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Zhao B, Shi G, Shi J, Li Z, Xiao Y, Qiu Y, He L, Xie F, Yu D, Cao H, Du H, Zhang J, Zhou Y, Jiang C, Li W, Li M, Wang Z. Research progress on the mechanism and treatment of cachexia based on tumor microenvironment. Nutrition 2025; 133:112697. [PMID: 39999652 DOI: 10.1016/j.nut.2025.112697] [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: 12/07/2024] [Revised: 01/26/2025] [Accepted: 01/28/2025] [Indexed: 02/27/2025]
Abstract
Cachexia is a prevalent multifactorial syndrome characterized by a substantial decrease in food intake, which results from processes such as proteolysis, lipolysis, inflammatory activation, and autophagy, ultimately leading to weight loss. In cancer patients, this condition is referred to as cancer-related cachexia (CRC) and affects over 50% of this population. A comprehensive understanding of the intricate interactions between tumors and the host organism is essential for the development of effective treatments for tumor cachexia. This review aims to elucidate the role of the tumor microenvironment (TME) in the pathogenesis of tumor-associated cachexia and to summarize the current evidence supporting treatment modalities that target the TME.
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Affiliation(s)
- Bochen Zhao
- School of Basic Medical Sciences, The Fourth Military Medical University, Xi'an, China
| | - Gege Shi
- State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, Xi'an, China
| | - Jiaxin Shi
- School of Basic Medical Sciences, The Fourth Military Medical University, Xi'an, China
| | - Zhaozhao Li
- State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, Xi'an, China
| | - Yang Xiao
- Department of Experiment Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Yueyuan Qiu
- State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, Xi'an, China
| | - Lei He
- State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, Xi'an, China
| | - Fei Xie
- State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, Xi'an, China
| | - Duo Yu
- State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, Xi'an, China
| | - Haiyan Cao
- State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, Xi'an, China
| | - Haichen Du
- State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, Xi'an, China
| | - Jieyu Zhang
- State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, Xi'an, China
| | - Yang Zhou
- School of Basic Medical Sciences, The Fourth Military Medical University, Xi'an, China
| | - Caiyi Jiang
- School of Basic Medical Sciences, The Fourth Military Medical University, Xi'an, China
| | - Weina Li
- State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, Xi'an, China
| | - Meng Li
- State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, Xi'an, China
| | - Zhaowei Wang
- State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, Xi'an, China.
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Cao Y, Yi Y, Han C, Shi B. NF-κB signaling pathway in tumor microenvironment. Front Immunol 2024; 15:1476030. [PMID: 39493763 PMCID: PMC11530992 DOI: 10.3389/fimmu.2024.1476030] [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: 08/05/2024] [Accepted: 09/30/2024] [Indexed: 11/05/2024] Open
Abstract
The genesis and progression of tumors are multifaceted processes influenced by genetic mutations within the tumor cells and the dynamic interplay with their surrounding milieu, which incessantly impacts the course of cancer. The tumor microenvironment (TME) is a complex and dynamic entity that encompasses not only the tumor cells but also an array of non-cancerous cells, signaling molecules, and the extracellular matrix. This intricate network is crucial in tumor progression, metastasis, and response to treatments. The TME is populated by diverse cell types, including immune cells, fibroblasts, endothelial cells, alongside cytokines and growth factors, all of which play roles in either suppressing or fostering tumor growth. Grasping the nuances of the interactions within the TME is vital for the advancement of targeted cancer therapies. Consequently, a thorough understanding of the alterations of TME and the identification of upstream regulatory targets have emerged as a research priority. NF-κB transcription factors, central to inflammation and innate immunity, are increasingly recognized for their significant role in cancer onset and progression. This review emphasizes the crucial influence of the NF-κB signaling pathway within the TME, underscoring its roles in the development and advancement of cancer. By examining the interactions between NF-κB and various components of the TME, targeting the NF-κB pathway appears as a promising cancer treatment approach.
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Affiliation(s)
- Yaning Cao
- Department of Blood Transfusion, Changzhou Hospital of Traditional Chinese Medicine, Changzhou, Jiangsu, China
| | - Yanan Yi
- Department of Laboratory Medicine, Northern Jiangsu People’s Hospital Affiliated to Yangzhou University, Yangzhou, Jiangsu, China
| | - Chongxu Han
- Department of Laboratory Medicine, Northern Jiangsu People’s Hospital Affiliated to Yangzhou University, Yangzhou, Jiangsu, China
| | - Bingwei Shi
- Department of Blood Transfusion, Changzhou Hospital of Traditional Chinese Medicine, Changzhou, Jiangsu, China
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Zhang Y, Ding X, Zhang X, Li Y, Xu R, Li HJ, Zuo D, Chen G. Unveiling the contribution of tumor-associated macrophages in driving epithelial-mesenchymal transition: a review of mechanisms and therapeutic Strategies. Front Pharmacol 2024; 15:1404687. [PMID: 39286635 PMCID: PMC11402718 DOI: 10.3389/fphar.2024.1404687] [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: 03/21/2024] [Accepted: 08/15/2024] [Indexed: 09/19/2024] Open
Abstract
Tumor-associated macrophages (TAMs), fundamental constituents of the tumor microenvironment (TME), significantly influence cancer development, primarily by promoting epithelial-mesenchymal transition (EMT). EMT endows cancer cells with increased motility, invasiveness, and resistance to therapies, marking a pivotal juncture in cancer progression. The review begins with a detailed exposition on the origins of TAMs and their functional heterogeneity, providing a foundational understanding of TAM characteristics. Next, it delves into the specific molecular mechanisms through which TAMs induce EMT, including cytokines, chemokines and stromal cross-talking. Following this, the review explores TAM-induced EMT features in select cancer types with notable EMT characteristics, highlighting recent insights and the impact of TAMs on cancer progression. Finally, the review concludes with a discussion of potential therapeutic targets and strategies aimed at mitigating TAM infiltration and disrupting the EMT signaling network, thereby underscoring the potential of emerging treatments to combat TAM-mediated EMT in cancer. This comprehensive analysis reaffirms the necessity for continued exploration into TAMs' regulatory roles within cancer biology to refine therapeutic approaches and improve patient outcomes.
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Affiliation(s)
- Yijia Zhang
- Department of Pharmacy, Taizhou Second People's Hospital (Mental Health Center affiliated to Taizhou University School of Medicine), Taizhou University, Taizhou, Zhejiang, China
- Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, China
| | - Xiaofei Ding
- Department of Pharmacology, Taizhou University, Taizhou, Zhejiang, China
| | - Xue Zhang
- Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, China
| | - Ye Li
- Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, China
| | - Rui Xu
- Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, China
| | - Hai-Jun Li
- Department of Pharmacy, Taizhou Second People's Hospital (Mental Health Center affiliated to Taizhou University School of Medicine), Taizhou University, Taizhou, Zhejiang, China
| | - Daiying Zuo
- Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, China
| | - Guang Chen
- Department of Pharmacy, Taizhou Second People's Hospital (Mental Health Center affiliated to Taizhou University School of Medicine), Taizhou University, Taizhou, Zhejiang, China
- Department of Pharmacology, Taizhou University, Taizhou, Zhejiang, China
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4
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Sun D, Sun X, Zhang X, Wu J, Shi X, Sun J, Luo C, He Z, Zhang S. Emerging Chemodynamic Nanotherapeutics for Cancer Treatment. Adv Healthc Mater 2024; 13:e2400809. [PMID: 38752756 DOI: 10.1002/adhm.202400809] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2024] [Revised: 05/09/2024] [Indexed: 05/24/2024]
Abstract
Chemodynamic therapy (CDT) has emerged as a transformative paradigm in the realm of reactive oxygen species -mediated cancer therapies, exhibiting its potential as a sophisticated strategy for precise and effective tumor treatment. CDT primarily relies on metal ions and hydrogen peroxide to initiate Fenton or Fenton-like reactions, generating cytotoxic hydroxyl radicals. Its notable advantages in cancer treatment are demonstrated, including tumor specificity, autonomy from external triggers, and a favorable side-effect profile. Recent advancements in nanomedicine are devoted to enhancing CDT, promising a comprehensive optimization of CDT efficacy. This review systematically elucidates cutting-edge achievements in chemodynamic nanotherapeutics, exploring strategies for enhanced Fenton or Fenton-like reactions, improved tumor microenvironment modulation, and precise regulation in energy metabolism. Moreover, a detailed analysis of diverse CDT-mediated combination therapies is provided. Finally, the review concludes with a comprehensive discussion of the prospects and intrinsic challenges to the application of chemodynamic nanotherapeutics in the domain of cancer treatment.
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Affiliation(s)
- Dongqi Sun
- Department of Pharmaceutics, Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, 110016, P. R. China
| | - Xinxin Sun
- Department of Pharmaceutics, Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, 110016, P. R. China
| | - Xuan Zhang
- Department of Pharmaceutics, Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, 110016, P. R. China
| | - Jiaping Wu
- Department of Pharmaceutics, Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, 110016, P. R. China
| | - Xianbao Shi
- Department of Pharmacy, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, 121001, China
| | - Jin Sun
- Department of Pharmaceutics, Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, 110016, P. R. China
| | - Cong Luo
- Department of Pharmaceutics, Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, 110016, P. R. China
| | - Zhonggui He
- Department of Pharmaceutics, Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, 110016, P. R. China
| | - Shenwu Zhang
- Department of Pharmaceutics, Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, 110016, P. R. China
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Stayoussef M, Weili X, Habel A, Barbirou M, Bedoui S, Attia A, Omrani Y, Zouari K, Maghrebi H, Almawi WY, Bouhaouala-Zahar B, Larbi A, Yacoubi-Loueslati B. Altered expression of cytokines, chemokines, growth factors, and soluble receptors in patients with colorectal cancer, and correlation with treatment outcome. Cancer Immunol Immunother 2024; 73:169. [PMID: 38954024 PMCID: PMC11219625 DOI: 10.1007/s00262-024-03746-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2023] [Accepted: 05/22/2024] [Indexed: 07/04/2024]
Abstract
Insofar as they play an important role in the pathogenesis of colorectal cancer (CRC), this study analyzes the serum profile of cytokines, chemokines, growth factors, and soluble receptors in patients with CRC and cancer-free controls as possible CRC signatures. Serum levels of 65 analytes were measured in patients with CRC and age- and sex-matched cancer-free controls using the ProcartaPlex Human Immune Monitoring 65-Plex Panel. Of the 65 tested analytes, 8 cytokines (CSF-3, IFN-γ, IL-12p70, IL-18, IL-20, MIF, TNF-α and TSLP), 8 chemokines (fractalkine, MIP-1β, BLC, Eotaxin-1, Eotaxin-2, IP-10, MIP-1a, MIP-3a), 2 growth factors (FGF-2, MMP-1), and 4 soluble receptors (APRIL, CD30, TNFRII, and TWEAK), were differentially expressed in CRC. ROC analysis confirmed the high association of TNF-α, BLC, Eotaxin-1, APRIL, and Tweak with AUC > 0.70, suggesting theranostic application. The expression of IFN-γ, IL-18, MIF, BLC, Eotaxin-1, Eotaxin-2, IP-10, and MMP1 was lower in metastatic compared to non-metastatic CRC; only AUC of MIF and MIP-1β were > 0.7. Moreover, MDC, IL-7, MIF, IL-21, and TNF-α are positively associated with tolerance to CRC chemotherapy (CT) (AUC > 0.7), whereas IL-31, Fractalkine, Eotaxin-1, and Eotaxin-2 were positively associated with resistance to CT. TNF-α, BLC, Eotaxin-1, APRIL, and Tweak may be used as first-line early detection of CRC. The variable levels of MIF and MIP-1β between metastatic and non-metastatic cases assign prognostic nature to these factors in CRC progression. Regarding tolerance to CT, MDC, IL-7, MIF, IL-21, and TNF-α are key when down-regulated or resistant to treatment is observed.
