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1
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Wen J, Zheng B, Fu T. CXCL12 expression and the survival of patients with gastric cancer: a meta-analysis. Clin Exp Med 2025; 25:191. [PMID: 40481962 PMCID: PMC12145318 DOI: 10.1007/s10238-025-01674-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2025] [Accepted: 04/05/2025] [Indexed: 06/11/2025]
Abstract
Gastric cancer (GC) remains a leading cause of cancer-related mortality worldwide. CXCL12, a chemokine involved in tumor progression and metastasis, has been inconsistently associated with GC survival. This meta-analysis aimed to evaluate the prognostic significance of CXCL12 expression in GC patients. A comprehensive literature search was conducted in PubMed, Embase, and Web of Science. Observational studies assessing tumor CXCL12 expression and survival outcomes in GC patients were included. Hazard ratios (HRs) with 95% confidence intervals (CIs) were pooled using a random-effects model by incorporating heterogeneity. Ten studies comprising 1361 GC patients were included. High CXCL12 expression was significantly associated with poorer overall survival (OS) (HR: 1.85, 95% CI 1.51-2.26, p < 0.001) with mild heterogeneity (I2 = 17%). Subgroup analyses revealed that the association between high CXCL12 expression and OS was stronger in studies defining high expression as above the median density value (HR: 2.63, 95% CI 1.79-3.86) than in those using any positive expression (HR: 1.61, 95% CI 1.30-2.00; p for subgroup difference = 0.03). Additionally, a more pronounced association was observed in studies with follow-up durations ≥ 36 months (HR: 2.42, 95% CI 1.84-3.18) compared to those with < 36 months (HR: 1.59, 95% CI 1.28-1.99; p = 0.03). The pooled results also indicated an association between high CXCL12 expression and worse progression-free survival (PFS) (HR: 1.52, 95% CI 1.05-2.20, p = 0.03). High CXCL12 expression is associated with poorer survival outcomes in GC patients.
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Affiliation(s)
- Jinxiu Wen
- Department of Gastrointestinal and Hernia Surgery, Heyuan People's Hospital, Guangdong Provincial People's Hospital Heyuan Hospital, No. 733, Wenxiang Road, Yuancheng District, Heyuan, 517000, China
| | - Bingbing Zheng
- Department of Gastrointestinal and Hernia Surgery, Heyuan People's Hospital, Guangdong Provincial People's Hospital Heyuan Hospital, No. 733, Wenxiang Road, Yuancheng District, Heyuan, 517000, China.
| | - Ting Fu
- Department of Gastrointestinal and Hernia Surgery, Heyuan People's Hospital, Guangdong Provincial People's Hospital Heyuan Hospital, No. 733, Wenxiang Road, Yuancheng District, Heyuan, 517000, China
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2
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Rueda A, Serna N, Mangues R, Villaverde A, Unzueta U. Targeting the chemokine receptor CXCR4 for cancer therapies. Biomark Res 2025; 13:68. [PMID: 40307933 PMCID: PMC12044942 DOI: 10.1186/s40364-025-00778-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2025] [Accepted: 04/13/2025] [Indexed: 05/02/2025] Open
Abstract
The C-X-C chemokine receptor type 4 (CXCR4) has emerged as a key molecular biomarker for cancer therapies due to its critical role in tumor progression and metastases by displaying a stem cells phenotype. Its overexpression has been observed in more than 20 types of cancers, including solid tumors and hematological malignancies, and it is often associated with tumor aggressiveness and poor prognosis. Being initially recognized as a co-receptor involved in HIV infection, numerous CXCR4-targeting ligands and antagonists, including small molecules, peptides and biologics have been identified over the past decades. While only few of them have been used in the context of cancer therapies, recent biotechnological advancements using CXCR4 as a molecular target are showing significant potential to revolutionize future cancer therapies. Therefore, this review highlights the biotechnological innovations developed for cancer therapy and diagnosis by targeting the chemokine receptor CXCR4. It also discusses future perspectives on emerging therapeutic strategies, ranging from the use of small molecule inhibitors that block receptor signaling to cutting-edge nanocarriers designed for the targeted delivery of innovative drugs and proteins into cancer stem cells, aiming at cell-selective precision nanomedicines.
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Affiliation(s)
- Ariana Rueda
- Institut de Recerca Sant Pau (IR SANT PAU), Sant Quintí 77 - 79, Barcelona, 08041, Spain
- CIBER de Bioingeniería, Biomateriales y Nanomedicina, Instituto de Salud Carlos III, Madrid, 28029, Spain
- Josep Carreras Leukaemia Research Institute (IJC Sant Pau), 08041, Barcelona, Spain
| | - Naroa Serna
- CIBER de Bioingeniería, Biomateriales y Nanomedicina, Instituto de Salud Carlos III, Madrid, 28029, Spain
- Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de Barcelona, 08193, Bellaterra, Spain
| | - Ramon Mangues
- Institut de Recerca Sant Pau (IR SANT PAU), Sant Quintí 77 - 79, Barcelona, 08041, Spain.
- CIBER de Bioingeniería, Biomateriales y Nanomedicina, Instituto de Salud Carlos III, Madrid, 28029, Spain.
- Josep Carreras Leukaemia Research Institute (IJC Sant Pau), 08041, Barcelona, Spain.
| | - Antonio Villaverde
- CIBER de Bioingeniería, Biomateriales y Nanomedicina, Instituto de Salud Carlos III, Madrid, 28029, Spain.
- Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de Barcelona, 08193, Bellaterra, Spain.
- Departament de Genètica i de Microbiologia, Universitat Autònoma de Barcelona, Bellaterra, 08193, Spain.
| | - Ugutz Unzueta
- Institut de Recerca Sant Pau (IR SANT PAU), Sant Quintí 77 - 79, Barcelona, 08041, Spain.
- CIBER de Bioingeniería, Biomateriales y Nanomedicina, Instituto de Salud Carlos III, Madrid, 28029, Spain.
- Josep Carreras Leukaemia Research Institute (IJC Sant Pau), 08041, Barcelona, Spain.
- Departament de Genètica i de Microbiologia, Universitat Autònoma de Barcelona, Bellaterra, 08193, Spain.
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3
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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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4
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Ciavattone NG, Bevoor A, Farfel A, Rehman A, Ho KKY, Rock EC, Chen YC, Luker KE, Humphries BA, Luker GD. Inhibiting CXCR4 reduces immunosuppressive effects of myeloid cells in breast cancer immunotherapy. Sci Rep 2025; 15:5204. [PMID: 39939722 PMCID: PMC11822021 DOI: 10.1038/s41598-025-89882-5] [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: 10/15/2024] [Accepted: 02/10/2025] [Indexed: 02/14/2025] Open
Abstract
Patients with triple negative breast cancer (TNBC) show only modest response rates to immune checkpoint inhibitor immunotherapy, motivating ongoing efforts to identify approaches to boost efficacy. Using an immunocompetent mouse model of TNBC, we investigated combination therapy with an anti-PD-1 immunotherapy antibody plus balixafortide, a cyclic peptide inhibitor of CXCR4. Cell-based assays demonstrated that balixafortide functions as an inverse agonist, establishing a mode of action distinct from most compounds targeting CXCR4. Combination anti-PD-1 plus balixafortide significantly reduced growth of orthotopic tumors and extended overall survival relative to single agent therapy or vehicle. Adding balixafortide to anti-PD-1 increased numbers of tertiary lymphoid structures, a marker of local tumor immune responses associated with favorable response to immunotherapy in TNBC. Single cell RNA sequencing revealed that combination anti-PD-1 plus balixafortide reduced T cell exhaustion and increased markers of effector T cell activity. Combination therapy also reduced signatures of immunosuppressive myeloid derived suppressor cells (MDSCs) in tumors. MDSCs isolated from mice treated with anti-PD-1 plus balixafortide showed reduced inhibition of T cell proliferation following ex vivo stimulation. These studies demonstrate that combining inhibition of CXCR4 with anti-PD-1 to enhances responses to checkpoint inhibitor immunotherapy in TNBC, supporting future clinical trials.
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Affiliation(s)
- Nicholas G Ciavattone
- Department of Radiology, Center for Molecular Imaging, 109 Zina Pitcher Place, A524 BSRB, Ann Arbor, MI, 48109-2200, USA
| | - Avinash Bevoor
- Department of Radiology, Center for Molecular Imaging, 109 Zina Pitcher Place, A524 BSRB, Ann Arbor, MI, 48109-2200, USA
| | - Alex Farfel
- Department of Radiology, Center for Molecular Imaging, 109 Zina Pitcher Place, A524 BSRB, Ann Arbor, MI, 48109-2200, USA
| | - Aasia Rehman
- Department of Radiology, Center for Molecular Imaging, 109 Zina Pitcher Place, A524 BSRB, Ann Arbor, MI, 48109-2200, USA
| | - Kenneth K Y Ho
- Department of Radiology, Center for Molecular Imaging, 109 Zina Pitcher Place, A524 BSRB, Ann Arbor, MI, 48109-2200, USA
| | - Edwin C Rock
- Department of Computational and Systems Biology and UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA
| | - Yu-Chih Chen
- Department of Computational and Systems Biology and UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA
| | - Kathryn E Luker
- Department of Radiology, Center for Molecular Imaging, 109 Zina Pitcher Place, A524 BSRB, Ann Arbor, MI, 48109-2200, USA
- Biointerfaces Institute, University of Michigan, Ann Arbor, MI, USA
| | - Brock A Humphries
- Department of Radiology, Center for Molecular Imaging, 109 Zina Pitcher Place, A524 BSRB, Ann Arbor, MI, 48109-2200, USA.
- Department of Computational and Systems Biology and UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA.
| | - Gary D Luker
- Department of Radiology, Center for Molecular Imaging, 109 Zina Pitcher Place, A524 BSRB, Ann Arbor, MI, 48109-2200, USA.
- Biointerfaces Institute, University of Michigan, Ann Arbor, MI, USA.
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA.
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5
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Cheng PSW, Zaccaria M, Biffi G. Functional heterogeneity of fibroblasts in primary tumors and metastases. Trends Cancer 2025; 11:135-153. [PMID: 39674792 DOI: 10.1016/j.trecan.2024.11.005] [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: 08/29/2024] [Revised: 10/29/2024] [Accepted: 11/18/2024] [Indexed: 12/16/2024]
Abstract
Cancer-associated fibroblasts (CAFs) are abundant components of the tumor microenvironment (TME) of most solid malignancies and have emerged as key regulators of cancer progression and therapy response. Although recent technological advances have uncovered substantial CAF molecular heterogeneity at the single-cell level, defining functional roles for most described CAF populations remains challenging. With the aim of bridging CAF molecular and functional heterogeneity, this review focuses on recently identified functional interactions of CAF subtypes with malignant cells, immune cells, and other stromal cells in primary tumors and metastases. Dissecting the heterogeneous functional crosstalk of specific CAF populations with other components is starting to uncover candidate combinatorial strategies for therapeutically targeting the TME and cancer progression.
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Affiliation(s)
- Priscilla S W Cheng
- Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, CB2 0RE, UK
| | - Marta Zaccaria
- Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, CB2 0RE, UK
| | - Giulia Biffi
- Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, CB2 0RE, UK.
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6
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Zhang Y, Tang X, Wang Y, Shi F, Gao X, Guo Y, Liu Q, Ma W. Recent advances targeting chemokines for breast cancer. Int Immunopharmacol 2025; 146:113865. [PMID: 39718056 DOI: 10.1016/j.intimp.2024.113865] [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: 10/14/2024] [Revised: 12/02/2024] [Accepted: 12/11/2024] [Indexed: 12/25/2024]
Abstract
Breast cancer (BC) is a complex and heterogeneous disease, and its onset and progression involve the interplay of multiple molecular mechanisms. Chemokines and their receptors are key regulators of cell migration and immune responses and contribute significantly to the pathophysiology of BC. This article reviews the classification, functions, and mechanisms of chemokines and their receptors in the proliferation, migration, invasion, and angiogenesis of BC cells. This study explores the regulatory roles of chemokines and their receptors in the immune microenvironment of BC, particularly the ways they influence the infiltration, polarization, and antitumor immune responses of immune cells. Finally, this article summarizes the current treatment strategies for breast cancer that utilize chemokines and their receptors and provides insights into future research directions and trends in this field.
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Affiliation(s)
- Yanan Zhang
- College of Biological and Chemical Engineering, Qilu Institute of Technology, Shandong, China.
| | - Xiufeng Tang
- Department of Pharmacy and Shandong Provincinal Key Traditional Chinese Medical Discipline of Clinical Chinese Pharmacy, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Shandong, China.
| | - Ying Wang
- College of Biological and Chemical Engineering, Qilu Institute of Technology, Shandong, China.
| | - Fengcui Shi
- College of Biological and Chemical Engineering, Qilu Institute of Technology, Shandong, China.
| | - Xing Gao
- College of Biological and Chemical Engineering, Qilu Institute of Technology, Shandong, China.
| | - Yingxin Guo
- College of Biological and Chemical Engineering, Qilu Institute of Technology, Shandong, China.
| | - Qian Liu
- College of Biological and Chemical Engineering, Qilu Institute of Technology, Shandong, China.
| | - Wenjian Ma
- College of Biological and Chemical Engineering, Qilu Institute of Technology, Shandong, China; College of Biotechnology, Tianjin University of Science and Technology, Tianjin, China.
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7
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Camps-Fajol C, Cavero D, Minguillón J, Surrallés J. Targeting protein-protein interactions in drug discovery: Modulators approved or in clinical trials for cancer treatment. Pharmacol Res 2025; 211:107544. [PMID: 39667542 DOI: 10.1016/j.phrs.2024.107544] [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: 10/16/2024] [Revised: 11/27/2024] [Accepted: 12/09/2024] [Indexed: 12/14/2024]
Abstract
Protein-protein interactions (PPIs) form complex cellular networks fundamental to many key biological processes, including signal transduction, cell proliferation and DNA repair. In consequence, their perturbation is often associated with many human diseases. Targeting PPIs offers a promising approach in drug discovery and ongoing advancements in this field hold the potential to provide highly specific therapies for a wide range of complex diseases. Despite the development of PPI modulators is challenging, advances in the genetic, proteomic and computational level have facilitated their discovery and optimization. Focusing on anticancer drugs, in the last years several PPI modulators have entered clinical trials and venetoclax, which targets Bcl-2 family proteins, has been approved for treating different types of leukemia. This review discusses the clinical development status of drugs modulating several PPIs, such as MDM2-4/p53, Hsp90/Hsp90, Hsp90/CDC37, c-Myc/Max, KRAS/SOS1, CCR5/CCL5, CCR2/CCL2 or Smac/XIAP, in cancer drug discovery.
