|
1
|
Ye J, Qin SS, Hughson AL, Hannon G, Salama NA, Vrooman TG, Lesch ML, Lesser S, Eckl SL, Jewell R, Benoodt L, Mills BN, Johnston CJ, Lord E, Belt BA, Calvi LM, Linehan D, Luheshi N, Eyles J, Gerber SA. Blocking LIF and PD-L1 enhances the antitumor efficacy of SBRT in murine PDAC models. J Immunother Cancer 2025; 13:e010820. [PMID: 40341024 PMCID: PMC12067785 DOI: 10.1136/jitc-2024-010820] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2024] [Accepted: 04/21/2025] [Indexed: 05/10/2025] Open
Abstract
BACKGROUND Recent preclinical and clinical data suggest that leukemia inhibitory factor (LIF) is a potential target for various tumor types including pancreatic ductal adenocarcinoma as LIF is involved in multiple protumor processes including cancer stem cell maintenance, epithelial-mesenchymal transition (EMT), immunosuppression, and chemo/radioresistance. Anti-LIF antibody therapy has demonstrated safety and tolerability but limited efficacy in phase 1 clinical trial in advanced solid tumors. This prompted us to explore combination therapies, suggesting that LIF blockade, when combined with standard-of-care chemotherapy, radiotherapy, and/or immunotherapy, could present a promising therapeutic strategy. METHODS We evaluated the impact of combining systemic inhibition of LIF/programmed death-ligand 1 (PD-L1) with localized stereotactic body radiotherapy (SBRT) on tumor progression across multiple murine orthotopic pancreatic tumor models and examined systemic antitumor immunity using a hepatic rechallenge model. The antitumor immune response was characterized throughflow cytometry and Luminex assays. To identify differentially expressed genes and signaling pathways following treatment, we performed bulk RNA sequencing on pancreatic tumors. Additionally, single-cell RNA sequencing was conducted to further examine changes in tumor-infiltrating immune cells and their signaling pathways. RESULTS We showed that simultaneous inhibition of LIF and PD-L1 significantly amplified the antitumor efficacy of SBRT, resulting in extended survival. The triple therapy (SBRT+anti-LIF+anti-PD-L1) generated an immunostimulatory tumor microenvironment, characterized by a proinflammatory shift in the cytokine/chemokine profile, increased infiltration of effector CD8+ T cells, and upregulated activation or maturation signals in tumor-infiltrating CD8+ T cells and macrophages. The beneficial effects of triple therapy were mostly abrogated by depletion of CD8+ T cells. In addition, triple therapy downregulated pathways related to tumor stemness, proliferation, and metabolism, and reduced EMT. Importantly, the combination of local SBRT treatment with systemic LIF and PD-L1 blockade resulted in long-term systemic antitumor memory.
Collapse
Affiliation(s)
- Jian Ye
- Department of Surgery, University of Rochester Medical Center, Rochester, New York, USA
- Center for Tumor Immunology Research, University of Rochester Medical Center, Rochester, New York, USA
| | - Shuyang S Qin
- Department of Surgery, University of Rochester Medical Center, Rochester, New York, USA
- Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York, USA
| | - Angela L Hughson
- Department of Surgery, University of Rochester Medical Center, Rochester, New York, USA
- Center for Tumor Immunology Research, University of Rochester Medical Center, Rochester, New York, USA
| | - Gary Hannon
- Department of Surgery, University of Rochester Medical Center, Rochester, New York, USA
- Center for Tumor Immunology Research, University of Rochester Medical Center, Rochester, New York, USA
| | - Noah A Salama
- Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York, USA
| | - Tara G Vrooman
- Department of Surgery, University of Rochester Medical Center, Rochester, New York, USA
- Center for Tumor Immunology Research, University of Rochester Medical Center, Rochester, New York, USA
- Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York, USA
| | - Maggie L Lesch
- Department of Surgery, University of Rochester Medical Center, Rochester, New York, USA
- Center for Tumor Immunology Research, University of Rochester Medical Center, Rochester, New York, USA
- Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York, USA
| | - Sidney Lesser
- Department of Surgery, University of Rochester Medical Center, Rochester, New York, USA
- Center for Tumor Immunology Research, University of Rochester Medical Center, Rochester, New York, USA
| | - Sarah L Eckl
- Department of Surgery, University of Rochester Medical Center, Rochester, New York, USA
- Center for Tumor Immunology Research, University of Rochester Medical Center, Rochester, New York, USA
- Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York, USA
| | - Rachel Jewell
- Department of Surgery, University of Rochester Medical Center, Rochester, New York, USA
- Center for Tumor Immunology Research, University of Rochester Medical Center, Rochester, New York, USA
| | - Lauren Benoodt
- Genomic Research Center, University of Rochester Medical Center, Rochester, New York, USA
| | - Bradley N Mills
- Department of Surgery, University of Rochester Medical Center, Rochester, New York, USA
- Center for Tumor Immunology Research, University of Rochester Medical Center, Rochester, New York, USA
- Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York, USA
| | - Carl J Johnston
- Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York, USA
- Department of Pediatrics, University of Rochester Medical Center, Rochester, New York, USA
| | - Edith Lord
- Center for Tumor Immunology Research, University of Rochester Medical Center, Rochester, New York, USA
- Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York, USA
| | - Brian A Belt
- Department of Surgery, University of Rochester Medical Center, Rochester, New York, USA
- Center for Tumor Immunology Research, University of Rochester Medical Center, Rochester, New York, USA
| | - Laura M Calvi
- Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York, USA
- Department of Medicine Hematology/Oncology, University of Rochester Medical Center, Rochester, New York, USA
| | - David Linehan
- Department of Surgery, University of Rochester Medical Center, Rochester, New York, USA
- Center for Tumor Immunology Research, University of Rochester Medical Center, Rochester, New York, USA
- Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York, USA
| | - Nadia Luheshi
- The Discovery Center, Cambridge Biomedical Campus, Cambridge, UK
| | - Jim Eyles
- Oncology R&D, Research and Early Development, AstraZeneca R&D, Cambridge, Cambridgeshire, UK
| | - Scott A Gerber
- Department of Surgery, University of Rochester Medical Center, Rochester, New York, USA
- Center for Tumor Immunology Research, University of Rochester Medical Center, Rochester, New York, USA
- Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York, USA
- Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York, USA
| |
Collapse
|
|
2
|
Chen M, Liu H, Xiao Y, Liang R, Xu H, Hong B, Qian Y. Predictive biomarkers of pancreatic cancer metastasis: A comprehensive review. Clin Chim Acta 2025; 569:120176. [PMID: 39914505 DOI: 10.1016/j.cca.2025.120176] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2025] [Revised: 01/26/2025] [Accepted: 01/28/2025] [Indexed: 02/12/2025]
Abstract
This review provides a comprehensive overview of predictive biomarkers associated with metastasis in pancreatic cancer (PC), one of the most aggressive malignancies characterized by late-stage diagnosis and poor prognosis. Metastasis, particularly to the liver, lungs, and lymph nodes, significantly worsens patient outcomes by compromising organ function and promoting disease progression. Reliable biomarkers for predicting and detecting metastasis at early stages are critical for improving survival rates and guiding personalized therapies. This paper highlights both general and specific biomarkers, including genetic mutations, protein expression changes, and carbohydrate tumor markers such as CA19-9. Immunological factors, including PD-L1, inflammatory cytokines, and chemokines, further influence the metastatic process within the tumor microenvironment (TME). Specific biomarkers play pivotal roles in promoting metastasis through mechanisms such as epithelial-to-mesenchymal transition (EMT), tumor microenvironment remodeling, and immune evasion. Emerging markers such as circulating tumor cells (CTCs) and volatile organic compounds (VOCs) offer promising non-invasive tools for metastasis detection and monitoring. This review not only consolidates existing knowledge but also highlights the mechanisms through which specific biomarkers facilitate metastasis. Despite recent progress, challenges such as biomarker standardization, technical variability, and clinical validation remain, and addressing these hurdles is essential for integrating predictive biomarkers into clinical practice. Ultimately, this review contributes to advancing early detection strategies, personalized treatment options, and improved prognosis for PC patients.