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Affiliation(s)
- M Stayoussef
- Laboratory of Mycology, Faculty of Sciences of Tunis (FST), Pathologies and Biomarkers (LR16ES05), University of Tunis El Manar (UTM), 1092, Tunis, Tunisia.
| | - X Weili
- Singapore Immunology Network (SIgN), Agency for Science Technology and Research (A*STAR), Immunos Building, Singapore, 138648, Singapore
| | - A Habel
- Laboratory of Mycology, Faculty of Sciences of Tunis (FST), Pathologies and Biomarkers (LR16ES05), University of Tunis El Manar (UTM), 1092, Tunis, Tunisia
| | - M Barbirou
- Center for Biomedical Informatics, University of Missouri School of Medicine, Columbia, MO, USA
| | - S Bedoui
- Laboratory of Mycology, Faculty of Sciences of Tunis (FST), Pathologies and Biomarkers (LR16ES05), University of Tunis El Manar (UTM), 1092, Tunis, Tunisia
| | - A Attia
- Laboratory of Mycology, Faculty of Sciences of Tunis (FST), Pathologies and Biomarkers (LR16ES05), University of Tunis El Manar (UTM), 1092, Tunis, Tunisia
| | - Y Omrani
- Laboratory of Biomolecules, Venoms and Theranostic Applications, University of Tunis El Manar (UTM), Pasteur Institute of Tunis, 13 Place Pasteur, B.P. 74, 1002, Tunis, Tunisia
| | - K Zouari
- Department of Digestive Surgery, Fattouma Bourguiba Hospital, University of Monastir, Monastir, Tunisia
| | - H Maghrebi
- Faculty of Medicine of Tunis, University of Tunis El Manar (UTM), Tunis, Tunisia
| | - W Y Almawi
- Laboratory of Mycology, Faculty of Sciences of Tunis (FST), Pathologies and Biomarkers (LR16ES05), University of Tunis El Manar (UTM), 1092, Tunis, Tunisia
| | - B Bouhaouala-Zahar
- Laboratory of Biomolecules, Venoms and Theranostic Applications, University of Tunis El Manar (UTM), Pasteur Institute of Tunis, 13 Place Pasteur, B.P. 74, 1002, Tunis, Tunisia
- University of Tunis El Manar (UTM), Medical School of Tunis, Rue Djebal Lakhdar, 1006, Tunis, Tunisia
| | - A Larbi
- Singapore Immunology Network (SIgN), Agency for Science Technology and Research (A*STAR), Immunos Building, Singapore, 138648, Singapore
- Department of Medicine, Faculty of Medicine and Health Sciences, University of Sherbrooke, Sherbrooke, QC, Canada
| | - B Yacoubi-Loueslati
- Laboratory of Mycology, Faculty of Sciences of Tunis (FST), Pathologies and Biomarkers (LR16ES05), University of Tunis El Manar (UTM), 1092, Tunis, Tunisia
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Ahmadpour S, Habibi MA, Ghazi FS, Molazadeh M, Pashaie MR, Mohammadpour Y. The effects of tumor-derived supernatants (TDS) on cancer cell progression: A review and update on carcinogenesis and immunotherapy. Cancer Treat Res Commun 2024; 40:100823. [PMID: 38875884 DOI: 10.1016/j.ctarc.2024.100823] [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: 04/25/2024] [Revised: 05/26/2024] [Accepted: 05/27/2024] [Indexed: 06/16/2024]
Abstract
Tumors can produce bioactive substances called tumor-derived supernatants (TDS) that modify the immune response in the host body. This can result in immunosuppressive effects that promote the growth and spread of cancer. During tumorigenesis, the exudation of these substances can disrupt the function of immune sentinels in the host and reinforce the support for cancer cell growth. Tumor cells produce cytokines, growth factors, and proteins, which contribute to the progression of the tumor and the formation of premetastatic niches. By understanding how cancer cells influence the host immune system through the secretion of these factors, we can gain new insights into cancer diagnosis and therapy.
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Affiliation(s)
- Sajjad Ahmadpour
- Patient Safety Research Center, Clinical Research Institute, Urmia University of Medical Sciences, Urmia, Iran
| | - Mohammad Amin Habibi
- Department of Neurosurgery, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Mikaeil Molazadeh
- Department of Medical Physics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Reza Pashaie
- Patient Safety Research Center, Clinical Research Institute, Urmia University of Medical Sciences, Urmia, Iran; Department of Internal Medicine, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Yousef Mohammadpour
- Department of Medical Education, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran.
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Huang LM, Zhang MJ. Kinesin 26B modulates M2 polarization of macrophage by activating cancer-associated fibroblasts to aggravate gastric cancer occurrence and metastasis. World J Gastroenterol 2024; 30:2689-2708. [PMID: 38855156 PMCID: PMC11154681 DOI: 10.3748/wjg.v30.i20.2689] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Revised: 02/28/2024] [Accepted: 04/19/2024] [Indexed: 05/27/2024] Open
Abstract
BACKGROUND The regulatory effects of KIF26B on gastric cancer (GC) have been confirmed, but the specific mechanism still needs further exploration. Pan-cancer analysis shows that the KIF26B expression is highly related to immune infiltration of cancer-associated fibroblasts (CAFs), and CAFs promote macrophage M2 polarization and affect cancers' progression. AIM To investigate the regulatory functions of KIF26B on immune and metastasis of GC. METHODS We analyzed genes' mRNA levels by quantitative real-time polymerase chain reaction. Expression levels of target proteins were detected by immunohistochemistry, ELISA, and Western blotting. We injected AGS cells into nude mice for the establishment of a xenograft tumor model and observed the occurrence and metastasis of GC. The degree of inflammatory infiltration in pulmonary nodes was observed through hematoxylin-eosin staining. Transwell and wound healing assays were performed for the evaluation of cell invasion and migration ability. Tube formation assay was used for detecting angiogenesis. M2-polarized macrophages were estimated by immunofluorescence and flow cytometry. RESULTS KIF26B was significantly overexpressed in cells and tissues of GC, and the higher expression of KIF26B was related to GC metastasis and prognosis. According to in vivo experiments, KIF26B promoted tumor formation and metastasis of GC. KIF26B expression was positively associated with CAFs' degree of infiltration. Moreover, CAFs could regulate M2-type polarization of macrophages, affecting GC cells' migration, angiogenesis, invasion, and epithelial-mesenchymal transition process. CONCLUSION KIF26B regulated M2 polarization of macrophage through activating CAFs, regulating the occurrence and metastasis of GC.
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Affiliation(s)
- Lian-Meng Huang
- Department of General Surgery, The 901st Hospital of PLA, Hefei 230031, Anhui Province, China
| | - Ming-Jin Zhang
- Department of General Surgery, The 901st Hospital of PLA, Hefei 230031, Anhui Province, China
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Ma Z, Sun Y, Yu Y, Xiao W, Xiao Z, Zhong T, Xiang X, Li Z. Extracellular vesicles containing MFGE8 from colorectal cancer facilitate macrophage efferocytosis. Cell Commun Signal 2024; 22:295. [PMID: 38802814 PMCID: PMC11131254 DOI: 10.1186/s12964-024-01669-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2024] [Accepted: 05/18/2024] [Indexed: 05/29/2024] Open
Abstract
BACKGROUND Colorectal cancer (CRC) commonly exhibits tolerance to cisplatin treatment, but the underlying mechanisms remain unclear. Within the tumor microenvironment, macrophages play a role in resisting the cytotoxic effects of chemotherapy by engaging in efferocytosis to clear apoptotic cells induced by chemotherapeutic agents. The involvement of extracellular vesicles (EVs), an intercellular communicator within the tumor microenvironment, in regulating the efferocytosis for the promotion of drug resistance has not been thoroughly investigated. METHODS We constructed GFP fluorescent-expressing CRC cell lines (including GFP-CT26 and GFP-MC38) to detect macrophage efferocytosis through flow cytometric analysis. We isolated and purified CRC-secreted EVs using a multi-step ultracentrifugation method and identified them through electron microscopy and nanoflow cytometry. Proteomic analysis was conducted to identify the protein molecules carried by CRC-EVs. MFGE8 knockout CRC cell lines were constructed using CRISPR-Cas9, and their effects were validated through in vitro and in vivo experiments using Western blotting, immunofluorescence, and flow cytometric analysis, confirming that these EVs activate the macrophage αvβ3-Src-FAK-STAT3 signaling pathway, thereby promoting efferocytosis. RESULTS In this study, we found that CRC-derived EVs (CRC-EVs) enhanced macrophage efferocytosis of cisplatin-induced apoptotic CRC cells. Analysis of The Cancer Genome Atlas (TCGA) database revealed a high expression of the efferocytosis-associated gene MFGE8 in CRC patients, suggesting a poorer prognosis. Additionally, mass spectrometry-based proteomic analysis identified a high abundance of MFGE8 protein in CRC-EVs. Utilizing CRISPR-Cas9 gene edition system, we generated MFGE8-knockout CRC cells, demonstrating that their EVs fail to upregulate macrophage efferocytosis in vitro and in vivo. Furthermore, we demonstrated that MFGE8 in CRC-EVs stimulated macrophage efferocytosis by increasing the expression of αvβ3 on the cell surface, thereby activating the intracellular Src-FAK-STAT3 signaling pathway. CONCLUSIONS Therefore, this study highlighted a mechanism in CRC-EVs carrying MFGE8 activated the macrophage efferocytosis. This activation promoted the clearance of cisplatin-induced apoptotic CRC cells, contributing to CRC resistance against cisplatin. These findings provide novel insights into the potential synergistic application of chemotherapy drugs, EVs inhibitors, and efferocytosis antagonists for CRC treatment.
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Affiliation(s)
- Zhixin Ma
- Scientific Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China
| | - Yu Sun
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China
| | - Yang Yu
- Scientific Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China
| | - Wenjun Xiao
- Scientific Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China
| | - Zhijie Xiao
- Scientific Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China
| | - Tianyu Zhong
- Department of Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, 341004, China
| | - Xi Xiang
- Scientific Research Center, The Seventh Affiliated Hospital, 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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9
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Zimarino C, Moody W, Davidson SE, Munir H, Shields JD. Disruption of CD47-SIRPα signaling restores inflammatory function in tumor-associated myeloid-derived suppressor cells. iScience 2024; 27:109546. [PMID: 38577107 PMCID: PMC10993187 DOI: 10.1016/j.isci.2024.109546] [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: 10/30/2023] [Revised: 01/26/2024] [Accepted: 03/18/2024] [Indexed: 04/06/2024] Open
Abstract
Myeloid-derived suppressor cells (MDSCs) are a heterogeneous immune population with diverse immunosuppressive functions in solid tumors. Here, we explored the role of the tumor microenvironment in regulating MDSC differentiation and immunosuppressive properties via signal-regulatory protein alpha (SIRPα)/CD47 signaling. In a murine melanoma model, we observed progressive increases in monocytic MDSCs and monocyte-derived dendritic cells that exhibited potent T cell-suppressive capabilities. These adaptations could be recapitulated in vitro by exposing hematopoietic stem cells to tumor-derived factors. Engagement of CD47 with SIRPα on myeloid cells reduced their phagocytic capability, enhanced expression of immune checkpoints, increased reactive oxygen species production, and suppressed T cell proliferation. Perturbation of SIRPα signaling restored phagocytosis and antigen presentation by MDSCs, which was accompanied by renewed T cell activity and delayed tumor growth in multiple solid cancers. These data highlight that therapeutically targeting myeloid functions in combination with immune checkpoint inhibitors could enhance anti-tumor immunity.
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Affiliation(s)
- Carlo Zimarino
- MRC Cancer Unit, Hutchison/MRC Research Centre, University of Cambridge, Cambridge, UK
| | - William Moody
- MRC Cancer Unit, Hutchison/MRC Research Centre, University of Cambridge, Cambridge, UK
| | - Sarah E. Davidson
- MRC Cancer Unit, Hutchison/MRC Research Centre, University of Cambridge, Cambridge, UK
- The Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK
| | - Hafsa Munir
- MRC Cancer Unit, Hutchison/MRC Research Centre, University of Cambridge, Cambridge, UK
- Helmholtz Institute for Translational Oncology Mainz (HI-TRON Mainz) – A Helmholtz Institute of the DKFZ, Mainz, Germany
- German Cancer Research Centre (DKFZ), Division of Dermal Oncoimmunology, Heidelberg, Germany
| | - Jacqueline D. Shields
- MRC Cancer Unit, Hutchison/MRC Research Centre, University of Cambridge, Cambridge, UK
- Comprehensive Cancer Centre, Kings College London, London, UK
- Centre for Cancer Sciences, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham, UK
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10
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Dawson A, Zarou MM, Prasad B, Bittencourt-Silvestre J, Zerbst D, Himonas E, Hsieh YC, van Loon I, Blanco GR, Ianniciello A, Kerekes Z, Krishnan V, Agarwal P, Almasoudi H, McCluskey L, Hopcroft LEM, Scott MT, Baquero P, Dunn K, Vetrie D, Copland M, Bhatia R, Coffelt SB, Tiong OS, Wheadon H, Zanivan S, Kirschner K, Helgason GV. Leukaemia exposure alters the transcriptional profile and function of BCR::ABL1 negative macrophages in the bone marrow niche. Nat Commun 2024; 15:1090. [PMID: 38316788 PMCID: PMC10844594 DOI: 10.1038/s41467-024-45471-0] [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: 04/29/2022] [Accepted: 01/25/2024] [Indexed: 02/07/2024] Open
Abstract
Macrophages are fundamental cells of the innate immune system that support normal haematopoiesis and play roles in both anti-cancer immunity and tumour progression. Here we use a chimeric mouse model of chronic myeloid leukaemia (CML) and human bone marrow (BM) derived macrophages to study the impact of the dysregulated BM microenvironment on bystander macrophages. Utilising single-cell RNA sequencing (scRNA-seq) of Philadelphia chromosome (Ph) negative macrophages we reveal unique subpopulations of immature macrophages residing in the CML BM microenvironment. CML exposed macrophages separate from their normal counterparts by reduced expression of the surface marker CD36, which significantly reduces clearance of apoptotic cells. We uncover aberrant production of CML-secreted factors, including the immune modulatory protein lactotransferrin (LTF), that suppresses efferocytosis, phagocytosis, and CD36 surface expression in BM macrophages, indicating that the elevated secretion of LTF is, at least partially responsible for the supressed clearance function of Ph- macrophages.