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Affiliation(s)
- Cristina Camps-Fajol
- Unitat Mixta de Recerca en Medicina Genòmica, Universitat Autònoma de Barcelona (UAB)-IR SANT PAU, Barcelona, Spain; Institut de Bioenginyeria de Catalunya (IBEC), Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras, Instituto de Salud Carlos III (CIBERER, ISCIII), Madrid, Spain
| | - Debora Cavero
- Unitat Mixta de Recerca en Medicina Genòmica, Universitat Autònoma de Barcelona (UAB)-IR SANT PAU, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras, Instituto de Salud Carlos III (CIBERER, ISCIII), Madrid, Spain
| | - Jordi Minguillón
- CIBERER-ISCIII, IdiPAZ-CNIO Translational Research Unit in Pediatric Hemato-Oncology, La Paz University Hospital Research Institute; Spanish National Cancer Center, Madrid, Spain; Hematopoietic Innovative Therapies Division, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT), Madrid, Spain
| | - Jordi Surrallés
- Unitat Mixta de Recerca en Medicina Genòmica, Universitat Autònoma de Barcelona (UAB)-IR SANT PAU, Barcelona, Spain; Institut de Bioenginyeria de Catalunya (IBEC), Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras, Instituto de Salud Carlos III (CIBERER, ISCIII), Madrid, Spain; Servei de Genètica, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; Departament de Genètica i Microbiologia, Universitat Autònoma de Barcelona, Spain.
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8
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Mastrogiovanni M, Donnadieu E, Pathak R, Di Bartolo V. Subverting Attachment to Prevent Attacking: Alteration of Effector Immune Cell Migration and Adhesion as a Key Mechanism of Tumor Immune Evasion. BIOLOGY 2024; 13:860. [PMID: 39596815 PMCID: PMC11591779 DOI: 10.3390/biology13110860] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/16/2024] [Revised: 10/19/2024] [Accepted: 10/22/2024] [Indexed: 11/29/2024]
Abstract
Cell adhesion regulates specific migratory patterns, location, communication with other cells, physical interactions with the extracellular matrix, and the establishment of effector programs. Proper immune control of cancer strongly depends on all these events occurring in a highly accurate spatiotemporal sequence. In response to cancer-associated inflammatory signals, effector immune cells navigating the bloodstream shift from their patrolling exploratory migration mode to establish adhesive interactions with vascular endothelial cells. This interaction enables them to extravasate through the blood vessel walls and access the cancer site. Further adhesive interactions within the tumor microenvironment (TME) are crucial for coordinating their distribution in situ and for mounting an effective anti-tumor immune response. In this review, we examine how alterations of adhesion cues in the tumor context favor tumor escape by affecting effector immune cell infiltration and trafficking within the TME. We discuss the mechanisms by which tumors directly modulate immune cell adhesion and migration patterns to affect anti-tumor immunity and favor tumor evasion. We also explore indirect immune escape mechanisms that involve modifications of TME characteristics, such as vascularization, immunogenicity, and structural topography. Finally, we highlight the significance of these aspects in designing more effective drug treatments and cellular immunotherapies.
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Affiliation(s)
- Marta Mastrogiovanni
- Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA
- Gottesman Institute for Stem Cell Biology and Regenerative Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA
| | - Emmanuel Donnadieu
- Equipe Labellisée Ligue Contre le Cancer, CNRS, INSERM, Institut Cochin, Université Paris Cité, F-75014 Paris, France;
| | - Rajiv Pathak
- Department of Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA;
| | - Vincenzo Di Bartolo
- Immunoregulation Unit, Institut Pasteur, Université Paris Cité, F-75015 Paris, France;
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9
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Cao C, Xu M, Wei Y, Peng T, Lin S, Liu X, Xu Y, Chu T, Liu S, Wu P, Hu B, Ding W, Li L, Ma D, Wu P. CXCR4 orchestrates the TOX-programmed exhausted phenotype of CD8 + T cells via JAK2/STAT3 pathway. CELL GENOMICS 2024; 4:100659. [PMID: 39317187 PMCID: PMC11602566 DOI: 10.1016/j.xgen.2024.100659] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/22/2024] [Revised: 06/17/2024] [Accepted: 08/22/2024] [Indexed: 09/26/2024]
Abstract
Evidence from clinical trials suggests that CXCR4 antagonists enhance immunotherapy effectiveness in several cancers. However, the specific mechanisms through which CXCR4 contributes to immune cell phenotypes are not fully understood. Here, we employed single-cell transcriptomic analysis and identified CXCR4 as a marker gene in T cells, with CD8+PD-1high exhausted T (Tex) cells exhibiting high CXCR4 expression. By blocking CXCR4, the Tex phenotype was attenuated in vivo. Mechanistically, CXCR4-blocking T cells mitigated the Tex phenotype by regulating the JAK2-STAT3 pathway. Single-cell RNA/TCR/ATAC-seq confirmed that Cxcr4-deficient CD8+ T cells epigenetically mitigated the transition from functional to exhausted phenotypes. Notably, clinical sample analysis revealed that CXCR4+CD8+ T cells showed higher expression in patients with a non-complete pathological response. Collectively, these findings demonstrate the mechanism by which CXCR4 orchestrates CD8+ Tex cells and provide a rationale for combining CXCR4 antagonists with immunotherapy in clinical trials.
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Affiliation(s)
- Canhui Cao
- Department of Gynecologic Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China; Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430199, China; Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China; National Clinical Research Center for Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
| | - Miaochun Xu
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China; Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430199, China; National Clinical Research Center for Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
| | - Ye Wei
- Department of Gynecologic Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China; Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430199, China; Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China; National Clinical Research Center for Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
| | - Ting Peng
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China; Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430199, China; National Clinical Research Center for Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
| | - Shitong Lin
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China; Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430199, China; National Clinical Research Center for Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
| | - Xiaojie Liu
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China; Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430199, China; National Clinical Research Center for Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
| | - Yashi Xu
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China; Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430199, China; National Clinical Research Center for Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
| | - Tian Chu
- Department of Gynecologic Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China; Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430199, China; Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China; National Clinical Research Center for Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
| | - Shiyi Liu
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China; Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430199, China; National Clinical Research Center for Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
| | - Ping Wu
- Department of Gynecologic Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China; Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430199, China; Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China; National Clinical Research Center for Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
| | - Bai Hu
- Department of Gynecologic Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China; Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430199, China; Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China; National Clinical Research Center for Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
| | - Wencheng Ding
- Department of Gynecologic Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China; Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430199, China; Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China; National Clinical Research Center for Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
| | - Li Li
- Department of Gynecologic Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China; Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430199, China; Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China; National Clinical Research Center for Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
| | - Ding Ma
- Department of Gynecologic Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China; Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430199, China; Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China; National Clinical Research Center for Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China.
| | - Peng Wu
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China; Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430199, China; National Clinical Research Center for Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China.
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10
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Zhang F, Ma Y, Li D, Wei J, Chen K, Zhang E, Liu G, Chu X, Liu X, Liu W, Tian X, Yang Y. Cancer associated fibroblasts and metabolic reprogramming: unraveling the intricate crosstalk in tumor evolution. J Hematol Oncol 2024; 17:80. [PMID: 39223656 PMCID: PMC11367794 DOI: 10.1186/s13045-024-01600-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Accepted: 08/20/2024] [Indexed: 09/04/2024] Open
Abstract
Metabolic reprogramming provides tumors with an energy source and biofuel to support their survival in the malignant microenvironment. Extensive research into the intrinsic oncogenic mechanisms of the tumor microenvironment (TME) has established that cancer-associated fibroblast (CAFs) and metabolic reprogramming regulates tumor progression through numerous biological activities, including tumor immunosuppression, chronic inflammation, and ecological niche remodeling. Specifically, immunosuppressive TME formation is promoted and mediators released via CAFs and multiple immune cells that collectively support chronic inflammation, thereby inducing pre-metastatic ecological niche formation, and ultimately driving a vicious cycle of tumor proliferation and metastasis. This review comprehensively explores the process of CAFs and metabolic regulation of the dynamic evolution of tumor-adapted TME, with particular focus on the mechanisms by which CAFs promote the formation of an immunosuppressive microenvironment and support metastasis. Existing findings confirm that multiple components of the TME act cooperatively to accelerate the progression of tumor events. The potential applications and challenges of targeted therapies based on CAFs in the clinical setting are further discussed in the context of advancing research related to CAFs.
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Affiliation(s)
- Fusheng Zhang
- Department of Hepatobiliary and Pancreatic Surgery, Peking University First Hospital, Beijing, 100034, China
| | - Yongsu Ma
- Department of Hepatobiliary and Pancreatic Surgery, Peking University First Hospital, Beijing, 100034, China
| | - Dongqi Li
- Department of Hepatobiliary and Pancreatic Surgery, Peking University First Hospital, Beijing, 100034, China
| | - Jianlei Wei
- Key laboratory of Microecology-immune Regulatory Network and Related Diseases School of Basic Medicine, Jiamusi University, Jiamusi, Heilongjiang Province, 154007, China
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Key Laboratory of Carcinogenesis and Translational Research, Peking University Health Science Center, Beijing, 100191, China
| | - Kai Chen
- Department of Hepatobiliary and Pancreatic Surgery, Peking University First Hospital, Beijing, 100034, China
| | - Enkui Zhang
- Department of Hepatobiliary and Pancreatic Surgery, Peking University First Hospital, Beijing, 100034, China
| | - Guangnian Liu
- Department of Hepatobiliary and Pancreatic Surgery, Peking University First Hospital, Beijing, 100034, China
| | - Xiangyu Chu
- Department of Hepatobiliary and Pancreatic Surgery, Peking University First Hospital, Beijing, 100034, China
| | - Xinxin Liu
- Department of Hepatobiliary and Pancreatic Surgery, Peking University First Hospital, Beijing, 100034, China
| | - Weikang Liu
- Department of Hepatobiliary and Pancreatic Surgery, Peking University First Hospital, Beijing, 100034, China
| | - Xiaodong Tian
- Department of Hepatobiliary and Pancreatic Surgery, Peking University First Hospital, Beijing, 100034, China.
| | - Yinmo Yang
- Department of Hepatobiliary and Pancreatic Surgery, Peking University First Hospital, Beijing, 100034, China.
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11
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Valdivia-Silva J, Chinney-Herrera A. Chemokine receptors and their ligands in breast cancer: The key roles in progression and metastasis. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2024; 388:124-161. [PMID: 39260935 DOI: 10.1016/bs.ircmb.2024.07.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/13/2024]
Abstract
Chemokines and their receptors are a family of chemotactic cytokines with important functions in the immune response in both health and disease. Their known physiological roles such as the regulation of leukocyte trafficking and the development of immune organs generated great interest when it was found that they were also related to the control of early and late inflammatory stages in the tumor microenvironment. In fact, in breast cancer, an imbalance in the synthesis of chemokines and/or in the expression of their receptors was attributed to be involved in the regulation of disease progression, including invasion and metastasis. Research in this area is progressing rapidly and the development of new agents based on chemokine and chemokine receptor antagonists are emerging as attractive alternative strategies. This chapter provides a snapshot of the different functions reported for chemokines and their receptors with respect to the potential to regulate breast cancer progression.
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Affiliation(s)
- Julio Valdivia-Silva
- Centro de Investigación en Bioingenieria (BIO), Universidad de Ingenieria y Tecnologia-UTEC, Barranco, Lima, Peru.
| | - Alberto Chinney-Herrera
- Facultad de Medicina, Universidad Nacional Autonoma de Mexico-UNAM, Ciudad Universitaria, Coyoacan, Ciudad de Mexico, Mexico
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12
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Zou Z, Luo T, Wang X, Wang B, Li Q. Exploring the interplay between triple-negative breast cancer stem cells and tumor microenvironment for effective therapeutic strategies. J Cell Physiol 2024; 239:e31278. [PMID: 38807378 DOI: 10.1002/jcp.31278] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2024] [Revised: 03/28/2024] [Accepted: 04/05/2024] [Indexed: 05/30/2024]
Abstract
Triple-negative breast cancer (TNBC) is a highly aggressive and metastatic malignancy with poor treatment outcomes. The interaction between the tumor microenvironment (TME) and breast cancer stem cells (BCSCs) plays an important role in the development of TNBC. Owing to their ability of self-renewal and multidirectional differentiation, BCSCs maintain tumor growth, drive metastatic colonization, and facilitate the development of drug resistance. TME is the main factor regulating the phenotype and metastasis of BCSCs. Immune cells, cancer-related fibroblasts (CAFs), cytokines, mesenchymal cells, endothelial cells, and extracellular matrix within the TME form a complex communication network, exert highly selective pressure on the tumor, and provide a conducive environment for the formation of BCSC niches. Tumor growth and metastasis can be controlled by targeting the TME to eliminate BCSC niches or targeting BCSCs to modify the TME. These approaches may improve the treatment outcomes and possess great application potential in clinical settings. In this review, we summarized the relationship between BCSCs and the progression and drug resistance of TNBC, especially focusing on the interaction between BCSCs and TME. In addition, we discussed therapeutic strategies that target the TME to inhibit or eliminate BCSCs, providing valuable insights into the clinical treatment of TNBC.
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Affiliation(s)
- Zhuoling Zou
- Queen Mary College, Nanchang University, Nanchang, Jiangxi, China
| | - Tinglan Luo
- Department of Oncology, The Seventh People's Hospital of Chongqing (Affiliated Central Hospital of Chongqing University of Technology), Chongqing, China
| | - Xinyuan Wang
- Department of Clinical Medicine, The Second Clinical College of Chongqing Medicine University, Chongqing, China
| | - Bin Wang
- Department of Oncology, The Seventh People's Hospital of Chongqing (Affiliated Central Hospital of Chongqing University of Technology), Chongqing, China
| | - Qing Li
- Department of Oncology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
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13
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Yi M, Li T, Niu M, Zhang H, Wu Y, Wu K, Dai Z. Targeting cytokine and chemokine signaling pathways for cancer therapy. Signal Transduct Target Ther 2024; 9:176. [PMID: 39034318 PMCID: PMC11275440 DOI: 10.1038/s41392-024-01868-3] [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: 02/28/2024] [Revised: 04/30/2024] [Accepted: 05/11/2024] [Indexed: 07/23/2024] Open
Abstract
Cytokines are critical in regulating immune responses and cellular behavior, playing dual roles in both normal physiology and the pathology of diseases such as cancer. These molecules, including interleukins, interferons, tumor necrosis factors, chemokines, and growth factors like TGF-β, VEGF, and EGF, can promote or inhibit tumor growth, influence the tumor microenvironment, and impact the efficacy of cancer treatments. Recent advances in targeting these pathways have shown promising therapeutic potential, offering new strategies to modulate the immune system, inhibit tumor progression, and overcome resistance to conventional therapies. In this review, we summarized the current understanding and therapeutic implications of targeting cytokine and chemokine signaling pathways in cancer. By exploring the roles of these molecules in tumor biology and the immune response, we highlighted the development of novel therapeutic agents aimed at modulating these pathways to combat cancer. The review elaborated on the dual nature of cytokines as both promoters and suppressors of tumorigenesis, depending on the context, and discussed the challenges and opportunities this presents for therapeutic intervention. We also examined the latest advancements in targeted therapies, including monoclonal antibodies, bispecific antibodies, receptor inhibitors, fusion proteins, engineered cytokine variants, and their impact on tumor growth, metastasis, and the tumor microenvironment. Additionally, we evaluated the potential of combining these targeted therapies with other treatment modalities to overcome resistance and improve patient outcomes. Besides, we also focused on the ongoing research and clinical trials that are pivotal in advancing our understanding and application of cytokine- and chemokine-targeted therapies for cancer patients.
