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De Palma ST, Hermans EC, Shamorkina TM, Trayford C, van Rijt S, Heck AJR, Nijboer CHA, de Theije CGM. Hypoxic Preconditioning Enhances the Potential of Mesenchymal Stem Cells to Treat Neonatal Hypoxic-Ischemic Brain Injury. Stroke 2025. [PMID: 40248869 DOI: 10.1161/strokeaha.124.048964] [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: 08/16/2024] [Revised: 03/16/2025] [Accepted: 04/04/2025] [Indexed: 04/19/2025]
Abstract
BACKGROUND Neonatal hypoxic-ischemic (HI) brain injury is one of the leading causes of long-term neurological morbidity in newborns. Current treatment options for HI brain injury are limited, but mesenchymal stem cell (MSC) therapy is a promising strategy to boost neuroregeneration after injury. Optimization strategies to further enhance the potential of MSCs are under development. The current study aimed to test the potency of hypoxic preconditioning of MSCs to enhance the therapeutic efficacy in a mouse model of neonatal HI injury. METHODS HI was induced on postnatal day 9 in C57Bl/6 mouse pups. MSCs were cultured under hypoxic (hypoxic-preconditioned MSCs [HP-MSCs], 1% O2) or normoxic-control (normoxic-preconditioned MSCs, 21% O2) conditions for 24 hours before use. At 10 days after HI, HP-MSCs, normoxic-preconditioned MSCs, or vehicle were intranasally administered. Gold nanoparticle-labeled MSCs were used to assess MSC migration 24 hours after intranasal administration. At 28 days post-HI, lesion size, sensorimotor outcome, and neuroinflammation were assessed by hematoxylin and eosin staining, cylinder rearing task, and IBA1 staining, respectively. In vitro, the effect of HP-MSCs was studied on transwell migration, neural stem cell differentiation and microglia activation, and the MSC intracellular proteomic content was profiled using quantitative LC-MS/ms. RESULTS Intranasally administered HP-MSCs were superior to normoxic-preconditioned MSCs in reducing lesion size and sensorimotor impairments post-HI. Moreover, hypoxic preconditioning enhanced MSC migration in an in vitro set-up, and in vivo to the lesioned hemisphere after intranasal application. In addition, HP-MSCs enhanced neural stem cell differentiation into more complex neurons in vitro but had similar anti-inflammatory effects compared with normoxic-preconditioned MSCs. Lastly, hypoxic preconditioning led to elevated abundances of proteins in MSCs related to extracellular matrix remodeling. CONCLUSIONS This study shows for the first time that hypoxic preconditioning enhanced the therapeutic efficacy of MSC therapy in a mouse model of neonatal HI brain injury by increasing the migratory and neuroregenerative capacity of MSCs.
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Affiliation(s)
- Sara T De Palma
- Department for Developmental Origins of Disease, University Medical Center Utrecht Brain Center and Wilhelmina Children's Hospital (S.T.D.P., E.C.H., C.H.A.N., C.G.M.d.T.)
| | - Eva C Hermans
- Department for Developmental Origins of Disease, University Medical Center Utrecht Brain Center and Wilhelmina Children's Hospital (S.T.D.P., E.C.H., C.H.A.N., C.G.M.d.T.)
| | - Tatiana M Shamorkina
- Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences (T.M.S., A.J.R.H.)
- Utrecht University, the Netherlands. Netherlands Proteomics Center, Utrecht (T.M.S., A.J.R.H.)
| | - Chloe Trayford
- Department of Instructive Biomaterials Engineering, MERLN Institute for Technology-Inspired Regenerative Medicine, Maastricht University, the Netherlands (C.T., S.v.R.)
| | - Sabine van Rijt
- Department of Instructive Biomaterials Engineering, MERLN Institute for Technology-Inspired Regenerative Medicine, Maastricht University, the Netherlands (C.T., S.v.R.)
| | - Albert J R Heck
- Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences (T.M.S., A.J.R.H.)
- Utrecht University, the Netherlands. Netherlands Proteomics Center, Utrecht (T.M.S., A.J.R.H.)
| | - Cora H A Nijboer
- Department for Developmental Origins of Disease, University Medical Center Utrecht Brain Center and Wilhelmina Children's Hospital (S.T.D.P., E.C.H., C.H.A.N., C.G.M.d.T.)
| | - Caroline G M de Theije
- Department for Developmental Origins of Disease, University Medical Center Utrecht Brain Center and Wilhelmina Children's Hospital (S.T.D.P., E.C.H., C.H.A.N., C.G.M.d.T.)
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Yu Y, Tao Y, Ma J, Li J, Song Z. Targeting the tumor microenvironment with mesenchymal stem cells based delivery approach for efficient delivery of anticancer agents: An updated review. Biochem Pharmacol 2025; 232:116725. [PMID: 39746456 DOI: 10.1016/j.bcp.2024.116725] [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: 09/02/2024] [Revised: 11/14/2024] [Accepted: 12/18/2024] [Indexed: 01/04/2025]
Abstract
Drug delivery to cancer cells continues to present a major therapeutic challenge. Mesenchymal stem cells (MSCs) possess an intrinsic ability to migrate specifically to tumor tissues, making them promising candidates for targeted drug delivery. Evidence from preclinical studies indicates that MSCs loaded with therapeutic anti-cancer agents exhibit considerable anti-tumor activity. Moreover, several clinical trials are currently evaluating their effectiveness in cancer patients. The integration of MSCs with synthetic nanoparticles (NPs) enhances their therapeutic potential, particularly through the use of cell membrane-coated NPs, which represent a significant advancement in the field. This review systematically investigates the tumor microenvironment, the sources of MSCs, the tumor homing mechanisms, and the methods of loading and releasing anticancer drugs from MSCs. Furthermore, cutting-edge strategies to improve the efficacy of MSCs based drug delivery systems (DDS) including the innovative use of MSC membrane coated nanoparticles have been discussed. The study concludes with an overview of the therapeutic use of MSCs as drug carriers, including a detailed analysis of the mechanisms by which MSCs deliver therapeutics to cancer cells, enabling targeted drug delivery. It aims to elucidate the current state of this approach, identify key areas for development, and outline potential future directions for advancing MSCs based cancer therapies.
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Affiliation(s)
- Yang Yu
- Department of Emergency and Critical Care, the Second Hospital of Jilin University, Changchun 130000, China
| | - Ying Tao
- Department of Anesthesiology, China-Japan Union Hospital of Jilin University, Changchun 130000, China
| | - Jingru Ma
- Department of Clinical Laboratory, the Second Hospital of Jilin University, Changchun 130000, China
| | - Jian Li
- Department of Emergency and Critical Care, the Second Hospital of Jilin University, Changchun 130000, China
| | - Zhidu Song
- Department of Ophthalmology, the Second Hospital of Jilin University, Changchun 130000, China.
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Baran Z, Çetinkaya M, Baran Y. Mesenchymal Stem Cells in Cancer Therapy. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2025; 1474:149-177. [PMID: 39470980 DOI: 10.1007/5584_2024_824] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/01/2024]
Abstract
The mesenchymal stem/stromal cells (MSCs) are multipotent cells that were initially discovered in the bone marrow in the late 1960s but have so far been discovered in almost all tissues of the body. The multipotent property of MSCs enables them to differentiate into various cell types and lineages, such as adipocytes, chondrocytes, and osteocytes. The immunomodulation capacity and tumor-targeting features of MSCs made their use crucial for cell-based therapies in cancer treatment, yet limited advancement could be observed in translational medicine prospects due to the need for more information regarding the controversial roles of MSCs in crosstalk tumors. In this review, we discuss the therapeutic potential of MSCs, the controversial roles played by MSCs in cancer progression, and the anticancer therapeutic strategies that are in association with MSCs. Finally, the clinical trials designed for the direct use of MSCs for cancer therapy or for their use in decreasing the side effects of other cancer therapies are also mentioned in this review to evaluate the current status of MSC-based cancer therapies.
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Affiliation(s)
- Züleyha Baran
- Laboratory of Molecular Pharmacology, Department of Pharmacology, Anadolu University, Eskişehir, Turkey
| | - Melisa Çetinkaya
- Laboratory of Cancer Genetics, Department of Molecular Biology and Genetics, İzmir Institute of Technology, İzmir, Turkey
| | - Yusuf Baran
- Laboratory of Cancer Genetics, Department of Molecular Biology and Genetics, İzmir Institute of Technology, İzmir, Turkey.
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Dunbar H, Hawthorne IJ, Tunstead C, Dunlop M, Volkova E, Weiss DJ, dos Santos CC, Armstrong ME, Donnelly SC, English K. The VEGF-Mediated Cytoprotective Ability of MIF-Licensed Mesenchymal Stromal Cells in House Dust Mite-Induced Epithelial Damage. Eur J Immunol 2025; 55:e202451205. [PMID: 39502000 PMCID: PMC11739667 DOI: 10.1002/eji.202451205] [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: 04/18/2024] [Revised: 10/16/2024] [Accepted: 10/23/2024] [Indexed: 01/06/2025]
Abstract
Enhancing mesenchymal stromal cell (MSC) therapeutic efficacy through licensing with proinflammatory cytokines is now well established. We have previously shown that macrophage migration inhibitory factor (MIF)-licensed MSCs exerted significantly enhanced therapeutic efficacy in reducing inflammation in house dust mite (HDM)-driven allergic asthma. Soluble mediators released into the MSC secretome boast cytoprotective properties equal to those associated with the cell itself. In asthma, epithelial barrier damage caused by the inhalation of allergens like HDM drives goblet cell hyperplasia. Vascular endothelial growth factor (VEGF) plays a pivotal role in the repair and maintenance of airway epithelial integrity. Human bone marrow-derived MSCs expressed the MIF receptors CD74, CXCR2, and CXCR4. Endogenous MIF from high MIF expressing CATT7 bone marrow-derived macrophages increased MSC production of VEGF through the MIF CXCR4 chemokine receptor, where preincubation with CXCR4 inhibitor mitigated this effect. CATT7-MIF licensed MSC conditioned media containing increased levels of VEGF significantly enhanced bronchial epithelial wound healing via migration and proliferation in vitro. Blocking VEGFR2 or the use of mitomycin C abrogated this effect. Furthermore, CATT7-MIF MSC CM significantly decreased goblet cell hyperplasia after the HDM challenge in vivo. This was confirmed to be VEGF-dependent, as the use of anti-human VEGF neutralising antibody abrogated this effect. Overall, this study highlights that MIF-licenced MSCs show enhanced production of VEGF, which has the capacity to repair the lung epithelium.
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Affiliation(s)
- Hazel Dunbar
- Kathleen Lonsdale Institute for Human Health ResearchMaynooth UniversityMaynooth, Co. KildareIreland
- Department of BiologyMaynooth UniversityMaynooth, Co. KildareIreland
| | - Ian J. Hawthorne
- Kathleen Lonsdale Institute for Human Health ResearchMaynooth UniversityMaynooth, Co. KildareIreland
- Department of BiologyMaynooth UniversityMaynooth, Co. KildareIreland
| | - Courteney Tunstead
- Kathleen Lonsdale Institute for Human Health ResearchMaynooth UniversityMaynooth, Co. KildareIreland
- Department of BiologyMaynooth UniversityMaynooth, Co. KildareIreland
| | - Molly Dunlop
- Kathleen Lonsdale Institute for Human Health ResearchMaynooth UniversityMaynooth, Co. KildareIreland
- Department of BiologyMaynooth UniversityMaynooth, Co. KildareIreland
| | - Evelina Volkova
- Kathleen Lonsdale Institute for Human Health ResearchMaynooth UniversityMaynooth, Co. KildareIreland
- Department of BiologyMaynooth UniversityMaynooth, Co. KildareIreland
| | - Daniel J. Weiss
- Department of Medicine, 226 Health Sciences Research Facility, Larner College of MedicineUniversity of VermontBurlingtonVermontUSA
| | - Claudia C. dos Santos
- The Keenan Research Centre for Biomedical Science of St. Michael's HospitalTorontoOntarioCanada
- Institute of Medical Sciences and Interdepartmental Division of Critical CareFaculty of MedicineUniversity of TorontoTorontoOntarioCanada
| | | | - Seamas C. Donnelly
- Department of MedicineTrinity College Dublin and Tallaght HospitalDublinIreland
| | - Karen English
- Kathleen Lonsdale Institute for Human Health ResearchMaynooth UniversityMaynooth, Co. KildareIreland
- Department of BiologyMaynooth UniversityMaynooth, Co. KildareIreland
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Sukegawa M, Miyagawa Y, Kuroda S, Yamazaki Y, Yamamoto M, Adachi K, Sato H, Sato Y, Taniai N, Yoshida H, Umezawa A, Sakai M, Okada T. Mesenchymal stem cell origin contributes to the antitumor effect of oncolytic virus carriers. MOLECULAR THERAPY. ONCOLOGY 2024; 32:200896. [PMID: 39554905 PMCID: PMC11568361 DOI: 10.1016/j.omton.2024.200896] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 03/21/2024] [Revised: 08/18/2024] [Accepted: 10/16/2024] [Indexed: 11/19/2024]
Abstract
Oncolytic virotherapy shows promise as a cancer treatment approach; however, its systemic application is hindered by antibody neutralization. This issue can be overcome by using mesenchymal stem cells (MSCs) as carrier cells for oncolytic viruses (OVs). However, it remains elusive whether MSC source influences the antitumor effect. Here, we demonstrate that their source affects the migration ability and oncolytic activity of OV-loaded MSCs. Among human MSCs derived from different tissues, bone marrow-derived MSCs (BMMSCs) showed a high migration ability toward cancer cells in two- and three-dimensional MSC-cancer cell co-culture models. Comprehensive gene expression and Gene Ontology-based functional analyses suggested that genes involved in cell migration and cytokine response influence the cancer-specific tropism of BMMSCs. Furthermore, MSC origin affected the susceptibility to OVs, including cytotoxicity resistance and OV release from MSCs. MSC-mediated OV delivery significantly increased the viral spread and antitumor activity compared with delivery by OVs alone, and OV-loaded BMMSCs demonstrated the most potent antitumor effect among OV-loaded MSCs. Our results offer promising insights into cancer gene therapy with carrier cells and can help with the selection of an appropriate MSC source for MSC-based OV therapy.