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Affiliation(s)
- Amy Dawson
- Wolfson Wohl Cancer Research Centre, School of Cancer Sciences, University of Glasgow, Glasgow, G61 1QH, UK
| | - Martha M Zarou
- Wolfson Wohl Cancer Research Centre, School of Cancer Sciences, University of Glasgow, Glasgow, G61 1QH, UK
| | - Bodhayan Prasad
- Wolfson Wohl Cancer Research Centre, School of Cancer Sciences, University of Glasgow, Glasgow, G61 1QH, UK
| | - Joana Bittencourt-Silvestre
- Paul O'Gorman Leukaemia Research Centre, School of Cancer Sciences, University of Glasgow, Glasgow, G12 0ZD, UK
| | - Désirée Zerbst
- Wolfson Wohl Cancer Research Centre, School of Cancer Sciences, University of Glasgow, Glasgow, G61 1QH, UK
| | - Ekaterini Himonas
- Wolfson Wohl Cancer Research Centre, School of Cancer Sciences, University of Glasgow, Glasgow, G61 1QH, UK
| | - Ya-Ching Hsieh
- Cancer Research UK Scotland Institute, Glasgow, G61 1BD, UK
| | - Isabel van Loon
- Wolfson Wohl Cancer Research Centre, School of Cancer Sciences, University of Glasgow, Glasgow, G61 1QH, UK
| | | | - Angela Ianniciello
- Wolfson Wohl Cancer Research Centre, School of Cancer Sciences, University of Glasgow, Glasgow, G61 1QH, UK
| | - Zsombor Kerekes
- Wolfson Wohl Cancer Research Centre, School of Cancer Sciences, University of Glasgow, Glasgow, G61 1QH, UK
| | - Vaidehi Krishnan
- Cancer & Stem Cell Biology Signature Research Programme, Duke-NUS Medical School, Singapore, Singapore
| | - Puneet Agarwal
- Division of Hematology and Oncology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Hassan Almasoudi
- Wolfson Wohl Cancer Research Centre, School of Cancer Sciences, University of Glasgow, Glasgow, G61 1QH, UK
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Najran University, Najran, 61441, Kingdom of Saudi Arabia
| | - Laura McCluskey
- Paul O'Gorman Leukaemia Research Centre, School of Cancer Sciences, University of Glasgow, Glasgow, G12 0ZD, UK
| | - Lisa E M Hopcroft
- Paul O'Gorman Leukaemia Research Centre, School of Cancer Sciences, University of Glasgow, Glasgow, G12 0ZD, UK
| | - Mary T Scott
- Wolfson Wohl Cancer Research Centre, School of Cancer Sciences, University of Glasgow, Glasgow, G61 1QH, UK
| | - Pablo Baquero
- Wolfson Wohl Cancer Research Centre, School of Cancer Sciences, University of Glasgow, Glasgow, G61 1QH, UK
- Universidad de Alcalá, Facultad de Medicina y Ciencias de la Salud, Dpto. de Biología de Sistemas, Unidad de Bioquímica y Biología Molecular, E-28805, Madrid, Spain
| | - Karen Dunn
- Paul O'Gorman Leukaemia Research Centre, School of Cancer Sciences, University of Glasgow, Glasgow, G12 0ZD, UK
| | - David Vetrie
- Wolfson Wohl Cancer Research Centre, School of Cancer Sciences, University of Glasgow, Glasgow, G61 1QH, UK
| | - Mhairi Copland
- Paul O'Gorman Leukaemia Research Centre, School of Cancer Sciences, University of Glasgow, Glasgow, G12 0ZD, UK
| | - Ravi Bhatia
- Division of Hematology and Oncology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Seth B Coffelt
- Wolfson Wohl Cancer Research Centre, School of Cancer Sciences, University of Glasgow, Glasgow, G61 1QH, UK
- Cancer Research UK Scotland Institute, Glasgow, G61 1BD, UK
| | - Ong Sin Tiong
- Cancer & Stem Cell Biology Signature Research Programme, Duke-NUS Medical School, Singapore, Singapore
| | - Helen Wheadon
- Paul O'Gorman Leukaemia Research Centre, School of Cancer Sciences, University of Glasgow, Glasgow, G12 0ZD, UK
| | - Sara Zanivan
- Wolfson Wohl Cancer Research Centre, School of Cancer Sciences, University of Glasgow, Glasgow, G61 1QH, UK
- Cancer Research UK Scotland Institute, Glasgow, G61 1BD, UK
| | - Kristina Kirschner
- Wolfson Wohl Cancer Research Centre, School of Cancer Sciences, University of Glasgow, Glasgow, G61 1QH, UK.
- Cancer Research UK Scotland Institute, Glasgow, G61 1BD, UK.
| | - G Vignir Helgason
- Wolfson Wohl Cancer Research Centre, School of Cancer Sciences, University of Glasgow, Glasgow, G61 1QH, UK.
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11
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Gulia S, Chandra P, Das A. The Prognosis of Cancer Depends on the Interplay of Autophagy, Apoptosis, and Anoikis within the Tumor Microenvironment. Cell Biochem Biophys 2023; 81:621-658. [PMID: 37787970 DOI: 10.1007/s12013-023-01179-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/15/2023] [Indexed: 10/04/2023]
Abstract
Within the tumor microenvironment, the fight between the immune system and cancer influences tumor transformation. Metastasis formation is an important stage in the progression of cancer. This process is aided by cellular detachment and resistance to anoikis, which are achieved by altering intercellular signaling. Autophagy, specifically pro-survival autophagy, aids cancer cells in developing treatment resistance. Numerous studies have shown that autophagy promotes tumor growth and resistance to anoikis. To regulate protective autophagy, cancer-related genes phosphorylate both pro- and anti-apoptotic proteins. Apoptosis, a type of controlled cell death, eliminates damaged or unwanted cells. Anoikis is a type of programmed cell death in which cells lose contact with the extracellular matrix. The dysregulation of these cellular pathways promotes tumor growth and spread. Apoptosis, anoikis, and autophagy interact meticulously and differently depending on the cellular circumstances. For instance, autophagy can protect cancer cells from apoptosis by removing cellular components that are damaged and might otherwise trigger apoptotic pathways. Similarly, anoikis dysregulation can trigger autophagy by causing cellular harm and metabolic stress. In order to prevent or treat metastatic disease, specifically, targeting these cellular mechanisms may present a promising prospect for cancer therapy. This review discourses the state of our understanding of the molecular and cellular mechanisms underlying tumor transformation and the establishment of metastatic tumors. To enhance the prognosis for cancer, we highlight and discuss potential therapeutic approaches that target these processes and genes involved in them.
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Affiliation(s)
- Shweta Gulia
- Department of Biotechnology, Delhi Technological University, Main Bawana Road, Delhi, 110042, India
| | - Prakash Chandra
- Department of Biotechnology, Delhi Technological University, Main Bawana Road, Delhi, 110042, India
| | - Asmita Das
- Department of Biotechnology, Delhi Technological University, Main Bawana Road, Delhi, 110042, India.
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12
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Sartorius D, Blume ML, Fleischer JR, Ghadimi M, Conradi LC, De Oliveira T. Implications of Rectal Cancer Radiotherapy on the Immune Microenvironment: Allies and Foes to Therapy Resistance and Patients' Outcome. Cancers (Basel) 2023; 15:5124. [PMID: 37958298 PMCID: PMC10650490 DOI: 10.3390/cancers15215124] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2023] [Revised: 10/16/2023] [Accepted: 10/19/2023] [Indexed: 11/15/2023] Open
Abstract
Aside from surgical resection, locally advanced rectal cancer is regularly treated with neoadjuvant chemoradiotherapy. Since the concept of cancer treatment has shifted from only focusing on tumor cells as drivers of disease progression towards a broader understanding including the dynamic tumor microenvironment (TME), the impact of radiotherapy on the TME and specifically the tumor immune microenvironment (TIME) is increasingly recognized. Both promoting as well as suppressing effects on anti-tumor immunity have been reported in response to rectal cancer (chemo-)radiotherapy and various targets for combination therapies are under investigation. A literature review was conducted searching the PubMed database for evidence regarding the pleiotropic effects of (chemo-)radiotherapy on the rectal cancer TIME, including alterations in cytokine levels, immune cell populations and activity as well as changes in immune checkpoint proteins. Radiotherapy can induce immune-stimulating and -suppressive alterations, potentially mediating radioresistance. The response is influenced by treatment modalities, including the dosage administered and the highly individual intrinsic pre-treatment immune status. Directly addressing the main immune cells of the TME, this review aims to highlight therapeutical implications since efficient rectal cancer treatment relies on personalized strategies combining conventional therapies with immune-modulating approaches, such as immune checkpoint inhibitors.
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Affiliation(s)
| | | | | | | | - Lena-Christin Conradi
- Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Robert-Koch-Straβe 40, 37075 Göttingen, Germany; (D.S.); (M.L.B.); (J.R.F.); (M.G.)
| | - Tiago De Oliveira
- Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Robert-Koch-Straβe 40, 37075 Göttingen, Germany; (D.S.); (M.L.B.); (J.R.F.); (M.G.)
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13
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Nirala BK, Patel TD, Kurenbekova L, Shuck R, Dasgupta A, Rainusso N, Coarfa C, Yustein JT. MYC regulates CSF1 expression via microRNA 17/20a to modulate tumor-associated macrophages in osteosarcoma. JCI Insight 2023; 8:e164947. [PMID: 37279073 PMCID: PMC10371352 DOI: 10.1172/jci.insight.164947] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Accepted: 05/25/2023] [Indexed: 06/07/2023] Open
Abstract
Osteosarcoma (OS) is the most common primary bone tumor of childhood. Approximately 20%-30% of OSs carry amplification of chromosome 8q24, which harbors the oncogene c-MYC and correlates with a poor prognosis. To understand the mechanisms that underlie the ability of MYC to alter both the tumor and its surrounding tumor microenvironment (TME), we generated and molecularly characterized an osteoblast-specific Cre-Lox-Stop-Lox-c-MycT58A p53fl/+ knockin genetically engineered mouse model (GEMM). Phenotypically, the Myc-knockin GEMM had rapid tumor development with a high incidence of metastasis. MYC-dependent gene signatures in our murine model demonstrated significant homology to the human hyperactivated MYC OS. We established that hyperactivation of MYC led to an immune-depleted TME in OS demonstrated by the reduced number of leukocytes, particularly macrophages. MYC hyperactivation led to the downregulation of macrophage colony-stimulating factor 1, through increased microRNA 17/20a expression, causing a reduction of macrophage population in the TME of OS. Furthermore, we developed cell lines from the GEMM tumors, including a degradation tag-MYC model system, which validated our MYC-dependent findings both in vitro and in vivo. Our studies utilized innovative and clinically relevant models to identify a potentially novel molecular mechanism through which MYC regulates the profile and function of the OS immune landscape.
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Affiliation(s)
- Bikesh K. Nirala
- Texas Children’s Cancer and Hematology Centers and The Faris D. Virani Ewing Sarcoma Center
| | - Tajhal D. Patel
- Texas Children’s Cancer and Hematology Centers and The Faris D. Virani Ewing Sarcoma Center
| | - Lyazat Kurenbekova
- Texas Children’s Cancer and Hematology Centers and The Faris D. Virani Ewing Sarcoma Center
| | - Ryan Shuck
- Texas Children’s Cancer and Hematology Centers and The Faris D. Virani Ewing Sarcoma Center
| | - Atreyi Dasgupta
- Texas Children’s Cancer and Hematology Centers and The Faris D. Virani Ewing Sarcoma Center
| | - Nino Rainusso
- Texas Children’s Cancer and Hematology Centers and The Faris D. Virani Ewing Sarcoma Center
| | - Cristian Coarfa
- Department of Molecular & Human Genetics, and
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA
| | - Jason T. Yustein
- Texas Children’s Cancer and Hematology Centers and The Faris D. Virani Ewing Sarcoma Center
- Aflac Cancer and Blood Disorders Center of Children’s Healthcare of Atlanta, Emory University, Atlanta, Georgia, USA
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14
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Chohan MH, Perry M, Laurance-Young P, Salih VM, Foey AD. Prognostic Role of CD68 + and CD163 + Tumour-Associated Macrophages and PD-L1 Expression in Oral Squamous Cell Carcinoma: A Meta-Analysis. Br J Biomed Sci 2023; 80:11065. [PMID: 37397243 PMCID: PMC10310926 DOI: 10.3389/bjbs.2023.11065] [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: 11/18/2022] [Accepted: 02/10/2023] [Indexed: 07/04/2023]
Abstract
Background: Oral squamous cell carcinoma (OSCC) is a common malignant cancer in humans. An abundance of tumour associated macrophages (TAMs) create an immunosuppressive tumour microenvironment (TME). TAM markers (CD163 and CD68) are seen to serve as prognostic factors in OSCC. PD-L1 has seen to widely modulate the TME but its prognostic significance remains controversial. The aim of this meta-analysis is to evaluate the prognostic role of CD163+, CD68+ TAMs and PD-L1 in OSCC patients. Methods: Searches in PubMed, Scopus and Web of Science were performed; 12 studies were included in this meta-analysis. Quality assessment of included studies was performed according to REMARK guidelines. Risk of bias across studies was investigated according to the rate of heterogeneity. Meta-analysis was performed to investigate the association of all three biomarkers with overall survival (OS). Results: High expression of CD163+ TAMs were associated with poor overall survival (HR = 2.64; 95% Cl: [1.65, 4.23]; p < 0.0001). Additionally, high stromal expression of CD163+ TAMs correlated with poor overall survival (HR = 3.56; 95% Cl: [2.33, 5.44]; p < 0.00001). Conversely, high CD68 and PD-L1 expression was not associated with overall survival (HR = 1.26; 95% Cl: [0.76, 2.07]; p = 0.37) (HR = 0.64; 95% Cl: [0.35, 1.18]; p = 0.15). Conclusion: In conclusion, our findings indicate CD163+ can provide prognostic utility in OSCC. However, our data suggests CD68+ TAMs were not associated with any prognostic relevance in OSCC patients, whereas PD-L1 expression may prove to be a differential prognostic marker dependent on tumour location and stage of progression.
