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1
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Masrour M, Moeinafshar A, Poopak A, Razi S, Rezaei N. The role of CXC chemokines and receptors in breast cancer. Clin Exp Med 2025; 25:128. [PMID: 40278951 PMCID: PMC12031896 DOI: 10.1007/s10238-025-01662-7] [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: 09/17/2024] [Accepted: 04/01/2025] [Indexed: 04/26/2025]
Abstract
CXC chemokines are a class of cytokines possessing chemotactic properties. Studies indicate that CXC chemokines exhibit dysregulation in miscellaneous cancer categories and are significantly associated with the advancement of tumors. Breast cancer is a commonly diagnosed and fatal cancer among the female population. Breast cancer pathogenesis and progression involve various mechanisms, including invasion, metastasis, angiogenesis, and inflammation. Chemokines and their receptors are involved in all of these processes. The CXC chemokine receptors (CXCRs) and their related ligands have attracted considerable attention due to their multifaceted functions in facilitating and controlling tumor proliferation. CXCRs are expressed by both cancer cells and immune cells, and they play a crucial role in regulating the tumor microenvironment and the immune response. This review aims to assess the potential of CXCRs and CXC chemokines as therapeutic targets or biomarkers for personalized therapy. Additionally, it provides an overview of the current understanding of the expression, function, and prognostic relevance of CXCRs in breast cancer. Furthermore, the challenges and potential prospects pertaining to CXCR investigation in breast cancer are deliberated.
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Affiliation(s)
- Mahdi Masrour
- School of Medicine, Tehran University of Medical Sciences (TUMS), Tehran, Iran
- Center for Orthopedic Trans-Disciplinary Applied Research, Tehran University of Medical Sciences, Tehran, Iran
| | - Aysan Moeinafshar
- School of Medicine, Tehran University of Medical Sciences (TUMS), Tehran, Iran
| | - Amirhossein Poopak
- School of Medicine, Tehran University of Medical Sciences (TUMS), Tehran, Iran
| | - Sepideh Razi
- Cancer Immunology Project (CIP), Universal Scientific and Education Network (USERN), Tehran, Iran
- Research Center for Immunodeficiencies, Children's Medical Center Hospital, Tehran University of Medical Sciences, Dr. Qarib St, Keshavarz Blvd, Tehran, 14194, Iran
| | - Nima Rezaei
- Research Center for Immunodeficiencies, Children's Medical Center Hospital, Tehran University of Medical Sciences, Dr. Qarib St, Keshavarz Blvd, Tehran, 14194, Iran.
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
- Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran.
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2
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Sang X, Jiao H, Meng Q, Fang X, Pan Q, Zhou J, Qian T, Zhang W, Xu Y, An J, Huang Z, Hu H. Structural mechanisms underlying the modulation of CXCR4 by diverse small-molecule antagonists. Proc Natl Acad Sci U S A 2025; 122:e2425795122. [PMID: 40063796 PMCID: PMC11929458 DOI: 10.1073/pnas.2425795122] [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: 12/22/2024] [Accepted: 01/22/2025] [Indexed: 03/22/2025] Open
Abstract
CXCR4 (CXC chemokine receptor type 4), a member of the G protein-coupled receptor superfamily, plays a role in cell migration and functions as a coreceptor for HIV entry. Molecular therapeutics targeting CXCR4 have been under intensive investigation. To date, only two small-molecule antagonist drugs targeting CXCR4, plerixafor (AMD3100) and mavorixafor (AMD070), have been approved. Here, we present the high-resolution structures of CXCR4 complexed with AMD3100 and AMD070, as well as a small-molecule antagonist HF51116 that has very different chemical structure and binding mechanism from AMD3100 and AMD070. The interactions between these antagonists and the receptor are analyzed in details, and the mechanisms of antagonism are elucidated. Both the major and minor subpockets on CXCR4 are found to be involved in binding of these small-molecule antagonists. The distinct conformations of Trp942.60 observed in these structures highlight the plasticity of the binding pocket on CXCR4, offering valuable insights into the exploration and refinement of therapeutic strategies targeting this chemokine receptor.
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Affiliation(s)
- Xiaohong Sang
- Ciechanover Institute of Precision and Regenerative Medicine, School of Medicine, The Chinese University of Hong Kong, Shenzhen518172, China
| | - Haizhan Jiao
- Kobilka Institute of Innovative Drug Discovery, School of Medicine, The Chinese University of Hong Kong, Shenzhen518172, China
| | - Qian Meng
- School of Life Sciences, Tsinghua University, Beijing100084, China
| | - Xiong Fang
- School of Life Sciences, Tsinghua University, Beijing100084, China
| | - Qi Pan
- Kobilka Institute of Innovative Drug Discovery, School of Medicine, The Chinese University of Hong Kong, Shenzhen518172, China
| | - Jiao Zhou
- Ciechanover Institute of Precision and Regenerative Medicine, School of Medicine, The Chinese University of Hong Kong, Shenzhen518172, China
| | - Tingli Qian
- Ciechanover Institute of Precision and Regenerative Medicine, School of Medicine, The Chinese University of Hong Kong, Shenzhen518172, China
| | - Wanqin Zhang
- Kobilka Institute of Innovative Drug Discovery, School of Medicine, The Chinese University of Hong Kong, Shenzhen518172, China
| | - Yan Xu
- Division of Infectious Diseases and Global Public Health, Department of Medicine, School of Medicine, University of California San Diego, San Diego, CA92037
| | - Jing An
- Division of Infectious Diseases and Global Public Health, Department of Medicine, School of Medicine, University of California San Diego, San Diego, CA92037
| | - Ziwei Huang
- Ciechanover Institute of Precision and Regenerative Medicine, School of Medicine, The Chinese University of Hong Kong, Shenzhen518172, China
- School of Life Sciences, Tsinghua University, Beijing100084, China
- Division of Infectious Diseases and Global Public Health, Department of Medicine, School of Medicine, University of California San Diego, San Diego, CA92037
| | - Hongli Hu
- Kobilka Institute of Innovative Drug Discovery, School of Medicine, The Chinese University of Hong Kong, Shenzhen518172, China
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3
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Cheng SL, Wu CH, Tsai YJ, Song JS, Chen HM, Yeh TK, Shen CT, Chiang JC, Lee HM, Huang KW, Chen Y, Qiu JT, Yen YT, Shia KS, Chen Y. CXCR4 antagonist-loaded nanoparticles reprogram the tumor microenvironment and enhance immunotherapy in hepatocellular carcinoma. J Control Release 2025; 379:967-981. [PMID: 39863023 DOI: 10.1016/j.jconrel.2025.01.066] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2024] [Revised: 01/20/2025] [Accepted: 01/22/2025] [Indexed: 01/27/2025]
Abstract
Hepatocellular carcinoma (HCC) is a leading cause of cancer death that has limited treatment options for advanced stages. Although PD-1 inhibitors such as nivolumab and pembrolizumab have been approved for advanced HCC treatment, their effectiveness is often hampered by the immunosuppressive tumor microenvironment (TME), which is due to hypoxia-driven CXCL12/CXCR4 axis activation. In this study, we developed 807-NPs, lipid-coated tannic acid (TA) nanoparticles that encapsulate BPRCX807, a potent CXCR4 antagonist to target HCC. 807-NPs enhance the pharmacokinetics and improve the tumor availability of BPRCX807 without causing systemic toxicity. Our findings show that 807-NPs block the CXCR4/CXCL12 pathway, inhibiting Akt and mTOR activation in HCC cells and M2 macrophages and promoting their repolarization toward the antitumor M1 phenotype. In orthotopic murine HCC models, systemic administration of 807-NPs significantly remodeled the immunosuppressive TME by reprogramming tumor-associated macrophages (TAMs) toward an immunostimulatory phenotype and promoting cytotoxic T-cell infiltration into tumors. This led to suppressed primary tumor growth and metastasis, while enhancing the efficacy of cancer immunotherapies, including PD-1 blockade and whole-cancer cell vaccines, by promoting T-cell activation. Our work demonstrates the potential of using nanotechnology to deliver CXCR4 antagonists for cancer immunotherapy.
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Affiliation(s)
- Sheng-Liang Cheng
- Institute of Biomedical Engineering, National Tsing Hua University, Hsinchu 30013, Taiwan; International Intercollegiate PhD Program, National Tsing Hua University, Hsinchu 30013, Taiwan
| | - Chien-Huang Wu
- Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 35053, Taiwan
| | - Yun-Jen Tsai
- Institute of Biomedical Engineering, National Tsing Hua University, Hsinchu 30013, Taiwan
| | - Jen-Shin Song
- Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 35053, Taiwan
| | - Hsin-Min Chen
- Institute of Biomedical Engineering, National Tsing Hua University, Hsinchu 30013, Taiwan
| | - Teng-Kuang Yeh
- Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 35053, Taiwan
| | - Chia-Tung Shen
- Institute of Biomedical Engineering, National Tsing Hua University, Hsinchu 30013, Taiwan
| | - Jou-Chien Chiang
- Institute of Biomedical Engineering, National Tsing Hua University, Hsinchu 30013, Taiwan
| | - Hsin-Mei Lee
- Institute of Biomedical Engineering, National Tsing Hua University, Hsinchu 30013, Taiwan
| | - Kuan-Wei Huang
- Institute of Biomedical Engineering, National Tsing Hua University, Hsinchu 30013, Taiwan
| | - Yuling Chen
- Institute of Biomedical Engineering, National Tsing Hua University, Hsinchu 30013, Taiwan
| | - J Timothy Qiu
- International PhD Program in Cell Therapy and Regenerative Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan; Department of Obstetrics and Gynecology, Taipei Medical University Hospital, Taipei 11031, Taiwan; Department of Obstetrics and Gynecology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110301, Taiwan
| | - Yu-Ting Yen
- Institute of Translational Medicine and New Drug Development, School of Medicine, China Medical University, Taichung, Taiwan.
| | - Kak-Shan Shia
- Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 35053, Taiwan.
| | - Yunching Chen
- Institute of Biomedical Engineering, National Tsing Hua University, Hsinchu 30013, Taiwan; Department of Chemistry, National Tsing Hua University, Hsinchu 30013, Taiwan.
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4
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Solomon B. Bone marrow-derived microglia confer neuroprotection to a mouse model of amyotrophic lateral sclerosis. Neural Regen Res 2024; 19:2586-2587. [PMID: 38808993 PMCID: PMC11168524 DOI: 10.4103/nrr.nrr-d-23-01763] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2023] [Revised: 01/23/2024] [Accepted: 02/04/2024] [Indexed: 05/30/2024] Open
Affiliation(s)
- Beka Solomon
- Department of Molecular Microbiology and Biotechnology, The Shmunis School of Biomedicine and Cancer Research, the George S. Wise Faculty of Life Sciences Tel-Aviv University, Ramat Aviv, Israel
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5
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García-Cuesta EM, Martínez P, Selvaraju K, Ulltjärn G, Gómez Pozo AM, D'Agostino G, Gardeta S, Quijada-Freire A, Blanco Gabella P, Roca C, Hoyo DD, Jiménez-Saiz R, García-Rubia A, Soler Palacios B, Lucas P, Ayala-Bueno R, Santander Acerete N, Carrasco Y, Oscar Sorzano C, Martinez A, Campillo NE, Jensen LD, Rodriguez Frade JM, Santiago C, Mellado M. Allosteric modulation of the CXCR4:CXCL12 axis by targeting receptor nanoclustering via the TMV-TMVI domain. eLife 2024; 13:RP93968. [PMID: 39248648 PMCID: PMC11383527 DOI: 10.7554/elife.93968] [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] [Indexed: 09/10/2024] Open
Abstract
CXCR4 is a ubiquitously expressed chemokine receptor that regulates leukocyte trafficking and arrest in both homeostatic and pathological states. It also participates in organogenesis, HIV-1 infection, and tumor development. Despite the potential therapeutic benefit of CXCR4 antagonists, only one, plerixafor (AMD3100), which blocks the ligand-binding site, has reached the clinic. Recent advances in imaging and biophysical techniques have provided a richer understanding of the membrane organization and dynamics of this receptor. Activation of CXCR4 by CXCL12 reduces the number of CXCR4 monomers/dimers at the cell membrane and increases the formation of large nanoclusters, which are largely immobile and are required for correct cell orientation to chemoattractant gradients. Mechanistically, CXCR4 activation involves a structural motif defined by residues in TMV and TMVI. Using this structural motif as a template, we performed in silico molecular modeling followed by in vitro screening of a small compound library to identify negative allosteric modulators of CXCR4 that do not affect CXCL12 binding. We identified AGR1.137, a small molecule that abolishes CXCL12-mediated receptor nanoclustering and dynamics and blocks the ability of cells to sense CXCL12 gradients both in vitro and in vivo while preserving ligand binding and receptor internalization.
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Affiliation(s)
- Eva M García-Cuesta
- Chemokine Signaling group, Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Campus de Cantoblanco, Madrid, Spain
| | - Pablo Martínez
- Chemokine Signaling group, Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Campus de Cantoblanco, Madrid, Spain
| | - Karthik Selvaraju
- Division of Diagnostics and Specialist Medicine, Department of Health, Medical and Caring Sciences, Linköping University, Linköping, Sweden
| | - Gabriel Ulltjärn
- Division of Diagnostics and Specialist Medicine, Department of Health, Medical and Caring Sciences, Linköping University, Linköping, Sweden
| | | | - Gianluca D'Agostino
- Chemokine Signaling group, Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Campus de Cantoblanco, Madrid, Spain
| | - Sofia Gardeta
- Chemokine Signaling group, Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Campus de Cantoblanco, Madrid, Spain
| | - Adriana Quijada-Freire
- Chemokine Signaling group, Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Campus de Cantoblanco, Madrid, Spain
| | | | - Carlos Roca
- Centro de Investigaciones Biológicas Margarita Salas (CIB-CSIC), Madrid, Spain
| | - Daniel Del Hoyo
- Biocomputing Unit, Centro Nacional de Biotecnología (CNB-CSIC), Campus de Cantoblanco, Madrid, Spain
| | - Rodrigo Jiménez-Saiz
- Chemokine Signaling group, Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Campus de Cantoblanco, Madrid, Spain
- Department of Immunology, Instituto de Investigación Sanitaria Hospital Universitario de La Princesa (IIS-Princesa), Madrid, Spain
- Department of Medicine, McMaster Immunology Research Centre (MIRC), Schroeder Allergy and Immunology Research Institute, McMaster University, Hamilton, Canada
- Faculty of Experimental Sciences, Universidad Francisco de Vitoria (UFV), Madrid, Spain
| | | | - Blanca Soler Palacios
- Chemokine Signaling group, Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Campus de Cantoblanco, Madrid, Spain
| | - Pilar Lucas
- Chemokine Signaling group, Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Campus de Cantoblanco, Madrid, Spain
| | - Rosa Ayala-Bueno
- Chemokine Signaling group, Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Campus de Cantoblanco, Madrid, Spain
| | - Noelia Santander Acerete
- Chemokine Signaling group, Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Campus de Cantoblanco, Madrid, Spain
| | - Yolanda Carrasco
- B Lymphocyte Dynamics, Department of Immunology and Oncology, Centro Nacional de Biotecnología (CNB)/CSIC, Campus de Cantoblanco, Madrid, Spain
| | - Carlos Oscar Sorzano
- Biocomputing Unit, Centro Nacional de Biotecnología (CNB-CSIC), Campus de Cantoblanco, Madrid, Spain
| | - Ana Martinez
- Centro de Investigaciones Biológicas Margarita Salas (CIB-CSIC), Madrid, Spain
- Neurodegenerative Diseases Biomedical Research Network Center (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain
| | - Nuria E Campillo
- Centro de Investigaciones Biológicas Margarita Salas (CIB-CSIC), Madrid, Spain
| | - Lasse D Jensen
- Division of Diagnostics and Specialist Medicine, Department of Health, Medical and Caring Sciences, Linköping University, Linköping, Sweden
| | - Jose Miguel Rodriguez Frade
- Chemokine Signaling group, Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Campus de Cantoblanco, Madrid, Spain
| | - César Santiago
- X-ray Crystallography Unit, Department of Macromolecules Structure, Centro Nacional de Biotecnología/CSIC, Campus de Cantoblanco, Madrid, Spain
| | - Mario Mellado
- Chemokine Signaling group, Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Campus de Cantoblanco, Madrid, Spain
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6
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Wang W, Brown TJ, Barth BM. Influences on the Hematopoietic Stem Cell Niche. SCIBASE HEMATOLOGY & BLOOD DISORDERS 2024; 1:1002. [PMID: 39429505 PMCID: PMC11486556] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Subscribe] [Scholar Register] [Indexed: 10/22/2024]
Abstract
Hematopoietic stem cells (HSCs) are supported by the bone marrow microenvironment to maintain normal production of blood cells. The niche may be considered an "ecosystem" that support the function of HSCs and other supportive cells. Alterations in the bone marrow niche are commonly observed in hematologic malignancies. Here, we review recent insights into the location and the molecular and cellular components of the bone marrow niche. Moreover, we discuss how the niche interacts with HSCs to drive the pathogenesis of hematopoietic malignancies. Overall, a better understanding of the influences on the HSC niche may drive therapeutic development targeting defective and aberrant hematopoiesis.