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Affiliation(s)
- Makoto Sukegawa
- Department of Biochemistry and Molecular Biology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan
- Department of Gastrointestinal Surgery, Graduate School of Medicine, Nippon Medical School Musashikosugi Hospital, Kawasaki, Japan
- Department of Surgery, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan
| | - Yoshitaka Miyagawa
- Department of Biochemistry and Molecular Biology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan
| | - Seiji Kuroda
- Department of Biochemistry and Molecular Biology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan
| | - Yoshiyuki Yamazaki
- Department of Biochemistry and Molecular Biology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan
| | - Motoko Yamamoto
- Department of Biochemistry and Molecular Biology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan
| | - Kumi Adachi
- Department of Biochemistry and Molecular Biology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan
| | - Hirofumi Sato
- Department of Biochemistry and Molecular Biology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan
| | - Yuriko Sato
- Department of Biochemistry and Molecular Biology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan
| | - Nobuhiko Taniai
- Department of Gastrointestinal Surgery, Graduate School of Medicine, Nippon Medical School Musashikosugi Hospital, Kawasaki, Japan
| | - Hiroshi Yoshida
- Department of Surgery, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan
| | - Akihiro Umezawa
- Center for Regenerative Medicine, National Center for Child Health and Development Research Institute, Tokyo, Japan
| | - Mashito Sakai
- Department of Biochemistry and Molecular Biology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan
| | - Takashi Okada
- Division of Molecular and Medical Genetics, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
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Shamsul Kamal AA, Fakiruddin KS, Bobbo KA, Ling KH, Vidyadaran S, Abdullah S. Engineered Mesenchymal Stem Cells as Treatment for Cancers: Opportunities, Clinical Applications and Challenges. Malays J Med Sci 2024; 31:56-82. [PMID: 39416732 PMCID: PMC11477465 DOI: 10.21315/mjms2024.31.5.5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2024] [Accepted: 06/27/2024] [Indexed: 10/19/2024] Open
Abstract
The insufficient and unspecific target of classical chemotherapies often leads to therapy resistance and cancer recurrence. Over the past decades, discoveries about mesenchymal stem cell (MSC) biology have provided new potential approaches to improve cancer therapy. Researchers have utilised the multipotent, regenerative and immunosuppressive qualities of MSCs and tropisms towards inflammatory, hypoxic and malignant sites in various therapeutic applications. Although MSC-based therapies have generally been demonstrated safe, their effectiveness remains limited when these cells are used alone. However, through genetic engineering, researchers have proven that MSCs can be modified to have specialised delivery roles to increase their therapeutic efficacy in cancer treatment. They can be made to overexpress therapeutic proteins through viral or non-viral genetic modification, which enhances their innate properties. Nevertheless, these engineering strategies must be optimised to increase therapeutic efficacy and targeting effectiveness while minimising any loss of MSC function. This review underscores the cutting-edge methods for engineering MSCs, discusses their promise and the difficulties in translating them into clinical settings, and offers some prospective suggestions for the future on achieving their full therapeutic potential.
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Affiliation(s)
- Aishah Amirah Shamsul Kamal
- UPM-MAKNA Cancer Research Laboratory, Institute of Bioscience, Universiti Putra Malaysia, Selangor, Malaysia
- Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Selangor, Malaysia
| | - Kamal Shaik Fakiruddin
- Haematology Unit, Cancer Research Centre, Institute for Medical Research, National Institutes of Health, Ministry of Health Malaysia, Selangor, Malaysia
| | - Khadijat Abubakar Bobbo
- UPM-MAKNA Cancer Research Laboratory, Institute of Bioscience, Universiti Putra Malaysia, Selangor, Malaysia
- Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Selangor, Malaysia
| | - King Hwa Ling
- Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Selangor, Malaysia
- Malaysian Research Institute on Ageing, Universiti Putra Malaysia, Selangor, Malaysia
| | - Sharmili Vidyadaran
- Department of Pathology, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Selangor, Malaysia
| | - Syahril Abdullah
- UPM-MAKNA Cancer Research Laboratory, Institute of Bioscience, Universiti Putra Malaysia, Selangor, Malaysia
- Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Selangor, Malaysia
- Malaysia Genome and Vaccine Institute, National Institutes of Biotechnology Malaysia, Selangor, Malaysia
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Christopoulou ME, Aletras AJ, Papakonstantinou E, Stolz D, Skandalis SS. WISP1 and Macrophage Migration Inhibitory Factor in Respiratory Inflammation: Novel Insights and Therapeutic Potentials for Asthma and COPD. Int J Mol Sci 2024; 25:10049. [PMID: 39337534 PMCID: PMC11432718 DOI: 10.3390/ijms251810049] [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: 07/08/2024] [Revised: 09/12/2024] [Accepted: 09/13/2024] [Indexed: 09/30/2024] Open
Abstract
Recent advancements highlight the intricate interplay between the extracellular matrix (ECM) and immune responses, notably in respiratory diseases such as asthma and Chronic Obstructive Pulmonary Disease (COPD). The ECM, a dynamic structural framework within tissues, orches-trates a plethora of cellular processes, including immune cell behavior and tissue repair mecha-nisms. WNT1-inducible-signaling pathway protein 1 (WISP1), a key ECM regulator, controls immune cell behavior, cytokine production, and tissue repair by modulating integrins, PI3K, Akt, β-catenin, and mTOR signaling pathways. WISP1 also induces macrophage migration inhibitory factor (MIF) expression via Src kinases and epidermal growth factor receptor (EGFR) activation. MIF, through its wide range of activities, enhances inflammation and tissue restructuring. Rec-ognized for its versatile roles in regulating the immune system, MIF interacts with multiple immune components, such as the NLRP3 inflammasome, thereby sustaining inflammatory pro-cesses. The WISP1-MIF axis potentially unveils complex molecular mechanisms governing im-mune responses and inflammation. Understanding the intricate roles of WISP1 and MIF in the pathogenesis of chronic respiratory diseases such as asthma and COPD could lead to the identi-fication of novel targets for therapeutic intervention to alleviate disease severity and enhance patient outcomes.
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Affiliation(s)
- Maria-Elpida Christopoulou
- Laboratory of Biochemistry, Department of Chemistry, University of Patras, 26504 Patras, Greece
- Clinic of Pneumology, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
| | - Alexios J Aletras
- Laboratory of Biochemistry, Department of Chemistry, University of Patras, 26504 Patras, Greece
| | - Eleni Papakonstantinou
- Clinic of Pneumology, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
| | - Daiana Stolz
- Clinic of Pneumology, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
| | - Spyros S Skandalis
- Laboratory of Biochemistry, Department of Chemistry, University of Patras, 26504 Patras, Greece
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Cao T, Sun Q, Shi X, Lin X, Lin Q, Zhu J, Xu J, Cui D, Shi Y, Jing Y, Guo W. EAF2 Downregulation Recruits Tumor-associated Macrophages in Prostate Cancer through Upregulation of MIF. Biol Proced Online 2024; 26:21. [PMID: 38969982 PMCID: PMC11225222 DOI: 10.1186/s12575-024-00247-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2024] [Accepted: 06/11/2024] [Indexed: 07/07/2024] Open
Abstract
BACKGROUND The role of tumor inflammatory microenvironment in the advancement of cancer, particularly prostate cancer, is widely acknowledged. ELL-associated factor 2 (EAF2), a tumor suppressor that has been identified in the prostate, is often downregulated in prostate cancer. Earlier investigations have shown that mice with EAF2 gene knockout exhibited a substantial infiltration of inflammatory cells into the prostatic stroma. METHODS A cohort comprising 38 patients who had been diagnosed with prostate cancer and subsequently undergone radical prostatectomy (RP) was selected. These patients were pathologically graded according to the Gleason scoring system and divided into two groups. The purpose of this selection was to investigate the potential correlation between EAF2 and CD163 using immunohistochemistry (IHC) staining. Additionally, in vitro experimentation was conducted to verify the relationship between EAF2 expression, macrophage migration and polarization. RESULTS Our study demonstrated that in specimens of human prostate cancer, the expression of EAF2 was notably downregulated, and this decrease was inversely associated with the number of CD163-positive macrophages that infiltrated the cancerous tissue. Cell co-culture experiments revealed that the chemotactic effect of tumor cells towards macrophages was intensified and that macrophages differentiated into tumor-associated macrophages (TAMs) when EAF2 was knocked out. Additionally, the application of cytokine protein microarray showed that the expression of chemokine macrophage migration inhibitory factor (MIF) increased after EAF2 knockout. CONCLUSIONS Our findings suggested that EAF2 was involved in the infiltration of CD163-positive macrophages in prostate cancer via MIF.
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Affiliation(s)
- Tianyu Cao
- Department of Pathology, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
- Department of Urology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Qian Sun
- Department of Urology, Tongren Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Xiaoqin Shi
- Department of Pathology , Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Xiuke Lin
- Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen, China
| | - Qingyuan Lin
- Department of Pathology, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Jinchao Zhu
- Department of Pathology, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Junhao Xu
- Department of Urology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Di Cui
- Department of Urology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
| | - Youwei Shi
- Department of Urology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
- Department of Urology, Chongqing University Three Gorges Hospital, Chongqing University, Chongqing, China.
| | - Yifeng Jing
- Department of Urology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
| | - Wenhuan Guo
- Department of Pathology, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
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Taheri M, Tehrani HA, Dehghani S, Alibolandi M, Arefian E, Ramezani M. Nanotechnology and bioengineering approaches to improve the potency of mesenchymal stem cell as an off-the-shelf versatile tumor delivery vehicle. Med Res Rev 2024; 44:1596-1661. [PMID: 38299924 DOI: 10.1002/med.22023] [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: 12/08/2022] [Revised: 11/28/2023] [Accepted: 01/10/2024] [Indexed: 02/02/2024]
Abstract
Targeting actionable mutations in oncogene-driven cancers and the evolution of immuno-oncology are the two prominent revolutions that have influenced cancer treatment paradigms and caused the emergence of precision oncology. However, intertumoral and intratumoral heterogeneity are the main challenges in both fields of precision cancer treatment. In other words, finding a universal marker or pathway in patients suffering from a particular type of cancer is challenging. Therefore, targeting a single hallmark or pathway with a single targeted therapeutic will not be efficient for fighting against tumor heterogeneity. Mesenchymal stem cells (MSCs) possess favorable characteristics for cellular therapy, including their hypoimmune nature, inherent tumor-tropism property, straightforward isolation, and multilineage differentiation potential. MSCs can be loaded with various chemotherapeutics and oncolytic viruses. The combination of these intrinsic features with the possibility of genetic manipulation makes them a versatile tumor delivery vehicle that can be used for in vivo selective tumor delivery of various chemotherapeutic and biological therapeutics. MSCs can be used as biofactory for the local production of chemical or biological anticancer agents at the tumor site. MSC-mediated immunotherapy could facilitate the sustained release of immunotherapeutic agents specifically at the tumor site, and allow for the achievement of therapeutic concentrations without the need for repetitive systemic administration of high therapeutic doses. Despite the enthusiasm evoked by preclinical studies that used MSC in various cancer therapy approaches, the translation of MSCs into clinical applications has faced serious challenges. This manuscript, with a critical viewpoint, reviewed the preclinical and clinical studies that have evaluated MSCs as a selective tumor delivery tool in various cancer therapy approaches, including gene therapy, immunotherapy, and chemotherapy. Then, the novel nanotechnology and bioengineering approaches that can improve the potency of MSC for tumor targeting and overcoming challenges related to their low localization at the tumor sites are discussed.
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Affiliation(s)
- Mojtaba Taheri
- Department of Medical Biotechnology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Hossein Abdul Tehrani
- Department of Medical Biotechnology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Sadegh Dehghani
- Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mona Alibolandi
- Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Pharmaceutical Biotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Ehsan Arefian
- Department of Microbiology, School of Biology, College of Science, University of Tehran, Tehran, Iran
- Pediatric Cell and Gene Therapy Research Center, Gene, Cell & Tissue Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Ramezani
- Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Pharmaceutical Biotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
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Švajger U, Kamenšek U. Interleukins and interferons in mesenchymal stromal stem cell-based gene therapy of cancer. Cytokine Growth Factor Rev 2024; 77:76-90. [PMID: 38508954 DOI: 10.1016/j.cytogfr.2024.03.002] [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: 02/05/2024] [Revised: 03/07/2024] [Accepted: 03/11/2024] [Indexed: 03/22/2024]
Abstract
The tumor microenvironment is importantly shaped by various cytokines, where interleukins (ILs) and interferons (IFNs) shape the balance of immune activity within tumor niche and associated lymphoid organs. Their importance in activation and tuning of both innate and adaptive immune responses prompted their use in several clinical trials, albeit with limited therapeutic efficacy and risk of toxicity due to systemic administration. Increasing preclinical evidence suggests that local delivery of ILs and IFNs could significantly increase their effectiveness, while simultaneously attenuate the known side effects and issues related to their biological activity. A prominent way to achieve this is to use cell-based delivery vehicles. For this purpose, mesenchymal stromal stem cells (MSCs) are considered an almost ideal candidate. Namely, MSCs can be obtained in large quantities and from obtainable sources (e.g. umbilical cord or adipose tissue), their ex vivo expansion is relatively straightforward compared to other cell types and they possess very low immunogenicity making them suitable for allogeneic use. Importantly, MSCs have shown an intrinsic capacity to respond to tumor-directed chemotaxis. This review provides a focused and detailed discussion on MSC-based gene therapy using ILs and IFNs, engineering techniques and insights on potential future advancements.
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Affiliation(s)
- Urban Švajger
- Slovenian Institute for Transfusion Medicine, Department for Therapeutic Services, Šlajmerjeva Ulica 6, Ljubljana SI-1000, Slovenia; Faculty of Pharmacy, University of Ljubljana, Aškerčeva Cesta 7, Ljubljana SI-1000, Slovenia.
| | - Urška Kamenšek
- Department of Experimental Oncology, Institute of Oncology Ljubljana, Zaloška Cesta 2, Ljubljana SI-1000, Slovenia; Biotechnical Faculty, University of Ljubljana, Jamnikarjeva Ulica 101, Ljubljana SI-1000, Slovenia
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11
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Fey RM, Nichols RA, Tran TT, Vandenbark AA, Kulkarni RP. MIF and CD74 as Emerging Biomarkers for Immune Checkpoint Blockade Therapy. Cancers (Basel) 2024; 16:1773. [PMID: 38730725 PMCID: PMC11082995 DOI: 10.3390/cancers16091773] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Revised: 04/18/2024] [Accepted: 04/26/2024] [Indexed: 05/13/2024] Open
Abstract
Immune checkpoint blockade (ICB) therapy is used to treat a wide range of cancers; however, some patients are at risk of developing treatment resistance and/or immune-related adverse events (irAEs). Thus, there is a great need for the identification of reliable predictive biomarkers for response and toxicity. The cytokine MIF (macrophage migration inhibitory factor) and its cognate receptor CD74 are intimately connected with cancer progression and have previously been proposed as prognostic biomarkers for patient outcome in various cancers, including solid tumors such as malignant melanoma. Here, we assess their potential as predictive biomarkers for response to ICB therapy and irAE development. We provide a brief overview of their function and roles in the context of cancer and autoimmune disease. We also review the evidence showing that MIF and CD74 may be of use as predictive biomarkers of patient response to ICB therapy and irAE development. We also highlight that careful consideration is required when assessing the potential of serum MIF levels as a biomarker due to its reported circadian expression in human plasma. Finally, we suggest future directions for the establishment of MIF and CD74 as predictive biomarkers for ICB therapy and irAE development to guide further research in this field.