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Affiliation(s)
- Mohammed Haseeb Chohan
- School of Biomedical Sciences, Faculty of Health, University of Plymouth, Plymouth, United Kingdom
- School of Dentistry, Faculty of Health, University of Plymouth, Plymouth, United Kingdom
| | - Matthew Perry
- School of Biomedical Sciences, Faculty of Health, University of Plymouth, Plymouth, United Kingdom
- School of Dentistry, Faculty of Health, University of Plymouth, Plymouth, United Kingdom
| | - Paul Laurance-Young
- School of Biomedical Sciences, Faculty of Health, University of Plymouth, Plymouth, United Kingdom
| | - Vehid M. Salih
- School of Dentistry, Faculty of Health, University of Plymouth, Plymouth, United Kingdom
| | - Andrew D. Foey
- School of Biomedical Sciences, Faculty of Health, University of Plymouth, Plymouth, United Kingdom
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15
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Wang S, Hu G, Chen L, Ma K, Hu C, Zhu H, Xu N, Zhou C, Liu M. Celastrol acts as a new histone deacetylase inhibitor to inhibit colorectal cancer cell growth via regulating macrophage polarity. Cell Biol Int 2023; 47:492-501. [PMID: 36317450 DOI: 10.1002/cbin.11952] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Revised: 10/13/2022] [Accepted: 10/16/2022] [Indexed: 11/07/2022]
Abstract
The tumorigenesis and progression of colorectal cancer are closely related to the tumor microenvironment, especially inflammatory response. Inhibitors of histone deacetylase (HDAC) have been reported as epigenetic regulators of the immune system to treat cancer and inflammatory diseases and our results demonstrated that Celastrol could act as a new HDAC inhibitor. Considering macrophages as important members of the tumor microenvironment, we further found that Celastrol could influence the polarization of macrophages to inhibit colorectal cancer cell growth. Specially, we used the supernatant of HCT116 and SW480 cells to induce Ana-1 cells in vitro and chose the spontaneous colorectal cancer model APCmin/+ mice as an animal model to validate in vivo. The results indicated that Celastrol could reverse the polarization of macrophages from M2 to M1 through impacting the colorectal tumor microenvironment both in vitro and in vivo. Furthermore, using bioinformatics analysis, we found that Celastrol might mechanistically polarize the macrophages through MAPK signaling pathway. In conclusion, our findings identified that Celastrol as a new HDAC inhibitor and suggested that Celastrol could modulate macrophage polarization, thus inhibiting colorectal cancer growth, which may provide some novel therapeutic strategies for colorectal cancer.
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Affiliation(s)
- Shuren Wang
- Laboratory of Cell and Molecular Biology & State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,School of Medicine and Institute for Immunology, Tsinghua University, Beijing, China
| | - Guanghui Hu
- Laboratory of Cell and Molecular Biology & State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Lechuang Chen
- Laboratory of Cell and Molecular Biology & State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Kai Ma
- Laboratory of Cell and Molecular Biology & State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Chenfei Hu
- Laboratory of Cell and Molecular Biology & State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Hongxia Zhu
- Laboratory of Cell and Molecular Biology & State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Ningzhi Xu
- Laboratory of Cell and Molecular Biology & State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Changchun Zhou
- Biobank, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Mei Liu
- Laboratory of Cell and Molecular Biology & State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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16
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Shao MM, Pei XB, Chen QY, Wang F, Wang Z, Zhai K. Macrophage-derived exosome promotes regulatory T cell differentiation in malignant pleural effusion. Front Immunol 2023; 14:1161375. [PMID: 37143656 PMCID: PMC10151820 DOI: 10.3389/fimmu.2023.1161375] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Accepted: 04/03/2023] [Indexed: 05/06/2023] Open
Abstract
Introduction Tumor-associated macrophages are one of the key components of the tumor microenvironment. The immunomodulatory activity and function of macrophages in malignant pleural effusion (MPE), a special tumor metastasis microenvironment, have not been clearly defined. Methods MPE-based single-cell RNA sequencing data was used to characterize macrophages. Subsequently, the regulatory effect of macrophages and their secreted exosomes on T cells was verified by experiments. Next, miRNA microarray was used to analyze differentially expressed miRNAs in MPE and benign pleural effusion, and data from The Cancer Genome Atlas (TCGA) was used to evaluate the correlation between miRNAs and patient survival. Results Single-cell RNA sequencing data showed macrophages were mainly M2 polarized in MPE and had higher exosome secretion function compared with those in blood. We found that exosomes released from macrophages could promote the differentiation of naïve T cells into Treg cells in MPE. We detected differential expression miRNAs in macrophage-derived exosomes between MPE and benign pleural effusion by miRNA microarray and found that miR-4443 was significantly overexpressed in MPE exosomes. Gene functional enrichment analysis showed that the target genes of miR-4443 were involved in the regulation of protein kinase B signaling and lipid biosynthetic process. Conclusions Taken together, these results reveal that exosomes mediate the intercellular communication between macrophages and T cells, yielding an immunosuppressive environment for MPE. miR-4443 expressed by macrophages, but not total miR-4443, might serve as a prognostic marker in patients with metastatic lung cancer.
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17
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Shen X, Zhou S, Yang Y, Hong T, Xiang Z, Zhao J, Zhu C, Zeng L, Zhang L. TAM-targeted reeducation for enhanced cancer immunotherapy: Mechanism and recent progress. Front Oncol 2022; 12:1034842. [PMID: 36419877 PMCID: PMC9677115 DOI: 10.3389/fonc.2022.1034842] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Accepted: 10/10/2022] [Indexed: 11/09/2022] Open
Abstract
Tumor-associated macrophage (TAM) as an important component of tumor microenvironment (TME) are closely related with the occurrence, development, and metastasis of malignant tumors. TAMs are generally identified as two distinct functional populations in TME, i.e., inflammatory/anti-tumorigenic (M1) and regenerative/pro-tumorigenic (M2) phenotype. Evidence suggests that occupation of the TME by M2-TAMs is closely related to the inactivation of anti-tumor immune cells such as T cells in TME. Recently, efforts have been made to reeducate TAMs from M2- to M1- phenotype to enhance cancer immunotherapy, and great progress has been made in realizing efficient modulation of TAMs using nanomedicines. To help readers better understand this emerging field, the potential TAM reeducation targets for potentiating cancer immunotherapy and the underlying mechanisms are summarized in this review. Moreover, the most recent advances in utilizing nanomedicine for the TAM immunomodulation for augmented cancer immunotherapy are introduced. Finally, we conclude with our perspectives on the future development in this field.
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Affiliation(s)
- Xinyuan Shen
- Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang Province, School of Medicine, Zhejiang University City College, Hangzhou, China
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Shengcheng Zhou
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Yidong Yang
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Tu Hong
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Ze Xiang
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Jing Zhao
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Chaojie Zhu
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Linghui Zeng
- Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang Province, School of Medicine, Zhejiang University City College, Hangzhou, China
| | - Lingxiao Zhang
- Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang Province, School of Medicine, Zhejiang University City College, Hangzhou, China
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
- Key Laboratory of Diagnosis and Treatment of Digestive System Tumors of Zhejiang Province, Ningbo Hwa Mei Hospital, University of Chinese Academy of Sciences, Ningbo, China
- Ningbo Institute of Life and Health Industry, University of Chinese Academy of Sciences, Ningbo, China
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18
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Cervical Cancer Outcome and Tumor-Associated Macrophages: Research Evidence. IMMUNO 2022. [DOI: 10.3390/immuno2030028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Inflammation is a key factor in cancer promotion. Tumor-associated macrophages (TAMs), as part of the tumor microenvironment, are often associated with the progression of tumors and a worse prognosis in many cancers, namely on cervical cancer. This work exhaustively summarizes the conclusions of the different studies published concerning TAMs function in cervical cancer, from in vitro studies using cancer cell lines to the clinical perspective (histological samples-based studies). Most studies have led to the conclusion that TAMs increased density is directly related to increased severity of a malignant cervical lesion. Additionally, TAMs are normally polarized into an M2 phenotype, benefiting and promoting tumor progression, resulting in a worse disease outcome. The tumor microenvironment is also a highly critical contributor that not only influences tumor natural history but also modulates the specific immune response.
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19
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Pernot S, Evrard S, Khatib AM. The Give-and-Take Interaction Between the Tumor Microenvironment and Immune Cells Regulating Tumor Progression and Repression. Front Immunol 2022; 13:850856. [PMID: 35493456 PMCID: PMC9043524 DOI: 10.3389/fimmu.2022.850856] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2022] [Accepted: 03/28/2022] [Indexed: 11/29/2022] Open
Abstract
A fundamental concern of the majority of cancer scientists is related to the identification of mechanisms involved in the evolution of neoplastic cells at the cellular and molecular level and how these processes are able to control cancer cells appearance and death. In addition to the genome contribution, such mechanisms involve reciprocal interactions between tumor cells and stromal cells within the tumor microenvironment (TME). Indeed, tumor cells survival and growth rely on dynamic properties controlling pro and anti-tumorigenic processes. The anti-tumorigenic function of the TME is mainly regulated by immune cells such as dendritic cells, natural killer cells, cytotoxic T cells and macrophages and normal fibroblasts. The pro-tumorigenic function is also mediated by other immune cells such as myeloid-derived suppressor cells, M2-tumor-associated macrophages (TAMs) and regulatory T (Treg) cells, as well as carcinoma-associated fibroblasts (CAFs), adipocytes (CAA) and endothelial cells. Several of these cells can show both, pro- and antitumorigenic activity. Here we highlight the importance of the reciprocal interactions between tumor cells and stromal cells in the self-centered behavior of cancer cells and how these complex cellular interactions control tumor progression and repression.
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Affiliation(s)
- Simon Pernot
- Reprograming Tumor Activity and Associated Microenvironment (RYTME), Bordeaux Institute of Oncology (BRIC)-Unité Mixte de Recherche (UMR) 1312 Inserm, Pessac, France
| | | | - Abdel-Majid Khatib
- Reprograming Tumor Activity and Associated Microenvironment (RYTME), Bordeaux Institute of Oncology (BRIC)-Unité Mixte de Recherche (UMR) 1312 Inserm, Pessac, France.,Institut Bergonié, Bordeaux, France
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20
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Vitale C, Marzagalli M, Scaglione S, Dondero A, Bottino C, Castriconi R. Tumor Microenvironment and Hydrogel-Based 3D Cancer Models for In Vitro Testing Immunotherapies. Cancers (Basel) 2022; 14:1013. [PMID: 35205760 PMCID: PMC8870468 DOI: 10.3390/cancers14041013] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Revised: 02/12/2022] [Accepted: 02/14/2022] [Indexed: 02/05/2023] Open
Abstract
In recent years, immunotherapy has emerged as a promising novel therapeutic strategy for cancer treatment. In a relevant percentage of patients, however, clinical benefits are lower than expected, pushing researchers to deeply analyze the immune responses against tumors and find more reliable and efficient tools to predict the individual response to therapy. Novel tissue engineering strategies can be adopted to realize in vitro fully humanized matrix-based models, as a compromise between standard two-dimensional (2D) cell cultures and animal tests, which are costly and hardly usable in personalized medicine. In this review, we describe the main mechanisms allowing cancer cells to escape the immune surveillance, which may play a significant role in the failure of immunotherapies. In particular, we discuss the role of the tumor microenvironment (TME) in the establishment of a milieu that greatly favors cancer malignant progression and impact on the interactions with immune cells. Then, we present an overview of the recent in vitro engineered preclinical three-dimensional (3D) models that have been adopted to resemble the interplays between cancer and immune cells and for testing current therapies and immunotherapeutic approaches. Specifically, we focus on 3D hydrogel-based tools based on different types of polymers, discussing the suitability of each of them in reproducing the TME key features based on their intrinsic or tunable characteristics. Finally, we introduce the possibility to combine the 3D models with technological fluid dynamics platforms, reproducing the dynamic complex interactions between tumor cells and immune effectors migrated in situ via the systemic circulation, pointing out the challenges that still have to be overcome for setting more predictive preclinical assays.
