, p<0.004), (r=0.509, p<0.001), (r=0.550, p<0.0015), in group II respectively and a high negative one with adiponectin at (r=-0.410, p<0.0001). We concluded that central obesity lowers adiponectin plasma level through increasing proinflammatory adipokines such as TNF-α, IL-1β, leptin. Further studies are needed to explore the positive correlation we found between central obesity and the anti-inflammatory cytokines IL-4 and IL-5 known to be associated with bronchial asthma.
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Affiliation(s)
- Amany El-Wakkad
- Department of Medical Physiology, National Research Centre, Cairo, Egypt.
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Carpenter B, Hemsworth GR, Wu Z, Maamra M, Strasburger CJ, Ross RJ, Artymiuk PJ. Structure of the human obesity receptor leptin-binding domain reveals the mechanism of leptin antagonism by a monoclonal antibody. Structure 2012; 20:487-97. [PMID: 22405007 DOI: 10.1016/j.str.2012.01.019] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2011] [Revised: 01/13/2012] [Accepted: 01/22/2012] [Indexed: 11/16/2022]
Abstract
Leptin regulates energy homeostasis, fertility, and the immune system, making it an important drug target. However, due to a complete lack of structural data for the obesity receptor (ObR), leptin's mechanism of receptor activation remains poorly understood. We have crystallized the Fab fragment of a leptin-blocking monoclonal antibody (9F8), both in its uncomplexed state and bound to the leptin-binding domain (LBD) of human ObR. We describe the structure of the LBD-9F8 Fab complex and the conformational changes in 9F8 associated with LBD binding. A molecular model of the putative leptin-LBD complex reveals that 9F8 Fab blocks leptin binding through only a small (10%) overlap in their binding sites, and that leptin binding is likely to involve an induced fit mechanism. This crystal structure of the leptin-binding domain of the obesity receptor will facilitate the design of therapeutics to modulate leptin signaling.
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Affiliation(s)
- Byron Carpenter
- Academic Unit of Diabetes, Endocrinology and Reproduction, Department of Human Metabolism, University of Sheffield, Sheffield S10 2JF, UK
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