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Siemińska I, Lenart M. Immunometabolism of Innate Immune Cells in Gastrointestinal Cancer. Cancers (Basel) 2025; 17:1467. [PMID: 40361394 PMCID: PMC12071029 DOI: 10.3390/cancers17091467] [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: 03/05/2025] [Revised: 04/11/2025] [Accepted: 04/23/2025] [Indexed: 05/15/2025] Open
Abstract
Cancer cells are often described as voracious consumers of nutrients, with glucose frequently cited as a key energy source; however, their metabolic plasticity allows them to adapt and utilize various substrates, including lipids and amino acids, to sustain growth and survival. However, the metabolic demands of immune cells within the tumor microenvironment (TME) are less commonly discussed despite their critical role in shaping the immune response. In this review, we explored the intricate interplay between immunometabolism and innate immunity cells in gastrointestinal cancers. We focused on how metabolic pathways, including glycolysis, fatty acid oxidation, and amino acid metabolism, drive the immunosuppressive functions of myeloid-derived suppressor cells (MDSCs) and tumor-associated neutrophils (TANs), tumor-associated macrophages (TAMs) and innate lymphocyte subsets such as NK cells. These cells contribute to a hostile immune landscape, supporting tumor growth and evasion from immune surveillance in a phenomenon of tumor-derived immunosuppression. Additionally, we investigated the influence of dietary interventions on the metabolic reprogramming of these immune cells, highlighting how nutrition can modulate the TME. Finally, we discussed emerging therapeutic strategies that target metabolic vulnerabilities in MDSCs, TANs, NK cells, and monocytes, offering a novel avenue for enhancing antitumor immunity. By dissecting these mechanisms, we aim to provide insights into how metabolic pathways can be harnessed to improve cancer treatment outcomes. This review underscores the importance of understanding immunometabolism not only as a driver of immune suppression but also as a potential therapeutic target in gastrointestinal cancer.
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Affiliation(s)
- Izabela Siemińska
- Institute of Veterinary Sciences, University Center of Veterinary Medicine JU-AU, University of Agriculture in Krakow, Mickiewicza 24/28, 30-059 Krakow, Poland
- Department of Clinical Immunology, Institute of Paediatrics, Faculty of Medicine, Jagiellonian University Medical College, Wielicka 265, 30-663 Krakow, Poland
| | - Marzena Lenart
- Department of Clinical Immunology, Institute of Paediatrics, Faculty of Medicine, Jagiellonian University Medical College, Wielicka 265, 30-663 Krakow, Poland
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Zhang W, Xia M, Li J, Liu G, Sun Y, Chen X, Zhong J. Warburg effect and lactylation in cancer: mechanisms for chemoresistance. Mol Med 2025; 31:146. [PMID: 40264038 PMCID: PMC12016192 DOI: 10.1186/s10020-025-01205-6] [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: 02/18/2025] [Accepted: 04/09/2025] [Indexed: 04/24/2025] Open
Abstract
In the clinical management of cancers, the emergence of chemoresistance represents a profound and imperative "pain point" that requires immediate attention. Understanding the mechanisms of chemoresistance is essential for developing effective therapeutic strategies. Importantly, existing studies have demonstrated that glucose metabolic reprogramming, commonly referred to as the Warburg effect or aerobic glycolysis, is a major contributor to chemoresistance. Additionally, lactate, a byproduct of aerobic glycolysis, functions as a signaling molecule that supports lysine lactylation modification of proteins, which also plays a critical role in chemoresistance. However, it is insufficient to discuss the role of glycolysis or lactylation in chemoresistance from a single perspective. The intricate relationship between aerobic glycolysis and lactylation plays a crucial role in promoting chemoresistance. Thus, a thorough elucidation of the mechanisms underlying chemoresistance mediated by aerobic glycolysis and lactylation is essential. This review provides a comprehensive overview of these mechanisms and further outlines that glycolysis and lactylation exert synergistic effects, promoting the development of chemoresistance and creating a positive feedback loop that continues to mediate this resistance. The close link between aerobic glycolysis and lactylation suggests that the application of glycolysis-related drugs or inhibitors in cancer therapy may represent a promising anticancer strategy. Furthermore, the targeted application of lactylation, either alone or in combination with other treatments, may offer new therapeutic avenues for overcoming chemoresistance.
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Affiliation(s)
- Wenjie Zhang
- Clinical Medical Research Center, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China
- Institute of Cancer Research, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China
| | - Min Xia
- Clinical Medical Research Center, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China
- Institute of Cancer Research, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China
| | - Jiahui Li
- Clinical Medical Research Center, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China
- Institute of Cancer Research, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China
| | - Gaohua Liu
- Clinical Medical Research Center, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China
- Institute of Cancer Research, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China
| | - Yan Sun
- Clinical Medical Research Center, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China
- Institute of Cancer Research, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China
| | - Xisha Chen
- Clinical Medical Research Center, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China.
- Institute of Cancer Research, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China.
| | - Jing Zhong
- Clinical Medical Research Center, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China.
- Institute of Cancer Research, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China.
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Fan X, Brunetti TM, Jackson K, Roop DR. Single-Cell Profiling Reveals Global Immune Responses During the Progression of Murine Epidermal Neoplasms. Cancers (Basel) 2025; 17:1379. [PMID: 40282557 PMCID: PMC12025564 DOI: 10.3390/cancers17081379] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2025] [Revised: 04/01/2025] [Accepted: 04/11/2025] [Indexed: 04/29/2025] Open
Abstract
BACKGROUND/OBJECTIVES Immune cells determine the role of the tumor microenvironment during tumor progression, either suppressing tumor formation or promoting tumorigenesis. This study aimed to fully characterize immune cell responses during skin tumor progression. METHODS Using single-cell RNA sequencing, we analyzed the profile of immune cells in the tumor microenvironment of control mouse skins and skin tumors at the single-cell level. RESULTS We identified 15 CD45+ immune cell clusters, which broadly represent the most functionally characterized immune cell types including macrophages, Langerhans cells (LC), conventional type 1 dendritic cells (cDC1), conventional type 2 dendritic cells (cDC2), migratory/mature dendritic cells (mDC), dendritic epidermal T cells (DETC), dermal γδ T cells (γδT), T cells, regulatory T cells (Tregs), natural killer cells (NK), type 2 innate lymphoid cells (ILC2), neutrophils (Neu), mast cells (Mast), and two proliferating populations (Prolif.1 and Prolif.2). Skin tumor progression reprogramed immune cells and led to a marked increase in the relative percentages of macrophages, cDC2, mDC, Tregs, and Neu. Macrophages, the largest cell cluster of immune cells in skin tumors. In addition, macrophages emerged as the predominant communication 'hub' in skin tumors, highlighting the importance of macrophages during skin tumor progression. In contrast, other immune cell clusters decreased during skin tumor progression, including DETC, γδT, ILC2, and LC. In addition, skin tumor progression dramatically upregulated Jak2/Stat3 expression and the interferon response across various immune cell clusters. Further, skin tumor progression activated T cells and NK cells indicated by elevated expression of IFN-γ and Granzyme B in skin tumors. Meanwhile, a pronounced infiltration of M2-macrophages and Tregs in skin tumors created an immunosuppressive microenvironment, consistent with the elevated expression of the Stat3 pathway in skin tumors. CONCLUSIONS Our study elucidates the immune cell landscape of epidermal neoplasms, offering a comprehensive understanding of the immune response during skin tumor progression and providing new insights into cancer immune evasion mechanisms.
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Affiliation(s)
- Xiying Fan
- Department of Dermatology, University of Colorado Anschutz Medical Campus, 12700 E. 19th Ave., Room 4007, Aurora, CO 80045, USA;
- Gates Institute, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Tonya M. Brunetti
- Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA;
| | - Kelsey Jackson
- Department of Dermatology, University of Colorado Anschutz Medical Campus, 12700 E. 19th Ave., Room 4007, Aurora, CO 80045, USA;
- Gates Institute, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Dennis R. Roop
- Department of Dermatology, University of Colorado Anschutz Medical Campus, 12700 E. 19th Ave., Room 4007, Aurora, CO 80045, USA;
- Gates Institute, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
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Tasbihi K, Bruns H. Selinexor's Immunomodulatory Impact in Advancing Multiple Myeloma Treatment. Cells 2025; 14:430. [PMID: 40136679 PMCID: PMC11940887 DOI: 10.3390/cells14060430] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2025] [Revised: 03/06/2025] [Accepted: 03/11/2025] [Indexed: 03/27/2025] Open
Abstract
Despite the major advancements in the repertoire for multiple myeloma (MM) treatment, this disease remains a chronically progressive plasma cell malignancy. Drug resistance and high relapse rates complicate the extended treatment strategies. However, the tumor microenvironment (TME) in MM is decisive for the success of a therapy or relapse. Aiming to improve the outcome of relapsed and refractory MM patients, Selinexor has entered the drug arsenal of myeloma therapy through the implementation of a novel therapeutic approach by selectively inhibiting the nuclear export receptor Exportin-1 (XPO1). Selinexor leads to the inactivation of cancer-related proteins and induces apoptosis by disrupting the nucleocytoplasmic flow in myeloma cells. While this drug is selectively cytotoxic to neoplastic cells, Selinexor's immunomodulatory impact on the TME is currently being investigated. The aim of this review was to elucidate Selinexor's capacity to influence the cell interaction network of the TME from an immunological perspective. Deciphering the complex interplay of highly plastic immune cells provides a contribution to the molecular-biological exploration of disease initiation and progression in MM. Unraveling the novel therapeutic targets of the immunological TME and evaluating the advanced immunotherapeutic regimens implementing Selinexor will shape the future directions of immune-oncotherapy in MM.
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Affiliation(s)
| | - Heiko Bruns
- Department of Medicine 5—Hematology and Oncology, University Hospital Erlangen, 91054 Erlangen, Germany;
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He X, Guan XY, Li Y. Clinical significance of the tumor microenvironment on immune tolerance in gastric cancer. Front Immunol 2025; 16:1532605. [PMID: 40028336 PMCID: PMC11868122 DOI: 10.3389/fimmu.2025.1532605] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2024] [Accepted: 01/30/2025] [Indexed: 03/05/2025] Open
Abstract
In the realm of oncology, the tumor microenvironment (TME)-comprising extracellular matrix components, immune cells, fibroblasts, and endothelial cells-plays a pivotal role in tumorigenesis, progression, and response to therapeutic interventions. Initially, the TME exhibits tumor-suppressive properties that can inhibit malignant transformation. However, as the tumor progresses, various factors induce immune tolerance, resulting in TME behaving in a state that promotes tumor growth and metastasis in later stages. This state of immunosuppression is crucial as it enables TME to change from a role of killing tumor cells to a role of promoting tumor progression. Gastric cancer is a common malignant tumor of the gastrointestinal tract with an alarmingly high mortality rate. While chemotherapy has historically been the cornerstone of treatment, its efficacy in prolonging survival remains limited. The emergence of immunotherapy has opened new therapeutic pathways, yet the challenge of immune tolerance driven by the gastric cancer microenvironment complicates these efforts. This review aims to elucidate the intricate role of the TME in mediating immune tolerance in gastric cancer and to spotlight innovative strategies and clinical trials designed to enhance the efficacy of immunotherapeutic approaches. By providing a comprehensive theoretical framework, this review seeks to advance the understanding and application of immunotherapy in the treatment of gastric cancer, ultimately contributing to improved patient outcomes.