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Affiliation(s)
- Chiara Vitale
- Department of Experimental Medicine (DIMES), University of Genova, 16132 Genova, Italy; (C.V.); (A.D.); (R.C.)
| | | | - Silvia Scaglione
- React4life SRL, 16121 Genova, Italy; (M.M.); (S.S.)
- National Research Council of Italy, Institute of Electronics, Information Engineering and Telecommunications (IEIIT), 16149 Genova, Italy
| | - Alessandra Dondero
- Department of Experimental Medicine (DIMES), University of Genova, 16132 Genova, Italy; (C.V.); (A.D.); (R.C.)
| | - Cristina Bottino
- Department of Experimental Medicine (DIMES), University of Genova, 16132 Genova, Italy; (C.V.); (A.D.); (R.C.)
- IRCCS Istituto Giannina Gaslini, 16147 Genova, Italy
| | - Roberta Castriconi
- Department of Experimental Medicine (DIMES), University of Genova, 16132 Genova, Italy; (C.V.); (A.D.); (R.C.)
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21
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Zhang Y, Liu Y, Wang J, Jiang Z, Zhang L, Cui Y, Zhao D, Wang Y. Atractylenolide II inhibits tumor-associated macrophages (TAMs)-induced lung cancer cell metastasis. Immunopharmacol Immunotoxicol 2022; 44:227-237. [PMID: 35166628 DOI: 10.1080/08923973.2022.2037629] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
OBJECTIVE M2-like tumor-associated macrophages (TAMs) play a crucial role in promoting tumor proliferation, angiogenesis, and metastasis. In the current study, we investigated the relationship between macrophage polarization and the antitumor effect of Atractylenolide II (AT-II) in lung cancer cells. MATERIALS AND METHODS Cell viability, migration, and invasion were determined by MTT assay, wound healing assay, and transwell assay, respectively. Flow cytometry analysis showed the percentage of CD206+ cells. Gene expression was determined by real-time PCR, western blotting, and immunofluorescence staining. Lewis lung carcinoma mouse xenograft and metastasis models were used to examine the effects of AT-II on lung cancer in vivo. RESULTS AT-II (2.5 and 5 µM) did not cause significant inhibition of A549 cell viability but markedly inhibited IL-4/IL-13-induced M2-like polarization, evidenced by the decreased expression of the M2 surface marker CD206, down-regulation of specific M2-marker genes (Arg-1, IL-10 and TGF-β) as well as inhibition of M2 macrophages-mediated invasion and migration of A549 cells. In addition, AT-II inhibited IL-4/IL-13-induced activation of the STAT6 signaling pathway that is vital in the M2-like polarization of macrophages. In animal models, administration of AT-II (50 mg kg-1, i.g., QD for 21 days) significantly inhibited tumor growth, reduced pulmonary metastatic nodules, and down-regulated the percentages of M2 macrophages (F4/80+ and CD206+) in total macrophages (F4/80+) in tumor tissues and pulmonary metastatic nodules. CONCLUSIONS AT-II effectively inhibits M2-like polarization, thereby inhibiting lung cancer cell metastasis both in vivo and in vitro, revealing a novel potential strategy for the antitumor effect of AT-II.
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Affiliation(s)
- Yunting Zhang
- College of Integrated Chinese and Western Medicine, Liaoning University of Traditional Chinese Medicine, Shenyang, P.R. China
| | - Yuxi Liu
- College of Integrated Chinese and Western Medicine, Liaoning University of Traditional Chinese Medicine, Shenyang, P.R. China
| | - Jianguang Wang
- College of Integrated Chinese and Western Medicine, Liaoning University of Traditional Chinese Medicine, Shenyang, P.R. China
| | - Zongying Jiang
- College of Integrated Chinese and Western Medicine, Liaoning University of Traditional Chinese Medicine, Shenyang, P.R. China
| | - Lin Zhang
- College of Integrated Chinese and Western Medicine, Liaoning University of Traditional Chinese Medicine, Shenyang, P.R. China
| | - Yong Cui
- College of Integrated Chinese and Western Medicine, Liaoning University of Traditional Chinese Medicine, Shenyang, P.R. China
| | - Danyu Zhao
- College of Integrated Chinese and Western Medicine, Liaoning University of Traditional Chinese Medicine, Shenyang, P.R. China
| | - Yanjie Wang
- College of Integrated Chinese and Western Medicine, Liaoning University of Traditional Chinese Medicine, Shenyang, P.R. China
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22
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Singh SK, Singh R. Cytokines and Chemokines in Cancer Cachexia and Its Long-Term Impact on COVID-19. Cells 2022; 11:cells11030579. [PMID: 35159388 PMCID: PMC8834385 DOI: 10.3390/cells11030579] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Revised: 02/02/2022] [Accepted: 02/04/2022] [Indexed: 02/04/2023] Open
Abstract
Cancer cachexia remains a serious public health concern worldwide, particularly as cancer rates rise. Treatment is endangered, and survival is reduced, because this illness is commonly misdiagnosed and undertreated. Although weight loss is the most evident sign of cachexia, there are other early metabolic and inflammatory changes that occur before the most obvious symptoms appear. Cachexia-related inflammation is induced by a combination of factors, one of which is the release of inflammation-promoting chemicals by the tumor. Today, more scientists are beginning to believe that the development of SARS-CoV-2 (COVID-19) related cachexia is similar to cancer-related cachexia. It is worth noting that patients infected with COVID-19 have a significant inflammatory response and can develop cachexia. These correlations provide feasible reasons for the variance in the occurrence and severity of cachexia in human malignancies, therefore, specific therapeutic options for these individuals must be addressed based on disease types. In this review, we highlighted the role of key chemokines, cytokines, and clinical management in relation to cancer cachexia and its long-term impact on COVID-19 patients.
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Affiliation(s)
- Santosh Kumar Singh
- Department of Microbiology, Biochemistry, and Immunology, Morehouse School of Medicine, Atlanta, GA 30310, USA;
| | - Rajesh Singh
- Department of Microbiology, Biochemistry, and Immunology, Morehouse School of Medicine, Atlanta, GA 30310, USA;
- Cancer Health Equity Institute, Morehouse School of Medicine, Atlanta, GA 30310, USA
- Correspondence: ; Tel.: +1-404-756-6661; Fax: +1-404-752-1179
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23
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Li Q, Sun L, Liu L, Ran Q, Du X, Yang Q, Wang Y, Li Y, Chen Y, Weng X, Cai W, Zhu X. Chamaejasmenin B, an Inhibitor for Metastatic Outgrowth, Reversed M2-Dominant Macrophage Polarization in Breast Tumor Microenvironment. Front Immunol 2022; 12:774230. [PMID: 35027915 PMCID: PMC8750059 DOI: 10.3389/fimmu.2021.774230] [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: 09/11/2021] [Accepted: 11/25/2021] [Indexed: 11/25/2022] Open
Abstract
Metastasis is a multistep process that depends on the interactions between tumor cells and their microenvironment. Macrophages in the tumor microenvironment show high polarization plasticity and have a paradoxical role in cancer progression. Hijacked by tumor-promoting signals, the polarization status of macrophages was pathologically disturbed and believed to be the decisive mechanism forcing the progression of metastasis. In this study, we explored the immunological activity of Chamaejasmin B (ICJ), a previously proved inhibitor for metastasis, in macrophages from metastatic microenvironment. When intravenously injected of 4T1 cells in mice, ICJ significantly inhibited its metastatic outgrowth. Taking tumor cell and macrophage as a functional integrity, an adoptive transfer model was established in vitro to exclude the direct effect of ICJ on tumor. The findings suggest a dual influence of ICJ on both tumors and macrophages, as indicated by the rebalance of macrophage polarization and suppression of clonogenic potential in tumor cells. Mechanistically, ICJ redirected M2-dominant polarization of tumor-associated macrophage in an IL-4-mTOR-dependent manner. Collectively, our study revealed that ICJ rebalanced macrophage polarization in malignant microenvironment and showed promising effect in suppressing metastatic outgrowth in breast cancer model.
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Affiliation(s)
- Qi Li
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China
| | - Lidong Sun
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China
| | - Li Liu
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China
| | - Qingsen Ran
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China
| | - Xinke Du
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China
| | - Qing Yang
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China
| | - Yajie Wang
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China
| | - Yujie Li
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China
| | - Ying Chen
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China
| | - Xiaogang Weng
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China
| | - Weiyan Cai
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China
| | - Xiaoxin Zhu
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China
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24
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Antoñana-Vildosola A, Zanetti SR, Palazon A. Enabling CAR-T cells for solid tumors: Rage against the suppressive tumor microenvironment. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2022; 370:123-147. [PMID: 35798503 DOI: 10.1016/bs.ircmb.2022.03.004] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/22/2023]
Abstract
Adoptive T cell therapies based on chimeric antigen receptors (CAR-T) are emerging as genuine therapeutic options for the treatment of hematological malignancies. The observed clinical success has not yet been extended into solid tumor indications as a result of multiple factors including immunosuppressive features of the tumor microenvironment (TME). In this context, an emerging strategy is to design CAR-T cells for the elimination of defined cellular components of the TME, with the objective of re-shaping the tumor immune contexture to control tumor growth. Relevant cell components that are currently under investigation as targets of CAR-T therapies include the tumor vasculature, cancer-associated fibroblasts (CAFs), and immunosuppressive tumor associated macrophages (TAMs) and myeloid derived suppressor cells (MDSCs). In this review, we recapitulate the rapidly expanding field of CAR-T cell therapies that directly target cellular components within the TME with the ultimate objective of promoting immune function, either alone or in combination with other cancer therapies.
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Affiliation(s)
- Asier Antoñana-Vildosola
- Cancer Immunology and Immunotherapy Lab, CIC bioGUNE, Basque Research and Technology Alliance (BRTA), Bizkaia, Spain
| | - Samanta Romina Zanetti
- Cancer Immunology and Immunotherapy Lab, CIC bioGUNE, Basque Research and Technology Alliance (BRTA), Bizkaia, Spain
| | - Asis Palazon
- Cancer Immunology and Immunotherapy Lab, CIC bioGUNE, Basque Research and Technology Alliance (BRTA), Bizkaia, Spain; Ikerbasque, Basque Foundation for Science, Bizkaia, Spain.
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25
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Czajka-Francuz P, Cisoń-Jurek S, Czajka A, Kozaczka M, Wojnar J, Chudek J, Francuz T. Systemic Interleukins' Profile in Early and Advanced Colorectal Cancer. Int J Mol Sci 2021; 23:124. [PMID: 35008550 PMCID: PMC8745135 DOI: 10.3390/ijms23010124] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2021] [Revised: 12/18/2021] [Accepted: 12/20/2021] [Indexed: 02/05/2023] Open
Abstract
Tumor microenvironment (TME) is characterized by mutual interactions of the tumor, stromal and immune cells. Early and advanced colorectal tumors differ in structure and present altered serum cytokine levels. Mutual crosstalk among TME infiltrating cells may shift the balance into immune suppressive or pro-inflammatory, antitumor response this way influencing patients' prognosis. Cancer-related inflammation affects all the body and this way, the systemic level of cytokines could reflect TME processes. Despite numerous studies, it is still not known how systemic cytokines levels change during colorectal cancer (CRC) tumor development. Better understanding tumor microenvironment processes could help in planning therapeutic interventions and more accurate patient prognosis. To contribute to the comprehension of these processes within TME, we reviewed cytokines levels from clinical trials in early and advanced colorectal cancer. Presented data were analyzed in the context of experimental studies and studies analyzing tumor infiltration with immune cells. The review summarizes clinical data of cytokines secreted by tumor microenvironment cells: lymphocytes T helper 1 (Th1), lymphocytes T helper 2 (Th2), lymphocytes T helper 17 (Th17), regulatory T cells (Treg cells), regulatory T cells (Breg cells), M1/M2 macrophages, N1/N2 neutrophils, myeloid-derived suppressor cells (MDSC), dendritic cells (DC), innate lymphoid cells (ILC) natural killer (NK) cells and tumor cells.