Collapse
Affiliation(s)
- Mengting Chen
- Department of Clinical Laboratory, Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Hangzhou 310000, China
| | - Hongsen Liu
- Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Engineering Research Center of Oral Biomaterials and Devices of Zhejiang Province, Hangzhou 310000, China
| | - Yufei Xiao
- Department of Clinical Laboratory, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China
| | - Ruijin Liang
- The Queen's University of Belfast Joint College, China Medical University, Shenyang 110122, China
| | - Hong Xu
- Departments of Pathology, Quzhou Second People's Hospital, Quzhou 324022, China
| | - Bo Hong
- Department of Pathology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China.
| | - Yun Qian
- Department of Clinical Laboratory, Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Hangzhou 310000, China.
| |
Collapse
|
|
3
|
Skapinker E, Aucoin EB, Kombargi HL, Yaish AM, Li Y, Baghaie L, Szewczuk MR. Contemporaneous Inflammatory, Angiogenic, Fibrogenic, and Angiostatic Cytokine Profiles of the Time-to-Tumor Development by Cancer Cells to Orchestrate Tumor Neovascularization, Progression, and Metastasis. Cells 2024; 13:1739. [PMID: 39451257 PMCID: PMC11506673 DOI: 10.3390/cells13201739] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2024] [Revised: 10/15/2024] [Accepted: 10/16/2024] [Indexed: 10/26/2024] Open
Abstract
Cytokines can promote various cancer processes, such as angiogenesis, epithelial to mesenchymal transition (EMT), invasion, and tumor progression, and maintain cancer stem-cell-like (CSCs) cells. The mechanism(s) that continuously promote(s) tumors to progress in the TME still need(s) to be investigated. The data in the present study analyzed the inflammatory, angiogenic, fibrogenic, and angiostatic cytokine profiles in the host serum during tumor development in a mouse model of human pancreatic cancer. Pancreatic MiaPaCa-2-eGFP cancer cells were subcutaneously implanted in RAG2xCγ double mutant mice. Blood samples were collected before cancer cell implantation and every week until the end point of the study. The extracted serum from the blood of each mouse at different time points during tumor development was analyzed using a Bio-Plex microarray analysis and a Bio-Plex 200 system for proinflammatory (IL-1β, IL-10, IFN-γ, and TNF-α) and angiogenic and fibrogenic (IL-15, IL-18, basic FGF, LIF, M-CSF, MIG, MIP-2, PDGF-BB, and VEGF) cytokines. Here, we find that during cancer cell colonization for tumor development, host angiogenic, fibrogenic, and proinflammatory cytokine profiling in the tumor-bearing mice has been shown to significantly reduce host angiostatic and proinflammatory cytokines that restrain tumor development and increase those for tumor growth. The proinflammatory cytokines IL-15, IL-18, and IL-1β profiles reveal a significant host serum increase after day 35 when the tumor began to progress in growth. In contrast, the angiostatic cytokine profiles of TNFα, MIG, M-CSF, IL-10, and IFNγ in the host serum revealed a dramatic and significant decrease after day 5 post-implantation of cancer cells. OP treatment of tumor-bearing mice on day 35 maintained high levels of angiostatic and fibrogenic cytokines. The data suggest an entirely new regulation by cancer cells for tumor development. The findings identify for the first time how pancreatic cancer cells use host cytokine profiling to orchestrate the initiation of tumor development.
Collapse
Affiliation(s)
- Elizabeth Skapinker
- Faculty of Arts and Science, Queen’s University, Kingston, ON K7L 3N9, Canada; (E.S.); (Y.L.)
| | - Emilyn B. Aucoin
- Faculty of Science, Biology (Biomedical Science), York University, Toronto, ON M3J 1P3, Canada;
| | - Haley L. Kombargi
- Faculty of Health Sciences, Queen’s University, Kingston, ON K7L 3N9, Canada; (H.L.K.); (A.M.Y.)
| | - Abdulrahman M. Yaish
- Faculty of Health Sciences, Queen’s University, Kingston, ON K7L 3N9, Canada; (H.L.K.); (A.M.Y.)
| | - Yunfan Li
- Faculty of Arts and Science, Queen’s University, Kingston, ON K7L 3N9, Canada; (E.S.); (Y.L.)