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Affiliation(s)
- Xiangyang He
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Xin-Yuan Guan
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
- Department of Clinical Oncology, The University of Hongkong, Hong Kong, Hong Kong SAR, China
| | - Yan Li
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
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Li Z, Chen L, Wei Z, Liu H, Zhang L, Huang F, Wen X, Tian Y. A novel classification method for LUAD that guides personalized immunotherapy on the basis of the cross-talk of coagulation- and macrophage-related genes. Front Immunol 2025; 16:1518102. [PMID: 40018029 PMCID: PMC11866059 DOI: 10.3389/fimmu.2025.1518102] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Accepted: 01/27/2025] [Indexed: 03/01/2025] Open
Abstract
Purpose The coagulation process and infiltration of macrophages affect the progression and prognosis of lung adenocarcinoma (LUAD) patients. This study was designed to explore novel classification methods that better guide the precise treatment of LUAD patients on the basis of coagulation and macrophages. Methods Weighted gene coexpression network analysis (WGCNA) was applied to identify M2 macrophage-related genes, and TAM marker genes were acquired through the analysis of scRNA-seq data. The MSigDB and KEGG databases were used to obtain coagulation-associated genes. The intersecting genes were defined as coagulation and macrophage-related (COMAR) genes. Unsupervised clustering analysis was used to evaluate distinct COMAR patterns for LUAD patients on the basis of the COMAR genes. The R package "limma" was used to identify differentially expressed genes (DEGs) between COMAR patterns. A prognostic risk score model, which was validated through external data cohorts and clinical samples, was constructed on the basis of the COMAR DEGs. Results In total, 33 COMAR genes were obtained, and three COMAR LUAD subtypes were identified on the basis of the 33 COMAR genes. There were 341 DEGs identified between the three COMAR subtypes, and 60 prognostic genes were selected for constructing the COMAR risk score model. Finally, 15 prognosis-associated genes (CORO1A, EPHA4, FOXM1, HLF, IFIH1, KYNU, LY6D, MUC16, PPARG, S100A8, SPINK1, SPINK5, SPP1, VSIG4, and XIST) were included in the model, which was efficient and robust in predicting LUAD patient prognosis and clinical outcomes in patients receiving anti-PD-1/PD-L1 immunotherapy. Conclusions LUAD can be classified into three subtypes according to COMAR genes, which may provide guidance for precise treatment.
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Affiliation(s)
- Zhuoqi Li
- Department of Radiotherapy Oncology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Ling Chen
- Department of Oncology, Qingdao Municipal Hospital, Qingdao, China
| | - Zhigang Wei
- Department of Oncology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Lung Cancer Institute, Jinan, China
| | - Hongtao Liu
- Department of Pathology, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Shandong Medicine and Health Key Laboratory of Clinical Pathology, Shandong Lung Cancer Institute, Shandong Institute of Nephrology, Jinan, China
| | - Lu Zhang
- Department of Radiotherapy Oncology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Fujing Huang
- Department of Radiotherapy Oncology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Xiao Wen
- Department of Radiotherapy Oncology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Yuan Tian
- Department of Radiotherapy Oncology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
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Xuan W, Song D, Hou J, Meng X. Regulation of Hippo-YAP1/TAZ pathway in metabolic dysfunction-associated steatotic liver disease. Front Pharmacol 2025; 16:1505117. [PMID: 39917623 PMCID: PMC11798981 DOI: 10.3389/fphar.2025.1505117] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2024] [Accepted: 01/07/2025] [Indexed: 02/09/2025] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) has become the most prevalent chronic liver disease worldwide, but effective treatments are still lacking. Metabolic disorders such as iron overload, glycolysis, insulin resistance, lipid dysregulation, and glutaminolysis are found to induce liver senescence and ferroptosis, which are hot topics in the research of MASLD. Recent studies have shown that Hippo-YAP1/TAZ pathway is involved in the regulations of metabolism disorders, senescence, ferroptosis, inflammation, and fibrosis in MASLD, but their complex connections and contrast roles are also reported. In addition, therapeutics based on the Hippo-YAP1/TAZ pathway hold promising for MASLD treatment. In this review, we highlight the regulation and molecular mechanism of the Hippo-YAP1/TAZ pathway in MASLD and summarize potential therapeutic strategies for MASLD by regulating Hippo-YAP1/TAZ pathway.
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Affiliation(s)
- Wei Xuan
- Department of Hepatopancreaticobiliary Surgery, China-Japan Union Hospital, Jilin University, Changchun, China
| | - Dandan Song
- Department of Clinical Laboratory, Second Hospital of Jilin University, Changchun, China
| | - Jianghua Hou
- Department of Endodontics, Hospital of Stomatology, Jilin University, Changchun, China
| | - Xiuping Meng
- Department of Endodontics, Hospital of Stomatology, Jilin University, Changchun, China
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Jumaniyazova E, Lokhonina A, Dzhalilova D, Miroshnichenko E, Kosyreva A, Fatkhudinov T. The Role of Macrophages in Various Types of Tumors and the Possibility of Their Use as Targets for Antitumor Therapy. Cancers (Basel) 2025; 17:342. [PMID: 39941714 PMCID: PMC11815841 DOI: 10.3390/cancers17030342] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2024] [Revised: 01/07/2025] [Accepted: 01/16/2025] [Indexed: 02/16/2025] Open
Abstract
In solid tumors, tumor-associated macrophages (TAMs) are one of the most numerous populations and play an important role in the processes of tumor cell invasion, metastasis, and angiogenesis. Therefore, TAMs are considered promising diagnostic and prognostic biomarkers of tumors, and many attempts have been made to influence these cells as part of antitumor therapy. There are several key principles of action on ТАМs: the inhibition of monocyte/macrophage transition; the destruction of macrophages; the reprogramming of macrophage phenotypes (polarization of M2 macrophages to M1); the stimulation of phagocytic activity of macrophages and CAR-M therapy. Despite the large number of studies in this area, to date, there are no adequate approaches using antitumor therapy based on alterations in TAM functioning that would show high efficacy when administered in a mono-regimen for the treatment of malignant neoplasms. Studies devoted to the evaluation of the efficacy of drugs acting on TAMs are characterized by a small sample and the large heterogeneity of patient groups; in addition, in such studies, chemotherapy or immunotherapy is used, which significantly complicates the evaluation of the effectiveness of the agent acting on TAMs. In this review, we attempted to systematize the evidence on attempts to influence TAMs in malignancies such as lung cancer, breast cancer, colorectal cancer, cervical cancer, prostate cancer, gastric cancer, head and neck squamous cell cancer, and soft tissue sarcomas.
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Affiliation(s)
- Enar Jumaniyazova
- Research Institute of Molecular and Cellular Medicine, Peoples’ Friendship University of Russia (RUDN University), 6 Miklukho-Maklaya Street, 117198 Moscow, Russia
| | - Anastasiya Lokhonina
- Research Institute of Molecular and Cellular Medicine, Peoples’ Friendship University of Russia (RUDN University), 6 Miklukho-Maklaya Street, 117198 Moscow, Russia
- Avtsyn Research Institute of Human Morphology, FSBSI Petrovsky National Research Centre of Surgery, 3 Tsyurupy Street, 117418 Moscow, Russia
- National Medical Research Center for Obstetrics, Gynecology and Perinatology Named after Academician V.I. Kulakov, Ministry of Healthcare of Russian Federation, 4 Oparina Street, 117997 Moscow, Russia
| | - Dzhuliia Dzhalilova
- Research Institute of Molecular and Cellular Medicine, Peoples’ Friendship University of Russia (RUDN University), 6 Miklukho-Maklaya Street, 117198 Moscow, Russia
- Avtsyn Research Institute of Human Morphology, FSBSI Petrovsky National Research Centre of Surgery, 3 Tsyurupy Street, 117418 Moscow, Russia
| | - Ekaterina Miroshnichenko
- Research Institute of Molecular and Cellular Medicine, Peoples’ Friendship University of Russia (RUDN University), 6 Miklukho-Maklaya Street, 117198 Moscow, Russia
- Avtsyn Research Institute of Human Morphology, FSBSI Petrovsky National Research Centre of Surgery, 3 Tsyurupy Street, 117418 Moscow, Russia
| | - Anna Kosyreva
- Research Institute of Molecular and Cellular Medicine, Peoples’ Friendship University of Russia (RUDN University), 6 Miklukho-Maklaya Street, 117198 Moscow, Russia
- Avtsyn Research Institute of Human Morphology, FSBSI Petrovsky National Research Centre of Surgery, 3 Tsyurupy Street, 117418 Moscow, Russia
| | - Timur Fatkhudinov
- Research Institute of Molecular and Cellular Medicine, Peoples’ Friendship University of Russia (RUDN University), 6 Miklukho-Maklaya Street, 117198 Moscow, Russia
- Avtsyn Research Institute of Human Morphology, FSBSI Petrovsky National Research Centre of Surgery, 3 Tsyurupy Street, 117418 Moscow, Russia
- National Medical Research Center for Obstetrics, Gynecology and Perinatology Named after Academician V.I. Kulakov, Ministry of Healthcare of Russian Federation, 4 Oparina Street, 117997 Moscow, Russia
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Fan X, Brunetti TM, Jackson K, Roop DR. Single-Cell Profiling Reveals Global Immune Responses during the Progression of Murine Epidermal Neoplasms. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.12.24.630251. [PMID: 39763798 PMCID: PMC11703249 DOI: 10.1101/2024.12.24.630251] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/30/2025]
Abstract
Immune cells determine the role of the tumor microenvironment during tumor progression, either suppressing tumor formation or promoting tumorigenesis. We analyzed the profile of immune cells in the tumor microenvironment of control mouse skins and skin tumors at the single-cell level. We identified 15 CD45 + immune cell clusters, which broadly represent the most functionally characterized immune cell types including macrophages, Langerhans cells (LC), conventional type 1 dendritic cells (cDC1), conventional type 2 dendritic cells (cDC2), migratory/mature dendritic cells (mDC), dendritic epidermal T cells (DETC), dermal γδ T cells (γδT), T cells, regulatory T cells (Tregs), natural killer cells (NK), type 2 innate lymphoid cells (ILC2), neutrophils (Neu), mast cells (Mast), and two proliferating populations (Prolif.1 and Prolif.2). Skin tumor progression reprogramed immune cells and led to a marked increase in the relative percentages of macrophages, cDC2, mDC, Tregs, and Neu. Macrophages, the largest cell cluster of immune cells in skin tumors. In addition, macrophages emerged as the predominant communication 'hub' in skin tumors, highlighting the importance of macrophages during skin tumor progression. In contrast, other immune cell clusters decreased during skin tumor progression, including DETC, γδT, ILC2, and LC. In addition, skin tumor progression dramatically upregulated Jak2/Stat3 expression and the interferon response across various immune cell clusters. Further, skin tumor progression activated T cells and NK cells indicated by elevated expression of IFN-γ and Granzyme B in skin tumors. Meanwhile, a pronounced infiltration of M2-macrophages and Tregs in skin tumors created an immunosuppressive microenvironment, consistent with the elevated expression of the Stat3 pathway in skin tumors. In summary, our study elucidates the immune cell landscape of epidermal neoplasms, offering a comprehensive understanding of the immune response during skin tumor progression and providing new insights into cancer immune evasion mechanisms.
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10
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Yang S, Lin M, Hao S, Ye H, Zhang X. Current hotspots and trends in cancer metabolic reprogramming: a scientometric analysis. Front Immunol 2024; 15:1497461. [PMID: 39588377 PMCID: PMC11586341 DOI: 10.3389/fimmu.2024.1497461] [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: 09/17/2024] [Accepted: 10/18/2024] [Indexed: 11/27/2024] Open
Abstract
Background Metabolic reprogramming (MR) in cancer (CA) has been a focus of intense research in the recent two decades. This phenomenon has attracted great interest because it offers potential targets for cancer therapy. To capture the intellectual landscape of this field, we conducted a bibliometric analysis to assess the scientific output, major contributors, and trends in the MR/CA research. Methods We performed a systematic search using the Web of Science to retrieve articles published on MR of cancer from 2006 until 2023. The bibliometric tools such as Biblioshiny, VOSviewer, and Microsoft Excel were used to identify the most prolific authors, institutions, citation patterns, and keywords. We also used co-citation analysis to map the conceptual structure of the field and identify influential publications. Furthermore, we examined the literature by analyzing publication years, citations, and research impact factors. Results A total of 4,465 publications about MR/CA were retrieved. Publications on MR/CA increased rapidly from 2006 to 2023. Frontiers in Oncology published the most papers, while Cell Metabolism had the most citations. Highly cited papers were mainly published in Cancer Cell, Nature, Cell, Science and Cell Metabolism. China and the United States led the way in publications and contributed the most to MR/CA research. The University of Texas System, Chinese Academy of Sciences, and Fudan University were the most productive institutions. The profitable authors were Deberardinis Ralph J and Chiarugi Paola. The current topics included MR in tumorigenesis and progression of CA, MR of tumor cells and tumor microenvironment, the effect of MR on the CA treatment, the underlying mechanisms of MR (such as gene regulation, epigenetics, extracellular vesicles, and gut microbiota), and the modulation of MR. Some topics such as tumor microenvironment, lipid MR, circular RNA, long noncoding RNA, exosome, prognostic model, and immunotherapy may be the focus of MR/CA research in the next few years. Conclusion This study evaluated the global scientific output in the field of MR/CA research, analyzing its quantitative characteristics. It identified some significant and distinguished papers and compiled information regarding the current status and evolving trends of MR/CA research.