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Affiliation(s)
- Paulina Czajka-Francuz
- Department of Internal Medicine and Oncological Chemotherapy, Faculty of Medical Sciences in Katowice, Medical University of Silesia, 40-027 Katowice, Poland; (S.C.-J.); (J.W.); (J.C.); (T.F.)
| | - Sylwia Cisoń-Jurek
- Department of Internal Medicine and Oncological Chemotherapy, Faculty of Medical Sciences in Katowice, Medical University of Silesia, 40-027 Katowice, Poland; (S.C.-J.); (J.W.); (J.C.); (T.F.)
| | - Aleksander Czajka
- Department of General Surgery, Vascular Surgery, Angiology and Phlebology, Faculty of Medical Sciences in Katowice, Medical University of Silesia, 40-635 Katowice, Poland;
| | - Maciej Kozaczka
- Department of Radiotherapy and Chemotherapy, National Institute of Oncology, Public Research Institute in Gliwice, 44-101 Gliwice, Poland;
| | - Jerzy Wojnar
- Department of Internal Medicine and Oncological Chemotherapy, Faculty of Medical Sciences in Katowice, Medical University of Silesia, 40-027 Katowice, Poland; (S.C.-J.); (J.W.); (J.C.); (T.F.)
| | - Jerzy Chudek
- Department of Internal Medicine and Oncological Chemotherapy, Faculty of Medical Sciences in Katowice, Medical University of Silesia, 40-027 Katowice, Poland; (S.C.-J.); (J.W.); (J.C.); (T.F.)
| | - Tomasz Francuz
- Department of Internal Medicine and Oncological Chemotherapy, Faculty of Medical Sciences in Katowice, Medical University of Silesia, 40-027 Katowice, Poland; (S.C.-J.); (J.W.); (J.C.); (T.F.)
- Department of Biochemistry, Faculty of Medical Sciences in Katowice, Medical University of Silesia, 40-752 Katowice, Poland
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26
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Wierzbicki J, Lipiński A, Bednarz-Misa I, Lewandowski Ł, Neubauer K, Lewandowska P, Krzystek-Korpacka M. Monocyte Chemotactic Proteins (MCP) in Colorectal Adenomas Are Differently Expressed at the Transcriptional and Protein Levels: Implications for Colorectal Cancer Prevention. J Clin Med 2021; 10:jcm10235559. [PMID: 34884259 PMCID: PMC8658354 DOI: 10.3390/jcm10235559] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Revised: 11/08/2021] [Accepted: 11/25/2021] [Indexed: 11/27/2022] Open
Abstract
The expression of monocyte chemotactic proteins (MCPs) in colorectal polyps and their suitability as targets for chemoprevention is unknown, although MCP expression and secretion can be modulated by non-steroidal inflammatory drugs. This study was designed to determine the expression patterns of MCP-1/CCL2, MCP-2/CCL8, and MCP-3/CCL7 at the protein (immunohistochemistry; n = 62) and transcriptional levels (RTqPCR; n = 173) in colorectal polyps with reference to the polyp malignancy potential. All chemokines were significantly upregulated in polyps at the protein level but downregulated at the transcriptional level by 1.4-(CCL2), 1.7-(CCL7), and 2.3-fold (CCL8). There was an inverse relation between the immunoreactivity toward chemokine proteins and the number of corresponding transcripts in polyps (CCL2 and CCL7) or in normal mucosa (CCL8). The downregulation of chemokine transcripts correlated with the presence of multiple polyps (CCL2 and CCL8), a larger polyp size (CCL2, CCL7, and CCL8), predominant villous growth patterns (CCL2, CCL7 and CCL8), and high-grade dysplasia (CCL2 and CCL8). In conclusion, MCP-1/CCL2, MCP-2/CCL8, and MCP-3/CCL7 chemokines are counter-regulated at the protein and transcriptional levels. Chemokine-directed chemopreventive strategies should therefore directly neutralize MCP proteins or target molecular pathways contributing to their enhanced translation or reduced degradation, rather than aiming at CCL2, CCL7 or CCL8 expression.
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Affiliation(s)
- Jarosław Wierzbicki
- Department of Minimally Invasive Surgery and Proctology, Wroclaw Medical University, 50-556 Wroclaw, Poland
- Correspondence: (J.W.); (M.K.-K.)
| | - Artur Lipiński
- Department of Clinical Pathology, Wroclaw Medical University, 50-556 Wroclaw, Poland;
| | - Iwona Bednarz-Misa
- Department of Medical Biochemistry, Wroclaw Medical University, 50-368 Wroclaw, Poland; (I.B.-M.); (Ł.L.); (P.L.)
| | - Łukasz Lewandowski
- Department of Medical Biochemistry, Wroclaw Medical University, 50-368 Wroclaw, Poland; (I.B.-M.); (Ł.L.); (P.L.)
| | - Katarzyna Neubauer
- Department of Gastroenterology and Hepatology, Wroclaw Medical University, 50-556 Wroclaw, Poland;
| | - Paulina Lewandowska
- Department of Medical Biochemistry, Wroclaw Medical University, 50-368 Wroclaw, Poland; (I.B.-M.); (Ł.L.); (P.L.)
| | - Małgorzata Krzystek-Korpacka
- Department of Medical Biochemistry, Wroclaw Medical University, 50-368 Wroclaw, Poland; (I.B.-M.); (Ł.L.); (P.L.)
- Correspondence: (J.W.); (M.K.-K.)
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27
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Jesser EA, Brady NJ, Huggins DN, Witschen PM, O'Connor CH, Schwertfeger KL. STAT5 is activated in macrophages by breast cancer cell-derived factors and regulates macrophage function in the tumor microenvironment. Breast Cancer Res 2021; 23:104. [PMID: 34743736 PMCID: PMC8573892 DOI: 10.1186/s13058-021-01481-0] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2021] [Accepted: 10/25/2021] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND In breast cancer, complex interactions between tumor cells and cells within the surrounding stroma, such as macrophages, are critical for tumor growth, progression, and therapeutic response. Recent studies have highlighted the complex nature and heterogeneous populations of macrophages associated with both tumor-promoting and tumor-inhibiting phenotypes. Defining the pathways that drive macrophage function is important for understanding their complex phenotypes within the tumor microenvironment. Signal transducer and activator of transcription (STAT) transcription factors, such as STAT5, are key regulators of immune cell function. The studies described here investigate the functional contributions of STAT5 to tumor-associated macrophage function in breast cancer. METHODS Initial studies were performed using a panel of human breast cancer and mouse mammary tumor cell lines to determine the ability of tumor cell-derived factors to induce STAT5 activation in macrophages. Further studies used these models to identify soluble factors that activate STAT5 in macrophages. To delineate STAT5-specific contributions to macrophage function, a conditional model of myeloid STAT5 deletion was used for in vitro, RNA-sequencing, and in vivo studies. The effects of STAT5 deletion in macrophages on tumor cell migration and metastasis were evaluated using in vitro co-culture migration assays and an in vivo tumor cell-macrophage co-injection model. RESULTS We demonstrate here that STAT5 is robustly activated in macrophages by tumor cell-derived factors and that GM-CSF is a key cytokine stimulating this pathway. The analysis of RNA-seq studies reveals that STAT5 promotes expression of immune stimulatory genes in macrophages and that loss of STAT5 in macrophages results in increased expression of tissue remodeling factors. Finally, we demonstrate that loss of STAT5 in macrophages promotes tumor cell migration in vitro and mammary tumor metastasis in vivo. CONCLUSIONS Breast cancer cells produce soluble factors, such as GM-CSF, that activate the STAT5 pathway in macrophages and drive expression of inflammatory factors. STAT5 deletion in myeloid cells enhances metastasis, suggesting that STAT5 activation in tumor-associated macrophages protects against tumor progression. Understanding mechanisms that drive macrophage function in the tumor microenvironment will ultimately lead to new approaches that suppress tumor-promoting functions while enhancing their anti-tumor functions.
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Affiliation(s)
- Emily A Jesser
- Microbiology, Immunology and Cancer Biology Graduate Program, University of Minnesota, Minneapolis, MN, USA
| | - Nicholas J Brady
- Microbiology, Immunology and Cancer Biology Graduate Program, University of Minnesota, Minneapolis, MN, USA
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, 10021, USA
| | - Danielle N Huggins
- Department of Laboratory Medicine and Pathology, 6Th St SE, University of Minnesota, Minneapolis, MN, USA
| | - Patrice M Witschen
- Comparative and Molecular Biosciences Graduate Program, University of Minnesota, Minneapolis, USA
| | - Christine H O'Connor
- Department of Laboratory Medicine and Pathology, 6Th St SE, University of Minnesota, Minneapolis, MN, USA
- University of Minnesota Supercomputing Institute, University of Minnesota, Minneapolis, MN, USA
| | - Kathryn L Schwertfeger
- Department of Laboratory Medicine and Pathology, 6Th St SE, University of Minnesota, Minneapolis, MN, USA.
- Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.
- Center for Immunology, University of Minnesota, Minneapolis, USA.
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28
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Medina-Andrade I, Olguín JE, Guerrero-García S, Espinosa JA, Garduño-Javier E, Hernández-Gómez V, Vaca-Paniagua F, Rodríguez-Sosa M, Terrazas LI. Recruitment of M1 Macrophages May Not Be Critical for Protection against Colitis-Associated Tumorigenesis. Int J Mol Sci 2021; 22:11204. [PMID: 34681866 PMCID: PMC8536994 DOI: 10.3390/ijms222011204] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Revised: 10/08/2021] [Accepted: 10/12/2021] [Indexed: 11/16/2022] Open
Abstract
A close connection between inflammation and the risk of developing colon cancer has been suggested in the last few years. It has been estimated that patients diagnosed with some types of inflammatory bowel disease, such as ulcerative colitis or Crohn's disease, have up to a 30% increased risk of developing colon cancer. However, there is also evidence showing that the activation of anti-inflammatory pathways, such as the IL-4 receptor-mediated pathway, may favor the development of colon tumors. Using an experimental model of colitis-associated colon cancer (CAC), we found that the decrease in tumor development in global IL4Rα knockout mice (IL4RαKO) was apparently associated with an inflammatory response mediated by the infiltration of M1 macrophages (F480+TLR2+STAT1+) and iNOS expression in colon tissue. However, when we developed mice with a specific deletion of IL4Rα in macrophages (LysMcreIL4Rα-/lox mice) and subjected them to CAC, it was found that despite presenting a large infiltration of M1 macrophages into the colon, these mice were as susceptible to colon-tumorigenesis as WT mice. These data suggest that in the tumor microenvironment the absence of IL4Rα expression on macrophages, as well as the recruitment of M1 macrophages, may not be directly associated with resistance to developing colon tumors. Therefore, it is possible that IL4Rα expression in other cell types, such as colonic epithelial cells, could have an important role in promoting the development of colitis-associated colon tumorigenesis.
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Affiliation(s)
- Itzel Medina-Andrade
- Laboratorio Nacional en Salud FES-Iztacala, Universidad Nacional Autónoma de México, Av. De los Barrios 1, Los Reyes Iztacala, Tlalnepantla 54090, Estado de México, Mexico; (I.M.-A.); (J.E.O.); (S.G.-G.); (J.A.E.); (E.G.-J.); (V.H.-G.); (F.V.-P.); (M.R.-S.)
| | - Jonadab E. Olguín
- Laboratorio Nacional en Salud FES-Iztacala, Universidad Nacional Autónoma de México, Av. De los Barrios 1, Los Reyes Iztacala, Tlalnepantla 54090, Estado de México, Mexico; (I.M.-A.); (J.E.O.); (S.G.-G.); (J.A.E.); (E.G.-J.); (V.H.-G.); (F.V.-P.); (M.R.-S.)
| | - Stephanie Guerrero-García
- Laboratorio Nacional en Salud FES-Iztacala, Universidad Nacional Autónoma de México, Av. De los Barrios 1, Los Reyes Iztacala, Tlalnepantla 54090, Estado de México, Mexico; (I.M.-A.); (J.E.O.); (S.G.-G.); (J.A.E.); (E.G.-J.); (V.H.-G.); (F.V.-P.); (M.R.-S.)
| | - Jossael A. Espinosa
- Laboratorio Nacional en Salud FES-Iztacala, Universidad Nacional Autónoma de México, Av. De los Barrios 1, Los Reyes Iztacala, Tlalnepantla 54090, Estado de México, Mexico; (I.M.-A.); (J.E.O.); (S.G.-G.); (J.A.E.); (E.G.-J.); (V.H.-G.); (F.V.-P.); (M.R.-S.)
| | - Elizabeth Garduño-Javier
- Laboratorio Nacional en Salud FES-Iztacala, Universidad Nacional Autónoma de México, Av. De los Barrios 1, Los Reyes Iztacala, Tlalnepantla 54090, Estado de México, Mexico; (I.M.-A.); (J.E.O.); (S.G.-G.); (J.A.E.); (E.G.-J.); (V.H.-G.); (F.V.-P.); (M.R.-S.)
| | - Victoria Hernández-Gómez
- Laboratorio Nacional en Salud FES-Iztacala, Universidad Nacional Autónoma de México, Av. De los Barrios 1, Los Reyes Iztacala, Tlalnepantla 54090, Estado de México, Mexico; (I.M.-A.); (J.E.O.); (S.G.-G.); (J.A.E.); (E.G.-J.); (V.H.-G.); (F.V.-P.); (M.R.-S.)
| | - Felipe Vaca-Paniagua
- Laboratorio Nacional en Salud FES-Iztacala, Universidad Nacional Autónoma de México, Av. De los Barrios 1, Los Reyes Iztacala, Tlalnepantla 54090, Estado de México, Mexico; (I.M.-A.); (J.E.O.); (S.G.-G.); (J.A.E.); (E.G.-J.); (V.H.-G.); (F.V.-P.); (M.R.-S.)