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Affiliation(s)
- Weiyuan Wang
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta GA 30322 USA
- Department of Molecular, Cellular and Biomedical Sciences, University of New Hampshire, Durham NH 03824 USA
| | - Timothy J. Brown
- Division of Hematology and Oncology, Department of Medicine, University of Texas Southwestern Medical Center, Dallas TX 75390 USA
| | - Brian M. Barth
- Department of Molecular, Cellular and Biomedical Sciences, University of New Hampshire, Durham NH 03824 USA
- Department of Natural Sciences, University of Alaska Southeast, Juneau AK 99801 USA
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7
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Kim N, Na S, Pyo J, Jang J, Lee SM, Kim K. A Bioinformatics Investigation of Hub Genes Involved in Treg Migration and Its Synergistic Effects, Using Immune Checkpoint Inhibitors for Immunotherapies. Int J Mol Sci 2024; 25:9341. [PMID: 39273290 PMCID: PMC11395080 DOI: 10.3390/ijms25179341] [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: 08/07/2024] [Revised: 08/23/2024] [Accepted: 08/27/2024] [Indexed: 09/15/2024] Open
Abstract
This study aimed to identify hub genes involved in regulatory T cell (Treg) function and migration, offering insights into potential therapeutic targets for cancer immunotherapy. We performed a comprehensive bioinformatics analysis using three gene expression microarray datasets from the GEO database. Differentially expressed genes (DEGs) were identified to pathway enrichment analysis to explore their functional roles and potential pathways. A protein-protein interaction network was constructed to identify hub genes critical for Treg activity. We further evaluated the co-expression of these hub genes with immune checkpoint proteins (PD-1, PD-L1, CTLA4) and assessed their prognostic significance. Through this comprehensive analysis, we identified CCR8 as a key player in Treg migration and explored its potential synergistic effects with ICIs. Our findings suggest that CCR8-targeted therapies could enhance cancer immunotherapy outcomes, with breast invasive carcinoma (BRCA) emerging as a promising indication for combination therapy. This study highlights the potential of CCR8 as a biomarker and therapeutic target, contributing to the development of targeted cancer treatment strategies.
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Affiliation(s)
- Nari Kim
- Biomedical Research Center, Asan Institute for Life Sciences, Asan Medical Center, Seoul 05505, Republic of Korea
| | - Seoungwon Na
- Biomedical Research Center, Asan Institute for Life Sciences, Asan Medical Center, Seoul 05505, Republic of Korea
| | - Junhee Pyo
- College of Pharmacy, Chungbuk National University, Cheongju 28644, Republic of Korea
| | - Jisung Jang
- Trial Informatics Inc., Seoul 05544, Republic of Korea
| | - Soo-Min Lee
- Samjin Pharmaceutical Co., Ltd., Seoul 04054, Republic of Korea
| | - Kyungwon Kim
- Trial Informatics Inc., Seoul 05544, Republic of Korea
- Departments of Radiology and Research Institute of Radiology, Asan Medical Center, College of Medicine, University of Ulsan, Olymphic-ro 43 Gil 88, Songpa-gu, Seoul 05505, Republic of Korea
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8
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Sagini MN, Zepp M, Eyol E, Ali DM, Gromova S, Dahlmann M, Behrens D, Groeschel C, Tischmeier L, Hoffmann J, Berger MR, Forssmann WG. EPI-X4, a CXCR4 antagonist inhibits tumor growth in pancreatic cancer and lymphoma models. Peptides 2024; 175:171111. [PMID: 38036098 DOI: 10.1016/j.peptides.2023.171111] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2023] [Revised: 10/20/2023] [Accepted: 10/25/2023] [Indexed: 12/02/2023]
Abstract
Endogenous peptide inhibitor for CXCR4 (EPI-X4) is a CXCR4 antagonist with potential for cancer therapy. It is a processed fragment of serum albumin from the hemofiltrate of dialysis patients. This study reports the efficacy of fifteen EPI-X4 derivatives in pancreatic cancer and lymphoma models. In vitro, the peptides were investigated for antiproliferation (cytotoxicity) by MTT assay. The mRNA expression for CXCR4 and CXCL12 was determined by RT-PCR, chip array and RNA sequencing. Chip array analysis yielded 634 genes associated with CXCR4/CXCL12 signaling. About 21% of these genes correlated with metastasis in the context of cell motility, proliferation, and survival. Expression levels of these genes were altered in pancreatic cancer (36%), lymphoma models (53%) and in patients' data (58%). EPI-X4 derivatives failed to inhibit cell proliferation due to low expression of CXCR4 in vitro, but inhibited tumor growth in the bioassays with significant efficacy. In the pancreatic cancer model, EPI-X4a, f and k inhibited mean tumor growth by > 50% and even caused complete remissions. In the lymphoma model, EPI-X4b, n and p inhibited mean tumor growth by > 70% and caused stable disease. Given the non-toxic and non-immunogenic properties of EPI-X4, these findings underscore its status as a promising therapy of pancreatic cancer and lymphoma and warrant further studies. SIMPLE SUMMARY: This study examined the value of chemokine receptor CXCR4 as an antineoplastic target for the endogenous peptide inhibitor of CXCR4 (EPI-X4), a 12-meric peptide derived from serum albumin. EPI-X4 inhibits CXCR4 interaction with its natural ligand, CXCL12 (SDF1). Therefore, malignancies (including pancreatic cancer and lymphoma) that depend on the CXCR4/CXCL12 pathway for progression can be targeted with EPI-X4. Of 634 genes that were linked to the CXCR4/CXCL12 pathway, 21% were associated with metastasis. In cultured human Suit2-007 pancreatic cancer cells, CXCR4 showed low to undetectable expression, which was why EPI-X4 did not inhibit pancreatic cancer cell proliferation. These findings were different in vivo, where CXCR4 was highly expressed and EPI-X4 inhibited tumor growth in rodents harboring pancreatic cancer or lymphoma. In the pancreatic cancer model, EPI-X4 derivatives a, f and k caused complete remissions, while in lymphomas EPI-X4 derivatives b, n and p caused stable disease.
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Affiliation(s)
- Micah N Sagini
- Toxicology and Chemotherapy Unit, German Cancer Research Centre (DKFZ), Heidelberg, Germany
| | - Michael Zepp
- Toxicology and Chemotherapy Unit, German Cancer Research Centre (DKFZ), Heidelberg, Germany
| | - Ergül Eyol
- Toxicology and Chemotherapy Unit, German Cancer Research Centre (DKFZ), Heidelberg, Germany
| | - Doaa M Ali
- Toxicology and Chemotherapy Unit, German Cancer Research Centre (DKFZ), Heidelberg, Germany
| | - Svetlana Gromova
- EPO, Experimental Pharmacology & Oncology Berlin-Buch GmbH, Germany
| | - Mathias Dahlmann
- EPO, Experimental Pharmacology & Oncology Berlin-Buch GmbH, Germany
| | - Diana Behrens
- EPO, Experimental Pharmacology & Oncology Berlin-Buch GmbH, Germany
| | - Christian Groeschel
- NeoPep Pharma GmbH & Co. KG., Hannover, Germany and Hannover Medical School, Department of Internal Medicine, Germany
| | - Linus Tischmeier
- NeoPep Pharma GmbH & Co. KG., Hannover, Germany and Hannover Medical School, Department of Internal Medicine, Germany
| | - Jens Hoffmann
- EPO, Experimental Pharmacology & Oncology Berlin-Buch GmbH, Germany
| | - Martin R Berger
- Toxicology and Chemotherapy Unit, German Cancer Research Centre (DKFZ), Heidelberg, Germany.
| | - Wolf-Georg Forssmann
- NeoPep Pharma GmbH & Co. KG., Hannover, Germany and Hannover Medical School, Department of Internal Medicine, Germany.
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9
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D'Andrea V, Gallo G. Editorial: Updates on ulcerative colitis and Crohn's disease: from bench to bedside. Front Med (Lausanne) 2023; 10:1285660. [PMID: 37780561 PMCID: PMC10539646 DOI: 10.3389/fmed.2023.1285660] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Accepted: 09/01/2023] [Indexed: 10/03/2023] Open
Affiliation(s)
- Vito D'Andrea
- Department of Surgery, Sapienza University of Rome, Rome, Italy
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10
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Khorramdelazad H, Bagherzadeh K, Rahimi A, Safari E, Hassanshahi G, Khoshmirsafa M, Karimi M, Mohammadi M, Darehkordi A, Falak R. Antitumor activities of a novel fluorinated small molecule (A1) in CT26 colorectal cancer cells: molecular docking and in vitro studies. J Biomol Struct Dyn 2023; 42:10175-10188. [PMID: 37705281 DOI: 10.1080/07391102.2023.2256406] [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: 06/09/2023] [Accepted: 09/02/2023] [Indexed: 09/15/2023]
Abstract
Chemotherapeutic treatment of colorectal cancer (CRC) has not been satisfactory until now; therefore, the discovery of more efficient medications is of great significance. Based on available knowledge, the CXCL12/CXCR4 axis plays a significant role in tumorigenesis, and inhibition of CXCR4 chemokine receptor with AMD3100 is one of the most known therapeutic modalities in cancer therapy. Herein, N, N''-thiocarbonylbis(N'-(3,4-dimethylphenyl)-2,2,2-trifluoroacetimidamide) (A1) was synthesized as a potent CXCR4 inhibitor. A1 inhibitory activity was first evaluated employing Molecular Docking simulations in comparison with the most potent CXCR4 inhibitors. Then, the antiproliferative and cytotoxic effect of A1 on CT26 mouse CRC cells was investigated by MTT assay technique and compared with those of the control molecule, AMD3100. The impact of the target compounds IC50 on apoptosis, cell cycle arrest, and CXCR4 expression was determined by flow cytometry technique. Our finding demonstrated that A1 induces a cytotoxic effect on CT26 cells at 60 μg/mL concentration within 72 h and provokes cell apoptosis and G2/M cell cycle arrest in comparison with the untreated cells, while AMD3100 did not show a cytotoxic effect up to 800 μg/mL dose. The obtained results show that A1 (at a concentration of 40 μg/mL) significantly reduced the proliferation of CT26 cells treated with 100 ng/mL of CXCL12 in 72 h. Moreover, treatment with 60 μg/mL of A1 and 100 ng/mL of CXCL12 for 72 h significantly decreased the number of cells expressing the CXCR4 receptor compared to the control group treated with CXCL12. Eventually, the obtained results indicate that A1, as a dual-function fluorinated small molecule, may benefit CRC treatment through inhibition of CXCR4 and exert a cytotoxic effect on tumor cells.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Hossein Khorramdelazad
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Kowsar Bagherzadeh
- Eye Research Center, the Five Senses Health Institute, Rassoul Akram Hospital, Iran University of Medical Sciences, Tehran, Iran
- Stem Cell and Regenerative Medicine Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Ali Rahimi
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Elaheh Safari
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Gholamhossein Hassanshahi
- Department of Immunology, School of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Majid Khoshmirsafa
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Milad Karimi
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Mahdi Mohammadi
- Department of Chemistry, Vali-e-Asr University of Rafsanjan, Rafsanjan, Iran
| | - Ali Darehkordi
- Department of Chemistry, Vali-e-Asr University of Rafsanjan, Rafsanjan, Iran
| | - Reza Falak
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
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11
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Cao J, Chow L, Dow S. Strategies to overcome myeloid cell induced immune suppression in the tumor microenvironment. Front Oncol 2023; 13:1116016. [PMID: 37114134 PMCID: PMC10126309 DOI: 10.3389/fonc.2023.1116016] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Accepted: 03/17/2023] [Indexed: 04/29/2023] Open
Abstract
Cancer progression and metastasis due to tumor immune evasion and drug resistance is strongly associated with immune suppressive cellular responses, particularly in the case of metastatic tumors. The myeloid cell component plays a key role within the tumor microenvironment (TME) and disrupts both adaptive and innate immune cell responses leading to loss of tumor control. Therefore, strategies to eliminate or modulate the myeloid cell compartment of the TME are increasingly attractive to non-specifically increase anti-tumoral immunity and enhance existing immunotherapies. This review covers current strategies targeting myeloid suppressor cells in the TME to enhance anti-tumoral immunity, including strategies that target chemokine receptors to deplete selected immune suppressive myeloid cells and relieve the inhibition imposed on the effector arms of adaptive immunity. Remodeling the TME can in turn improve the activity of other immunotherapies such as checkpoint blockade and adoptive T cell therapies in immunologically "cold" tumors. When possible, in this review, we have provided evidence and outcomes from recent or current clinical trials evaluating the effectiveness of the specific strategies used to target myeloid cells in the TME. The review seeks to provide a broad overview of how myeloid cell targeting can become a key foundational approach to an overall strategy for improving tumor responses to immunotherapy.