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Affiliation(s)
- Rosalyn M. Fey
- Department of Dermatology, Oregon Health & Science University, Portland, OR 97239, USA (R.A.N.)
| | - Rebecca A. Nichols
- Department of Dermatology, Oregon Health & Science University, Portland, OR 97239, USA (R.A.N.)
| | - Thuy T. Tran
- Yale Cancer Center, Yale University School of Medicine, New Haven, CT 06510, USA
| | - Arthur A. Vandenbark
- Neuroimmunology Research, R&D-31, VA Portland Health Care System, Portland, OR 97239, USA
- Department of Neurology, Oregon Health & Science University, Portland, OR 97239, USA
- Department of Molecular Microbiology and Immunology, Oregon Health & Science University, Portland, OR 97239, USA
| | - Rajan P. Kulkarni
- Department of Dermatology, Oregon Health & Science University, Portland, OR 97239, USA (R.A.N.)
- Cancer Early Detection Advanced Research Center (CEDAR), Portland, OR 97239, USA
- Knight Cancer Institute, Oregon Health and Science University, Portland, OR 97239, USA
- Operative Care Division, U.S. Department of Veterans Affairs Portland Health Care System, Portland, OR 97239, USA
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12
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Karami Fath M, Bagherzadeh Torbati SM, Saqagandomabadi V, Yousefi Afshar O, Khalilzad M, Abedi S, Moliani A, Daneshdoust D, Barati G. The therapeutic effect of MSCs and their extracellular vesicles on neuroblastoma. PROGRESS IN BIOPHYSICS AND MOLECULAR BIOLOGY 2024; 187:51-60. [PMID: 38373516 DOI: 10.1016/j.pbiomolbio.2024.02.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/29/2023] [Revised: 10/04/2023] [Accepted: 02/16/2024] [Indexed: 02/21/2024]
Abstract
Neuroblastoma is a common inflammatory-related cancer during infancy. Standard treatment modalities including surgical interventions, high-dose chemotherapy, radiotherapy, and immunotherapy are not able to increase survival rate and reduce tumor relapse in high-risk patients. Mesenchymal stem cells (MSCs) are known for their tumor-targeting and immunomodulating properties. MSCs could be engineered to express anticancer agents (i.e., growth factors, cytokines, pro-apoptotic agents) or deliver oncolytic viruses in the tumor microenvironment. As many functions of MSCs are mediated through their secretome, researchers have tried to use extracellular vesicles (EVs) from MSCs for targeted therapy of neuroblastoma. Here, we reviewed the studies to figure out whether the use of MSCs could be worthwhile in neuroblastoma therapy or not. Native MSCs have shown a promoting or inhibiting role in cancers including neuroblastoma. Therefore, MSCs are proposed as a vehicle to deliver anticancer agents such as oncolytic viruses to the neuroblastoma tumor microenvironment. Although modified MSCs or their EVs have been shown to suppress the tumorigenesis of neuroblastoma, further pre-clinical and clinical studies are required to come to a conclusion.
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Affiliation(s)
- Mohsen Karami Fath
- Department of Cellular and Molecular Biology, Faculty of Biological Sciences, Kharazmi University, Tehran, Iran
| | | | - Vahid Saqagandomabadi
- Department of Biomedicine, Neuroscience and Advanced Diagnostics, University of Palermo, Palermo, Italy
| | | | - Mohammad Khalilzad
- Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Sara Abedi
- Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran
| | - Afshin Moliani
- Isfahan Medical Students Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Danyal Daneshdoust
- Faculty of Medicine, Babol University of Medical Sciences, Mazandaran, Iran
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13
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Lin S, Li D, Yang Y, Yu M, Zhao R, Li J, Peng L. Single-cell RNA-Seq Elucidates the Crosstalk Between Cancer Stem Cells and the Tumor Microenvironment in Hepatocellular Carcinoma. J Cancer 2024; 15:1093-1109. [PMID: 38230205 PMCID: PMC10788724 DOI: 10.7150/jca.92185] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2023] [Accepted: 12/16/2023] [Indexed: 01/18/2024] Open
Abstract
Background: The challenge of systemic treatment for hepatocellular carcinoma (HCC) stems from the development of drug resistance, primarily driven by the interplay between cancer stem cells (CSCs) and the tumor microenvironment (TME). However, there is a notable dearth of comprehensive research investigating the crosstalk between CSCs and stromal cells or immune cells within the TME of HCC. Methods: We procured single-cell RNA sequencing (scRNA-Seq) data from 16 patients diagnosed with HCC. Employing meticulous data quality control and cell annotation procedures, we delineated distinct CSCs subtypes and performed multi-omics analyses encompassing metabolic activity, cell communication, and cell trajectory. These analyses shed light on the potential molecular mechanisms governing the interaction between CSCs and the TME, while also identifying CSCs' developmental genes. By combining these developmental genes, we employed machine learning algorithms and RT-qPCR to construct and validate a prognostic risk model for HCC. Results: We successfully identified CSCs subtypes residing within malignant cells. Through meticulous enrichment analysis and assessment of metabolic activity, we discovered anomalous metabolic patterns within the CSCs microenvironment, including hypoxia and glucose deprivation. Moreover, CSCs exhibited aberrant activity in signaling pathways associated with lipid metabolism. Furthermore, our investigations into cell communication unveiled that CSCs possess the capacity to modulate stromal cells and immune cells through the secretion of MIF or MDK, consequently exerting regulatory control over the TME. Finally, through cell trajectory analysis, we found developmental genes of CSCs. Leveraging these genes, we successfully developed and validated a prognostic risk model (APCS, ADH4, FTH1, and HSPB1) with machine learning and RT-qPCR. Conclusions: By means of single-cell multi-omics analysis, this study offers valuable insights into the potential molecular mechanisms governing the interaction between CSCs and the TME, elucidating the pivotal role CSCs play within the TME. Additionally, we have successfully established a comprehensive clinical prognostic model through bulk RNA-Seq data.
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Affiliation(s)
- Sen Lin
- The Fourth Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Danfei Li
- The Fourth Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yan Yang
- The Fourth Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Mengjiao Yu
- The Fourth Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Ruiqi Zhao
- The Fourth Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Jinghao Li
- Department of Traditional Chinese Medicine, The Sixth Affiliated Hospital, South China University of Technology, Foshan, China
| | - Lisheng Peng
- Department of Hepatology, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, China
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14
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Rosu A, Ghaemi B, Bulte JW, Shakeri-Zadeh A. Tumor-tropic Trojan horses: Using mesenchymal stem cells as cellular nanotheranostics. Theranostics 2024; 14:571-591. [PMID: 38169524 PMCID: PMC10758060 DOI: 10.7150/thno.90187] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2023] [Accepted: 11/21/2023] [Indexed: 01/05/2024] Open
Abstract
Various classes of nanotheranostics have been developed for enhanced tumor imaging and therapy. However, key limitations for a successful use of nanotheranostics include their targeting specificity with limited off-site tissue accumulation as well as their distribution and prolonged retention throughout the entire tumor. Due to their inherent tumor-tropic properties, the use of mesenchymal stem cells (MSCs) as a "Trojan horse" has recently been proposed to deliver nanotheranostics more effectively. This review discusses the current status of "cellular nanotheranostics" for combined (multimodal) imaging and therapy in preclinical cancer models. Emphasis is placed on the limited knowledge of the signaling pathways and molecular mechanisms of MSC tumor-tropism, and how such information may be exploited to engineer MSCs in order to further improve tumor homing and nanotheranostic delivery using image-guided procedures.
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Affiliation(s)
| | | | | | - Ali Shakeri-Zadeh
- The Russell H. Morgan Department of Radiology and Radiological Science, Division of MR Research and Cellular Imaging Section and Vascular Biology Program, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
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15
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Lee J, Jang J, Cha SR, Lee SB, Hong SH, Bae HS, Lee YJ, Yang SR. Recombinant Human Bone Morphogenetic Protein-2 Priming of Mesenchymal Stem Cells Ameliorate Acute Lung Injury by Inducing Regulatory T Cells. Immune Netw 2023; 23:e48. [PMID: 38188599 PMCID: PMC10767548 DOI: 10.4110/in.2023.23.e48] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Revised: 12/11/2023] [Accepted: 12/11/2023] [Indexed: 01/09/2024] Open
Abstract
Mesenchymal stromal/stem cells (MSCs) possess immunoregulatory properties and their regulatory functions represent a potential therapy for acute lung injury (ALI). However, uncertainties remain with respect to defining MSCs-derived immunomodulatory pathways. Therefore, this study aimed to investigate the mechanism underlying the enhanced effect of human recombinant bone morphogenic protein-2 (rhBMP-2) primed ES-MSCs (MSCBMP2) in promoting Tregs in ALI mice. MSC were preconditioned with 100 ng/ml rhBMP-2 for 24 h, and then administrated to mice by intravenous injection after intratracheal injection of 1 mg/kg LPS. Treating MSCs with rhBMP-2 significantly increased cellular proliferation and migration, and cytokines array reveled that cytokines release by MSCBMP2 were associated with migration and growth. MSCBMP2 ameliorated LPS induced lung injury and reduced myeloperoxidase activity and permeability in mice exposed to LPS. Levels of inducible nitric oxide synthase were decreased while levels of total glutathione and superoxide dismutase activity were further increased via inhibition of phosphorylated STAT1 in ALI mice treated with MSCBMP2. MSCBMP2 treatment increased the protein level of IDO1, indicating an increase in Treg cells, and Foxp3+CD25+ Treg of CD4+ cells were further increased in ALI mice treated with MSCBMP2. In co-culture assays with MSCs and RAW264.7 cells, the protein level of IDO1 was further induced in MSCBMP2. Additionally, cytokine release of IL-10 was enhanced while both IL-6 and TNF-α were further inhibited. In conclusion, these findings suggest that MSCBMP2 has therapeutic potential to reduce massive inflammation of respiratory diseases by promoting Treg cells.
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Affiliation(s)
- Jooyeon Lee
- Department of Thoracic and Cardiovascular Surgery, School of Medicine, Kangwon National University, Chuncheon 24341, Korea
| | - Jimin Jang
- Department of Thoracic and Cardiovascular Surgery, School of Medicine, Kangwon National University, Chuncheon 24341, Korea
| | - Sang-Ryul Cha
- Department of Thoracic and Cardiovascular Surgery, School of Medicine, Kangwon National University, Chuncheon 24341, Korea
| | - Se Bi Lee
- Department of Thoracic and Cardiovascular Surgery, School of Medicine, Kangwon National University, Chuncheon 24341, Korea
| | - Seok-Ho Hong
- Department of Internal Medicine, School of Medicine, Kangwon National University, Chuncheon 24341, Korea
| | - Han-Sol Bae
- Cellular Therapeutics Team, Daewoong Pharmaceutical, Yongin 17028, Korea
| | - Young Jin Lee
- Cellular Therapeutics Team, Daewoong Pharmaceutical, Yongin 17028, Korea
| | - Se-Ran Yang
- Department of Thoracic and Cardiovascular Surgery, School of Medicine, Kangwon National University, Chuncheon 24341, Korea
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16
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Shen K, Ke S, Chen B, Gao W. Integrated analysis of single-cell and bulk RNA-sequencing reveals the poor prognostic value of ABCA1 in gastric adenocarcinoma. Discov Oncol 2023; 14:189. [PMID: 37874419 PMCID: PMC10597929 DOI: 10.1007/s12672-023-00807-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Accepted: 10/17/2023] [Indexed: 10/25/2023] Open
Abstract
PURPOSE ATP-binding cassette A1 (ABCA1) is a potential prognostic marker for various tumor types. However, the biological effects and prognostic value of ABCA1 in gastric adenocarcinoma (GAC) remain unknown. METHODS GAC-associated single-cell RNA and bulk RNA-sequencing (bulk-seq) data were obtained from the Gene Expression Omnibus and The Cancer Genome Atlas databases, respectively. The differential expression of ABCA1 between GAC and normal gastric tissues was analyzed based on the bulk-seq data. Additionally, the relationship between ABCA1 expression and various clinicopathological features was explored. Furthermore, Kaplan-Meier survival and Cox regression analyses were performed to establish the prognostic value of ABCA1. The relationships between ABCA1 expression and anti-tumor drug sensitivity and immune checkpoints were also explored. Finally, the biological functions of ABCA1 were evaluated at the single-cell level, and in vitro studies were performed to assess the effects of ABCA1 on GAC cell proliferation and invasion. RESULTS ABCA1 expression is significantly elevated in GAC samples compared with that in normal gastric tissues. Clinical features and survival analysis revealed that high ABCA1 expression is associated with poor clinical phenotypes and prognosis, whereas Cox analysis identified ABCA1 as an independent risk factor for patients with GAC. Furthermore, high ABCA1 expression suppresses sensitivity to various chemotherapeutic drugs, including cisplatin and mitomycin, while upregulating immune checkpoints. ABCA1-overexpressing macrophages are associated with adverse clinical phenotypes in GAC and express unique ligand-receptor pairs that drive GAC progression. In vitro, ABCA1-knockdown GAC cells exhibit significantly inhibited proliferative and invasive properties. CONCLUSION High ABCA1 expression promotes an adverse immune microenvironment and low survival rates in patients with GAC. Furthermore, ABCA1 and ABCA1-producing macrophages may serve as novel molecular targets in GAC treatment.
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Affiliation(s)
- Kaiyu Shen
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Shuaiyi Ke
- Department of Internal Medicine, Affiliated Xianju's Hospital, XianJu People's Hospital, Zhejiang Southeast Campus of Zhejiang Provincial People's Hospital, Hangzhou Medical College, XianJu, 317399, China
| | - Binyu Chen
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Wencang Gao
- Department of Oncology, the Second Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou, 310005, China.