| | - Leili Baghaie
- Department of Biomedical and Molecular Sciences, Queen’s University, Kingston, ON K7L 3N9, Canada;
| | - Myron R. Szewczuk
- Department of Biomedical and Molecular Sciences, Queen’s University, Kingston, ON K7L 3N9, Canada;
| |
Collapse
|
|
4
|
Shahraz A, Penney M, Candido J, Opoku‐Ansah G, Neubauer M, Eyles J, Ojo O, Liu N, Luheshi NM, Phipps A, Vishwanathan K. A mechanistic PK/PD model of AZD0171 (anti-LIF) to support Phase II dose selection. CPT Pharmacometrics Syst Pharmacol 2024; 13:1670-1681. [PMID: 39041713 PMCID: PMC11494920 DOI: 10.1002/psp4.13204] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2024] [Revised: 06/04/2024] [Accepted: 07/02/2024] [Indexed: 07/24/2024] Open
Abstract
AZD0171 (INN: Falbikitug) is being developed as a humanized monoclonal antibody (mAb), immunoglobulin G subclass 1 (IgG1), which binds specifically to the immunosuppressive human cytokine leukemia inhibitory factor (LIF) and inhibits downstream signaling by blocking recruitment of glycoprotein 130 (gp130) to the LIF receptor (LIFR) subunit (gp190) and the phosphorylation of signal transducer and activator of transcription 3 (STAT3) and is intended to treat adult participants with advanced solid tumors. LIF is a pleiotropic cytokine (and a member of the IL-6 family of cytokines) involved in many physiological and pathological processes and is highly expressed in a subset of solid tumors, including non-small cell lung cancer (NSCLC), colon, ovarian, prostate, and pancreatic cancer. The aim of this work was to develop a mechanistic PK/PD model to investigate the effect of AZD0171 on tumor LIF levels, predict the level of downstream signaling complex (LIF:LIFR:gp130) inhibition, and examine the dose-response relationship to support dose selection for a Phase II clinical study. Modeling results show that tumor LIF is inhibited in a dose-dependent manner with >90% inhibition for 95% of patients at the Phase II clinical dose of 1500 mg Q2W.
Collapse
Affiliation(s)
- Azar Shahraz
- Clinical Pharmacology & Quantitative PharmacologyBioPharmaceuticals R&D, AstraZenecaWalthamMassachusettsUSA
| | - Mark Penney
- Early Oncology DMPK, Oncology R&D, AstraZenecaCambridgeUK
| | | | | | | | - Jim Eyles
- Oncology R&D, AstraZenecaCambridgeUK
| | | | | | | | - Alex Phipps
- Clinical Pharmacology & Quantitative PharmacologyBioPharmaceuticals R&D, AstraZenecaCambridgeUK
| | - Karthick Vishwanathan
- Clinical Pharmacology & Quantitative PharmacologyBioPharmaceuticals R&D, AstraZenecaWalthamMassachusettsUSA
| |
Collapse
|
|
5
|
Zhang L, Feng Y, Zhang Y, Sun X, Ma Q, Ma F. The Sweet Relationship between the Endometrium and Protein Glycosylation. Biomolecules 2024; 14:770. [PMID: 39062484 PMCID: PMC11274983 DOI: 10.3390/biom14070770] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2024] [Revised: 06/17/2024] [Accepted: 06/25/2024] [Indexed: 07/28/2024] Open
Abstract
The endometrium is an important part of women's bodies for menstruation and pregnancy. Various proteins are widely expressed on the surface of endometrial cells, and glycosylation is an important post-translational modification of proteins. Glycosylation modification is closely related not only to endometrial receptivity but also to common diseases related to endometrial receptivity. Glycosylation can improve endometrial receptivity, promote embryo localization and trophoblast cell adhesion and invasion, and contribute to successful implantation. Two diseases related to endometrial receptivity include endometriosis and endometrial cancer. As a common benign disease in women, endometriosis is often accompanied by an increased menstrual volume, prolonged menstrual periods, progressive and aggravated dysmenorrhea, and may be accompanied by infertility. Protein glycosylation modification of the endometrial surface indicates the severity of the disease and may be an important pathogenesis of endometriosis. In cancer, glycosylation modifications on the surface of tumor cells can be a marker to distinguish the type and severity of endometrial cancer. This review highlights the role of protein glycosylation in embryo-maternal endometrial dialogue and explores its potential mechanisms in diseases related to endometrial receptivity, which could provide a new clinical approach for their diagnosis and treatment.
Collapse
Affiliation(s)
- Linyu Zhang
- Center for Translational Medicine, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu 610041, China
- Department of Obstetrics and Gynecology, West China Second Hospital, Sichuan University, Chengdu 610041, China
| | - Ying Feng
- West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu 610041, China
| | - Yue Zhang
- Center for Translational Medicine, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu 610041, China
- Department of Obstetrics and Gynecology, West China Second Hospital, Sichuan University, Chengdu 610041, China
| | - Xinrui Sun
- Center for Translational Medicine, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu 610041, China
- Department of Obstetrics and Gynecology, West China Second Hospital, Sichuan University, Chengdu 610041, China
| | - Qianhong Ma
- Department of Obstetrics and Gynecology, West China Second Hospital, Sichuan University, Chengdu 610041, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu 610041, China
| | - Fang Ma
- Center for Translational Medicine, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu 610041, China
- Department of Obstetrics and Gynecology, West China Second Hospital, Sichuan University, Chengdu 610041, China
| |
Collapse
|
|
6
|
Zheng R, Liu X, Zhang Y, Liu Y, Wang Y, Guo S, Jin X, Zhang J, Guan Y, Liu Y. Frontiers and future of immunotherapy for pancreatic cancer: from molecular mechanisms to clinical application. Front Immunol 2024; 15:1383978. [PMID: 38756774 PMCID: PMC11096556 DOI: 10.3389/fimmu.2024.1383978] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2024] [Accepted: 04/22/2024] [Indexed: 05/18/2024] Open
Abstract
Pancreatic cancer is a highly aggressive malignant tumor, that is becoming increasingly common in recent years. Despite advances in intensive treatment modalities including surgery, radiotherapy, biological therapy, and targeted therapy, the overall survival rate has not significantly improved in patients with pancreatic cancer. This may be attributed to the insidious onset, unknown pathophysiology, and poor prognosis of the disease. It is therefore essential to identify and develop more effective and safer treatments for pancreatic cancer. Tumor immunotherapy is the new and fourth pillar of anti-tumor therapy after surgery, radiotherapy, and chemotherapy. Significant progress has made in the use of immunotherapy for a wide variety of malignant tumors in recent years; a breakthrough has also been made in the treatment of pancreatic cancer. This review describes the advances in immune checkpoint inhibitors, cancer vaccines, adoptive cell therapy, oncolytic virus, and matrix-depletion therapies for the treatment of pancreatic cancer. At the same time, some new potential biomarkers and potential immunotherapy combinations for pancreatic cancer are discussed. The molecular mechanisms of various immunotherapies have also been elucidated, and their clinical applications have been highlighted. The current challenges associated with immunotherapy and proposed strategies that hold promise in overcoming these limitations have also been discussed, with the aim of offering new insights into immunotherapy for pancreatic cancer.