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Affiliation(s)
- Jennifer Cao
- Flint Animal Cancer Center, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO, United States
- Department of Microbiology, Immunology, and Pathology, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO, United States
| | - Lyndah Chow
- Flint Animal Cancer Center, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO, United States
- Department of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO, United States
| | - Steven Dow
- Flint Animal Cancer Center, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO, United States
- Department of Microbiology, Immunology, and Pathology, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO, United States
- Department of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO, United States
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12
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Drouillard D, Craig BT, Dwinell MB. Physiology of chemokines in the cancer microenvironment. Am J Physiol Cell Physiol 2023; 324:C167-C182. [PMID: 36317799 PMCID: PMC9829481 DOI: 10.1152/ajpcell.00151.2022] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Revised: 10/20/2022] [Accepted: 10/21/2022] [Indexed: 01/07/2023]
Abstract
Chemokines are chemotactic cytokines whose canonical functions govern movement of receptor-expressing cells along chemical gradients. Chemokines are a physiological system that is finely tuned by ligand and receptor expression, ligand or receptor oligomerization, redundancy, expression of atypical receptors, and non-GPCR binding partners that cumulatively influence discrete pharmacological signaling responses and cellular functions. In cancer, chemokines play paradoxical roles in both the directed emigration of metastatic, receptor-expressing cancer cells out of the tumor as well as immigration of tumor-infiltrating immune cells that culminate in a tumor-unique immune microenvironment. In the age of precision oncology, strategies to effectively harness the power of immunotherapy requires consideration of chemokine gradients within the unique spatial topography and temporal influences with heterogeneous tumors. In this article, we review current literature on the diversity of chemokine ligands and their cellular receptors that detect and process chemotactic gradients and illustrate how differences between ligand recognition and receptor activation influence the signaling machinery that drives cellular movement into and out of the tumor microenvironment. Facets of chemokine physiology across discrete cancer immune phenotypes are contrasted to existing chemokine-centered therapies in cancer.
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Affiliation(s)
- Donovan Drouillard
- Medical Scientist Training Program, Medical College of Wisconsin, Milwaukee, Wisconsin
- Department of Microbiology & Immunology, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Brian T Craig
- Department of Microbiology & Immunology, Medical College of Wisconsin, Milwaukee, Wisconsin
- Department of Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Michael B Dwinell
- Department of Microbiology & Immunology, Medical College of Wisconsin, Milwaukee, Wisconsin
- Center for Immunology, Medical College of Wisconsin, Milwaukee, Wisconsin
- Department of Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin
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13
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Tian R, Sun Y, Han X, Wang J, Gu H, Wang W, Liang L. Identification and validation of prognostic autophagy-related genes associated with immune microenvironment in human gastric cancer. Aging (Albany NY) 2022; 14:7617-7634. [PMID: 36173625 PMCID: PMC9550254 DOI: 10.18632/aging.204313] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Accepted: 09/17/2022] [Indexed: 12/24/2022]
Abstract
Autophagy-related genes (ATGs) play critical roles in tumorigenesis and progression in gastric cancer (GC). The present study aimed to identify immune-based prognostic ATGs and verify their functions in tumor immune microenvironment (TIME) in GC. Macrophage infiltration was found to negatively correlate with prognosis in GC patients. After stratifying by infiltration levels of macrophages, we screened The Cancer Genome Atlas and Human Autophagy Database to identify the differentially expressed ATGs (DE-ATGs). Of 1,433 differentially expressed genes between the two groups, seven genes qualified as DE-ATGs. Of these, CXCR4, DLC1, and MAP1LC3C, exhibited strong prognostic prediction ability in Kaplan-Meier survival–log-rank test. High expression of these genes correlated with increased occurrence of advanced grade 3 tumors and poor prognoses. Furthermore, GSEA indicated that they were significantly associated with oncogenic and immune-related pathways. The comprehensive evaluation of TIME via GEPIA, ESTIMATE, CIBERSORT, and TIMER suggested that the three DE-ATGs were closely associated with immune condition, both in terms of immune cells and immune scores. Thus, the outcome of this study may aid in better understanding of the ATGs and their interaction with the immune microenvironment, which would allow the development of novel inhibitors, personalized treatment, and immunotherapy in gastric cancer.
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Affiliation(s)
- Ruyue Tian
- Department of Ultrasound, Aero Space Central Hospital, Beijing 100050, China.,Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Beijing 100050, China
| | - Ya Sun
- Department of Ultrasound, Aero Space Central Hospital, Beijing 100050, China
| | - Xuedi Han
- Department of Ultrasound, Aero Space Central Hospital, Beijing 100050, China
| | - Jiajun Wang
- Department of Ultrasound, Aero Space Central Hospital, Beijing 100050, China
| | - Hongli Gu
- Department of Ultrasound, Aero Space Central Hospital, Beijing 100050, China
| | - Wenhai Wang
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Beijing 100050, China
| | - Lei Liang
- Department of Ultrasound, Aero Space Central Hospital, Beijing 100050, China
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14
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Chemokines and NSCLC: Emerging role in prognosis, heterogeneity, and therapeutics. Semin Cancer Biol 2022; 86:233-246. [PMID: 35787939 DOI: 10.1016/j.semcancer.2022.06.010] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Revised: 06/15/2022] [Accepted: 06/24/2022] [Indexed: 12/11/2022]
Abstract
Lung cancer persists to contribute to one-quarter of cancer-associated deaths. Among the different histologies, non-small cell lung cancer (NSCLC) alone accounts for 85% of the cases. The development of therapies involving immune checkpoint inhibitors and angiogenesis inhibitors has increased patients' survival probability and reduced mortality rates. Developing targeted therapies against essential genetic alterations also translates to better treatment strategies. But the benefits still seem farfetched due to the development of drug resistance and refractory tumors. In this review, we have highlighted the interplay of different tumor microenvironment components, essentially discussing the chemokine families (CC, CXC, C, and CX3C) that regulate the tumor biology in NSCLC and promote tumor growth, metastasis, and associated heterogeneity. The development of therapeutics and prognostic markers is a complex and multipronged approach. However, some essential chemokines can act as critical players for being considered potential prognostic markers and therapeutic targets.
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15
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Zheng M, Oh SH, Choi N, Choi YJ, Kim J, Sung JH. CXCL12 inhibits hair growth through CXCR4. Biomed Pharmacother 2022; 150:112996. [PMID: 35462338 DOI: 10.1016/j.biopha.2022.112996] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2022] [Revised: 04/12/2022] [Accepted: 04/17/2022] [Indexed: 11/26/2022] Open
Abstract
CXCL12 and its receptors, which are highly expressed in the skin, are associated with various cutaneous diseases, including androgenic alopecia. However, their expression and role during the hair cycle are unknown. This study aims to investigate the expression of CXCL12 and its receptor, CXCR4, in the vicinity of hair follicles and their effect on hair growth. CXCL12 was highly expressed in dermal fibroblasts (DFs) and its level was elevated throughout the catagen and telogen phases of the hair cycle. CXCR4 is expressed in the dermal papilla (DP) and outer root sheath (ORS). In hair organ culture, hair loss was induced by recombinant CXCL12 therapy, which delayed the telogen-to-anagen transition and decreased hair length. In contrast, the suppression of CXCL12 using a neutralizing antibody and siRNA triggered the telogen-to-anagen transition and increased hair length in hair organ culture. Neutralization of CXCR7, one of the two receptors for CXCL12, only slightly affected hair growth. However, inhibition of CXCR4, the other receptor for CXCL12, increased hair growth to a considerable extent. In addition, in hair organ culture, the conditioned medium from DFs with CXCL12 siRNA considerably increased the hair length and induced proliferation of DP and ORS cells. CXCL12, through CXCR4 activation, increased STAT3 and STAT5 phosphorylation in DP and ORS cells. In contrast, blocking CXCL12 and CXCR4 decreased the phosphorylation of STAT3 and STAT5. In summary, these findings suggest that CXCL12 inhibits hair growth via the CXCR4/STAT signaling pathway and that CXCL12/CXCR4 pathway inhibitors are a promising treatment option for hair growth.
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Affiliation(s)
- Mei Zheng
- Epi Biotech Co., Ltd., Incheon 21983, South Korea
| | - Sang Ho Oh
- Department of Dermatology and Cutaneous Biology Research Institute, Severance Hospital, Yonsei University College of Medicine, Seoul 03722, South Korea
| | - Nahyun Choi
- Epi Biotech Co., Ltd., Incheon 21983, South Korea
| | | | - Jino Kim
- New Hair Institute, Seoul 06134, South Korea
| | - Jong-Hyuk Sung
- Epi Biotech Co., Ltd., Incheon 21983, South Korea; College of Pharmacy, Institute of Pharmaceutical Sciences, Yonsei University, Incheon 21983, South Korea.
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16
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Wu S, Luo W, Wu X, Shen Z, Wang X. Functional Phenotypes of Peritoneal Macrophages Upon AMD3100 Treatment During Colitis-Associated Tumorigenesis. Front Med (Lausanne) 2022; 9:840704. [PMID: 35615089 PMCID: PMC9126482 DOI: 10.3389/fmed.2022.840704] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Accepted: 04/19/2022] [Indexed: 11/13/2022] Open
Abstract
CXCL12 and its receptor CXCR4 are independent prognostic factors in colorectal cancer. AMD3100 is the most frequently used FDA-approved antagonist that targets the CXCL12-CXCR4 axis in clinical trials. We aimed to explore the role of AMD3100 and its effect on peritoneal macrophages' functional phenotypes during colitis-associated tumorigenesis. We treated AMD3100 in a colitis-associated colon cancer mouse model and evaluated its effect on tumorigenesis. The phagocytosis activities of peritoneal macrophages were measured by flow cytometry. The proportions of macrophages and M1/M2 subpopulations were investigated by flow cytometry, ELISA, and immunochemistry. Serum levels of pro-inflammatory and anti-inflammatory cytokines were measured by LEGENDplex™ kits. Transwell assay and qRT-PCR were performed to investigate the direct effect of CXCL12 on macrophages in vitro. We demonstrated that AMD3100 treatment reduced the inflammatory damages in the colonic mucosal and ameliorated tumor development in experimental mice. We found that the phagocytosis activities of peritoneal macrophages fluctuated during colitis-associated tumorigenesis. The proportions of peritoneal macrophages and M1/M2 subpopulations, together with their metabolite and cytokines, changed dynamically in the process. Moreover, AMD3100 regulated the functional phenotypes of macrophages, including reducing the recruiting activity, promoting polarization to the M1 subpopulation, and reducing IL-12 and IL-23 levels in serum. Our study contributes to understanding dynamic changes of peritoneal macrophages upon AMD3100 treatment during tumorigenesis and sheds light on the potential therapeutic target of AMD3100 and peritoneal macrophages against colitis-associated colon cancer.
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Affiliation(s)
- Shuai Wu
- Department of Gastroenterology, The Third Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory of Non-resolving Inflammation and Cancer of the Hunan Province, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Weiwei Luo
- Department of Gastroenterology, The Third Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory of Non-resolving Inflammation and Cancer of the Hunan Province, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Xing Wu
- Department of Gastroenterology, The Third Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory of Non-resolving Inflammation and Cancer of the Hunan Province, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Zhaohua Shen
- Department of Gastroenterology, The Third Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory of Non-resolving Inflammation and Cancer of the Hunan Province, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Xiaoyan Wang
- Department of Gastroenterology, The Third Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory of Non-resolving Inflammation and Cancer of the Hunan Province, The Third Xiangya Hospital, Central South University, Changsha, China
- *Correspondence: Xiaoyan Wang
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17
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Lei HW, Huang BR, Cai J, Li CM, Shang CB, Liao ZY, Wan ZD. CXCR4 antagonist AMD3100 enhances therapeutic efficacy of transcatheter arterial chemoembolization in rats with hepatocellular carcinoma. Kaohsiung J Med Sci 2022; 38:781-789. [PMID: 35467082 DOI: 10.1002/kjm2.12540] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Revised: 12/28/2021] [Accepted: 03/09/2022] [Indexed: 11/09/2022] Open
Abstract
This study aims to discover the therapeutic effect of chemokine (CXC motif) receptor 4 (CXCR4) antagonist AMD3100 combined with transcatheter arterial chemoembolization (TACE) in a rat model with hepatocellular carcinoma (HCC). An orthotopic model of HCC was established and treated with TACE (doxorubicin-lipiodol emulsion) with or without AMD3100. The tumor volume was measured by magnetic resonance imaging (MRI). Histopathological changes were detected by hematoxylin-eosin (HE) staining. HCC cell apoptosis was assessed by terminal deoxyribonucleotidyl transferase (TdT)-mediated biotin-16-dUTP nick-end labeling (TUNEL) staining. Immunohistochemistry was used to detect the expression of CD34, hypoxia-inducible factor 1α (HIF-1α), vascular endothelial growth factor (VEGF), and Ki67. Gene and protein expressions were quantified by quantitative reverse-transcription polymerase chain reaction (qRT-PCR) and western blotting, respectively. Both TACE and AMD3100 reduced the tumor volume in orthotopic rat model of HCC with the decreased CXCR4 expression in tumor tissues, and the combination had better effect. However, TACE increased the microvessel density (MVD) in HCC tissues of rats, while AMD3100 treatment reduced MVD in HCC tissues. AMD3100 reduced the TACE induced MVD in HCC tissues with the reduction of HIF-1α and VEGF expression. Either AMD3100 or TACE could promote HCC cell apoptosis accompanying by decreased cell proliferation, and their combined use had better therapeutic effects. CXCR4 antagonist AMD3100 enhance therapeutic efficacy of TACE in rats with HCC via promoting the HCC cell apoptosis, reducing cell proliferation, and inhibiting MVD, thus reducing tumor volume.
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Affiliation(s)
- Hong-Wei Lei
- Department of Interventional Vascular Surgery, The First Affiliated Hospital of Yangtze University, Jingzhou, China
| | - Bi-Run Huang
- Department of Interventional Vascular Surgery, The First Affiliated Hospital of Yangtze University, Jingzhou, China
| | - Jie Cai
- Department of Interventional Vascular Surgery, The First Affiliated Hospital of Yangtze University, Jingzhou, China
| | - Cheng-Ming Li
- Department of Interventional Vascular Surgery, The First Affiliated Hospital of Yangtze University, Jingzhou, China
| | - Chun-Bo Shang
- Department of Interventional Vascular Surgery, The First Affiliated Hospital of Yangtze University, Jingzhou, China
| | - Zhi-Yang Liao
- Department of Interventional Vascular Surgery, The First Affiliated Hospital of Yangtze University, Jingzhou, China
| | - Zheng-Dong Wan
- Department of Interventional Vascular Surgery, The First Affiliated Hospital of Yangtze University, Jingzhou, China
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18
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Mollah F, Varamini P. Overcoming Therapy Resistance and Relapse in TNBC: Emerging Technologies to Target Breast Cancer-Associated Fibroblasts. Biomedicines 2021; 9:1921. [PMID: 34944738 PMCID: PMC8698629 DOI: 10.3390/biomedicines9121921] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Revised: 12/10/2021] [Accepted: 12/11/2021] [Indexed: 12/12/2022] Open
Abstract
Breast cancer is the most diagnosed cancer and is the leading cause of cancer mortality in women. Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer. Often, TNBC is not effectively treated due to the lack of specificity of conventional therapies and results in relapse and metastasis. Breast cancer-associated fibroblasts (BCAFs) are the predominant cells that reside in the tumor microenvironment (TME) and regulate tumorigenesis, progression and metastasis, and therapy resistance. BCAFs secrete a wide range of factors, including growth factors, chemokines, and cytokines, some of which have been proved to lead to a poor prognosis and clinical outcomes. This TME component has been emerging as a promising target due to its crucial role in cancer progression and chemotherapy resistance. A number of therapeutic candidates are designed to effectively target BCAFs with a focus on their tumor-promoting properties and tumor immune response. This review explores various agents targeting BCAFs in TNBC, including small molecules, nucleic acid-based agents, antibodies, proteins, and finally, nanoparticles.
