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Qi Y, Sun D, Zhai X, Chen F, Niu J, Zhu H. Macrophages in the premetastatic and metastatic niche: key functions and therapeutic directions. J Transl Med 2025; 23:602. [PMID: 40448239 DOI: 10.1186/s12967-025-06556-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2024] [Accepted: 04/30/2025] [Indexed: 06/02/2025] Open
Abstract
Metastasis plays a significant role in the high mortality rates associated with cancer and is usually the endpoint of a series of sequential and dynamic events. A crucial step in metastasis development and progression is the formation of a premetastatic niche (PMN), which provides a conducive microenvironment for the settlement and colonization of disseminated tumor cells at distant metastatic sites. Extensive research has demonstrated the significance of macrophage populations within primary tumors in promoting metastatic progression. Nevertheless, the contribution of macrophages at secondary sites to the regulation of PMN formation is frequently overlooked. This review systematically explores the role of macrophages in priming the PMN to facilitate cancer metastasis. Additionally, we provide a compendium of existing strategies to target macrophages in cancer therapy.
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Affiliation(s)
- Yana Qi
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University, Shandong Academy of Medical Sciences, 440 Jiyan Road, Jinan, Shandong Province, 250117, China
| | - Dongmei Sun
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University, Shandong Academy of Medical Sciences, 440 Jiyan Road, Jinan, Shandong Province, 250117, China
| | - Xiaoyang Zhai
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University, Shandong Academy of Medical Sciences, 440 Jiyan Road, Jinan, Shandong Province, 250117, China
| | - Feihu Chen
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University, Shandong Academy of Medical Sciences, 440 Jiyan Road, Jinan, Shandong Province, 250117, China
| | - Jiling Niu
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University, Shandong Academy of Medical Sciences, 440 Jiyan Road, Jinan, Shandong Province, 250117, China
| | - Hui Zhu
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University, Shandong Academy of Medical Sciences, 440 Jiyan Road, Jinan, Shandong Province, 250117, China.
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Sheikh SM, Staab J, Bleyer M, Ivetic A, Lühder F, Wirths O, Meyer T. N-terminal truncation of STAT1 transcription factor causes CD3- and CD20-negative non-Hodgkin lymphoma through upregulation of STAT3-mediated oncogenic functions. Cell Commun Signal 2025; 23:201. [PMID: 40287766 PMCID: PMC12034123 DOI: 10.1186/s12964-025-02183-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2024] [Accepted: 03/29/2025] [Indexed: 04/29/2025] Open
Abstract
The cytokine-driven transcription factor STAT1 (signal transducer and activator of transcription 1) executes anti-microbial and pro-apoptotic functions, and loss-of-function mutations are associated with increased susceptibility to various infections and the development of tumors. A targeted mutation in mice expressing an N-terminally truncated STAT1 protein (STAT1-ΔN) typically develops splenomegaly in animals older than 6 months due to the formation of splenic non-Hodgkin lymphomas. The expression of the STAT1-ΔN variant resulted in the disruption of normal spleen architecture by malignant CD3- and CD20-negative tumor cells, which stained positively for both tyrosine-phosphorylated STAT1 and STAT3. Immunoblotting of lysates from isolated tumor cells revealed the cytokine-independent hyperphosphorylation of both STAT proteins, whereas the expression level of NF-κB was significantly reduced. Gel-shift assays showed that the DNA-binding activity of STAT1-ΔN was increased compared to the wild-type protein. This elevated level of tyrosine-phosphorylated STAT1-ΔN did not further increase upon stimulation of isolated tumor cells with either interferon-γ (IFNγ), lipopolysaccharide (LPS), or the combination of both. Since the truncation mutant was unable to accumulate in the nucleus upon cytokine stimulation, real-time PCR data from tumor tissue as well as from isolated, IFNγ/LPS-treated lymphoma cells demonstrated significantly reduced STAT1-regulated target gene expression despite its observed hyperphosphorylation. The nuclear import defect of tyrosine-phosphorylated STAT1-ΔN was associated with an elevated tyrosine-phosphorylation level of its antagonistic homolog STAT3, which is a known oncogene. These data demonstrate that the lack of STAT1 nuclear accumulation interferes with the functional balance between the two STAT proteins and, thereby, promotes the formation of phospho-STAT3-expressing CD3-/- CD20-/- non-Hodgkin lymphomas in the spleens of the diseased animals.
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Affiliation(s)
- Sana Mumtaz Sheikh
- Department of Psychosomatic Medicine and Psychotherapy, University Medical Center Göttingen, Göttingen, Germany
- Institute of Pathology, University Medical Center Düsseldorf, Düsseldorf, Germany
| | - Julia Staab
- Department of Psychosomatic Medicine and Psychotherapy, University Medical Center Göttingen, Göttingen, Germany
| | - Martina Bleyer
- German Primate Center, Leibniz Institute for Primate Research, Göttingen, Germany
| | - Aleksandar Ivetic
- School of Cardiovascular and Metabolic Medicine & Sciences, BHF Centre of Research Excellence, King's College London, London, United Kingdom
| | - Fred Lühder
- Institute for Neuroimmunology and Multiple Sclerosis Research, University Medical Center Göttingen, Göttingen, Germany
| | - Oliver Wirths
- Department of Psychiatry and Psychotherapy, University Medical Center Göttingen, Göttingen, Germany
| | - Thomas Meyer
- Department of Psychosomatic Medicine and Psychotherapy, University Medical Center Göttingen, Göttingen, Germany.
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Ma JA, Orbach SM, Griffin KV, Kang K, Zhang Y, Pereles RS, Schrack IA, Escalona G, Jeruss JS, Shea LD. Early metastasis is characterized by Gr1+ cell dysregulation and is inhibited by immunomodulatory nanoparticles. Mol Oncol 2025. [PMID: 40269509 DOI: 10.1002/1878-0261.70040] [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: 07/23/2024] [Revised: 01/27/2025] [Accepted: 04/03/2025] [Indexed: 04/25/2025] Open
Abstract
Cancer metastasis is supported by dysregulated myeloid-derived suppressor cells, but myeloid cells are highly heterogeneous populations with distinct subsets that may support or inhibit tumor cell colonization. We hypothesize that Gr1+ myeloid cells transform in phenotype to support tumor cell colonization at the metastatic niche. In the 4T1 model of metastatic breast cancer, we investigate changes in the composition and phenotype of Gr1+ cells between premetastatic disease and early metastasis. Gr1+ cells in the lung were found to transition towards immunosuppressive and tumor-supportive phenotypes with disease progression. While the composition of myeloid cells becomes dysregulated systemically, cells in the blood do not develop tumor-supportive phenotypes, indicating that protumor functions are specific to the lung. In vitro assays demonstrate that Gr1+ cells from early metastatic lungs support tumor cell survival, migration, and proliferation, which is linked to chitinase-3-like protein 1 (CHI3L1) signaling. The intravenous injection of polymeric nanoparticles reprograms Gr1+ cell phenotypes, reduces the secretion of CHI3L1, and inhibits metastasis. These findings indicate that dysregulated Gr1+ cells are a therapeutic target for early metastasis and can be targeted with polymeric nanoparticles.
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Affiliation(s)
- Jeffrey A Ma
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA
| | - Sophia M Orbach
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA
| | - Kate V Griffin
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA
| | - Kathryn Kang
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA
| | - Yining Zhang
- Department of Chemical Engineering, University of Michigan, Ann Arbor, MI, USA
| | - Rebecca S Pereles
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA
| | - Ian A Schrack
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA
| | - Guillermo Escalona
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA
| | - Jacqueline S Jeruss
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA
- Department of Surgery, University of Michigan, Ann Arbor, MI, USA
- Department of Pathology, University of Michigan, Ann Arbor, MI, USA
| | - Lonnie D Shea
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA
- Department of Chemical Engineering, University of Michigan, Ann Arbor, MI, USA
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Zheng Q, Zhou T, Yao D. The roles of immune cells and non-immune cells in Pre-Metastatic Niche of Breast Cancer. Crit Rev Oncol Hematol 2025; 211:104744. [PMID: 40274245 DOI: 10.1016/j.critrevonc.2025.104744] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2025] [Revised: 04/18/2025] [Accepted: 04/19/2025] [Indexed: 04/26/2025] Open
Abstract
Distant metastasis is a pivotal and important event in patients with breast cancer, and inhibition of metastasis has always been the focus of clinical research. Recent advances have established that the metastasis of breast cancer is exacerbated not only by cancer cells and the tumor microenvironment but also by the pre-metastatic niche (PMN). Primary tumor secretory factors, immune cells including bone marrow-derived cells mobilized by tumors and non-immune cells within the local matrix microenvironment of the host are three key factors for PMN formation. This article reviews the roles of bone marrow-derived cells, lymphocytes, fibroblasts, endothelial cells, epithelial cells and cancer stem cells in the establishment of PMN before metastasis to further understand the metastasis mechanism of breast cancer and to explore clues for the inhibition of distant metastasis. Different cells play distinct but important roles in the establishment of the PMN and the induction of breast cancer metastasis. The interaction between different cells and tumor cells determines whether CTCs can be attached, survive and proliferate to promote distant metastasis.
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Affiliation(s)
- Qiao Zheng
- Department of Oncology, Hospital of Chengdu Uiversity of Traditional Chinese Medicine, 610075 Chengdu, China
| | - Tiecheng Zhou
- Department of Oncology, Sichuan Integrative Medicine Hospital, 610042 Chengdu, China,.
| | - Dejiao Yao
- Department of Oncology, Hospital of Chengdu Uiversity of Traditional Chinese Medicine, 610075 Chengdu, China
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Lepland A, Peranzoni E, Haljasorg U, Asciutto EK, Crespí‐Amer M, Modesti L, Kilk K, Lombardia M, Acosta G, Royo M, Peterson P, Marigo I, Teesalu T, Scodeller P. Peptide-Drug Conjugate for Therapeutic Reprogramming of Tumor-Associated Macrophages in Breast Cancer. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2410288. [PMID: 39840532 PMCID: PMC11904948 DOI: 10.1002/advs.202410288] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/26/2024] [Revised: 12/23/2024] [Indexed: 01/23/2025]
Abstract
In triple-negative breast cancer (TNBC), pro-tumoral macrophages promote metastasis and suppress the immune response. To target these cells, a previously identified CD206 (mannose receptor)-binding peptide, mUNO was engineered to enhance its affinity and proteolytic stability. The new rationally designed peptide, MACTIDE, includes a trypsin inhibitor loop, from the Sunflower Trypsin Inhibitor-I. Binding studies to recombinant CD206 revealed a 15-fold lower KD for MACTIDE compared to parental mUNO. Mass spectrometry further demonstrated a 5-fold increase in MACTIDE's half-life in tumor lysates compared to mUNO. Homing studies in TNBC-bearing mice shows that fluorescein (FAM)-MACTIDE precisely targeted CD206+ tumor-associated macrophages (TAM) upon intravenous, intraperitoneal, and even oral administration, with minimal liver accumulation. MACTIDE was conjugated to Verteporfin, an FDA-approved photosensitizer and YAP/TAZ pathway inhibitor to create the conjugate MACTIDE-V. In the orthotopic 4T1 TNBC mouse model, non-irradiated MACTIDE-V-treated mice exhibited anti-tumoral effects comparable to those treated with irradiated MACTIDE-V, with fewer signs of toxicity, prompting further investigation into the laser-independent activity of the conjugate. In vitro studies using bone marrow-derived mouse macrophages showed that MACTIDE-V excluded YAP from the nucleus, increased phagocytic activity, and upregulated several genes associated with cytotoxic anti-tumoral macrophages. In mouse models of TNBC, MACTIDE-V slowed primary tumor growth, suppressed lung metastases, and increased markers of phagocytosis and antigen presentation in TAM and monocytes, increasing the tumor infiltration of several lymphocyte subsets. MACTIDE-V is proposed as a promising peptide-drug conjugate for modulating macrophage function in breast cancer immunotherapy.
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Affiliation(s)
- Anni Lepland
- Institute of Biomedicine and Translational MedicineUniversity of TartuRavila 14BTartu50411Estonia
| | - Elisa Peranzoni
- Immunology and Molecular Oncology DiagnosticsVeneto Institute of Oncology IOV – IRCCSPadua35128Italy
| | - Uku Haljasorg
- Molecular Pathology Research GroupInstitute of Biomedicine and Translational MedicineUniversity of TartuTartu50411Estonia
| | - Eliana K. Asciutto
- Instituto de Ciencias FísicasUniversidad Nacional de San Martin (UNSAM) and CONICETCampus Migueletes25 de Mayo y FranciaBuenos AiresCP 1650Argentina
| | - Maria Crespí‐Amer
- Institute for Advanced Chemistry of CataloniaIQAC‐CSICJordi Girona 18–26Barcelona08034Spain
| | - Lorenzo Modesti
- Immunology and Molecular Oncology DiagnosticsVeneto Institute of Oncology IOV – IRCCSPadua35128Italy
| | - Kalle Kilk
- Department of biochemistryInstitute of Biomedicine and Translational MedicineUniversity of TartuRavila 19Tartu50411Estonia
| | - Manuel Lombardia
- Proteomics core facilityCentro Nacional de BiotecnologiaCNB‐CSICCalle Darwin 3Madrid28049Spain
| | - Gerardo Acosta
- Institute for Advanced Chemistry of CataloniaIQAC‐CSICJordi Girona 18–26Barcelona08034Spain
- CIBER‐BBNNetworking Centre on BioengineeringBiomaterials and NanomedicineIQAC‐CSICBarcelona08034Spain
| | - Miriam Royo
- Institute for Advanced Chemistry of CataloniaIQAC‐CSICJordi Girona 18–26Barcelona08034Spain
- CIBER‐BBNNetworking Centre on BioengineeringBiomaterials and NanomedicineIQAC‐CSICBarcelona08034Spain
| | - Pärt Peterson
- Molecular Pathology Research GroupInstitute of Biomedicine and Translational MedicineUniversity of TartuTartu50411Estonia
| | - Ilaria Marigo
- Immunology and Molecular Oncology DiagnosticsVeneto Institute of Oncology IOV – IRCCSPadua35128Italy
- Department of SurgeryOncology and Gastroenterology (DISCOG)University of PadovaPadova35128Italy
| | - Tambet Teesalu
- Institute of Biomedicine and Translational MedicineUniversity of TartuRavila 14BTartu50411Estonia
| | - Pablo Scodeller
- Institute of Biomedicine and Translational MedicineUniversity of TartuRavila 14BTartu50411Estonia
- Institute for Advanced Chemistry of CataloniaIQAC‐CSICJordi Girona 18–26Barcelona08034Spain
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Li Y, Liu F, Cai Q, Deng L, Ouyang Q, Zhang XHF, Zheng J. Invasion and metastasis in cancer: molecular insights and therapeutic targets. Signal Transduct Target Ther 2025; 10:57. [PMID: 39979279 PMCID: PMC11842613 DOI: 10.1038/s41392-025-02148-4] [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: 05/09/2024] [Revised: 12/24/2024] [Accepted: 01/16/2025] [Indexed: 02/22/2025] Open
Abstract
The progression of malignant tumors leads to the development of secondary tumors in various organs, including bones, the brain, liver, and lungs. This metastatic process severely impacts the prognosis of patients, significantly affecting their quality of life and survival rates. Research efforts have consistently focused on the intricate mechanisms underlying this process and the corresponding clinical management strategies. Consequently, a comprehensive understanding of the biological foundations of tumor metastasis, identification of pivotal signaling pathways, and systematic evaluation of existing and emerging therapeutic strategies are paramount to enhancing the overall diagnostic and treatment capabilities for metastatic tumors. However, current research is primarily focused on metastasis within specific cancer types, leaving significant gaps in our understanding of the complex metastatic cascade, organ-specific tropism mechanisms, and the development of targeted treatments. In this study, we examine the sequential processes of tumor metastasis, elucidate the underlying mechanisms driving organ-tropic metastasis, and systematically analyze therapeutic strategies for metastatic tumors, including those tailored to specific organ involvement. Subsequently, we synthesize the most recent advances in emerging therapeutic technologies for tumor metastasis and analyze the challenges and opportunities encountered in clinical research pertaining to bone metastasis. Our objective is to offer insights that can inform future research and clinical practice in this crucial field.
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Affiliation(s)
- Yongxing Li
- Department of Urology, Urologic Surgery Center, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing, China
- State Key Laboratory of Trauma and Chemical Poisoning, Third Military Medical University (Army Medical University), Chongqing, China
| | - Fengshuo Liu
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, USA
- Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA
- McNair Medical Institute, Baylor College of Medicine, Houston, TX, USA
- Graduate School of Biomedical Science, Cancer and Cell Biology Program, Baylor College of Medicine, Houston, TX, USA
| | - Qingjin Cai
- Department of Urology, Urologic Surgery Center, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing, China
- State Key Laboratory of Trauma and Chemical Poisoning, Third Military Medical University (Army Medical University), Chongqing, China
| | - Lijun Deng
- Department of Medicinal Chemistry, Third Military Medical University (Army Medical University), Chongqing, China
| | - Qin Ouyang
- Department of Medicinal Chemistry, Third Military Medical University (Army Medical University), Chongqing, China.
| | - Xiang H-F Zhang
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, USA.
- Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA.
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
- McNair Medical Institute, Baylor College of Medicine, Houston, TX, USA.
| | - Ji Zheng
- Department of Urology, Urologic Surgery Center, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing, China.
- State Key Laboratory of Trauma and Chemical Poisoning, Third Military Medical University (Army Medical University), Chongqing, China.
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Rivas CH, Liu F, Zhang XHF. The Roles of Myeloid Cells in Breast Cancer Progression. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2025; 1464:397-412. [PMID: 39821035 DOI: 10.1007/978-3-031-70875-6_19] [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: 01/19/2025]
Abstract
This chapter reviews tumor-associated myeloid cells, including macrophages, neutrophils, and other innate immune cells, and their multifaceted roles in supporting breast cancer progression and metastasis. In primary tumors, myeloid cells play key roles in promoting tumor epithelial-mesenchymal transition (EMT) and invasion. They can facilitate intravasation (entry into the bloodstream) and colonization, disrupting the endothelial cell layer and reshaping the extracellular matrix. They can also stimulate angiogenesis, suppress immune cell responses, and enhance cancer cell adaptability. In the bloodstream, circulating myeloid cells enable the survival of disseminated tumor cells via immunosuppressive effects and physical shielding. At the metastatic sites, they prime the premetastatic niche, facilitate tumor cell extravasation, and support successful colonization and outgrowth. Mechanistically, myeloid cells enhance cancer cell survival, dormancy escape, proliferation, and mesenchymal-epithelial transition (MET). Nonetheless, substantial gaps in our understanding persist regarding the functional and spatiotemporal diversity, as well as the evolutionary patterns, of myeloid cells during metastatic progression. Myeloid cell plasticity and differential responses to therapies present key barriers to successful treatments. Identifying specific pro-tumoral myeloid cell subpopulations and disrupting their interactions with cancer cells represent promising therapeutic opportunities. Emerging evidence suggests combining immunomodulators or stromal normalizers with conventional therapies could help overcome therapy-induced immunosuppression and improve patient outcomes. Overall, further elucidating myeloid cell heterogeneity and function throughout the process of breast cancer progression and metastasis will enable more effective therapeutic targeting of these critical stromal cells.
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Affiliation(s)
- Charlotte Helena Rivas
- Cancer and Cell Biology Program, Graduate School of Biomedical Sciences, San Antonio, TX, USA
| | - Fengshuo Liu
- Cancer and Cell Biology Program, Graduate School of Biomedical Sciences, San Antonio, TX, USA
| | - Xiang H-F Zhang
- Lester and Sue Smith Breast Center, Houston, TX, USA.
- Department of Molecular and Cellular Biology, Berkeley, CA, USA.
- Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA.
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Chen Y, Zhang X, Huang S, Febbraio M. Hidden features: CD36/SR-B2, a master regulator of macrophage phenotype/function through metabolism. Front Immunol 2024; 15:1468957. [PMID: 39742252 PMCID: PMC11685046 DOI: 10.3389/fimmu.2024.1468957] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2024] [Accepted: 11/30/2024] [Indexed: 01/03/2025] Open
Abstract
Once thought to be in a terminally differentiated state, macrophages are now understood to be highly pliable, attuned and receptive to environmental cues that control and align responses. In development of purpose, the centrality of metabolic pathways has emerged. Thus, macrophage inflammatory or reparative phenotypes are tightly linked to catabolic and anabolic metabolism, with further fine tuning of specific gene expression patterns in specific settings. Single-cell transcriptome analyses have revealed a breadth of macrophage signatures, with some new influencers driving phenotype. CD36/Scavenger Receptor B2 has established roles in immunity and lipid metabolism. Macrophage CD36 is a key functional player in metabolic expression profiles that determine phenotype. Emerging data show that alterations in the microenvironment can recast metabolic pathways and modulate macrophage function, with the potential to be leveraged for therapeutic means. This review covers recent data on phenotypic characterization of homeostatic, atherosclerotic, lipid-, tumor- and metastatic-associated macrophages, with the integral role of CD36 highlighted.
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Affiliation(s)
- Yuge Chen
- Mike Petryk School of Dentistry, Faculty of Medicine and Dentistry, College of Health Sciences, University of Alberta, Edmonton, AB, Canada
| | - Xuejia Zhang
- Mike Petryk School of Dentistry, Faculty of Medicine and Dentistry, College of Health Sciences, University of Alberta, Edmonton, AB, Canada
- School and Hospital of Stomatology, Wenzhou Medical University, Wenzhou, China
| | - Shengbin Huang
- Institute of Stomatology, School and Hospital of Stomatology, Wenzhou Medical University, Wenzhou, China
- Department of Prosthodontics, School and Hospital of Stomatology, Wenzhou Medical University, Wenzhou, China
| | - Maria Febbraio
- Mike Petryk School of Dentistry, Faculty of Medicine and Dentistry, College of Health Sciences, University of Alberta, Edmonton, AB, Canada
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Arleo A, Montagner A, Giovannini C, Suzzi F, Piscaglia F, Gramantieri L. Multifaceted Aspects of Dysfunctional Myelopoiesis in Cancer and Therapeutic Perspectives with Focus on HCC. Biomolecules 2024; 14:1496. [PMID: 39766202 PMCID: PMC11673139 DOI: 10.3390/biom14121496] [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: 10/10/2024] [Revised: 11/14/2024] [Accepted: 11/20/2024] [Indexed: 01/04/2025] Open
Abstract
Myelopoiesis provides for the formation and continued renewal of cells belonging primarily to the innate immune system. It is a highly plastic process that secures the response to external and internal stimuli to face acute and changing needs. Infections and chronic diseases including cancer can modulate it by producing several factors, impacting proliferation and differentiation programs. While the lymphocytic compartment has attracted major attention due to the role of adaptive immunity in anticancer immune response, in recent years, research has found convincing evidence that confirms the importance of innate immunity and the key function played by emergency myelopoiesis. Due to cancer's ability to manipulate myelopoiesis to its own advantage, the purpose of this review is to outline myelopoiesis processes within the tumor microenvironment and suggest possible therapeutic lines of research to restore the physiological functioning of the host's immune system, with a special outlook on hepatocellular carcinoma (HCC).
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Affiliation(s)
- Andrea Arleo
- Department of Medical and Surgical Sciences, Bologna University, 40138 Bologna, Italy; (A.M.); (C.G.); (F.S.); (F.P.)
| | - Annapaola Montagner
- Department of Medical and Surgical Sciences, Bologna University, 40138 Bologna, Italy; (A.M.); (C.G.); (F.S.); (F.P.)
| | - Catia Giovannini
- Department of Medical and Surgical Sciences, Bologna University, 40138 Bologna, Italy; (A.M.); (C.G.); (F.S.); (F.P.)
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
| | - Fabrizia Suzzi
- Department of Medical and Surgical Sciences, Bologna University, 40138 Bologna, Italy; (A.M.); (C.G.); (F.S.); (F.P.)
| | - Fabio Piscaglia
- Department of Medical and Surgical Sciences, Bologna University, 40138 Bologna, Italy; (A.M.); (C.G.); (F.S.); (F.P.)
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
| | - Laura Gramantieri
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
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10
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Dacheux MA, Norman DD, Shin Y, Tigyi GJ, Lee SC. Deleting autotaxin in LysM+ myeloid cells impairs innate tumor immunity in models of metastatic melanoma. iScience 2024; 27:110971. [PMID: 39398245 PMCID: PMC11467674 DOI: 10.1016/j.isci.2024.110971] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2024] [Revised: 08/04/2024] [Accepted: 09/13/2024] [Indexed: 10/15/2024] Open
Abstract
Autotaxin (ATX) is a lysophospholipase D that generates lysophosphatidic acid (LPA) and regulates cancer metastasis, therapeutic resistance, and tumor immunity. We found that myeloid cells in human melanoma biopsies abundantly express ATX and investigated its role in modulating innate tumor immunity using two models of melanoma metastasis-spontaneous and experimental. Targeted knockout of ATX in LysM+ myeloid cells in mice (LysM-KO) reduced both spontaneous and experimental B16-F10 melanoma metastases by ≥ 50%. Immunoprofiling revealed differences in M2-like alveolar macrophages, neutrophils and regulatory T cells in the metastatic lungs of LysM-WT versus LysM-KO that are model-dependent. These differences extend systemically, with LysM-KO mice bearing experimental metastasis having fewer neutrophils in the spleen than LysM-WT mice. Our results show that (1) LysM+ myeloid cells are an important source of ATX/LPA that promote melanoma metastasis by altering innate tumor immunity, and (2) intratumor and systemic immune profiles vary dynamically during disease progression and are model-dependent.
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Affiliation(s)
- Mélanie A. Dacheux
- Department of Physiology, University of Tennessee Health Science Center Memphis, 3N. Dunlap Street, Memphis, TN 38163, USA
| | - Derek D. Norman
- Department of Physiology, University of Tennessee Health Science Center Memphis, 3N. Dunlap Street, Memphis, TN 38163, USA
| | - Yoojin Shin
- Department of Physiology, University of Tennessee Health Science Center Memphis, 3N. Dunlap Street, Memphis, TN 38163, USA
| | - Gábor J. Tigyi
- Department of Physiology, University of Tennessee Health Science Center Memphis, 3N. Dunlap Street, Memphis, TN 38163, USA
| | - Sue Chin Lee
- Department of Physiology, University of Tennessee Health Science Center Memphis, 3N. Dunlap Street, Memphis, TN 38163, USA
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Wang Y, Jia J, Wang F, Fang Y, Yang Y, Zhou Q, Yuan W, Gu X, Hu J, Yang S. Pre-metastatic niche: formation, characteristics and therapeutic implication. Signal Transduct Target Ther 2024; 9:236. [PMID: 39317708 PMCID: PMC11422510 DOI: 10.1038/s41392-024-01937-7] [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: 06/29/2024] [Accepted: 07/23/2024] [Indexed: 09/26/2024] Open
Abstract
Distant metastasis is a primary cause of mortality and contributes to poor surgical outcomes in cancer patients. Before the development of organ-specific metastasis, the formation of a pre-metastatic niche is pivotal in promoting the spread of cancer cells. This review delves into the intricate landscape of the pre-metastatic niche, focusing on the roles of tumor-derived secreted factors, extracellular vesicles, and circulating tumor cells in shaping the metastatic niche. The discussion encompasses cellular elements such as macrophages, neutrophils, bone marrow-derived suppressive cells, and T/B cells, in addition to molecular factors like secreted substances from tumors and extracellular vesicles, within the framework of pre-metastatic niche formation. Insights into the temporal mechanisms of pre-metastatic niche formation such as epithelial-mesenchymal transition, immunosuppression, extracellular matrix remodeling, metabolic reprogramming, vascular permeability and angiogenesis are provided. Furthermore, the landscape of pre-metastatic niche in different metastatic organs like lymph nodes, lungs, liver, brain, and bones is elucidated. Therapeutic approaches targeting the cellular and molecular components of pre-metastatic niche, as well as interventions targeting signaling pathways such as the TGF-β, VEGF, and MET pathways, are highlighted. This review aims to enhance our understanding of pre-metastatic niche dynamics and provide insights for developing effective therapeutic strategies to combat tumor metastasis.
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Affiliation(s)
- Yuhang Wang
- Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, 1 East Jianshe Road, Zhengzhou, 450000, China
| | - Jiachi Jia
- College of Medicine, Zhengzhou University, Zhengzhou, 450001, China
| | - Fuqi Wang
- Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, 1 East Jianshe Road, Zhengzhou, 450000, China
| | - Yingshuai Fang
- College of Medicine, Zhengzhou University, Zhengzhou, 450001, China
| | - Yabing Yang
- College of Medicine, Zhengzhou University, Zhengzhou, 450001, China
| | - Quanbo Zhou
- Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, 1 East Jianshe Road, Zhengzhou, 450000, China
| | - Weitang Yuan
- Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, 1 East Jianshe Road, Zhengzhou, 450000, China
| | - Xiaoming Gu
- Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, 1 East Jianshe Road, Zhengzhou, 450000, China.
| | - Junhong Hu
- Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, 1 East Jianshe Road, Zhengzhou, 450000, China.
| | - Shuaixi Yang
- Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, 1 East Jianshe Road, Zhengzhou, 450000, China.
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12
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Gerashchenko T, Frolova A, Patysheva M, Fedorov A, Stakheyeva M, Denisov E, Cherdyntseva N. Breast Cancer Immune Landscape: Interplay Between Systemic and Local Immunity. Adv Biol (Weinh) 2024; 8:e2400140. [PMID: 38727796 DOI: 10.1002/adbi.202400140] [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: 03/12/2024] [Revised: 04/16/2024] [Indexed: 07/13/2024]
Abstract
Breast cancer (BC) is one of the most common malignancies in women worldwide. Numerous studies in immuno-oncology and successful trials of immunotherapy have demonstrated the causal role of the immune system in cancer pathogenesis. The interaction between the tumor and the immune system is known to have a dual nature. Despite cytotoxic lymphocyte activity against transformed cells, a tumor can escape immune surveillance and leverage chronic inflammation to maintain its own development. Research on antitumor immunity primarily focuses on the role of the tumor microenvironment, whereas the systemic immune response beyond the tumor site is described less thoroughly. Here, a comprehensive review of the formation of the immune profile in breast cancer patients is offered. The interplay between systemic and local immune reactions as self-sustaining mechanism of tumor progression is described and the functional activity of the main cell populations related to innate and adaptive immunity is discussed. Additionally, the interaction between different functional levels of the immune system and their contribution to the development of the pro- or anti-tumor immune response in BC is highlighted. The presented data can potentially inform the development of new immunotherapy strategies in the treatment of patients with BC.
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Affiliation(s)
- Tatiana Gerashchenko
- Laboratory of Cancer Progression Biology, Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Kooperativny Str. 5, Tomsk, 634009, Russia
| | - Anastasia Frolova
- Laboratory of Molecular Oncology and Immunology, Cancer Research Institute, Tomsk National Researc, Medical Center, Russian Academy of Sciences, Kooperativny Str. 5, Tomsk, 634009, Russia
- Tomsk State University, 36 Lenin Ave., Tomsk, 634050, Russia
| | - Marina Patysheva
- Laboratory of Cancer Progression Biology, Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Kooperativny Str. 5, Tomsk, 634009, Russia
| | - Anton Fedorov
- Laboratory of Cancer Progression Biology, Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Kooperativny Str. 5, Tomsk, 634009, Russia
| | - Marina Stakheyeva
- Laboratory of Molecular Oncology and Immunology, Cancer Research Institute, Tomsk National Researc, Medical Center, Russian Academy of Sciences, Kooperativny Str. 5, Tomsk, 634009, Russia
| | - Evgeny Denisov
- Laboratory of Cancer Progression Biology, Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Kooperativny Str. 5, Tomsk, 634009, Russia
| | - Nadezda Cherdyntseva
- Laboratory of Molecular Oncology and Immunology, Cancer Research Institute, Tomsk National Researc, Medical Center, Russian Academy of Sciences, Kooperativny Str. 5, Tomsk, 634009, Russia
- Tomsk State University, 36 Lenin Ave., Tomsk, 634050, Russia
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13
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Su P, Li O, Ke K, Jiang Z, Wu J, Wang Y, Mou Y, Jin W. Targeting tumor‑associated macrophages: Critical players in tumor progression and therapeutic strategies (Review). Int J Oncol 2024; 64:60. [PMID: 38695252 PMCID: PMC11087038 DOI: 10.3892/ijo.2024.5648] [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: 03/01/2024] [Accepted: 04/19/2024] [Indexed: 05/12/2024] Open
Abstract
Tumor‑associated macrophages (TAMs) are essential components of the tumor microenvironment (TME) and display phenotypic heterogeneity and plasticity associated with the stimulation of bioactive molecules within the TME. TAMs predominantly exhibit tumor‑promoting phenotypes involved in tumor progression, such as tumor angiogenesis, metastasis, immunosuppression and resistance to therapies. In addition, TAMs have the potential to regulate the cytotoxic elimination and phagocytosis of cancer cells and interact with other immune cells to engage in the innate and adaptive immune systems. In this context, targeting TAMs has been a popular area of research in cancer therapy, and a comprehensive understanding of the complex role of TAMs in tumor progression and exploration of macrophage‑based therapeutic approaches are essential for future therapeutics against cancers. The present review provided a comprehensive and updated overview of the function of TAMs in tumor progression, summarized recent advances in TAM‑targeting therapeutic strategies and discussed the obstacles and perspectives of TAM‑targeting therapies for cancers.