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Affiliation(s)
- Shanshan Yang
- Traditional Chinese Medicine and Integrative Medicine Department, Peking University First Hospital, Beijing, China
| | - Miaomiao Lin
- Traditional Chinese Medicine and Integrative Medicine Department, Peking University First Hospital, Beijing, China
| | - Shaodong Hao
- Spleen and Stomach Disease Department, Fangshan Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Hui Ye
- Traditional Chinese Medicine and Integrative Medicine Department, Peking University First Hospital, Beijing, China
| | - Xuezhi Zhang
- Traditional Chinese Medicine and Integrative Medicine Department, Peking University First Hospital, Beijing, China
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11
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Zhou Y, Na C, Li Z. Novel insights into immune cells modulation of tumor resistance. Crit Rev Oncol Hematol 2024; 202:104457. [PMID: 39038527 DOI: 10.1016/j.critrevonc.2024.104457] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2024] [Revised: 07/16/2024] [Accepted: 07/17/2024] [Indexed: 07/24/2024] Open
Abstract
Tumor resistance poses a significant challenge to effective cancer treatment, making it imperative to explore new therapeutic strategies. Recent studies have highlighted the profound involvement of immune cells in the development of tumor resistance. Within the tumor microenvironment, macrophages undergo polarization into the M2 phenotype, thus promoting the emergence of drug-resistant tumors. Neutrophils contribute to tumor resistance by forming extracellular traps. While T cells and natural killer (NK) cells exert their impact through direct cytotoxicity against tumor cells. Additionally, dendritic cells (DCs) have been implicated in preventing tumor drug resistance by stimulating T cell activation. In this review, we provide a comprehensive summary of the current knowledge regarding immune cell-mediated modulation of tumor resistance at the molecular level, with a particular focus on macrophages, neutrophils, DCs, T cells, and NK cells. The targeting of immune cell modulation exhibits considerable potential for addressing drug resistance, and an in-depth understanding of the molecular interactions between immune cells and tumor cells holds promise for the development of innovative therapies. Furthermore, we explore the clinical implications of these immune cells in the treatment of drug-resistant tumors. This review emphasizes the exploration of novel approaches that harness the functional capabilities of immune cells to effectively overcome drug-resistant tumors.
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Affiliation(s)
- Yi Zhou
- Scientific Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen 518107, China; School of Medicine, Sun Yat-sen University, Shenzhen 518107, China
| | - Chuhan Na
- Scientific Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen 518107, China; School of Medicine, Sun Yat-sen University, Shenzhen 518107, China
| | - Zhigang Li
- Scientific Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen 518107, China; Shenzhen Key Laboratory of Chinese Medicine Active Substance Screening and Translational Research, Shenzhen 518107, China.
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12
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Zhao M, Chen YL, Yang LH. Advancements in the study of glucose metabolism in relation to tumor progression and treatment. PROGRESS IN BIOPHYSICS AND MOLECULAR BIOLOGY 2024; 192:11-18. [PMID: 39111717 DOI: 10.1016/j.pbiomolbio.2024.08.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/03/2024] [Revised: 07/31/2024] [Accepted: 08/05/2024] [Indexed: 08/13/2024]
Abstract
Sugar serves as the primary energy source for mammals, with glucose metabolism facilitating energy acquisition in human cells. The proper functioning of intracellular glucose metabolism is essential for the maintenance of orderly and healthy physiological activities. Tumor cells, characterized by uncontrolled growth, exhibit dysregulated proliferation and apoptosis processes, leading to abnormal alterations in glucose metabolism. Specifically, tumor cells exhibit a shift towards aerobic glycolysis, resulting in the production of lactic acid that can be utilized as a metabolic intermediate for sustained tumor cell growth. This article provides a comprehensive overview of the enzymes involved in glucose metabolism and the alterations in gene expression that occur during tumor progression. It also examines the current research on targeting abnormal glucose metabolism processes for tumor treatment and discusses potential future directions for utilizing glucose metabolism as a therapeutic target.
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Affiliation(s)
- Meng Zhao
- Clinical Biochemistry Teaching and Research Office, Medical College, Henan University of Traditional Chinese Medicine, Zhengzhou, China
| | - Yu-Long Chen
- Department of Pathophysiology, College of Traditional Chinese Medicine, Henan University of Traditional Chinese Medicine, Zhengzhou, China.
| | - Lian-He Yang
- Clinical Biochemistry Teaching and Research Office, Medical College, Henan University of Traditional Chinese Medicine, Zhengzhou, China.
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13
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Liu W, Ou C, Xue R, Yang X, Ye Y, Wang X, Xie J. Opioid-free anesthesia attenuates perioperative immunosuppression by regulating macrophages polarization in gastric cancer patients treated with neoadjuvant PD-1 inhibitor. Front Immunol 2024; 15:1438859. [PMID: 39430763 PMCID: PMC11488646 DOI: 10.3389/fimmu.2024.1438859] [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: 05/26/2024] [Accepted: 09/04/2024] [Indexed: 10/22/2024] Open
Abstract
Background Opioid anesthesia can modulate the impaired immune response and opioid-sparing anesthesia may preserve immune functions. This study was performed to assess the effects of opioid-free anesthesia (OFA) and opioid-based anesthesia (OA) on perioperative macrophages differentiation, cytokine changes, and perioperative complications in locally advanced GC (LAGC) patients. Methods We used quality of recovery-15 (QoR-15) questionnaire scores and visual analog scale (VAS) scores to compare postoperative quality of recovery and pain level. In addition, the adverse reactions of patients in the two groups were compared. The perioperative serum level of inflammatory cytokines and the ratio of macrophage subtypes were detected. Results The OFA group had significantly longer extubation time and PACU stay, whereas the OA group had significantly higher rate of hypotension, higher doses of norepinephrine, higher PONV and dizziness rate, and delayed flatus passage time. The QoR-15 score on postoperative 24 h was significantly higher in OFA group than in OA group. At the end of or after the surgery, the OFA group had higher levels of interleukin (IL)-12, IL-1β, tumor necrosis factor (TNF)-α, CD68+CD163- macrophage rate, but lower levels of IL-10, transforming growth factor (TGF)-β, and CD68+CD163+ macrophage rate, indicating OFA attenuated perioperative immunosuppression by diminishing M2 and promoting M1 macrophage polarization. And the reversal tendency is more obvious in LAGC patients with neoadjuvant PD-1 inhibitor. Conclusions The OFA may attenuate perioperative immunosuppression by diminishing M2 and promoting M1 macrophage polarization in LAGC patients with neoadjuvant PD-1 inhibitor. Clinical trial registration http://gcpgl.sysucc.org.cn, identifier 2022-FXY-001.
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Affiliation(s)
- Wenjian Liu
- Department of Anesthesiology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
| | - Chaopeng Ou
- Department of Anesthesiology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
| | - Ruifeng Xue
- Department of Anesthesiology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
| | - Xiaohua Yang
- Department of Anesthesiology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
- Department of Anatomy and Neurobiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Yaqi Ye
- Department of Anesthesiology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
| | - Xudong Wang
- Department of Anesthesiology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
| | - Jingdun Xie
- Department of Anesthesiology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
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14
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Tang Q, Wu S, Zhao B, Li Z, Zhou Q, Yu Y, Yang X, Wang R, Wang X, Wu W, Wang S. Reprogramming of glucose metabolism: The hallmark of malignant transformation and target for advanced diagnostics and treatments. Biomed Pharmacother 2024; 178:117257. [PMID: 39137648 DOI: 10.1016/j.biopha.2024.117257] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Revised: 07/30/2024] [Accepted: 08/02/2024] [Indexed: 08/15/2024] Open
Abstract
Reprogramming of cancer metabolism has become increasingly concerned over the last decade, particularly the reprogramming of glucose metabolism, also known as the "Warburg effect". The reprogramming of glucose metabolism is considered a novel hallmark of human cancers. A growing number of studies have shown that reprogramming of glucose metabolism can regulate many biological processes of cancers, including carcinogenesis, progression, metastasis, and drug resistance. In this review, we summarize the major biological functions, clinical significance, potential targets and signaling pathways of glucose metabolic reprogramming in human cancers. Moreover, the applications of natural products and small molecule inhibitors targeting glucose metabolic reprogramming are analyzed, some clinical agents targeting glucose metabolic reprogramming and trial statuses are summarized, as well as the pros and cons of targeting glucose metabolic reprogramming for cancer therapy are analyzed. Overall, the reprogramming of glucose metabolism plays an important role in the prediction, prevention, diagnosis and treatment of human cancers. Glucose metabolic reprogramming-related targets have great potential to serve as biomarkers for improving individual outcomes and prognosis in cancer patients. The clinical innovations related to targeting the reprogramming of glucose metabolism will be a hotspot for cancer therapy research in the future. We suggest that more high-quality clinical trials with more abundant drug formulations and toxicology experiments would be beneficial for the development and clinical application of drugs targeting reprogramming of glucose metabolism.This review will provide the researchers with the broader perspective and comprehensive understanding about the important significance of glucose metabolic reprogramming in human cancers.
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Affiliation(s)
- Qing Tang
- State Key Laboratory of Traditional Chinese Medicine Syndrome, Clinical and Basic Research Team of TCM Prevention and Treatment of NSCLC, Guangdong Provincial Hospital of Chinese Medicine; State Key Laboratory of Dampness Syndrome of Chinese Medicine, Guangdong Provincial Key Laboratory of Chinese Medicine for Prevention and Treatment of Refractory Chronic Diseases, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510120, P. R. China; The Second Clinical Medical College, The Second Affiliated Hospital, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510120, P. R. China; Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangdong Provincial Hospital of Chinese Medicine, Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, Guangdong, 510120, P. R. China; Department of Oncology, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, Guangdong 510120, P. R. China.
| | - Siqi Wu
- The First Clinical School of Guangzhou University of Chinese Medicine；Department of Oncology, the First Affiliated Hospital of Guangzhou University of Chinese Medicine,Guangzhou 510000, China; Zhongshan Institute for Drug Discovery, SIMM, CAS, Zhongshan 528400, China
| | - Baiming Zhao
- The Second Clinical Medical College, The Second Affiliated Hospital, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510120, P. R. China; Department of Traditional Chinese Medicine, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510630, P.R. China
| | - Zhanyang Li
- School of Biosciences and Biopharmaceutics, Guangdong Province Key Laboratory for Biotechnology Drug Candidates, Guangdong Pharmaceutical University, Guangzhou, 510006, China
| | - Qichun Zhou
- State Key Laboratory of Traditional Chinese Medicine Syndrome, Clinical and Basic Research Team of TCM Prevention and Treatment of NSCLC, Guangdong Provincial Hospital of Chinese Medicine; State Key Laboratory of Dampness Syndrome of Chinese Medicine, Guangdong Provincial Key Laboratory of Chinese Medicine for Prevention and Treatment of Refractory Chronic Diseases, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510120, P. R. China; The Second Clinical Medical College, The Second Affiliated Hospital, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510120, P. R. China; Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangdong Provincial Hospital of Chinese Medicine, Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, Guangdong, 510120, P. R. China; Department of Oncology, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, Guangdong 510120, P. R. China
| | - Yaya Yu
- The Second Clinical Medical College, The Second Affiliated Hospital, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510120, P. R. China
| | - Xiaobing Yang
- The Second Clinical Medical College, The Second Affiliated Hospital, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510120, P. R. China; Department of Oncology, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, Guangdong 510120, P. R. China
| | - Rui Wang
- State Key Laboratory of Traditional Chinese Medicine Syndrome, Clinical and Basic Research Team of TCM Prevention and Treatment of NSCLC, Guangdong Provincial Hospital of Chinese Medicine; State Key Laboratory of Dampness Syndrome of Chinese Medicine, Guangdong Provincial Key Laboratory of Chinese Medicine for Prevention and Treatment of Refractory Chronic Diseases, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510120, P. R. China; The Second Clinical Medical College, The Second Affiliated Hospital, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510120, P. R. China; Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangdong Provincial Hospital of Chinese Medicine, Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, Guangdong, 510120, P. R. China; Department of Oncology, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, Guangdong 510120, P. R. China
| | - Xi Wang
- State Key Laboratory of Traditional Chinese Medicine Syndrome, Clinical and Basic Research Team of TCM Prevention and Treatment of NSCLC, Guangdong Provincial Hospital of Chinese Medicine; State Key Laboratory of Dampness Syndrome of Chinese Medicine, Guangdong Provincial Key Laboratory of Chinese Medicine for Prevention and Treatment of Refractory Chronic Diseases, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510120, P. R. China; The Second Clinical Medical College, The Second Affiliated Hospital, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510120, P. R. China; Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangdong Provincial Hospital of Chinese Medicine, Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, Guangdong, 510120, P. R. China; Department of Oncology, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, Guangdong 510120, P. R. China
| | - Wanyin Wu
- State Key Laboratory of Traditional Chinese Medicine Syndrome, Clinical and Basic Research Team of TCM Prevention and Treatment of NSCLC, Guangdong Provincial Hospital of Chinese Medicine; State Key Laboratory of Dampness Syndrome of Chinese Medicine, Guangdong Provincial Key Laboratory of Chinese Medicine for Prevention and Treatment of Refractory Chronic Diseases, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510120, P. R. China; The Second Clinical Medical College, The Second Affiliated Hospital, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510120, P. R. China; Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangdong Provincial Hospital of Chinese Medicine, Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, Guangdong, 510120, P. R. China; Department of Oncology, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, Guangdong 510120, P. R. China.