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Affiliation(s)
- Farhana Mollah
- Faculty of Medicine and Health, School of Pharmacy, University of Sydney, Sydney, NSW 2006, Australia;
| | - Pegah Varamini
- Faculty of Medicine and Health, School of Pharmacy, University of Sydney, Sydney, NSW 2006, Australia;
- Sydney Nano Institute, University of Sydney, Sydney, NSW 2006, Australia
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19
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Fang H, Huang Y, Luo Y, Tang J, Yu M, Zhang Y, Zhong M. SIRT1 induces the accumulation of TAMs at colorectal cancer tumor sites via the CXCR4/CXCL12 axis. Cell Immunol 2021; 371:104458. [PMID: 34847407 DOI: 10.1016/j.cellimm.2021.104458] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Revised: 10/21/2021] [Accepted: 11/15/2021] [Indexed: 12/24/2022]
Abstract
Our previous work suggested that high SIRT1 expression by cancer cells predicted a poor colorectal cancer (CRC) prognosis, but its role in the tumor microenvironment was unclear. Here, we examined tumor-infiltrating lymphocytes (TILs) in CRC expressing different levels of SIRT1. We also established a co-culture system with monocytes, CD8+ T cells and patient-derived tumor organoids (PDOs) to study the relationships between immune cells and cancer cells. The percentage of CD8+ T cells was decreased and the percentage of macrophages was increased in SIRT1-high (SIRT1-hi) CRC. Co-culture results showed that tumor-associated macrophages (TAMs) from SIRT1-hi CRC inhibited the proliferation and anti-tumor activity of CD8+ T cells. Importantly, SIRT1-hi CRC were shown to modulate the migration and the activity of TAMs. RNA sequencing revealed that CD14+ monocytes in SIRT1-hi patients expressed higher levels of CXCR4. Mechanistically, SIRT1 expression was shown to promote CXCL12 expression by inhibiting the acetylation of p53. Our findings indicate that SIRT1 in CRC induces TAM migration through the CXCR4/CXCL12 pathway, and inhibits the proliferation and activity of CD8+ T cells, resulting in promotion of CRC progression.
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Affiliation(s)
- Hongsheng Fang
- Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Yizhou Huang
- Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Yang Luo
- Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Jiayin Tang
- Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Minhao Yu
- Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Yan Zhang
- Med-X Research Institute & School of Biomedical Engineering, Shanghai Jiaotong University, Shanghai, China; State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Stem Cell Research Center, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
| | - Ming Zhong
- Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
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20
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Gavriel Y, Rabinovich-Nikitin I, Ezra A, Barbiro B, Solomon B. Subcutaneous Administration of AMD3100 into Mice Models of Alzheimer's Disease Ameliorated Cognitive Impairment, Reduced Neuroinflammation, and Improved Pathophysiological Markers. J Alzheimers Dis 2021; 78:653-671. [PMID: 33016905 DOI: 10.3233/jad-200506] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
BACKGROUND Alzheimer's disease (AD), the prevalent dementia in the elderly, involves many related and interdependent pathologies that manifest simultaneously, leading to cognitive impairment and death. Amyloid-β (Aβ) accumulation in the brain triggers the onset of AD, accompanied by neuroinflammatory response and pathological changes. The CXCR4/CXCL12 (SDF1) axis is one of the major signal transduction cascades involved in the inflammation process and regulation of homing of hematopoietic stem cells (HSCs) within the bone marrow niche. Inhibition of the axis with AMD3100, a reversible antagonist of CXCR4 mobilizes endogenous HSCs from the bone marrow into the periphery, facilitating the recruitment of bone marrow-derived microglia-like cells into the brain, attenuates the neuroinflammation process that involves release of excitotoxic markers such as TNFα, intracellular Ca2 +, and glutamate and upregulates monocarboxylate transporter 1, the major L-lactate transporter in the brain. OBJECTIVE Herein, we investigate if administration of a combination of AMD3100 and L-lactate may have beneficial effects in the treatment of AD. METHODS We tested the feasibility of the combined treatment for short- and long-term efficacy for inducing endogenous stem cells' mobilization and attenuation of neuroinflammation in two distinct amyloid-β-induced AD mouse models. RESULTS The combined treatment did not demonstrate any adverse effects on the mice, and resulted in a significant improvement in cognitive/memory functions, attenuated neuroinflammation, and alleviated AD pathologies compared to each treatment alone. CONCLUSION This study showed AMD3100's beneficial effect in ameliorating AD pathogenesis, suggesting an alternative to the multistep procedures of transplantation of stem cells in the treatment of AD.
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Affiliation(s)
- Yuval Gavriel
- The Shmunis School of Biomedicine and Cancer Research, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel
| | - Inna Rabinovich-Nikitin
- The Shmunis School of Biomedicine and Cancer Research, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel
| | - Assaf Ezra
- The Shmunis School of Biomedicine and Cancer Research, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel
| | - Becki Barbiro
- The Shmunis School of Biomedicine and Cancer Research, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel
| | - Beka Solomon
- The Shmunis School of Biomedicine and Cancer Research, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel
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21
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Baghdadi NE, Burke BP, Alresheedi T, Nigam S, Saeed A, Almutairi F, Domarkas J, Khan A, Archibald SJ. Multivalency in CXCR4 chemokine receptor targeted iron oxide nanoparticles. Dalton Trans 2021; 50:1599-1603. [PMID: 33502425 DOI: 10.1039/d0dt02626c] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The CXCR4 chemokine receptor is an important biomolecular target in cancer diagnostics and therapeutics. In a new multivalent approach, iron oxide nanoparticles were conjugated with multiple binding units of a low affinity azamacrocylic CXCR4 antagonist. The silica coated nanostructure has good suspension stability, a mode size of 72 nm and high affinity for CXCR4, showing >98% inhibition of anti-CXCR4 mAb binding in a receptor binding competition assay on Jurkat cells.
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Affiliation(s)
- Neazar E Baghdadi
- Centre of Nanotechnology, King Abdul-Aziz University, Jeddah, Saudi Arabia and Department of Chemistry, University of Hull, Cottingham Road, Hull, HU6 7RX, UK.
| | - Benjamin P Burke
- Department of Biomedical Sciences and PET Research Centre, University of Hull Cottingham Road, Hull, HU6 7RX, UK
| | - Tahani Alresheedi
- Department of Chemistry, University of Hull, Cottingham Road, Hull, HU6 7RX, UK. and Department of Biomedical Sciences and PET Research Centre, University of Hull Cottingham Road, Hull, HU6 7RX, UK and Department of Chemistry, College of Science and Art, Qassim University, Qassim, Saudi Arabia
| | - Shubhanchi Nigam
- Department of Chemistry, University of Hull, Cottingham Road, Hull, HU6 7RX, UK. and Department of Biomedical Sciences and PET Research Centre, University of Hull Cottingham Road, Hull, HU6 7RX, UK
| | - Abdu Saeed
- Department of Physics, Faculty of Science, King Abdul-Aziz University, Jeddah 21589, Saudi Arabia
| | - Farooq Almutairi
- Department of Chemistry, University of Hull, Cottingham Road, Hull, HU6 7RX, UK. and College of Applied Medical Sciences, University of Hafar Al-Batin, Hafar Al-Batin, Saudi Arabia
| | - Juozas Domarkas
- Department of Chemistry, University of Hull, Cottingham Road, Hull, HU6 7RX, UK. and Department of Biomedical Sciences and PET Research Centre, University of Hull Cottingham Road, Hull, HU6 7RX, UK
| | - Abid Khan
- Department of Biomedical Sciences and PET Research Centre, University of Hull Cottingham Road, Hull, HU6 7RX, UK and Division of Pharmacy and Optometry, School of Health Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
| | - Stephen J Archibald
- Department of Chemistry, University of Hull, Cottingham Road, Hull, HU6 7RX, UK. and Department of Biomedical Sciences and PET Research Centre, University of Hull Cottingham Road, Hull, HU6 7RX, UK
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22
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Schütz D, Ruiz-Blanco YB, Münch J, Kirchhoff F, Sanchez-Garcia E, Müller JA. Peptide and peptide-based inhibitors of SARS-CoV-2 entry. Adv Drug Deliv Rev 2020; 167:47-65. [PMID: 33189768 PMCID: PMC7665879 DOI: 10.1016/j.addr.2020.11.007] [Citation(s) in RCA: 123] [Impact Index Per Article: 24.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Revised: 11/08/2020] [Accepted: 11/10/2020] [Indexed: 12/18/2022]
Abstract
To date, no effective vaccines or therapies are available against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative pandemic agent of the coronavirus disease 2019 (COVID-19). Due to their safety, efficacy and specificity, peptide inhibitors hold great promise for the treatment of newly emerging viral pathogens. Based on the known structures of viral proteins and their cellular targets, antiviral peptides can be rationally designed and optimized. The resulting peptides may be highly specific for their respective targets and particular viral pathogens or exert broad antiviral activity. Here, we summarize the current status of peptides inhibiting SARS-CoV-2 entry and outline the strategies used to design peptides targeting the ACE2 receptor or the viral spike protein and its activating proteases furin, transmembrane serine protease 2 (TMPRSS2), or cathepsin L. In addition, we present approaches used against related viruses such as SARS-CoV-1 that might be implemented for inhibition of SARS-CoV-2 infection.
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Affiliation(s)
- Desiree Schütz
- Institute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Germany
| | - Yasser B Ruiz-Blanco
- Computational Biochemistry, Center of Medical Biotechnology, University of Duisburg-Essen, 45117 Essen, Germany
| | - Jan Münch
- Institute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Germany
| | - Frank Kirchhoff
- Institute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Germany
| | - Elsa Sanchez-Garcia
- Computational Biochemistry, Center of Medical Biotechnology, University of Duisburg-Essen, 45117 Essen, Germany.
| | - Janis A Müller
- Institute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Germany.
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23
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Borges BC, Uehara IA, Dos Santos MA, Martins FA, de Souza FC, Junior ÁF, da Luz FAC, da Costa MS, Notário AFO, Lopes DS, Teixeira SC, Teixeira TL, de Castilhos P, da Silva CV, Silva MJB. The Recombinant Protein Based on Trypanosoma cruzi P21 Interacts With CXCR4 Receptor and Abrogates the Invasive Phenotype of Human Breast Cancer Cells. Front Cell Dev Biol 2020; 8:569729. [PMID: 33195200 PMCID: PMC7604327 DOI: 10.3389/fcell.2020.569729] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Accepted: 09/22/2020] [Indexed: 01/07/2023] Open
Abstract
Trypanosoma cruzi P21 is a protein secreted by the parasite that plays biological roles directly involved in the progression of Chagas disease. The recombinant protein (rP21) demonstrates biological properties, such as binding to CXCR4 receptors in macrophages, chemotactic activity of immune cells, and inhibiting angiogenesis. This study aimed to verify the effects of rP21 interaction with CXCR4 from non-tumoral cells (MCF-10A) and triple-negative breast cancer cells (MDA-MB-231). Our data showed that the MDA-MB-231 cells expressed higher levels of CXCR4 than did the non-tumor cell lines. Besides, cytotoxicity assays using different concentrations of rP21 showed that the recombinant protein was non-toxic and was able to bind to the cell membranes of both cell lineages. In addition, rP21 reduced the migration and invasion of MDA-MB-231 cells by the downregulation of MMP-9 gene expression. In addition, treatment with rP21 blocked the cell cycle, arresting it in the G1 phase, mainly in MDA-MB-231 cells. Finally, rP21 prevents the chemotaxis and proliferation induced by CXCL12. Our data showed that rP21 binds to the CXCR4 receptors in both cells, downregulates CXCR4 gene expression, and decreases the receptors in the cytoplasm of MDA-MB-231 cells, suggesting CXCR4 internalization. This internalization may explain the desensitization of the receptors in these cells. Thus, rP21 prevents migration, invasion, and progression in MDA-MB-231 cells.
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Affiliation(s)
- Bruna Cristina Borges
- Laboratório de Tripanosomatídeos, Departamento de Imunologia, Instituto de Ciências Biomédicas, Universidade Federal de Uberlândia, Uberlândia, Brazil.,Laboratório de Biomarcadores Tumorais e Osteoimunologia, Departamento de Imunologia, Instituto de Ciências Biomédicas, Universidade Federal de Uberlândia, Uberlândia, Brazil
| | - Isadora Akemi Uehara
- Laboratório de Biomarcadores Tumorais e Osteoimunologia, Departamento de Imunologia, Instituto de Ciências Biomédicas, Universidade Federal de Uberlândia, Uberlândia, Brazil
| | - Marlus Alves Dos Santos
- Laboratório de Tripanosomatídeos, Departamento de Imunologia, Instituto de Ciências Biomédicas, Universidade Federal de Uberlândia, Uberlândia, Brazil
| | - Flávia Alves Martins
- Laboratório de Tripanosomatídeos, Departamento de Imunologia, Instituto de Ciências Biomédicas, Universidade Federal de Uberlândia, Uberlândia, Brazil
| | - Fernanda Carvalho de Souza
- Laboratório de Biomarcadores Tumorais e Osteoimunologia, Departamento de Imunologia, Instituto de Ciências Biomédicas, Universidade Federal de Uberlândia, Uberlândia, Brazil
| | - Álvaro Ferreira Junior
- Departamento de MedicinaVeterinária, Escola de Veterinária e Zootecnia, Universidade Federal de Goiás, Goiânia, Brazil
| | - Felipe Andrés Cordero da Luz
- Laboratório de Biomarcadores Tumorais e Osteoimunologia, Departamento de Imunologia, Instituto de Ciências Biomédicas, Universidade Federal de Uberlândia, Uberlândia, Brazil
| | - Mylla Spirandelli da Costa
- Laboratório de Tripanosomatídeos, Departamento de Imunologia, Instituto de Ciências Biomédicas, Universidade Federal de Uberlândia, Uberlândia, Brazil
| | - Ana Flávia Oliveira Notário
- Laboratório de Nanobiotecnologia, Instituto de Genético e Bioquímica, Universidade Federal de Uberlândia, Uberlândia, Brazil
| | - Daiana Silva Lopes
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista, Brazil
| | - Samuel Cota Teixeira
- Laboratório de Tripanosomatídeos, Departamento de Imunologia, Instituto de Ciências Biomédicas, Universidade Federal de Uberlândia, Uberlândia, Brazil
| | - Thaise Lara Teixeira
- Laboratório de Biologia Molecular de Trypanosoma Cruzi, Departamento de Parasitologia, Universidade Federal de São Paulo, São Paulo, Brazil
| | - Patrícia de Castilhos
- Laboratório de Tripanosomatídeos, Departamento de Imunologia, Instituto de Ciências Biomédicas, Universidade Federal de Uberlândia, Uberlândia, Brazil
| | - Claudio Vieira da Silva
- Laboratório de Tripanosomatídeos, Departamento de Imunologia, Instituto de Ciências Biomédicas, Universidade Federal de Uberlândia, Uberlândia, Brazil
| | - Marcelo José Barbosa Silva
- Laboratório de Biomarcadores Tumorais e Osteoimunologia, Departamento de Imunologia, Instituto de Ciências Biomédicas, Universidade Federal de Uberlândia, Uberlândia, Brazil
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24
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The Signaling Duo CXCL12 and CXCR4: Chemokine Fuel for Breast Cancer Tumorigenesis. Cancers (Basel) 2020; 12:cancers12103071. [PMID: 33096815 PMCID: PMC7590182 DOI: 10.3390/cancers12103071] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Revised: 10/05/2020] [Accepted: 10/18/2020] [Indexed: 12/16/2022] Open
Abstract
Simple Summary Breast cancer remains the most common malignancy in women. In this review, we explore the role of the CXCL12/CXCR4 pathway in breast cancer. We show that the CXCL12/CXCR4 cascade is involved in nearly every aspect of breast cancer tumorigenesis including proliferation, cell motility and distant metastasis. Moreover, we summarize current knowledge about the CXCL12/CXCR4-targeted therapies. Due to the critical roles of this pathway in breast cancer and other malignancies, we believe that audiences in different fields will find this overview helpful. Abstract The CXCL12/CXCR4 signaling pathway has emerged in the recent years as a key player in breast cancer tumorigenesis. This pathway controls many aspects of breast cancer development including cancer cell proliferation, motility and metastasis to all target organs. Moreover, the CXCL12/CXCR4 cascade affects both immune and stromal cells, creating tumor-supporting microenvironment. In this review, we examine state-of-the-art knowledge about detrimental roles of the CXCL12/CXCR4 signaling, discuss its therapeutic potential and suggest further research directions beneficial both for basic research and personalized medicine in breast cancer.