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17
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Xiao K, Liu C, Wang H, Hou F, Shi Y, Qian ZR, Zhang H, Deng DYB, Xie L. Umbilical cord mesenchymal stem cells overexpressing CXCR7 facilitate treatment of ARDS-associated pulmonary fibrosis via inhibition of Notch/Jag1 mediated by the Wnt/β-catenin pathway. Biomed Pharmacother 2023; 165:115124. [PMID: 37454589 DOI: 10.1016/j.biopha.2023.115124] [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: 05/12/2023] [Revised: 06/29/2023] [Accepted: 07/02/2023] [Indexed: 07/18/2023] Open
Abstract
The therapeutic efficacy of umbilical cord mesenchymal stem cells (UCMSCs) in acute respiratory distress syndrome (ARDS) is mainly limited by the efficiency of homing of UCMSCs toward tissue damage. C-X-C chemokine receptor type 7 (CXCR7), which is involved in the mobilization of UCMSCs, is only expressed on the surface of a small proportion of UCMSCs. This study examined whether overexpression of CXCR7 in UCMSCs (UCMSCsOE-CXCR7) could improve their homing efficiency, and therefore, improve their effectiveness in fibrosis repair at the site of lung injury caused by ARDS. A lentiviral vector expressing CXCR7 was built and then transfect into UCMSCs. The impacts of CXCR7 expression of the proliferationand homing of UCMSCs were examined in a lipopolysaccharide-induced ARDS mouse model. The potential role and underlying mechanism of CXCR7 were examined by performing scratch assays, transwell assays, and immunoassays. The therapeutic dose and treatment time of UCMSCsOE-CXCR7 were directly proportional to their therapeutic effect on lung injury. In addition, overexpression of CXCR7 increased SDF-1-induced proliferation and migration of lung epithelial cells (Base-2b cells), and upregulation of CXCR7 inhibited α-SMA expression, suggesting that CXCR7 may have a role in alleviating pulmonary fibrosis caused by ARDS. Overexpression of CXCR7 in UCMSCs may improve their therapeutic effect of acute lung injury mouse, The mechanism of fibrosis repair by CXCR7 is inhibition of Jag1 via suppression of the Wnt/β-catenin pathway under the chemotaxis of SDF-1.
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Affiliation(s)
- Kun Xiao
- College of Pulmonary & Critical Care Medicine, Chinese PLA General Hospital, Beijing 100853, China
| | - Chang Liu
- College of Pulmonary & Critical Care Medicine, Chinese PLA General Hospital, Beijing 100853, China; School of medicine Nankai university, Tianjin 300071, China
| | - Heming Wang
- Hainan Key Laboratory for Sustainable Utilization of Tropical Bioresource, Hainan University, Haikou 570228, China
| | - Fei Hou
- College of Pulmonary & Critical Care Medicine, Chinese PLA General Hospital, Beijing 100853, China
| | - Yinghan Shi
- College of Pulmonary & Critical Care Medicine, Chinese PLA General Hospital, Beijing 100853, China
| | - Zhi Rong Qian
- Department of Scientific Research Center, The Seventh Affiliated Hospital of Sun YatSen University, Shenzhen 518106, China; Department of Radiation Oncology, Fujian Medical University Union Hospital, Fuzhou 350001, China
| | - Hao Zhang
- Institute of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou, China.
| | - David Y B Deng
- Department of Scientific Research Center, The Seventh Affiliated Hospital of Sun YatSen University, Shenzhen 518106, China.
| | - Lixin Xie
- College of Pulmonary & Critical Care Medicine, Chinese PLA General Hospital, Beijing 100853, China.
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18
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Slama Y, Ah-Pine F, Khettab M, Arcambal A, Begue M, Dutheil F, Gasque P. The Dual Role of Mesenchymal Stem Cells in Cancer Pathophysiology: Pro-Tumorigenic Effects versus Therapeutic Potential. Int J Mol Sci 2023; 24:13511. [PMID: 37686315 PMCID: PMC10488262 DOI: 10.3390/ijms241713511] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2023] [Revised: 08/29/2023] [Accepted: 08/30/2023] [Indexed: 09/10/2023] Open
Abstract
Mesenchymal stem/stromal cells (MSCs) are multipotent cells involved in numerous physiological events, including organogenesis, the maintenance of tissue homeostasis, regeneration, or tissue repair. MSCs are increasingly recognized as playing a major, dual, and complex role in cancer pathophysiology through their ability to limit or promote tumor progression. Indeed, these cells are known to interact with the tumor microenvironment, modulate the behavior of tumor cells, influence their functions, and promote distant metastasis formation through the secretion of mediators, the regulation of cell-cell interactions, and the modulation of the immune response. This dynamic network can lead to the establishment of immunoprivileged tissue niches or the formation of new tumors through the proliferation/differentiation of MSCs into cancer-associated fibroblasts as well as cancer stem cells. However, MSCs exhibit also therapeutic effects including anti-tumor, anti-proliferative, anti-inflammatory, or anti-oxidative effects. The therapeutic interest in MSCs is currently growing, mainly due to their ability to selectively migrate and penetrate tumor sites, which would make them relevant as vectors for advanced therapies. Therefore, this review aims to provide an overview of the double-edged sword implications of MSCs in tumor processes. The therapeutic potential of MSCs will be reviewed in melanoma and lung cancers.
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Affiliation(s)
- Youssef Slama
- Unité de Recherche Études Pharmaco-Immunologiques (EPI), Université de La Réunion, CHU de La Réunion, Allée des Topazes, 97400 Saint-Denis, La Réunion, France; (F.A.-P.); (M.K.); (P.G.)
- Service de Radiothérapie, Clinique Sainte-Clotilde, Groupe Clinifutur, 127 Route de Bois de Nèfles, 97400 Saint-Denis, La Réunion, France; (M.B.); (F.D.)
- Laboratoire Interdisciplinaire de Recherche en Santé (LIRS), RunResearch, Clinique Sainte-Clotilde, 127 Route de Bois de Nèfles, 97400 Saint-Denis, La Réunion, France;
| | - Franck Ah-Pine
- Unité de Recherche Études Pharmaco-Immunologiques (EPI), Université de La Réunion, CHU de La Réunion, Allée des Topazes, 97400 Saint-Denis, La Réunion, France; (F.A.-P.); (M.K.); (P.G.)
- Service d’Anatomie et Cytologie Pathologiques, CHU de La Réunion sites SUD—Saint-Pierre, Avenue François Mitterrand, 97448 Saint-Pierre Cedex, La Réunion, France
| | - Mohamed Khettab
- Unité de Recherche Études Pharmaco-Immunologiques (EPI), Université de La Réunion, CHU de La Réunion, Allée des Topazes, 97400 Saint-Denis, La Réunion, France; (F.A.-P.); (M.K.); (P.G.)
- Service d’Oncologie Médicale, CHU de La Réunion sites SUD—Saint-Pierre, Avenue François Mitterrand, 97448 Saint-Pierre Cedex, La Réunion, France
| | - Angelique Arcambal
- Laboratoire Interdisciplinaire de Recherche en Santé (LIRS), RunResearch, Clinique Sainte-Clotilde, 127 Route de Bois de Nèfles, 97400 Saint-Denis, La Réunion, France;
| | - Mickael Begue
- Service de Radiothérapie, Clinique Sainte-Clotilde, Groupe Clinifutur, 127 Route de Bois de Nèfles, 97400 Saint-Denis, La Réunion, France; (M.B.); (F.D.)
- Laboratoire Interdisciplinaire de Recherche en Santé (LIRS), RunResearch, Clinique Sainte-Clotilde, 127 Route de Bois de Nèfles, 97400 Saint-Denis, La Réunion, France;
| | - Fabien Dutheil
- Service de Radiothérapie, Clinique Sainte-Clotilde, Groupe Clinifutur, 127 Route de Bois de Nèfles, 97400 Saint-Denis, La Réunion, France; (M.B.); (F.D.)
- Laboratoire Interdisciplinaire de Recherche en Santé (LIRS), RunResearch, Clinique Sainte-Clotilde, 127 Route de Bois de Nèfles, 97400 Saint-Denis, La Réunion, France;
| | - Philippe Gasque
- Unité de Recherche Études Pharmaco-Immunologiques (EPI), Université de La Réunion, CHU de La Réunion, Allée des Topazes, 97400 Saint-Denis, La Réunion, France; (F.A.-P.); (M.K.); (P.G.)
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19
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TomyTomcy A, Sindhu ER. Mesenchymal stem cells- an excellent therapeutic agent for cancer. Asia Pac J Clin Oncol 2023. [PMID: 37190944 DOI: 10.1111/ajco.13969] [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: 01/13/2023] [Revised: 03/27/2023] [Accepted: 05/06/2023] [Indexed: 05/17/2023]
Abstract
Despite rapid advancement in research of diagnostics and therapeutics, cancer is the most dangerous disease-causing millions of deaths worldwide. Many of the conventional anticancer therapies can even lead to developing resistance to therapy and recurrence of cancer. To find a new, alternative treatment strategy for a variety of ailments scientists and researchers have turned their attention to cell therapies and regenerative medicine. Stem cells are now being researched for their extensive potential application in therapy for several incurable illnesses including cancer. One of the most often employed cell types for regenerative medicine is mesenchymal stem cells. Mesenchymal stem cells (MSCs) are considered a promising source of stem cells in personalized cell-based therapies. The inherent tumor tropic and immune-modulatory properties of MSCs can be used to target cancer cells. This review aims to focus on the anticancer properties of MSCs and their effect on different signaling pathways. Later on, we discuss the advantages of engineered MSCs over non-engineered MSCsin cancer therapy.
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Affiliation(s)
- Anjilikal TomyTomcy
- Department of Human Genetics and Molecular Medicine, Central University of Punjab, Bathinda, India
| | - Edakkadath Raghavan Sindhu
- Division of Biochemistry, Department of Clinical Laboratory Services and Translational Research, Malabar Cancer Centre, Kannur, Kerala, India
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20
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Karami Fath M, Moayedi Banan Z, Barati R, Mohammadrezakhani O, Ghaderi A, Hatami A, Ghiabi S, Zeidi N, Asgari K, Payandeh Z, Barati G. Recent advancements to engineer mesenchymal stem cells and their extracellular vesicles for targeting and destroying tumors. PROGRESS IN BIOPHYSICS AND MOLECULAR BIOLOGY 2023; 178:1-16. [PMID: 36781149 DOI: 10.1016/j.pbiomolbio.2023.02.001] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Revised: 01/24/2023] [Accepted: 02/10/2023] [Indexed: 02/13/2023]
Abstract
Mesenchymal stem cells (MSCs) have the ability to migrate into tumor sites and release growth factors to modulate the tumor microenvironment. MSC therapy have shown a dual role in cancers, promoting or inhibiting. However, MSCs could be used as a carrier of anticancer agents for targeted tumor therapy. Recent technical improvements also allow engineering MSCs to improve tumor-targeting properties, protect anticancer agents, and decrease the cytotoxicity of drugs. While some of MSC functions are mediated through their secretome, MSCs-derived extracellular vesicles (EVs) are also proposed as a possible viechle for cancer therapy. EVs allow efficient loading of anticancer agents and have an intrinsic ability to target tumor cells, making them suitable for targeted therapy of tumors. In addition, the specificity and selectivity of EVs to the tumor sites could be enhanced by surface modification. In this review, we addressed the current approaches used for engineering MSCs and EVs to effectively target tumor sites and deliver anticancer agents.
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Affiliation(s)
- Mohsen Karami Fath
- Department of Cellular and Molecular Biology, Faculty of Biological Sciences, Kharazmi University, Tehran, Iran
| | - Zahra Moayedi Banan
- School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Reza Barati
- School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Omid Mohammadrezakhani
- Faculty of Pharmacy, Ramsar Campus, Mazandaran University of Medical Sciences, Sari, Iran
| | - Aliasghar Ghaderi
- Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Ali Hatami
- School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Shamim Ghiabi
- Department of Medical Chemistry, Faculty of Pharmacy, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Nazanin Zeidi
- Division of Pharmaceutical Science, Long Island University, Brooklyn, NY, USA
| | - Katayoon Asgari
- Department of Clinical Biochemistry, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Zahra Payandeh
- Department Medical Biochemistry and Biophysics, Division Medical Inflammation Research, Karolinska Institute, Stockholm, Sweden
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21
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Garg A, Khan S, Luu N, Nicholas DJ, Day V, King AL, Fear J, Lalor PF, Newsome PN. TGFβ 1 priming enhances CXCR3-mediated mesenchymal stromal cell engraftment to the liver and enhances anti-inflammatory efficacy. J Cell Mol Med 2023; 27:864-878. [PMID: 36824012 PMCID: PMC10002976 DOI: 10.1111/jcmm.17698] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Revised: 02/07/2023] [Accepted: 02/11/2023] [Indexed: 02/25/2023] Open
Abstract
The immunomodulatory characteristics of mesenchymal stromal cells (MSC) confers them with potential therapeutic value in the treatment of inflammatory/immune-mediated conditions. Previous studies have reported only modest beneficial effects in murine models of liver injury. In our study we explored the role of MSC priming to enhance their effectiveness. Herein we demonstrate that stimulation of human MSC with cytokine TGβ1 enhances their homing and engraftment to human and murine hepatic sinusoidal endothelium in vivo and in vitro, which was mediated by increased expression of CXCR3. Alongside improved hepatic homing there was also greater reduction in liver inflammation and necrosis, with no adverse effects, in the CCL4 murine model of liver injury treated with primed MSC. Priming of MSCs with TGFβ1 is a novel strategy to improve the anti-inflammatory efficacy of MSCs.
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Affiliation(s)
- Abhilok Garg
- National Institute for Health Research Birmingham Biomedical Research Centre, University Hospitals Birmingham NHS Foundation Trust, University of Birmingham, Birmingham, UK.,Centre for Liver & Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
| | - Sheeba Khan
- National Institute for Health Research Birmingham Biomedical Research Centre, University Hospitals Birmingham NHS Foundation Trust, University of Birmingham, Birmingham, UK.,Centre for Liver & Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
| | - N Luu
- National Institute for Health Research Birmingham Biomedical Research Centre, University Hospitals Birmingham NHS Foundation Trust, University of Birmingham, Birmingham, UK.,Centre for Liver & Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
| | - Davies J Nicholas
- National Institute for Health Research Birmingham Biomedical Research Centre, University Hospitals Birmingham NHS Foundation Trust, University of Birmingham, Birmingham, UK.,Centre for Liver & Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
| | - Victoria Day
- National Institute for Health Research Birmingham Biomedical Research Centre, University Hospitals Birmingham NHS Foundation Trust, University of Birmingham, Birmingham, UK.,Centre for Liver & Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
| | - Andrew L King
- National Institute for Health Research Birmingham Biomedical Research Centre, University Hospitals Birmingham NHS Foundation Trust, University of Birmingham, Birmingham, UK.,Centre for Liver & Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
| | - Janine Fear
- National Institute for Health Research Birmingham Biomedical Research Centre, University Hospitals Birmingham NHS Foundation Trust, University of Birmingham, Birmingham, UK.,Centre for Liver & Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
| | - Patricia F Lalor
- National Institute for Health Research Birmingham Biomedical Research Centre, University Hospitals Birmingham NHS Foundation Trust, University of Birmingham, Birmingham, UK.,Centre for Liver & Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
| | - Philip N Newsome
- National Institute for Health Research Birmingham Biomedical Research Centre, University Hospitals Birmingham NHS Foundation Trust, University of Birmingham, Birmingham, UK.,Centre for Liver & Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK.,Liver Unit, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
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22
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The Role of Mesenchymal Stem Cells and Exosomes in Tumor Development and Targeted Antitumor Therapies. Stem Cells Int 2023; 2023:7059289. [PMID: 36824409 PMCID: PMC9943627 DOI: 10.1155/2023/7059289] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2022] [Revised: 01/17/2023] [Accepted: 02/03/2023] [Indexed: 02/17/2023] Open
Abstract
Mesenchymal stem cells (MSCs) can be isolated from various tissues in adults and differentiated into cells of the osteoblasts, adipocytes, chondrocytes, and myocytes. Recruitments of MSCs towards tumors have a crucial contribution to tumor development. However, the role of MSCs in the tumor microenvironment is uncertain. In addition, due to its tropism to the tumor and low immunogenic properties, more and more pieces of evidence indicate that MSCs may be an ideal carrier for antitumor biologics such as cytokines, chemotherapeutic agents, and oncolytic viruses. Here, we review the existing knowledge on the anti- and protumorigenic effect of MSCs and their extracellular vesicles and exosomes, the role of MSCs, and their extracellular vesicles and exosomes as antitumor vectors.