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Affiliation(s)
- Pengfei Su
- Department of General Surgery, Cancer Center, Division of Gastrointestinal and Pancreatic Surgery, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang 310000, P.R. China
- Key Laboratory of Gastroenterology of Zhejiang Province, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang 310000, P.R. China
| | - Ou Li
- Department of General Surgery, Cancer Center, Division of Gastrointestinal and Pancreatic Surgery, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang 310000, P.R. China
- Key Laboratory of Gastroenterology of Zhejiang Province, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang 310000, P.R. China
| | - Kun Ke
- Department of General Surgery, Cancer Center, Division of Gastrointestinal and Pancreatic Surgery, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang 310000, P.R. China
- Key Laboratory of Gastroenterology of Zhejiang Province, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang 310000, P.R. China
| | - Zhichen Jiang
- Department of General Surgery, Cancer Center, Division of Gastrointestinal and Pancreatic Surgery, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang 310000, P.R. China
- Key Laboratory of Gastroenterology of Zhejiang Province, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang 310000, P.R. China
| | - Jianzhang Wu
- Department of General Surgery, Cancer Center, Division of Gastrointestinal and Pancreatic Surgery, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang 310000, P.R. China
| | - Yuanyu Wang
- Department of General Surgery, Cancer Center, Division of Gastrointestinal and Pancreatic Surgery, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang 310000, P.R. China
| | - Yiping Mou
- Department of General Surgery, Cancer Center, Division of Gastrointestinal and Pancreatic Surgery, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang 310000, P.R. China
- Key Laboratory of Gastroenterology of Zhejiang Province, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang 310000, P.R. China
| | - Weiwei Jin
- Department of General Surgery, Cancer Center, Division of Gastrointestinal and Pancreatic Surgery, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang 310000, P.R. China
- Key Laboratory of Gastroenterology of Zhejiang Province, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang 310000, P.R. China
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14
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Blériot C, Dunsmore G, Alonso-Curbelo D, Ginhoux F. A temporal perspective for tumor-associated macrophage identities and functions. Cancer Cell 2024; 42:747-758. [PMID: 38670090 DOI: 10.1016/j.ccell.2024.04.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Revised: 02/13/2024] [Accepted: 04/04/2024] [Indexed: 04/28/2024]
Abstract
Cancer is a progressive disease that can develop and evolve over decades, with inflammation playing a central role at each of its stages, from tumor initiation to metastasis. In this context, macrophages represent well-established bridges reciprocally linking inflammation and cancer via an array of diverse functions that have spurred efforts to classify them into subtypes. Here, we discuss the intertwines between macrophages, inflammation, and cancer with an emphasis on temporal dynamics of macrophage diversity and functions in pre-malignancy and cancer. By instilling temporal dynamism into the more static classic view of tumor-associated macrophage biology, we propose a new framework to better contextualize their significance in the inflammatory processes that precede and result from the onset of cancer and shape its evolution.
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Affiliation(s)
- Camille Blériot
- Gustave Roussy, INSERM, Villejuif, France; Institut Necker des Enfants Malades (INEM), INSERM, CNRS, Université Paris Cité, Paris, France
| | | | - Direna Alonso-Curbelo
- Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain.
| | - Florent Ginhoux
- Gustave Roussy, INSERM, Villejuif, France; Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A∗STAR), Singapore, Singapore; Shanghai Institute of Immunology, Shanghai JiaoTong University School of Medicine, Shanghai, China; Translational Immunology Institute, SingHealth Duke-NUS, Singapore, Singapore.
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15
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Ashaq MS, Zhang S, Xu M, Li Y, Zhao B. The regulatory role of CD36 in hematopoiesis beyond fatty acid uptake. Life Sci 2024; 339:122442. [PMID: 38244916 DOI: 10.1016/j.lfs.2024.122442] [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: 11/20/2023] [Revised: 01/07/2024] [Accepted: 01/15/2024] [Indexed: 01/22/2024]
Abstract
CD36 is a transmembrane glycoprotein, located on surface of numerous cell types. This review is aimed to explore regulatory role of CD36 in hematopoiesis beyond fatty acid uptake. CD36 acts as a pattern recognition receptor, regulates cellular fatty acid homeostasis, and negatively monitors angiogenesis. CD36 also mediates free fatty acid transportation to hematopoietic stem cells in response to infections. During normal physiology and pathophysiology, CD36 significantly participates in the activation and metabolic needs of platelets, macrophages, monocytes, T cells, B cells, and dendritic cells. CD36 has shown a unique relationship with Plasmodium falciparum-infected erythrocytes (PfIEs) as a beneficiary for both parasite and host. CD36 actively participates in pathogenesis of various hematological cancers as a significant prognostic biomarker including AML, HL, and NHL. CD36-targeting antibodies, CD36 antagonists (small molecules), and CD36 expression inhibitors/modulators are used to target CD36, depicting its therapeutic potential. Many preclinical studies or clinical trials were performed to assess CD36 as a therapeutic target; some are still under investigation. This review reflects the role of CD36 in hematopoiesis which requires more consideration in future research.
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Affiliation(s)
- Muhammad Sameer Ashaq
- Key Lab of Chemical Biology (MOE), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China; NMPA Key Laboratory for Technology Research and Evaluation of Drug Products, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China; Department of Pharmacology, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China
| | - Shujing Zhang
- Key Lab of Chemical Biology (MOE), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China; NMPA Key Laboratory for Technology Research and Evaluation of Drug Products, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China; Department of Pharmacology, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China
| | - Miaomiao Xu
- Key Lab of Chemical Biology (MOE), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China; NMPA Key Laboratory for Technology Research and Evaluation of Drug Products, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China; Department of Pharmacology, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China
| | - Yuan Li
- Key Lab of Chemical Biology (MOE), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China; NMPA Key Laboratory for Technology Research and Evaluation of Drug Products, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China; Department of Pharmacology, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China
| | - Baobing Zhao
- Key Lab of Chemical Biology (MOE), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China; NMPA Key Laboratory for Technology Research and Evaluation of Drug Products, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China; Department of Pharmacology, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China.
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16
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Amin R, Ha NH, Qiu T, Holewinski R, Lam KC, Lopès A, Liu H, Tran AD, Lee MP, Gamage ST, Andresson T, Goldszmid RS, Meier JL, Hunter KW. Loss of NAT10 disrupts enhancer organization via p300 mislocalization and suppresses transcription of genes necessary for metastasis progression. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.01.24.577116. [PMID: 38410432 PMCID: PMC10896336 DOI: 10.1101/2024.01.24.577116] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/28/2024]
Abstract
Acetylation of protein and RNA represent a critical event for development and cancer progression. NAT10 is the only known RNA acetylase that catalyzes the N4-actylcytidine (ac4C) modification of RNAs. Here, we show that the loss of NAT10 significantly decreases lung metastasis in allograft and genetically engineered mouse models of breast cancer. NAT10 interacts with a mechanosensitive, metastasis susceptibility protein complex at the nuclear pore. In addition to its canonical role in RNA acetylation, we find that NAT10 interacts with p300 at gene enhancers. NAT10 loss is associated with p300 mislocalization into heterochromatin regions. NAT10 depletion disrupts enhancer organization, leading to alteration of gene transcription necessary for metastatic progression, including reduced myeloid cell-recruiting chemokines that results in a less metastasis-prone tumor microenvironment. Our study uncovers a distinct role of NAT10 in enhancer organization of metastatic tumor cells and suggests its involvement in the tumor-immune crosstalk dictating metastatic outcomes.
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17
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Hao S, Cai D, Gou S, Li Y, Liu L, Tang X, Chen Y, Zhao Y, Shen J, Wu X, Li M, Chen M, Li X, Sun Y, Gu L, Li W, Wang F, Cho CH, Xiao Z, Du F. Does each Component of Reactive Oxygen Species have a Dual Role in the Tumor Microenvironment? Curr Med Chem 2024; 31:4958-4986. [PMID: 37469162 PMCID: PMC11340293 DOI: 10.2174/0929867331666230719142202] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Revised: 05/14/2023] [Accepted: 06/02/2023] [Indexed: 07/21/2023]
Abstract
Reactive oxygen species (ROS) are a class of highly reactive oxidizing molecules, including superoxide anion (O2 •-) and hydrogen peroxide (H2O2), among others. Moderate levels of ROS play a crucial role in regulating cellular signaling and maintaining cellular functions. However, abnormal ROS levels or persistent oxidative stress can lead to changes in the tumor microenvironment (TME) that favor cancer development. This review provides an overview of ROS generation, structure, and properties, as well as their effects on various components of the TME. Contrary to previous studies, our findings reveal a dual effect of ROS on different components of the TME, whereby ROS can either enhance or inhibit certain factors, ultimately leading to the promotion or suppression of the TME. For example, H2O2 has dual effects on immune cells and non-- cellular components within the TME, while O2 •- has dual effects on T cells and fibroblasts. Furthermore, each component demonstrates distinct mechanisms of action and ranges of influence. In the final section of the article, we summarize the current clinical applications of ROS in cancer treatment and identify certain limitations associated with existing therapeutic approaches. Therefore, this review aims to provide a comprehensive understanding of ROS, highlighting their dual effects on different components of the TME, and exploring the potential clinical applications that may pave the way for future treatment and prevention strategies.
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Affiliation(s)
- Siyu Hao
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Sichuan Luzhou 646600, China
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Sichuan Luzhou, 646000, China
| | - Dan Cai
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Sichuan Luzhou 646600, China
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Sichuan Luzhou, 646000, China
- South Sichuan Institute of Translational Medicine, Sichuan Luzhou 646600, China
| | - Shuang Gou
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Sichuan Luzhou 646600, China
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Sichuan Luzhou, 646000, China
| | - Yan Li
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Sichuan Luzhou 646600, China
| | - Lin Liu
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Sichuan Luzhou 646600, China
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Sichuan Luzhou, 646000, China
- South Sichuan Institute of Translational Medicine, Sichuan Luzhou 646600, China
| | - Xiaolong Tang
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Sichuan Luzhou 646600, China
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Sichuan Luzhou, 646000, China
| | - Yu Chen
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Sichuan Luzhou 646600, China
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Sichuan Luzhou, 646000, China
- South Sichuan Institute of Translational Medicine, Sichuan Luzhou 646600, China
| | - Yueshui Zhao
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Sichuan Luzhou 646600, China
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Sichuan Luzhou, 646000, China
- South Sichuan Institute of Translational Medicine, Sichuan Luzhou 646600, China
| | - Jing Shen
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Sichuan Luzhou 646600, China
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Sichuan Luzhou, 646000, China
- South Sichuan Institute of Translational Medicine, Sichuan Luzhou 646600, China
| | - Xu Wu
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Sichuan Luzhou 646600, China
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Sichuan Luzhou, 646000, China
- South Sichuan Institute of Translational Medicine, Sichuan Luzhou 646600, China
| | - Mingxing Li
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Sichuan Luzhou 646600, China
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Sichuan Luzhou, 646000, China
- South Sichuan Institute of Translational Medicine, Sichuan Luzhou 646600, China
| | - Meijuan Chen
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Sichuan Luzhou 646600, China
| | - Xiaobing Li
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Sichuan Luzhou 646600, China
| | - Yuhong Sun
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Sichuan Luzhou 646600, China
| | - Li Gu
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Sichuan Luzhou 646600, China
| | - Wanping Li
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Sichuan Luzhou 646600, China
| | - Fang Wang
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Sichuan Luzhou 646600, China
| | - Chi Hin Cho
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Sichuan Luzhou 646600, China
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China;
| | - Zhangang Xiao
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Sichuan Luzhou 646600, China
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Sichuan Luzhou, 646000, China
- South Sichuan Institute of Translational Medicine, Sichuan Luzhou 646600, China
- Department of Oncology, Affiliated Hospital of Southwest Medical University, Sichuan Luzhou 646600, China
| | - Fukuan Du
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Sichuan Luzhou 646600, China
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Sichuan Luzhou, 646000, China
- South Sichuan Institute of Translational Medicine, Sichuan Luzhou 646600, China
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18
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Bied M, Ho WW, Ginhoux F, Blériot C. Roles of macrophages in tumor development: a spatiotemporal perspective. Cell Mol Immunol 2023; 20:983-992. [PMID: 37429944 PMCID: PMC10468537 DOI: 10.1038/s41423-023-01061-6] [Citation(s) in RCA: 102] [Impact Index Per Article: 51.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2023] [Accepted: 06/16/2023] [Indexed: 07/12/2023] Open
Abstract
Macrophages are critical regulators of tissue homeostasis but are also abundant in the tumor microenvironment (TME). In both primary tumors and metastases, such tumor-associated macrophages (TAMs) seem to support tumor development. While we know that TAMs are the dominant immune cells in the TME, their vast heterogeneity and associated functions are only just being unraveled. In this review, we outline the various known TAM populations found thus far and delineate their specialized roles associated with the main stages of cancer progression. We discuss how macrophages may prime the premetastatic niche to enable the growth of a metastasis and then how subsequent metastasis-associated macrophages can support secondary tumor growth. Finally, we speculate on the challenges that remain to be overcome in TAM research.
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Affiliation(s)
- Mathilde Bied
- Institut Gustave Roussy, INSERM U1015, Villejuif, France
| | - William W Ho
- Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A∗STAR), Singapore, Singapore
| | - Florent Ginhoux
- Institut Gustave Roussy, INSERM U1015, Villejuif, France.
- Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A∗STAR), Singapore, Singapore.
- Shanghai Institute of Immunology, Shanghai JiaoTong University School of Medicine, Shanghai, China.
- Translational Immunology Institute, SingHealth Duke-NUS, Singapore, Singapore.
| | - Camille Blériot
- Institut Gustave Roussy, INSERM U1015, Villejuif, France.
- Institut Necker des Enfants Malades, INSERM, CNRS, Université Paris Cité, Paris, France.
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19
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Wang YN, Wang YY, Wang J, Bai WJ, Miao NJ, Wang J. Vinblastine resets tumor-associated macrophages toward M1 phenotype and promotes antitumor immune response. J Immunother Cancer 2023; 11:e007253. [PMID: 37652576 PMCID: PMC10476141 DOI: 10.1136/jitc-2023-007253] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/15/2023] [Indexed: 09/02/2023] Open
Abstract
BACKGROUND Massive tumor-associated macrophage (TAM) infiltration is observed in many tumors, which usually display the immune-suppressive M2-like phenotype but can also be converted to an M1-like antitumor phenotype due to their high degree of plasticity. The macrophage polarization state is associated with changes in cell shape, macrophage morphology is associated with activation status. M1 macrophages appeared large and rounded, while M2 macrophages were stretched and elongated cells. Manipulating cell morphology has been shown to affect the polarization state of macrophages. The shape of the cell is largely dependent on cytoskeletal proteins, especially, microtubules. As a microtubule-targetting drug, vinblastine (VBL) has been used in chemotherapy. However, no study to date has explored the effect of VBL on TAM shape changes and its role in tumor immune response. METHOD We used fluorescent staining of the cytoskeleton and quantitative analysis to reveal the morphological differences between M0, M1, M2, TAM and VBL-treated TAM. Flow cytometry was used to confirm the polarization states of these macrophages using a cell surface marker-based classification. In vivo antibody depletion experiments in tumor mouse models were performed to test whether macrophages and CD8+ T cell populations were required for the antitumor effect of VBL. VBL and anti-PD-1 combination therapy was then investigated in comparison with monotherapy. RNA-seq of TAM of treated and untreated with VBL was performed to explore the changes in pathway activities. siRNA mediated knockdown experiments were performed to verify the target pathway that was affected by VBL treatment. RESULTS Here, we showed that VBL, an antineoplastic agent that destabilizes microtubule, drove macrophage polarization into the M1-like phenotype both in vitro and in tumor models. The antitumor effect of VBL was attenuated in the absence of macrophages or CD8+ T cells. Mechanistically, VBL induces the activation of NF-κB and Cyba-dependent reactive oxygen species generation, thus polarizing TAMs to the M1 phenotype. In parallel, VBL promotes the nuclear translocation of transcription factor EB, inducing lysosome biogenesis and a dramatic increase in phagocytic activity in macrophages. CONCLUSIONS This study explored whether manipulating cellular morphology affects macrophage polarization and consequently induces an antitumor response. Our data reveal a previously unrecognized antitumor mechanism of VBL and suggest a drug repurposing strategy combining VBL with immune checkpoint inhibitors to improve malignant tumor immunotherapy.