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25
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Morein D, Erlichman N, Ben-Baruch A. Beyond Cell Motility: The Expanding Roles of Chemokines and Their Receptors in Malignancy. Front Immunol 2020; 11:952. [PMID: 32582148 PMCID: PMC7287041 DOI: 10.3389/fimmu.2020.00952] [Citation(s) in RCA: 93] [Impact Index Per Article: 18.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Accepted: 04/23/2020] [Indexed: 01/10/2023] Open
Abstract
The anti-tumor activities of some members of the chemokine family are often overcome by the functions of many chemokines that are strongly and causatively linked with increased tumor progression. Being key leukocyte attractants, chemokines promote the presence of inflammatory pro-tumor myeloid cells and immune-suppressive cells in tumors and metastases. In parallel, chemokines elevate additional pro-cancerous processes that depend on cell motility: endothelial cell migration (angiogenesis), recruitment of mesenchymal stem cells (MSCs) and site-specific metastasis. However, the array of chemokine activities in cancer expands beyond such “typical” migration-related processes and includes chemokine-induced/mediated atypical functions that do not activate directly motility processes; these non-conventional chemokine functions provide the tumor cells with new sets of detrimental tools. Within this scope, this review article addresses the roles of chemokines and their receptors at atypical levels that are exerted on the cancer cell themselves: promoting tumor cell proliferation and survival; controlling tumor cell senescence; enriching tumors with cancer stem cells; inducing metastasis-related functions such as epithelial-to-mesenchymal transition (EMT) and elevated expression of matrix metalloproteinases (MMPs); and promoting resistance to chemotherapy and to endocrine therapy. The review also describes atypical effects of chemokines at the tumor microenvironment: their ability to up-regulate/stabilize the expression of inhibitory immune checkpoints and to reduce the efficacy of their blockade; to induce bone remodeling and elevate osteoclastogenesis/bone resorption; and to mediate tumor-stromal interactions that promote cancer progression. To illustrate this expanding array of atypical chemokine activities at the cancer setting, the review focuses on major metastasis-promoting inflammatory chemokines—including CXCL8 (IL-8), CCL2 (MCP-1), and CCL5 (RANTES)—and their receptors. In addition, non-conventional activities of CXCL12 which is a key regulator of tumor progression, and its CXCR4 receptor are described, alongside with the other CXCL12-binding receptor CXCR7 (RDC1). CXCR7, a member of the subgroup of atypical chemokine receptors (ACKRs) known also as ACKR3, opens the gate for discussion of atypical activities of additional ACKRs in cancer: ACKR1 (DARC, Duffy), ACKR2 (D6), and ACKR4 (CCRL1). The mechanisms involved in chemokine activities and the signals delivered by their receptors are described, and the clinical implications of these findings are discussed.
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Affiliation(s)
- Dina Morein
- School of Molecular Cell Biology and Biotechnology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel
| | - Nofar Erlichman
- School of Molecular Cell Biology and Biotechnology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel
| | - Adit Ben-Baruch
- School of Molecular Cell Biology and Biotechnology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel
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26
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Sadeghi L, Arvidsson G, Merrien M, Wasik AM, Görgens A, Smith CE, Sander B, P. Wright A. Differential B-Cell Receptor Signaling Requirement for Adhesion of Mantle Cell Lymphoma Cells to Stromal Cells. Cancers (Basel) 2020; 12:cancers12051143. [PMID: 32370190 PMCID: PMC7281289 DOI: 10.3390/cancers12051143] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2020] [Revised: 04/28/2020] [Accepted: 04/29/2020] [Indexed: 01/01/2023] Open
Abstract
Interactions between lymphoma cells and stromal cells play a key role in promoting tumor survival and development of drug resistance. We identified differences in key signaling pathways between the JeKo-1 and REC-1 mantle cell lymphoma (MCL) cell lines, displaying different patterns of stromal cell adhesion and chemotaxis towards stroma-conditioned medium. The identified adhesion-regulated genes reciprocated important aspects of microenvironment-mediated gene modulation in MCL patients. Five-hundred and ninety genes were differently regulated between the cell lines upon adhesion to stromal cells, while 32 genes were similarly regulated in both cell lines. Regulation of B-cell Receptor (BCR) signature genes in adherent cells was specific for JeKo-1. Inhibition of BCR using siRNA or clinically approved inhibitors, Ibrutinib and Acalabrutinib, decreased adhesion of JeKo-1, but not REC-1 cells. Cell surface levels of chemokine receptor CXCR4 were higher in JeKo-1, facilitating migration and adhesion of JeKo-1 but not REC-1 cells. Surface levels of ICAM1 adhesion protein differ for REC-1 and JeKo-1. While ICAM1 played a positive role in adherence of both cell lines to stromal cells, S1PR1 had an inhibitory effect. Our results provide a model framework for further investigation of mechanistic differences in patient-response to new pathway-specific drugs.
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Affiliation(s)
- Laia Sadeghi
- Department of Laboratory Medicine, Division of Biomedical and Cellular Medicine, Karolinska Institutet, 141 57 Stockholm, Sweden; (L.S.); (G.A.); (A.G.); (C.I.E.S.)
| | - Gustav Arvidsson
- Department of Laboratory Medicine, Division of Biomedical and Cellular Medicine, Karolinska Institutet, 141 57 Stockholm, Sweden; (L.S.); (G.A.); (A.G.); (C.I.E.S.)
| | - Magali Merrien
- Department of Laboratory Medicine, Division of Pathology, Karolinska Institutet, 141 52 Stockholm, Sweden; (M.M.); (A.M.W.); (B.S.)
| | - Agata M. Wasik
- Department of Laboratory Medicine, Division of Pathology, Karolinska Institutet, 141 52 Stockholm, Sweden; (M.M.); (A.M.W.); (B.S.)
| | - André Görgens
- Department of Laboratory Medicine, Division of Biomedical and Cellular Medicine, Karolinska Institutet, 141 57 Stockholm, Sweden; (L.S.); (G.A.); (A.G.); (C.I.E.S.)
- Institute for Transfusion Medicine, University Hospital Essen, University of Duisburg, 45 147 Essen, Germany
| | - C.I. Edvard Smith
- Department of Laboratory Medicine, Division of Biomedical and Cellular Medicine, Karolinska Institutet, 141 57 Stockholm, Sweden; (L.S.); (G.A.); (A.G.); (C.I.E.S.)
| | - Birgitta Sander
- Department of Laboratory Medicine, Division of Pathology, Karolinska Institutet, 141 52 Stockholm, Sweden; (M.M.); (A.M.W.); (B.S.)
| | - Anthony P. Wright
- Department of Laboratory Medicine, Division of Biomedical and Cellular Medicine, Karolinska Institutet, 141 57 Stockholm, Sweden; (L.S.); (G.A.); (A.G.); (C.I.E.S.)
- Correspondence:
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27
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Oral lichen planus interactome reveals CXCR4 and CXCL12 as candidate therapeutic targets. Sci Rep 2020; 10:5454. [PMID: 32214134 PMCID: PMC7096434 DOI: 10.1038/s41598-020-62258-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2019] [Accepted: 03/12/2020] [Indexed: 01/03/2023] Open
Abstract
Today, we face difficulty in generating new hypotheses and understanding oral lichen planus due to the large amount of biomedical information available. In this research, we have used an integrated bioinformatics approach assimilating information from data mining, gene ontologies, protein–protein interaction and network analysis to predict candidate genes related to oral lichen planus. A detailed pathway analysis led us to propose two promising therapeutic targets: the stromal cell derived factor 1 (CXCL12) and the C-X-C type 4 chemokine receptor (CXCR4). We further validated our predictions and found that CXCR4 was upregulated in all oral lichen planus tissue samples. Our bioinformatics data cumulatively support the pathological role of chemokines and chemokine receptors in oral lichen planus. From a clinical perspective, we suggest a drug (plerixafor) and two therapeutic targets for future research.
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28
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Miao M, De Clercq E, Li G. Clinical significance of chemokine receptor antagonists. Expert Opin Drug Metab Toxicol 2020; 16:11-30. [PMID: 31903790 DOI: 10.1080/17425255.2020.1711884] [Citation(s) in RCA: 85] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Introduction: Chemokine receptors are important therapeutic targets for the treatment of many human diseases. This study will provide an overview of approved chemokine receptor antagonists and promising candidates in advanced clinical trials.Areas covered: We will describe clinical aspects of chemokine receptor antagonists regarding their clinical efficacy, mechanisms of action, and re-purposed applications.Expert opinion: Three chemokine antagonists have been approved: (i) plerixafor is a small-molecule CXCR4 antagonist that mobilizes hematopoietic stem cells; (ii) maraviroc is a small-molecule CCR5 antagonist for anti-HIV treatment; and (iii) mogamulizumab is a monoclonal-antibody CCR4 antagonist for the treatment of mycosis fungoides or Sézary syndrome. Moreover, phase 3 trials are ongoing to evaluate many potent candidates, including CCR5 antagonists (e.g. leronlimab), dual CCR2/CCR5 antagonists (e.g. cenicriviroc), and CXCR4 antagonists (e.g. balixafortide, mavorixafor, motixafortide). The success of chemokine receptor antagonists depends on the selective blockage of disease-relevant chemokine receptors which are indispensable for disease progression. Although clinical translation has been slow, antagonists targeting chemokine receptors with multifaced functions offer the potential to treat a broad spectrum of human diseases.
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Affiliation(s)
- Miao Miao
- Department of Epidemiology and Health Statistics, Xiangya School of Public Health, Central South University, Hunan, China
| | - Erik De Clercq
- KU Leuven, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Leuven, Belgium
| | - Guangdi Li
- Department of Epidemiology and Health Statistics, Xiangya School of Public Health, Central South University, Hunan, China
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29
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Bragg R, Gilbert W, Elmansi AM, Isales CM, Hamrick MW, Hill WD, Fulzele S. Stromal cell-derived factor-1 as a potential therapeutic target for osteoarthritis and rheumatoid arthritis. Ther Adv Chronic Dis 2019; 10:2040622319882531. [PMID: 31695863 PMCID: PMC6820172 DOI: 10.1177/2040622319882531] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2019] [Accepted: 09/11/2019] [Indexed: 01/13/2023] Open
Abstract
With age, joints become subject to chronic inflammatory processes that lead to degeneration of articular cartilage. Although multifactorial, cytokines have been shown to play a role in the pathogenesis of these chronic disease states. Stromal cell-derived factor 1 (SDF-1) is a chemokine that has been shown to be active in homeostatic mechanisms and developmental processes throughout the body, such as endochondral bone formation. SDF-1 plays a role in the transition from cartilage to bone. Although it has been shown to be a factor in normal development, it has also been shown to involve in the pathogenesis of rheumatoid arthritis (RA) and osteoarthritis (OA). In RA, SDF-1 has been shown to stimulate the recruitment of proinflammatory cells, as well as osteoclasts to the synovium, aiding in the facilitation of synovial degradation. Similarly, in OA, SDF-1 has been shown to regulate key proteins involved in the degradation of the cartilage of the joint. Because of its role in degenerative joint disease, SDF-1 has been investigated as a potential therapeutic target. Animal studies have been employing SDF-1 inhibitors, such as AMD3100 and T140, to study their effects on attenuating degenerative joint disease. These studies have shown promising results in slowing the progression of cartilage degradation and could potentially be used as therapeutic target for humans OA and RA.
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Affiliation(s)
- Robert Bragg
- Departments of Orthopedic Surgery, Augusta University, Augusta, GA, USA
| | - William Gilbert
- Departments of Orthopedic Surgery, Augusta University, Augusta, GA, USA
| | - Ahmed M. Elmansi
- Department of Pathology and Laboratory Medicine, Medical University of South Carolina, and the Ralph H. Johnson VAMC, Charleston, SC, USA
| | | | - Mark W. Hamrick
- Department of Cell Biology and Anatomy, Augusta University, Augusta, GA, USA
| | - William D. Hill
- Department of Pathology and Laboratory Medicine, Medical University of South Carolina, and the Ralph H. Johnson VAMC, Charleston, SC, USA
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30
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Houshmand M, Blanco TM, Circosta P, Yazdi N, Kazemi A, Saglio G, Zarif MN. Bone marrow microenvironment: The guardian of leukemia stem cells. World J Stem Cells 2019; 11:476-490. [PMID: 31523368 PMCID: PMC6716085 DOI: 10.4252/wjsc.v11.i8.476] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2019] [Revised: 06/13/2019] [Accepted: 06/20/2019] [Indexed: 02/06/2023] Open
Abstract
Bone marrow microenvironment (BMM) is the main sanctuary of leukemic stem cells (LSCs) and protects these cells against conventional therapies. However, it may open up an opportunity to target LSCs by breaking the close connection between LSCs and the BMM. The elimination of LSCs is of high importance, since they follow cancer stem cell theory as a part of this population. Based on cancer stem cell theory, a cell with stem cell-like features stands at the apex of the hierarchy and produces a heterogeneous population and governs the disease. Secretion of cytokines, chemokines, and extracellular vesicles, whether through autocrine or paracrine mechanisms by activation of downstream signaling pathways in LSCs, favors their persistence and makes the BMM less hospitable for normal stem cells. While all details about the interactions of the BMM and LSCs remain to be elucidated, some clinical trials have been designed to limit these reciprocal interactions to cure leukemia more effectively. In this review, we focus on chronic myeloid leukemia and acute myeloid leukemia LSCs and their milieu in the bone marrow, how to segregate them from the normal compartment, and finally the possible ways to eliminate these cells.