- Unidad de Biomedicina, Facultad de Estudios Superiores (FES)-Iztacala, Universidad Nacional Autónoma de México, Av. De los Barrios 1, Los Reyes Iztacala, Tlalnepantla 54090, Estado de México, Mexico
| | - Miriam Rodríguez-Sosa
- Laboratorio Nacional en Salud FES-Iztacala, Universidad Nacional Autónoma de México, Av. De los Barrios 1, Los Reyes Iztacala, Tlalnepantla 54090, Estado de México, Mexico; (I.M.-A.); (J.E.O.); (S.G.-G.); (J.A.E.); (E.G.-J.); (V.H.-G.); (F.V.-P.); (M.R.-S.)
| | - Luis I. Terrazas
- Laboratorio Nacional en Salud FES-Iztacala, Universidad Nacional Autónoma de México, Av. De los Barrios 1, Los Reyes Iztacala, Tlalnepantla 54090, Estado de México, Mexico; (I.M.-A.); (J.E.O.); (S.G.-G.); (J.A.E.); (E.G.-J.); (V.H.-G.); (F.V.-P.); (M.R.-S.)
- Unidad de Biomedicina, Facultad de Estudios Superiores (FES)-Iztacala, Universidad Nacional Autónoma de México, Av. De los Barrios 1, Los Reyes Iztacala, Tlalnepantla 54090, Estado de México, Mexico
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Jones JO, Moody WM, Shields JD. Microenvironmental modulation of the developing tumour: an immune-stromal dialogue. Mol Oncol 2021; 15:2600-2633. [PMID: 32741067 PMCID: PMC8486574 DOI: 10.1002/1878-0261.12773] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Revised: 07/03/2020] [Accepted: 07/27/2020] [Indexed: 12/17/2022] Open
Abstract
Successful establishment of a tumour relies on a cascade of interactions between cancer cells and stromal cells within an evolving microenvironment. Both immune and nonimmune cellular components are key factors in this process, and the individual players may change their role from tumour elimination to tumour promotion as the microenvironment develops. While the tumour-stroma crosstalk present in an established tumour is well-studied, aspects in the early tumour or premalignant microenvironment have received less attention. This is in part due to the challenges in studying this process in the clinic or in mouse models. Here, we review the key anti- and pro-tumour factors in the early microenvironment and discuss how understanding this process may be exploited in the clinic.
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Affiliation(s)
- James O. Jones
- MRC Cancer UnitHutchison/MRC Research CentreUniversity of CambridgeCambridgeUK
- Department of OncologyCambridge University Hospitals NHS Foundation TrustCambridgeUK
| | - William M. Moody
- MRC Cancer UnitHutchison/MRC Research CentreUniversity of CambridgeCambridgeUK
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Wei Z, Yang M, Feng M, Wu Z, Rosin-Arbesfeld R, Dong J, Zhu D. Inhibition of BCL9 Modulates the Cellular Landscape of Tumor-Associated Macrophages in the Tumor Immune Microenvironment of Colorectal Cancer. Front Pharmacol 2021; 12:713331. [PMID: 34566638 PMCID: PMC8461101 DOI: 10.3389/fphar.2021.713331] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2021] [Accepted: 08/20/2021] [Indexed: 01/01/2023] Open
Abstract
Tumor-associated macrophages (TAMs) are an indispensable part of the tumor microenvironment (TME), and they likely play a negative rather than positive role in cancer treatment. However, the cellular landscape and transcriptional profile regulation of TAMs in the case of tumor gene inactivation or chemical interference remains unclear. The B-cell lymphoma 9/B-cell lymphoma 9-like (BCL9/BCL9L) is a critical transcription co-factor of β-catenin. Suppression of Bcl9 inhibits tumor growth in mouse models of colorectal cancer (CRC). Here, we studied the TAMs of CRC by single-cell sequencing. Bcl9 depletion caused macrophage polarization inhibition from M0 to M2 and changed the CRC TME, which further interferes with the inflammation of M0 and M1. The transcription factor regulating these processes may be related to the Wnt signaling pathway from multiple levels. Furthermore, we also found that the cells delineated from monocyte to NK-like non-functioning cells were significantly different in the BCL9-deprived population. Combining these data, we proposed a TAM-to-NK score to evaluate the dynamic balance in TME of monocyte/TAM cells and NK-like non-functioning cells in The Cancer Genome Atlas (TCGA) clinical samples to verify the clinical significance. We demonstrated that the cell type balance and transcription differences of TAMs regulated by BCL9-driven Wnt signaling affected immune surveillance and inflammation of cancer, ultimately affecting patients' prognosis. We thereby highlighted the potential of targeting Wnt signaling pathway through cancer immunotherapy.
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Affiliation(s)
- Zhuang Wei
- Department of Pharmacology, School of Basic Medical Sciences, Fudan University, Shanghai, China.,Key Laboratory of Systems Biology, Innovation Center for Cell Signaling Network, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Mengxuan Yang
- Minhang Branch, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Mei Feng
- Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, China
| | - Zhongen Wu
- Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, China
| | - Rina Rosin-Arbesfeld
- Department of Microbiology and Immunology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Jibin Dong
- Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, China
| | - Di Zhu
- Department of Pharmacology, School of Basic Medical Sciences, Fudan University, Shanghai, China.,Key Laboratory of Smart Drug Delivery, State Key Laboratory of Molecular Engineering of Polymers, School of Pharmacy, Ministry of Education, Fudan University, Shanghai, China.,Shanghai Engineering Research Center of ImmunoTherapeutics, Fudan University, Shanghai, China
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31
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Budithi A, Su S, Kirshtein A, Shahriyari L. Data Driven Mathematical Model of FOLFIRI Treatment for Colon Cancer. Cancers (Basel) 2021; 13:2632. [PMID: 34071939 PMCID: PMC8198096 DOI: 10.3390/cancers13112632] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 05/21/2021] [Accepted: 05/21/2021] [Indexed: 12/12/2022] Open
Abstract
Many colon cancer patients show resistance to their treatments. Therefore, it is important to consider unique characteristic of each tumor to find the best treatment options for each patient. In this study, we develop a data driven mathematical model for interaction between the tumor microenvironment and FOLFIRI drug agents in colon cancer. Patients are divided into five distinct clusters based on their estimated immune cell fractions obtained from their primary tumors' gene expression data. We then analyze the effects of drugs on cancer cells and immune cells in each group, and we observe different responses to the FOLFIRI drugs between patients in different immune groups. For instance, patients in cluster 3 with the highest T-reg/T-helper ratio respond better to the FOLFIRI treatment, while patients in cluster 2 with the lowest T-reg/T-helper ratio resist the treatment. Moreover, we use ROC curve to validate the model using the tumor status of the patients at their follow up, and the model predicts well for the earlier follow up days.
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Affiliation(s)
- Aparajita Budithi
- Department of Mathematics and Statistics, University of Massachusetts Amherst, Amherst, MA 01003, USA; (A.B.); (S.S.)
| | - Sumeyye Su
- Department of Mathematics and Statistics, University of Massachusetts Amherst, Amherst, MA 01003, USA; (A.B.); (S.S.)
| | - Arkadz Kirshtein
- Department of Mathematics, Tufts University, Medford, MA 02155, USA;
| | - Leili Shahriyari
- Department of Mathematics and Statistics, University of Massachusetts Amherst, Amherst, MA 01003, USA; (A.B.); (S.S.)
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Ma J, Shayiti F, Ma J, Wei M, Hua T, Zhang R, Su J, Chen P. Tumor-associated macrophage-derived CCL5 promotes chemotherapy resistance and metastasis in prostatic cancer. Cell Biol Int 2021; 45:2054-2062. [PMID: 34003531 DOI: 10.1002/cbin.11630] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Revised: 03/25/2021] [Accepted: 05/16/2021] [Indexed: 01/06/2023]
Abstract
The crosstalk between tumor microenvironment and cancer cells is emerging as a critical determinant in tumor progression. However, the underlying mechanism of tumor microenvironment-induced cancer development remains controversial. Here, our study provides evidence to suggest that tumor-associated macrophage (TAM) enrichment is found in chemoresistant prostatic tumor tissues. Those TAMs are demonstrated to promote chemoresistance and distant metastasis in prostatic cancer through secretion of CCL5. Mechanistically, TAM coculture or additional CCL5 can mediate the STAT3-dependent epithelial-mesenchymal transition process, resulting in distant metastasis in prostatic cancer. Meanwhile, activation of STAT3 induced by CCL5 can mediate upregulation of the transcription factor Nanog, leading to drug resistance. In vivo study further demonstrated that blockade of STAT3 signals significantly reverses chemoresistance and suppresses lung metastasis in colorectal tumor-bearing mice, suggesting a novel strategy for clinical prostatic cancer treatment.
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Affiliation(s)
- Jian Ma
- Urology Department, Xinjiang Medical University Affiliated Tumor Hospital, Ürümqi, Xinjiang, China
| | - Fuerhaiti Shayiti
- Urology Department, Xinjiang Medical University Affiliated Tumor Hospital, Ürümqi, Xinjiang, China
| | - Jing Ma
- Comprehensive Internal Medicine Department, First Affiliated Hospital of Xinjiang Medical University, Ürümqi, Xinjiang, China
| | - Meng Wei
- Department of Medical Analysis, Xinjiang Zhizhen Medical Laboratory Science Co., Ltd., Xinjiang, China
| | - Tingting Hua
- Department of Ultrasound, Xinjiang Medical University Affiliated Tumor Hospital, Ürümqi, Xinjiang, China
| | - Rong Zhang
- Urology Department, Xinjiang Medical University Affiliated Tumor Hospital, Ürümqi, Xinjiang, China
| | - Junyan Su
- Department of Medical, Lifehealthcare Clinical Laboratories, Beijing, China
| | - Peng Chen
- Urology Department, Xinjiang Medical University Affiliated Tumor Hospital, Ürümqi, Xinjiang, China
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Granulocyte Colony Stimulating Factor Expression in Breast Cancer and Its Association with Carbonic Anhydrase IX and Immune Checkpoints. Cancers (Basel) 2021; 13:cancers13051022. [PMID: 33804486 PMCID: PMC7957699 DOI: 10.3390/cancers13051022] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Revised: 02/10/2021] [Accepted: 02/23/2021] [Indexed: 01/15/2023] Open
Abstract
Simple Summary Preclinical studies suggest that interactions between granulocyte colony-stimulating factor (G-CSF) and hypoxia-induced carbonic anhydrase IX regulate the trafficking and function of immune cells in the tumour microenvironment. We investigated the clinical significance of this crosstalk by analyzing the protein expression of G-CSF and macrophage markers by immunohistochemistry on a well-characterized tissue microarray series of invasive breast cancers. We report that high expression of G-CSF on breast carcinoma cells is linked with significantly improved survival in an important group of breast cancers that do not respond to hormonal therapy. These tumours were infiltrated by immune cells expressing biomarkers that can be targeted with immune checkpoint inhibitor drugs. In contrast, carbonic anhydrase IX expression was associated with unfavourable outcomes. Abstract Purpose: Granulocyte colony-stimulating factor (G-CSF) and hypoxia modulate the tumour immune microenvironment. In model systems, hypoxia-induced carbonic anhydrase IX (CAIX) has been associated with G-CSF and immune responses, including M2 polarization of macrophages. We investigated whether these associations exist in human breast cancer specimens, their relation to breast cancer subtypes, and clinical outcome. Methods: Using validated protocols and prespecified scoring methodology, G-CSF expression on carcinoma cells and CD163 expression on tumour-associated macrophages were assayed by immunohistochemistry and applied to a tissue microarray series of 2960 primary excision specimens linked to clinicopathologic, biomarker, and outcome data. Results: G-CSFhigh expression showed a significant positive association with ER negativity, HER2 positivity, presence of CD163+ M2 macrophages, and CAIX expression. In univariate analysis, G-CSFhigh phenotype was associated with improved survival in non-luminal cases, although the CAIX+ subset had a significantly adverse prognosis. A significant positive association was observed between immune checkpoint biomarkers on tumour-infiltrating lymphocytes and both G-CSF- and CAIX-expressing carcinoma cells. Immune checkpoint biomarkers correlated significantly with favourable prognosis in G-CSFhigh/non-luminal cases independent of standard clinicopathological features. Conclusions: The prognostic associations linking G-CSF to immune biomarkers and CAIX strongly support their immunomodulatory roles in the tumour microenvironment.