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Affiliation(s)
- Yi-Na Wang
- Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yuan-Yuan Wang
- Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jin Wang
- Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Wen-Juan Bai
- Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Nai-Jun Miao
- Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Center for Immune-related Diseases at Shanghai Institute of Immunology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jing Wang
- Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Center for Immune-related Diseases at Shanghai Institute of Immunology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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20
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Abstract
Tumour cells migrate very early from primary sites to distant sites, and yet metastases often take years to manifest themselves clinically or never even surface within a patient's lifetime. This pause in cancer progression emphasizes the existence of barriers that constrain the growth of disseminated tumour cells (DTCs) at distant sites. Although the nature of these barriers to metastasis might include DTC-intrinsic traits, recent studies have established that the local microenvironment also controls the formation of metastases. In this Perspective, I discuss how site-specific differences of the immune system might be a major selective growth restraint on DTCs, and argue that harnessing tissue immunity will be essential for the next stage in immunotherapy development that reliably prevents the establishment of metastases.
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21
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Sun G, Wang Y, Yang L, Zhang Z, Zhao Y, Shen Z, Han X, Du X, Jin H, Li C, Wang S, Zhang Z, Zhang D. Rebalancing liver-infiltrating CCR3 + and CD206 + monocytes improves diet-induced NAFLD. Cell Rep 2023; 42:112753. [PMID: 37421620 DOI: 10.1016/j.celrep.2023.112753] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Revised: 05/17/2023] [Accepted: 06/21/2023] [Indexed: 07/10/2023] Open
Abstract
Melatonin has been reported to improve nonalcoholic fatty liver disease (NAFLD), and exploring the underlying mechanisms will be beneficial for better treatment of NAFLD. Choline-deficient high-fat diet (CDHFD)- and methionine/choline-deficient diet (MCD)-fed mice with melatonin intervention exhibit significantly decreased liver steatosis, lobular inflammation, and focal liver necrosis. Single-cell RNA sequencing reveals that melatonin selectively inhibits pro-inflammatory CCR3+ monocyte-derived macrophages (MoMFs) and upregulates anti-inflammatory CD206+ MoMFs in NAFLD mice. Liver-infiltrating CCR3+CD14+ MoMFs are also significantly increased in patients with NAFLD. Mechanistically, melatonin receptor-independent BTG2-ATF4 signaling plays a role in the regulation of CCR3+ MoMF endoplasmic reticulum stress, survival, and inflammation. In contrast, melatonin upregulates CD206+ MoMF survival and polarization via MT1/2 receptors. Melatonin stimulation also regulates human CCR3+ MoMF and CD206+ MoMF survival and inflammation in vitro. Furthermore, CCR3 depletion antibody monotherapy inhibits liver inflammation and improves NAFLD in mice. Thus, therapies targeting CCR3+ MoMFs may have potential benefits in NAFLD treatment.
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Affiliation(s)
- Guangyong Sun
- General Surgery Department, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China; Immunology Research Center for Oral and Systemic Health, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China; Beijing Key Laboratory of Tolerance Induction and Organ Protection in Transplantation, Beijing 100050, China; Beijing Clinical Research Institute, Beijing 100050, China; National Clinical Research Center for Digestive Diseases, Beijing 100050, China; Beijing Laboratory of Oral Health, Capital Medical University School of Basic Medicine, Beijing 100069, China
| | - Yaning Wang
- Immunology Research Center for Oral and Systemic Health, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China; Beijing Key Laboratory of Tolerance Induction and Organ Protection in Transplantation, Beijing 100050, China; Beijing Clinical Research Institute, Beijing 100050, China; National Clinical Research Center for Digestive Diseases, Beijing 100050, China
| | - Lu Yang
- General Surgery Department, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
| | - Zihan Zhang
- Immunology Research Center for Oral and Systemic Health, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China; Beijing Key Laboratory of Tolerance Induction and Organ Protection in Transplantation, Beijing 100050, China; Beijing Clinical Research Institute, Beijing 100050, China; National Clinical Research Center for Digestive Diseases, Beijing 100050, China; Beijing Laboratory of Oral Health, Capital Medical University School of Basic Medicine, Beijing 100069, China
| | - Yushang Zhao
- Immunology Research Center for Oral and Systemic Health, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China; Beijing Key Laboratory of Tolerance Induction and Organ Protection in Transplantation, Beijing 100050, China; Beijing Clinical Research Institute, Beijing 100050, China; National Clinical Research Center for Digestive Diseases, Beijing 100050, China; Beijing Laboratory of Oral Health, Capital Medical University School of Basic Medicine, Beijing 100069, China
| | - Zongshan Shen
- Immunology Research Center for Oral and Systemic Health, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China; National Clinical Research Center for Digestive Diseases, Beijing 100050, China
| | - Xiaotong Han
- Immunology Research Center for Oral and Systemic Health, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China; Beijing Key Laboratory of Tolerance Induction and Organ Protection in Transplantation, Beijing 100050, China; Beijing Clinical Research Institute, Beijing 100050, China; National Clinical Research Center for Digestive Diseases, Beijing 100050, China; Beijing Laboratory of Oral Health, Capital Medical University School of Basic Medicine, Beijing 100069, China
| | - Xiaonan Du
- Immunology Research Center for Oral and Systemic Health, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China; Beijing Key Laboratory of Tolerance Induction and Organ Protection in Transplantation, Beijing 100050, China; Beijing Clinical Research Institute, Beijing 100050, China; National Clinical Research Center for Digestive Diseases, Beijing 100050, China; Beijing Laboratory of Oral Health, Capital Medical University School of Basic Medicine, Beijing 100069, China
| | - Hua Jin
- Immunology Research Center for Oral and Systemic Health, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China; Beijing Key Laboratory of Tolerance Induction and Organ Protection in Transplantation, Beijing 100050, China; Beijing Clinical Research Institute, Beijing 100050, China; National Clinical Research Center for Digestive Diseases, Beijing 100050, China; Beijing Laboratory of Oral Health, Capital Medical University School of Basic Medicine, Beijing 100069, China
| | - Changying Li
- Immunology Research Center for Oral and Systemic Health, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China; Beijing Key Laboratory of Tolerance Induction and Organ Protection in Transplantation, Beijing 100050, China; Beijing Clinical Research Institute, Beijing 100050, China; National Clinical Research Center for Digestive Diseases, Beijing 100050, China; Beijing Laboratory of Oral Health, Capital Medical University School of Basic Medicine, Beijing 100069, China
| | - Songlin Wang
- Immunology Research Center for Oral and Systemic Health, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China; National Clinical Research Center for Digestive Diseases, Beijing 100050, China
| | - Zhongtao Zhang
- General Surgery Department, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China; National Clinical Research Center for Digestive Diseases, Beijing 100050, China
| | - Dong Zhang
- General Surgery Department, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China; Immunology Research Center for Oral and Systemic Health, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China; Beijing Key Laboratory of Tolerance Induction and Organ Protection in Transplantation, Beijing 100050, China; Beijing Clinical Research Institute, Beijing 100050, China; National Clinical Research Center for Digestive Diseases, Beijing 100050, China; Beijing Laboratory of Oral Health, Capital Medical University School of Basic Medicine, Beijing 100069, China.
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22
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Arena GO, Forte S, Abdouh M, Vanier C, Corbeil D, Lorico A. Horizontal Transfer of Malignant Traits and the Involvement of Extracellular Vesicles in Metastasis. Cells 2023; 12:1566. [PMID: 37371036 PMCID: PMC10297028 DOI: 10.3390/cells12121566] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2023] [Revised: 05/31/2023] [Accepted: 06/02/2023] [Indexed: 06/29/2023] Open
Abstract
Metastases are responsible for the vast majority of cancer deaths, yet most therapeutic efforts have focused on targeting and interrupting tumor growth rather than impairing the metastatic process. Traditionally, cancer metastasis is attributed to the dissemination of neoplastic cells from the primary tumor to distant organs through blood and lymphatic circulation. A thorough understanding of the metastatic process is essential to develop new therapeutic strategies that improve cancer survival. Since Paget's original description of the "Seed and Soil" hypothesis over a hundred years ago, alternative theories and new players have been proposed. In particular, the role of extracellular vesicles (EVs) released by cancer cells and their uptake by neighboring cells or at distinct anatomical sites has been explored. Here, we will outline and discuss these alternative theories and emphasize the horizontal transfer of EV-associated biomolecules as a possibly major event leading to cell transformation and the induction of metastases. We will also highlight the recently discovered intracellular pathway used by EVs to deliver their cargoes into the nucleus of recipient cells, which is a potential target for novel anti-metastatic strategies.
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Affiliation(s)
- Goffredo O. Arena
- Department of Surgery, McGill University, Montréal, QC H3A 0G4, Canada;
- Fondazione Istituto G. Giglio, 90015 Cefalù, Italy
- Mediterranean Institute of Oncology, 95029 Viagrande, Italy;
| | - Stefano Forte
- Mediterranean Institute of Oncology, 95029 Viagrande, Italy;
| | - Mohamed Abdouh
- Cancer Research Program, Research Institute, McGill University Health Centre, Montréal, QC H3A 0G4, Canada;
| | - Cheryl Vanier
- Touro University Nevada College of Medicine, Henderson, NV 89014, USA;
| | - Denis Corbeil
- Biotechnology Center (BIOTEC) and Center for Molecular and Cellular Bioengineering, Technische Universität Dresden, 01307 Dresden, Germany;
| | - Aurelio Lorico
- Mediterranean Institute of Oncology, 95029 Viagrande, Italy;
- Touro University Nevada College of Medicine, Henderson, NV 89014, USA;
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23
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Wu C, Zhong Q, Shrestha R, Wang J, Hu X, Li H, Rouchka EC, Yan J, Ding C. Reactive myelopoiesis and FX-expressing macrophages triggered by chemotherapy promote cancer lung metastasis. JCI Insight 2023; 8:e167499. [PMID: 36976637 PMCID: PMC10243818 DOI: 10.1172/jci.insight.167499] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Accepted: 03/22/2023] [Indexed: 03/29/2023] Open
Abstract
Several preclinical studies have demonstrated that certain cytotoxic drugs enhance metastasis, but the importance of host responses triggered by chemotherapy in regulating cancer metastasis has not been fully explored. Here, we showed that multidose gemcitabine (GEM) treatment promoted breast cancer lung metastasis in a transgenic spontaneous breast cancer model. GEM treatment significantly increased accumulation of CCR2+ macrophages and monocytes in the lungs of tumor-bearing as well as tumor-free mice. These changes were largely caused by chemotherapy-induced reactive myelopoiesis biased toward monocyte development. Mechanistically, enhanced production of mitochondrial ROS was observed in GEM-treated BM Lin-Sca1+c-Kit+ cells and monocytes. Treatment with the mitochondria targeted antioxidant abrogated GEM-induced hyperdifferentiation of BM progenitors. In addition, GEM treatment induced upregulation of host cell-derived CCL2, and knockout of CCR2 signaling abrogated the pro-metastatic host response induced by chemotherapy. Furthermore, chemotherapy treatment resulted in the upregulation of coagulation factor X (FX) in lung interstitial macrophages. Targeting activated FX (FXa) using FXa inhibitor or F10 gene knockdown reduced the pro-metastatic effect of chemotherapy. Together, these studies suggest a potentially novel mechanism for chemotherapy-induced metastasis via the host response-induced accumulation of monocytes/macrophages and interplay between coagulation and inflammation in the lungs.
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Affiliation(s)
- Caijun Wu
- UofL Health - Brown Cancer Center and
| | | | - Rejeena Shrestha
- Department of Microbiology and Immunology, University of Louisville School of Medicine, Louisville, Kentucky, USA
| | | | | | - Hong Li
- UofL Health - Brown Cancer Center and
| | - Eric C. Rouchka
- Department of Computer Science and Engineering, University of Louisville J.B. Speed School of Engineering, Louisville, Kentucky, USA
| | - Jun Yan
- UofL Health - Brown Cancer Center and
- Department of Microbiology and Immunology, University of Louisville School of Medicine, Louisville, Kentucky, USA
- Department of Surgery, Division of Immunotherapy, UofL Health - Brown Cancer Center, University of Louisville School of Medicine, Louisville, Kentucky, USA
| | - Chuanlin Ding
- UofL Health - Brown Cancer Center and
- Department of Surgery, Division of Immunotherapy, UofL Health - Brown Cancer Center, University of Louisville School of Medicine, Louisville, Kentucky, USA
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24
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The Chemokine Receptor CCR1 Mediates Microglia Stimulated Glioma Invasion. Int J Mol Sci 2023; 24:ijms24065136. [PMID: 36982211 PMCID: PMC10049042 DOI: 10.3390/ijms24065136] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Revised: 02/22/2023] [Accepted: 03/02/2023] [Indexed: 03/10/2023] Open
Abstract
Glioblastoma multiforme (GBM) is the most aggressive form of adult brain tumor which is highly resistant to conventional treatment and therapy. Glioma cells are highly motile resulting in infiltrative tumors with poorly defined borders. Another hallmark of GBM is a high degree of tumor macrophage/microglia infiltration. The level of these tumor-associated macrophages/microglia (TAMs) correlates with higher malignancy and poorer prognosis. We previously demonstrated that inhibition of TAM infiltration into glioma tumors with the CSF-1R antagonist pexidartinib (PLX3397) can inhibit glioma cell invasion in-vitro and in-vivo. In this study, we demonstrate an important role for the chemokine receptor CCR1 in mediating microglia/TAM stimulated glioma invasion. Using two structurally distinct CCR1 antagonists, including a novel inhibitor “MG-1-5”, we were able to block microglial activated GL261 glioma cell invasion in a dose dependent manner. Interestingly, treatment of a murine microglia cell line with glioma conditioned media resulted in a strong induction of CCR1 gene and protein expression. This induction was attenuated by inhibition of CSF-1R. In addition, glioma conditioned media treatment of microglia resulted in a rapid upregulation of gene expression of several CCR1 ligands including CCL3, CCL5, CCL6 and CCL9. These data support the existence of tumor stimulated autocrine loop within TAMs which ultimately mediates tumor cell invasion.
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25
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Jain N, Srinivasarao DA, Famta P, Shah S, Vambhurkar G, Shahrukh S, Singh SB, Srivastava S. The portrayal of macrophages as tools and targets: A paradigm shift in cancer management. Life Sci 2023; 316:121399. [PMID: 36646378 DOI: 10.1016/j.lfs.2023.121399] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Revised: 01/02/2023] [Accepted: 01/12/2023] [Indexed: 01/15/2023]
Abstract
Macrophages play a major role in maintaining an organism's physiology, such as development, homeostasis, tissue repair, and immunity. These immune cells are known to be involved in tumor progression and modulation. Monocytes can be polarized to two types of macrophages (M1 macrophages and pro-tumor M2 macrophages). Through this article, we aim to emphasize the potential of targeting macrophages in order to improve current strategies for tumor management. Various strategies that target macrophages as a therapeutic target have been discussed along with ongoing clinical trials. We have discussed the role of macrophages in various stages of tumor progression epithelial-to-mesenchymal transition (EMT), invasion, maintaining the stability of circulating tumor cells (CTCs) in blood, and establishing a premetastatic niche along with the role of various cytokines and chemokines involved in these processes. Intriguingly macrophages can also serve as drug carriers due to their tumor tropism along the chemokine gradient. They surpass currently explored nanotherapeutics in tumor accumulation and circulation half-life. We have emphasized on macrophage-based biomimetic formulations and macrophage-hitchhiking as a strategy to effectively target tumors. We firmly believe that targeting macrophages or utilizing them as an indigenous carrier system could transform cancer management.
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Affiliation(s)
- Naitik Jain
- Pharmaceutical Innovation and Translational Research Lab (PITRL), Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, India
| | - Dadi A Srinivasarao
- Pharmaceutical Innovation and Translational Research Lab (PITRL), Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, India
| | - Paras Famta
- Pharmaceutical Innovation and Translational Research Lab (PITRL), Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, India
| | - Saurabh Shah
- Pharmaceutical Innovation and Translational Research Lab (PITRL), Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, India
| | - Ganesh Vambhurkar
- Pharmaceutical Innovation and Translational Research Lab (PITRL), Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, India
| | - Syed Shahrukh
- Pharmaceutical Innovation and Translational Research Lab (PITRL), Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, India
| | - Shashi Bala Singh
- Department of Biological Sciences, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, India
| | - Saurabh Srivastava
- Pharmaceutical Innovation and Translational Research Lab (PITRL), Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, India.