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23
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Rivera-Cruz CM, Figueiredo ML. Evaluation of human adipose-derived mesenchymal stromal cell Toll-like receptor priming and effects on interaction with prostate cancer cells. Cytotherapy 2023; 25:33-45. [PMID: 36257875 DOI: 10.1016/j.jcyt.2022.09.009] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Revised: 07/20/2022] [Accepted: 09/26/2022] [Indexed: 01/06/2023]
Abstract
BACKGROUND AIMS Mesenchymal stromal cells (MSCs) are a multipotent cell population of clinical interest because of their ability to migrate to injury and tumor sites, where they may participate in tissue repair and modulation of immune response. Although the processes regulating MSC function are incompletely understood, it has been shown that stimulation of Toll-like receptors (TLRs) can alter MSC activity. More specifically, it has been reported that human bone marrow-derived MSCs can be "polarized" by TLR priming into contrasting immunomodulatory functions, with opposite (supportive or suppressive) roles in tumor progression and inflammation. Adipose-derived MSCs (ASCs) represent a promising alternative MSC subpopulation for therapeutic development because of their relative ease of isolation and higher abundance compared with their bone marrow-derived counterparts; however, the polarization of ASCs remains unreported. METHODS In this study, we evaluated the phenotypic and functional consequences of short-term, low-level stimulation of ASCs with TLR3 and TLR4 agonists. RESULTS In these assays, we identified transient gene expression changes resembling the reported pro-inflammatory and anti-inflammatory MSC phenotypes. Furthermore, these priming strategies led to changes in the functional properties of ASCs, affecting their ability to migrate and modulate immune-mediated responses to prostate cancer cells in vitro. CONCLUSIONS TLR3 stimulation significantly decreased ASC migration, and TLR4 stimulation increased ASC immune-mediated killing potential against prostate cancer cells.
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Affiliation(s)
- Cosette M Rivera-Cruz
- Department of Basic Medical Sciences, Purdue University, West Lafayette, Indiana, USA
| | - Marxa L Figueiredo
- Department of Basic Medical Sciences, Purdue University, West Lafayette, Indiana, USA.
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24
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Zhu Z, Shi L, Dong Y, Zhang Y, Yang F, Wei J, Huo M, Li P, Liu X. Effect of crosstalk among conspirators in tumor microenvironment on niche metastasis of gastric cancer. Am J Cancer Res 2022; 12:5375-5402. [PMID: 36628284 PMCID: PMC9827080] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2022] [Accepted: 11/16/2022] [Indexed: 01/12/2023] Open
Abstract
In Traditional Chinese medicine, the metaphoric views of the human body are based on observations of nature guided by the theory of "Yin-Yang". The direct meanings of yin and yang are the bright and dark sides of an object, which often represent a wider range of opposite properties. When we shifted our view to gastric cancer (GC), we found that there are more distinctive Yin and Yang features in the mechanism of GC development and metastasis, which is observed in many mechanisms such as GC metastasis, immune escape, and stem cell homing. When illustrating this process from the yin-yang perspective, categorizing different cells in the tumor microenvironment enables new and different perspectives to be put forward on the mechanism and treatment of GC metastasis.
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Affiliation(s)
- Zhongbo Zhu
- Key Laboratory of Gansu Provincial Prescription Mining and Innovative Translational Laboratory, Gansu University of Chinese MedicineLanzhou 730000, Gansu, P. R. China,Gansu Provincial Traditional Chinese Medicine New Product Creation Engineering Laboratory, Gansu University of Chinese MedicineLanzhou 730000, Gansu, P. R. China
| | - Lijuan Shi
- Key Laboratory of Gansu Provincial Prescription Mining and Innovative Translational Laboratory, Gansu University of Chinese MedicineLanzhou 730000, Gansu, P. R. China,Gansu Provincial Traditional Chinese Medicine New Product Creation Engineering Laboratory, Gansu University of Chinese MedicineLanzhou 730000, Gansu, P. R. China
| | - Yawei Dong
- Key Laboratory of Gansu Provincial Prescription Mining and Innovative Translational Laboratory, Gansu University of Chinese MedicineLanzhou 730000, Gansu, P. R. China,Gansu Provincial Traditional Chinese Medicine New Product Creation Engineering Laboratory, Gansu University of Chinese MedicineLanzhou 730000, Gansu, P. R. China
| | - Yanmei Zhang
- Key Laboratory of Gansu Provincial Prescription Mining and Innovative Translational Laboratory, Gansu University of Chinese MedicineLanzhou 730000, Gansu, P. R. China,Gansu Provincial Traditional Chinese Medicine New Product Creation Engineering Laboratory, Gansu University of Chinese MedicineLanzhou 730000, Gansu, P. R. China
| | - Fan Yang
- Key Laboratory of Gansu Provincial Prescription Mining and Innovative Translational Laboratory, Gansu University of Chinese MedicineLanzhou 730000, Gansu, P. R. China,Gansu Provincial Traditional Chinese Medicine New Product Creation Engineering Laboratory, Gansu University of Chinese MedicineLanzhou 730000, Gansu, P. R. China
| | - Jingjing Wei
- Key Laboratory of Gansu Provincial Prescription Mining and Innovative Translational Laboratory, Gansu University of Chinese MedicineLanzhou 730000, Gansu, P. R. China,Gansu Provincial Traditional Chinese Medicine New Product Creation Engineering Laboratory, Gansu University of Chinese MedicineLanzhou 730000, Gansu, P. R. China
| | - Minfeng Huo
- Key Laboratory of Gansu Provincial Prescription Mining and Innovative Translational Laboratory, Gansu University of Chinese MedicineLanzhou 730000, Gansu, P. R. China,Gansu Provincial Traditional Chinese Medicine New Product Creation Engineering Laboratory, Gansu University of Chinese MedicineLanzhou 730000, Gansu, P. R. China
| | - Peiqing Li
- Key Laboratory of Gansu Provincial Prescription Mining and Innovative Translational Laboratory, Gansu University of Chinese MedicineLanzhou 730000, Gansu, P. R. China,Gansu Provincial Traditional Chinese Medicine New Product Creation Engineering Laboratory, Gansu University of Chinese MedicineLanzhou 730000, Gansu, P. R. China
| | - Xiping Liu
- Key Laboratory of Gansu Provincial Prescription Mining and Innovative Translational Laboratory, Gansu University of Chinese MedicineLanzhou 730000, Gansu, P. R. China,Gansu Provincial Traditional Chinese Medicine New Product Creation Engineering Laboratory, Gansu University of Chinese MedicineLanzhou 730000, Gansu, P. R. China
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25
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Ho YK, Loke KM, Woo JY, Lee YL, Too HP. Cryopreservation does not change the performance and characteristics of allogenic mesenchymal stem cells highly over-expressing a cytoplasmic therapeutic transgene for cancer treatment. Stem Cell Res Ther 2022; 13:519. [PMID: 36376945 PMCID: PMC9663191 DOI: 10.1186/s13287-022-03198-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Accepted: 10/26/2022] [Indexed: 11/16/2022] Open
Abstract
Background Mesenchymal stem cells (MSCs) driven gene directed enzyme prodrug therapy is a promising approach to deliver therapeutic agents to target heterogenous solid tumours. To democratize such a therapy, cryopreservation along with cold chain transportation is an essential part of the logistical process and supply chain. Previously, we have successfully engineered MSCs by a non-viral DNA transfection approach for prolonged and exceptionally high expression of the fused transgene cytosine deaminase, uracil phosphoribosyl transferase and green fluorescent protein (CD::UPRT::GFP). The aim of this study was to determine the effects of cryopreservation of MSCs engineered to highly overexpress this cytoplasmic therapeutic transgene. Methods Modified MSCs were preserved in a commercially available, GMP-grade cryopreservative—CryoStor10 (CS10) for up to 11 months. Performance of frozen-modified MSCs was compared to freshly modified equivalents in vitro. Cancer killing potency was evaluated using four different cancer cell lines. Migratory potential was assessed using matrigel invasion assay and flow cytometric analysis for CXCR4 expression. Frozen-modified MSC was used to treat canine patients via intra-tumoral injections, or by intravenous infusion followed by a daily dose of 5-flucytosine (5FC). Results We found that cryopreservation did not affect the transgene expression, cell viability, adhesion, phenotypic profile, and migration of gene modified canine adipose tissue derived MSCs. In the presence of 5FC, the thawed and freshly modified MSCs showed comparable cytotoxicity towards one canine and three human cancer cell lines in vitro. These cryopreserved cells were stored for about a year and then used to treat no-option-left canine patients with two different types of cancers and notably, the patients showed progression-free interval of more than 20 months, evidence of the effectiveness in treating spontaneously occurring cancers. Conclusion This study supports the use of cryopreserved, off-the-shelf transiently transfected MSCs for cancer treatment. Supplementary Information The online version contains supplementary material available at 10.1186/s13287-022-03198-z.
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26
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Zhang Z, Zhou X, Guo J, Zhang F, Qian Y, Wang G, Duan M, Wang Y, Zhao H, Yang Z, Liu Z, Jiang X. TA-MSCs, TA-MSCs-EVs, MIF: their crosstalk in immunosuppressive tumor microenvironment. J Transl Med 2022; 20:320. [PMID: 35842634 PMCID: PMC9287873 DOI: 10.1186/s12967-022-03528-y] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Accepted: 07/08/2022] [Indexed: 11/24/2022] Open
Abstract
As an important component of the immunosuppressive tumor microenvironment (TME), it has been established that mesenchymal stem cells (MSCs) promote the progression of tumor cells. MSCs can directly promote the proliferation, migration, and invasion of tumor cells via cytokines and chemokines, as well as promote tumor progression by regulating the functions of anti-tumor immune and immunosuppressive cells. MSCs-derived extracellular vesicles (MSCs-EVs) contain part of the plasma membrane and signaling factors from MSCs; therefore, they display similar effects on tumors in the immunosuppressive TME. The tumor-promoting role of macrophage migration inhibitory factor (MIF) in the immunosuppressive TME has also been revealed. Interestingly, MIF exerts similar effects to those of MSCs in the immunosuppressive TME. In this review, we summarized the main effects and related mechanisms of tumor-associated MSCs (TA-MSCs), TA-MSCs-EVs, and MIF on tumors, and described their relationships. On this basis, we hypothesized that TA-MSCs-EVs, the MIF axis, and TA-MSCs form a positive feedback loop with tumor cells, influencing the occurrence and development of tumors. The functions of these three factors in the TME may undergo dynamic changes with tumor growth and continuously affect tumor development. This provides a new idea for the targeted treatment of tumors with EVs carrying MIF inhibitors.
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Affiliation(s)
- Zhenghou Zhang
- Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
| | - Xiangyu Zhou
- Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
| | - Jinshuai Guo
- Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
| | - Fusheng Zhang
- Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
| | - Yiping Qian
- Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
| | - Guang Wang
- Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
| | - Meiqi Duan
- Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
| | - Yutian Wang
- Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
| | - Haiying Zhao
- Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
| | - Zhi Yang
- Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
| | - Zunpeng Liu
- Department of Orthopedics, The Fourth Affiliated Hospital of China Medical University, Shenyang, China.
| | - Xiaofeng Jiang
- Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning, China.
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27
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Mesenchymal stem cells: A living carrier for active tumor-targeted delivery. Adv Drug Deliv Rev 2022; 185:114300. [PMID: 35447165 DOI: 10.1016/j.addr.2022.114300] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2021] [Revised: 03/22/2022] [Accepted: 04/12/2022] [Indexed: 12/16/2022]
Abstract
The strategy of using mesenchymal stem cells (MSCs) as a living carrier for active delivery of therapeutic agents targeting tumor sites has been attempted in a wide range of studies to validate the feasibility and efficacy for tumor treatment. This approach reveals powerful tumor targeting and tumor penetration. In addition, MSCs have been confirmed to actively participate in immunomodulation of the tumor microenvironment. Thus, MSCs are not inert delivery vehicles but have a strong impact on the fate of tumor cells. In this review, these active properties of MSCs are addressed to highlight the advantages and challenges of using MSCs for tumor-targeted delivery. In addition, some of the latest examples of using MSCs to carry a variety of anti-tumor agents for tumor-targeted therapy are summarized. Recent technologies to improve the performance and safety of this delivery strategy will be introduced. The advances, applications, and challenges summarized in this review will provide a general understanding of this promising strategy for actively delivering drugs to tumor tissues.
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28
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Immunotherapy by mesenchymal stromal cell delivery of oncolytic viruses for treating metastatic tumors. Mol Ther Oncolytics 2022; 25:78-97. [PMID: 35434272 PMCID: PMC8989711 DOI: 10.1016/j.omto.2022.03.008] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Oncolytic viruses (OVs) have emerged as a very promising anti-cancer therapeutic strategy in the past decades. However, despite their pre-clinical promise, many OV clinical evaluations for cancer therapy have highlighted the continued need for their improved delivery and targeting. Mesenchymal stromal cells (MSCs) have emerged as excellent candidate vehicles for the delivery of OVs due to their tumor-homing properties and low immunogenicity. MSCs can enhance OV delivery by protecting viruses from rapid clearance following administration and also by more efficiently targeting tumor sites, consequently augmenting the therapeutic potential of OVs. MSCs can function as “biological factories,” enabling OV amplification within these cells to promote tumor lysis following MSC-OV arrival at the tumor site. MSC-OVs can promote enhanced safety profiles and therapeutic effects relative to OVs alone. In this review we explore the general characteristics of MSCs as delivery tools for cancer therapeutic agents. Furthermore, we discuss the potential of OVs as immune therapeutics and highlight some of the promising applications stemming from combining MSCs to achieve enhanced delivery and anti-tumor effectiveness of OVs at different pre-clinical and clinical stages. We further provide potential pitfalls of the MSC-OV platform and the strategies under development for enhancing the efficacy of these emerging therapeutics.