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Affiliation(s)
- Mohammad Houshmand
- Department of Clinical and Biological Sciences, University of Turin, Turin 10126, Italy
| | - Teresa Mortera Blanco
- Center for Hematology and Regenerative Medicine, Karolinska Institutet, Department of Medicine, Karolinska University Hospital Huddinge, Stockholm 14183, Sweden
| | - Paola Circosta
- Department of Clinical and Biological Sciences, University of Turin, Turin 10126, Italy
| | - Narjes Yazdi
- Department of Molecular Genetics, Tehran Medical Branch, Islamic Azad University, Tehran 1916893813, Iran
| | - Alireza Kazemi
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran 1985717443, Iran
| | - Giuseppe Saglio
- Department of Clinical and Biological Sciences, University of Turin, Turin 10126, Italy
| | - Mahin Nikougoftar Zarif
- Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine, Tehran 146651157, Iran
- Center for Hematology and Regenerative Medicine, Karolinska Institutet, Department of Medicine, Karolinska University Hospital Huddinge, Stockholm 14183, Sweden
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31
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Heusinkveld LE, Majumdar S, Gao JL, McDermott DH, Murphy PM. WHIM Syndrome: from Pathogenesis Towards Personalized Medicine and Cure. J Clin Immunol 2019; 39:532-556. [PMID: 31313072 PMCID: PMC6698215 DOI: 10.1007/s10875-019-00665-w] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2019] [Accepted: 06/26/2019] [Indexed: 12/15/2022]
Abstract
WHIM syndrome is a rare combined primary immunodeficiency disease named by acronym for the diagnostic tetrad of warts, hypogammaglobulinemia, infections, and myelokathexis. Myelokathexis is a unique form of non-cyclic severe congenital neutropenia caused by accumulation of mature and degenerating neutrophils in the bone marrow; monocytopenia and lymphopenia, especially B lymphopenia, also commonly occur. WHIM syndrome is usually caused by autosomal dominant mutations in the G protein-coupled chemokine receptor CXCR4 that impair desensitization, resulting in enhanced and prolonged G protein- and β-arrestin-dependent responses. Accordingly, CXCR4 antagonists have shown promise as mechanism-based treatments in phase 1 clinical trials. This review is based on analysis of all 105 published cases of WHIM syndrome and covers current concepts, recent advances, unresolved enigmas and controversies, and promising future research directions.
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Affiliation(s)
- Lauren E Heusinkveld
- Molecular Signaling Section, Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, 20892, USA
- Cleveland Clinic, Cleveland Clinic Lerner College of Medicine, Cleveland, OH, 44195, USA
| | - Shamik Majumdar
- Molecular Signaling Section, Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Ji-Liang Gao
- Molecular Signaling Section, Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, 20892, USA
| | - David H McDermott
- Molecular Signaling Section, Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Philip M Murphy
- Molecular Signaling Section, Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, 20892, USA.
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32
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Breun M, Monoranu CM, Kessler AF, Matthies C, Löhr M, Hagemann C, Schirbel A, Rowe SP, Pomper MG, Buck AK, Wester HJ, Ernestus RI, Lapa C. [ 68Ga]-Pentixafor PET/CT for CXCR4-Mediated Imaging of Vestibular Schwannomas. Front Oncol 2019; 9:503. [PMID: 31245296 PMCID: PMC6581743 DOI: 10.3389/fonc.2019.00503] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2019] [Accepted: 05/28/2019] [Indexed: 12/25/2022] Open
Abstract
We have recently demonstrated CXCR4 overexpression in vestibular schwannomas (VS). This study investigated the feasibility of CXCR4-directed positron emission tomography/computed tomography (PET/CT) imaging of VS using the radiolabeled chemokine ligand [68Ga]Pentixafor. Methods: 4 patients with 6 primarily diagnosed or pre-treated/observed VS were enrolled. All subjects underwent [68Ga]Pentixafor PET/CT prior to surgical resection. Images were analyzed visually and semi-quantitatively for CXCR4 expression including calculation of tumor-to-background ratios (TBR). Immunohistochemistry served as standard of reference in three patients. Results: [68Ga]Pentixafor PET/CT was visually positive in all cases. SUVmean and SUVmax were 3.0 ± 0.3 and 3.8 ± 0.4 and TBRmean and TBRmax were 4.0 ± 1.4 and 5.0 ± 1.7, respectively. Histological analysis confirmed CXCR4 expression in tumors. Conclusion: Non-invasive imaging of CXCR4 expression using [68Ga]Pentixafor PET/CT of VS is feasible and could prove useful for in vivo assessment of CXCR4 expression.
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Affiliation(s)
- Maria Breun
- Department of Neurosurgery, University Hospital Würzburg, Würzburg, Germany
| | - Camelia M Monoranu
- Department of Neuropathology, University of Würzburg, Institute of Pathology, Würzburg, Germany.,Comprehensive Cancer Center (CCC) Mainfranken, Würzburg, Germany
| | - Almuth F Kessler
- Department of Neurosurgery, University Hospital Würzburg, Würzburg, Germany
| | - Cordula Matthies
- Department of Neurosurgery, University Hospital Würzburg, Würzburg, Germany
| | - Mario Löhr
- Department of Neurosurgery, University Hospital Würzburg, Würzburg, Germany
| | - Carsten Hagemann
- Department of Neurosurgery, University Hospital Würzburg, Würzburg, Germany
| | - Andreas Schirbel
- Department of Nuclear Medicine, University Hospital Würzburg, Würzburg, Germany
| | - Steven P Rowe
- Division of Nuclear Medicine and Molecular Imaging, The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Martin G Pomper
- Division of Nuclear Medicine and Molecular Imaging, The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Andreas K Buck
- Department of Nuclear Medicine, University Hospital Würzburg, Würzburg, Germany
| | - Hans-Jürgen Wester
- Pharmaceutical Radiochemistry, Technische Universität München, Munich, Germany
| | - Ralf-Ingo Ernestus
- Department of Neurosurgery, University Hospital Würzburg, Würzburg, Germany
| | - Constantin Lapa
- Department of Nuclear Medicine, University Hospital Würzburg, Würzburg, Germany
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33
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Agarwal P, Isringhausen S, Li H, Paterson AJ, He J, Gomariz Á, Nagasawa T, Nombela-Arrieta C, Bhatia R. Mesenchymal Niche-Specific Expression of Cxcl12 Controls Quiescence of Treatment-Resistant Leukemia Stem Cells. Cell Stem Cell 2019; 24:769-784.e6. [PMID: 30905620 PMCID: PMC6499704 DOI: 10.1016/j.stem.2019.02.018] [Citation(s) in RCA: 138] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2017] [Revised: 10/01/2018] [Accepted: 02/25/2019] [Indexed: 12/25/2022]
Abstract
Chronic myeloid leukemia (CML) originates in a hematopoietic stem cell (HSC) transformed by the breakpoint cluster region (BCR)-abelson (ABL) oncogene and is effectively treated with tyrosine kinase inhibitors (TKIs). TKIs do not eliminate disease-propagating leukemic stem cells (LSCs), suggesting a deeper understanding of niche-dependent regulation of CML LSCs is required to eradicate disease. Cxcl12 is expressed in bone marrow niches and controls HSC maintenance, and here, we show that targeted deletion of Cxcl12 from mesenchymal stromal cells (MSCs) reduces normal HSC numbers but promotes LSC expansion by increasing self-renewing cell divisions, possibly through enhanced Ezh2 activity. In contrast, endothelial cell-specific Cxcl12 deletion decreases LSC proliferation, suggesting niche-specific effects. During CML development, abnormal clusters of colocalized MSCs and LSCs form but disappear upon Cxcl12 deletion. Moreover, MSC-specific deletion of Cxcl12 increases LSC elimination by TKI treatment. These findings highlight a critical role of niche-specific effects of Cxcl12 expression in maintaining quiescence of TKI-resistant LSC populations.
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MESH Headings
- Animals
- Apoptosis
- Cell Line, Tumor
- Chemokine CXCL12/genetics
- Chemokine CXCL12/metabolism
- Drug Resistance, Neoplasm
- Enhancer of Zeste Homolog 2 Protein/genetics
- Enhancer of Zeste Homolog 2 Protein/metabolism
- Fusion Proteins, bcr-abl/genetics
- Fusion Proteins, bcr-abl/metabolism
- Hematopoietic Stem Cells/physiology
- Humans
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/metabolism
- Mesenchymal Stem Cells/physiology
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Neoplastic Stem Cells/physiology
- Organ Specificity
- Protein Kinase Inhibitors/therapeutic use
- Stem Cell Niche/physiology
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Affiliation(s)
- Puneet Agarwal
- Division of Hematology & Oncology, University of Alabama, Birmingham, Birmingham, AL, USA
| | - Stephan Isringhausen
- Department of Hematology and Oncology, Division of Hematology, University Hospital and University of Zurich, Zurich, Switzerland
| | - Hui Li
- Division of Hematology & Oncology, University of Alabama, Birmingham, Birmingham, AL, USA
| | - Andrew J Paterson
- Division of Hematology & Oncology, University of Alabama, Birmingham, Birmingham, AL, USA
| | - Jianbo He
- Division of Hematology & Oncology, University of Alabama, Birmingham, Birmingham, AL, USA
| | - Álvaro Gomariz
- Department of Hematology and Oncology, Division of Hematology, University Hospital and University of Zurich, Zurich, Switzerland
| | - Takashi Nagasawa
- Laboratory of Stem Cell Biology & Developmental Immunology, Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan
| | - César Nombela-Arrieta
- Department of Hematology and Oncology, Division of Hematology, University Hospital and University of Zurich, Zurich, Switzerland
| | - Ravi Bhatia
- Division of Hematology & Oncology, University of Alabama, Birmingham, Birmingham, AL, USA.
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Abstract
Cysteine-X-cysteine chemokine receptor 4 (CXCR4) is a broadly expressed and multifunctional G protein-coupled chemokine receptor critical for organogenesis, hematopoiesis, and antimicrobial host defense. In the hematopoietic system, the binding of CXCR4 to its cognate chemokine ligand, CXCL12, mediates leukocyte trafficking, distribution, survival, activation, and proliferation. Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome is a rare, autosomal dominant, combined immunodeficiency disorder caused by mutations in the C-terminus of CXCR4 that prevent receptor downregulation and therefore result in pathologically increased signaling. The "M" in the acronym WHIM refers to myelokathexis, the retention of neutrophils in the bone marrow resulting in neutropenia, which explains in part the increased susceptibility to bacterial infection. However, WHIM patients also present with B and T lymphopenia, which may explain the susceptibility to human papillomavirus (HPV), the cause of warts. The impact of WHIM mutations on lymphocytes and adaptive immunity has received less attention than myelokathexis and is the focus of this review.
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Affiliation(s)
- Shamik Majumdar
- Molecular Signaling Section, Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA.
| | - Philip M Murphy
- Molecular Signaling Section, Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA.
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Boddu P, Borthakur G, Koneru M, Huang X, Naqvi K, Wierda W, Bose P, Jabbour E, Estrov Z, Burger J, Alvarado Y, Deshmukh A, Patel A, Cavazos A, Han L, Cortes JE, Kantarjian H, Andreeff M, Konopleva M. Initial Report of a Phase I Study of LY2510924, Idarubicin, and Cytarabine in Relapsed/Refractory Acute Myeloid Leukemia. Front Oncol 2018; 8:369. [PMID: 30319961 PMCID: PMC6167965 DOI: 10.3389/fonc.2018.00369] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2018] [Accepted: 08/20/2018] [Indexed: 11/13/2022] Open
Abstract
Background: The CXCR4/SDF-1α axis plays a vital role in the retention of stem cells within the bone marrow and downstream activation of cell survival signaling pathways. LY2510924, a second generation CXCR4, showed significant anti-leukemia activity in a murine AML model. Methods: We conducted a phase I study to determine the safety and toxicity of LY2510924, idarubicin and cytarabine (IA) combination therapy in relapsed/refractory (R/R) AML. Eligible patients were 18–70 years of age receiving up to salvage 3 therapy. A peripheral blood absolute blast count of < 20,000/μL was required for inclusion. LY2510924 was administered daily for 7 days followed by IA from day 8. Two dose escalation levels (10 and 20 mg) were evaluated, with a plan to enroll up to 12 patients in the phase I portion. Results: The median age of the enrolled patients (n = 11) was 55 years (range, 19–70). Median number of prior therapies was 1 (1–3). Six and five patients were treated at dose-levels “0” (10 mg) and “1” (20 mg), respectively. Only one patient experiencing a dose limiting toxicity (grade 3 rash and myelosuppression). Three and one complete responses were observed at dose-levels “0” and “1,” respectively; the overall response rate (ORR) was 36% (4 of 11 patients). A ≥ 50% decrease in CXCR4 mean fluorescence intensity was observed in 4 of 9 patients by flow cytometry, indicating incomplete suppression of CXCR4-receptor occupancy. Conclusions: The combination of LY2510924 with IA is safe in R/R AML. Dose-escalation to a 30 mg LY2510924 dose is planned to achieve complete blockade of CXCR4 receptor occupancy, followed by expansion phase at the recommended phase 2 dose-level.
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Affiliation(s)
- Prajwal Boddu
- Department of Leukemia, University of Texas at MD Anderson Cancer Center, Houston, TX, United States
| | - Gautam Borthakur
- Department of Leukemia, University of Texas at MD Anderson Cancer Center, Houston, TX, United States
| | | | - Xuelin Huang
- Department of Leukemia, University of Texas at MD Anderson Cancer Center, Houston, TX, United States
| | - Kiran Naqvi
- Department of Leukemia, University of Texas at MD Anderson Cancer Center, Houston, TX, United States
| | - William Wierda
- Department of Leukemia, University of Texas at MD Anderson Cancer Center, Houston, TX, United States
| | - Prithviraj Bose
- Department of Leukemia, University of Texas at MD Anderson Cancer Center, Houston, TX, United States
| | - Elias Jabbour
- Department of Leukemia, University of Texas at MD Anderson Cancer Center, Houston, TX, United States
| | - Zeev Estrov
- Department of Leukemia, University of Texas at MD Anderson Cancer Center, Houston, TX, United States
| | - Jan Burger
- Department of Leukemia, University of Texas at MD Anderson Cancer Center, Houston, TX, United States
| | - Yesid Alvarado
- Department of Leukemia, University of Texas at MD Anderson Cancer Center, Houston, TX, United States
| | - April Deshmukh
- Department of Leukemia, University of Texas at MD Anderson Cancer Center, Houston, TX, United States
| | - Ami Patel
- Department of Leukemia, University of Texas at MD Anderson Cancer Center, Houston, TX, United States
| | - Antonio Cavazos
- Department of Leukemia, University of Texas at MD Anderson Cancer Center, Houston, TX, United States
| | - Lina Han
- Department of Leukemia, University of Texas at MD Anderson Cancer Center, Houston, TX, United States
| | - Jorge E Cortes
- Department of Leukemia, University of Texas at MD Anderson Cancer Center, Houston, TX, United States
| | - Hagop Kantarjian
- Department of Leukemia, University of Texas at MD Anderson Cancer Center, Houston, TX, United States
| | - Michael Andreeff
- Department of Leukemia, University of Texas at MD Anderson Cancer Center, Houston, TX, United States
| | - Marina Konopleva
- Department of Leukemia, University of Texas at MD Anderson Cancer Center, Houston, TX, United States
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36
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Hersh TA, Dimond AL, Ruth BA, Lupica NV, Bruce JC, Kelley JM, King BL, Lutton BV. A role for the CXCR4-CXCL12 axis in the little skate, Leucoraja erinacea. Am J Physiol Regul Integr Comp Physiol 2018; 315:R218-R229. [PMID: 29641231 PMCID: PMC6139610 DOI: 10.1152/ajpregu.00322.2017] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
The interaction between C-X-C chemokine receptor type 4 (CXCR4) and its cognate ligand C-X-C motif chemokine ligand 12 (CXCL12) plays a critical role in regulating hematopoietic stem cell activation and subsequent cellular mobilization. Extensive studies of these genes have been conducted in mammals, but much less is known about the expression and function of CXCR4 and CXCL12 in non-mammalian vertebrates. In the present study, we identify simultaneous expression of CXCR4 and CXCL12 orthologs in the epigonal organ (the primary hematopoietic tissue) of the little skate, Leucoraja erinacea. Genetic and phylogenetic analyses were functionally supported by significant mobilization of leukocytes following administration of Plerixafor, a CXCR4 antagonist and clinically important drug. Our results provide evidence that, as in humans, Plerixafor disrupts CXCR4/CXCL12 binding in the little skate, facilitating release of leukocytes into the bloodstream. Our study illustrates the value of the little skate as a model organism, particularly in studies of hematopoiesis and potentially for preclinical research on hematological and vascular disorders.