Collapse
Affiliation(s)
- Rui Zheng
- Department of Medical Immunology, Medical College of Yan’an University, Yanan, Shaanxi, China
| | - Xiaobin Liu
- Department of Medical Immunology, Medical College of Yan’an University, Yanan, Shaanxi, China
| | - Yufu Zhang
- Department of Hepatobiliary Surgery, The Affiliated Hospital of Yan’an University, Yan’an, Shaanxi, China
| | - Yongxian Liu
- Department of Medical Immunology, Medical College of Yan’an University, Yanan, Shaanxi, China
| | - Yaping Wang
- Department of Medical Immunology, Medical College of Yan’an University, Yanan, Shaanxi, China
| | - Shutong Guo
- Department of Medical Immunology, Medical College of Yan’an University, Yanan, Shaanxi, China
| | - Xiaoyan Jin
- Department of Medical Immunology, Medical College of Yan’an University, Yanan, Shaanxi, China
| | - Jing Zhang
- Department of Medical Immunology, Medical College of Yan’an University, Yanan, Shaanxi, China
| | - Yuehong Guan
- Department of Medical Immunology, Medical College of Yan’an University, Yanan, Shaanxi, China
| | - Yusi Liu
- Department of Medical Immunology, Medical College of Yan’an University, Yanan, Shaanxi, China
| |
Collapse
|
|
7
|
Mohammadjani N, Karimi S, Moetasam Zorab M, Ashengroph M, Alavi M. Comparative molecular docking and toxicity between carbon-capped metal oxide nanoparticles and standard drugs in cancer and bacterial infections. BIOIMPACTS : BI 2023; 14:27778. [PMID: 38505671 PMCID: PMC10945298 DOI: 10.34172/bi.2023.27778] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Revised: 07/20/2023] [Accepted: 08/01/2023] [Indexed: 03/21/2024]
Abstract
Introduction Nanoparticles (NPs) are of great interest in the design of various drugs due to their high surface-to-volume ratio, which result from their unique physicochemical properties. Because of the importance of examining the interactions between newly designed particles with different targets in the case of various diseases, techniques for examining the interactions between these particles with different targets, many of which are proteins, are now very common. Methods In this study, the interactions between metal oxide nanoparticles (MONPs) covered with a carbon layer (Ag2O3, CdO, CuO, Fe2O3, FeO, MgO, MnO, and ZnO NPs) and standard drugs related to the targets of Cancer and bacterial infections were investigated using the molecular docking technique with AutoDock 4.2.6 software tool. Finally, the PRO TOX-II online tool was used to compare the toxicity (LD50) and molecular weight of these MONPs to standard drugs. Results According to the data obtained from the semi flexible molecular docking process, MgO and Fe2O3 NPs performed better than standard drugs in several cases. MONPs typically have a lower 50% lethal dose (LD50) and a higher molecular weight than standard drugs. MONPs have shown a minor difference in binding energy for different targets in three diseases, which probably can be attributed to the specific physicochemical and pharmacophoric properties of MONPs. Conclusion The toxicity of MONPs is one of the major challenges in the development of drugs based on them. According to the results of these molecular docking studies, MgO and Fe2O3 NPs had the highest efficiency among the investigated MONPs.
Collapse
Affiliation(s)
- Navid Mohammadjani
- Department of Biological Science, Faculty of Science, University of Kurdistan, Sanandaj, Kurdistan, Iran
| | - Sahand Karimi
- Department of Biological Science, Faculty of Science, University of Kurdistan, Sanandaj, Kurdistan, Iran
| | | | - Morahem Ashengroph
- Department of Biological Science, Faculty of Science, University of Kurdistan, Sanandaj, Kurdistan, Iran
| | - Mehran Alavi
- Department of Biological Science, Faculty of Science, University of Kurdistan, Sanandaj, Kurdistan, Iran
- Nanobiotechnology Department, Faculty of Innovative Science and Technology, Razi University, Kermanshah, Iran
| |
Collapse
|
|
8
|
Szymoński K, Chmura Ł, Lipiec E, Adamek D. Vibrational spectroscopy – are we close to finding a solution for early pancreatic cancer diagnosis? World J Gastroenterol 2023; 29:96-109. [PMID: 36683712 PMCID: PMC9850953 DOI: 10.3748/wjg.v29.i1.96] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Revised: 10/03/2022] [Accepted: 10/31/2022] [Indexed: 01/04/2023] Open
Abstract
Pancreatic cancer (PC) is an aggressive and lethal neoplasm, ranking seventh in the world for cancer deaths, with an overall 5-year survival rate of below 10%. The knowledge about PC pathogenesis is rapidly expanding. New aspects of tumor biology, including its molecular and morphological heterogeneity, have been reported to explain the complicated “cross-talk” that occurs between the cancer cells and the tumor stroma or the nature of pancreatic ductal adenocarcinoma-associated neural remodeling. Nevertheless, currently, there are no specific and sensitive diagnosis options for PC. Vibrational spectroscopy (VS) shows a promising role in the development of early diagnosis technology. In this review, we summarize recent reports about improvements in spectroscopic methodologies, briefly explain and highlight the drawbacks of each of them, and discuss available solutions. The important aspects of spectroscopic data evaluation with multivariate analysis and a convolutional neural network methodology are depicted. We conclude by presenting a study design for systemic verification of the VS-based methods in the diagnosis of PC.