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29
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Injectable immunomodulation-based porous chitosan microspheres/HPCH hydrogel composites as a controlled drug delivery system for osteochondral regeneration. Biomaterials 2022; 285:121530. [DOI: 10.1016/j.biomaterials.2022.121530] [Citation(s) in RCA: 86] [Impact Index Per Article: 28.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Revised: 03/23/2022] [Accepted: 04/14/2022] [Indexed: 12/16/2022]
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30
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The CXCL12/CXCR4/ACKR3 Signaling Axis Regulates PKM2 and Glycolysis. Cells 2022; 11:cells11111775. [PMID: 35681470 PMCID: PMC9179862 DOI: 10.3390/cells11111775] [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: 03/01/2022] [Revised: 05/13/2022] [Accepted: 05/24/2022] [Indexed: 02/06/2023] Open
Abstract
In response to CXCL12, CXCR4 and ACKR3 both recruit β-arrestin 2, regulating the assembly of interacting proteins that drive signaling and contribute to the functions of both receptors in cancer and multiple other diseases. A prior proteomics study revealed that β-arrestin 2 scaffolds pyruvate kinase M2 (PKM2), an enzyme implicated in shifting cells to glycolytic metabolism and poor prognosis in cancer. We hypothesized that CXCL12 signaling regulates PKM2 protein interactions, oligomerization, and glucose metabolism. We used luciferase complementation in cell-based assays and a tumor xenograft model of breast cancer in NSG mice to quantify how CXCR4 and ACKR3 change protein interactions in the β-arrestin-ERK-PKM2 pathway. We also used mass spectrometry to analyze the effects of CXCL12 on glucose metabolism. CXCL12 signaling through CXCR4 and ACKR3 stimulated protein interactions among β-arrestin 2, PKM2, ERK2, and each receptor, leading to the dissociation of PKM2 from β-arrestin 2. The activation of both receptors reduced the oligomerization of PKM2, reflecting a shift from tetramers to dimers or monomers with low enzymatic activity. Mass spectrometry with isotopically labeled glucose showed that CXCL12 signaling increased intermediate metabolites in glycolysis and the pentose phosphate pathway, with ACKR3 mediating greater effects. These data establish how CXCL12 signaling regulates PKM2 and reprograms cellular metabolism.
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31
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Ray SK, Mukherjee S. Mesenchymal Stem Cells Derived from Umbilical Cord Blood having Excellent Stemness Properties with Therapeutic Benefits - a New Era in Cancer Treatment. Curr Stem Cell Res Ther 2022; 17:328-338. [PMID: 35469574 DOI: 10.2174/1574888x17666220425102154] [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: 12/25/2021] [Revised: 02/18/2022] [Accepted: 03/03/2022] [Indexed: 11/22/2022]
Abstract
Mesenchymal stem cells (MSCs) are the most promising candidates for cellular therapies, and most therapeutic applications have focused on MSCs produced from adult bone marrow, despite mounting evidence that MSCs are present in a wide range of conditions. Umbilical cord blood (UCB) is a valuable source of hematopoietic stem cells, but its therapeutic potential extends beyond the hematopoietic component, which also suggests solid organ regenerative potential. With potential ranging from embryonic-like to lineage-committed progenitor cells, many different stems and progenitor cell populations have been postulated. MSC is currently inferred by numerous clinical applications for human UCB. aAs stem cell therapy kicks off some new research and these cells show such a boon to stem cell therapy, it is nevertheless characteristic that the prospect of UCB conservation is gaining momentum. Taken together, the experience described here shows that MSCs derived from UCB are seen as attractive therapeutic candidates for various human disorders including cancer. It is argued that a therapeutic stem cell transplant, using stem cells from UCB, provides a reliable repository of early precursor cells that can be useful in a large number of different conditions, considering issues of safety, availability, transplant methodology, rejection, and side effects. In particular, we focus on the concept of isolation and expansion, comparing the phenotype with MSC derived from the UCB, describing the ability to differentiate, and lastly, the therapeutic potential concerning stromal support, stemness characteristic, immune modulation, and cancer stem cell therapy. Thus it is an overview of the therapeutic application of UCB derived MSCs, with a special emphasis on cancer. Besides, the current evidence on the double-edged sword of MSCs in cancer treatment and the latest advances in UCB-derived MSC in cancer research will be discussed.
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Affiliation(s)
| | - Sukhes Mukherjee
- Department of Biochemistry, All India Institute of Medical Sciences, Bhopal, Madhya Pradesh-462020, India
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32
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Goïta AA, Guenot D. Colorectal Cancer: The Contribution of CXCL12 and Its Receptors CXCR4 and CXCR7. Cancers (Basel) 2022; 14:1810. [PMID: 35406582 PMCID: PMC8997717 DOI: 10.3390/cancers14071810] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Revised: 03/22/2022] [Accepted: 03/29/2022] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer is one of the most common cancers, and diagnosis at late metastatic stages is the main cause of death related to this cancer. This progression to metastasis is complex and involves different molecules such as the chemokine CXCL12 and its two receptors CXCR4 and CXCR7. The high expression of receptors in CRC is often associated with a poor prognosis and aggressiveness of the tumor. The interaction of CXCL12 and its receptors activates signaling pathways that induce chemotaxis, proliferation, migration, and cell invasion. To this end, receptor inhibitors were developed, and their use in preclinical and clinical studies is ongoing. This review provides an overview of studies involving CXCR4 and CXCR7 in CRC with an update on their targeting in anti-cancer therapies.
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Affiliation(s)
| | - Dominique Guenot
- INSERM U1113/Unistra, IRFAC—Interface de Recherche Fondamentale et Appliquée en Cancérologie, 67200 Strasbourg, France;
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33
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Vicinanza C, Lombardi E, Da Ros F, Marangon M, Durante C, Mazzucato M, Agostini F. Modified mesenchymal stem cells in cancer therapy: A smart weapon requiring upgrades for wider clinical applications. World J Stem Cells 2022; 14:54-75. [PMID: 35126828 PMCID: PMC8788179 DOI: 10.4252/wjsc.v14.i1.54] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 08/06/2021] [Accepted: 12/23/2021] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal stem stromal cells (MSC) are characterized by the intriguing capacity to home toward cancer cells after systemic administration. Thus, MSC can be harnessed as targeted delivery vehicles of cytotoxic agents against tumors. In cancer patients, MSC based advanced cellular therapies were shown to be safe but their clinical efficacy was limited. Indeed, the amount of systemically infused MSC actually homing to human cancer masses is insufficient to reduce tumor growth. Moreover, induction of an unequivocal anticancer cytotoxic phenotype in expanded MSC is necessary to achieve significant therapeutic efficacy. Ex vivo cell modifications are, thus, required to improve anti-cancer properties of MSC. MSC based cellular therapy products must be handled in compliance with good manufacturing practice (GMP) guidelines. In the present review we include MSC-improving manipulation approaches that, even though actually tested at preclinical level, could be compatible with GMP guidelines. In particular, we describe possible approaches to improve MSC homing on cancer, including genetic engineering, membrane modification and cytokine priming. Similarly, we discuss appropriate modalities aimed at inducing a marked cytotoxic phenotype in expanded MSC by direct chemotherapeutic drug loading or by genetic methods. In conclusion, we suggest that, to configure MSC as a powerful weapon against cancer, combinations of clinical grade compatible modification protocols that are currently selected, should be introduced in the final product. Highly standardized cancer clinical trials are required to test the efficacy of ameliorated MSC based cell therapies.
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Affiliation(s)
- Carla Vicinanza
- Stem Cell Unit, Centro di Riferimento Oncologico di Aviano, IRCCS, Aviano 33081, Italy
| | - Elisabetta Lombardi
- Stem Cell Unit, Centro di Riferimento Oncologico di Aviano, IRCCS, Aviano 33081, Italy
| | - Francesco Da Ros
- Stem Cell Unit, Centro di Riferimento Oncologico di Aviano, IRCCS, Aviano 33081, Italy
| | - Miriam Marangon
- Stem Cell Unit, Centro di Riferimento Oncologico di Aviano, IRCCS, Aviano 33081, Italy
| | - Cristina Durante
- Stem Cell Unit, Centro di Riferimento Oncologico di Aviano, IRCCS, Aviano 33081, Italy
| | - Mario Mazzucato
- Stem Cell Unit, Centro di Riferimento Oncologico di Aviano, IRCCS, Aviano 33081, Italy
| | - Francesco Agostini
- Stem Cell Unit, Centro di Riferimento Oncologico di Aviano, IRCCS, Aviano 33081, Italy
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Murad HAS, Rafeeq MM, Alqurashi TMA. Role and implications of the CXCL12/CXCR4/CXCR7 axis in atherosclerosis: still a debate. Ann Med 2021; 53:1598-1612. [PMID: 34494495 PMCID: PMC8439212 DOI: 10.1080/07853890.2021.1974084] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Accepted: 08/23/2021] [Indexed: 01/20/2023] Open
Abstract
Atherosclerosis is one of the leading causes of mortality and morbidity worldwide. Chemokines and their receptors are implicated in the pathogenesis of atherosclerosis. CXCL12 is a member of the chemokine family exerting a myriad role in atherosclerosis through its classical CXCR4 and atypical ACKR3 (CXCR7) receptors. The modulatory and regulatory functional spectrum of CXCL12/CXCR4/ACKR3 axis in atherosclerosis spans from proatherogenic, prothrombotic and proinflammatory to atheroprotective, plaque stabilizer and dyslipidemia rectifier. This diverse continuum is executed in a wide range of biological units including endothelial cells (ECs), progenitor cells, macrophages, monocytes, platelets, lymphocytes, neutrophils and vascular smooth muscle cells (VSMCs) through complex heterogeneous and homogenous coupling of CXCR4 and ACKR3 receptors, employing different downstream signalling pathways, which often cross-talk among themselves and with other signalling interactomes. Hence, a better understanding of this structural and functional heterogeneity and complex phenomenon involving CXCL12/CXCR4/ACKR3 axis in atherosclerosis would not only help in formulation of novel therapeutics, but also in elucidation of the CXCL12 ligand and its receptors, as possible diagnostic and prognostic biomarkers.Key messagesThe role of CXCL12 per se is proatherogenic in atherosclerosis development and progression.The CXCL12 receptors, CXCR4 and ACKR3 perform both proatherogenic and athero-protective functions in various cell typesDue to functional heterogeneity and cross talk of CXCR4 and ACKR3 at receptor level and downstream pathways, regional boosting with specific temporal and spatial modulators of CXCL12, CXCR4 and ACKR3 need to be explored.
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Affiliation(s)
- Hussam A. S. Murad
- Department of Pharmacology, Faculty of Medicine, Rabigh, King Abdulaziz University (KAU), Jeddah, Saudi Arabia
| | - Misbahuddin M. Rafeeq
- Department of Pharmacology, Faculty of Medicine, Rabigh, King Abdulaziz University (KAU), Jeddah, Saudi Arabia
| | - Thamer M. A. Alqurashi
- Department of Pharmacology, Faculty of Medicine, Rabigh, King Abdulaziz University (KAU), Jeddah, Saudi Arabia
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Xuan X, Tian C, Zhao M, Sun Y, Huang C. Mesenchymal stem cells in cancer progression and anticancer therapeutic resistance. Cancer Cell Int 2021; 21:595. [PMID: 34736460 PMCID: PMC8570012 DOI: 10.1186/s12935-021-02300-4] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2021] [Accepted: 10/26/2021] [Indexed: 12/26/2022] Open
Abstract
Increasing evidence indicates that the tumor microenvironment appears to play an increasingly important role in cancer progression and therapeutic resistance. Several types of cells within the tumor stroma had distinct impacts on cancer progression, either promoting or inhibiting cancer cell growth. Mesenchymal stem cells (MSCs) are a distinct type of cells that is linked to tumor development. MSCs are recognized for homing to tumor locations and promoting or inhibiting cancer cell proliferation, angiogenesis and metastasis. Moreover, emerging studies suggests that MSCs are also involved in therapeutic resistance. In this review, we analyzed the existing researches and elaborate on the functions of MSCs in cancer progression and anticancer therapeutic resistance, demonstrating that MSCs may be a viable cancer therapeutic target.
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Affiliation(s)
- Xiuyun Xuan
- Department of Dermatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei, China
| | - Chunxia Tian
- Department of Cardiology, Hubei Provincial Hospital of TCM, Wuhan, 430022, Hubei, China
| | - Mengjie Zhao
- Department of Dermatology, Zhongnan Hospital, Wuhan University, Wuhan, 430022, Hubei, China.
| | - Yanhong Sun
- Department of Dermatology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, Zhejiang, China.
| | - Changzheng Huang
- Department of Dermatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei, China.
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Warrier NM, Agarwal P, Kumar P. Integrative Analysis to Identify Genes Associated with Stemness and Immune Infiltration in Glioblastoma. Cells 2021; 10:2765. [PMID: 34685742 PMCID: PMC8534801 DOI: 10.3390/cells10102765] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Revised: 10/11/2021] [Accepted: 10/12/2021] [Indexed: 12/15/2022] Open
Abstract
It is imperative to identify the mechanisms that confer stemness to the cancer cells for more effective targeting. Moreover, there are not many studies on the link between stemness characteristics and the immune response in tumours. Therefore, in the current study involving GBM, we started with the study of BIRC5 (one of the rare genes differentially expressed in normal and cancer cells) and CXCR4 (gene involved in the survival and proliferation of CSCs). Together, these genes have not been systematically explored. We used a set of 27 promoter methylated regions in GBM. Our analysis showed that four genes corresponding to these regions, namely EOMES, BDNF, HLA-A, and PECAM1, were involved with BIRC5 and CXCR4. Interestingly, we found EOMES to be very significantly involved in stemness and immunology and it was positively correlated to CXCR4. Additionally, BDNF, which was significant in methylation, was negatively correlated to BIRC5.