| | - Sumei Wang
- State Key Laboratory of Traditional Chinese Medicine Syndrome, Clinical and Basic Research Team of TCM Prevention and Treatment of NSCLC, Guangdong Provincial Hospital of Chinese Medicine; State Key Laboratory of Dampness Syndrome of Chinese Medicine, Guangdong Provincial Key Laboratory of Chinese Medicine for Prevention and Treatment of Refractory Chronic Diseases, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510120, P. R. China; The Second Clinical Medical College, The Second Affiliated Hospital, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510120, P. R. China; Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangdong Provincial Hospital of Chinese Medicine, Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, Guangdong, 510120, P. R. China; Department of Oncology, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, Guangdong 510120, P. R. China.
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Fu Q, Wu X, Lu Z, Chang Y, Jin Q, Jin T, Zhang M. TMEM205 induces TAM/M2 polarization to promote cisplatin resistance in gastric cancer. Gastric Cancer 2024; 27:998-1015. [PMID: 38850316 PMCID: PMC11335886 DOI: 10.1007/s10120-024-01517-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2023] [Accepted: 05/26/2024] [Indexed: 06/10/2024]
Abstract
Cisplatin (DDP) is a basic chemotherapy drug for gastric cancer (GC). With the increase of DDP drug concentration in clinical treatment, cancer cells gradually became resistant. Therefore, it is necessary to find effective therapeutic targets to enhance the sensitivity of GC to DDP. Studies have shown that Transmembrane protein 205 (TMEM205) is overexpressed in DDP-resistant human epidermoid carcinoma cells and correlates with drug resistance, and database analyses show that TMEM 205 is also overexpressed in GC, but its role in cisplatin-resistant gastric cancer remains unclear. In this study, we chose a variety of experiments in vivo and vitro, aiming to investigate the role of TMEM 205 in cisplatin resistance in gastric cancer. The results showed that TMEM 205 promoted proliferation, stemness, epithelial-mesenchymal transition (EMT), migration and angiogenesis of gastric cancer cells through activation of the Wnt/β-catenin signaling pathway. In addition, TMEM205 promotes GC progression by inducing M2 polarization of tumor-associated macrophages (TAMs). These results suggest that TMEM205 may be an effective target to regulate the sensitivity of GC to DDP, providing a new therapeutic direction for clinical treatment.
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Affiliation(s)
- Qiang Fu
- Department of Ultrasound Medicine, Affiliated Hospital of Yanbian University, Yanji, 133000, Jilin, China
- Department of Pathology and Cancer Research Center, Yanbian University Medical College, Yanji, 133002, China
- Key Laboratory of the Science and Technology Department of Jilin Province, Yanji, China
| | - Xuwei Wu
- Department of Pathology and Cancer Research Center, Yanbian University Medical College, Yanji, 133002, China
- Key Laboratory of the Science and Technology Department of Jilin Province, Yanji, China
- Department of Pathology, Chifeng Municipal Hospital, Chifeng, 024000, China
| | - Zhongqi Lu
- Department of Ultrasound Medicine, Affiliated Hospital of Yanbian University, Yanji, 133000, Jilin, China
- Department of Pathology and Cancer Research Center, Yanbian University Medical College, Yanji, 133002, China
- Key Laboratory of the Science and Technology Department of Jilin Province, Yanji, China
| | - Ying Chang
- Department of Ultrasound Medicine, Affiliated Hospital of Yanbian University, Yanji, 133000, Jilin, China
- Department of Pathology and Cancer Research Center, Yanbian University Medical College, Yanji, 133002, China
- Key Laboratory of the Science and Technology Department of Jilin Province, Yanji, China
| | - Quanxin Jin
- Department of Immunology and Pathogenic Biology, Yanbian University Medical College, Yanji, China
| | - Tiefeng Jin
- Department of Pathology and Cancer Research Center, Yanbian University Medical College, Yanji, 133002, China
- Key Laboratory of the Science and Technology Department of Jilin Province, Yanji, China
| | - Meihua Zhang
- Department of Health Examination Centre, Yanbian University Hospital, Yanji, 133002, China.
- Department of Ultrasound Medicine, Affiliated Hospital of Yanbian University, Yanji, 133000, Jilin, China.
- Department of Pathology and Cancer Research Center, Yanbian University Medical College, Yanji, 133002, China.
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Kokilakanit P, Koontongkaew S, Utispan K. Nitric oxide has diverse effects on head and neck cancer cell proliferation and glycolysis. Biomed Rep 2024; 21:106. [PMID: 38868526 PMCID: PMC11168032 DOI: 10.3892/br.2024.1794] [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: 02/09/2024] [Accepted: 05/13/2024] [Indexed: 06/14/2024] Open
Abstract
Glycolysis is a key energy-providing process and one of the hallmarks of cancer. Nitric oxide (NO), a free radical molecule, regulates glycolysis in various cancers. NO can alter the cell cycle and apoptosis in head and neck squamous cell carcinoma (HNSCC) cells. However, the effect of NO on glycolysis in HNSCC cells remains unresolved. The present study investigated the effects of NO on cell proliferation, glucose transporter (GLUT) gene expression and glycolytic indicators in HNSCC cell lines. Two pairs of isogenic HNSCC cell lines, HN18/HN17 and HN30/HN31, were treated with a NO donor, diethylamine NONOate (DEA-NONOate), for 24, 48 and 72 h. Cell proliferation was assessed using MTT assay and NO concentration was measured using the Griess Reagent System. GLUT1, GLUT2, GLUT3, and GLUT4 gene expression was analyzed using reverse transcription-quantitative PCR. Furthermore, hexokinase (HK) activity and lactate production were measured in NO-treated cells using colorimetric assay. NO exhibited concentration-dependent pro- and anti-proliferative effects on the HNSCC cell lines. Lower NO concentrations (5-200 µM) had pro-proliferative effects, whereas NO >200 µM had an anti-proliferative effect on HNSCC cells. NO (5 µM) promoted proliferation and glycolysis in HN18 cells by upregulating GLUT1 and GLUT2 gene expression and increasing HK activity and lactate levels. At 5-20 µM, NO-induced HN17 and HN30 cells demonstrated enhanced proliferation and GLUT2, GLUT3 and GLUT4 gene expression, whereas the glycolytic pathway was not affected. In conclusion, the present study demonstrated distinct proliferative effects of NO on HNSCC cells. NO may promote cell proliferation by stimulating glucose consumption and the glycolytic rate in HN18 cells. The effects of NO in other cell lines may be mediated by a non-glycolysis mechanism and require further investigation.
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Affiliation(s)
- Paopanga Kokilakanit
- Oral Biology Research Unit, Faculty of Dentistry, Thammasat University (Rangsit Campus), Khlong Luang, Pathum Thani 12120, Thailand
| | - Sittichai Koontongkaew
- Department of Oral Health Science, International College of Dentistry, Walailak University, Dusit, Bangkok 10300, Thailand
| | - Kusumawadee Utispan
- Oral Biology Research Unit, Faculty of Dentistry, Thammasat University (Rangsit Campus), Khlong Luang, Pathum Thani 12120, Thailand
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Liu J, Wang T, Zhang W, Huang Y, Wang X, Li Q. Association between Metabolic Reprogramming and Immune Regulation in Digestive Tract Tumors. Oncol Res Treat 2024; 47:273-286. [PMID: 38636467 DOI: 10.1159/000538659] [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] [Accepted: 03/28/2024] [Indexed: 04/20/2024]
Abstract
BACKGROUND The cancers of the digestive tract, including colorectal cancer (CRC), gastric cancer, and esophageal cancer, are part of the most common cancers as well as one of the most important leading causes of cancer death worldwide. SUMMARY Despite the emergence of immune checkpoint inhibitors (e.g., anti-CTLA-4 and anti-PD-1/PD-L1) in the past decade, offering renewed optimism in cancer treatment, only a fraction of patients derive benefit from these therapies. This limited efficacy may stem from tumor heterogeneity and the impact of metabolic reprogramming on both tumor cells and immune cells within the tumor microenvironment (TME). The metabolic reprogramming of glucose, lipids, amino acids, and other nutrients represents a pivotal hallmark of cancer, serving to generate energy, reducing equivalent and biological macromolecule, thereby fostering tumor proliferation and invasion. Significantly, the metabolic reprogramming of tumor cells can orchestrate changes within the TME, rendering patients unresponsive to immunotherapy. KEY MESSAGES In this review, we predominantly encapsulate recent strides on metabolic reprogramming among digestive tract cancer, especially CRC, in the TME with a focus on how these alterations influence anti-tumor immunity. Additionally, we deliberate on potential strategies to address these abnormities in metabolic pathways and the viability of combined therapy within the realm of anti-cancer immunotherapy.
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Affiliation(s)
- Jiafeng Liu
- Department of Pharmacy, Huashan Hospital, Fudan University, Shanghai, China
| | - Tianxiao Wang
- Department of Pharmacy, Huashan Hospital, Fudan University, Shanghai, China
| | - Wenxin Zhang
- Department of Pharmacy, Huashan Hospital, Fudan University, Shanghai, China
| | - Yuxin Huang
- Department of Pharmacy, Huashan Hospital, Fudan University, Shanghai, China
| | - Xinhai Wang
- Department of Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Qunyi Li
- Department of Pharmacy, Huashan Hospital, Fudan University, Shanghai, China
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Fan Z, Cui Y, Chen L, Liu P, Duan W. 23-Hydroxybetulinic acid attenuates 5-fluorouracil resistance of colorectal cancer by modulating M2 macrophage polarization via STAT6 signaling. Cancer Immunol Immunother 2024; 73:83. [PMID: 38554148 PMCID: PMC10981607 DOI: 10.1007/s00262-024-03662-0] [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: 01/01/2024] [Accepted: 02/23/2024] [Indexed: 04/01/2024]
Abstract
Macrophage polarization is closely associated with the inflammatory processes involved in the development and chemoresistance of colorectal cancer (CRC). M2 macrophages, the predominant subtype of tumor-associated macrophages (TAMs) in a wide variety of malignancies, have been demonstrated to promote the resistance of CRC to multiple chemotherapeutic drugs, such as 5-fluorouracil (5-FU). In our study, we investigated the potential of 23-Hydroxybetulinic Acid (23-HBA), a significant active component of Pulsatilla chinensis (P. chinensis), to inhibit the polarization of M2 macrophages induced by IL-4. Our results showed that 23-HBA reduced the expression of M2 specific marker CD206, while downregulating the mRNA levels of M2 related genes (CD206, Arg1, IL-10, and CCL2). Additionally, 23-HBA effectively attenuated the inhibitory effects of the conditioned medium from M2 macrophages on apoptosis in colorectal cancer SW480 cells. Mechanistically, 23-HBA prevented the phosphorylation and nuclear translocation of the STAT6 protein, resulting in the inhibition of IL-10 release in M2 macrophages. Moreover, it interfered with the activation of the IL-10/STAT3/Bcl-2 signaling pathway in SW480 cells, ultimately reducing M2 macrophage-induced resistance to 5-FU. Importantly, depleting STAT6 expression in macrophages abolished the suppressive effect of 23-HBA on M2 macrophage polarization, while also eliminating its ability to decrease M2 macrophage-induced 5-FU resistance in cancer cells. Furthermore, 23-HBA significantly diminished the proportion of M2 macrophages in the tumor tissues of colorectal cancer mice, simultaneously enhancing the anti-cancer efficacy of 5-FU. The findings presented in this study highlight the capacity of 23-HBA to inhibit M2 macrophage polarization, a process that contributes to reduced 5-FU resistance in colorectal cancer.