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Affiliation(s)
- Ming Yi
- Department of Breast Surgery, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310000, People's Republic of China
| | - Tianye Li
- Department of Gynecology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310000, People's Republic of China
| | - Mengke Niu
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China
| | - Haoxiang Zhang
- Department of Hepatopancreatobiliary Surgery, Fujian Provincial Hospital, Fuzhou, 350001, People's Republic of China
| | - Yuze Wu
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China
| | - Kongming Wu
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China.
| | - Zhijun Dai
- Department of Breast Surgery, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310000, People's Republic of China.
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14
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Bao G, Wang Z, Liu L, Zhang B, Song S, Wang D, Cheng S, Moon ES, Roesch F, Zhao J, Yu B, Zhu X. Targeting CXCR4/CXCL12 axis via [ 177Lu]Lu-DOTAGA.(SA.FAPi) 2 with CXCR4 antagonist in triple-negative breast cancer. Eur J Nucl Med Mol Imaging 2024; 51:2744-2757. [PMID: 38587644 PMCID: PMC11224082 DOI: 10.1007/s00259-024-06704-y] [Citation(s) in RCA: 10] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Accepted: 03/16/2024] [Indexed: 04/09/2024]
Abstract
PURPOSE Radiopharmaceutical therapies targeting fibroblast activation protein (FAP) have shown promising efficacy against many tumor types. But radiopharmaceuticals alone in most cases are insufficient to completely eradicate tumor cells, which can partially be attributed to the protective interplay between tumor cells and cancer-associated fibroblasts (CAFs). The C-X-C chemokine receptor type 4/C-X-C motif chemokine 12 (CXCR4/CXCL12) interaction plays an important role in orchestrating tumor cells and CAFs. We hereby investigated the feasibility and efficacy of [177Lu]Lu-DOTAGA.(SA.FAPi)2, a FAP-targeting radiopharmaceutical, in combination with AMD3100, a CXCR4 antagonist, in a preclinical murine model of triple-negative breast cancer (TNBC). METHODS Public database was first interrogated to reveal the correlation between CAFs' scores and the prognosis of TNBC patients, as well as the expression levels of FAP and CXCR4 in normal tissues and tumors. In vitro therapeutic efficacy regarding cell proliferation, migration, and colony formation was assessed in BALB/3T3 fibroblasts and 4T1 murine breast cancer cells. In vivo therapeutic efficacy was longitudinally monitored using serial 18F-FDG, [18F]AlF-NOTA-FAPI-04, and [68Ga]Ga-DOTA-Pentixafor PET/CT scans and validated using tumor sections through immunohistochemical staining of Ki-67, α-SMA, CXCR4, and CXCL12. Intratumoral abundance of myeloid-derived suppressive cells (MDSCs) was analyzed using flow cytometry in accordance with the PET/CT schedules. Treatment toxicity was evaluated by examining major organs including heart, lung, liver, kidney, and spleen. RESULTS CAFs' scores negatively correlated with the survival of TNBC patients (p < 0.05). The expression of CXCR4 and FAP was both significantly higher in tumors than in normal tissues. The combination of [177Lu]Lu-DOTAGA.(SA.FAPi)2 and AMD3100 significantly suppressed cell proliferation, migration, and colony formation in cell culture, and exhibited synergistic effects in 4T1 tumor models along with a decreased number of MDSCs. PET/CT imaging revealed lowest tumor accumulation of 18F-FDG and [18F]AlF-NOTA-FAPI-04 on day 13 and day 14 after treatment started, both of which gradually increased at later time points. A similar trend was observed in the IHC staining of Ki-67, α-SMA, and CXCL12. CONCLUSION The combination of [177Lu]Lu-DOTAGA.(SA.FAPi)2 and AMD3100 is a feasible treatment against TNBC with minimal toxicity in main organs.
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Affiliation(s)
- Guangfa Bao
- Department of Nuclear Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan, 430030, China
| | - Ziqiang Wang
- Department of Nuclear Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan, 430030, China
| | - Luoxia Liu
- Department of Nuclear Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan, 430030, China
| | - Buchuan Zhang
- Department of Nuclear Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan, 430030, China
| | - Shuang Song
- Department of Nuclear Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan, 430030, China
| | - Dongdong Wang
- Department of Nuclear Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan, 430030, China
| | - Siyuan Cheng
- Department of Nuclear Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan, 430030, China
| | - Eu-Song Moon
- Department of Chemistry, Johannes Gutenberg University, 55131, Mainz, Germany
| | - Frank Roesch
- Department of Chemistry, Johannes Gutenberg University, 55131, Mainz, Germany
| | - Jun Zhao
- Department of Nuclear Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan, 430030, China
- Department of Anatomy, School of Basic Medicine, Huazhong University of Science and Technology, Wuhan, 430030, Hubei Province, China
- Cell Architecture Research Center, Huazhong University of Science and Technology, Wuhan, Hubei Province, 430030, China
| | - Bo Yu
- Department of Nuclear Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan, 430030, China
| | - Xiaohua Zhu
- Department of Nuclear Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan, 430030, China.
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15
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Oey O, Wijaya W, Redfern A. Eribulin in breast cancer: Current insights and therapeutic perspectives. World J Exp Med 2024; 14:92558. [PMID: 38948420 PMCID: PMC11212747 DOI: 10.5493/wjem.v14.i2.92558] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Revised: 02/21/2024] [Accepted: 03/20/2024] [Indexed: 06/19/2024] Open
Abstract
Eribulin is a non-taxane synthetic analogue approved in many countries as third-line treatment for the treatment of patients with metastatic breast cancer. In addition to its mitotic property, eribulin has non-mitotic properties including but not limited to, its ability to induce phenotypic reversal of epithelial to mesenchymal transition, vascular remodelling, reduction in immunosuppressive tumour microenvironment. Since approval, there has been a surge in studies investigating the application of eribulin as an earlier-line treatment and also in combination with other agents such as immunotherapy and targeted therapy across all breast cancer sub-types, including hormone receptor positive, HER2 positive and triple negative breast cancer, many demonstrating promising activity. This review will focus on the application of eribulin in the treatment of metastatic breast cancer across all subtypes including its role as an earlier-line agent, its toxicity profile, and potential future directions.
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Affiliation(s)
- Oliver Oey
- Faculty of Medicine, University of Western Australia, Nedlands 6009, Australia
- Department of Medical Oncology, Sir Charles Gairdner Hospital, Nedlands 6009, WA, Australia
| | - Wynne Wijaya
- Department of Oncology, University of Oxford, Oxford OX3 7DQ, United Kingdom
- Department of Internal Medicine, Universitas Gadjah Mada, Sleman 55281, Indonesia
| | - Andrew Redfern
- Department of Medical Oncology, Fiona Stanley Hospital, Murdoch 6150, WA, Australia
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16
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Ryan AT, Kim M, Lim K. Immune Cell Migration to Cancer. Cells 2024; 13:844. [PMID: 38786066 PMCID: PMC11120175 DOI: 10.3390/cells13100844] [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: 03/23/2024] [Revised: 04/27/2024] [Accepted: 05/03/2024] [Indexed: 05/25/2024] Open
Abstract
Immune cell migration is required for the development of an effective and robust immune response. This elegant process is regulated by both cellular and environmental factors, with variables such as immune cell state, anatomical location, and disease state that govern differences in migration patterns. In all cases, a major factor is the expression of cell surface receptors and their cognate ligands. Rapid adaptation to environmental conditions partly depends on intrinsic cellular immune factors that affect a cell's ability to adjust to new environment. In this review, we discuss both myeloid and lymphoid cells and outline key determinants that govern immune cell migration, including molecules required for immune cell adhesion, modes of migration, chemotaxis, and specific chemokine signaling. Furthermore, we summarize tumor-specific elements that contribute to immune cell trafficking to cancer, while also exploring microenvironment factors that can alter these cellular dynamics within the tumor in both a pro and antitumor fashion. Specifically, we highlight the importance of the secretome in these later aspects. This review considers a myriad of factors that impact immune cell trajectory in cancer. We aim to highlight the immunotherapeutic targets that can be harnessed to achieve controlled immune trafficking to and within tumors.
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Affiliation(s)
- Allison T. Ryan
- Department of Microbiology and Immunology, University of Rochester, Rochester, NY 14642, USA; (A.T.R.); (M.K.)
- David H. Smith Center for Vaccine Biology and Immunology, University of Rochester, Rochester, NY 14642, USA
| | - Minsoo Kim
- Department of Microbiology and Immunology, University of Rochester, Rochester, NY 14642, USA; (A.T.R.); (M.K.)
- David H. Smith Center for Vaccine Biology and Immunology, University of Rochester, Rochester, NY 14642, USA
| | - Kihong Lim
- Department of Microbiology and Immunology, University of Rochester, Rochester, NY 14642, USA; (A.T.R.); (M.K.)
- David H. Smith Center for Vaccine Biology and Immunology, University of Rochester, Rochester, NY 14642, USA
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17
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Guan M, Liu S, Yang YG, Song Y, Zhang Y, Sun T. Chemokine systems in oncology: From microenvironment modulation to nanocarrier innovations. Int J Biol Macromol 2024; 268:131679. [PMID: 38641274 DOI: 10.1016/j.ijbiomac.2024.131679] [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: 10/07/2023] [Revised: 04/16/2024] [Accepted: 04/16/2024] [Indexed: 04/21/2024]
Abstract
Over the past few decades, significant strides have been made in understanding the pivotal roles that chemokine networks play in tumor biology. These networks, comprising chemokines and their receptors, wield substantial influence over cancer immune regulation and therapeutic outcomes. As a result, targeting these chemokine systems has emerged as a promising avenue for cancer immunotherapy. However, therapies targeting chemokines face significant challenges in solid tumor treatment, due to the complex and fragile of the chemokine networks. A nuanced comprehension of the complicacy and functions of chemokine networks, and their impact on the tumor microenvironment, is essential for optimizing their therapeutic utility in oncology. This review elucidates the ways in which chemokine networks interact with cancer immunity and tumorigenesis. We particularly elaborate on recent innovations in manipulating these networks for cancer treatment. The review also highlights future challenges and explores potential biomaterial strategies for clinical applications.
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Affiliation(s)
- Meng Guan
- Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, Institute of Immunology, The First Hospital of Jilin University, Changchun, Jilin 130021, China; National-local Joint Engineering Laboratory of Animal Models for Human Diseases, Changchun, Jilin 130021, China; Cancer Center, The First Hospital of Jilin University, Changchun, Jilin 130021, China
| | - Shuhan Liu
- Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, Institute of Immunology, The First Hospital of Jilin University, Changchun, Jilin 130021, China; National-local Joint Engineering Laboratory of Animal Models for Human Diseases, Changchun, Jilin 130021, China; Cancer Center, The First Hospital of Jilin University, Changchun, Jilin 130021, China
| | - Yong-Guang Yang
- Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, Institute of Immunology, The First Hospital of Jilin University, Changchun, Jilin 130021, China; National-local Joint Engineering Laboratory of Animal Models for Human Diseases, Changchun, Jilin 130021, China; International Center of Future Science, Jilin University, Changchun, Jilin 130021, China
| | - Yanqiu Song
- Cancer Center, The First Hospital of Jilin University, Changchun, Jilin 130021, China.
| | - Yuning Zhang
- Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, Institute of Immunology, The First Hospital of Jilin University, Changchun, Jilin 130021, China; National-local Joint Engineering Laboratory of Animal Models for Human Diseases, Changchun, Jilin 130021, China.
| | - Tianmeng Sun
- Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, Institute of Immunology, The First Hospital of Jilin University, Changchun, Jilin 130021, China; National-local Joint Engineering Laboratory of Animal Models for Human Diseases, Changchun, Jilin 130021, China; International Center of Future Science, Jilin University, Changchun, Jilin 130021, China; State Key Laboratory of Supramolecular Structure and Materials, Jilin University, Changchun, Jilin 130021, China.
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18
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Wang F, Fu K, Wang Y, Pan C, Wang X, Liu Z, Yang C, Zheng Y, Li X, Lu Y, To KKW, Xia C, Zhang J, Shi Z, Hu Z, Huang M, Fu L. Small-molecule agents for cancer immunotherapy. Acta Pharm Sin B 2024; 14:905-952. [PMID: 38486980 PMCID: PMC10935485 DOI: 10.1016/j.apsb.2023.12.010] [Citation(s) in RCA: 13] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Revised: 11/28/2023] [Accepted: 12/06/2023] [Indexed: 03/17/2024] Open
Abstract
Cancer immunotherapy, exemplified by the remarkable clinical benefits of the immune checkpoint blockade and chimeric antigen receptor T-cell therapy, is revolutionizing cancer therapy. They induce long-term tumor regression and overall survival benefit in many types of cancer. With the advances in our knowledge about the tumor immune microenvironment, remarkable progress has been made in the development of small-molecule drugs for immunotherapy. Small molecules targeting PRR-associated pathways, immune checkpoints, oncogenic signaling, metabolic pathways, cytokine/chemokine signaling, and immune-related kinases have been extensively investigated. Monotherapy of small-molecule immunotherapeutic drugs and their combinations with other antitumor modalities are under active clinical investigations to overcome immune tolerance and circumvent immune checkpoint inhibitor resistance. Here, we review the latest development of small-molecule agents for cancer immunotherapy by targeting defined pathways and highlighting their progress in recent clinical investigations.