Collapse
Affiliation(s)
- Krzysztof Szymoński
- Department of Pathomorphology, Jagiellonian University Medical College, Cracow 33-332, Poland
- Department of Pathomorphology, University Hospital in Cracow, Cracow 31-501, Poland
| | - Łukasz Chmura
- Department of Pathomorphology, Jagiellonian University Medical College, Cracow 33-332, Poland
- Department of Pathomorphology, University Hospital in Cracow, Cracow 31-501, Poland
| | - Ewelina Lipiec
- M. Smoluchowski Institute of Physics, Jagiellonian University, Cracow 30-348, Poland
| | - Dariusz Adamek
- Department of Pathomorphology, University Hospital in Cracow, Cracow 31-501, Poland
- Department of Neuropathology, Jagiellonian University Medical College, Cracow 33-332, Poland
| |
Collapse
|
|
9
|
Di Giorgio C, Lupia A, Marchianò S, Bordoni M, Bellini R, Massa C, Urbani G, Roselli R, Moraca F, Sepe V, Catalanotti B, Morretta E, Monti MC, Biagioli M, Distrutti E, Zampella A, Fiorucci S. Repositioning Mifepristone as a Leukaemia Inhibitory Factor Receptor Antagonist for the Treatment of Pancreatic Adenocarcinoma. Cells 2022; 11:3482. [PMID: 36359879 PMCID: PMC9657739 DOI: 10.3390/cells11213482] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Revised: 10/27/2022] [Accepted: 11/01/2022] [Indexed: 11/12/2023] Open
Abstract
Pancreatic cancer is a leading cause of cancer mortality and is projected to become the second-most common cause of cancer mortality in the next decade. While gene-wide association studies and next generation sequencing analyses have identified molecular patterns and transcriptome profiles with prognostic relevance, therapeutic opportunities remain limited. Among the genes that are upregulated in pancreatic ductal adenocarcinomas (PDAC), the leukaemia inhibitory factor (LIF), a cytokine belonging to IL-6 family, has emerged as potential therapeutic candidate. LIF is aberrantly secreted by tumour cells and promotes tumour progression in pancreatic and other solid tumours through aberrant activation of the LIF receptor (LIFR) and downstream signalling that involves the JAK1/STAT3 pathway. Since there are no LIFR antagonists available for clinical use, we developed an in silico strategy to identify potential LIFR antagonists and drug repositioning with regard to LIFR antagonists. The results of these studies allowed the identification of mifepristone, a progesterone/glucocorticoid antagonist, clinically used in medical abortion, as a potent LIFR antagonist. Computational studies revealed that mifepristone binding partially overlapped the LIFR binding site. LIF and LIFR are expressed by human PDAC tissues and PDAC cell lines, including MIA-PaCa-2 and PANC-1 cells. Exposure of these cell lines to mifepristone reverses cell proliferation, migration and epithelial mesenchymal transition induced by LIF in a concentration-dependent manner. Mifepristone inhibits LIFR signalling and reverses STAT3 phosphorylation induced by LIF. Together, these data support the repositioning of mifepristone as a potential therapeutic agent in the treatment of PDAC.
Collapse
Affiliation(s)
- Cristina Di Giorgio
- Department of Medicine and Surgery, University of Perugia, 06123 Perugia, Italy
| | - Antonio Lupia
- Department of Pharmacy, University of Naples Federico II, 80131 Naples, Italy
- Campus Salvatore Venuta, Net4Science Srl, University “Magna Græcia”, Viale Europa, 88100 Catanzaro, Italy
| | - Silvia Marchianò
- Department of Medicine and Surgery, University of Perugia, 06123 Perugia, Italy
| | - Martina Bordoni
- Department of Medicine and Surgery, University of Perugia, 06123 Perugia, Italy
| | - Rachele Bellini
- Department of Medicine and Surgery, University of Perugia, 06123 Perugia, Italy
| | - Carmen Massa
- Department of Medicine and Surgery, University of Perugia, 06123 Perugia, Italy
| | - Ginevra Urbani
- Department of Medicine and Surgery, University of Perugia, 06123 Perugia, Italy
| | - Rosalinda Roselli
- Department of Pharmacy, University of Naples Federico II, 80131 Naples, Italy
| | - Federica Moraca
- Department of Pharmacy, University of Naples Federico II, 80131 Naples, Italy
- Campus Salvatore Venuta, Net4Science Srl, University “Magna Græcia”, Viale Europa, 88100 Catanzaro, Italy
| | - Valentina Sepe
- Department of Pharmacy, University of Naples Federico II, 80131 Naples, Italy
| | - Bruno Catalanotti
- Department of Pharmacy, University of Naples Federico II, 80131 Naples, Italy
| | - Elva Morretta
- Department of Pharmacy, University of Salerno, 84084 Salerno, Italy
| | | | - Michele Biagioli
- Department of Medicine and Surgery, University of Perugia, 06123 Perugia, Italy
| | | | - Angela Zampella
- Department of Pharmacy, University of Naples Federico II, 80131 Naples, Italy
| | - Stefano Fiorucci
- Department of Medicine and Surgery, University of Perugia, 06123 Perugia, Italy
| |
Collapse
|
|
10
|
Zhang Z, Zhang H, Shi L, Wang D, Tang D. Heterogeneous cancer-associated fibroblasts: A new perspective for understanding immunosuppression in pancreatic cancer. Immunology 2022; 167:1-14. [PMID: 35569095 DOI: 10.1111/imm.13496] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Accepted: 05/04/2022] [Indexed: 11/27/2022] Open
Abstract
Immunotherapy has shown promising efficacy in the treatment of a wide range of cancers; however, it has had little effect on pancreatic cancer. Cancer-associated fibroblasts (CAFs), the predominant mesenchymal cells present in the pancreatic cancer microenvironment, are powerful supporters of the malignant progression of pancreatic cancer. CAFs can modify the microenvironment, establish a refuge to aid cancer cells in immune escape by secreting large amounts of extracellular matrix, and produce soluble cytokines and exosomal vesicles. Hence, CAFs are important contributors to the failure of immunotherapy. Current in-depth studies of CAFs have shown that CAFs are a heterogeneous population of mesenchymal cells; therefore, the functional complexity of their populations needs in-depth explorations in future studies. This review summarizes how heterogeneous CAFs help cancer cells achieve immune escape and suggests potential directions for using CAFs as targets to address immune escape.