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Affiliation(s)
- Zeping Fan
- School of Pharmacy, Jiangxi University of Chinese Medicine, Nanchang, 330006, Jiangxi, China
- National Pharmaceutical Engineering Center for Solid Preparation of Chinese Herbal Medicine, Jiangxi University of Chinese Medicine, Nanchang, 330006, Jiangxi, China
| | - Yaru Cui
- School of Pharmacy, Jiangxi University of Chinese Medicine, Nanchang, 330006, Jiangxi, China
- National Pharmaceutical Engineering Center for Solid Preparation of Chinese Herbal Medicine, Jiangxi University of Chinese Medicine, Nanchang, 330006, Jiangxi, China
- Key Laboratory for Evaluation on Anti-Tumor Effect of Chinese Medicine by Strengthening Body Resistance to Eliminate Pathogenic Factors, Nanchang, 330006, Jiangxi, China
| | - Lanying Chen
- School of Pharmacy, Jiangxi University of Chinese Medicine, Nanchang, 330006, Jiangxi, China.
- National Pharmaceutical Engineering Center for Solid Preparation of Chinese Herbal Medicine, Jiangxi University of Chinese Medicine, Nanchang, 330006, Jiangxi, China.
- Key Laboratory for Evaluation on Anti-Tumor Effect of Chinese Medicine by Strengthening Body Resistance to Eliminate Pathogenic Factors, Nanchang, 330006, Jiangxi, China.
| | - Peng Liu
- School of Pharmacy, Jiangxi University of Chinese Medicine, Nanchang, 330006, Jiangxi, China
- National Pharmaceutical Engineering Center for Solid Preparation of Chinese Herbal Medicine, Jiangxi University of Chinese Medicine, Nanchang, 330006, Jiangxi, China
| | - Wenbin Duan
- School of Pharmacy, Jiangxi University of Chinese Medicine, Nanchang, 330006, Jiangxi, China
- National Pharmaceutical Engineering Center for Solid Preparation of Chinese Herbal Medicine, Jiangxi University of Chinese Medicine, Nanchang, 330006, Jiangxi, China
- Key Laboratory for Evaluation on Anti-Tumor Effect of Chinese Medicine by Strengthening Body Resistance to Eliminate Pathogenic Factors, Nanchang, 330006, Jiangxi, China
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Wang S, Wang J, Chen Z, Luo J, Guo W, Sun L, Lin L. Targeting M2-like tumor-associated macrophages is a potential therapeutic approach to overcome antitumor drug resistance. NPJ Precis Oncol 2024; 8:31. [PMID: 38341519 DOI: 10.1038/s41698-024-00522-z] [Citation(s) in RCA: 134] [Impact Index Per Article: 134.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2023] [Accepted: 01/19/2024] [Indexed: 02/12/2024] Open
Abstract
Tumor drug resistance emerges from the interaction of two critical factors: tumor cellular heterogeneity and the immunosuppressive nature of the tumor microenvironment (TME). Tumor-associated macrophages (TAMs) constitute essential components of the TME. M2-like TAMs are essential in facilitating tumor metastasis as well as augmenting the drug resistance of tumors. This review encapsulates the mechanisms that M2-like TAMs use to promote tumor drug resistance. We also describe the emerging therapeutic strategies that are currently targeting M2-like TAMs in combination with other antitumor drugs, with some still undergoing clinical trial evaluation. Furthermore, we summarize and analyze various existing approaches for developing novel drugs that target M2-like TAMs to overcome tumor resistance, highlighting how targeting M2-like TAMs can effectively stop tumor growth, metastasis, and overcome tumor drug resistance.
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Affiliation(s)
- Shujing Wang
- The First Clinical Medical School of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Jingrui Wang
- The First Clinical Medical School of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Zhiqiang Chen
- The First Clinical Medical School of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Jiamin Luo
- The First Clinical Medical School of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Wei Guo
- The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Lingling Sun
- The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Lizhu Lin
- The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China.
- Guangdong Clinical Research Academy of Chinese Medicine, Guangzhou, China.
- Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou, China.
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20
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Zheng S, Li H, Li Y, Chen X, Shen J, Chen M, Zhang C, Wu J, Sun Q. The emerging role of glycolysis and immune evasion in gastric cancer. Cancer Cell Int 2023; 23:317. [PMID: 38071310 PMCID: PMC10710727 DOI: 10.1186/s12935-023-03169-1] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Accepted: 11/27/2023] [Indexed: 08/21/2024] Open
Abstract
Gastric cancer (GC) is the fifth most common malignancy and the third leading cause of cancer-related deaths worldwide. Similar to other types of tumors, GC cells undergo metabolic reprogramming and switch to a "predominantly glycolytic" metabolic pattern to promote its survival and metastasis, also known as "the Warburg effect", which is characterized by enhanced glucose uptake and lactate production. A large number of studies have shown that targeting cancer cells to enhanced glycolysis is a promising strategy, that can make cancer cells more susceptible to other conventional treatment methods of treatment, including chemotherapy, radiotherapy and immunotherapy, and so on. Therefore, this review summarizes the metabolic characteristics of glycolysis in GC cells and focuses on how abnormal lactate concentration can lead to immunosuppression through its effects on the differentiation, metabolism, and function of infiltrating immune cells, and how targeting this phenomenon may be a potential strategy to improve the therapeutic efficacy of GC.
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Affiliation(s)
- Shanshan Zheng
- Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangyin Hospital of Traditional Chinese Medicine, Jiangyin Hospital Affiliated to Nanjing University of Chinese Medicine, Jiangsu, China
- No.1 Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210023, China
| | - Huaizhi Li
- Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangyin Hospital of Traditional Chinese Medicine, Jiangyin Hospital Affiliated to Nanjing University of Chinese Medicine, Jiangsu, China
- No.1 Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210023, China
| | - Yaqi Li
- Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangyin Hospital of Traditional Chinese Medicine, Jiangyin Hospital Affiliated to Nanjing University of Chinese Medicine, Jiangsu, China
- No.1 Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210023, China
| | - Xu Chen
- Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangyin Hospital of Traditional Chinese Medicine, Jiangyin Hospital Affiliated to Nanjing University of Chinese Medicine, Jiangsu, China
| | - Junyu Shen
- Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangyin Hospital of Traditional Chinese Medicine, Jiangyin Hospital Affiliated to Nanjing University of Chinese Medicine, Jiangsu, China
- No.1 Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210023, China
| | - Menglin Chen
- Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangyin Hospital of Traditional Chinese Medicine, Jiangyin Hospital Affiliated to Nanjing University of Chinese Medicine, Jiangsu, China
- No.1 Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210023, China
| | - Cancan Zhang
- Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangyin Hospital of Traditional Chinese Medicine, Jiangyin Hospital Affiliated to Nanjing University of Chinese Medicine, Jiangsu, China
- No.1 Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210023, China
| | - Jian Wu
- Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangyin Hospital of Traditional Chinese Medicine, Jiangyin Hospital Affiliated to Nanjing University of Chinese Medicine, Jiangsu, China.
| | - Qingmin Sun
- Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangyin Hospital of Traditional Chinese Medicine, Jiangyin Hospital Affiliated to Nanjing University of Chinese Medicine, Jiangsu, China.
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21
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Zhang J, Hu C, Zhang R, Xu J, Zhang Y, Yuan L, Zhang S, Pan S, Cao M, Qin J, Cheng X, Xu Z. The role of macrophages in gastric cancer. Front Immunol 2023; 14:1282176. [PMID: 38143746 PMCID: PMC10746385 DOI: 10.3389/fimmu.2023.1282176] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2023] [Accepted: 11/24/2023] [Indexed: 12/26/2023] Open
Abstract
As one of the deadliest cancers of the gastrointestinal tract, there has been limited improvement in long-term survival rates for gastric cancer (GC) in recent decades. The poor prognosis is attributed to difficulties in early detection, minimal opportunity for radical resection and resistance to chemotherapy and radiation. Macrophages are among the most abundant infiltrating immune cells in the GC stroma. These cells engage in crosstalk with cancer cells, adipocytes and other stromal cells to regulate metabolic, inflammatory and immune status, generating an immunosuppressive tumour microenvironment (TME) and ultimately promoting tumour initiation and progression. In this review, we summarise recent advances in our understanding of the origin of macrophages and their types and polarisation in cancer and provide an overview of the role of macrophages in GC carcinogenesis and development and their interaction with the GC immune microenvironment and flora. In addition, we explore the role of macrophages in preclinical and clinical trials on drug resistance and in treatment of GC to assess their potential therapeutic value in this disease.
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Affiliation(s)
- Jiaqing Zhang
- Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China
- Department of Gastric Surgery, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institutes of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
| | - Can Hu
- Department of Gastric Surgery, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institutes of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
- Key Laboratory of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province, Hangzhou, China
- Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, Zhejiang Cancer Hospital, Hangzhou, China
| | - Ruolan Zhang
- Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China
- Department of Gastric Surgery, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institutes of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
| | - Jingli Xu
- Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China
- Department of Gastric Surgery, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institutes of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
| | - Yanqiang Zhang
- Department of Gastric Surgery, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institutes of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
- Key Laboratory of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province, Hangzhou, China
- Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, Zhejiang Cancer Hospital, Hangzhou, China
| | - Li Yuan
- Department of Gastric Surgery, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institutes of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
- Key Laboratory of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province, Hangzhou, China
- Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, Zhejiang Cancer Hospital, Hangzhou, China
| | - Shengjie Zhang
- Department of Gastric Surgery, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institutes of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
- Key Laboratory of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province, Hangzhou, China
- Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, Zhejiang Cancer Hospital, Hangzhou, China
| | - Siwei Pan
- Department of Gastric Surgery, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institutes of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
- Key Laboratory of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province, Hangzhou, China
- Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, Zhejiang Cancer Hospital, Hangzhou, China
| | - Mengxuan Cao
- Department of Gastric Surgery, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institutes of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
- Key Laboratory of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province, Hangzhou, China
- Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, Zhejiang Cancer Hospital, Hangzhou, China
| | - Jiangjiang Qin
- Department of Gastric Surgery, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institutes of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
- Key Laboratory of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province, Hangzhou, China
- Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, Zhejiang Cancer Hospital, Hangzhou, China
| | - Xiangdong Cheng
- Department of Gastric Surgery, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institutes of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
- Key Laboratory of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province, Hangzhou, China
- Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, Zhejiang Cancer Hospital, Hangzhou, China
| | - Zhiyuan Xu
- Department of Gastric Surgery, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institutes of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
- Key Laboratory of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province, Hangzhou, China
- Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, Zhejiang Cancer Hospital, Hangzhou, China
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22
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Wang X, Zhou L, Wang H, Chen W, Jiang L, Ming G, Wang J. Metabolic reprogramming, autophagy, and ferroptosis: Novel arsenals to overcome immunotherapy resistance in gastrointestinal cancer. Cancer Med 2023; 12:20573-20589. [PMID: 37860928 PMCID: PMC10660574 DOI: 10.1002/cam4.6623] [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: 04/19/2023] [Revised: 09/05/2023] [Accepted: 09/29/2023] [Indexed: 10/21/2023] Open
Abstract
BACKGROUND Gastrointestinal cancer poses a serious health threat owing to its high morbidity and mortality. Although immune checkpoint blockade (ICB) therapies have achieved meaningful success in most solid tumors, the improvement in survival in gastrointestinal cancers is modest, owing to sparse immune response and widespread resistance. Metabolic reprogramming, autophagy, and ferroptosis are key regulators of tumor progression. METHODS A literature review was conducted to investigate the role of the metabolic reprogramming, autophagy, and ferroptosis in immunotherapy resistance of gastrointestinal cancer. RESULTS Metabolic reprogramming, autophagy, and ferroptosis play pivotal roles in regulating the survival, differentiation, and function of immune cells within the tumor microenvironment. These processes redefine the nutrient allocation blueprint between cancer cells and immune cells, facilitating tumor immune evasion, which critically impacts the therapeutic efficacy of immunotherapy for gastrointestinal cancers. Additionally, there exists profound crosstalk among metabolic reprogramming, autophagy, and ferroptosis. These interactions are paramount in anti-tumor immunity, further promoting the formation of an immunosuppressive microenvironment and resistance to immunotherapy. CONCLUSIONS Consequently, it is imperative to conduct comprehensive research on the roles of metabolic reprogramming, autophagy, and ferroptosis in the resistance of gastrointestinal tumor immunotherapy. This understanding will illuminate the clinical potential of targeting these pathways and their regulatory mechanisms to overcome immunotherapy resistance in gastrointestinal cancers.