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Affiliation(s)
- Fang Wang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Esophageal Cancer Institute, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
| | - Kai Fu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Esophageal Cancer Institute, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
| | - Yujue Wang
- School of Pharmaceutical Sciences, Tsinghua-Peking Center for Life Sciences, Beijing Frontier Research Center for Biological Structure, Tsinghua University, Beijing 100084, China
| | - Can Pan
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Esophageal Cancer Institute, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
| | - Xueping Wang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Esophageal Cancer Institute, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
| | - Zeyu Liu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Esophageal Cancer Institute, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
| | - Chuan Yang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Esophageal Cancer Institute, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
| | - Ying Zheng
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
| | - Xiaopeng Li
- Department of Cell Biology & Institute of Biomedicine, National Engineering Research Center of Genetic Medicine, MOE Key Laboratory of Tumor Molecular Biology, Guangdong Provincial Key Laboratory of Bioengineering Medicine, College of Life Science and Technology, Jinan University, Guangzhou 510632, China
| | - Yu Lu
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou 511436, China
| | - Kenneth Kin Wah To
- School of Pharmacy, The Chinese University of Hong Kong, Hong Kong 999077, China
| | - Chenglai Xia
- Affiliated Foshan Maternity and Child Healthcare Hospital, Southern Medical University, Foshan 528000, China
| | - Jianye Zhang
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou 511436, China
| | - Zhi Shi
- Department of Cell Biology & Institute of Biomedicine, National Engineering Research Center of Genetic Medicine, MOE Key Laboratory of Tumor Molecular Biology, Guangdong Provincial Key Laboratory of Bioengineering Medicine, College of Life Science and Technology, Jinan University, Guangzhou 510632, China
| | - Zeping Hu
- School of Pharmaceutical Sciences, Tsinghua-Peking Center for Life Sciences, Beijing Frontier Research Center for Biological Structure, Tsinghua University, Beijing 100084, China
| | - Min Huang
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
| | - Liwu Fu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Esophageal Cancer Institute, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
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19
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Qu B, Yuan J, Liu X, Zhang S, Ma X, Lu L. Anticancer activities of natural antimicrobial peptides from animals. Front Microbiol 2024; 14:1321386. [PMID: 38298540 PMCID: PMC10827920 DOI: 10.3389/fmicb.2023.1321386] [Citation(s) in RCA: 15] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2023] [Accepted: 12/27/2023] [Indexed: 02/02/2024] Open
Abstract
Cancer is the most common cause of human death worldwide, posing a serious threat to human health and having a negative impact on the economy. In the past few decades, significant progress has been made in anticancer therapies, but traditional anticancer therapies, including radiation therapy, surgery, chemotherapy, molecular targeted therapy, immunotherapy and antibody-drug conjugates (ADCs), have serious side effects, low specificity, and the emergence of drug resistance. Therefore, there is an urgent need to develop new treatment methods to improve efficacy and reduce side effects. Antimicrobial peptides (AMPs) exist in the innate immune system of various organisms. As the most promising alternatives to traditional drugs for treating cancers, some AMPs also have been proven to possess anticancer activities, which are defined as anticancer peptides (ACPs). These peptides have the advantages of being able to specifically target cancer cells and have less toxicity to normal tissues. More and more studies have found that marine and terrestrial animals contain a large amount of ACPs. In this article, we introduced the animal derived AMPs with anti-cancer activity, and summarized the types of tumor cells inhibited by ACPs, the mechanisms by which they exert anti-tumor effects and clinical applications of ACPs.
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Affiliation(s)
- Baozhen Qu
- Qingdao Cancer Prevention and Treatment Research Institute, Qingdao Central Hospital, University of Health and Rehabilitation Sciences (Qingdao Central Medical Group), Qingdao, China
| | - Jiangshui Yuan
- Department of Clinical Laboratory, Qingdao Hospital, University of Health and Rehabilitation Sciences (Qingdao Municipal Hospital), Qingdao, China
| | - Xueli Liu
- Qingdao Cancer Prevention and Treatment Research Institute, Qingdao Central Hospital, University of Health and Rehabilitation Sciences (Qingdao Central Medical Group), Qingdao, China
- Medical Ethics Committee Office, Qingdao Central Hospital, University of Health and Rehabilitation Sciences (Qingdao Central Medical Group), Qingdao, China
| | - Shicui Zhang
- College of Life and Geographic Sciences, Key Laboratory of Biological Resources and Ecology of Pamirs Plateau in Xinjiang Uygur Autonomous Region, Kashi University, Kashi, China
- Institute of Evolution & Marine Biodiversity, Ocean University of China, Qingdao, China
| | - Xuezhen Ma
- Department of Oncology, Qingdao Central Hospital, University of Health and Rehabilitation Sciences (Qingdao Central Medical Group), Qingdao, China
| | - Linlin Lu
- Qingdao Cancer Prevention and Treatment Research Institute, Qingdao Central Hospital, University of Health and Rehabilitation Sciences (Qingdao Central Medical Group), Qingdao, China
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20
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Li C, Jin K. Chemical Strategies towards the Development of Effective Anticancer Peptides. Curr Med Chem 2024; 31:1839-1873. [PMID: 37170992 DOI: 10.2174/0929867330666230426111157] [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: 11/01/2022] [Revised: 01/28/2023] [Accepted: 02/24/2023] [Indexed: 05/13/2023]
Abstract
Cancer is increasingly recognized as one of the primary causes of death and has become a multifaceted global health issue. Modern medical science has made significant advancements in the diagnosis and therapy of cancer over the past decade. The detrimental side effects, lack of efficacy, and multidrug resistance of conventional cancer therapies have created an urgent need for novel anticancer therapeutics or treatments with low cytotoxicity and drug resistance. The pharmaceutical groups have recognized the crucial role that peptide therapeutic agents can play in addressing unsatisfied healthcare demands and how these become great supplements or even preferable alternatives to biological therapies and small molecules. Anticancer peptides, as a vibrant therapeutic strategy against various cancer cells, have demonstrated incredible anticancer potential due to high specificity and selectivity, low toxicity, and the ability to target the surface of traditional "undruggable" proteins. This review will provide the research progression of anticancer peptides, mainly focusing on the discovery and modifications along with the optimization and application of these peptides in clinical practice.
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Affiliation(s)
- Cuicui Li
- Key Laboratory of Chemical Biology (Ministry of Education), Department of Medicinal Chemistry, School of Pharmacy, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China
| | - Kang Jin
- Key Laboratory of Chemical Biology (Ministry of Education), Department of Medicinal Chemistry, School of Pharmacy, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China
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21
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Zhu YY, Song L, Zhang YQ, Liu WL, Chen WL, Gao WL, Zhang LX, Wang JZ, Ming ZH, Zhang Y, Zhang GJ. Development of a Rare Earth Nanoprobe Enables In Vivo Real-Time Detection of Sentinel Lymph Node Metastasis of Breast Cancer Using NIR-IIb Imaging. Cancer Res 2023; 83:3428-3441. [PMID: 37540231 PMCID: PMC10570679 DOI: 10.1158/0008-5472.can-22-3432] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 05/09/2023] [Accepted: 08/02/2023] [Indexed: 08/05/2023]
Abstract
Sentinel lymph node (SLN) biopsy plays a critical role in axillary staging of breast cancer. However, traditional SLN mapping does not accurately discern the presence or absence of metastatic disease. Detection of SLN metastasis largely hinges on examination of frozen sections or paraffin-embedded tissues post-SLN biopsy. To improve detection of SLN metastasis, we developed a second near-infrared (NIR-II) in vivo fluorescence imaging system, pairing erbium-based rare-earth nanoparticles (ErNP) with bright down-conversion fluorescence at 1,556 nm. To visualize SLNs bearing breast cancer, ErNPs were modified by balixafortide (ErNPs@POL6326), a peptide antagonist of the chemokine receptor CXCR4. The ErNPs@POL6326 probes readily drained into SLNs when delivered subcutaneously, entering metastatic breast tumor cells specifically via CXCR4-mediated endocytosis. NIR fluorescence signals increased significantly in tumor-positive versus tumor-negative SLNs, enabling accurate determination of SLN breast cancer metastasis. In a syngeneic mouse mammary tumor model and a human breast cancer xenograft model, sensitivity for SLN metastasis detection was 92.86% and 93.33%, respectively, and specificity was 96.15% and 96.08%, respectively. Of note, the probes accurately detected both macrometastases and micrometastases in SLNs. These results overall underscore the potential of ErNPs@POL6326 for real-time visualization of SLNs and in vivo screening for SLN metastasis. SIGNIFICANCE NIR-IIb imaging of a rare-earth nanoprobe that is specifically taken up by breast cancer cells can accurately detect breast cancer macrometastases and micrometastases in sentinel lymph nodes.
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Affiliation(s)
- Yuan-Yuan Zhu
- Department of Breast-Thyroid-Surgery and Cancer Center, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
- Fujian Key Laboratory of Precision Diagnosis and Treatment in Breast Cancer (Xiang'an Hospital of Xiamen University), Xiamen, China
- Xiamen Key Laboratory for Endocrine Related Cancer Precision Medicine, Xiang'an Hospital of Xiamen University, Xiamen, China
- Xiamen Research Center of Clinical Medicine in Breast & Thyroid Cancers, Xiamen, China
| | - Liang Song
- State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, China
- Xiamen Key Laboratory of Rare Earth Photoelectric Functional Materials, Xiamen Institute of Rare Earth Materials, Haixi Institute, Chinese Academy of Sciences, Xiamen, China
| | - Yong-Qu Zhang
- Department of Breast-Thyroid-Surgery and Cancer Center, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
- Fujian Key Laboratory of Precision Diagnosis and Treatment in Breast Cancer (Xiang'an Hospital of Xiamen University), Xiamen, China
- Xiamen Key Laboratory for Endocrine Related Cancer Precision Medicine, Xiang'an Hospital of Xiamen University, Xiamen, China
- Xiamen Research Center of Clinical Medicine in Breast & Thyroid Cancers, Xiamen, China
| | - Wan-Ling Liu
- Department of Breast-Thyroid-Surgery and Cancer Center, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
- Fujian Key Laboratory of Precision Diagnosis and Treatment in Breast Cancer (Xiang'an Hospital of Xiamen University), Xiamen, China
- Xiamen Key Laboratory for Endocrine Related Cancer Precision Medicine, Xiang'an Hospital of Xiamen University, Xiamen, China
- Xiamen Research Center of Clinical Medicine in Breast & Thyroid Cancers, Xiamen, China
| | - Wei-Ling Chen
- Department of Breast-Thyroid-Surgery and Cancer Center, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
- Fujian Key Laboratory of Precision Diagnosis and Treatment in Breast Cancer (Xiang'an Hospital of Xiamen University), Xiamen, China
- Xiamen Key Laboratory for Endocrine Related Cancer Precision Medicine, Xiang'an Hospital of Xiamen University, Xiamen, China
- Xiamen Research Center of Clinical Medicine in Breast & Thyroid Cancers, Xiamen, China
| | - Wen-Liang Gao
- Department of Breast-Thyroid-Surgery and Cancer Center, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
- Fujian Key Laboratory of Precision Diagnosis and Treatment in Breast Cancer (Xiang'an Hospital of Xiamen University), Xiamen, China
- Xiamen Key Laboratory for Endocrine Related Cancer Precision Medicine, Xiang'an Hospital of Xiamen University, Xiamen, China
- Xiamen Research Center of Clinical Medicine in Breast & Thyroid Cancers, Xiamen, China
| | - Li-Xin Zhang
- Department of Breast-Thyroid-Surgery and Cancer Center, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
- Fujian Key Laboratory of Precision Diagnosis and Treatment in Breast Cancer (Xiang'an Hospital of Xiamen University), Xiamen, China
- Xiamen Key Laboratory for Endocrine Related Cancer Precision Medicine, Xiang'an Hospital of Xiamen University, Xiamen, China
- Xiamen Research Center of Clinical Medicine in Breast & Thyroid Cancers, Xiamen, China
| | - Jia-Zheng Wang
- Department of Breast-Thyroid-Surgery and Cancer Center, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
- Fujian Key Laboratory of Precision Diagnosis and Treatment in Breast Cancer (Xiang'an Hospital of Xiamen University), Xiamen, China
- Xiamen Key Laboratory for Endocrine Related Cancer Precision Medicine, Xiang'an Hospital of Xiamen University, Xiamen, China
- Xiamen Research Center of Clinical Medicine in Breast & Thyroid Cancers, Xiamen, China
| | - Zi-He Ming
- Department of Breast-Thyroid-Surgery and Cancer Center, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
- Fujian Key Laboratory of Precision Diagnosis and Treatment in Breast Cancer (Xiang'an Hospital of Xiamen University), Xiamen, China
- Xiamen Key Laboratory for Endocrine Related Cancer Precision Medicine, Xiang'an Hospital of Xiamen University, Xiamen, China
- Xiamen Research Center of Clinical Medicine in Breast & Thyroid Cancers, Xiamen, China
| | - Yun Zhang
- State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, China
- Xiamen Key Laboratory of Rare Earth Photoelectric Functional Materials, Xiamen Institute of Rare Earth Materials, Haixi Institute, Chinese Academy of Sciences, Xiamen, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Guo-Jun Zhang
- Department of Breast-Thyroid-Surgery and Cancer Center, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
- Fujian Key Laboratory of Precision Diagnosis and Treatment in Breast Cancer (Xiang'an Hospital of Xiamen University), Xiamen, China
- Xiamen Key Laboratory for Endocrine Related Cancer Precision Medicine, Xiang'an Hospital of Xiamen University, Xiamen, China
- Xiamen Research Center of Clinical Medicine in Breast & Thyroid Cancers, Xiamen, China
- Cancer Research Center, School of Medicine, Xiamen University, Xiamen, China
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22
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Robinson T, Escara-Wilke J, Dai J, Zimmermann J, Keller ET. A CXCR4 inhibitor (balixafortide) enhances docetaxel-mediated antitumor activity in a murine model of prostate cancer bone metastasis. Prostate 2023; 83:1247-1254. [PMID: 37244751 PMCID: PMC10576997 DOI: 10.1002/pros.24584] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2022] [Revised: 05/06/2023] [Accepted: 05/17/2023] [Indexed: 05/29/2023]
Abstract
BACKGROUND Prostate cancer (PCa) bone metastases have been shown to be more resistant to docetaxel than soft tissue metastases. The proinflammatory chemokine receptor CXCR4 has been shown to confer resistance to docetaxel (DOC) in PCa cells. Balixafortide (BLX) is a protein epitope mimetic inhibitor of CXCR4. Accordingly, we hypothesized that BLX would enhance DOC-mediated antitumor activity in PCa bone metastases. METHODS PC-3 luciferase-labeled cells were injected into the tibia of mice to model bone metastases. Four treatment groups were created: vehicle, DOC (5 mg/kg), BLX (20 mg/kg), and combo (receiving both DOC and BLX). Mice were injected twice daily subcutaneously with either vehicle or BLX starting on Day 1 and weekly intraperitoneally with DOC starting on Day 1. Tumor burden was measured weekly via bioluminescent imaging. At end of study (29 days), radiographs were taken of the tibiae and blood was collected. Serum levels of TRAcP, IL-2, and IFNγ levels were measured using ELISA. Harvested tibiae were decalcified and stained for Ki67, cleaved caspase-3, and CD34 positive cells or microvessels were quantified. RESULTS Tumor burden was lower in the combo group compared to the DOC alone group. Treatment with the combination had no impact on the number of mice with osteolytic lesions, however the area of osteolytic lesions was lower in the combo group compared to the vehicle and BLX groups, but not the DOC group. Serum TRAcP levels were lower in the combo compared to vehicle group, but not the other groups. No significant difference in Ki67 staining was found among the groups; whereas, cleaved caspase-3 staining was lowest in the Combo group and highest in the BLX group. The DOC and combo groups had more CD34+ microvessels than the control and BLX groups. There was no difference between the treatment groups for IL-2, but the combo group had increased levels of IFNγ compared to the DOC group. CONCLUSIONS Our data demonstrate that a combination of BAL and DOC has greater antitumor activity in a model of PCa bone metastases than either drug alone. These data support further evaluation of this combination in metastatic PCa.