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26
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Dioscin modulates macrophages polarization and MDSCs differentiation to inhibit tumorigenesis of colitis-associated colorectal cancer. Int Immunopharmacol 2023; 117:109839. [PMID: 36809720 DOI: 10.1016/j.intimp.2023.109839] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Revised: 01/17/2023] [Accepted: 01/30/2023] [Indexed: 02/22/2023]
Abstract
It has been reported that colitis is one of risk factors in colorectal cancer (CRC). Intervention of intestinal inflammation and in the early stage of tumorigenesis is of great significance to control the incidence and mortality of CRC. In recent years, natural active products of traditional Chinese medicine have been confirmed that they had made great progress in disease prevention. Here, we showed that Dioscin, a natural active product of Dioscorea nipponica Makino, inhibited initiation and tumorigenesis of AOM/DSS-induced colitis-associated colon cancer (CAC), including alleviating colonic inflammation, improving intestinal barrier function and decreasing tumor burden. In addition, we also explored the immunoregulatory effect of Dioscin on mice. The results showed that Dioscin modulated M1/M2 macrophages phenotype in spleen and decreased monocytic myeloid-derived suppressor cells (M-MDSCs) population in blood and spleen of mice. The in vitro assay demonstrated that Dioscin promoted M1 as well as inhibited M2 macrophages phenotype in LPS- or IL-4-induced bone marrow-derived macrophages (BMDMs) model. Based on the plasticity of MDSCs and its ability to differentiate into M1/M2 macrophages, we here found that Dioscin increased M1- and decreased M2-like phenotype during the process of MDSCs differentiation in vitro, suggesting Dioscin promoted MDSCs differentiate into M1 as well as inhibited its differentiation into M2 macrophages. Taken together, our study indicated that Dioscin had the inhibitory effect on the initial of tumorigenesis at early stage of CAC via the ant-inflammatory effect, which provided a natural active candidate for effective prevention of CAC.
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27
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Abstract
Tumour progression is modulated by the local microenvironment. This environment is populated by many immune cells, of which macrophages are among the most abundant. Clinical correlative data and a plethora of preclinical studies in mouse models of cancers have shown that tumour-associated macrophages (TAMs) play a cancer-promoting role. Within the primary tumour, TAMs promote tumour cell invasion and intravasation and tumour stem cell viability and induce angiogenesis. At the metastatic site, metastasis-associated macrophages promote extravasation, tumour cell survival and persistent growth, as well as maintain tumour cell dormancy in some contexts. In both the primary and metastatic sites, TAMs are suppressive to the activities of cytotoxic T and natural killer cells that have the potential to eradicate tumours. Such activities suggest that TAMs will be a major target for therapeutic intervention. In this Perspective article, we chronologically explore the evolution of our understanding of TAM biology put into the context of major enabling advances in macrophage biology.
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Affiliation(s)
| | - Jeffrey W Pollard
- MRC-Centre for Reproductive Health, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK.
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28
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Ye K, Xiao M, Li Z, He K, Wang J, Zhu L, Xiong W, Zhong Z, Tang Y. Preoperative systemic inflammation response index is an independent prognostic marker for BCG immunotherapy in patients with non-muscle-invasive bladder cancer. Cancer Med 2023; 12:4206-4217. [PMID: 36214475 PMCID: PMC9972176 DOI: 10.1002/cam4.5284] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Revised: 08/26/2022] [Accepted: 09/12/2022] [Indexed: 12/09/2022] Open
Abstract
BACKGROUND The Systemic Inflammatory Response Index (SIRI) is a novel prognostic biomarker based on peripheral blood counts of neutrophils, monocytes, and lymphocytes. Recent evidence suggests that it is associated with poor prognosis in various cancers. However, the predictive value of the SIRI in non-muscle-invasive bladder cancer (NMIBC) patients treated with intravesical Bacillus Calmette-Guerin (BCG) immunotherapy remains elusive. Therefore, this study aimed to evaluate the potential of SIRI as a prognostic factor in these patients. METHODS A total of 540 patients with NMIBC who underwent BCG immunotherapy following transurethral resection of bladder tumor (TURBT) were enrolled in this study. Using receiver operating characteristic (ROC) curves and the Youden index, patients were divided into high and low SIRI groups based on the cutoff values. Univariable and multivariable logistic regression analyses were performed to identify independent predictors of BCG non-response. Thereafter, propensity score matching (PSM) was used to eliminate bias due to confounding factors between the low and high SIRI groups. Finally, the Kaplan-Meier method was used to compare recurrence-free survival (RFS) and progression-free survival (PFS) between the two groups. RESULTS Multivariable logistic regression analysis revealed that high SIRI (p = 0.001), high MLR (p = 0.015), and high tumor pathological T stage (p = 0.015) were significantly correlated with non-response to BCG therapy. In addition, both RFS and PFS were shorter in the high SIRI group than in the other group before and after PSM (both p < 0.05). Collectively, our results indicate that the combination of tumor pathological T staging and the SIRI can enhance the predictive power of BCG response. CONCLUSION Pretreatment peripheral blood SIRI can be employed to predict the response to BCG immunotherapy and the prognosis of NMIBC patients. Taken together, the combination of T stage and SIRI demonstrated robust performance in predicting the response to BCG immunotherapy in NMIBC patients.
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Affiliation(s)
- Kun Ye
- Department of Urology, The Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai, Guangdong, China.,Guangdong Provincial Key Laboratory of Biomedical Imaging, The Fifth Affiliated Hospital, Sun Yat-Sen University, Zhuhai, Guangdong, China
| | - Ming Xiao
- Department of Urology, The Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai, Guangdong, China.,Guangdong Provincial Key Laboratory of Biomedical Imaging, The Fifth Affiliated Hospital, Sun Yat-Sen University, Zhuhai, Guangdong, China
| | - Zitaiyu Li
- Department of Urology, The Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai, Guangdong, China.,Guangdong Provincial Key Laboratory of Biomedical Imaging, The Fifth Affiliated Hospital, Sun Yat-Sen University, Zhuhai, Guangdong, China
| | - Kancheng He
- Department of Urology, The Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai, Guangdong, China.,Guangdong Provincial Key Laboratory of Biomedical Imaging, The Fifth Affiliated Hospital, Sun Yat-Sen University, Zhuhai, Guangdong, China
| | - Jinhua Wang
- Department of Urology, The Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai, Guangdong, China.,Guangdong Provincial Key Laboratory of Biomedical Imaging, The Fifth Affiliated Hospital, Sun Yat-Sen University, Zhuhai, Guangdong, China
| | - Liang Zhu
- Department of Urology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Wei Xiong
- Department of Urology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Zhaohui Zhong
- Department of Urology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Yuxin Tang
- Department of Urology, The Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai, Guangdong, China.,Guangdong Provincial Key Laboratory of Biomedical Imaging, The Fifth Affiliated Hospital, Sun Yat-Sen University, Zhuhai, Guangdong, China
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29
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Guerrero-Rodríguez SL, Mata-Cruz C, Pérez-Tapia SM, Velasco-Velázquez MA. Role of CD36 in cancer progression, stemness, and targeting. Front Cell Dev Biol 2022; 10:1079076. [PMID: 36568966 PMCID: PMC9772993 DOI: 10.3389/fcell.2022.1079076] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Accepted: 11/24/2022] [Indexed: 12/14/2022] Open
Abstract
CD36 is highly expressed in diverse tumor types and its expression correlates with advanced stages, poor prognosis, and reduced survival. In cancer cells, CD36: 1) increases fatty acid uptake, reprogramming lipid metabolism; 2) favors cancer cell proliferation, and 3) promotes epithelial-mesenchymal transition. Furthermore, CD36 expression correlates with the expression of cancer stem cell markers and CD36+ cancer cells display increased stemness functional properties, including clonogenicity, chemo- and radioresistance, and metastasis-initiating capability, suggesting CD36 is a marker of the cancer stem cell population. Thus, CD36 has been pointed as a potential therapeutic target in cancer. At present, at least three different types of molecules have been developed for reducing CD36-mediated functions: blocking monoclonal antibodies, small-molecule inhibitors, and compounds that knock-down CD36 expression. Herein, we review the role of CD36 in cancer progression, its participation in stemness control, as well as the efficacy of reported CD36 inhibitors in cancer cell cultures and animal models. Overall, the evidence compiled points that CD36 is a valid target for the development of new anti-cancer therapies.
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Affiliation(s)
| | - Cecilia Mata-Cruz
- Pharmacology Department, School of Medicine, Universidad Nacional Autónoma de México, Mexico City, Mexico
- Graduate Program in Biochemical Sciences, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Sonia M. Pérez-Tapia
- Research and Development in Biotherapeutics Unit, National School of Biological Sciences, National Polytechnic Institute, Mexico City, Mexico
- National Laboratory for Specialized Services of Investigation Development and Innovation (I+D+i) for Pharma Chemicals and Biotechnological products LANSEIDI-FarBiotec-CONACyT, Mexico City, Mexico
- Immunology Department, National School of Biological Sciences, National Polytechnic Institute, Mexico City, Mexico
| | - Marco A. Velasco-Velázquez
- Pharmacology Department, School of Medicine, Universidad Nacional Autónoma de México, Mexico City, Mexico
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30
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Sun L, Han X, Egeblad M. Isolation of mouse mammary carcinoma-derived macrophages and cancer cells for co-culture assays. STAR Protoc 2022; 3:101833. [PMID: 36386879 PMCID: PMC9664409 DOI: 10.1016/j.xpro.2022.101833] [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] [Indexed: 11/11/2022] Open
Abstract
We recently established an in vitro co-culture system in which monophosphoryl lipid A + interferon-γ (MPLA+IFNγ)-treated tumor-associated macrophages (TAMs) killed cancer cells. Here, we describe a step-by-step protocol for isolating TAMs and cancer cells from mouse primary mammary carcinomas, the setup of the co-culture system, and the image acquisition approach. The technical difficulties in the co-culture assay involve isolating pure TAMs and cancer cells from the same tumor and staining them with different dyes to track the macrophages' tumoricidal activity. For complete details on the use and execution of this protocol, please refer to Sun et al. (2021).1.
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Affiliation(s)
- Lijuan Sun
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA,Corresponding author
| | - Xiao Han
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA,Graduate Program in Genetics, Stony Brook University, Stony Brook, NY 11794, USA
| | - Mikala Egeblad
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA,Corresponding author
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31
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Jungles KM, Holcomb EA, Pearson AN, Jungles KR, Bishop CR, Pierce LJ, Green MD, Speers CW. Updates in combined approaches of radiotherapy and immune checkpoint inhibitors for the treatment of breast cancer. Front Oncol 2022; 12:1022542. [PMID: 36387071 PMCID: PMC9643771 DOI: 10.3389/fonc.2022.1022542] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2022] [Accepted: 09/27/2022] [Indexed: 12/05/2022] Open
Abstract
Breast cancer is the most prevalent non-skin cancer diagnosed in females and developing novel therapeutic strategies to improve patient outcomes is crucial. The immune system plays an integral role in the body’s response to breast cancer and modulating this immune response through immunotherapy is a promising therapeutic option. Although immune checkpoint inhibitors were recently approved for the treatment of breast cancer patients, not all patients respond to immune checkpoint inhibitors as a monotherapy, highlighting the need to better understand the biology underlying patient response. Additionally, as radiotherapy is a critical component of breast cancer treatment, understanding the interplay of radiation and immune checkpoint inhibitors will be vital as recent studies suggest that combined therapies may induce synergistic effects in preclinical models of breast cancer. This review will discuss the mechanisms supporting combined approaches with radiotherapy and immune checkpoint inhibitors for the treatment of breast cancer. Moreover, this review will analyze the current clinical trials examining combined approaches of radiotherapy, immunotherapy, chemotherapy, and targeted therapy. Finally, this review will evaluate data regarding treatment tolerance and potential biomarkers for these emerging therapies aimed at improving breast cancer outcomes.
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Affiliation(s)
- Kassidy M. Jungles
- Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, United States
- Rogel Cancer Center, University of Michigan, Ann Arbor, MI, United States
- Department of Pharmacology, University of Michigan, Ann Arbor, MI, United States
| | - Erin A. Holcomb
- Graduate Program in Immunology, University of Michigan Medical School, Ann Arbor, MI, United States
| | - Ashley N. Pearson
- Graduate Program in Immunology, University of Michigan Medical School, Ann Arbor, MI, United States
| | - Kalli R. Jungles
- Department of Biology, Saint Mary’s College, Notre Dame, IN, United States
| | - Caroline R. Bishop
- Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, United States
| | - Lori J. Pierce
- Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, United States
- Rogel Cancer Center, University of Michigan, Ann Arbor, MI, United States
| | - Michael D. Green
- Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, United States
- Rogel Cancer Center, University of Michigan, Ann Arbor, MI, United States
- Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI, United States
- Department of Radiation Oncology, Veterans Affairs Ann Arbor Healthcare System, Ann Arbor, MI, United States
- *Correspondence: Michael D. Green, ; Corey W. Speers,
| | - Corey W. Speers
- Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, United States
- Rogel Cancer Center, University of Michigan, Ann Arbor, MI, United States
- Department of Radiation Oncology, University Hospitals Cleveland Medical Center, Case Western Reserve University, Case Comprehensive Cancer Center, Cleveland, OH, United States
- *Correspondence: Michael D. Green, ; Corey W. Speers,
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32
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Tommasi C, Pellegrino B, Diana A, Palafox Sancez M, Orditura M, Scartozzi M, Musolino A, Solinas C. The Innate Immune Microenvironment in Metastatic Breast Cancer. J Clin Med 2022; 11:jcm11205986. [PMID: 36294305 PMCID: PMC9604853 DOI: 10.3390/jcm11205986] [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: 08/05/2022] [Revised: 09/27/2022] [Accepted: 10/09/2022] [Indexed: 11/30/2022] Open
Abstract
The immune system plays a fundamental role in neoplastic disease. In the era of immunotherapy, the adaptive immune response has been in the spotlight whereas the role of innate immunity in cancer development and progression is less known. The tumor microenvironment influences the terminal differentiation of innate immune cells, which can explicate their pro-tumor or anti-tumor effect. Different cells are able to recognize and eliminate no self and tumor cells: macrophages, natural killer cells, monocytes, dendritic cells, and neutrophils are, together with the elements of the complement system, the principal players of innate immunity in cancer development and evolution. Metastatic breast cancer is a heterogeneous disease from the stromal, immune, and biological point of view and requires deepened exploration to understand different patient outcomes. In this review, we summarize the evidence about the role of innate immunity in breast cancer metastatic sites and the potential targets for optimizing the innate response as a novel treatment opportunity.
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Affiliation(s)
- Chiara Tommasi
- Medical Oncology and Breast Unit, University Hospital of Parma, 43126 Parma, Italy
- Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy
- GOIRC (Gruppo Oncologico Italiano di Ricerca Clinica), 43126 Parma, Italy
- Correspondence:
| | - Benedetta Pellegrino
- Medical Oncology and Breast Unit, University Hospital of Parma, 43126 Parma, Italy
- Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy
- GOIRC (Gruppo Oncologico Italiano di Ricerca Clinica), 43126 Parma, Italy
| | - Anna Diana
- Medical Oncology Unit, Ospedale del Mare, 80147 Naples, Italy
| | - Marta Palafox Sancez
- Tumor Heterogeneity, Metastasis and Resistance Laboratory, University of Basel, 4001 Basel, Switzerland
| | - Michele Orditura
- Division of Medical Oncology, Department of Precision Medicine, University of Campania Luigi Vanvitelli, 80131 Naples, Italy
| | - Mario Scartozzi
- Medical Oncology Department, University of Cagliari, 09042 Cagliari, Italy
| | - Antonino Musolino
- Medical Oncology and Breast Unit, University Hospital of Parma, 43126 Parma, Italy
- Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy
- GOIRC (Gruppo Oncologico Italiano di Ricerca Clinica), 43126 Parma, Italy
| | - Cinzia Solinas
- Medical Oncology Department, University of Cagliari, 09042 Cagliari, Italy
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Barth ND, Van Dalen FJ, Karmakar U, Bertolini M, Mendive‐Tapia L, Kitamura T, Verdoes M, Vendrell M. Enzyme-Activatable Chemokine Conjugates for In Vivo Targeting of Tumor-Associated Macrophages. ANGEWANDTE CHEMIE (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2022; 134:e202207508. [PMID: 38505293 PMCID: PMC10946784 DOI: 10.1002/ange.202207508] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 05/21/2022] [Indexed: 03/21/2024]
Abstract
Increased levels of tumor-associated macrophages (TAMs) are indicators of poor prognosis in most cancers. Although antibodies and small molecules blocking the recruitment of macrophages to tumors are under evaluation as anticancer therapies, these strategies are not specific for macrophage subpopulations. Herein we report the first enzyme-activatable chemokine conjugates for effective targeting of defined macrophage subsets in live tumors. Our constructs exploit the high expression of chemokine receptors (e.g., CCR2) and the activity of cysteine cathepsins in TAMs to target these cells selectively over other macrophages and immune cells (e.g., neutrophils, T cells, B cells). Furthermore, we demonstrate that cathepsin-activatable chemokines are compatible with both fluorescent and therapeutic cargos, opening new avenues in the design of targeted theranostic probes for immune cells in the tumor microenvironment.