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Affiliation(s)
- Xiangwen Wang
- Department of General SurgeryThe First Hospital of Lanzhou UniversityLanzhouChina
| | - Liwen Zhou
- Department of StomatologyThe First Hospital of Lanzhou UniversityLanzhouChina
| | - Hongpeng Wang
- Department of General SurgeryThe First Hospital of Lanzhou UniversityLanzhouChina
| | - Wei Chen
- Department of General SurgeryThe First Hospital of Lanzhou UniversityLanzhouChina
| | - Lei Jiang
- Department of General SurgeryThe First Hospital of Lanzhou UniversityLanzhouChina
| | - Guangtao Ming
- Department of General SurgeryThe First Hospital of Lanzhou UniversityLanzhouChina
| | - Jun Wang
- Department of General SurgeryThe First Hospital of Lanzhou UniversityLanzhouChina
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23
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Jin J, Zhao Q, Wei Z, Chen K, Su Y, Hu X, Peng X. Glycolysis-cholesterol metabolic axis in immuno-oncology microenvironment: emerging role in immune cells and immunosuppressive signaling. Cell Biosci 2023; 13:189. [PMID: 37828561 PMCID: PMC10571292 DOI: 10.1186/s13578-023-01138-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2023] [Accepted: 09/21/2023] [Indexed: 10/14/2023] Open
Abstract
Cell proliferation and function require nutrients, energy, and biosynthesis activity to duplicate repertoires for each daughter. It is therefore not surprising that tumor microenvironment (TME) metabolic reprogramming primarily orchestrates the interaction between tumor and immune cells. Tumor metabolic reprogramming affords bioenergetic, signaling intermediates, and biosynthesis requirements for both malignant and immune cells. Different immune cell subsets are recruited into the TME, and these manifestations have distinct effects on tumor progression and therapeutic outcomes, especially the mutual contribution of glycolysis and cholesterol metabolism. In particularly, glycolysis-cholesterol metabolic axis interconnection plays a critical role in the TME modulation, and their changes in tumor metabolism appear to be a double-edged sword in regulating various immune cell responses and immunotherapy efficacy. Hence, we discussed the signature manifestation of the glycolysis-cholesterol metabolic axis and its pivotal role in tumor immune regulation. We also highlight how hypothetical combinations of immunotherapy and glycolysis/cholesterol-related metabolic interventions unleash the potential of anti-tumor immunotherapies, as well as developing more effective personalized treatment strategies.
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Affiliation(s)
- Jing Jin
- Department of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, People's Republic of China
- West China School of Medicine, Sichuan University, Chengdu, China
| | - Qijie Zhao
- Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Zhigong Wei
- West China School of Medicine, Sichuan University, Chengdu, China
| | - Keliang Chen
- West China School of Medicine, Sichuan University, Chengdu, China
| | - Yonglin Su
- Department of Rehabilitation, Cancer Center, West China Hospital, Sichuan University, Sichuan, People's Republic of China.
| | - Xiaolin Hu
- Department of Nursing, West China Hospital, Sichuan University, Chengdu, People's Republic of China.
| | - Xingchen Peng
- Department of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, People's Republic of China.
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24
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Chen W, Hu J, He Y, Yu L, Liu Y, Cheng Y, Jia B, Li X, Yu G, Wang Y. The Interaction Between SMAD1 and YAP1 Is Correlated with Increased Resistance of Gastric Cancer Cells to Cisplatin. Appl Biochem Biotechnol 2023; 195:6050-6067. [PMID: 36418715 DOI: 10.1007/s12010-022-04253-4] [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] [Accepted: 11/08/2022] [Indexed: 11/25/2022]
Abstract
Drug resistance is a major obstacle leading to treating failure and poor outcome in gastric cancer (GC). This study explores the interaction between SMAD family member 1 (SMAD1) and Yes1-associated transcriptional regulator (YAP1) and their roles in cisplatin (DDP) resistance in GC. Transcriptome analysis predicted that SMAD1 is highly expressed in DDP-resistant cells. Elevated SMAD1 expression was detected in GC tissue and cells, especially in DDP-resistant cells (MKN-45/DDP and AGS/DDP). SMAD1 downregulation in cells decreased 50% inhibition value of DDP, reduced proliferation, migration, and invasion, and promoted cell cycle arrest and apoptosis. A protein-protein interaction network suggested a possible SMAD1 and YAP1 interaction in GC. The SMAD1 and YAP1 interaction was validated by chromatin immunoprecipitation (ChIP), co-immunoprecipitation (Co-IP), and luciferase assays. SMAD1 bound to YAP1 and activated its transcription. SMAD1 formed complexes with YAP1 in nucleus, and YAP1 upregulation enhanced SMAD1 activity as well. Upregulation of YAP1 restored the malignant behaviors of GC cells suppressed by SMAD1 silencing. In vivo, SMAD1 silencing suppressed growth and DDP resistance of xenograft tumors in nude mice, and this suppression was blocked by YAP1 overexpression again. In conclusion, this study demonstrates that SMAD1 can interact with YAP1 to enhance the DDP resistance of GC cells.
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Affiliation(s)
- Wanjing Chen
- Department of General Surgery, The Second Hospital of Anhui Medical University, No. 678, Furong Road, Economic and Technological Development District, Hefei, 230601, Anhui, People's Republic of China
| | - Jingtao Hu
- Department of Aviation Health, Anhui Branch of China Eastern Airlines Co. LTD, Hefei, 230012, Anhui, People's Republic of China
| | - Yawei He
- Department of General Surgery, The Second Hospital of Anhui Medical University, No. 678, Furong Road, Economic and Technological Development District, Hefei, 230601, Anhui, People's Republic of China
| | - Liang Yu
- Department of General Surgery, The Second Hospital of Anhui Medical University, No. 678, Furong Road, Economic and Technological Development District, Hefei, 230601, Anhui, People's Republic of China
| | - Yanwei Liu
- Department of General Surgery, The Second Hospital of Anhui Medical University, No. 678, Furong Road, Economic and Technological Development District, Hefei, 230601, Anhui, People's Republic of China
| | - Yusheng Cheng
- Department of General Surgery, The Second Hospital of Anhui Medical University, No. 678, Furong Road, Economic and Technological Development District, Hefei, 230601, Anhui, People's Republic of China
| | - Benli Jia
- Department of General Surgery, The Second Hospital of Anhui Medical University, No. 678, Furong Road, Economic and Technological Development District, Hefei, 230601, Anhui, People's Republic of China
| | - Xianghua Li
- Department of Molecular Pathology, Hefei Da'an Medical Laboratory Co., LTD, Hefei, 230012, Anhui, People's Republic of China
| | - Gang Yu
- Department of General Surgery, The Second Hospital of Anhui Medical University, No. 678, Furong Road, Economic and Technological Development District, Hefei, 230601, Anhui, People's Republic of China.
| | - Yong Wang
- Department of General Surgery, The Second Hospital of Anhui Medical University, No. 678, Furong Road, Economic and Technological Development District, Hefei, 230601, Anhui, People's Republic of China.
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25
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Li J, Sun J, Zeng Z, Liu Z, Ma M, Zheng Z, He Y, Kang W. Tumour-associated macrophages in gastric cancer: From function and mechanism to application. Clin Transl Med 2023; 13:e1386. [PMID: 37608500 PMCID: PMC10444973 DOI: 10.1002/ctm2.1386] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Revised: 08/10/2023] [Accepted: 08/14/2023] [Indexed: 08/24/2023] Open
Abstract
BACKGROUND Gastric cancer (GC) is a malignant tumour, with high morbidity and mortality rates worldwide. The occurrence and development of GC is a complex process involving genetic changes in tumour cells and the influence of the surrounding tumour microenvironment (TME). Accumulative evidence shows that tumour-associated macrophages (TAMs) play a vital role in GC, acting as plentiful and active infiltrating inflammatory cells in the TME. MAIN BODY In this review, the different functions and mechanisms of TAMs in GC progression, including the conversion of phenotypic subtypes; promotion of tumour proliferation, invasion and migration; induction of chemoresistance; promotion of angiogenesis; modulation of immunosuppression; reprogramming of metabolism; and interaction with the microbial community are summarised. Although the role of TAMs in GC remains controversial in clinical settings, clarifying their significance in the treatment selection and prognostic prediction of GC could support optimising TAM-centred clinicaltherapy. CONCLUSION In summary, we reviewed the the phenotypic polarisation, function and molecular mechanism of TAMs and their potential applications in the treatment selection and prognostic prediction of GC.
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Affiliation(s)
- Jie Li
- Department of General SurgeryPeking Union Medical College HospitalChinese Academy of Medical Sciences & Peking Union Medical CollegeBeijingPeople's Republic of China
| | - Juan Sun
- Department of General SurgeryPeking Union Medical College HospitalChinese Academy of Medical Sciences & Peking Union Medical CollegeBeijingPeople's Republic of China
| | - Ziyang Zeng
- Department of General SurgeryPeking Union Medical College HospitalChinese Academy of Medical Sciences & Peking Union Medical CollegeBeijingPeople's Republic of China
| | - Zhen Liu
- Department of General SurgeryPeking Union Medical College HospitalChinese Academy of Medical Sciences & Peking Union Medical CollegeBeijingPeople's Republic of China
| | - Mingwei Ma
- Department of General SurgeryPeking Union Medical College HospitalChinese Academy of Medical Sciences & Peking Union Medical CollegeBeijingPeople's Republic of China
| | - Zicheng Zheng
- Department of General SurgeryPeking Union Medical College HospitalChinese Academy of Medical Sciences & Peking Union Medical CollegeBeijingPeople's Republic of China
| | - Yixuan He
- Department of General SurgeryPeking Union Medical College HospitalChinese Academy of Medical Sciences & Peking Union Medical CollegeBeijingPeople's Republic of China
| | - Weiming Kang
- Department of General SurgeryPeking Union Medical College HospitalChinese Academy of Medical Sciences & Peking Union Medical CollegeBeijingPeople's Republic of China
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26
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Julius P, Siyumbwa SN, Maate F, Moonga P, Kang G, Kaile T, West JT, Wood C, Angeletti PC. Yes-associated protein-1 overexpression in ocular surface squamous neoplasia; a potential diagnostic marker and therapeutic target. Front Oncol 2023; 13:1213426. [PMID: 37476371 PMCID: PMC10354641 DOI: 10.3389/fonc.2023.1213426] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Accepted: 06/20/2023] [Indexed: 07/22/2023] Open
Abstract
Yes-associated protein-1 (YAP-1) is a Hippo system transcription factor, which serves as an oncogene in squamous cell carcinoma, and several solid tumors when the Hippo pathway is dysregulated. Yet, the activity of YAP-1 in ocular surface squamous neoplasia (OSSN) has not been determined. Here, we investigate the relationship between YAP-1 overexpression and OSSN. Using a cross-sectional study design, we recruited 227 OSSN patients from the University Teaching Hospitals in Lusaka, Zambia. Immunohistochemistry was used to assess YAP-1 protein overexpression in tumor tissue relative to surrounding benign squamous epithelium. OSSN patient samples (preinvasive, n = 62, 27% and invasive, n = 165, 73%) were studied. One hundred forty-nine invasive tumors contained adjacent preinvasive tissue, bringing the total number of preinvasive lesions examined to 211 (62 + 149). There was adjacent benign squamous epithelium in 50.2% (114/227) of OSSN samples. Nuclear YAP- 1 was significantly overexpressed in preinvasive (Fisher's (F): p <.0001, Monte Carlo (MC): p <.0001) and invasive (F: p <.0001, MC: p <.0001) OSSN in comparison to adjacent benign squamous epithelium when analyzed for basal keratinocyte positive count, staining intensity, expression pattern, and Immunostaining intensity-distribution index. YAP-1 expression did not differ between preinvasive and invasive OSSN (p >.05), keratinizing and non- keratinizing cancer (p >.05), or between T1/T2 and T3/T4 stages in invasive tumors (p >.05). However, grade 2 and 3 tumors had significantly stronger nucleus YAP-1 overexpression intensity than grade 1 tumors (F: p = .0078, MC: p = .0489). By immunohistochemistry, we identified significant overexpression (upregulation of YAP-1 protein expression) in preinvasive and invasive OSSN lesions compared to neighboring benign squamous epithelium. YAP-1 expression was significantly higher in poorly and moderately differentiated invasive squamous cancer than in well-differentiated carcinomas. Overexpression of YAP-1 within the margin of preinvasive and invasive OSSN, but not in the neighboring normal epithelium, indicates that it plays a role in the development and progression of OSSN.