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Affiliation(s)
- Tyler Robinson
- Department of Urology, University of Michigan, Ann Arbor, MI 48109
| | | | - Jinlu Dai
- Department of Urology, University of Michigan, Ann Arbor, MI 48109
| | | | - Evan T Keller
- Department of Urology, University of Michigan, Ann Arbor, MI 48109
- Biointerfaces Institute, University of Michigan, Ann Arbor, MI 48109
- Single Cell Spatial Analysis Program, University of Michigan, Ann Arbor, MI 48109
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23
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Vorster M, Hadebe BP, Sathekge MM. Theranostics in breast cancer. FRONTIERS IN NUCLEAR MEDICINE (LAUSANNE, SWITZERLAND) 2023; 3:1236565. [PMID: 39355052 PMCID: PMC11440857 DOI: 10.3389/fnume.2023.1236565] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Accepted: 07/21/2023] [Indexed: 10/03/2024]
Abstract
Introduction Breast cancer is a complex disease and constitutes the leading cause of cancer in women globally. Conventional treatment modalities include surgery, chemotherapy, radiation therapy, and hormonal therapy; all of these have their limitations and often result in significant side effects or toxicity. Targeted radionuclide therapy based on a theranostic approach has been successfully applied in several malignancies, such as prostate cancer, thyroid cancer, and neuro-endocrine tumours. Several studies have also highlighted the potential of theranostic applications in breast cancer. Aim This review aims to provide an overview of the most promising current and future theranostic approaches in breast cancer. Discussion The discussion includes pre-clinical as well as clinical data on some of the most successful targets used to date. Examples of potential theranostic approaches include those targeting the Human epidermal growth factor receptor 2 (HER2) expression, angiogenesis, aspects of the tumour microenvironment, Gastrin-releasing peptide receptor (GRPR), Prostate-specific membrane antigen (PSMA) and Chemokine receptor 4 (CXCR-4) expression. Several challenges to widespread clinical implementation remain, which include regulatory approval, access to the various radiopharmaceuticals and imaging technology, cost-effectiveness, and the absence of robust clinical data. Conclusion Theranostic approaches have the potential to greatly improve diagnosis, treatment, and outcomes for patients with breast cancer. More research is needed to fully explore the potential of such approaches and to identify the best potential targets, considering feasibility, costs, efficacy, side effects and outcomes.
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Affiliation(s)
- M. Vorster
- Department of Nuclear Medicine, University of KwaZulu-Natal, Durban, South Africa
| | - B. P. Hadebe
- Department of Nuclear Medicine, University of KwaZulu-Natal, Durban, South Africa
| | - M. M. Sathekge
- Department of Nuclear Medicine, University of Pretoria, Pretoria, South Africa
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24
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Bao S, Darvishi M, H Amin A, Al-Haideri MT, Patra I, Kashikova K, Ahmad I, Alsaikhan F, Al-Qaim ZH, Al-Gazally ME, Kiasari BA, Tavakoli-Far B, Sidikov AA, Mustafa YF, Akhavan-Sigari R. CXC chemokine receptor 4 (CXCR4) blockade in cancer treatment. J Cancer Res Clin Oncol 2023; 149:7945-7968. [PMID: 36905421 DOI: 10.1007/s00432-022-04444-w] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Accepted: 10/19/2022] [Indexed: 03/12/2023]
Abstract
CXC chemokine receptor type 4 (CXCR4) is a member of the G protein-coupled receptors (GPCRs) superfamily and is specific for CXC chemokine ligand 12 (CXCL12, also known as SDF-1), which makes CXCL12/CXCR4 axis. CXCR4 interacts with its ligand, triggering downstream signaling pathways that influence cell proliferation chemotaxis, migration, and gene expression. The interaction also regulates physiological processes, including hematopoiesis, organogenesis, and tissue repair. Multiple evidence revealed that CXCL12/CXCR4 axis is implicated in several pathways involved in carcinogenesis and plays a key role in tumor growth, survival, angiogenesis, metastasis, and therapeutic resistance. Several CXCR4-targeting compounds have been discovered and used for preclinical and clinical cancer therapy, most of which have shown promising anti-tumor activity. In this review, we summarized the physiological signaling of the CXCL12/CXCR4 axis and described the role of this axis in tumor progression, and focused on the potential therapeutic options and strategies to block CXCR4.
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Affiliation(s)
- Shunshun Bao
- The First Clinical Medical College, Xuzhou Medical University, 221000, Xuzhou, China
| | - Mohammad Darvishi
- Infectious Diseases and Tropical Medicine Research Center (IDTMRC), Department of Aerospace and Subaquatic Medicine, AJA University of Medicinal Sciences, Tehran, Iran
| | - Ali H Amin
- Deanship of Scientific Research, Umm Al-Qura University, 21955, Makkah, Saudi Arabia
- Zoology Department, Faculty of Science, Mansoura University, 35516, Mansoura, Egypt
| | - Maysoon T Al-Haideri
- Department of Physiotherapy, Cihan University-Erbil, Erbil, Kurdistan Region, Iraq
| | - Indrajit Patra
- An Independent Researcher, National Institute of Technology Durgapur, Durgapur, West Bengal, India
| | | | - Irfan Ahmad
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Khalid University, Abha, Saudi Arabia
| | - Fahad Alsaikhan
- College of Pharmacy, Prince Sattam Bin Abdulaziz University, Alkharj, Saudi Arabia
| | | | | | - Bahman Abedi Kiasari
- Virology Department, Faculty of Veterinary Medicine, The University of Tehran, Tehran, Iran.
| | - Bahareh Tavakoli-Far
- Dietary Supplements and Probiotic Research Center, Alborz University of Medical Sciences, Karaj, Iran.
- Department of Physiology and Pharmacology, Faculty of Medicine, Alborz University of Medical Sciences, Karaj, Iran.
| | - Akmal A Sidikov
- Rector, Ferghana Medical Institute of Public Health, Ferghana, Uzbekistan
| | - Yasser Fakri Mustafa
- Department of Pharmaceutical Chemistry, College of Pharmacy, University of Mosul, Mosul, 41001, Iraq
| | - Reza Akhavan-Sigari
- Department of Neurosurgery, University Medical Center Tuebingen, Tübingen, Germany
- Department of Health Care Management and Clinical Research, Collegium Humanum Warsaw Management University, Warsaw, Poland
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25
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Costa L, Sousa E, Fernandes C. Cyclic Peptides in Pipeline: What Future for These Great Molecules? Pharmaceuticals (Basel) 2023; 16:996. [PMID: 37513908 PMCID: PMC10386233 DOI: 10.3390/ph16070996] [Citation(s) in RCA: 33] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2023] [Revised: 07/06/2023] [Accepted: 07/08/2023] [Indexed: 07/30/2023] Open
Abstract
Cyclic peptides are molecules that are already used as drugs in therapies approved for various pharmacological activities, for example, as antibiotics, antifungals, anticancer, and immunosuppressants. Interest in these molecules has been growing due to the improved pharmacokinetic and pharmacodynamic properties of the cyclic structure over linear peptides and by the evolution of chemical synthesis, computational, and in vitro methods. To date, 53 cyclic peptides have been approved by different regulatory authorities, and many others are in clinical trials for a wide diversity of conditions. In this review, the potential of cyclic peptides is presented, and general aspects of their synthesis and development are discussed. Furthermore, an overview of already approved cyclic peptides is also given, and the cyclic peptides in clinical trials are summarized.
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Affiliation(s)
- Lia Costa
- Laboratório de Química Orgânica e Farmacêutica, Departamento de Ciências Químicas, Faculdade de Farmácia, Universidade do Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal;
- Interdisciplinary Centre of Marine and Environmental Research (CIIMAR), Edifício do Terminal de Cruzeiros do Porto de Leixões, Av. General Norton de Matos s/n, 4050-208 Matosinhos, Portugal
| | - Emília Sousa
- Laboratório de Química Orgânica e Farmacêutica, Departamento de Ciências Químicas, Faculdade de Farmácia, Universidade do Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal;
- Interdisciplinary Centre of Marine and Environmental Research (CIIMAR), Edifício do Terminal de Cruzeiros do Porto de Leixões, Av. General Norton de Matos s/n, 4050-208 Matosinhos, Portugal
| | - Carla Fernandes
- Laboratório de Química Orgânica e Farmacêutica, Departamento de Ciências Químicas, Faculdade de Farmácia, Universidade do Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal;
- Interdisciplinary Centre of Marine and Environmental Research (CIIMAR), Edifício do Terminal de Cruzeiros do Porto de Leixões, Av. General Norton de Matos s/n, 4050-208 Matosinhos, Portugal
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26
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Wieder R. Fibroblasts as Turned Agents in Cancer Progression. Cancers (Basel) 2023; 15:2014. [PMID: 37046676 PMCID: PMC10093070 DOI: 10.3390/cancers15072014] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Revised: 03/19/2023] [Accepted: 03/23/2023] [Indexed: 03/30/2023] Open
Abstract
Differentiated epithelial cells reside in the homeostatic microenvironment of the native organ stroma. The stroma supports their normal function, their G0 differentiated state, and their expansion/contraction through the various stages of the life cycle and physiologic functions of the host. When malignant transformation begins, the microenvironment tries to suppress and eliminate the transformed cells, while cancer cells, in turn, try to resist these suppressive efforts. The tumor microenvironment encompasses a large variety of cell types recruited by the tumor to perform different functions, among which fibroblasts are the most abundant. The dynamics of the mutual relationship change as the sides undertake an epic battle for control of the other. In the process, the cancer "wounds" the microenvironment through a variety of mechanisms and attracts distant mesenchymal stem cells to change their function from one attempting to suppress the cancer, to one that supports its growth, survival, and metastasis. Analogous reciprocal interactions occur as well between disseminated cancer cells and the metastatic microenvironment, where the microenvironment attempts to eliminate cancer cells or suppress their proliferation. However, the altered microenvironmental cells acquire novel characteristics that support malignant progression. Investigations have attempted to use these traits as targets of novel therapeutic approaches.
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Affiliation(s)
- Robert Wieder
- Rutgers New Jersey Medical School and the Cancer Institute of New Jersey, Newark, NJ 07103, USA
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27
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Hadebe B, Harry L, Ebrahim T, Pillay V, Vorster M. The Role of PET/CT in Breast Cancer. Diagnostics (Basel) 2023; 13:diagnostics13040597. [PMID: 36832085 PMCID: PMC9955497 DOI: 10.3390/diagnostics13040597] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Revised: 01/05/2023] [Accepted: 01/16/2023] [Indexed: 02/08/2023] Open
Abstract
Female breast cancer has surpassed lung cancer as the most commonly diagnosed cancer worldwide, with an estimated 2.3 million new cases (11.7%), followed by lung cancer (11.4%) The current literature and the National Comprehensive Cancer Network (NCCN) guidelines state that 18F-FDG PET/CT is not routine for early diagnosis of breast cancer, and rather PET/CT scanning should be performed for patients with stage III disease or when conventional staging studies yield non-diagnostic or suspicious results because this modality has been shown to upstage patients compared to conventional imaging and thus has an impact on disease management and prognosis. Furthermore, with the growing interest in precision therapy in breast cancer, numerous novel radiopharmaceuticals have been developed that target tumor biology and have the potential to non-invasively guide the most appropriate targeted therapy. This review discusses the role of 18F-FDG PET and other PET tracers beyond FDG in breast cancer imaging.
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Affiliation(s)
- Bawinile Hadebe
- Department of Nuclear Medicine, College of Health Sciences, University of KwaZulu Natal, Private Bag X54001, Durban 4001, South Africa
- Inkosi Albert Luthuli Central Hospital, Durban 4001, South Africa
- Correspondence:
| | - Lerwine Harry
- Department of Nuclear Medicine, College of Health Sciences, University of KwaZulu Natal, Private Bag X54001, Durban 4001, South Africa
- Inkosi Albert Luthuli Central Hospital, Durban 4001, South Africa
| | - Tasmeera Ebrahim
- Department of Nuclear Medicine, College of Health Sciences, University of KwaZulu Natal, Private Bag X54001, Durban 4001, South Africa
- Inkosi Albert Luthuli Central Hospital, Durban 4001, South Africa
| | - Venesen Pillay
- Department of Nuclear Medicine, College of Health Sciences, University of KwaZulu Natal, Private Bag X54001, Durban 4001, South Africa
- Inkosi Albert Luthuli Central Hospital, Durban 4001, South Africa
| | - Mariza Vorster
- Department of Nuclear Medicine, College of Health Sciences, University of KwaZulu Natal, Private Bag X54001, Durban 4001, South Africa
- Inkosi Albert Luthuli Central Hospital, Durban 4001, South Africa
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George S, Martin JAJ, Graziani V, Sanz-Moreno V. Amoeboid migration in health and disease: Immune responses versus cancer dissemination. Front Cell Dev Biol 2023; 10:1091801. [PMID: 36699013 PMCID: PMC9869768 DOI: 10.3389/fcell.2022.1091801] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Accepted: 12/15/2022] [Indexed: 01/07/2023] Open
Abstract
Cell migration is crucial for efficient immune responses and is aberrantly used by cancer cells during metastatic dissemination. Amoeboid migrating cells use myosin II-powered blebs to propel themselves, and change morphology and direction. Immune cells use amoeboid strategies to respond rapidly to infection or tissue damage, which require quick passage through several barriers, including blood, lymph and interstitial tissues, with complex and varied environments. Amoeboid migration is also used by metastatic cancer cells to aid their migration, dissemination and survival, whereby key mechanisms are hijacked from professionally motile immune cells. We explore important parallels observed between amoeboid immune and cancer cells. We also consider key distinctions that separate the lifespan, state and fate of these cell types as they migrate and/or fulfil their function. Finally, we reflect on unexplored areas of research that would enhance our understanding of how tumour cells use immune cell strategies during metastasis, and how to target these processes.