Collapse
Affiliation(s)
- Zhilin Zhang
- Clinical Medical College, Yangzhou University, Yangzhou, China
| | - Huan Zhang
- Clinical Medical College, Yangzhou University, Yangzhou, China
| | - Lin Shi
- Clinical Medical College, Yangzhou University, Yangzhou, China
| | - Daorong Wang
- Department of General Surgery, Institute of General Surgery, Clinical Medical College, Yangzhou University, Northern Jiangsu People's Hospital, Yangzhou, China
| | - Dong Tang
- Department of General Surgery, Institute of General Surgery, Clinical Medical College, Yangzhou University, Northern Jiangsu People's Hospital, Yangzhou, China
| |
Collapse
|
|
11
|
Zhong W, Liu H, Li F, lin Y, Ye Y, Xu L, Li S, Chen H, Li C, Lin Y, Zhuang W, Lin Y, Wang Q. Elevated expression of LIF predicts a poor prognosis and promotes cell migration and invasion of clear cell renal cell carcinoma. Front Oncol 2022; 12:934128. [PMID: 35992780 PMCID: PMC9382297 DOI: 10.3389/fonc.2022.934128] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Accepted: 07/06/2022] [Indexed: 11/13/2022] Open
Abstract
Background Renal cell carcinoma (RCC) is the seventh most common cancer in humans, of which clear cell renal cell carcinoma (ccRCC) accounts for the majority. Recently, although there have been significant breakthroughs in the treatment of ccRCC, the prognosis of targeted therapy is still poor. Leukemia inhibitory factor (LIF) is a pleiotropic protein, which is overexpressed in many cancers and plays a carcinogenic role. In this study, we explored the expression and potential role of LIF in ccRCC. Methods The expression levels and prognostic effects of the LIF gene in ccRCC were detected using TCGA, GEO, ICGC, and ArrayExpress databases. The function of LIF in ccRCC was investigated using a series of cell function approaches. LIF-related genes were identified by weighted gene correlation network analysis (WGCNA). GO and KEGG analyses were performed subsequently. Cox univariate and LASSO analyses were used to develop risk signatures based on LIF-related genes, and the prognostic model was validated in the ICGC and E-MTAB-1980 databases. Then, a nomogram model was constructed for survival prediction and validation of ccRCC patients. To further explore the drug sensitivity between LIF-related genes, we also conducted a drug sensitivity analysis based on the GDSC database. Results The mRNA and protein expression levels of LIF were significantly increased in ccRCC patients. In addition, a high expression of LIF has a poor prognostic effect in ccRCC patients. LIF knockdown can inhibit the migration and invasion of ccRCC cells. By using WGCNA, 97 LIF-related genes in ccRCC were identified. Next, a prognostic risk prediction model including eight LIF-related genes (TOB2, MEPCE, LIF, RGS2, RND3, KLF6, RRP12, and SOCS3) was developed and validated. Survival analysis and ROC curve analysis indicated that the eight LIF-related-gene predictive model had good performance in evaluating patients’ prognosis in different subgroups of ccRCC. Conclusion Our study revealed that LIF plays a carcinogenic role in ccRCC. In addition, we firstly integrated multiple LIF-related genes to set up a risk-predictive model. The model could accurately predict the prognosis of ccRCC, which offers clinical implications for risk stratification, drug screening, and therapeutic decision.
Collapse
Affiliation(s)
- Wenting Zhong
- Central Laboratory at the Second Affiliated Hospital of Fujian Traditional Chinese Medical University, Fujian-Macao Science and Technology Cooperation Base of Traditional Chinese Medicine-Oriented Chronic Disease Prevention and Treatment, Innovation and Transformation Center, Fujian University of Traditional Chinese Medicine, Fuzhou, China
- College of Life Sciences, Fujian Normal University, Fuzhou, China
| | - Hongxia Liu
- College of Life Sciences, Fujian Normal University, Fuzhou, China
| | - Feng Li
- Department of Pathology, Fujian Provincial Hospital, Fuzhou, China
| | - Youyu lin
- College of Life Sciences, Fujian Normal University, Fuzhou, China
| | - Yan Ye
- College of Life Sciences, Fujian Normal University, Fuzhou, China
| | - Luyun Xu
- College of Life Sciences, Fujian Normal University, Fuzhou, China
| | - ShengZhao Li
- College of Life Sciences, Fujian Normal University, Fuzhou, China
| | - Hui Chen
- College of Life Sciences, Fujian Normal University, Fuzhou, China
| | - Chengcheng Li
- College of Life Sciences, Fujian Normal University, Fuzhou, China
| | - Yuxuan Lin
- College of Life Sciences, Fujian Normal University, Fuzhou, China
| | - Wei Zhuang
- Department of Urology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
- *Correspondence: Qingshui Wang, ; Yao Lin, ; ; Wei Zhuang,
| | - Yao Lin
- Central Laboratory at the Second Affiliated Hospital of Fujian Traditional Chinese Medical University, Fujian-Macao Science and Technology Cooperation Base of Traditional Chinese Medicine-Oriented Chronic Disease Prevention and Treatment, Innovation and Transformation Center, Fujian University of Traditional Chinese Medicine, Fuzhou, China
- *Correspondence: Qingshui Wang, ; Yao Lin, ; ; Wei Zhuang,
| | - Qingshui Wang
- Central Laboratory at the Second Affiliated Hospital of Fujian Traditional Chinese Medical University, Fujian-Macao Science and Technology Cooperation Base of Traditional Chinese Medicine-Oriented Chronic Disease Prevention and Treatment, Innovation and Transformation Center, Fujian University of Traditional Chinese Medicine, Fuzhou, China
- College of Life Sciences, Fujian Normal University, Fuzhou, China
- *Correspondence: Qingshui Wang, ; Yao Lin, ; ; Wei Zhuang,
| |
Collapse
|
|
12
|
Halder S, Parte S, Kshirsagar P, Muniyan S, Nair HB, Batra SK, Seshacharyulu P. The Pleiotropic role, functions and targeted therapies of LIF/LIFR axis in cancer: Old spectacles with new insights. Biochim Biophys Acta Rev Cancer 2022; 1877:188737. [PMID: 35680099 PMCID: PMC9793423 DOI: 10.1016/j.bbcan.2022.188737] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Revised: 05/09/2022] [Accepted: 05/28/2022] [Indexed: 12/30/2022]
Abstract
The dysregulation of leukemia inhibitory factor (LIF) and its cognate receptor (LIFR) has been associated with multiple cancer initiation, progression, and metastasis. LIF plays a significant tumor-promoting role in cancer, while LIFR functions as a tumor promoter and suppressor. Epithelial and stromal cells secrete LIF via autocrine and paracrine signaling mechanism(s) that bind with LIFR and subsequently with co-receptor glycoprotein 130 (gp130) to activate JAK/STAT1/3, PI3K/AKT, mTORC1/p70s6K, Hippo/YAP, and MAPK signaling pathways. Clinically, activating the LIF/LIFR axis is associated with poor survival and anti-cancer therapy resistance. This review article provides an overview of the structure and ligands of LIFR, LIF/LIFR signaling in developmental biology, stem cells, cancer stem cells, genetics and epigenetics of LIFR, LIFR regulation by long non-coding RNAs and miRNAs, and LIF/LIFR signaling in cancers. Finally, neutralizing antibodies and small molecule inhibitors preferentially blocking LIF interaction with LIFR and antagonists against LIFR under pre-clinical and early-phase pre-clinical trials were discussed.