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Affiliation(s)
- Neerada Meenakshi Warrier
- Department of Biotechnology, Manipal Institute of Technology, Manipal Academy of Higher Education, Manipal 576104, Karnataka, India;
| | - Prasoon Agarwal
- KTH Royal Institute of Technology, School of Electrical Engineering and Computer Science, 10044 Stockholm, Sweden
- Science for Life Laboratory, 17121 Solna, Sweden
| | - Praveen Kumar
- Department of Biotechnology, Manipal Institute of Technology, Manipal Academy of Higher Education, Manipal 576104, Karnataka, India;
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Karimi-Shahri M, Javid H, Sharbaf Mashhad A, Yazdani S, Hashemy SI. Mesenchymal stem cells in cancer therapy; the art of harnessing a foe to a friend. IRANIAN JOURNAL OF BASIC MEDICAL SCIENCES 2021; 24:1307-1323. [PMID: 35096289 PMCID: PMC8769515 DOI: 10.22038/ijbms.2021.58227.12934] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Accepted: 08/04/2021] [Indexed: 12/09/2022]
Abstract
For a long time, mesenchymal stem cells (MSCs) were discussed only as stem cells which could give rise to different types of cells. However, when it became clear that their presence in the tumor microenvironment (TME) was like a green light for tumorigenesis, they emerged from the ashes. This review was arranged to provide a comprehensive and precise description of MSCs' role in regulating tumorigenesis and to discuss the dark and the bright sides of cancer treatment strategies using MSCs. To gather the details about MSCs, we made an intensive literature review using keywords, including MSCs, tumor microenvironment, tumorigenesis, and targeted therapy. Through transferring cytokines, growth factors, and microRNAs, MSCs maintain the cancer stem cell population, increase angiogenesis, provide a facility for cancer metastasis, and shut down the anti-tumor activity of the immune system. Although MSCs progress tumorigenesis, there is a consensus that these cells could be used as a vehicle to transfer anti-cancer agents into the tumor milieu. This feature opened a new chapter in MSCs biology, this time from the therapeutic perspective. Although the data are not sufficient, the advent of new genetic engineering methods might make it possible to engage these cells as Trojan horses to eliminate the malignant population. So many years of investigation showed that MSCs are an important group of cells, residing in the TME, studying the function of which not only could add a delicate series of information to the process of tumorigenesis but also could revolutionize cancer treatment strategies.
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Affiliation(s)
- Mehdi Karimi-Shahri
- Department of Pathology, School of Medicine, Gonabad University of Medical Sciences, Gonabad, Iran
- Department of Pathology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hossein Javid
- Department of Medical Laboratory Sciences, Varastegan Institute for Medical Sciences, Mashhad, Iran
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Alireza Sharbaf Mashhad
- Department of Medical Laboratory Sciences, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Shaghayegh Yazdani
- Department of Medical Laboratory Sciences, Ilam Institute for Medical Sciences, Ilam, Iran
| | - Seyed Isaac Hashemy
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Surgical Oncology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
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Takayama Y, Kusamori K, Nishikawa M. Mesenchymal stem/stromal cells as next-generation drug delivery vehicles for cancer therapeutics. Expert Opin Drug Deliv 2021; 18:1627-1642. [PMID: 34311638 DOI: 10.1080/17425247.2021.1960309] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
INTRODUCTION Drug delivery to solid tumors remains a significant therapeutic challenge. Mesenchymal stem/stromal cells (MSCs) home to tumor tissues and can be employed as tumor targeted drug/gene delivery vehicles. Reportedly, therapeutic gene- or anti-cancer drug-loaded MSCs have shown remarkable anti-tumor effects in preclinical studies, and some clinical trials for assessing therapeutic MSCs in patients with cancer have been registered. AREAS COVERED In the present review, we first discuss the source and interdonor heterogeneity of MSCs, their tumor-homing mechanism, and the route of MSC administration in MSC-based cancer therapy. We then summarize the therapeutic applications of MSCs as a drug delivery vehicle for therapeutic genes or anti-cancer drugs and the drug delivery mechanism from drug-loaded MSCs to cancer cells. EXPERT OPINION Although numerous preclinical studies have revealed significant anti-tumor effects, several clinical trials assessing MSC-based cancer gene therapy have failed to demonstrate corroborative results, documenting limited therapeutic effects. Notably, a successful clinical outcome with MSC-based cancer therapy would require the interdonor heterogeneity of administered MSCs to be resolved, along with improved tumor-homing efficiency and optimized drug delivery efficiency from MSCs to cancer cells.
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Affiliation(s)
- Yukiya Takayama
- Laboratory of Biopharmaceutics, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Chiba Japan
| | - Kosuke Kusamori
- Laboratory of Biopharmaceutics, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Chiba Japan
| | - Makiya Nishikawa
- Laboratory of Biopharmaceutics, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Chiba Japan
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Wang WJ, Wang J, Ouyang C, Chen C, Xu XF, Ye XQ. Overview of serpin B9 and its roles in cancer (Review). Oncol Rep 2021; 46:190. [PMID: 34278491 DOI: 10.3892/or.2021.8141] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2021] [Accepted: 06/25/2021] [Indexed: 11/06/2022] Open
Abstract
Serine proteinase inhibitor B9 (serpin B9) is a member of the serine protease inhibitor superfamily, which is widely found in animals, plants and microorganisms. Serpin B9 has been reported to protect cells from the immune‑killing effect of granzyme B (GrB) released by lymphocytes. In recent years, an increasing number of studies have indicated that serpin B9 is involved in tumour apoptosis, immune evasion, tumorigenesis, progression, metastasis, drug resistance and even in maintaining the stemness of cancer stem cells (CSCs). Moreover, according to clinical studies, serpin B9 has been demonstrated to be significantly associated with the development of precancerous lesions, a poor prognosis and ineffective therapies, suggesting that serpin B9 may be a potential target for cancer treatment and an indicator of cancer diagnosis; thus, it has begun to attract increased attention from scholars. The present review concisely described the structure and biological functions of the serpin superfamily and serpin B9. In addition, related research on serpins in cancer is discussed in order to provide a comprehensive understanding of the role of serpin B9 in cancer, as well as its clinical significance for cancer diagnosis and prognosis.
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Affiliation(s)
- Wen-Jun Wang
- Department of Respiratory Diseases, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Jiao Wang
- Department of Respiratory Diseases, Jiujiang First People's Hospital, Jiujiang, Jiangxi 332000, P.R. China
| | - Chao Ouyang
- Department of Respiratory Diseases, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Chong Chen
- Department of Respiratory Diseases, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Xiao-Feng Xu
- Department of Respiratory Diseases, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Xiao-Qun Ye
- Department of Respiratory Diseases, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
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Britton C, Poznansky MC, Reeves P. Polyfunctionality of the CXCR4/CXCL12 axis in health and disease: Implications for therapeutic interventions in cancer and immune-mediated diseases. FASEB J 2021; 35:e21260. [PMID: 33715207 DOI: 10.1096/fj.202001273r] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Revised: 11/12/2020] [Accepted: 11/25/2020] [Indexed: 12/19/2022]
Abstract
Historically the chemokine receptor CXCR4 and its canonical ligand CXCL12 are associated with the bone marrow niche and hematopoiesis. However, CXCL12 exhibits broad tissue expression including brain, thymus, heart, lung, liver, kidney, spleen, and bone marrow. CXCR4 can be considered as a node which is integrating and transducing inputs from a range of ligand-receptor interactions into a responsive and divergent network of intracellular signaling pathways that impact multiple cellular processes such as proliferation, migration, and stress resistance. Dysregulation of the CXCR4/CXCL12 axis and consequent fundamental cellular processes, are associated with a panoply of disease. This review frames the polyfunctionality of the receptor at a molecular, physiological, and pathophysiological levels. Transitioning our perspective of this axis from a single gene/protein:single function model to a polyfunctional signaling cascade highlights the potential for finer therapeutic intervention and cautions against a reductionist approach.
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Affiliation(s)
- C Britton
- Vaccine and Immunotherapy Center, Boston, MA, USA
| | | | - P Reeves
- Vaccine and Immunotherapy Center, Boston, MA, USA.,Department of Medicine, Imperial College School of Medicine, London, England
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King JL, Benhabbour SR. Glioblastoma Multiforme-A Look at the Past and a Glance at the Future. Pharmaceutics 2021; 13:pharmaceutics13071053. [PMID: 34371744 PMCID: PMC8309001 DOI: 10.3390/pharmaceutics13071053] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2021] [Revised: 06/29/2021] [Accepted: 07/05/2021] [Indexed: 01/14/2023] Open
Abstract
Gliomas are the most common type of brain tumor that occur in adults and children. Glioblastoma multiforme (GBM) is the most common, aggressive form of brain cancer in adults and is universally fatal. The current standard-of-care options for GBM include surgical resection, radiotherapy, and concomitant and/or adjuvant chemotherapy. One of the major challenges that impedes success of chemotherapy is the presence of the blood–brain barrier (BBB). Because of the tightly regulated BBB, immune surveillance in the central nervous system (CNS) is poor, contributing to unregulated glioma cell growth. This review gives a comprehensive overview of the latest advances in treatment of GBM with emphasis on the significant advances in immunotherapy and novel therapeutic delivery strategies to enhance treatment for GBM.
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Affiliation(s)
- Jasmine L. King
- Joint Department of Biomedical Engineering, North Carolina State University and The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA;
- Division of Pharmacoengineering and Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Soumya Rahima Benhabbour
- Joint Department of Biomedical Engineering, North Carolina State University and The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA;
- Division of Pharmacoengineering and Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
- Correspondence: ; Tel.: +1-919-843-6142
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King JL, Benhabbour SR. Glioblastoma Multiforme-A Look at the Past and a Glance at the Future. Pharmaceutics 2021; 13:1053. [PMID: 34371744 PMCID: PMC8309001 DOI: 10.3390/pharmaceutics13071053;] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/03/2022] Open
Abstract
Gliomas are the most common type of brain tumor that occur in adults and children. Glioblastoma multiforme (GBM) is the most common, aggressive form of brain cancer in adults and is universally fatal. The current standard-of-care options for GBM include surgical resection, radiotherapy, and concomitant and/or adjuvant chemotherapy. One of the major challenges that impedes success of chemotherapy is the presence of the blood-brain barrier (BBB). Because of the tightly regulated BBB, immune surveillance in the central nervous system (CNS) is poor, contributing to unregulated glioma cell growth. This review gives a comprehensive overview of the latest advances in treatment of GBM with emphasis on the significant advances in immunotherapy and novel therapeutic delivery strategies to enhance treatment for GBM.
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Affiliation(s)
- Jasmine L. King
- Joint Department of Biomedical Engineering, North Carolina State University and The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA;
- Division of Pharmacoengineering and Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Soumya Rahima Benhabbour
- Joint Department of Biomedical Engineering, North Carolina State University and The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA;
- Division of Pharmacoengineering and Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
- Correspondence: ; Tel.: +1-919-843-6142
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Ho CT, Wu MH, Chen MJ, Lin SP, Yen YT, Hung SC. Combination of Mesenchymal Stem Cell-Delivered Oncolytic Virus with Prodrug Activation Increases Efficacy and Safety of Colorectal Cancer Therapy. Biomedicines 2021; 9:548. [PMID: 34068264 PMCID: PMC8153168 DOI: 10.3390/biomedicines9050548] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Revised: 05/04/2021] [Accepted: 05/11/2021] [Indexed: 12/24/2022] Open
Abstract
Although oncolytic viruses are currently being evaluated for cancer treatment in clinical trials, systemic administration is hindered by many factors that prevent them from reaching the tumor cells. When administered systemically, mesenchymal stem cells (MSCs) target tumors, and therefore constitute good cell carriers for oncolytic viruses. MSCs were primed with trichostatin A under hypoxia, which upregulated the expression of CXCR4, a chemokine receptor involved in tumor tropism, and coxsackievirus and adenovirus receptor that plays an important role in adenoviral infection. After priming, MSCs were loaded with conditionally replicative adenovirus that exhibits limited proliferation in cells with a functional p53 pathway and encodes Escherichia coli nitroreductase (NTR) enzymes (CRAdNTR) for targeting tumor cells. Primed MSCs increased tumor tropism and susceptibility to adenoviral infection, and successfully protected CRAdNTR from neutralization by anti-adenovirus antibodies both in vitro and in vivo, and specifically targeted p53-deficient colorectal tumors when infused intravenously. Analyses of deproteinized tissues by UPLC-MS/QTOF revealed that these MSCs converted the co-administered prodrug CB1954 into cytotoxic metabolites, such as 4-hydroxylamine and 2-amine, inducing oncolysis and tumor growth inhibition without being toxic for the host vital organs. This study shows that the combination of oncolytic viruses delivered by MSCs with the activation of prodrugs is a new cancer treatment strategy that provides a new approach for the development of oncolytic viral therapy for various cancers.
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Affiliation(s)
- Chun-Te Ho
- Drug Development Center, Institute of New Drug Development, Institute of Biomedical Sciences, School of Medicine, China Medical University, Taichung 404, Taiwan; (C.-T.H.); (Y.-T.Y.)
- Integrative Stem Cell Center, Department of Orthopaedics, China Medical University Hospital, Taichung 404, Taiwan
| | - Mei-Hsuan Wu
- Institute of Clinical Medicine, School of Medicine, National Yang-Ming University, Taipei 112, Taiwan; (M.-H.W.); (S.-P.L.)
| | - Ming-Jen Chen
- Department of Surgery, MacKay Memorial Hospital & Department of Medicine, MacKay Medical College, New Taipei City 252, Taiwan;
| | - Shih-Pei Lin
- Institute of Clinical Medicine, School of Medicine, National Yang-Ming University, Taipei 112, Taiwan; (M.-H.W.); (S.-P.L.)
| | - Yu-Ting Yen
- Drug Development Center, Institute of New Drug Development, Institute of Biomedical Sciences, School of Medicine, China Medical University, Taichung 404, Taiwan; (C.-T.H.); (Y.-T.Y.)
- Integrative Stem Cell Center, Department of Orthopaedics, China Medical University Hospital, Taichung 404, Taiwan
| | - Shih-Chieh Hung
- Drug Development Center, Institute of New Drug Development, Institute of Biomedical Sciences, School of Medicine, China Medical University, Taichung 404, Taiwan; (C.-T.H.); (Y.-T.Y.)