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29
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Fang Z, Meng Q, Xu J, Wang W, Zhang B, Liu J, Liang C, Hua J, Zhao Y, Yu X, Shi S. Signaling pathways in cancer-associated fibroblasts: recent advances and future perspectives. Cancer Commun (Lond) 2023; 43:3-41. [PMID: 36424360 PMCID: PMC9859735 DOI: 10.1002/cac2.12392] [Citation(s) in RCA: 124] [Impact Index Per Article: 62.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 09/20/2022] [Accepted: 11/04/2022] [Indexed: 11/26/2022] Open
Abstract
As a critical component of the tumor microenvironment (TME), cancer-associated fibroblasts (CAFs) play important roles in cancer initiation and progression. Well-known signaling pathways, including the transforming growth factor-β (TGF-β), Hedgehog (Hh), Notch, Wnt, Hippo, nuclear factor kappa-B (NF-κB), Janus kinase (JAK)/signal transducer and activator of transcription (STAT), mitogen-activated protein kinase (MAPK), and phosphoinositide 3-kinase (PI3K)/AKT pathways, as well as transcription factors, including hypoxia-inducible factor (HIF), heat shock transcription factor 1 (HSF1), P53, Snail, and Twist, constitute complex regulatory networks in the TME to modulate the formation, activation, heterogeneity, metabolic characteristics and malignant phenotype of CAFs. Activated CAFs remodel the TME and influence the malignant biological processes of cancer cells by altering the transcriptional and secretory characteristics, and this modulation partially depends on the regulation of signaling cascades. The results of preclinical and clinical trials indicated that therapies targeting signaling pathways in CAFs demonstrated promising efficacy but were also accompanied by some failures (e.g., NCT01130142 and NCT01064622). Hence, a comprehensive understanding of the signaling cascades in CAFs might help us better understand the roles of CAFs and the TME in cancer progression and may facilitate the development of more efficient and safer stroma-targeted cancer therapies. Here, we review recent advances in studies of signaling pathways in CAFs and briefly discuss some future perspectives on CAF research.
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Affiliation(s)
- Zengli Fang
- Department of Pancreatic SurgeryFudan University Shanghai Cancer CenterShanghai200032P. R. China
- Department of OncologyShanghai Medical CollegeFudan UniversityShanghai200032P. R. China
- Shanghai Pancreatic Cancer InstituteShanghai200032P. R. China
- Pancreatic Cancer InstituteFudan UniversityShanghai200032P. R. China
| | - Qingcai Meng
- Department of Pancreatic SurgeryFudan University Shanghai Cancer CenterShanghai200032P. R. China
- Department of OncologyShanghai Medical CollegeFudan UniversityShanghai200032P. R. China
- Shanghai Pancreatic Cancer InstituteShanghai200032P. R. China
- Pancreatic Cancer InstituteFudan UniversityShanghai200032P. R. China
| | - Jin Xu
- Department of Pancreatic SurgeryFudan University Shanghai Cancer CenterShanghai200032P. R. China
- Department of OncologyShanghai Medical CollegeFudan UniversityShanghai200032P. R. China
- Shanghai Pancreatic Cancer InstituteShanghai200032P. R. China
- Pancreatic Cancer InstituteFudan UniversityShanghai200032P. R. China
| | - Wei Wang
- Department of Pancreatic SurgeryFudan University Shanghai Cancer CenterShanghai200032P. R. China
- Department of OncologyShanghai Medical CollegeFudan UniversityShanghai200032P. R. China
- Shanghai Pancreatic Cancer InstituteShanghai200032P. R. China
- Pancreatic Cancer InstituteFudan UniversityShanghai200032P. R. China
| | - Bo Zhang
- Department of Pancreatic SurgeryFudan University Shanghai Cancer CenterShanghai200032P. R. China
- Department of OncologyShanghai Medical CollegeFudan UniversityShanghai200032P. R. China
- Shanghai Pancreatic Cancer InstituteShanghai200032P. R. China
- Pancreatic Cancer InstituteFudan UniversityShanghai200032P. R. China
| | - Jiang Liu
- Department of Pancreatic SurgeryFudan University Shanghai Cancer CenterShanghai200032P. R. China
- Department of OncologyShanghai Medical CollegeFudan UniversityShanghai200032P. R. China
- Shanghai Pancreatic Cancer InstituteShanghai200032P. R. China
- Pancreatic Cancer InstituteFudan UniversityShanghai200032P. R. China
| | - Chen Liang
- Department of Pancreatic SurgeryFudan University Shanghai Cancer CenterShanghai200032P. R. China
- Department of OncologyShanghai Medical CollegeFudan UniversityShanghai200032P. R. China
- Shanghai Pancreatic Cancer InstituteShanghai200032P. R. China
- Pancreatic Cancer InstituteFudan UniversityShanghai200032P. R. China
| | - Jie Hua
- Department of Pancreatic SurgeryFudan University Shanghai Cancer CenterShanghai200032P. R. China
- Department of OncologyShanghai Medical CollegeFudan UniversityShanghai200032P. R. China
- Shanghai Pancreatic Cancer InstituteShanghai200032P. R. China
- Pancreatic Cancer InstituteFudan UniversityShanghai200032P. R. China
| | - Yingjun Zhao
- Department of OncologyShanghai Medical CollegeFudan UniversityShanghai200032P. R. China
- Institutes of Biomedical SciencesShanghai Medical CollegeFudan UniversityShanghai200032P. R. China
| | - Xianjun Yu
- Department of Pancreatic SurgeryFudan University Shanghai Cancer CenterShanghai200032P. R. China
- Department of OncologyShanghai Medical CollegeFudan UniversityShanghai200032P. R. China
- Shanghai Pancreatic Cancer InstituteShanghai200032P. R. China
- Pancreatic Cancer InstituteFudan UniversityShanghai200032P. R. China
| | - Si Shi
- Department of Pancreatic SurgeryFudan University Shanghai Cancer CenterShanghai200032P. R. China
- Department of OncologyShanghai Medical CollegeFudan UniversityShanghai200032P. R. China
- Shanghai Pancreatic Cancer InstituteShanghai200032P. R. China
- Pancreatic Cancer InstituteFudan UniversityShanghai200032P. R. China
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Lai S, Zhang Q, Jin L. Natural and Man-Made Cyclic Peptide-Based Antibiotics. Antibiotics (Basel) 2022; 12:antibiotics12010042. [PMID: 36671244 PMCID: PMC9855121 DOI: 10.3390/antibiotics12010042] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2022] [Revised: 12/21/2022] [Accepted: 12/23/2022] [Indexed: 12/29/2022] Open
Abstract
In recent years, an increasing number of drug-resistant bacterial strains have been identified due to the abuse of antibiotics, which seriously threatens human and animal health. Antimicrobial peptides (AMPs) have become one of the most effective weapons to solve this problem. AMPs have little tendency to induce drug resistance and have outstanding antimicrobial effects. The study of AMPs, especially cyclic peptides, has become a hot topic. Among them, macrocyclic AMPs have received extensive attention. This mini-review discusses the structures and functions of the dominant cyclic natural and synthetic AMPs and provides a little outlook on the future direction of cyclic AMPs.
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Affiliation(s)
- Shian Lai
- Small Molecule Drugs Sichuan Key Laboratory, Institute of Materia Medica, School of Pharmacy, Chengdu Medical College, Chengdu 610500, China
- Department of Molecular Chemistry and Biochemistry, Faculty of Science and Engineering, Doshisha University, Kyotanabe 610-0394, Japan
| | - Quan Zhang
- Small Molecule Drugs Sichuan Key Laboratory, Institute of Materia Medica, School of Pharmacy, Chengdu Medical College, Chengdu 610500, China
| | - Lin Jin
- Small Molecule Drugs Sichuan Key Laboratory, Institute of Materia Medica, School of Pharmacy, Chengdu Medical College, Chengdu 610500, China
- College of Veterinary Medicine, Shanxi Agricultural University, Jinzhong 030801, China
- Correspondence:
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31
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Reversing the PAI-1-induced fibrotic immune exclusion of solid tumor by multivalent CXCR4 antagonistic nano-permeator. Acta Pharm Sin B 2022. [PMID: 37521859 PMCID: PMC10372828 DOI: 10.1016/j.apsb.2022.12.012] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Fibrosis is one of the key factors that lead to the immune exclusion of solid tumors. Although degradation of fiber is a promising strategy, its application was still bottlenecked by the side effects of causing metastasis, resulting in the failure of immunotherapy. Here, we developed an antimetastatic polymer (HPA) for the delivery of chemo-drug and antifibrotic siPAI-1 to form the nano-permeator. Nano-permeator shrank after protonation and deeply penetrated into the tumor core to down-regulate the expression of PAI-1 for antifibrosis, and further promoted the sustained infiltration and activation of T cells for killing tumor cells. Moreover, metastasis after fiber elimination was prevented by multivalent CXCR4 antagonistic HPA to reduce the attraction of CXCL12 secreted by distant organs. The administration of stroma-alleviated immunotherapy increased the infiltration of CD8+ T cells to 52.5% in tumor tissues, inhibiting nearly 90% metastasis by HPA in distant organs. The nano-permeator reveals the mechanism and correlation between antifibrosis and antimetastasis and was believed to be the optimizing immunotherapy for solid fibrotic tumors.
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Yang J, Zhu Q, Wu Y, Qu X, Liu H, Jiang B, Ge D, Song X. Utilization of macrocyclic peptides to target protein-protein interactions in cancer. Front Oncol 2022; 12:992171. [PMID: 36465350 PMCID: PMC9714258 DOI: 10.3389/fonc.2022.992171] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Accepted: 10/24/2022] [Indexed: 07/30/2023] Open
Abstract
Protein-protein interactions (PPIs) play vital roles in normal cellular processes. Dysregulated PPIs are involved in the process of various diseases, including cancer. Thus, these PPIs may serve as potential therapeutic targets in cancer treatment. However, despite rapid advances in small-molecule drugs and biologics, it is still hard to target PPIs, especially for those intracellular PPIs. Macrocyclic peptides have gained growing attention for their therapeutic properties in targeting dysregulated PPIs. Macrocyclic peptides have some unique features, such as moderate sizes, high selectivity, and high binding affinities, which make them good drug candidates. In addition, some oncology macrocyclic peptide drugs have been approved by the US Food and Drug Administration (FDA) for clinical use. Here, we reviewed the recent development of macrocyclic peptides in cancer treatment. The opportunities and challenges were also discussed to inspire new perspectives.
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Affiliation(s)
- Jiawen Yang
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
- Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, China
- Shanghai Clinical Research and Trial Center, Shanghai, China
| | - Qiaoliang Zhu
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yifan Wu
- Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, China
- School of Life Science and Technology, ShanghaiTech University, Shanghai, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Xiaojuan Qu
- Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, China
- School of Life Science and Technology, ShanghaiTech University, Shanghai, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Haixia Liu
- Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, China
- University of Chinese Academy of Sciences, Beijing, China
- School of Physical Science and Technology, ShanghaiTech University, Shanghai, China
| | - Biao Jiang
- Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, China
- School of Physical Science and Technology, ShanghaiTech University, Shanghai, China
| | - Di Ge
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Xiaoling Song
- Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, China
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Maurya SK, Khan P, Rehman AU, Kanchan RK, Perumal N, Mahapatra S, Chand HS, Santamaria-Barria JA, Batra SK, Nasser MW. Rethinking the chemokine cascade in brain metastasis: Preventive and therapeutic implications. Semin Cancer Biol 2022; 86:914-930. [PMID: 34968667 PMCID: PMC9234104 DOI: 10.1016/j.semcancer.2021.12.009] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Revised: 12/22/2021] [Accepted: 12/23/2021] [Indexed: 01/27/2023]
Abstract
Brain metastasis (BrM) is one of the major causes of death in cancer patients and is associated with an estimated 10-40 % of total cancer cases. The survival rate of brain metastatic patients has not improved due to intratumor heterogeneity, the survival adaptations of brain homing metastatic cells, and the lack of understanding of underlying molecular mechanisms that limit the availability of effective therapies. The heterogeneous population of immune cells and tumor-initiating cells or cancer stem cells in the tumor microenvironment (TME) release various factors, such as chemokines that upon binding to their cognate receptors enhance tumor growth at primary sites and help tumor cells metastasize to the brain. Furthermore, brain metastatic sites have unique heterogeneous microenvironment that fuels cancer cells in establishing BrM. This review explores the crosstalk of chemokines with the heterogeneous TME during the progression of BrM and recognizes potential therapeutic approaches. We also discuss and summarize different targeted, immunotherapeutic, chemotherapeutic, and combinatorial strategies (with chemo-/immune- or targeted-therapies) to attenuate chemokines mediated BrM.
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Affiliation(s)
- Shailendra Kumar Maurya
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68108, USA
| | - Parvez Khan
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68108, USA
| | - Asad Ur Rehman
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68108, USA
| | - Ranjana K Kanchan
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68108, USA
| | - Naveenkumar Perumal
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68108, USA
| | - Sidharth Mahapatra
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68108, USA; Department of Pediatrics, University of Nebraska Medical Center, Omaha, NE, 68108, USA; Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68108, USA
| | - Hitendra S Chand
- Department of Immunology and Nanomedicine, Herbert Wertheim College of Medicine, Florida International University, Miami, FL, 33199, USA
| | | | - Surinder K Batra
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68108, USA; Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68108, USA; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, 68108, USA
| | - Mohd Wasim Nasser
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68108, USA; Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68108, USA.
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Targeting CXCR4 and CD47 Receptors: An Overview of New and Old Molecules for a Biological Personalized Anticancer Therapy. Int J Mol Sci 2022; 23:ijms232012499. [PMID: 36293358 PMCID: PMC9604048 DOI: 10.3390/ijms232012499] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Revised: 10/14/2022] [Accepted: 10/14/2022] [Indexed: 11/26/2022] Open
Abstract
Biological therapy, with its multifaceted applications, has revolutionized the treatment of tumors, mainly due to its ability to exclusively target cancer cells and reduce the adverse effects on normal tissues. This review focuses on the therapies targeting the CXCR4 and CD47 receptors. We surveyed the results of early clinical trials testing compounds classified as nonpeptides, small peptides, CXCR4 antagonists or specific antibodies whose activity reduces or completely blocks the intracellular signaling pathways and cell proliferation. We then examined antibodies and fusion proteins against CD47, the receptor that acts as a “do not eat me” signal to phagocytes escaping immune surveillance. Despite these molecules being tested in early clinical trials, some drawbacks are emerging that impair their use in practice. Finally, we examined the ImmunoGenic Surrender mechanism that involves crosstalk and co-internalization of CXCR4 and CD47 upon engagement of CXCR4 by ligands or other molecules. The favorable effect of such compounds is dual as CD47 surface reduction impact on the immune response adds to the block of CXCR4 proliferative potential. These results suggest that a combination of different therapeutic approaches has more beneficial effects on patients’ survival and may pave the way for new accomplishments in personalized anticancer therapy.