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Affiliation(s)
- Taylor A Hersh
- Mount Desert Island Biological Laboratory , Bar Harbor, Maine
| | - Alexandria L Dimond
- Mount Desert Island Biological Laboratory , Bar Harbor, Maine
- School of Arts and Sciences, Endicott College , Beverly, Massachusetts
| | - Brittany A Ruth
- Mount Desert Island Biological Laboratory , Bar Harbor, Maine
- School of Arts and Sciences, Endicott College , Beverly, Massachusetts
| | - Noah V Lupica
- Mount Desert Island Biological Laboratory , Bar Harbor, Maine
| | - Jacob C Bruce
- Mount Desert Island Biological Laboratory , Bar Harbor, Maine
| | - John M Kelley
- School of Arts and Sciences, Endicott College , Beverly, Massachusetts
- Beth Israel Deaconess Medical Center, Program in Placebo Studies, Harvard Medical School , Boston, Massachusetts
| | - Benjamin L King
- Department of Molecular and Biomedical Sciences, University of Maine , Orono, Maine
| | - Bram V Lutton
- Mount Desert Island Biological Laboratory , Bar Harbor, Maine
- School of Arts and Sciences, Endicott College , Beverly, Massachusetts
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37
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Intrathymic Notch3 and CXCR4 combinatorial interplay facilitates T-cell leukemia propagation. Oncogene 2018; 37:6285-6298. [PMID: 30038265 PMCID: PMC6284016 DOI: 10.1038/s41388-018-0401-2] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2017] [Revised: 05/20/2018] [Accepted: 06/10/2018] [Indexed: 12/27/2022]
Abstract
Notch hyperactivation dominates T-cell acute lymphoblastic leukemia development, but the mechanisms underlying “pre-leukemic” cell dissemination are still unclear. Here we describe how deregulated Notch3 signaling enhances CXCR4 cell-surface expression and migratory ability of CD4+CD8+ thymocytes, possibly contributing to “pre-leukemic” cell propagation, early in disease progression. In transgenic mice overexpressing the constitutively active Notch3 intracellular domain, we detect the progressive increase in circulating blood and bone marrow of CD4+CD8+ cells, characterized by high and combined surface expression of Notch3 and CXCR4. We report for the first time that transplantation of such CD4+CD8+ cells reveals their competence in infiltrating spleen and bone marrow of immunocompromised recipient mice. We also show that CXCR4 surface expression is central to the migratory ability of CD4+CD8+ cells and such an expression is regulated by Notch3 through β-arrestin in human leukemia cells. De novo, we propose that hyperactive Notch3 signaling by boosting CXCR4-dependent migration promotes anomalous egression of CD4+CD8+ cells from the thymus in early leukemia stages. In fact, in vivo CXCR4 antagonism prevents bone marrow colonization by such CD4+CD8+ cells in young Notch3 transgenic mice. Therefore, our data suggest that combined therapies precociously counteracting intrathymic Notch3/CXCR4 crosstalk may prevent dissemination of “pre-leukemic” CD4+CD8+ cells, by a “thymus-autonomous” mechanism.
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38
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He W, Yang T, Gong XH, Qin RZ, Zhang XD, Liu WD. Targeting CXC motif chemokine receptor 4 inhibits the proliferation, migration and angiogenesis of lung cancer cells. Oncol Lett 2018; 16:3976-3982. [PMID: 30128017 DOI: 10.3892/ol.2018.9076] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2017] [Accepted: 04/20/2018] [Indexed: 12/13/2022] Open
Abstract
An increasing volume of data indicates that disrupting the interaction between CXC motif chemokine receptor 4 (CXCR4) and its specific ligand, CXC motif chemokine 12 (CXCL12), may reduce tumor growth and metastasis. However, the translation from bench to bedside must be performed with extreme caution, as the CXCR4/CXCL12 axis is crucial for the normal development and maintenance of tissues and organs. In the present study, Cell Counting Kit-8 and Transwell migration assays were used to detect in vitro proliferation and chemotaxis of CXCR4-expressing A549 cells, a cell strain originating from human non-small-cell lung cancer (NSCLC), with or without the presence of AMD3100, a small-molecule inhibitor specific to CXCR4 signaling. In a xenograft model established by injecting nude mice with A549 cells, tumor growth, CXCR4 expression and microvessel density (MVD) in the tumor mass were determined through tumor size measurements and immunohistochemical staining following intraperitoneal administration of AMD3100 or vehicle. The results demonstrated that CXCR4 blockade inhibited the proliferation of A549 cells and their migration towards CXCL12 in vitro. Tumor growth, CXCR4 expression and MVD were markedly reduced in nude mice treated with AMD3100 compared with mice treated with the vehicle. In conclusion, the present data demonstrated that CXCR4 targeting impaired NSCLC cell growth, angiogenesis and metastatic spread, indicating that it may represent a novel treatment strategy for NSCLC.
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Affiliation(s)
- Wei He
- Department of Medical Oncology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 511447, P.R. China
| | - Tong Yang
- Department of Pathology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 511447, P.R. China
| | - Xin-Hua Gong
- Department of General Medicine, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 511447, P.R. China
| | - Ru-Zhai Qin
- Department of Medical Oncology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 511447, P.R. China
| | - Xiao-Dong Zhang
- Department of Medical Oncology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 511447, P.R. China
| | - Wen-Dan Liu
- Department of Medical Oncology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 511447, P.R. China
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39
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Recasens-Zorzo C, Cardesa-Salzmann T, Petazzi P, Ros-Blanco L, Esteve-Arenys A, Clot G, Guerrero-Hernández M, Rodríguez V, Soldini D, Valera A, Moros A, Climent F, González-Barca E, Mercadal S, Arenillas L, Calvo X, Mate JL, Gutiérrez-García G, Casanova I, Mangues R, Sanjuan-Pla A, Bueno C, Menéndez P, Martínez A, Colomer D, Tejedor RE, Teixidó J, Campo E, López-Guillermo A, Borrell JI, Colomo L, Pérez-Galán P, Roué G. Pharmacological modulation of CXCR4 cooperates with BET bromodomain inhibition in diffuse large B-cell lymphoma. Haematologica 2018; 104:778-788. [PMID: 29954928 PMCID: PMC6442946 DOI: 10.3324/haematol.2017.180505] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2017] [Accepted: 06/25/2018] [Indexed: 01/15/2023] Open
Abstract
Constitutive activation of the chemokine receptor CXCR4 has been associated with tumor progression, invasion, and chemotherapy resistance in different cancer subtypes. Although the CXCR4 pathway has recently been suggested as an adverse prognostic marker in diffuse large B-cell lymphoma, its biological relevance in this disease remains underexplored. In a homogeneous set of 52 biopsies from patients, an antibody-based cytokine array showed that tissue levels of CXCL12 correlated with high microvessel density and bone marrow involvement at diagnosis, supporting a role for the CXCL12-CXCR4 axis in disease progression. We then identified the tetra-amine IQS-01.01RS as a potent inverse agonist of the receptor, preventing CXCL12-mediated chemotaxis and triggering apoptosis in a panel of 18 cell lines and primary cultures, with superior mobilizing properties in vivo than those of the standard agent. IQS-01.01RS activity was associated with downregulation of p-AKT, p-ERK1/2 and destabilization of MYC, allowing a synergistic interaction with the bromodomain and extra-terminal domain inhibitor, CPI203. In a xenotransplant model of diffuse large B-cell lymphoma, the combination of IQS-01.01RS and CPI203 decreased tumor burden through MYC and p-AKT downregulation, and enhanced the induction of apoptosis. Thus, our results point out an emerging role of CXCL12-CXCR4 in the pathogenesis of diffuse large B-cell lymphoma and support the simultaneous targeting of CXCR4 and bromodomain proteins as a promising, rationale-based strategy for the treatment of this disease.
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Affiliation(s)
- Clara Recasens-Zorzo
- Division of Hemato-Oncology, Institut d'Investigacions Biomediques August Pi I Sunyer (IDIBAPS), CIBERONC, Barcelona
| | | | - Paolo Petazzi
- Josep Carreras Leukemia Research Institute, Department of Biomedicine, School of Medicine, University of Barcelona
| | - Laia Ros-Blanco
- Grup d'Enginyeria Molecular, IQS School of Engineering, Universitat Ramon Llull, Barcelona
| | - Anna Esteve-Arenys
- Division of Hemato-Oncology, Institut d'Investigacions Biomediques August Pi I Sunyer (IDIBAPS), CIBERONC, Barcelona
| | - Guillem Clot
- Division of Hemato-Oncology, Institut d'Investigacions Biomediques August Pi I Sunyer (IDIBAPS), CIBERONC, Barcelona
| | - Martina Guerrero-Hernández
- Division of Hemato-Oncology, Institut d'Investigacions Biomediques August Pi I Sunyer (IDIBAPS), CIBERONC, Barcelona
| | - Vanina Rodríguez
- Division of Hemato-Oncology, Institut d'Investigacions Biomediques August Pi I Sunyer (IDIBAPS), CIBERONC, Barcelona
| | - Davide Soldini
- Hematopathology Unit, Department of Pathology, Hospital Clinic, Barcelona
| | - Alexandra Valera
- Hematopathology Unit, Department of Pathology, Hospital Clinic, Barcelona
| | - Alexandra Moros
- Division of Hemato-Oncology, Institut d'Investigacions Biomediques August Pi I Sunyer (IDIBAPS), CIBERONC, Barcelona
| | - Fina Climent
- Pathology Department, Hospital Universitari de Bellvitge, L'Hospitalet de Llobregat
| | - Eva González-Barca
- Institut Catalá d'Oncología, Hospital Duran I Reynals, L'Hospitalet de Llobregat
| | - Santiago Mercadal
- Institut Catalá d'Oncología, Hospital Duran I Reynals, L'Hospitalet de Llobregat
| | | | - Xavier Calvo
- Pathology Department, IMIM, Hospital del Mar, Barcelona
| | - José Luís Mate
- Pathology Department, Hospital Universitari Germans Trias i Pujol, Badalona
| | | | - Isolda Casanova
- Josep Carreras Leukemia Research Institute, Department of Biomedicine, School of Medicine, University of Barcelona.,Grup d'Oncogènesi i Antitumorals, lnstitut d'Investigacions Biomèdiques Sant Pau (IIB-Sant Pau) and Centro de Investigación Biomédica en Red CIBER-BBN, Barcelona
| | - Ramón Mangues
- Josep Carreras Leukemia Research Institute, Department of Biomedicine, School of Medicine, University of Barcelona.,Grup d'Oncogènesi i Antitumorals, lnstitut d'Investigacions Biomèdiques Sant Pau (IIB-Sant Pau) and Centro de Investigación Biomédica en Red CIBER-BBN, Barcelona
| | | | - Clara Bueno
- Josep Carreras Leukemia Research Institute, Department of Biomedicine, School of Medicine, University of Barcelona
| | - Pablo Menéndez
- Josep Carreras Leukemia Research Institute, Department of Biomedicine, School of Medicine, University of Barcelona.,Institucio Catalana de Recerca I Estudis Avançats (ICREA), CIBERONC, Barcelona
| | - Antonio Martínez
- Division of Hemato-Oncology, Institut d'Investigacions Biomediques August Pi I Sunyer (IDIBAPS), CIBERONC, Barcelona.,Hematopathology Unit, Department of Pathology, Hospital Clinic, Barcelona
| | - Dolors Colomer
- Division of Hemato-Oncology, Institut d'Investigacions Biomediques August Pi I Sunyer (IDIBAPS), CIBERONC, Barcelona.,Hematopathology Unit, Department of Pathology, Hospital Clinic, Barcelona
| | - Roger Estrada Tejedor
- Grup d'Enginyeria Molecular, IQS School of Engineering, Universitat Ramon Llull, Barcelona
| | - Jordi Teixidó
- Grup d'Enginyeria Molecular, IQS School of Engineering, Universitat Ramon Llull, Barcelona
| | - Elias Campo
- Division of Hemato-Oncology, Institut d'Investigacions Biomediques August Pi I Sunyer (IDIBAPS), CIBERONC, Barcelona.,Hematopathology Unit, Department of Pathology, Hospital Clinic, Barcelona
| | - Armando López-Guillermo
- Division of Hemato-Oncology, Institut d'Investigacions Biomediques August Pi I Sunyer (IDIBAPS), CIBERONC, Barcelona.,Department of Hematology, Hospital Clinic, Barcelona
| | - José Ignacio Borrell
- Grup d'Enginyeria Molecular, IQS School of Engineering, Universitat Ramon Llull, Barcelona
| | - Luis Colomo
- Hematopathology Unit, Department of Pathology, Hospital Clinic, Barcelona.,Pathology Department, IMIM, Hospital del Mar, Barcelona
| | - Patricia Pérez-Galán
- Division of Hemato-Oncology, Institut d'Investigacions Biomediques August Pi I Sunyer (IDIBAPS), CIBERONC, Barcelona
| | - Gaël Roué
- Division of Hemato-Oncology, Institut d'Investigacions Biomediques August Pi I Sunyer (IDIBAPS), CIBERONC, Barcelona .,Laboratory of Experimental Hematology, Department of Hematology, Vall d'Hebron Institute of Oncology, Vall d'Hebron University Hospital, Barcelona, Spain
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40
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Heon Lee I, Palombo MS, Zhang X, Szekely Z, Sinko PJ. Design and evaluation of a CXCR4 targeting peptide 4DV3 as an HIV entry inhibitor and a ligand for targeted drug delivery. Eur J Pharm Biopharm 2018; 138:11-22. [PMID: 29894816 DOI: 10.1016/j.ejpb.2018.06.004] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2018] [Revised: 04/27/2018] [Accepted: 06/04/2018] [Indexed: 12/09/2022]
Abstract
The feasibility of utilizing the cell surface chemokine receptor CXCR4 for human immunodeficiency virus (HIV) entry inhibition and as an intracellular portal for targeted drug delivery was evaluated. Novel DV3 ligands (1DV3, 2DV3, and 4DV3) were designed, synthesized and conjugated to various probes (fluorescein isothiocyanate (FITC) or biotin) and cargos with sizes ranging from 10 to 50 nm (polyethylene glycol (PEG), streptavidin, and a polymeric nanoparticle). 4DV3 conjugated probes inhibited HIV-1 entry into the CXCR4-expressing reporter cell line TZM-bl (IC50 at 553 nM) whereas 1DV3 and 2DV3 did not. 4DV3 also inhibited binding of anti-CXCR4 antibody 44,708 to TZM-bl cells with nanomolar potency, while the small-molecule CXCR4 antagonist AMD3100 did not. Molecular modeling suggested simultaneous binding of a single 4DV3 molecule to four CXCR4 molecules. Differences in CXCR4-binding sites could explain the discrete inhibitory effects observed for 4DV3, the 44,708 antibody and AMD3100. In the Sup-T1 cell chemotaxis assay, the 4DV3 ligand functioned as a CXCR4 allosteric enhancer. In addition, 4DV3 ligand-conjugated cargos with sizes ranging from 10 to 50 nm were taken up into CXCR4-expressing Sup-T1 and TZM-bl cells, demonstrating that CXCR4 could serve as a drug delivery portal for nanocarriers. The uptake of 4DV3 functionalized nanocarriers combined with the allosteric interaction with CXCR4 suggests enhanced endocytosis occurs when 4DV3 is the targeting ligand. The current results indicate that 4DV3 might serve as a prototype for a new type of dual function ligand, one that acts as a HIV-1 entry inhibitor and a CXCR4 drug delivery targeting ligand.