Collapse
Affiliation(s)
- Sushanta Halder
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA
| | - Seema Parte
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA
| | - Prakash Kshirsagar
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA
| | - Sakthivel Muniyan
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA
| | | | - Surinder K. Batra
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA,Eppley Institute for Research in Cancer and Allied Diseases, USA,Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA,Corresponding authors at: Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA. (S.K. Batra), (P. Seshacharyulu)
| | - Parthasarathy Seshacharyulu
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA,Eppley Institute for Research in Cancer and Allied Diseases, USA,Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA,Corresponding authors at: Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA. (S.K. Batra), (P. Seshacharyulu)
| |
Collapse
|
|
13
|
The Molecular Basis and Therapeutic Potential of Leukemia Inhibitory Factor in Cancer Cachexia. Cancers (Basel) 2022; 14:cancers14122955. [PMID: 35740622 PMCID: PMC9221449 DOI: 10.3390/cancers14122955] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Revised: 06/01/2022] [Accepted: 06/11/2022] [Indexed: 02/06/2023] Open
Abstract
Simple Summary The mechanism of cancer cachexia is linked to a variety of factors, and inflammatory factors are thought to play a key role. We summarize the main roles of LIF in the development of cancer cachexia, including promoting fat loss, inducing skeletal muscle atrophy and causing anorexia nervosa. The main aim of this review is to increase the understanding of the effects of LIF in cachexia and to provide new insights into the treatment of cancer cachexia. Abstract Cachexia is a chronic metabolic syndrome that is characterized by sustained weight and muscle mass loss and anorexia. Cachexia can be secondary to a variety of diseases and affects the prognosis of patients significantly. The increase in inflammatory cytokines in plasma is deeply related to the occurrence of cachexia. As a member of the IL-6 cytokine family, leukemia inhibitory factor (LIF) exerts multiple biological functions. LIF is over-expressed in the cancer cells and stromal cells of various tumors, promoting the malignant development of tumors via the autocrine and paracrine systems. Intriguingly, increasing studies have confirmed that LIF contributes to the progression of cachexia, especially in patients with metastatic tumors. This review combines all of the evidence to summarize the mechanism of LIF-induced cachexia from the following four aspects: (i) LIF and cancer-associated cachexia, (ii) LIF and alterations of adipose tissue in cachexia, (iii) LIF and anorexia nervosa in cachexia, and (iv) LIF and muscle atrophy in cachexia. Considering the complex mechanisms in cachexia, we also focus on the interactions between LIF and other key cytokines in cachexia and existing therapeutics targeting LIF.
Collapse
|
|
14
|
Szymoński K, Milian-Ciesielska K, Lipiec E, Adamek D. Current Pathology Model of Pancreatic Cancer. Cancers (Basel) 2022; 14:2321. [PMID: 35565450 PMCID: PMC9105915 DOI: 10.3390/cancers14092321] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Revised: 04/29/2022] [Accepted: 05/05/2022] [Indexed: 02/01/2023] Open
Abstract
Pancreatic cancer (PC) is one of the most aggressive and lethal malignant neoplasms, ranking in seventh place in the world in terms of the incidence of death, with overall 5-year survival rates still below 10%. The knowledge about PC pathomechanisms is rapidly expanding. Daily reports reveal new aspects of tumor biology, including its molecular and morphological heterogeneity, explain complicated "cross-talk" that happens between the cancer cells and tumor stroma, or the nature of the PC-associated neural remodeling (PANR). Staying up-to-date is hard and crucial at the same time. In this review, we are focusing on a comprehensive summary of PC aspects that are important in pathologic reporting, impact patients' outcomes, and bring meaningful information for clinicians. Finally, we show promising new trends in diagnostic technologies that might bring a difference in PC early diagnosis.
Collapse
Affiliation(s)
- Krzysztof Szymoński
- Department of Pathomorphology, Jagiellonian University Medical College, 31-531 Cracow, Poland;
- Department of Pathomorphology, University Hospital, 30-688 Cracow, Poland;
| | | | - Ewelina Lipiec
- M. Smoluchowski Institute of Physics, Jagiellonian University, 30-348 Cracow, Poland;
| | - Dariusz Adamek
- Department of Pathomorphology, Jagiellonian University Medical College, 31-531 Cracow, Poland;
| |
Collapse
|
|
15
|
Ropa J, Cooper S, Broxmeyer HE. Leukemia Inhibitory Factor Promotes Survival of Hematopoietic Progenitors Ex Vivo and Is Post-Translationally Regulated by DPP4. Stem Cells 2022; 40:346-357. [PMID: 35293568 PMCID: PMC9199847 DOI: 10.1093/stmcls/sxac004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Accepted: 01/06/2022] [Indexed: 01/30/2023]
Abstract
Hematopoietic cells are regulated in part by extracellular cues from cytokines. Leukemia inhibitory factor (LIF) promotes survival, self-renewal, and pluripotency of mouse embryonic stem cells (mESC). While genetic deletion of LIF affects hematopoietic progenitor cells (HPCs), the direct effect of LIF protein exposure on HPC survival is not known. Furthermore, post-translational modifications (PTM) of LIF and their effects on its function have not been evaluated. We demonstrate that treatment with recombinant LIF preserves mouse and human HPC numbers in stressed conditions when growth factor addition is delayed ex vivo. We show that Lif is upregulated in response to irradiation-induced stress. We reveal novel PTM of LIF where it is cleaved twice by dipeptidyl peptidase 4 (DPP4) protease so that it loses its 4 N-terminal amino acids. This truncation of LIF down-modulates LIF's ability to preserve functional HPC numbers ex vivo following delayed growth factor addition. DPP4-truncated LIF blocks the ability of full-length LIF to preserve functional HPC numbers. This LIF role and its novel regulation by DPP4 have important implications for normal and stress hematopoiesis, as well as for other cellular contexts in which LIF and DPP4 are implicated.