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35
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Belli C, Antonarelli G, Repetto M, Boscolo Bielo L, Crimini E, Curigliano G. Targeting Cellular Components of the Tumor Microenvironment in Solid Malignancies. Cancers (Basel) 2022; 14:4278. [PMID: 36077813 PMCID: PMC9454727 DOI: 10.3390/cancers14174278] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Revised: 08/25/2022] [Accepted: 08/30/2022] [Indexed: 11/17/2022] Open
Abstract
Cancers are composed of transformed cells, characterized by aberrant growth and invasiveness, in close relationship with non-transformed healthy cells and stromal tissue. The latter two comprise the so-called tumor microenvironment (TME), which plays a key role in tumorigenesis, cancer progression, metastatic seeding, and therapy resistance. In these regards, cancer-TME interactions are complex and dynamic, with malignant cells actively imposing an immune-suppressive and tumor-promoting state on surrounding, non-transformed, cells. Immune cells (both lymphoid and myeloid) can be recruited from the circulation and/or bone marrow by means of chemotactic signals, and their functionality is hijacked upon arrival at tumor sites. Molecular characterization of tumor-TME interactions led to the introduction of novel anti-cancer therapies targeting specific components of the TME, such as immune checkpoint blockers (ICB) (i.e., anti-programmed death 1, anti-PD1; anti-Cytotoxic T-Lymphocyte Antigen 4, anti-CTLA4). However, ICB resistance often develops and, despite the introduction of newer technologies able to study the TME at the single-cell level, a detailed understanding of all tumor-TME connections is still largely lacking. In this work, we highlight the main cellular and extracellular components of the TME, discuss their dynamics and functionality, and provide an outlook on the most relevant clinical data obtained with novel TME-targeting agents, with a focus on T lymphocytes, macrophages, and cancer-associated fibroblasts.
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Affiliation(s)
- Carmen Belli
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS, Via Ripamonti 435, 20141 Milan, Italy
| | - Gabriele Antonarelli
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS, Via Ripamonti 435, 20141 Milan, Italy
- Department of Oncology and Haematology (DIPO), University of Milan, 20141 Milan, Italy
| | - Matteo Repetto
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS, Via Ripamonti 435, 20141 Milan, Italy
- Department of Oncology and Haematology (DIPO), University of Milan, 20141 Milan, Italy
| | - Luca Boscolo Bielo
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS, Via Ripamonti 435, 20141 Milan, Italy
- Department of Oncology and Haematology (DIPO), University of Milan, 20141 Milan, Italy
| | - Edoardo Crimini
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS, Via Ripamonti 435, 20141 Milan, Italy
- Department of Oncology and Haematology (DIPO), University of Milan, 20141 Milan, Italy
| | - Giuseppe Curigliano
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS, Via Ripamonti 435, 20141 Milan, Italy
- Department of Oncology and Haematology (DIPO), University of Milan, 20141 Milan, Italy
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Li Y, Zhang H, Merkher Y, Chen L, Liu N, Leonov S, Chen Y. Recent advances in therapeutic strategies for triple-negative breast cancer. J Hematol Oncol 2022; 15:121. [PMID: 36038913 PMCID: PMC9422136 DOI: 10.1186/s13045-022-01341-0] [Citation(s) in RCA: 401] [Impact Index Per Article: 133.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2022] [Accepted: 08/18/2022] [Indexed: 01/03/2023] Open
Abstract
Triple-negative breast cancer (TNBC) is the most malignant subtype of breast cancer (BC) with a poor prognosis. Current treatment options are limited to surgery, adjuvant chemotherapy and radiotherapy; however, a proportion of patients have missed the surgical window at the time of diagnosis. TNBC is a highly heterogeneous cancer with specific mutations and aberrant activation of signaling pathways. Hence, targeted therapies, such as those targeting DNA repair pathways, androgen receptor signaling pathways, and kinases, represent promising treatment options against TNBC. In addition, immunotherapy has also been demonstrated to improve overall survival and response in TNBC. In this review, we summarize recent key advances in therapeutic strategies based on molecular subtypes in TNBC.
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Affiliation(s)
- Yun Li
- Department of Oncology, NHC Key Laboratory of Cancer Proteomics, Laboratory of Structural Biology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
| | - Huajun Zhang
- Department of Oncology, NHC Key Laboratory of Cancer Proteomics, Laboratory of Structural Biology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
| | - Yulia Merkher
- School of Biological and Medical Physics, Moscow Institute of Physics and Technology, Dolgoprudny, Moscow Region, Russia, 141700
| | - Lin Chen
- Department of Oncology, NHC Key Laboratory of Cancer Proteomics, Laboratory of Structural Biology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
| | - Na Liu
- Department of Endocrinology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
| | - Sergey Leonov
- School of Biological and Medical Physics, Moscow Institute of Physics and Technology, Dolgoprudny, Moscow Region, Russia, 141700. .,Institute of Cell Biophysics, Russian Academy of Sciences, Pushchino, Russia, 142290.
| | - Yongheng Chen
- Department of Oncology, NHC Key Laboratory of Cancer Proteomics, Laboratory of Structural Biology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China. .,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.
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Zhao R, Liu J, Li Z, Zhang W, Wang F, Zhang B. Recent Advances in CXCL12/CXCR4 Antagonists and Nano-Based Drug Delivery Systems for Cancer Therapy. Pharmaceutics 2022; 14:pharmaceutics14081541. [PMID: 35893797 PMCID: PMC9332179 DOI: 10.3390/pharmaceutics14081541] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Revised: 07/15/2022] [Accepted: 07/22/2022] [Indexed: 01/27/2023] Open
Abstract
Chemokines can induce chemotactic cell migration by interacting with G protein-coupled receptors to play a significant regulatory role in the development of cancer. CXC chemokine-12 (CXCL12) can specifically bind to CXC chemokine receptor 4 (CXCR4) and is closely associated with the progression of cancer via multiple signaling pathways. Over recent years, many CXCR4 antagonists have been tested in clinical trials; however, Plerixafor (AMD3100) is the only drug that has been approved for marketing thus far. In this review, we first summarize the mechanisms that mediate the physiological effects of the CXCL12/CXCR4 axis. Then, we describe the use of CXCL12/CXCR4 antagonists. Finally, we discuss the use of nano-based drug delivery systems that exert action on the CXCL12/CXCR4 biological axis.
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Affiliation(s)
| | | | | | | | - Feng Wang
- Correspondence: (F.W.); (B.Z.); Tel.: +86-536-8462490 (B.Z.)
| | - Bo Zhang
- Correspondence: (F.W.); (B.Z.); Tel.: +86-536-8462490 (B.Z.)
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38
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Xu J, Li JQ, Chen QL, Shestakova EA, Misyurin VA, Pokrovsky VS, Tchevkina EM, Chen HB, Song H, Zhang JY. Advances in Research on the Effects and Mechanisms of Chemokines and Their Receptors in Cancer. Front Pharmacol 2022; 13:920779. [PMID: 35770088 PMCID: PMC9235028 DOI: 10.3389/fphar.2022.920779] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Accepted: 05/05/2022] [Indexed: 01/10/2023] Open
Abstract
Cancer is a common and intractable disease that seriously affects quality of life of patients and imposes heavy economic burden on families and the entire society. Current medications and intervention strategies for cancer have respective shortcomings. In recent years, it has been increasingly spotlighted that chemokines and their receptors play vital roles in the pathophysiology of cancer. Chemokines are a class of structurally similar short-chain secreted proteins that initiate intracellular signaling pathways through the activation of corresponding G protein-coupled receptors and participate in physiological and pathological processes such as cell migration and proliferation. Studies have shown that chemokines and their receptors have close relationships with cancer epigenetic regulation, growth, progression, invasion, metastasis, and angiogenesis. Chemokines and their receptors may also serve as potential targets for cancer treatment. We herein summarize recent research progresses on anti-tumor effects and mechanisms of chemokines and their receptors, suggesting avenues for future studies. Perspectives for upcoming explorations, such as development of multi-targeted chemokine-based anti-tumor drugs, are also discussed in the present review.
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Affiliation(s)
- Jing Xu
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
- Department of Biochemistry and Molecular Biology, School of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei, China
| | - Jing-quan Li
- The First Affiliated Hospital, Hainan Medical University, Haikou, China
| | - Qi-lei Chen
- School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China
| | - Elena A. Shestakova
- N.N. Blokhin National Medical Research Center of Oncology of the Ministry of Health of the Russian Federation, Moscow, Russia
| | - Vsevolod A. Misyurin
- N.N. Blokhin National Medical Research Center of Oncology of the Ministry of Health of the Russian Federation, Moscow, Russia
| | - Vadim S. Pokrovsky
- N.N. Blokhin National Medical Research Center of Oncology of the Ministry of Health of the Russian Federation, Moscow, Russia
- Department of Biochemistry, People’s Friendship University, Moscow, Russia
| | - Elena M. Tchevkina
- N.N. Blokhin National Medical Research Center of Oncology of the Ministry of Health of the Russian Federation, Moscow, Russia
| | - Hu-biao Chen
- School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China
| | - Hang Song
- Department of Biochemistry and Molecular Biology, School of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei, China
| | - Jian-ye Zhang
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
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Masih M, Agarwal S, Kaur R, Gautam PK. Role of chemokines in breast cancer. Cytokine 2022; 155:155909. [PMID: 35597171 DOI: 10.1016/j.cyto.2022.155909] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Revised: 05/02/2022] [Accepted: 05/09/2022] [Indexed: 02/06/2023]
Abstract
Chemokines belong to a family of chemoattractant cytokines and are well known to have an essential role in various cancer aetiologies. Multiplesubsets of immune cells are recruited and enrolled into the tumor microenvironment through interactions between chemokines and their specific receptors. These populations and their interactions have a distinct impact on tumor growth, progression, and treatment outcomes. While it is clear that many chemokines and their cognate receptors can be detected in breast and other cancers, the role of each chemokine and receptor has yet to be determined. This review focuses on the main chemokines that play a crucial role in the tumor microenvironment, emphasizing breast cancer. We have also discussed the techniques used to identify the chemokines and their future implication in the early diagnosis of cancer. In-depth knowledge of chemokines and their role in breast cancer progression can provide specific targets for breast cancer biotherapy.
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Affiliation(s)
- Marilyn Masih
- Department of Biochemistry, AIIMS, New Delhi -110029, India.
| | - Sonam Agarwal
- Department of Biochemistry, AIIMS, New Delhi -110029, India.
| | - Rupinder Kaur
- Department of Biochemistry, AIIMS, New Delhi -110029, India.
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Molecular sensors for detection of tumor-stroma crosstalk. Adv Cancer Res 2022; 154:47-91. [PMID: 35459472 DOI: 10.1016/bs.acr.2022.01.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
In most solid tumors, malignant cells coexist with non-cancerous host tissue comprised of a variety of extracellular matrix components and cell types, notably fibroblasts, immune cells, and endothelial cells. It is becoming increasingly evident that the non-cancerous host tissue, often referred to as the tumor stroma or the tumor microenvironment, wields tremendous influence in the proliferation, survival, and metastatic ability of cancer cells. The tumor stroma has an active biological role in the transmission of signals, such as growth factors and chemokines that activate oncogenic signaling pathways by autocrine and paracrine mechanisms. Moreover, the constituents of the stroma define the mechanical properties and the physical features of solid tumors, which influence cancer progression and response to therapy. Inspired by the emerging importance of tumor-stroma crosstalk and oncogenic physical forces, numerous biosensors, or advanced imaging and analysis techniques have been developed and applied to investigate complex and challenging questions in cancer research. These techniques facilitate measurements and biological readouts at scales ranging from subcellular to tissue-level with unprecedented level of spatial and temporal precision. Here we examine the application of biosensor technology for studying the complex and dynamic multiscale interactions of the tumor-host system.
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A Novel CXCR4-Targeted Diphtheria Toxin Nanoparticle Inhibits Invasion and Metastatic Dissemination in a Head and Neck Squamous Cell Carcinoma Mouse Model. Pharmaceutics 2022; 14:pharmaceutics14040887. [PMID: 35456719 PMCID: PMC9032726 DOI: 10.3390/pharmaceutics14040887] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 04/07/2022] [Accepted: 04/15/2022] [Indexed: 12/31/2022] Open
Abstract
Loco-regional recurrences and metastasis represent the leading causes of death in head and neck squamous cell carcinoma (HNSCC) patients, highlighting the need for novel therapies. Chemokine receptor 4 (CXCR4) has been related to loco-regional and distant recurrence and worse patient prognosis. In this regard, we developed a novel protein nanoparticle, T22-DITOX-H6, aiming to selectively deliver the diphtheria toxin cytotoxic domain to CXCR4+ HNSCC cells. The antimetastatic effect of T22-DITOX-H6 was evaluated in vivo in an orthotopic mouse model. IVIS imaging system was utilized to assess the metastatic dissemination in the mouse model. Immunohistochemistry and histopathological analyses were used to study the CXCR4 expression in the cancer cells, to evaluate the effect of the nanotoxin treatment, and its potential off-target toxicity. In this study, we report that CXCR4+ cancer cells were present in the invasive tumor front in an orthotopic mouse model. Upon repeated T22-DITOX-H6 administration, the number of CXCR4+ cancer cells was significantly reduced. Similarly, nanotoxin treatment effectively blocked regional and distant metastatic dissemination in the absence of systemic toxicity in the metastatic HNSCC mouse model. The repeated administration of T22-DITOX-H6 clearly abrogates tumor invasiveness and metastatic dissemination without inducing any off-target toxicity. Thus, T22-DITOX-H6 holds great promise for the treatment of CXCR4+ HNSCC patients presenting worse prognosis.
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Propper DJ, Balkwill FR. Harnessing cytokines and chemokines for cancer therapy. Nat Rev Clin Oncol 2022; 19:237-253. [PMID: 34997230 DOI: 10.1038/s41571-021-00588-9] [Citation(s) in RCA: 532] [Impact Index Per Article: 177.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/06/2021] [Indexed: 12/14/2022]
Abstract
During the past 40 years, cytokines and cytokine receptors have been extensively investigated as either cancer targets or cancer treatments. A strong preclinical rationale supports therapeutic strategies to enhance the growth inhibitory and immunostimulatory effects of interferons and interleukins, including IL-2, IL-7, IL-12 and IL-15, or to inhibit the inflammatory and tumour-promoting actions of cytokines such as TNF, IL-1β and IL-6. This rationale is underscored by the discovery of altered and dysregulated cytokine expression in all human cancers. These findings prompted clinical trials of several cytokines or cytokine antagonists, revealing relevant biological activity but limited therapeutic efficacy. However, most trials involved patients with advanced-stage disease, which might not be the optimal setting for cytokine-based therapy. The advent of more effective immunotherapies and an increased understanding of the tumour microenvironment have presented new approaches to harnessing cytokine networks in the treatment of cancer, which include using cytokine-based therapies to enhance the activity or alleviate the immune-related toxicities of other treatments as well as to target early stage cancers. Many challenges remain, especially concerning delivery methods, context dependencies, and the pleiotropic, redundant and often conflicting actions of many cytokines. Herein, we discuss the lessons learnt from the initial trials of single-agent cytokine-based therapies and subsequent efforts to better exploit such agents for the treatment of solid tumours.