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Affiliation(s)
- In Heon Lee
- Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 160 Frelinghuysen Rd, Piscataway, NJ 08854, USA.
| | - Matthew S Palombo
- Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 160 Frelinghuysen Rd, Piscataway, NJ 08854, USA.
| | - Xiaoping Zhang
- Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 160 Frelinghuysen Rd, Piscataway, NJ 08854, USA.
| | - Zoltan Szekely
- Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 160 Frelinghuysen Rd, Piscataway, NJ 08854, USA.
| | - Patrick J Sinko
- Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 160 Frelinghuysen Rd, Piscataway, NJ 08854, USA.
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Breun M, Schwerdtfeger A, Martellotta DD, Kessler AF, Perez JM, Monoranu CM, Ernestus RI, Matthies C, Löhr M, Hagemann C. CXCR4: A new player in vestibular schwannoma pathogenesis. Oncotarget 2018; 9:9940-9950. [PMID: 29515781 PMCID: PMC5839412 DOI: 10.18632/oncotarget.24119] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2017] [Accepted: 12/03/2017] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND CXCR4 is a chemokine receptor that recruits blood stem cells and increases tumor cell growth and invasiveness. We examined CXCR4 expression in vestibular schwannomas (VS) from patients with and without neurofibromatosis type 2 (NF2) and correlated the levels with the patients' clinical characteristics. The aim was to determine whether CXCR4 can be used as a prognostic marker and as a target for systemic therapy. RESULTS Overall, CXCR4 mRNA levels were 4.6-fold higher in VS versus control; the levels were 4.9-fold higher in NF2 patients and 4.2-fold higher in sporadic VS patients. IHC and WB showed heterogeneous protein expression, and CXCR4 was expressed mainly in S100-positive Schwann cells. There was no correlation between the CXCR4 protein levels and tumor extension. However, there was a trend towards correlation between higher expression levels and greater hearing loss. MATERIALS AND METHODS CXCR4 mRNA and protein levels were determined in VS samples (n = 60); of these, 30 samples were from patients with NF2. Healthy nerves from autopsies served as controls. CXCR4 mRNA levels were measured by PCR, and protein levels were measured by immunohistochemistry (IHC) and Western blotting (WB). Tumor extension and hearing loss were categorized according to the Hannover Classification as clinical parameters. CONCLUSIONS CXCR4 mRNA was overexpressed in VS relative to healthy vestibular nerves, and there was a trend towards higher CXCR4 expression levels being correlated with greater functional impairment. Thus, CXCR4 may be a prognostic marker of VS, and CXCR4 inhibition has potential as a systemic approach for the treatment of VS.
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Affiliation(s)
- Maria Breun
- Department of Neurosurgery, University Hospital Würzburg, 97080 Würzburg, Germany
| | | | | | - Almuth F. Kessler
- Department of Neurosurgery, University Hospital Würzburg, 97080 Würzburg, Germany
| | - Jose M. Perez
- Department of Neurosurgery, University Hospital Würzburg, 97080 Würzburg, Germany
| | - Camelia M Monoranu
- Department of Neuropathology, University of Würzburg, Institute of Pathology, 97080 Würzburg, Germany
- Comprehensive Cancer Center (CCC), Mainfranken, Würzburg
| | - Ralf-Ingo Ernestus
- Department of Neurosurgery, University Hospital Würzburg, 97080 Würzburg, Germany
| | - Cordula Matthies
- Department of Neurosurgery, University Hospital Würzburg, 97080 Würzburg, Germany
| | - Mario Löhr
- Department of Neurosurgery, University Hospital Würzburg, 97080 Würzburg, Germany
| | - Carsten Hagemann
- Department of Neurosurgery, University Hospital Würzburg, 97080 Würzburg, Germany
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Akinduro O, Weber TS, Ang H, Haltalli MLR, Ruivo N, Duarte D, Rashidi NM, Hawkins ED, Duffy KR, Lo Celso C. Proliferation dynamics of acute myeloid leukaemia and haematopoietic progenitors competing for bone marrow space. Nat Commun 2018; 9:519. [PMID: 29410432 PMCID: PMC5802720 DOI: 10.1038/s41467-017-02376-5] [Citation(s) in RCA: 65] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2017] [Accepted: 11/24/2017] [Indexed: 02/01/2023] Open
Abstract
Leukaemia progressively invades bone marrow (BM), outcompeting healthy haematopoiesis by mechanisms that are not fully understood. Combining cell number measurements with a short-timescale dual pulse labelling method, we simultaneously determine the proliferation dynamics of primitive haematopoietic compartments and acute myeloid leukaemia (AML). We observe an unchanging proportion of AML cells entering S phase per hour throughout disease progression, with substantial BM egress at high levels of infiltration. For healthy haematopoiesis, we find haematopoietic stem cells (HSCs) make a significant contribution to cell production, but we phenotypically identify a quiescent subpopulation with enhanced engraftment ability. During AML progression, we observe that multipotent progenitors maintain a constant proportion entering S phase per hour, despite a dramatic decrease in the overall population size. Primitive populations are lost from BM with kinetics that are consistent with ousting irrespective of cell cycle state, with the exception of the quiescent HSC subpopulation, which is more resistant to elimination. How leukaemia cells invade the bone marrow by outcompeting haematopoietic cells is still unclear. Here, the authors used detailed cell number measurements in conjunction with a dual pulse labelling method to determine proliferation rates and followed the in vivo dynamics of AML disease progression.
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Affiliation(s)
- O Akinduro
- Department of Life Sciences, Sir Alexander Fleming Building, Imperial College London, London, SW7 2AZ, UK
| | - T S Weber
- Hamilton Institute, Maynooth University, Maynooth, Co Kildare, W23 WK26, Ireland.,The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, 3052, Australia.,Department of Medical Biology, The University of Melbourne, Parkville, VIC, 3010, Australia
| | - H Ang
- Department of Life Sciences, Sir Alexander Fleming Building, Imperial College London, London, SW7 2AZ, UK
| | - M L R Haltalli
- Department of Life Sciences, Sir Alexander Fleming Building, Imperial College London, London, SW7 2AZ, UK
| | - N Ruivo
- Department of Life Sciences, Sir Alexander Fleming Building, Imperial College London, London, SW7 2AZ, UK
| | - D Duarte
- Department of Life Sciences, Sir Alexander Fleming Building, Imperial College London, London, SW7 2AZ, UK.,The Francis Crick Institute, 1 Midland Road, London, NW1A 1AT, UK
| | - N M Rashidi
- Department of Life Sciences, Sir Alexander Fleming Building, Imperial College London, London, SW7 2AZ, UK
| | - E D Hawkins
- Department of Life Sciences, Sir Alexander Fleming Building, Imperial College London, London, SW7 2AZ, UK.,The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, 3052, Australia.,Department of Medical Biology, The University of Melbourne, Parkville, VIC, 3010, Australia
| | - K R Duffy
- Hamilton Institute, Maynooth University, Maynooth, Co Kildare, W23 WK26, Ireland.
| | - C Lo Celso
- Department of Life Sciences, Sir Alexander Fleming Building, Imperial College London, London, SW7 2AZ, UK. .,The Francis Crick Institute, 1 Midland Road, London, NW1A 1AT, UK.
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43
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Nazari A, Khorramdelazad H, Hassanshahi G. Biological/pathological functions of the CXCL12/CXCR4/CXCR7 axes in the pathogenesis of bladder cancer. Int J Clin Oncol 2017; 22:991-1000. [PMID: 29022185 DOI: 10.1007/s10147-017-1187-x] [Citation(s) in RCA: 56] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2017] [Accepted: 08/21/2017] [Indexed: 12/14/2022]
Abstract
CXC chemokine ligand 12 (CXCL12) is an important member of the CXC subfamily of chemokines, and has been extensively studied in various human body organs and systems, both in physiological and clinical states. Ligation of CXCL12 to CXCR4 and CXCR7 as its receptors on peripheral immune cells gives rise to pleiotropic activities. CXCL12 itself is a highly effective chemoattractant which conservatively attracts lymphocytes and monocytes, whereas there exists no evidence to show attraction for neutrophils. CXCL12 regulates inflammation, neo-vascularization, metastasis, and tumor growth, phenomena which are all pivotally involved in cancer development and further metastasis. Generation and secretion of CXCL12 by stromal cells facilitate attraction of cancer cells, acting through its cognate receptor, CXCR4, which is expressed by both hematopoietic and non-hematopoietic tumor cells. CXCR4 stimulates tumor progression by different mechanisms and is required for metastatic spread to organs where CXCL12 is expressed, thereby allowing tumor cells to access cellular niches, such as the marrow, which favor tumor cell survival and proliferation. It has also been demonstrated that CXCL12 binds to another seven-transmembrane G-protein receptor or G-protein-coupled receptor, namely CXCR7. These studies indicated critical roles for CXCR4 and CXCR7 mediation of tumor metastasis in several types of cancers, suggesting their contributions as biomarkers of tumor behavior as well as potential therapeutic targets. Furthermore, CXCL12 itself has the capability to stimulate survival and growth of neoplastic cells in a paracrine fashion. CXCL12 is a supportive chemokine for tumor neovascularization via attracting endothelial cells to the tumor microenvironment. It has been suggested that elevated protein and mRNA levels of CXCL12/CXCR4/CXCR7 are associated with human bladder cancer (BC). Taken together, mounting evidence suggests a role for CXCR4, CXCR7, and their ligand CXCL12 during the genesis of BC and its further development. However, a better understanding is still required before exploring CXCL12/CXCR4/CXCR7 targeting in the clinic.
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Affiliation(s)
- Alireza Nazari
- Department of Surgery, School of Medicine, Rafsanjan University of Medical Science, Rafsanjan, Iran.,Molecular Medicine Research Center, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Hossein Khorramdelazad
- Molecular Medicine Research Center, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Gholamhossein Hassanshahi
- Molecular Medicine Research Center, Rafsanjan University of Medical Sciences, Rafsanjan, Iran. .,Department of Immunology, Rafsanjan University of Medical Sciences, Rafsanjan, Iran.
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44
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Walenkamp AME, Lapa C, Herrmann K, Wester HJ. CXCR4 Ligands: The Next Big Hit? J Nucl Med 2017; 58:77S-82S. [PMID: 28864616 DOI: 10.2967/jnumed.116.186874] [Citation(s) in RCA: 111] [Impact Index Per Article: 13.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2017] [Accepted: 06/02/2017] [Indexed: 12/12/2022] Open
Abstract
The G protein-coupled protein receptor C-X-C chemokine receptor 4 (CXCR4) is an attractive target for cancer diagnosis and treatment, as it is overexpressed in many solid and hematologic cancers. Binding of its ligand, C-X-C chemokine ligand 12 (CXCL12), results in receptor internalization and activation of several signal transduction pathways, such as phosphoinositide 3-kinase/protein kinase B, which are critical in cell proliferation, angiogenesis, development of metastasis, and survival. Also, the CXCR4-CXCL12 axis is involved in the interaction between hematopoietic stem cells (as well as hematologic and solid tumor cells) and their protective microenvironment. This interaction can be disrupted by CXCR4 antagonists. This concept is being used clinically to harvest hematopoietic stem or progenitor cells from bone marrow and to sensitize cancer cells to conventional chemotherapy and radiotherapy, and the potential to overcome tumor microenvironment-driven immunosuppression is being explored. This review focuses on new strategies for improvement of cancer treatment by targeting of the CXCR4-CXCL12 interaction. Because of its critical role in cancer, many peptidic and nonpeptidic ligands with different modes of antagonistic activity against the CXCR4-CXCL12 axis have been developed, with some of them reaching clinical trials. Molecular imaging with recently developed radiolabeled CXCR4 ligands could facilitate the selection of patients who might benefit from directed targeted therapy, including CXCR4-directed endoradiotherapy.
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Affiliation(s)
- Annemiek M E Walenkamp
- Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Constantin Lapa
- Department of Nuclear Medicine, University Hospital Würzburg, Würzburg, Germany
| | - Ken Herrmann
- Department of Nuclear Medicine, University Hospital Essen, Essen, Germany.,Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, UCLA, Los Angeles, California
| | - Hans-Jürgen Wester
- Pharmaceutical Radiochemistry, Technische Universität München, Munich, Germany; and.,Scintomics GmbH, Fuerstenfeldbruck, Germany
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Lappano R, Maggiolini M. Pharmacotherapeutic Targeting of G Protein-Coupled Receptors in Oncology: Examples of Approved Therapies and Emerging Concepts. Drugs 2017; 77:951-965. [PMID: 28401445 DOI: 10.1007/s40265-017-0738-9] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
G protein-coupled receptors (GPCRs) are involved in numerous physio-pathological processes, including the stimulation of cancer progression. In this regard, it should be mentioned that although GPCRs may represent major pharmaceutical targets, only a few drugs acting as GPCR inhibitors are currently used in anti-tumor therapies. For instance, certain pro-malignancy effects mediated by GPCRs are actually counteracted by the use of small molecules and peptides that function as receptor antagonists or inverse agonists. Recently, humanized monoclonal antibodies targeting GPCRs have also been developed. Here, we review the current GPCR-targeted therapies for cancer treatment, summarizing the clinical studies that led to their official approval. We provide a broad overview of the mechanisms of action of the available anti-cancer drugs targeting gonadotropin-releasing hormone, somatostatin, chemokine, and Smoothened receptors. In addition, we discuss the anti-tumor potential of novel non-approved molecules and antibodies able to target some of the aforementioned GPCRs in different experimental models and clinical trials. Likewise, we focus on the repurposing in cancer patients of non-oncological GPCR-based drugs, elucidating the rationale behind this approach and providing clinical evidence on their safety and efficacy.
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Affiliation(s)
- Rosamaria Lappano
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, Italy.
| | - Marcello Maggiolini
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, Italy.
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