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Affiliation(s)
- Peter Julius
- Department of Pathology and Microbiology, School of Medicine, University of Zambia, Lusaka, Zambia
| | - Stepfanie N. Siyumbwa
- Department of Pathology and Microbiology, School of Medicine, University of Zambia, Lusaka, Zambia
| | - Fred Maate
- Department of Pathology and Microbiology, School of Medicine, University of Zambia, Lusaka, Zambia
| | - Phyllis Moonga
- University Teaching Hospital, Eye Hospital, Lusaka, Zambia
| | - Guobin Kang
- Department of Interdisciplinary Oncology, Louisiana State University Health Science Center, New Orleans, LA, United States
| | - Trevor Kaile
- Department of Pathology and Microbiology, School of Medicine, University of Zambia, Lusaka, Zambia
| | - John T. West
- Department of Interdisciplinary Oncology, Louisiana State University Health Science Center, New Orleans, LA, United States
| | - Charles Wood
- Department of Interdisciplinary Oncology, Louisiana State University Health Science Center, New Orleans, LA, United States
- Nebraska Center for Virology and the School of Biological Sciences, University of Nebraska-Lincoln, NE, United States
| | - Peter C. Angeletti
- Nebraska Center for Virology and the School of Biological Sciences, University of Nebraska-Lincoln, NE, United States
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27
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Shen Y, Chen JX, Li M, Xiang Z, Wu J, Wang YJ. Role of tumor-associated macrophages in common digestive system malignant tumors. World J Gastrointest Oncol 2023; 15:596-616. [PMID: 37123058 PMCID: PMC10134211 DOI: 10.4251/wjgo.v15.i4.596] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2022] [Revised: 02/12/2023] [Accepted: 03/30/2023] [Indexed: 04/12/2023] Open
Abstract
Many digestive system malignant tumors are characterized by high incidence and mortality rate. Increasing evidence has revealed that the tumor microenvironment (TME) is involved in cancer initiation and tumor progression. Tumor-associated macrophages (TAMs) are a predominant constituent of the TME, and participate in the regulation of various biological behaviors and influence the prognosis of digestive system cancer. TAMs can be mainly classified into the antitumor M1 phenotype and protumor M2 phenotype. The latter especially are crucial drivers of tumor invasion, growth, angiogenesis, metastasis, immunosuppression, and resistance to therapy. TAMs are of importance in the occurrence, development, diagnosis, prognosis, and treatment of common digestive system malignant tumors. In this review, we summarize the role of TAMs in common digestive system malignant tumors, including esophageal, gastric, colorectal, pancreatic and liver cancers. How TAMs promote the development of tumors, and how they act as potential therapeutic targets and their clinical applications are also described.
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Affiliation(s)
- Yue Shen
- Department of Dermatology, Suzhou Municipal Hospital, Suzhou 215008, Jiangsu Province, China
| | - Jia-Xi Chen
- School of Medicine, Zhejiang University, Hangzhou 310009, Zhejiang Province, China
| | - Ming Li
- Department of Pathology, Suzhou Municipal Hospital, Suzhou 215008, Jiangsu Province, China
| | - Ze Xiang
- School of Medicine, Zhejiang University, Hangzhou 310009, Zhejiang Province, China
| | - Jian Wu
- Department of Clinical Laboratory, Suzhou Municipal Hospital, Suzhou 215008, Jiangsu Province, China
| | - Yi-Jin Wang
- School of Medicine, Southern University of Science and Technology, Shenzhen 518055, Guangdong Province, China
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28
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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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29
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Liu Y, Li C, Lu Y, Liu C, Yang W. Tumor microenvironment-mediated immune tolerance in development and treatment of gastric cancer. Front Immunol 2022; 13:1016817. [PMID: 36341377 PMCID: PMC9630479 DOI: 10.3389/fimmu.2022.1016817] [Citation(s) in RCA: 81] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Accepted: 10/07/2022] [Indexed: 11/24/2022] Open
Abstract
Tumor microenvironment is the general term for all non-cancer components and their metabolites in tumor tissue. These components include the extracellular matrix, fibroblasts, immune cells, and endothelial cells. In the early stages of tumors, the tumor microenvironment has a tumor suppressor function. As the tumor progresses, tumor immune tolerance is induced under the action of various factors, such that the tumor suppressor microenvironment is continuously transformed into a tumor-promoting microenvironment, which promotes tumor immune escape. Eventually, tumor cells manifest the characteristics of malignant proliferation, invasion, metastasis, and drug resistance. In recent years, stress effects of the extracellular matrix, metabolic and phenotypic changes of innate immune cells (such as neutrophils, mast cells), and adaptive immune cells in the tumor microenvironment have been revealed to mediate the emerging mechanisms of immune tolerance, providing us with a large number of emerging therapeutic targets to relieve tumor immune tolerance. Gastric cancer is one of the most common digestive tract malignancies worldwide, whose mortality rate remains high. According to latest guidelines, the first-line chemotherapy of advanced gastric cancer is the traditional platinum and fluorouracil therapy, while immunotherapy for gastric cancer is extremely limited, including only Human epidermal growth factor receptor 2 (HER-2) and programmed death ligand 1 (PD-L1) targeted drugs, whose benefits are limited. Clinical experiments confirmed that cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), vascular endothelial growth factor receptor (VEGFR) and other targeted drugs alone or in combination with other drugs have limited efficacy in patients with advanced gastric cancer, far less than in lung cancer, colon cancer, and other tumors. The failure of immunotherapy is mainly related to the induction of immune tolerance in the tumor microenvironment of gastric cancer. Therefore, solving the immune tolerance of tumors is key to the success of gastric cancer immunotherapy. In this study, we summarize the latest mechanisms of various components of the tumor microenvironment in gastric cancer for inducing immune tolerance and promoting the formation of the malignant phenotype of gastric cancer, as well as the research progress of targeting the tumor microenvironment to overcome immune tolerance in the treatment of gastric cancer.
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Affiliation(s)
- Yuanda Liu
- Department of Endoscopy Center, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Changfeng Li
- Department of Endoscopy Center, China-Japan Union Hospital of Jilin University, Changchun, China
- *Correspondence: Changfeng Li, ; Wei Yang,
| | - Yaoping Lu
- Department of Immunology, College of Basic Medical Sciences, Jilin University, Changchun, China
| | - Chang Liu
- Department of Endoscopy Center, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Wei Yang
- Department of Immunology, College of Basic Medical Sciences, Jilin University, Changchun, China
- *Correspondence: Changfeng Li, ; Wei Yang,
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30
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Wen Y, Zhu Y, Zhang C, Yang X, Gao Y, Li M, Yang H, Liu T, Tang H. Chronic inflammation, cancer development and immunotherapy. Front Pharmacol 2022; 13:1040163. [PMID: 36313280 PMCID: PMC9614255 DOI: 10.3389/fphar.2022.1040163] [Citation(s) in RCA: 81] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Key Words] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2022] [Accepted: 10/03/2022] [Indexed: 12/03/2022] Open
Abstract
Chronic inflammation plays a pivotal role in cancer development. Cancer cells interact with adjacent cellular components (pro-inflammatory cells, intrinsic immune cells, stromal cells, etc.) and non-cellular components to form the inflammatory tumor microenvironment (TME). Interleukin 6 (IL-6), macrophage migration inhibitory factor (MIF), immune checkpoint factors and other pro-inflammatory cytokines produced by intrinsic immune cells in TME are the main mediators of intercellular communication in TME, which link chronic inflammation to cancer by stimulating different oncogenic signaling pathways and improving immune escape to promote cancer development. In parallel, the ability of monocytes, T regulatory cells (Tregs) and B regulatory cells (Bregs) to perform homeostatic tolerogenic functions is hijacked by cancer cells, leading to local or systemic immunosuppression. Standard treatments for advanced malignancies such as chemotherapy and radiotherapy have improved in the last decades. However, clinical outcomes of certain malignant cancers are not satisfactory due to drug resistance and side effects. The clinical application of immune checkpoint therapy (ICT) has brought hope to cancer treatment, although therapeutic efficacy are still limited due to the immunosuppressive microenvironment. Emerging evidences reveal that ideal therapies including clearance of tumor cells, disruption of tumor-induced immunosuppression by targeting suppressive TME as well as reactivation of anti-tumor T cells by ICT. Here, we review the impacts of the major pro-inflammatory cells, mediators and their downstream signaling molecules in TME on cancer development. We also discuss the application of targeting important components in the TME in the clinical management of cancer.
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Affiliation(s)
- Yalei Wen
- College of Pharmacy/International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education (MOE) of China, Jinan University, Guangzhou, China
| | - Yingjie Zhu
- College of Pharmacy/International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education (MOE) of China, Jinan University, Guangzhou, China
| | - Caishi Zhang
- College of Pharmacy/International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education (MOE) of China, Jinan University, Guangzhou, China
| | - Xiao Yang
- College of Pharmacy/International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education (MOE) of China, Jinan University, Guangzhou, China
| | - Yuchen Gao
- College of Pharmacy/International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education (MOE) of China, Jinan University, Guangzhou, China
| | - Mei Li
- College of Pharmacy/International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education (MOE) of China, Jinan University, Guangzhou, China
| | - Hongyan Yang
- Department of Central Laboratory, The First Affiliated Hospital of Jinan University, Guangzhou, China,*Correspondence: Hongyan Yang, ; Tongzheng Liu, ; Hui Tang,
| | - Tongzheng Liu
- College of Pharmacy/International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education (MOE) of China, Jinan University, Guangzhou, China,*Correspondence: Hongyan Yang, ; Tongzheng Liu, ; Hui Tang,
| | - Hui Tang
- Department of Central Laboratory, The First Affiliated Hospital of Jinan University, Guangzhou, China,Department of Clinical Laboratory, The Fifth Affiliated Hospital of Jinan University (Heyuan Shenhe People’s Hospital), Heyuan, China,*Correspondence: Hongyan Yang, ; Tongzheng Liu, ; Hui Tang,
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31
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Yu L, Liu X, Wang X, Yan H, Pu Q, Xie Y, Du J, Yang Z. Glycometabolism-related gene signature of hepatocellular carcinoma predicts prognosis and guides immunotherapy. Front Cell Dev Biol 2022; 10:940551. [PMID: 35938165 PMCID: PMC9354664 DOI: 10.3389/fcell.2022.940551] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Accepted: 06/29/2022] [Indexed: 12/20/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a severe cancer endangering human health. We constructed a novel glycometabolism-related risk score to predict prognosis and immunotherapy strategies in HCC patients. The HCC data sets were obtained from the Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) database, and the glycometabolism-related gene sets were obtained from the Molecular Signature Database. The least absolute contraction and selection operator (LASSO) regression model was used to construct a risk score based on glycometabolism-related genes. A simple visual nomogram model with clinical indicators was constructed and its effectiveness in calibration, accuracy, and clinical value was evaluated. We also explored the correlation between glycometabolism-related risk scores and molecular pathways, immune cells, and functions. Patients in the low-risk group responded better to anti-CTLA-4 immune checkpoint treatment and benefited from immune checkpoint inhibitor (ICI) therapy. The study found that glycometabolism-related risk score can effectively distinguish the prognosis, molecular and immune-related characteristics of HCC patients, and may provide a new strategy for individualized treatment.