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Affiliation(s)
- Nicole D. Barth
- Centre for Inflammation ResearchUniversity of EdinburghUK
- Cancer Research UK Edinburgh CentreUniversity of EdinburghUK
| | - Floris J. Van Dalen
- Dept. Tumor Immunology and Institute for Chemical ImmunologyRadboud Institute for Molecular Life SciencesRadboud University Medical CenterThe Netherlands
| | - Utsa Karmakar
- Centre for Inflammation ResearchUniversity of EdinburghUK
| | | | | | | | - Martijn Verdoes
- Dept. Tumor Immunology and Institute for Chemical ImmunologyRadboud Institute for Molecular Life SciencesRadboud University Medical CenterThe Netherlands
| | - Marc Vendrell
- Centre for Inflammation ResearchUniversity of EdinburghUK
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Barth ND, Van Dalen FJ, Karmakar U, Bertolini M, Mendive‐Tapia L, Kitamura T, Verdoes M, Vendrell M. Enzyme-Activatable Chemokine Conjugates for In Vivo Targeting of Tumor-Associated Macrophages. Angew Chem Int Ed Engl 2022; 61:e202207508. [PMID: 35993914 PMCID: PMC9826351 DOI: 10.1002/anie.202207508] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2022] [Indexed: 01/11/2023]
Abstract
Increased levels of tumor-associated macrophages (TAMs) are indicators of poor prognosis in most cancers. Although antibodies and small molecules blocking the recruitment of macrophages to tumors are under evaluation as anticancer therapies, these strategies are not specific for macrophage subpopulations. Herein we report the first enzyme-activatable chemokine conjugates for effective targeting of defined macrophage subsets in live tumors. Our constructs exploit the high expression of chemokine receptors (e.g., CCR2) and the activity of cysteine cathepsins in TAMs to target these cells selectively over other macrophages and immune cells (e.g., neutrophils, T cells, B cells). Furthermore, we demonstrate that cathepsin-activatable chemokines are compatible with both fluorescent and therapeutic cargos, opening new avenues in the design of targeted theranostic probes for immune cells in the tumor microenvironment.
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Affiliation(s)
- Nicole D. Barth
- Centre for Inflammation ResearchUniversity of EdinburghUK
- Cancer Research UK Edinburgh CentreUniversity of EdinburghUK
| | - Floris J. Van Dalen
- Dept. Tumor Immunology and Institute for Chemical ImmunologyRadboud Institute for Molecular Life SciencesRadboud University Medical CenterThe Netherlands
| | - Utsa Karmakar
- Centre for Inflammation ResearchUniversity of EdinburghUK
| | | | | | | | - Martijn Verdoes
- Dept. Tumor Immunology and Institute for Chemical ImmunologyRadboud Institute for Molecular Life SciencesRadboud University Medical CenterThe Netherlands
| | - Marc Vendrell
- Centre for Inflammation ResearchUniversity of EdinburghUK
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35
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Loh AHP, Angelina C, Wong MK, Tan SH, Sukhatme SA, Yeo T, Lim SB, Lee YT, Soh SY, Leung W, Chang KTE, Chua YW, Alkaff SMF, Lim TKH, Lim CT, Chen ZX. Pro-metastatic and mesenchymal gene expression signatures characterize circulating tumor cells of neuroblastoma patients with bone marrow metastases and relapse. Front Oncol 2022; 12:939460. [PMID: 36176417 PMCID: PMC9513238 DOI: 10.3389/fonc.2022.939460] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Accepted: 08/12/2022] [Indexed: 11/13/2022] Open
Abstract
Existing marker-based methods of minimal residual disease (MRD) determination in neuroblastoma do not effectively enrich for the circulating disease cell population. Given the relative size differential of neuroblastoma tumor cells over normal hematogenous cells, we hypothesized that cell size-based separation could enrich circulating tumor cells (CTCs) from blood samples and disseminated tumor cells (DTCs) from bone marrow aspirates (BMA) of neuroblastoma patients, and that their gene expression profiles could vary dynamically with various disease states over the course of treatment. Using a spiral microfluidic chip, peripheral blood of 17 neuroblastoma patients at 3 serial treatment timepoints (diagnosis, n=17; post-chemotherapy, n=11; and relapse, n=3), and bone marrow samples at diagnosis were enriched for large intact circulating cells. Profiling the resulting enriched samples with immunohistochemistry and mRNA expression of 1490 cancer-related genes via NanoString, 13 of 17 samples contained CTCs displaying cytologic atypia, TH and PHOX2B expression and/or upregulation of cancer-associated genes. Gene signatures reflecting pro-metastatic processes and the neuroblastoma mesenchymal super-enhancer state were consistently upregulated in 7 of 13 samples, 6 of which also had metastatic high-risk disease. Expression of 8 genes associated with PI3K and GCPR signaling were significantly upregulated in CTCs of patients with bone marrow metastases versus patients without. Correspondingly, in patients with marrow metastases, differentially-expressed gene signatures reflected upregulation of immune regulation in bone marrow DTCs versus paired CTCs samples. In patients who later developed disease relapse, 5 genes involved in immune cell regulation, JAK/STAT signaling and the neuroblastoma mesenchymal super-enhancer state (OLFML2B, STAT1, ARHGDIB, STAB1, TLR2) were upregulated in serial CTC samples over their disease course, despite urinary catecholamines and bone marrow aspirates not indicating the disease recurrences. In summary, using a label-free cell size-based separation method, we enriched and characterized intact circulating cells in peripheral blood indicative of neuroblastoma CTCs, as well as their DTC counterparts in the bone marrow. Expression profiles of pro-metastatic genes in CTCs correlated with the presence of bone marrow metastases at diagnosis, while longitudinal profiling identified persistently elevated expression of genes in CTCs that may serve as novel predictive markers of hematogenous MRD in neuroblastoma patients that subsequently relapse.
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Affiliation(s)
- Amos H. P. Loh
- VIVA-KKH Paediatric Brain and Solid Tumour Programme, Children’s Blood and Cancer Centre, KK Women’s and Children’s Hospital, Singapore, Singapore
- Department of Paediatric Surgery, KK Women’s and Children’s Hospital, Singapore, Singapore
- Duke NUS Medical School, Singapore, Singapore
| | - Clara Angelina
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Meng Kang Wong
- VIVA-KKH Paediatric Brain and Solid Tumour Programme, Children’s Blood and Cancer Centre, KK Women’s and Children’s Hospital, Singapore, Singapore
| | - Sheng Hui Tan
- VIVA-KKH Paediatric Brain and Solid Tumour Programme, Children’s Blood and Cancer Centre, KK Women’s and Children’s Hospital, Singapore, Singapore
| | - Sarvesh A. Sukhatme
- Mechanobiology Institute of Singapore, National University of Singapore, Singapore, Singapore
| | - Trifanny Yeo
- Department of Biomedical Engineering, National University of Singapore, Singapore, Singapore
| | - Su Bin Lim
- Department of Biomedical Engineering, National University of Singapore, Singapore, Singapore
- NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore, Singapore
| | - York Tien Lee
- VIVA-KKH Paediatric Brain and Solid Tumour Programme, Children’s Blood and Cancer Centre, KK Women’s and Children’s Hospital, Singapore, Singapore
- Department of Paediatric Surgery, KK Women’s and Children’s Hospital, Singapore, Singapore
- Duke NUS Medical School, Singapore, Singapore
| | - Shui Yen Soh
- VIVA-KKH Paediatric Brain and Solid Tumour Programme, Children’s Blood and Cancer Centre, KK Women’s and Children’s Hospital, Singapore, Singapore
- Duke NUS Medical School, Singapore, Singapore
- Department of Paediatric Subspecialties Haematology/Oncology Service, KK Women’s and Children’s Hospital, Singapore, Singapore
| | - Wing Leung
- VIVA-KKH Paediatric Brain and Solid Tumour Programme, Children’s Blood and Cancer Centre, KK Women’s and Children’s Hospital, Singapore, Singapore
- Duke NUS Medical School, Singapore, Singapore
- Department of Paediatric Subspecialties Haematology/Oncology Service, KK Women’s and Children’s Hospital, Singapore, Singapore
| | - Kenneth T. E. Chang
- VIVA-KKH Paediatric Brain and Solid Tumour Programme, Children’s Blood and Cancer Centre, KK Women’s and Children’s Hospital, Singapore, Singapore
- Duke NUS Medical School, Singapore, Singapore
- Department of Pathology and Laboratory Medicine, KK Women’s and Children’s Hospital, Singapore, Singapore
| | - Yong Wei Chua
- Department of Anatomic Pathology, Singapore General Hospital, Singapore, Singapore
| | - Syed M. F. Alkaff
- Department of Anatomic Pathology, Singapore General Hospital, Singapore, Singapore
| | - Tony K. H. Lim
- Duke NUS Medical School, Singapore, Singapore
- Department of Anatomic Pathology, Singapore General Hospital, Singapore, Singapore
| | - Chwee Teck Lim
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Mechanobiology Institute of Singapore, National University of Singapore, Singapore, Singapore
- Department of Biomedical Engineering, National University of Singapore, Singapore, Singapore
- Institute of Health Innovation and Technology, National University of Singapore, Singapore, Singapore
| | - Zhi Xiong Chen
- VIVA-KKH Paediatric Brain and Solid Tumour Programme, Children’s Blood and Cancer Centre, KK Women’s and Children’s Hospital, Singapore, Singapore
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- National University Cancer Institute, National University Health System, Singapore, Singapore
- NUS Centre for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- *Correspondence: Zhi Xiong Chen,
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36
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Rodriguez-Tirado C, Entenberg D, Li J, Qian BZ, Condeelis JS, Pollard JW. Interleukin 4 Controls the Pro-Tumoral Role of Macrophages in Mammary Cancer Pulmonary Metastasis in Mice. Cancers (Basel) 2022; 14:4336. [PMID: 36077870 PMCID: PMC9454655 DOI: 10.3390/cancers14174336] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Revised: 08/31/2022] [Accepted: 09/01/2022] [Indexed: 11/16/2022] Open
Abstract
Metastasis is the systemic manifestation of cancer and the main cause of death from breast cancer. In mouse models of lung metastases, recruitment of classical monocytes from blood to the lung and their differentiation to metastasis-associated macrophages (MAMs) facilitate cancer cell extravasation, survival and growth. Ablation of MAMs or their monocytic progenitors inhibits metastasis. We hypothesized that factors controlling macrophage polarization modulate tumor cell extravasation in the lung. We evaluated whether signaling by Th1 or Th2 cytokines in macrophages affected transendothelial migration of tumor cells in vitro. Interferon gamma and LPS inhibited macrophage-dependent tumor cell extravasation while the Th2 cytokine interleukin-4 (IL4) enhanced this process. We demonstrated that IL4 receptor (IL4rα)-null mice developed fewer and smaller lung metastasis in E0771-LG mammary cancer models of this disease. Adoptive transfer of wild-type monocytes to IL4rα-deficient mice partially rescued this phenotype. IL4 signaling in macrophages controlled the expression of the chemokine receptor CXCR2, necessary for IL4-mediated tumor cell extravasation in vitro. Furthermore, IL4 signaling in macrophages regulated the transcript abundance of several other genes already causally associated with mammary cancer lung metastasis including Ccl2, Csf1, Ccr1, Hgf and Flt1. The central role of IL4 signaling in MAMs was confirmed by high-resolution intravital imaging of the lung in mice at the time of metastatic seeding, which showed reduced physical interaction between tumor cells and IL4rα-deficient macrophages. This interaction with wild-type MAMs enhanced tumor cell survival and seeding, which was lost in the IL4rα mice. These data indicate that IL4 signaling in monocytes and macrophages is key during seeding and growth of breast metastasis in the lung, as it regulates pro-tumoral paracrine signaling between cancer cells and macrophages.
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Affiliation(s)
- Carolina Rodriguez-Tirado
- Department of Developmental and Molecular Biology, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY 10461, USA
- Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - David Entenberg
- Department of Pathology, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY 10461, USA
- Gruss-Lipper Biophotonics Center, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY 10461, USA
- Integrated Imaging Program, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY 10461, USA
| | - Jiufeng Li
- Department of Developmental and Molecular Biology, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY 10461, USA
| | - Bin-Zhi Qian
- Department of Developmental and Molecular Biology, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY 10461, USA
- Medical Research Council Centre for Reproductive Health, Queen’s Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK
| | - John S. Condeelis
- Gruss-Lipper Biophotonics Center, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY 10461, USA
- Integrated Imaging Program, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY 10461, USA
- Department of Surgery, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY 10461, USA
| | - Jeffrey W. Pollard
- Department of Developmental and Molecular Biology, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY 10461, USA
- Integrated Imaging Program, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY 10461, USA
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37
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Makela AV, Schott MA, Sehl OC, Gevaert JJ, Foster PJ, Contag CH. Tracking the fates of iron-labeled tumor cells in vivo using magnetic particle imaging. NANOSCALE ADVANCES 2022; 4:3617-3623. [PMID: 36134351 PMCID: PMC9400501 DOI: 10.1039/d2na00008c] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/03/2022] [Accepted: 07/20/2022] [Indexed: 06/16/2023]
Abstract
The use of imaging to detect and monitor the movement and accumulation of cells in living subjects can provide significant insights that can improve our understanding of metastasis and guide therapeutic development. For cell tracking using Magnetic Resonance Imaging (MRI), cells are labeled with iron oxides and the effects of the iron on water provides contrast. However, due to low specificity and difficulties in quantification with MRI, other modalities and approaches need to be developed. Magnetic Particle Imaging (MPI) is an emerging imaging technique which directly detects iron, allowing for a specific, quantitative and sensitive readout. Here, we use MPI to image iron-labeled tumor cells longitudinally, from implantation and growth at a primary site to movement to distant anatomic sites. In vivo bioluminescent imaging (BLI) was used to localize tumor metastases and computed tomography (CT) allowed for correlation of these signals to anatomic locations. These three imaging modalities provide information on immune escape and metastasis of iron-labeled, and unlabeled, tumor cells, and the accumulation of cell-free iron contrast over time. We localized iron signals by MPI and tumor cells via BLI, and correlated these positive contrast images with CT scans to reveal the anatomic sites with cancer cells; histologic analysis confirmed the presence of iron-labeled tumor cells in the tissues, suggesting that the metastatic cells retained enough iron for MPI detection. The use of multi-modality cell tracking reveals the movement, accumulation and fates of labeled cells that will be helpful understanding cancer progression and guiding the development of targeted therapies.
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Affiliation(s)
- Ashley V Makela
- Michigan State University, Institute for Quantitative Health Science and Engineering East Lansing MI USA
| | - Melissa A Schott
- Michigan State University, Institute for Quantitative Health Science and Engineering East Lansing MI USA
| | - Olivia C Sehl
- Western University, Robarts Research Institute, Department of Medical Biophysics London ON Canada
| | - Julia J Gevaert
- Western University, Robarts Research Institute, Department of Medical Biophysics London ON Canada
| | - Paula J Foster
- Western University, Robarts Research Institute, Department of Medical Biophysics London ON Canada
| | - Christopher H Contag
- Michigan State University, Institute for Quantitative Health Science and Engineering East Lansing MI USA
- Department of Biomedical Engineering, MSU East Lansing MI USA
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38
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Gianni C, Palleschi M, Schepisi G, Casadei C, Bleve S, Merloni F, Sirico M, Sarti S, Cecconetto L, Di Menna G, Schettini F, De Giorgi U. Circulating inflammatory cells in patients with metastatic breast cancer: Implications for treatment. Front Oncol 2022; 12:882896. [PMID: 36003772 PMCID: PMC9393759 DOI: 10.3389/fonc.2022.882896] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Accepted: 07/05/2022] [Indexed: 11/20/2022] Open
Abstract
Adaptive and innate immune cells play a crucial role as regulators of cancer development. Inflammatory cells in blood flow seem to be involved in pro-tumor activities and contribute to breast cancer progression. Circulating lymphocyte ratios such as the platelet-lymphocytes ratio (PLR), the monocyte-lymphocyte ratio (MLR) and the neutrophil-lymphocyte ratio (NLR) are new reproducible, routinely feasible and cheap biomarkers of immune response. These indexes have been correlated to prognosis in many solid tumors and there is growing evidence on their clinical applicability as independent prognostic markers also for breast cancer. In this review we give an overview of the possible value of lymphocytic indexes in advanced breast cancer prognosis and prediction of outcome. Furthermore, targeting the immune system appear to be a promising therapeutic strategy for breast cancer, especially macrophage-targeted therapies. Herein we present an overview of the ongoing clinical trials testing systemic inflammatory cells as therapeutic targets in breast cancer.