Collapse
Affiliation(s)
- James Ropa
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202, USA,Corresponding author: James Ropa, PhD, Department of Microbiology and Immunology, Indiana University School of Medicine, 950 West Walnut Street, Bldg. R2, Room 302, Indianapolis, IN 46202, USA. Tel: 317-274-7553;
| | - Scott Cooper
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Hal E Broxmeyer
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| |
Collapse
|
|
16
|
Wu D, Guo J, Qi B, Xiao H. TGF-β1 induced proliferation, migration, and ECM accumulation through the SNHG11/miR-34b/LIF pathway in human pancreatic stellate cells. Endocr J 2021; 68:1347-1357. [PMID: 34261825 DOI: 10.1507/endocrj.ej21-0176] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Chronic pancreatitis (CP) is a chronic inflammatory and fibrotic disease of the pancreas, and activated pancreatic stellate cells (PSCs) play a vital role in the progression of pancreatic fibrosis in CP. It has been reported that long non-coding RNA small nucleolar RNA host gene 11 (SNHG11) is highly expressed in chronic pancreatitis (CP) patients. However, the role of SNHG11 in CP progression is unclear. The purport of the study was to survey the role of SNHG11 in CP. We employed transforming growth factor (TGF)-beta1 (TGF-β1) to activate human pancreatic stellate cells (PSCs). Expression of SNHG11 was assessed with qRT-PCR. Loss-of-function experiments were executed to evaluate the effects of SNHG11 on the proliferation and migration of TGF-β1-treated PSCs. Some protein levels were detected by western blotting. The regulatory mechanism of SNHG11 was verified by the dual-luciferase reporter and RIP assays. As a result, SNHG11 was upregulated in plasma of CP patients and TGF-β1-treated PSCs. Also, SNHG11 inhibition reduced TGF-β1-induced proliferation, migration, and ECM accumulation in PSCs. Mechanistically, SNHG11 regulated leukemia inhibitory factor (LIF) expression by sponging miR-34b. Furthermore, miR-34b inhibitor abolished SNHG11 silencing-mediated effects on TGF-β1-treated PSC proliferation, migration, and ECM accumulation. LIF overexpression counteracted the repressive influence of miR-34b mimic on proliferation, migration, and ECM accumulation of TGF-β1-treated PSCs. In conclusion, SNHG11 knockdown reduced TGF-β1-induced PSC proliferation, migration, and ECM accumulation by the miR-34b/LIF axis.
Collapse
Affiliation(s)
- Desheng Wu
- Department of Emergency Medicine, The First Affiliated Hospital of Bengbu Medical College, Bengbu 233000, China
| | - Jin Guo
- Department of Emergency Medicine, The First Affiliated Hospital of Bengbu Medical College, Bengbu 233000, China
| | - Benquan Qi
- Department of Emergency Medicine, The First Affiliated Hospital of Bengbu Medical College, Bengbu 233000, China
| | - Heng Xiao
- Department of Emergency Medicine, The First Affiliated Hospital of Bengbu Medical College, Bengbu 233000, China
| |
Collapse
|
|
17
|
Bernardi O, Estienne A, Reverchon M, Bigot Y, Froment P, Dupont J. Adipokines in metabolic and reproductive functions in birds: An overview of current knowns and unknowns. Mol Cell Endocrinol 2021; 534:111370. [PMID: 34171419 DOI: 10.1016/j.mce.2021.111370] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2021] [Revised: 06/04/2021] [Accepted: 06/14/2021] [Indexed: 01/09/2023]
Abstract
Adipose tissue is now recognized as an active endocrine organ, which synthesizes and secretes numerous peptides factors called adipokines. In mammals, they exert pleiotropic effects affecting energy metabolism but also fertility. In mammals, secretion of adipokines is altered in adipose tissue dysfunctions and may participate to obesity-associated disorders. Thus, adipokines are promising candidates both for novel pharmacological treatment strategies and as diagnostic tools. As compared to mammals, birds exhibit several unique physiological features, which make them an interesting model for comparative studies on endocrine control of metabolism and adiposity and reproductive functions. Some adipokines such as leptin and visfatin may have different roles in avian species as compared to mammals. In addition, some of them found in mammals such as CCL2 (chemokine ligand 2), resistin, omentin and FGF21 (Fibroblast Growth factor 21) have not yet been mapped to the chicken genome model and among its annotated gene models. This brief review aims to summarize data (structure, metabolic and reproductive roles and molecular mechanisms involved) related to main avian adipokines (leptin, adiponectin, visfatin, and chemerin) and we will briefly discuss the adipokines that are still lacking in avian species.
Collapse
Affiliation(s)
- Ophélie Bernardi
- CNRS, IFCE, INRAE, Université de Tours, PRC, F-37380, Nouzilly, France; SYSAAF-Syndicat des Sélectionneurs Avicoles et Aquacoles Français, Centre INRA Val de Loire, F-37380, Nouzilly, France
| | - Anthony Estienne
- CNRS, IFCE, INRAE, Université de Tours, PRC, F-37380, Nouzilly, France
| | - Maxime Reverchon
- SYSAAF-Syndicat des Sélectionneurs Avicoles et Aquacoles Français, Centre INRA Val de Loire, F-37380, Nouzilly, France
| | - Yves Bigot
- CNRS, IFCE, INRAE, Université de Tours, PRC, F-37380, Nouzilly, France
| | - Pascal Froment
- CNRS, IFCE, INRAE, Université de Tours, PRC, F-37380, Nouzilly, France
| | - Joëlle Dupont
- CNRS, IFCE, INRAE, Université de Tours, PRC, F-37380, Nouzilly, France.
| |
Collapse
|