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Affiliation(s)
- Lihua Yu
- Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Xiaoli Liu
- Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Xinhui Wang
- Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Huiwen Yan
- Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Qing Pu
- Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Yuqing Xie
- Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, China
- First Clinical Medical College, Beijing University of Chinese Medicine, Beijing, China
| | - Juan Du
- Beijing Key Laboratory of Emerging Infectious Diseases, Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, China
- Beijing Institute of Infectious Diseases, Beijing, China
- National Center for Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Zhiyun Yang
- Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, China
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32
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Zhang Y, Zhang X, Meng Y, Xu X, Zuo D. The role of glycolysis and lactate in the induction of tumor-associated macrophages immunosuppressive phenotype. Int Immunopharmacol 2022; 110:108994. [PMID: 35777265 DOI: 10.1016/j.intimp.2022.108994] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Revised: 05/30/2022] [Accepted: 06/20/2022] [Indexed: 11/17/2022]
Abstract
Growing evidence highlights that glycolysis and tumor-derived lactate could skew tumor-associated macrophages (TAMs) toward an immunosuppressive phenotype. However, the updated research has not been systematically summarized yet. TAMs are educated by the tumor microenvironment (TME) and exert immunosuppressive functions and tumorigenic effects via multiple biological processes. It is well known that lactate generated by aerobic glycolysis is significantly accumulated in TME and promotes tumor progression in solid tumors. Moreover, some recent research demonstrated that glycolysis is activated in TAMs to support M2-like polarization, which is absolutely in contrast with the metabolic profile of M2 macrophages in inflammation. Notably, lactate produced by high levels of glycolysis is not only a metabolic by-product but also an oncometabolite. TAMs could access the biological information delivered by lactate and further enhance protumor functions such as immunosuppression and angiogenesis. Here, we outline the connection between glycolysis and TAM phenotype to elucidate the metabolic characteristics of TAMs. Further, insights into the specific molecular mechanisms of lactate-induced TAM polarization and potential therapeutic targets are summarized. We sought to discuss the reciprocal interaction between tumor cells and TAMs mediated by lactate, which will lay a foundation for the research aiming to elucidate the complex functions of TAMs.
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Affiliation(s)
- Yijia Zhang
- Department of Pharmacology, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, China
| | - Xue Zhang
- Department of Pharmacology, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, China
| | - Yuting Meng
- Department of Pharmacology, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, China
| | - Xiaobo Xu
- Department of Pharmacology, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, China
| | - Daiying Zuo
- Department of Pharmacology, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, China.
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33
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Macrophages Are a Double-Edged Sword: Molecular Crosstalk between Tumor-Associated Macrophages and Cancer Stem Cells. Biomolecules 2022; 12:biom12060850. [PMID: 35740975 PMCID: PMC9221070 DOI: 10.3390/biom12060850] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2022] [Revised: 06/15/2022] [Accepted: 06/16/2022] [Indexed: 02/07/2023] Open
Abstract
Cancer stem cells (CSCs) are a subset of highly tumorigenic cells in tumors. They have enhanced self-renewal properties, are usually chemo-radioresistant, and can promote tumor recurrence and metastasis. They can recruit macrophages into the tumor microenvironment and differentiate them into tumor-associated macrophages (TAMs). TAMs maintain CSC stemness and construct niches that are favorable for CSC survival. However, how CSCs and TAMs interact is not completely understood. An understanding on these mechanisms can provide additional targeting strategies for eliminating CSCs. In this review, we comprehensively summarize the reported mechanisms of crosstalk between CSCs and TAMs and update the related signaling pathways involved in tumor progression. In addition, we discuss potential therapies targeting CSC–TAM interaction, including targeting macrophage recruitment and polarization by CSCs and inhibiting the TAM-induced promotion of CSC stemness. This review also provides the perspective on the major challenge for developing potential therapeutic strategies to overcome CSC-TAM crosstalk.
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34
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Zhao YY, Wang MM, Cui JF. New progress in the mechanism of microenvironment-driven chemoradiotherapy resistance in digestive system tumors. Shijie Huaren Xiaohua Zazhi 2022; 30:341-348. [DOI: 10.11569/wcjd.v30.i8.341] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Tumor microenvironment (TME) is the cornerstone of the survival of tumor cells. It generally presents unique physical and chemical characteristics such as hypoxia, immunosuppression, metabolic reprogramming, and matrix stiffening, which not only offer suitable soil to support tumorigenesis and progression, but also resist the effects of radiotherapy and chemotherapy. Here, we summarize new progress in the mechanism of hypoxia, immunosuppression, metabolic reprogramming, and matrix stiffness-driven chemoradiotherapy resistance in digestive system tumors, and discuss the new intervention strategy against matrix stiffness-driven chemoradiotherapy resistance, which underlines the contribution of physical and chemical characteristics of tumor microenvironment in drug resistance.
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Affiliation(s)
- Ying-Ying Zhao
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Mi-Mi Wang
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Jie-Feng Cui
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China
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35
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Zhao L, Liu Y, Zhang S, Wei L, Cheng H, Wang J, Wang J. Impacts and mechanisms of metabolic reprogramming of tumor microenvironment for immunotherapy in gastric cancer. Cell Death Dis 2022; 13:378. [PMID: 35444235 PMCID: PMC9021207 DOI: 10.1038/s41419-022-04821-w] [Citation(s) in RCA: 53] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2022] [Accepted: 04/04/2022] [Indexed: 02/07/2023]
Abstract
Metabolic disorders and abnormal immune function changes occur in tumor tissues and cells to varying degrees. There is increasing evidence that reprogrammed energy metabolism contributes to the development of tumor suppressive immune microenvironment and influences the course of gastric cancer (GC). Current studies have found that tumor microenvironment (TME) also has important clinicopathological significance in predicting prognosis and therapeutic efficacy. Novel approaches targeting TME therapy, such as immune checkpoint blockade (ICB), metabolic inhibitors and key enzymes of immune metabolism, have been involved in the treatment of GC. However, the interaction between GC cells metabolism and immune metabolism and how to make better use of these immunotherapy methods in the complex TME in GC are still being explored. Here, we discuss how metabolic reprogramming of GC cells and immune cells involved in GC immune responses modulate anti-tumor immune responses, as well as the effects of gastrointestinal flora in TME and GC. It is also proposed how to enhance anti-tumor immune response by understanding the targeted metabolism of these metabolic reprogramming to provide direction for the treatment and prognosis of GC.
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Affiliation(s)
- Lin Zhao
- The First Clinical College, Changzhi Medical College, Changzhi, Shanxi, 046000, China
| | - Yuanyuan Liu
- The First Clinical College, Changzhi Medical College, Changzhi, Shanxi, 046000, China
| | - Simiao Zhang
- The First Clinical College, Changzhi Medical College, Changzhi, Shanxi, 046000, China
| | - Lingyu Wei
- Collaborative Innovation Center for Aging Mechanism Research and Transformation, Center for Healthy Aging, Changzhi Medical College, Changzhi, Shanxi, 046000, China.,Key Laboratory of Esophageal Cancer Basic Research and Clinical Transformation, Heping Hospital Affiliated to Changzhi Medical College, Changzhi, Shanxi, 046000, China
| | - Hongbing Cheng
- Collaborative Innovation Center for Aging Mechanism Research and Transformation, Center for Healthy Aging, Changzhi Medical College, Changzhi, Shanxi, 046000, China.,Department of Microbiology, Changzhi Medical College, Changzhi, Shanxi, 046000, China
| | - Jinsheng Wang
- Collaborative Innovation Center for Aging Mechanism Research and Transformation, Center for Healthy Aging, Changzhi Medical College, Changzhi, Shanxi, 046000, China. .,Key Laboratory of Esophageal Cancer Basic Research and Clinical Transformation, Heping Hospital Affiliated to Changzhi Medical College, Changzhi, Shanxi, 046000, China.
| | - Jia Wang
- Collaborative Innovation Center for Aging Mechanism Research and Transformation, Center for Healthy Aging, Changzhi Medical College, Changzhi, Shanxi, 046000, China. .,Department of Immunology, Center for Healthy Aging, Changzhi Medical College, Changzhi, Shanxi, 046000, China.
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36
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Xu J, Liu XY, Zhang Q, Liu H, Zhang P, Tian ZB, Zhang CP, Li XY. Crosstalk Among YAP, LncRNA, and Tumor-Associated Macrophages in Tumorigenesis Development. Front Oncol 2022; 11:810893. [PMID: 35071016 PMCID: PMC8770286 DOI: 10.3389/fonc.2021.810893] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Accepted: 12/13/2021] [Indexed: 12/14/2022] Open
Abstract
Long non-coding RNAs (ncRNAs), which do not encode proteins, regulate cell proliferation, tumor angiogenesis, and metastasis and are closely associated with the development, progression, and metastasis of many cancers. Tumor-associated macrophages (TAMs) in the tumor microenvironment play an important role in cancer progression. The Hippo signaling pathway regulates cell proliferation and apoptosis, maintains tissue and organ size, and homeostasis of the internal environment of organisms. Abnormal expression of Yes-associated protein (YAP), the Hippo signaling pathway key component, is widely observed in various malignancies. Further, TAM, lncRNA, and YAP are currently valuable targets for cancer immunotherapy. In this review, we have logically summarized recent studies, clarified the close association between the three factors and tumorigenesis, and analyzed the outlook of tumor immunotherapy.
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Affiliation(s)
- Jing Xu
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University, Qingdao, China.,Innovation Platform of Marine Drug Screening & Evaluation, Qingdao Pilot National Laboratory for Marine Science and Technology, Qingdao, China
| | - Xin-Yuan Liu
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Qi Zhang
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Hua Liu
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Peng Zhang
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Zi-Bin Tian
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Cui-Ping Zhang
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Xiao-Yu Li
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University, Qingdao, China
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37
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Liu C, Jin Y, Fan Z. The Mechanism of Warburg Effect-Induced Chemoresistance in Cancer. Front Oncol 2021; 11:698023. [PMID: 34540667 PMCID: PMC8446599 DOI: 10.3389/fonc.2021.698023] [Citation(s) in RCA: 73] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Accepted: 08/11/2021] [Indexed: 12/26/2022] Open
Abstract
Although chemotherapy can improve the overall survival and prognosis of cancer patients, chemoresistance remains an obstacle due to the diversity, heterogeneity, and adaptability to environmental alters in clinic. To determine more possibilities for cancer therapy, recent studies have begun to explore changes in the metabolism, especially glycolysis. The Warburg effect is a hallmark of cancer that refers to the preference of cancer cells to metabolize glucose anaerobically rather than aerobically, even under normoxia, which contributes to chemoresistance. However, the association between glycolysis and chemoresistance and molecular mechanisms of glycolysis-induced chemoresistance remains unclear. This review describes the mechanism of glycolysis-induced chemoresistance from the aspects of glycolysis process, signaling pathways, tumor microenvironment, and their interactions. The understanding of how glycolysis induces chemoresistance may provide new molecular targets and concepts for cancer therapy.
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Affiliation(s)
- Chang Liu
- Department of Breast Surgery, The First Hospital of Jilin University, Changchun, China
| | - Ying Jin
- Department of Breast Surgery, The First Hospital of Jilin University, Changchun, China
| | - Zhimin Fan
- Department of Breast Surgery, The First Hospital of Jilin University, Changchun, China
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