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Affiliation(s)
- David J Propper
- Centre for the Tumour Microenvironment, Barts Cancer Institute, Queen Mary University of London, London, UK
| | - Frances R Balkwill
- Centre for the Tumour Microenvironment, Barts Cancer Institute, Queen Mary University of London, London, UK.
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Mehraj U, Alshehri B, Khan AA, Bhat AA, Bagga P, Wani NA, Mir MA. Expression Pattern and Prognostic Significance of Chemokines in Breast cancer: An Integrated Bioinformatics Analysis. Clin Breast Cancer 2022; 22:567-578. [DOI: 10.1016/j.clbc.2022.04.008] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2021] [Revised: 03/24/2022] [Accepted: 04/20/2022] [Indexed: 12/24/2022]
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Mehraj U, Mushtaq U, Mir MA, Saleem A, Macha MA, Lone MN, Hamid A, Zargar MA, Ahmad SM, Wani NA. Chemokines in Triple-Negative Breast Cancer Heterogeneity: New Challenges for Clinical Implications. Semin Cancer Biol 2022; 86:769-783. [PMID: 35278636 DOI: 10.1016/j.semcancer.2022.03.008] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Revised: 03/01/2022] [Accepted: 03/07/2022] [Indexed: 12/12/2022]
Abstract
Tumor heterogeneity is a hallmark of cancer and one of the primary causes of resistance to therapies. Triple-negative breast cancer (TNBC), which accounts for 15% to 20% of all breast cancers and is the most aggressive subtype, is very diverse, connected to metastatic potential and response to therapy. It is a very diverse disease at the molecular, pathologic, and clinical levels. TNBC is substantially more likely to recur and has a worse overall survival rate following diagnosis than other breast cancer subtypes. Chemokines, low molecular weight proteins that stimulate chemotaxis, have been shown to control the cues responsible for TNBC heterogeneity. In this review, we have focused on tumor heterogeneity and the role of chemokines in modulating tumor heterogeneity, since this is the most critical issue in treating TNBC. Additionally, we examined numerous cues mediated by chemokine networks that contribute to the heterogeneity of TNBC. Recent developments in our knowledge of the chemokine networks that regulate TNBC heterogeneity may pave the door for developing difficult-to-treat TNBC treatment options.
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Affiliation(s)
- Umar Mehraj
- Department of Bioresources, School of Life Sciences, University of Kashmir, Srinagar, Jammu & Kashmir India
| | - Umer Mushtaq
- Department of Biotechnology, School of Life Sciences, Central University of Kashmir, Ganderbal, J&K, India
| | - Manzoor A Mir
- Department of Bioresources, School of Life Sciences, University of Kashmir, Srinagar, Jammu & Kashmir India
| | - Afnan Saleem
- Division of Animal Biotechnology Faculty of Veterinary Sciences and Animal Husbandry, Shuhama Sher-e- Kashmir University of Agricultural Sciences and Technology-Kashmir, India
| | - Muzafar A Macha
- Watson-Crick Centre for Molecular Medicine, Islamic University of Science & Technology Awantipora, Jammu & Kashmir, India
| | - Mohammad Nadeem Lone
- Department of Chemistry, School of Physical & Chemical Sciences, Central University of Kashmir, Ganderbal J & K, India
| | - Abid Hamid
- Department of Biotechnology, School of Life Sciences, Central University of Kashmir, Ganderbal, J&K, India
| | - Mohammed A Zargar
- Department of Biotechnology, School of Life Sciences, Central University of Kashmir, Ganderbal, J&K, India
| | - Syed Mudasir Ahmad
- Division of Animal Biotechnology Faculty of Veterinary Sciences and Animal Husbandry, Shuhama Sher-e- Kashmir University of Agricultural Sciences and Technology-Kashmir, India
| | - Nissar Ahmad Wani
- Department of Biotechnology, School of Life Sciences, Central University of Kashmir, Ganderbal, J&K, India.
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Arora S, Khan S, Zaki A, Tabassum G, Mohsin M, Bhutto HN, Ahmad T, Fatma T, Syed MA. Integration of chemokine signaling with non-coding RNAs in tumor microenvironment and heterogeneity in different cancers. Semin Cancer Biol 2022; 86:720-736. [DOI: 10.1016/j.semcancer.2022.03.002] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 02/15/2022] [Accepted: 03/02/2022] [Indexed: 02/07/2023]
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Sethakorn N, Heninger E, Sánchez-de-Diego C, Ding AB, Yada RC, Kerr SC, Kosoff D, Beebe DJ, Lang JM. Advancing Treatment of Bone Metastases through Novel Translational Approaches Targeting the Bone Microenvironment. Cancers (Basel) 2022; 14:757. [PMID: 35159026 PMCID: PMC8833657 DOI: 10.3390/cancers14030757] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Revised: 01/21/2022] [Accepted: 01/29/2022] [Indexed: 02/04/2023] Open
Abstract
Bone metastases represent a lethal condition that frequently occurs in solid tumors such as prostate, breast, lung, and renal cell carcinomas, and increase the risk of skeletal-related events (SREs) including pain, pathologic fractures, and spinal cord compression. This unique metastatic niche consists of a multicellular complex that cancer cells co-opt to engender bone remodeling, immune suppression, and stromal-mediated therapeutic resistance. This review comprehensively discusses clinical challenges of bone metastases, novel preclinical models of the bone and bone marrow microenviroment, and crucial signaling pathways active in bone homeostasis and metastatic niche. These studies establish the context to summarize the current state of investigational agents targeting BM, and approaches to improve BM-targeting therapies. Finally, we discuss opportunities to advance research in bone and bone marrow microenvironments by increasing complexity of humanized preclinical models and fostering interdisciplinary collaborations to translational research in this challenging metastatic niche.
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Affiliation(s)
- Nan Sethakorn
- University of Wisconsin Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI 53705, USA; (N.S.); (E.H.); (C.S.-d.-D.); (A.B.D.); (S.C.K.); (D.K.); (D.J.B.)
- Division of Hematology/Oncology, University of Wisconsin-Madison, 1111 Highland Ave., Madison, WI 53705, USA
- Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA
| | - Erika Heninger
- University of Wisconsin Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI 53705, USA; (N.S.); (E.H.); (C.S.-d.-D.); (A.B.D.); (S.C.K.); (D.K.); (D.J.B.)
| | - Cristina Sánchez-de-Diego
- University of Wisconsin Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI 53705, USA; (N.S.); (E.H.); (C.S.-d.-D.); (A.B.D.); (S.C.K.); (D.K.); (D.J.B.)
- Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA;
| | - Adeline B. Ding
- University of Wisconsin Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI 53705, USA; (N.S.); (E.H.); (C.S.-d.-D.); (A.B.D.); (S.C.K.); (D.K.); (D.J.B.)
| | - Ravi Chandra Yada
- Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA;
| | - Sheena C. Kerr
- University of Wisconsin Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI 53705, USA; (N.S.); (E.H.); (C.S.-d.-D.); (A.B.D.); (S.C.K.); (D.K.); (D.J.B.)
- Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA;
| | - David Kosoff
- University of Wisconsin Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI 53705, USA; (N.S.); (E.H.); (C.S.-d.-D.); (A.B.D.); (S.C.K.); (D.K.); (D.J.B.)
- Division of Hematology/Oncology, University of Wisconsin-Madison, 1111 Highland Ave., Madison, WI 53705, USA
- Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA
| | - David J. Beebe
- University of Wisconsin Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI 53705, USA; (N.S.); (E.H.); (C.S.-d.-D.); (A.B.D.); (S.C.K.); (D.K.); (D.J.B.)
- Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA;
- Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI 53705, USA
| | - Joshua M. Lang
- University of Wisconsin Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI 53705, USA; (N.S.); (E.H.); (C.S.-d.-D.); (A.B.D.); (S.C.K.); (D.K.); (D.J.B.)
- Division of Hematology/Oncology, University of Wisconsin-Madison, 1111 Highland Ave., Madison, WI 53705, USA
- Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA
- Wisconsin Institutes for Medical Research, 1111 Highland Ave., Madison, WI 53705, USA
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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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Multifaceted Roles of Chemokines and Chemokine Receptors in Tumor Immunity. Cancers (Basel) 2021; 13:cancers13236132. [PMID: 34885241 PMCID: PMC8656932 DOI: 10.3390/cancers13236132] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Revised: 11/26/2021] [Accepted: 12/02/2021] [Indexed: 12/22/2022] Open
Abstract
Simple Summary Various immune cells are involved in host immune responses to cancer. T-helper (Th) 1 cells, cytotoxic CD8+ T cells, and natural killer cells are the major effector cells in anti-tumor immunity, whereas cells such as regulatory T cells and myeloid-derived suppressor cells are negatively involved in anti-tumor immunity. Th2 cells and Th17 cells have been shown to have both pro-tumor and anti-tumor activities. The migratory properties of various immune cells are essential for their function and critically regulated by the chemokine superfamily. In this review, we summarize the roles of various immune cells in tumor immunity and their migratory regulation by the chemokine superfamily. We also assess the therapeutic possibilities of targeting chemokines and chemokine receptors in cancer immunotherapy. Abstract Various immune cells are involved in host tumor immune responses. In particular, there are many T cell subsets with different roles in tumor immunity. T-helper (Th) 1 cells are involved in cellular immunity and thus play the major role in host anti-tumor immunity by inducing and activating cytotoxic T lymphocytes (CTLs). On the other hand, Th2 cells are involved in humoral immunity and suppressive to Th1 responses. Regulatory T (Treg) cells negatively regulate immune responses and contribute to immune evasion of tumor cells. Th17 cells are involved in inflammatory responses and may play a role in tumor progression. However, recent studies have also shown that Th17 cells are capable of directly inducting CTLs and thus may promote anti-tumor immunity. Besides these T cell subsets, there are many other innate immune cells such as dendritic cells (DCs), natural killer (NK) cells, and myeloid-derived suppressor cells (MDSCs) that are involved in host immune responses to cancer. The migratory properties of various immune cells are critical for their functions and largely regulated by the chemokine superfamily. Thus, chemokines and chemokine receptors play vital roles in the orchestration of host immune responses to cancer. In this review, we overview the various immune cells involved in host responses to cancer and their migratory properties regulated by the chemokine superfamily. Understanding the roles of chemokines and chemokine receptors in host immune responses to cancer may provide new therapeutic opportunities for cancer immunotherapy.
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Corti C, Nicolò E, Curigliano G. Novel immune targets for the treatment of triple-negative breast cancer. Expert Opin Ther Targets 2021; 25:815-834. [PMID: 34763593 DOI: 10.1080/14728222.2021.2006187] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
INTRODUCTION To overcome mechanisms of primary and secondary resistance to the anti-tumor immune response, novel targets such as ICOS, LAG3, and TIM3 are currently being explored at preclinical and early-phase clinical levels. AREAS COVERED This article examines the landscape of the immune therapeutics investigated in early-phase clinical trials for TNBC. Preclinical rationale is provided for each immune target, predominant expression, and function. Clinical implications and preliminary available trial results are discussed and finally, we reflect on aspects of future expectations and challenges in this field. EXPERT OPINION Several immune strategies have been investigated in TNBC, including co-inhibitory molecules beyond PD1-PD-L1 axis, co-stimulatory checkpoints, cancer vaccines, adoptive cell transfer, combination therapies, as well as different routes of administration. Most of approaches showed signs of anti-cancer activity and a good safety profile in early-phase clinical trials. Since IO provided benefit only to a small subgroup of TNBC patients so far, identifying predictive biomarkers is a priority to refine patient-selection. Data from ongoing clinical trials, with the gradually improving interpretation of the breast tumor immune environment, will hopefully refine the role of new immune targets for the treatment of TNBC.
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Affiliation(s)
- Chiara Corti
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, Irccs, Milan, Italy.,Department of Oncology and Hematology (DIPO), University of Milano, Milano, Italy
| | - Eleonora Nicolò
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, Irccs, Milan, Italy.,Department of Oncology and Hematology (DIPO), University of Milano, Milano, Italy
| | - Giuseppe Curigliano
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, Irccs, Milan, Italy.,Department of Oncology and Hematology (DIPO), University of Milano, Milano, Italy
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Bule P, Aguiar SI, Aires-Da-Silva F, Dias JNR. Chemokine-Directed Tumor Microenvironment Modulation in Cancer Immunotherapy. Int J Mol Sci 2021; 22:9804. [PMID: 34575965 PMCID: PMC8464715 DOI: 10.3390/ijms22189804] [Citation(s) in RCA: 117] [Impact Index Per Article: 29.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2021] [Revised: 09/07/2021] [Accepted: 09/07/2021] [Indexed: 12/11/2022] Open
Abstract
Chemokines are a large family of small chemotactic cytokines that coordinates immune cell trafficking. In cancer, they have a pivotal role in the migration pattern of immune cells into the tumor, thereby shaping the tumor microenvironment immune profile, often towards a pro-tumorigenic state. Furthermore, chemokines can directly target non-immune cells in the tumor microenvironment, including cancer, stromal and vascular endothelial cells. As such, chemokines participate in several cancer development processes such as angiogenesis, metastasis, cancer cell proliferation, stemness and invasiveness, and are therefore key determinants of disease progression, with a strong influence in patient prognosis and response to therapy. Due to their multifaceted role in the tumor immune response and tumor biology, the chemokine network has emerged as a potential immunotherapy target. Under the present review, we provide a general overview of chemokine effects on several tumoral processes, as well as a description of the currently available chemokine-directed therapies, highlighting their potential both as monotherapy or in combination with standard chemotherapy or other immunotherapies. Finally, we discuss the most critical challenges and prospects of developing targeted chemokines as therapeutic options.
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Affiliation(s)
| | | | | | - Joana Nunes Ribeiro Dias
- Centro de Investigação Interdisciplinar em Sanidade Animal, Faculdade de Medicina Veterinária, Universidade de Lisboa, 1300-477 Lisbon, Portugal; (P.B.); (S.I.A.); (F.A.-D.-S.)
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