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Affiliation(s)
- Caterina Gianni
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, Italy
- *Correspondence: Caterina Gianni,
| | - Michela Palleschi
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, Italy
| | - Giuseppe Schepisi
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, Italy
| | - Chiara Casadei
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, Italy
| | - Sara Bleve
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, Italy
| | - Filippo Merloni
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, Italy
| | - Marianna Sirico
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, Italy
| | - Samanta Sarti
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, Italy
| | - Lorenzo Cecconetto
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, Italy
| | - Giandomenico Di Menna
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, Italy
| | - Francesco Schettini
- Department of Medical Oncology, Hospital Clinic of Barcelona, Barcelona, Spain
- Translational Genomics and Targeted Therapies in Solid Tumors Group, August Pi I Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain
- Faculty of Medicine, University of Barcelona, Barcelona, Spain
| | - Ugo De Giorgi
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, Italy
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39
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Abstract
Organ-specific metastasis to secondary organs is dependent on the formation of a supportive pre-metastatic niche. This tissue-specific microenvironmental response is thought to be mediated by mutational and epigenetic changes to primary tumour cells resulting in altered cross-talk between cell types. This response is augmented through the release of tumour and stromal signalling mediators including cytokines, chemokines, exosomes and growth factors. Although researchers have elucidated some of the cancer-promoting features that are bespoke to organotropic metastasis to the lungs, it remains unclear if these are organ-specific or generic between organs. Understanding the mechanisms that mediate the metastasis-promoting synergy between the host microenvironment, immunity, and pulmonary structures may elucidate predictive, prognostic and therapeutic markers that could be targeted to reduce the metastatic burden of disease. Herein, we give an updated summary of the known cellular and molecular mechanisms that contribute to the formation of the lung pre-metastatic niche and tissue-specific metastasis.
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Affiliation(s)
- Oliver Cucanic
- Peter MacCallum Cancer Centre, Melbourne, Australia
- Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Australia
| | - Rae H Farnsworth
- Peter MacCallum Cancer Centre, Melbourne, Australia
- Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Australia
| | - Steven A Stacker
- Peter MacCallum Cancer Centre, Melbourne, Australia
- Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Australia
- Department of Surgery, Royal Melbourne Hospital, University of Melbourne, Parkville, Australia
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40
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Tajaldini M, Saeedi M, Amiriani T, Amiriani AH, Sedighi S, Mohammad Zadeh F, Dehghan M, Jahanshahi M, Zanjan Ghandian M, Khalili P, Poorkhani AH, Alizadeh AM, Khori V. Cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs); where do they stand in tumorigenesis and how they can change the face of cancer therapy? Eur J Pharmacol 2022; 928:175087. [PMID: 35679891 DOI: 10.1016/j.ejphar.2022.175087] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2022] [Revised: 05/18/2022] [Accepted: 06/03/2022] [Indexed: 11/03/2022]
Abstract
The tumor microenvironment (TME) and its components have recently attracted tremendous attention in cancer treatment strategies, as alongside the genetic and epigenetic alterations in tumor cells, TME could also provide a fertile background for malignant cells to survive and proliferate. Interestingly, TME plays a vital role in the mediation of cancer metastasis and drug resistance even against immunotherapeutic agents. Among different cells that are presenting in TME, tumor-associated macrophages (TAMs) and cancer-associated fibroblasts (CAFs) have shown to have significant value in the regulation of angiogenesis, tumor metastasis, and drug-resistance through manipulating the composition as well as the organization of extracellular matrix (ECM). Evidence has shown that the presence of both TAMs and CAFs in TME is associated with poor prognosis and failure of chemotherapeutic agents. It seems that these cells together with ECM form a shield around tumor cells to protect them from the toxic agents and even the adaptive arm of the immune system, which is responsible for tumor surveillance. Given this, targeting TAMs and CAFs seems to be an essential approach to potentiate the cytotoxic effects of anti-cancer agents, either conventional chemotherapeutic drugs or immunotherapies. In the present review, we aimed to take a deep look at the mechanobiology of CAFs and TAMs in tumor progression and to discuss the available therapeutic approaches for harnessing these cells in TME.
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Affiliation(s)
- Mahboubeh Tajaldini
- Ischemic Disorder Research Center, Golestan University of Medical Sciences, Gorgan, Iran
| | - Mohsen Saeedi
- Stem Cell Research Center, Golestan University of Medical Sciences, Gorgan, Iran
| | - Taghi Amiriani
- Ischemic Disorder Research Center, Golestan University of Medical Sciences, Gorgan, Iran
| | - Amir Hossein Amiriani
- Ischemic Disorder Research Center, Golestan University of Medical Sciences, Gorgan, Iran
| | - Sima Sedighi
- Ischemic Disorder Research Center, Golestan University of Medical Sciences, Gorgan, Iran
| | - Fatemeh Mohammad Zadeh
- Ischemic Disorder Research Center, Golestan University of Medical Sciences, Gorgan, Iran
| | - Mohammad Dehghan
- Ischemic Disorder Research Center, Golestan University of Medical Sciences, Gorgan, Iran
| | - Mehrdad Jahanshahi
- Neuroscience Research Center, Golestan University of Medical Sciences, Gorgan, Iran
| | - Maziar Zanjan Ghandian
- Ischemic Disorder Research Center, Golestan University of Medical Sciences, Gorgan, Iran
| | - Pedram Khalili
- Ischemic Disorder Research Center, Golestan University of Medical Sciences, Gorgan, Iran
| | | | - Ali Mohammad Alizadeh
- Cancer Research Center, Cancer Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Vahid Khori
- Ischemic Disorder Research Center, Golestan University of Medical Sciences, Gorgan, Iran.
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41
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Lepland A, Malfanti A, Haljasorg U, Asciutto EK, Pickholz M, Bringas M, Đorđević S, Salumäe L, Peterson P, Teesalu T, Vicent MJ, Scodeller P. Depletion of Mannose Receptor-Positive Tumor-associated Macrophages via a Peptide-targeted Star-shaped Polyglutamate Inhibits Breast Cancer Progression in Mice. CANCER RESEARCH COMMUNICATIONS 2022; 2:533-551. [PMID: 36923553 PMCID: PMC10010335 DOI: 10.1158/2767-9764.crc-22-0043] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Revised: 05/03/2022] [Accepted: 06/03/2022] [Indexed: 12/31/2022]
Abstract
Although many studies have explored the depletion of tumor-associated macrophages (TAM) as a therapeutic strategy for solid tumors, currently available compounds suffer from poor efficacy and dose-limiting side effects. Here, we developed a novel TAM-depleting agent ("OximUNO") that specifically targets CD206+ TAMs and demonstrated efficacy in a triple-negative breast cancer (TNBC) mouse model. OximUNO comprises a star-shaped polyglutamate (St-PGA) decorated with the CD206-targeting peptide mUNO that carries the chemotherapeutic drug doxorubicin (DOX). In the TNBC model, a fluorescently labeled mUNO-decorated St-PGA homed to CD206+ TAMs within primary lesions and metastases. OximUNO exhibited no acute liver or kidney toxicity in vivo. Treatment with OximUNO reduced the progression of primary tumor lesions and pulmonary metastases, significantly diminished the number of CD206+ TAMs and increased the CD8/FOXP3 expression ratio (indicating immunomodulation). Our findings suggest the potential benefit of OximUNO as a TAM-depleting agent for TNBC treatment. Importantly, our studies also represent a novel design of a peptide-targeted St-PGA as a targeted therapeutic nanoconjugate. Significance A peptide-targeted nanoformulation of DOX exclusively eliminates mannose receptor+ TAMs in breast cancer models, generating response without off-target effects (a drawback of many TAM-depleting agents under clinical study).
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Affiliation(s)
- Anni Lepland
- Laboratory of Precision and Nanomedicine, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia
| | - Alessio Malfanti
- Polymer Therapeutics Laboratory, Prince Felipe Research Centre, Valencia, Spain
| | - Uku Haljasorg
- Molecular Pathology Research Group, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia
| | - Eliana K. Asciutto
- School of Science and Technology, National University of San Martin (UNSAM) ICIFI and CONICET, Buenos Aires, Argentina
| | - Monica Pickholz
- Departamento de Física, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina
- Instituto de Física de Buenos Aires (IFIBA), CONICET-Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Mauro Bringas
- Departamento de Química Inorgánica, Analítica y Química Física, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina
- Fundación Instituto Leloir, Instituto de Investigaciones Bioquímicas de Buenos Aires (IIBBA-CONICET), C1405BWE Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina
| | - Snežana Đorđević
- Polymer Therapeutics Laboratory, Prince Felipe Research Centre, Valencia, Spain
| | - Liis Salumäe
- Pathology Department, Tartu University Hospital, Tartu, Estonia
| | - Pärt Peterson
- Molecular Pathology Research Group, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia
| | - Tambet Teesalu
- Laboratory of Precision and Nanomedicine, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia
- Centre for Nanomedicine and Department of Cell, Molecular and Developmental Biology, University of California, Santa Barbara, California
| | - María J. Vicent
- Polymer Therapeutics Laboratory, Prince Felipe Research Centre, Valencia, Spain
| | - Pablo Scodeller
- Laboratory of Precision and Nanomedicine, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia
- Department of Immunology and Oncology, Centro Nacional de Biotecnología (CNB-CSIC), Madrid, Spain
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42
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Mohammad Mirzaei N, Tatarova Z, Hao W, Changizi N, Asadpoure A, Zervantonakis IK, Hu Y, Chang YH, Shahriyari L. A PDE Model of Breast Tumor Progression in MMTV-PyMT Mice. J Pers Med 2022; 12:807. [PMID: 35629230 PMCID: PMC9145520 DOI: 10.3390/jpm12050807] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Revised: 05/12/2022] [Accepted: 05/12/2022] [Indexed: 02/04/2023] Open
Abstract
The evolution of breast tumors greatly depends on the interaction network among different cell types, including immune cells and cancer cells in the tumor. This study takes advantage of newly collected rich spatio-temporal mouse data to develop a data-driven mathematical model of breast tumors that considers cells' location and key interactions in the tumor. The results show that cancer cells have a minor presence in the area with the most overall immune cells, and the number of activated immune cells in the tumor is depleted over time when there is no influx of immune cells. Interestingly, in the case of the influx of immune cells, the highest concentrations of both T cells and cancer cells are in the boundary of the tumor, as we use the Robin boundary condition to model the influx of immune cells. In other words, the influx of immune cells causes a dominant outward advection for cancer cells. We also investigate the effect of cells' diffusion and immune cells' influx rates in the dynamics of cells in the tumor micro-environment. Sensitivity analyses indicate that cancer cells and adipocytes' diffusion rates are the most sensitive parameters, followed by influx and diffusion rates of cytotoxic T cells, implying that targeting them is a possible treatment strategy for breast cancer.
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Affiliation(s)
- Navid Mohammad Mirzaei
- Department of Mathematics and Statistics, University of Massachusetts Amherst, Amherst, MA 01003, USA; (N.M.M.); (Y.H.)
| | - Zuzana Tatarova
- Department of Radiology, Brigham & Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA;
| | - Wenrui Hao
- Department of Mathematics, The Pennsylvania State University, University Park, PA 16802, USA;
| | - Navid Changizi
- Department of Civil and Environmental Engineering, University of Massachusetts, Dartmouth, MA 02747, USA; (N.C.); (A.A.)
| | - Alireza Asadpoure
- Department of Civil and Environmental Engineering, University of Massachusetts, Dartmouth, MA 02747, USA; (N.C.); (A.A.)
| | - Ioannis K. Zervantonakis
- Department of Bioengineering, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA 15219, USA;
| | - Yu Hu
- Department of Mathematics and Statistics, University of Massachusetts Amherst, Amherst, MA 01003, USA; (N.M.M.); (Y.H.)
| | - Young Hwan Chang
- Department of Biomedical Engineering, Oregon Health & Science University, Portland, OR 97239, USA;
| | - Leili Shahriyari
- Department of Mathematics and Statistics, University of Massachusetts Amherst, Amherst, MA 01003, USA; (N.M.M.); (Y.H.)
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43
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Blaye C, Boyer T, Peyraud F, Domblides C, Larmonier N. Beyond Immunosuppression: The Multifaceted Functions of Tumor-Promoting Myeloid Cells in Breast Cancers. Front Immunol 2022; 13:838040. [PMID: 35309358 PMCID: PMC8927658 DOI: 10.3389/fimmu.2022.838040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Accepted: 02/02/2022] [Indexed: 11/20/2022] Open
Abstract
Breast cancers are commonly associated with an immunosuppressive microenvironment responsible for tumor escape from anti-cancer immunity. Cells of the myeloid lineage account for a major part of this tumor-promoting landscape. These myeloid cells are composed of heterogeneous subsets at different stages of differentiation and have traditionally been described by their cardinal ability to suppress innate and adaptive anticancer immunity. However, evidence has accumulated that, beyond their immunosuppressive properties, breast cancer-induced myeloid cells are also equipped with a broad array of “non-immunological” tumor-promoting functions. They therefore represent major impediments for anticancer therapies, particularly for immune-based interventions. We herein analyze and discuss current literature related to the versatile properties of the different myeloid cell subsets engaged in breast cancer development. We critically assess persisting difficulties and challenges in unequivocally discriminate dedicated subsets, which has so far prevented both the selective targeting of these immunosuppressive cells and their use as potential biomarkers. In this context, we propose the concept of IMCGL, “pro-tumoral immunosuppressive myeloid cells of the granulocytic lineage”, to more accurately reflect the contentious nature and origin of granulocytic cells in the breast tumor microenvironment. Future research prospects related to the role of this myeloid landscape in breast cancer are further considered.
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Affiliation(s)
- Céline Blaye
- Centre National de la Recherche Scientific (CNRS) Unité Mixte de Recherche (UMR) 5164, ImmunoConcEpT, Bordeaux, France.,Department of Medical Oncology, Institut Bergonié, Bordeaux, France
| | - Thomas Boyer
- Centre National de la Recherche Scientific (CNRS) Unité Mixte de Recherche (UMR) 5164, ImmunoConcEpT, Bordeaux, France
| | - Florent Peyraud
- Centre National de la Recherche Scientific (CNRS) Unité Mixte de Recherche (UMR) 5164, ImmunoConcEpT, Bordeaux, France
| | - Charlotte Domblides
- Centre National de la Recherche Scientific (CNRS) Unité Mixte de Recherche (UMR) 5164, ImmunoConcEpT, Bordeaux, France.,Service d'Oncologie Médicale, Centre Hospitalo-Universitaire (CHU) Bordeaux, Bordeaux, France
| | - Nicolas Larmonier
- Centre National de la Recherche Scientific (CNRS) Unité Mixte de Recherche (UMR) 5164, ImmunoConcEpT, Bordeaux, France.,Department of Biological and Medical Sciences, University of Bordeaux, Bordeaux, France
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44
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Scott JI, Mendive-Tapia L, Gordon D, Barth ND, Thompson EJ, Cheng Z, Taggart D, Kitamura T, Bravo-Blas A, Roberts EW, Juarez-Jimenez J, Michel J, Piet B, de Vries IJ, Verdoes M, Dawson J, Carragher NO, Connor RAO, Akram AR, Frame M, Serrels A, Vendrell M. A fluorogenic probe for granzyme B enables in-biopsy evaluation and screening of response to anticancer immunotherapies. Nat Commun 2022; 13:2366. [PMID: 35501326 PMCID: PMC9061857 DOI: 10.1038/s41467-022-29691-w] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2021] [Accepted: 03/29/2022] [Indexed: 02/06/2023] Open
Abstract
Immunotherapy promotes the attack of cancer cells by the immune system; however, it is difficult to detect early responses before changes in tumor size occur. Here, we report the rational design of a fluorogenic peptide able to detect picomolar concentrations of active granzyme B as a biomarker of immune-mediated anticancer action. Through a series of chemical iterations and molecular dynamics simulations, we synthesize a library of FRET peptides and identify probe H5 with an optimal fit into granzyme B. We demonstrate that probe H5 enables the real-time detection of T cell-mediated anticancer activity in mouse tumors and in tumors from lung cancer patients. Furthermore, we show image-based phenotypic screens, which reveal that the AKT kinase inhibitor AZD5363 shows immune-mediated anticancer activity. The reactivity of probe H5 may enable the monitoring of early responses to anticancer treatments using tissue biopsies.
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Affiliation(s)
- Jamie I Scott
- Centre for Inflammation Research, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, UK
| | - Lorena Mendive-Tapia
- Centre for Inflammation Research, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, UK
| | - Doireann Gordon
- Centre for Inflammation Research, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, UK
| | - Nicole D Barth
- Centre for Inflammation Research, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, UK
| | - Emily J Thompson
- Centre for Inflammation Research, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, UK
| | - Zhiming Cheng
- Centre for Inflammation Research, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, UK
| | - David Taggart
- Centre for Inflammation Research, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, UK
| | - Takanori Kitamura
- MRC Centre for Reproductive Health, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, UK
| | | | | | - Jordi Juarez-Jimenez
- EaStChem School of Chemistry, Joseph Black Building, The University of Edinburgh, Edinburgh, UK
| | - Julien Michel
- EaStChem School of Chemistry, Joseph Black Building, The University of Edinburgh, Edinburgh, UK
| | - Berber Piet
- Department of Pulmonary Diseases, Radboud University Medical Centre, Nijmegen, Netherlands
| | - I Jolanda de Vries
- Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Centre, Nijmegen, Netherlands
| | - Martijn Verdoes
- Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Centre, Nijmegen, Netherlands
| | - John Dawson
- Cancer Research UK Edinburgh Centre, The University of Edinburgh, Edinburgh, UK
| | - Neil O Carragher
- Cancer Research UK Edinburgh Centre, The University of Edinburgh, Edinburgh, UK
| | - Richard A O' Connor
- Centre for Inflammation Research, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, UK
| | - Ahsan R Akram
- Centre for Inflammation Research, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, UK
| | - Margaret Frame
- Cancer Research UK Edinburgh Centre, The University of Edinburgh, Edinburgh, UK
| | - Alan Serrels
- Centre for Inflammation Research, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, UK
| | - Marc Vendrell
- Centre for Inflammation Research, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, UK.