- Integrative Stem Cell Center, Department of Orthopaedics, China Medical University Hospital, Taichung 404, Taiwan
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Seyed-Khorrami SM, Soleimanjahi H, Soudi S, Habibian A. MSCs loaded with oncolytic reovirus: migration and in vivo virus delivery potential for evaluating anti-cancer effect in tumor-bearing C57BL/6 mice. Cancer Cell Int 2021; 21:244. [PMID: 33933086 PMCID: PMC8088007 DOI: 10.1186/s12935-021-01848-5] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Accepted: 02/20/2021] [Indexed: 02/07/2023] Open
Abstract
Background and aims Several oncolytic viruses applications have been approved in the clinic or in different phases of clinical trials. However, these methods have some rudimentary problems. Therefore, to enhance the delivery and quality of treatment, considering the advantage of cell carrier-based methods such as Mesenchymal Stem Cells (MSC) have been proposed. This study was designed to evaluate the performance and quality of cancer treatment based on MSCs loaded by oncolytic reovirus in the cancerous C57BL/6 mouse model. Also, we evaluated MSCs migration potency in vitro and in vivo following the oncolytic reovirus infection. Methods C57BL/6 mice were inoculated with TC-1 cell lines and tumors were established in the right flank. Mice were systemically treated with reovirus, MSCs-loaded with reovirus, MSCs, and PBS as a control in separated groups. Effects of infected AD-MSCs with reovirus on tumor growth and penetration in the tumor site were monitored. All groups of mice were monitored for two months in order to therapeutic and anticancer potential. After treatments, tumor size alteration and apoptosis rate, as well as cytokine release pattern was assessed. Results The results of the current study indicated that the effect of reovirus infection on AD-MSCs is not devastating the migration capacity especially in MOI 1 and 5 while intact cells remain. On the other hand, MSCs play an efficient role as a carrier to deliver oncolytic virus into the tumor site in comparison with systemic administration of reovirus alone. Apoptosis intensity relies on viral titration and passing time. Followed by systemic administration, treatment with oncolytic reovirus-infected AD-MSCs and MSCs alone had shown significant inhibition in tumor growth. Also, treatment by reovirus causes an increase in IFN-γ secretion. Conclusion The results of in vitro and in vivo study confirmed the tumor-homing properties of infected AD-MSCs and the significant antitumor activity of this platform. Hence, our results showed that the cell carrier strategy using oncolytic reovirus-loaded AD-MSCs enhanced virus delivery, infiltration, and antitumor activity can be effectively applied in most cancers.
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Affiliation(s)
| | - Hoorieh Soleimanjahi
- Department of Virology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.
| | - Sara Soudi
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Ala Habibian
- Department of Virology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
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Saeedi M, Nezhad MS, Mehranfar F, Golpour M, Esakandari MA, Rashmeie Z, Ghorbani M, Nasimi F, Hoseinian SN. Biological Aspects and Clinical Applications of Mesenchymal Stem Cells: Key Features You Need to be Aware of. Curr Pharm Biotechnol 2021; 22:200-215. [PMID: 32895040 DOI: 10.2174/1389201021666200907121530] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Revised: 08/01/2020] [Accepted: 08/03/2020] [Indexed: 11/22/2022]
Abstract
Mesenchymal Stem Cells (MSCs), a form of adult stem cells, are known to have a selfrenewing property and the potential to specialize into a multitude of cells and tissues such as adipocytes, cartilage cells, and fibroblasts. MSCs can migrate and home to the desired target zone where inflammation is present. The unique characteristics of MSCs in repairing, differentiation, regeneration, and the high capacity of immune modulation have attracted tremendous attention for exerting them in clinical purposes, as they contribute to the tissue regeneration process and anti-tumor activity. The MSCs-based treatment has demonstrated remarkable applicability towards various diseases such as heart and bone malignancies, and cancer cells. Importantly, genetically engineered MSCs, as a stateof- the-art therapeutic approach, could address some clinical hurdles by systemic secretion of cytokines and other agents with a short half-life and high toxicity. Therefore, understanding the biological aspects and the characteristics of MSCs is an imperative issue of concern. Herein, we provide an overview of the therapeutic application and the biological features of MSCs against different inflammatory diseases and cancer cells. We further shed light on MSCs' physiological interaction, such as migration, homing, and tissue repairing mechanisms in different healthy and inflamed tissues.
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Affiliation(s)
- Mohammad Saeedi
- Department of Laboratory Science, Faculty of Medicine, Semnan University of Medical Sciences, Semnan, Iran
| | - Muhammad S Nezhad
- Stem Cells and Regenerative Medicine Center of Excellence, Tehran University of Medical Sciences, Tehran, Iran
| | - Fatemeh Mehranfar
- Department of Laboratory Science, Faculty of medicine, Semnan University of Medical Sciences, Semnan, Iran
| | - Mahdieh Golpour
- School of Paramedical Sciences, Semnan University of Medical Sciences, Sorkheh, Semnan, Iran
| | - Mohammad A Esakandari
- Student Research Committee, Faculty of Medicine, Semnan University of Medical Sciences, Semnan, Iran
| | - Zahra Rashmeie
- Department of Laboratory Science, Faculty of medicine, Semnan University of Medical Sciences, Semnan, Iran
| | - Maryam Ghorbani
- Department of Laboratory Science, Faculty of medicine, Semnan University of Medical Sciences, Semnan, Iran
| | - Fatemeh Nasimi
- Department of Laboratory Science, Faculty of medicine, Semnan University of Medical Sciences, Semnan, Iran
| | - Seyed N Hoseinian
- Department of Laboratory Science, Faculty of medicine, Semnan University of Medical Sciences, Semnan, Iran
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Ivolgin DA, Kudlay DA. Mesenchymal multipotent stromal cells and cancer safety: two sides of the same coin or a double-edged sword (review of foreign literature). RUSSIAN JOURNAL OF PEDIATRIC HEMATOLOGY AND ONCOLOGY 2021; 8:64-84. [DOI: 10.21682/2311-1267-2021-8-1-64-84] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
Abstract
Knowledge about the mechanisms of action of mesenchymal multipotent stromal cells (MSC) has undergone a significant evolution since their discovery. From the first attempts to use the remarkable properties of MSC in restoring the functions of organs and tissues, the most important question arose – how safe their use would be? One of the aspects of safety of the use of such biomaterial is tumorogenicity and oncogenicity. Numerous studies have shown that the mechanisms by which MSC realize their regenerative potential can, in principle, have a stimulating effect on tumor cells. This review presents specific mechanisms that have a potentially pro-tumor effect, which include the homing of MSC to the tumor site, support for replicative and proliferative signaling of both cancer cells and cancer stem cells, angiogenesis, and effects on the epithelial-mesenchymal transition. Along with pro-tumor mechanisms, the mechanisms of possible antitumor action are also described – direct suppression of tumor growth, loading and transportation of chemotherapeutic agents, oncolytic viruses, genetic modifications for targeting cancer, delivery of “suicide genes” to the tumor. Also, in conclusion, a small review of the current clinical trials of MSC as antitumor agents for malignant neoplasms of various localization (gastrointestinal tract, lungs, ovaries) is given.
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Affiliation(s)
- D. A. Ivolgin
- I.I. Mechnikov North-Western State Medical University, Ministry of Health of Russia
| | - D. A. Kudlay
- JSC “GENERIUM”;
I.M. Sechenov First Moscow State Medical University, Ministry of Health of Russia (Sechenov University);
National Research Center – Institute of Immunology Federal Medical-Biological Agency of Russia
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Mei Y, Tang L, Xiao Q, Zhang Z, Zhang Z, Zang J, Zhou J, Wang Y, Wang W, Ren M. Reconstituted high density lipoprotein (rHDL), a versatile drug delivery nanoplatform for tumor targeted therapy. J Mater Chem B 2021; 9:612-633. [PMID: 33306079 DOI: 10.1039/d0tb02139c] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
rHDL is a synthesized drug delivery nanoplatform exhibiting excellent biocompatibility, which possesses most of the advantages of HDL. rHDL shows almost no toxicity and can be degraded to non-toxic substances in vivo. The severe limitation of the application of various antitumor agents is mainly due to their low bioavailability, high toxicity, poor stability, etc. Favorably, antitumor drug-loaded rHDL nanoparticles (NPs), which are known as an important drug delivery system (DDS), help to change the situation a lot. This DDS shows an outstanding active-targeting ability towards tumor cells and improves the therapeutic effect during antitumor treatment while overcoming the shortcomings mentioned above. In the following text, we will mainly focus on the various applications of rHDL in tumor targeted therapy by describing the properties, preparation, receptor active-targeting ability and antitumor effects of antineoplastic drug-loaded rHDL NPs.
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Affiliation(s)
- Yijun Mei
- State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China.
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48
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Stem cell-based therapy treating glioblastoma multiforme. Hematol Oncol Stem Cell Ther 2021; 14:1-15. [PMID: 32971031 DOI: 10.1016/j.hemonc.2020.08.001] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2020] [Revised: 07/20/2020] [Accepted: 08/14/2020] [Indexed: 01/27/2023] Open
Abstract
Glioblastoma (GB) is one of the most malignant types of central nervous system tumours, classified as grade IV by the World Health Organization. Despite the therapeutic advances, the prognosis is ominous, with a median survival of about 12-15 months post diagnosis. Although therapeutic options available can increase the survival, they are ineffective in treating patients with GB. Impairing factors such as the blood-brain barrier, cancer stem cells, and infiltration into brain parenchyma lead to failure of current therapies. Therefore, clinicians need novel/alternative effective strategies to treat GB. Due to their ability to preserve healthy tissues and to provide an effective and long-lasting response, stem cells (SCs) with tropism for tumour cells have attracted considerable attention in the scientific community. As is the case here, SCs can be used to target brain tumour cancer cells, especially high-grade malignant gliomas like GB, by overcoming the resistance and exerting benefits for patients affected with such lethal disease. Herein, we will discuss the research knowledge regarding SC-based therapy for the treatment of GB, focalising our attention on SCs and SC-released extracellular vesicles modified to express/load different antitumour payloads, as well as on SCs exploited as a diagnostic tool. Advantages and unresolved issues of anticancer SC-based therapy will also be considered.
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Kaiser LM, Hunter ZR, Treon SP, Buske C. CXCR4 in Waldenström's Macroglobulinema: chances and challenges. Leukemia 2021; 35:333-345. [PMID: 33273682 PMCID: PMC7862063 DOI: 10.1038/s41375-020-01102-3] [Citation(s) in RCA: 59] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Revised: 10/09/2020] [Accepted: 11/17/2020] [Indexed: 02/06/2023]
Abstract
It is one of the major aims in cancer research to improve our understanding of the underlying mechanisms which initiate and maintain tumor growth and to translate these findings into novel clinical diagnostic and therapeutic concepts with the ultimate goal to improve patient care. One of the greater success stories in this respect has been Waldenström's Macroglobulinemia (WM), which is an incurable B-cell neoplasm characterized by serum monoclonal immunoglobulin M (IgM) and clonal lymphoplasmacytic cells infiltrating the bone marrow. Recent years have succeeded to describe the molecular landscape of WM in detail, highlighting two recurrently mutated genes, the MYD88 and the CXCR4 genes: MYD88 with an almost constant and recurrent point mutation present in over 90% of patients and CXCR4 with over 40 different mutations in the coding region affecting up to 40% of patients. Intriguingly, both mutations are activating mutations leading in the case of CXCR4 to an indelible activation and perpetual signaling of the chemokine receptor. These data have shed light on the essential role of CXCR4 in this disease and have paved the way to use these findings for predicting treatment response to the Bruton tyrosine kinase (BTK) inhibitor ibrutinib and novel therapeutic approaches in WM, which might be transferable to other related CXCR4 positive diseases. Well known for its central role in cancer progression and distribution, CXCR4 is highlighted in this review with regard to its biology, prognostic and predictive relevance and therapeutic implications in WM.
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Affiliation(s)
- Lisa Marie Kaiser
- Institute of Experimental Cancer Research, CCC and University Hospital Ulm, Germany, 89081, Ulm, Germany
| | - Zachary R Hunter
- Bing Center for Waldenström's Macroglobulinemia, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Steven P Treon
- Bing Center for Waldenström's Macroglobulinemia, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Christian Buske
- Institute of Experimental Cancer Research, CCC and University Hospital Ulm, Germany, 89081, Ulm, Germany.
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Li X, Chen M, Lu W, Tang J, Deng L, Wen Q, Huang M, Deng R, Ye G, Ye W, Zhang D. Targeting FAPα-expressing tumor-associated mesenchymal stromal cells inhibits triple-negative breast cancer pulmonary metastasis. Cancer Lett 2021; 503:32-42. [PMID: 33482262 DOI: 10.1016/j.canlet.2021.01.013] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Revised: 12/08/2020] [Accepted: 01/13/2021] [Indexed: 02/08/2023]
Abstract
Tumor metastasis is the main cause of death in patients with triple-negative breast cancer (TNBC). Bone marrow-derived mesenchymal stem cells (BM-MSCs) have tropism towards tumor tissues, and can be converted into tumor-associated mesenchymal stromal cells (TA-MSCs) to facilitate TNBC metastasis through interactions with tumor-associated macrophages (TAMs). However, the underlying molecular mechanisms are complex and unclear, and effective strategies to suppress tumor metastasis via eliminating TA-MSCs are still lacking. Here, we demonstrate that fibroblast activation protein alpha (FAPα) was overexpressed in TA-MSCs, which prompts TA-MSCs to secrete multiple C-C motif chemokine ligands, promoting C-C motif chemokine receptor 2 (CCR2)+ TAM recruitment and facilitating TAM polarization into the M2 phenotype, thereby promoting TNBC pulmonary metastasis. Z-GP-DAVLBH, an FAPα-activated vinblastine prodrug, induces FAPα+ TA-MSC apoptosis, which significantly suppresses CCR2+ TAM recruitment and polarization, thus inhibiting pulmonary metastasis of orthotopic TNBC cell-derived xenografts and patient-derived xenografts. This study provides insight into an important role of FAPα in mediating TA-MSC-induced TNBC metastasis and provides compelling evidence that targeting TA-MSCs with an FAPα-activated prodrug is a promising strategy for suppressing TNBC metastasis.
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Affiliation(s)
- Xiaobo Li
- College of Pharmacy, Jinan University, Guangzhou, 510632, PR China
| | - Minfeng Chen
- College of Pharmacy, Jinan University, Guangzhou, 510632, PR China
| | - Weijin Lu
- College of Pharmacy, Jinan University, Guangzhou, 510632, PR China
| | - Jun Tang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, 510060, PR China; Department of Breast Oncology, Sun Yat-sen University Cancer Center, Guangzhou, 510060, PR China
| | - Lijuan Deng
- Formula-pattern Research Center, School of Traditional Chinese Medicine, Jinan University, Guangzhou, 510632, PR China
| | - Qing Wen
- College of Pharmacy, Jinan University, Guangzhou, 510632, PR China
| | - Maohua Huang
- College of Pharmacy, Jinan University, Guangzhou, 510632, PR China
| | - Rong Deng
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, 510060, PR China
| | - Geni Ye
- College of Pharmacy, Jinan University, Guangzhou, 510632, PR China
| | - Wencai Ye
- College of Pharmacy, Jinan University, Guangzhou, 510632, PR China.
| | - Dongmei Zhang
- College of Pharmacy, Jinan University, Guangzhou, 510632, PR China.
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