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45
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Liu N, Jiang X, Guo L, Zhang C, Jiang M, Sun Z, Zhang Y, Mi W, Li J, Fu Y, Wang F, Zhang L, Zhang Y. Mutant p53 achieved Gain-of-Function by promoting tumor growth and immune escape through PHLPP2/AKT/PD-L1 pathway. Int J Biol Sci 2022; 18:2419-2438. [PMID: 35414774 PMCID: PMC8990467 DOI: 10.7150/ijbs.67200] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2021] [Accepted: 02/24/2022] [Indexed: 11/09/2022] Open
Abstract
The most frequent genetic alterations of the TP53 gene in human cancer were reported. TP53 mutation gains new function as a target of genetic instability, which is associated with increased tumor progression and poor survival rate in patients. In this study, more than three hundred colorectal cancer patients' samples were firstly analyzed, and the results showed that patients with mutant p53 had higher levels of AKT phosphorylation and PD-L1 expression, which were next verified both in cell lines in vitro and patients' samples in vivo. Further studies demonstrated that the hotspot of mutant p53 directly binds to the promoter of PHLPP2 to inhibit its transcription, and resulting in down-regulating its protein expressional level. Subsequently, AKT was released and activated, promoting tumor proliferation and metastasis. In parallel, 4EBP1/eIF4E was identified as downstream executors of AKT to enhance the translational level of PD-L1, which decreased the activation of T cells. Besides, inhibiting AKT/mTOR pathway significantly suppressed PD-L1 expression, tumor growth, and immune escape in p53 mutated cells. In conclusion, mutant p53 achieved its Gain-of-Function by transcriptionally inhibiting PHLPP2 and activating AKT, which suppresses immune response and advances tumor growth. Thus, this study provides an excellent basis for a further understanding of the clinical treatment of neoplastic diseases for patients with mutant p53, with an emphasis on immunotherapy.
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Affiliation(s)
- Nannan Liu
- School of Biomedical Sciences, Hunan University, Changsha, China
| | - Xinxiu Jiang
- School of Biomedical Sciences, Hunan University, Changsha, China
- Department of Laboratory Medicine, the Third Xiangya Hospital, Central South University, Changsha, China
| | - Leiming Guo
- Department of Gastroenterology, Huadong Hospital, Shanghai Medical College, Fudan University, Shanghai, China
- Department of R&D, Shanghai Creative Immune Therapeutics Co., Ltd, Shanghai, China
| | - Chuchu Zhang
- School of Biomedical Sciences, Hunan University, Changsha, China
| | - Meimei Jiang
- School of Biomedical Sciences, Hunan University, Changsha, China
| | - Zhuoran Sun
- Department of Laboratory Medicine, the Third Xiangya Hospital, Central South University, Changsha, China
| | - Yizheng Zhang
- School of Biomedical Sciences, Hunan University, Changsha, China
- Department of Gastroenterology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Wunan Mi
- School of Biomedical Sciences, Hunan University, Changsha, China
- Department of Gastroenterology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Jiehan Li
- School of Biomedical Sciences, Hunan University, Changsha, China
- Department of Gastroenterology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Yang Fu
- Department of Gastroenterology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Feng Wang
- Department of Gastroenterology, Huadong Hospital, Shanghai Medical College, Fudan University, Shanghai, China
| | - Lingling Zhang
- Department of Laboratory Medicine, the Third Xiangya Hospital, Central South University, Changsha, China
| | - Yingjie Zhang
- School of Biomedical Sciences, Hunan University, Changsha, China
- College of Biology, Hunan University, Changsha, China
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46
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Ko MW, Kaur K, Safaei T, Chen W, Sutanto C, Wong P, Jewett A. Defective Patient NK Function Is Reversed by AJ2 Probiotic Bacteria or Addition of Allogeneic Healthy Monocytes. Cells 2022; 11:cells11040697. [PMID: 35203349 PMCID: PMC8870139 DOI: 10.3390/cells11040697] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Accepted: 02/09/2022] [Indexed: 02/01/2023] Open
Abstract
In this paper, we present the role of autologous and allogeneic monocytes from healthy individuals and those of the cancer patients, with a number of distinct cancers, in activating the function of natural killer (NK) cells, in particular, in induction of IFN-γ secretion by the NK cells and the functional capability of secreted IFN-γ in driving differentiation of the tumor cells. In addition, we compared the roles of CD16 signaling as well as sonicated probiotic bacteria AJ2 (sAJ2)-mediated induction and function of IFN-γ-mediated differentiation in tumor cells. We found that monocytes from cancer patients had lower capability to induce functional IFN-γ secretion by the autologous CD16 mAb-treated NK cells in comparison to those from healthy individuals. In addition, when patient monocytes were cultured with NK cells from healthy individuals, they had lower capability to induce functional IFN-γ secretion by the NK cells when compared to those from autologous monocyte/NK cultures from healthy individuals. Activation by sAJ2 or addition of monocytes from healthy individuals to patient NK cells increased the secretion of functional IFN-γ by the NK cells and elevated its functional capability to differentiate tumors. Monocytes from cancer patients were found to express lower CD16 receptors, providing a potential mechanism for their lack of ability to trigger secretion of functional IFN-γ. In addition to in vitro studies, we also conducted in vivo studies in which cancer patients were given oral supplementation of AJ2 and the function of NK cells were studied. Oral ingestion of AJ2 improved the secretion of IFN-γ by patient derived NK cells and resulted in the better functioning of NK cells in cancer patients. Thus, our studies indicate that for successful NK cell immunotherapy, not only the defect in NK cells but also those in monocytes should be corrected. In this regard, AJ2 probiotic bacteria may serve to provide a potential adjunct treatment strategy.
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Affiliation(s)
- Meng-Wei Ko
- The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, Division of Oral Biology and Medicine, School of Dentistry, University of California Los Angeles, Los Angeles, CA 90095, USA; (M.-W.K.); (K.K.); (T.S.); (W.C.); (C.S.); (P.W.)
| | - Kawaljit Kaur
- The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, Division of Oral Biology and Medicine, School of Dentistry, University of California Los Angeles, Los Angeles, CA 90095, USA; (M.-W.K.); (K.K.); (T.S.); (W.C.); (C.S.); (P.W.)
| | - Tahmineh Safaei
- The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, Division of Oral Biology and Medicine, School of Dentistry, University of California Los Angeles, Los Angeles, CA 90095, USA; (M.-W.K.); (K.K.); (T.S.); (W.C.); (C.S.); (P.W.)
| | - Wuyang Chen
- The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, Division of Oral Biology and Medicine, School of Dentistry, University of California Los Angeles, Los Angeles, CA 90095, USA; (M.-W.K.); (K.K.); (T.S.); (W.C.); (C.S.); (P.W.)
| | - Christine Sutanto
- The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, Division of Oral Biology and Medicine, School of Dentistry, University of California Los Angeles, Los Angeles, CA 90095, USA; (M.-W.K.); (K.K.); (T.S.); (W.C.); (C.S.); (P.W.)
| | - Paul Wong
- The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, Division of Oral Biology and Medicine, School of Dentistry, University of California Los Angeles, Los Angeles, CA 90095, USA; (M.-W.K.); (K.K.); (T.S.); (W.C.); (C.S.); (P.W.)
| | - Anahid Jewett
- The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, Division of Oral Biology and Medicine, School of Dentistry, University of California Los Angeles, Los Angeles, CA 90095, USA; (M.-W.K.); (K.K.); (T.S.); (W.C.); (C.S.); (P.W.)
- The Jonsson Comprehensive Cancer Center, UCLA School of Dentistry and Medicine, Los Angeles, CA 90095, USA
- Correspondence: ; Tel.: +1-310-206-3970; Fax: +1-301-794-7109
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47
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Robinson A, Burgess M, Webb S, Louwe PA, Ouyang Z, Skola D, Han CZ, Batada NN, González-Huici V, Cassetta L, Glass CK, Jenkins SJ, Pollard JW. Systemic Influences of Mammary Cancer on Monocytes in Mice. Cancers (Basel) 2022; 14:833. [PMID: 35159100 PMCID: PMC8834227 DOI: 10.3390/cancers14030833] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Revised: 01/27/2022] [Accepted: 02/02/2022] [Indexed: 12/15/2022] Open
Abstract
There is a growing body of evidence that cancer causes systemic changes. These influences are most evident in the bone marrow and the blood, particularly in the myeloid compartment. Here, we show that there is an increase in the number of bone marrow, circulating and splenic monocytes by using mouse models of breast cancer caused by the mammary epithelial expression of the polyoma middle T antigen. Cancer does not affect ratios of classical to non-classical populations of monocytes in the circulation nor does it affect their half-lives. Single cell RNA sequencing also indicates that cancer does not induce any new monocyte populations. Cancer does not change the monocytic progenitor number in the bone marrow, but the proliferation rate of monocytes is higher, thus providing an explanation for the expansion of the circulating numbers. Deep RNA sequencing of these monocytic populations reveals that cancer causes changes in the classical monocyte compartment, with changes evident in bone marrow monocytes and even more so in the blood, suggesting influences in both compartments, with the down-regulation of interferon type 1 signaling and antigen presentation being the most prominent of these. Consistent with this analysis, down-regulated genes are enriched with STAT1/STAT2 binding sites in their promoter, which are transcription factors required for type 1 interferon signaling. However, these transcriptome changes in mice did not replicate those found in patients with breast cancer. Consequently, this mouse model of breast cancer may be insufficient to study the systemic influences of human cancer.
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Affiliation(s)
- Amy Robinson
- MRC-Centre for Reproductive Health, Queen’s Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK; (A.R.); (S.W.); (L.C.)
| | - Matthew Burgess
- Centre for Inflammation Research, Queen’s Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK; (M.B.); (P.A.L.)
| | - Sheila Webb
- MRC-Centre for Reproductive Health, Queen’s Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK; (A.R.); (S.W.); (L.C.)
| | - Pieter A. Louwe
- Centre for Inflammation Research, Queen’s Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK; (M.B.); (P.A.L.)
| | - Zhengyu Ouyang
- Department of Cellular & Molecular Medicine, University of San Diego, LA Jolla, CA 92037, USA; (Z.O.); (D.S.); (C.Z.H.); (C.K.G.)
| | - Dylan Skola
- Department of Cellular & Molecular Medicine, University of San Diego, LA Jolla, CA 92037, USA; (Z.O.); (D.S.); (C.Z.H.); (C.K.G.)
| | - Claudia Z. Han
- Department of Cellular & Molecular Medicine, University of San Diego, LA Jolla, CA 92037, USA; (Z.O.); (D.S.); (C.Z.H.); (C.K.G.)
| | - Nizar N. Batada
- Institute of Genetic and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK; (N.N.B.); (V.G.-H.)
| | - Víctor González-Huici
- Institute of Genetic and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK; (N.N.B.); (V.G.-H.)
| | - Luca Cassetta
- MRC-Centre for Reproductive Health, Queen’s Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK; (A.R.); (S.W.); (L.C.)
| | - Chris K. Glass
- Department of Cellular & Molecular Medicine, University of San Diego, LA Jolla, CA 92037, USA; (Z.O.); (D.S.); (C.Z.H.); (C.K.G.)
| | - Stephen J. Jenkins
- Centre for Inflammation Research, Queen’s Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK; (M.B.); (P.A.L.)
| | - Jeffery W. Pollard
- MRC-Centre for Reproductive Health, Queen’s Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK; (A.R.); (S.W.); (L.C.)
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Ceafalan LC, Niculae AM, Ioghen O, Gherghiceanu M, Hinescu ME. Metastatic potential. UNRAVELING THE COMPLEXITIES OF METASTASIS 2022:153-173. [DOI: 10.1016/b978-0-12-821789-4.00005-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Guo D, Liu J, Li Y, Li C, Liu Q, Ji S, Zhu S. Evaluation of Predictive Values of Naples Prognostic Score in Patients with Unresectable Stage III Non-Small Cell Lung Cancer. J Inflamm Res 2021; 14:6129-6141. [PMID: 34848991 PMCID: PMC8627309 DOI: 10.2147/jir.s341399] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2021] [Accepted: 11/06/2021] [Indexed: 12/28/2022] Open
Abstract
Background Naples prognosis score (NPS) is a new prognostic score according to host inflammatory and nutritional state, and it could be useful for predicting tumor prognosis based on albumin level, total cholesterol level, neutrophil-to-lymphocyte ratio, and lymphocyte-to-monocyte ratio. This study aimed to evaluate the clinical significance of Naples prognostic score (NPS) in stage III non-small cell lung cancer patients (NSCLC). Patients and Methods In this study, 206 patients diagnosed with locally advanced NCCLC receiving chemoradiotherapy were retrospectively reviewed from January 2013 to January 2017. The included patients were divided into 3 groups according to NPS (group 0, group 1, and group 2), and the associations of the NPS with clinical characteristics and outcomes were evaluated among the groups. Survival curves for the NPS were analyzed using the Kaplan-Meier method. Univariate and multivariate analyses were performed using the Cox proportional hazards regression model to evaluate the prognostic value of overall survival (OS) and progression-free survival (PFS). Results The median follow-up time of this study was 37.0 (range, 13-59) months. The median OS was 27 months in group 0, 23 months in group 1, and 21 months in group 2, and median PFS was 15, 12 and 13 in group 0, group 1 and group 2, respectively. Age was significantly different among the 3 groups. The NPS was superior to other host inflammatory and nutritional indexes for prognostic risk stratification. In the multivariate analysis, NPS was identified as an independent prognostic indicator for OS and PFS (all P<0.05). Conclusion The NPS system is considered to be a useful predictor of outcomes in patients with stage III NSCLC.
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Affiliation(s)
- Dong Guo
- Department of Radiation Oncology, Fourth Hospital of Hebei Medical University, Shijiazhuang, People's Republic of China
| | - Jiafeng Liu
- Department of Radiotherapy, Rizhao Center Hospital, Rizhao, People's Republic of China
| | - Yanping Li
- Sunshine Union Hospital, Weifang, People's Republic of China
| | - Chao Li
- Sunshine Union Hospital, Weifang, People's Republic of China
| | - Quan Liu
- Sunshine Union Hospital, Weifang, People's Republic of China
| | - Shengjun Ji
- Department of Radiotherapy & Oncology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, People's Republic of China
| | - Shuchai Zhu
- Department of Radiation Oncology, Fourth Hospital of Hebei Medical University, Shijiazhuang, People's Republic of China
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Conte E. Targeting monocytes/macrophages in fibrosis and cancer diseases: Therapeutic approaches. Pharmacol Ther 2021; 234:108031. [PMID: 34774879 DOI: 10.1016/j.pharmthera.2021.108031] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 10/19/2021] [Accepted: 11/02/2021] [Indexed: 02/08/2023]
Abstract
Over almost 140 years since their identification, the knowledge about macrophages has unbelievably evolved. The 'big eaters' from being thought of as simple phagocytic cells have been recognized as master regulators in immunity, homeostasis, healing/repair and organ development. Long considered to originate exclusively from bone marrow-derived circulating monocytes, macrophages have been also demonstrated to be the first immune cells colonizing tissues in the developing embryo and persisting in adult life by self-renewal, as long-lived tissue resident macrophages. Therefore, heterogeneous populations of macrophages with different ontogeny and functions co-exist in tissues. Macrophages act as sentinels of homeostasis and are intrinsically programmed to lead the wound healing and repair processes that occur after injury. However, in certain pathological circumstances macrophages get dysfunctional, and impaired or aberrant macrophage activities become key features of diseases. For instance, in both fibrosis and cancer, that have been defined 'wounds that do not heal', dysfunctional monocyte-derived macrophages overall play a key detrimental role. On the other hand, due to their plasticity these cells can be 're-educated' and exert anti-fibrotic and anti-cancer functions. Therefore macrophages represent an important therapeutic target in both fibrosis and cancer diseases. The current review will illustrate new insights into the role of monocytes/macrophages in these devastating diseases and summarize new therapeutic strategies and applications of macrophage-targeted drug development in their clinical setting.
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