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Kasprzak A. The Role of Tumor Microenvironment Cells in Colorectal Cancer (CRC) Cachexia. Int J Mol Sci 2021; 22:ijms22041565. [PMID: 33557173 PMCID: PMC7913937 DOI: 10.3390/ijms22041565] [Citation(s) in RCA: 94] [Impact Index Per Article: 23.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 01/27/2021] [Accepted: 02/01/2021] [Indexed: 02/07/2023] Open
Abstract
Cancer cachexia (CC) is a multifactorial syndrome in patients with advanced cancer characterized by weight loss via skeletal-muscle and adipose-tissue atrophy, catabolic activity, and systemic inflammation. CC is correlated with functional impairment, reduced therapeutic responsiveness, and poor prognosis, and is a major cause of death in cancer patients. In colorectal cancer (CRC), cachexia affects around 50–61% of patients, but remains overlooked, understudied, and uncured. The mechanisms driving CC are not fully understood but are related, at least in part, to the local and systemic immune response to the tumor. Accumulating evidence demonstrates a significant role of tumor microenvironment (TME) cells (e.g., macrophages, neutrophils, and fibroblasts) in both cancer progression and tumor-induced cachexia, through the production of multiple procachectic factors. The most important role in CRC-associated cachexia is played by pro-inflammatory cytokines, including the tumor necrosis factor α (TNFα), originally known as cachectin, Interleukin (IL)-1, IL-6, and certain chemokines (e.g., IL-8). Heterogeneous CRC cells themselves also produce numerous cytokines (including chemokines), as well as novel factors called “cachexokines”. The tumor microenvironment (TME) contributes to systemic inflammation and increased oxidative stress and fibrosis. This review summarizes the current knowledge on the role of TME cellular components in CRC-associated cachexia, as well as discusses the potential role of selected mediators secreted by colorectal cancer cells in cooperation with tumor-associated immune and non-immune cells of tumor microenvironment in inducing or potentiating cancer cachexia. This knowledge serves to aid the understanding of the mechanisms of this process, as well as prevent its consequences.
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Affiliation(s)
- Aldona Kasprzak
- Department of Histology and Embryology, University of Medical Sciences, Święcicki Street 6, 60-781 Poznań, Poland
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35
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Bai H, Wang J, Phan CU, Chen Q, Hu X, Shao G, Zhou J, Lai L, Tang G. Cyclodextrin-based host-guest complexes loaded with regorafenib for colorectal cancer treatment. Nat Commun 2021; 12:759. [PMID: 33536421 PMCID: PMC7858623 DOI: 10.1038/s41467-021-21071-0] [Citation(s) in RCA: 66] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2019] [Accepted: 01/11/2021] [Indexed: 12/11/2022] Open
Abstract
The malignancy of colorectal cancer (CRC) is connected with inflammation and tumor-associated macrophages (TAMs), but effective therapeutics for CRC are limited. To integrate therapeutic targeting with tumor microenvironment (TME) reprogramming, here we develop biocompatible, non-covalent channel-type nanoparticles (CNPs) that are fabricated through host-guest complexation and self-assemble of mannose-modified γ-cyclodextrin (M-γ-CD) with Regorafenib (RG), RG@M-γ-CD CNPs. In addition to its carrier role, M-γ-CD serves as a targeting device and participates in TME regulation. RG@M-γ-CD CNPs attenuate inflammation and inhibit TAM activation by targeting macrophages. They also improve RG's anti-tumor effect by potentiating kinase suppression. In vivo application shows that the channel-type formulation optimizes the pharmacokinetics and bio-distribution of RG. In colitis-associated cancer and CT26 mouse models, RG@M-γ-CD is proven to be a targeted, safe and effective anti-tumor nanomedicine that suppresses tumor cell proliferation, lesions neovascularization, and remodels TME. These findings indicate RG@M-γ-CD CNPs as a potential strategy for CRC treatment.
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Affiliation(s)
- Hongzhen Bai
- Department of Chemistry, Zhejiang University, 310028, Hangzhou, PR China
| | - Jianwei Wang
- Department of Chemistry, Zhejiang University, 310028, Hangzhou, PR China
| | - Chi Uyen Phan
- Department of Chemistry, Zhejiang University, 310028, Hangzhou, PR China
| | - Qi Chen
- Department of Chemistry, Zhejiang University, 310028, Hangzhou, PR China
| | - Xiurong Hu
- Department of Chemistry, Zhejiang University, 310028, Hangzhou, PR China
| | - Guoqiang Shao
- Department of Nuclear Medicine, Nanjing First Hospital, Nanjing Medical University, 210029, Nanjing, PR China
| | - Jun Zhou
- Department of Chemistry, Zhejiang University, 310028, Hangzhou, PR China
| | - Lihua Lai
- Department of Pharmacology, School of Medicine, Zhejiang University, 310058, Hangzhou, PR China.
| | - Guping Tang
- Department of Chemistry, Zhejiang University, 310028, Hangzhou, PR China.
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The Combinatorial Effect of Cisplatin and Moxibustion on Tumor Growth Inhibition with Special Reference to Modulation of the Immune Microenvironment in Lewis Lung Cancer Mice. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2021; 2020:3170803. [PMID: 33456484 PMCID: PMC7785363 DOI: 10.1155/2020/3170803] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Revised: 11/08/2020] [Accepted: 11/27/2020] [Indexed: 12/15/2022]
Abstract
Objective As a first-line treatment for non-small cell lung cancer (NSCLC), the efficacy of chemotherapy is still unsatisfactory. Moxibustion has been shown to improve the side effects of radiotherapy and chemotherapy and regulate immune function. This study aimed to explore the antitumor effects and potential mechanisms of combinatorial cisplatin and moxibustion treatment for NSCLC by targeting the tumor microenvironment. Methods Lewis lung cancer (LLC)-bearing mice were induced and treated with cisplatin or/and moxibustion at ST36 (Zusanli), and the growth, weight, and area of the tumor were evaluated. The numbers of various T cell subsets and myeloid cells in the tumor were assessed by flow cytometry, and the gene expression of related markers and cytokines was detected with real-time quantitative polymerase chain reaction (RT-qPCR). In addition, the tumor vascular structure was investigated using CD31 and α-smooth muscle actin (α-SMA) immunofluorescence staining. The expression of the vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-1α (HIF-1α) was detected by immunohistochemical staining. Results Both cisplatin and moxibustion inhibited LLC tumor growth and reduced both the tumor area and weight, with the combinatorial therapy showing superior outcomes. Moxibustion upregulated the infiltration of CD4+ T cells and Th1 cells in the tumor, and the combinatorial therapy increased the proportion of CD8+ cytotoxic T cells (CTLs), CD4+T cells, Th1, Th9 cells, and M1 macrophages, as well as the expression of Cd69, Ifng, and Cd86 mRNA. The combinatorial therapy improved vascular normalization by increasing both the microvessel density (MVD) and pericyte coverage (α-SMA area density) and inhibiting the expression of the VEGF. Conclusions Combinatorial cisplatin and moxibustion treatment inhibited the LLC tumor growth by mechanisms related to the improvement of the tumor immune microenvironment and vascular normalization, providing an effective combinatorial therapy beneficial for patients with NSCLC.
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Kirshtein A, Akbarinejad S, Hao W, Le T, Su S, Aronow RA, Shahriyari L. Data Driven Mathematical Model of Colon Cancer Progression. J Clin Med 2020; 9:E3947. [PMID: 33291412 PMCID: PMC7762015 DOI: 10.3390/jcm9123947] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Revised: 11/28/2020] [Accepted: 12/02/2020] [Indexed: 12/13/2022] Open
Abstract
Every colon cancer has its own unique characteristics, and therefore may respond differently to identical treatments. Here, we develop a data driven mathematical model for the interaction network of key components of immune microenvironment in colon cancer. We estimate the relative abundance of each immune cell from gene expression profiles of tumors, and group patients based on their immune patterns. Then we compare the tumor sensitivity and progression in each of these groups of patients, and observe differences in the patterns of tumor growth between the groups. For instance, in tumors with a smaller density of naive macrophages than activated macrophages, a higher activation rate of macrophages leads to an increase in cancer cell density, demonstrating a negative effect of macrophages. Other tumors however, exhibit an opposite trend, showing a positive effect of macrophages in controlling tumor size. Although the results indicate that for all patients the size of the tumor is sensitive to the parameters related to macrophages, such as their activation and death rate, this research demonstrates that no single biomarker could predict the dynamics of tumors.
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Affiliation(s)
- Arkadz Kirshtein
- Department of Mathematics and Statistics, University of Massachusetts Amherst, Amherst, MA 01003-9305, USA; (A.K.); (S.A.); (T.L.); (S.S.); (R.A.A.)
| | - Shaya Akbarinejad
- Department of Mathematics and Statistics, University of Massachusetts Amherst, Amherst, MA 01003-9305, USA; (A.K.); (S.A.); (T.L.); (S.S.); (R.A.A.)
| | - Wenrui Hao
- Department of Mathematics, Pennsylvania State University, University Park, State College, PA 16802, USA;
| | - Trang Le
- Department of Mathematics and Statistics, University of Massachusetts Amherst, Amherst, MA 01003-9305, USA; (A.K.); (S.A.); (T.L.); (S.S.); (R.A.A.)
| | - Sumeyye Su
- Department of Mathematics and Statistics, University of Massachusetts Amherst, Amherst, MA 01003-9305, USA; (A.K.); (S.A.); (T.L.); (S.S.); (R.A.A.)
| | - Rachel A. Aronow
- Department of Mathematics and Statistics, University of Massachusetts Amherst, Amherst, MA 01003-9305, USA; (A.K.); (S.A.); (T.L.); (S.S.); (R.A.A.)
| | - Leili Shahriyari
- Department of Mathematics and Statistics, University of Massachusetts Amherst, Amherst, MA 01003-9305, USA; (A.K.); (S.A.); (T.L.); (S.S.); (R.A.A.)
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Ma J, Zhang H, Tang K, Huang B. Tumor-derived microparticles in tumor immunology and immunotherapy. Eur J Immunol 2020; 50:1653-1662. [PMID: 32976623 PMCID: PMC7702100 DOI: 10.1002/eji.202048548] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Revised: 08/11/2020] [Accepted: 09/22/2020] [Indexed: 12/13/2022]
Abstract
Microvesicles or microparticles, a type of cytoplasm membrane-derived extracellular vesicles, can be released by cancer cells or normal cell types. Alteration of F-actin cytoskeleton by various signals may lead to the cytoplasm membrane encapsulating cellular contents to form microparticles, which contain various messenger molecules, including enzymes, RNAs and even DNA fragments, and are released to extracellular space. The release of microparticles by tumor cells (T-MPs) is a very common event in tumor microenvironments. As a result, T-MPs not only influence tumor cell biology but also profoundly forge tumor immunology. Moreover, T-MPs can act as a natural vehicle that delivers therapeutic drugs to tumor cells and immune cells, thus, remodeling tumor microenvironments and resetting antitumor immune responses, thus, conferring T-MPs a potential role in tumor immunotherapies and tumor vaccines. In this review, we focus on the double-edged sword role of T-MPs in tumor immunology, specifically in TAMs and DCs, and emphasize the application of drug-packaging T-MPs in cancer patients. We aim to provide a new angle to understand immuno-oncology and new strategies for cancer immunotherapy.
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Affiliation(s)
- Jingwei Ma
- Department of Immunology, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, P. R. China
| | - Huafeng Zhang
- Department of Pathology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, P. R. China
| | - Ke Tang
- Department of Biochemistry & Molecular Biology, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, P. R. China
| | - Bo Huang
- Department of Biochemistry & Molecular Biology, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, P. R. China.,Department of Immunology & National Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) & Peking Union Medical College, Beijing, P. R. China.,Clinical Immunology Center, CAMS, Beijing, P. R. China
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Najdaghi S, Razi S, Rezaei N. An overview of the role of interleukin-8 in colorectal cancer. Cytokine 2020; 135:155205. [PMID: 32721849 DOI: 10.1016/j.cyto.2020.155205] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2020] [Revised: 07/08/2020] [Accepted: 07/09/2020] [Indexed: 02/07/2023]
Abstract
Colorectal Cancer (CRC), a common malignancy, is developing globally among people. Mutagenic insults activate peripheral nucleated cells to secrete chemokines in order to cause an inflammatory state. Despite the presence of multi-retrieving factors, elevated production of minor cytokines may speed-up the sever stages of the baseline inflammation targeting normal compensatory mechanism. IL-8 is a pro-inflammatory cytokine that is believed to be up-regulated in CRC to proceed primary condition into tumor behavior via induction of proliferation, angiogenesis and metastasis. Here, we assess the role of IL-8 in every step of CRC from signaling pathway and formation to invasion and discuss around new perspective therapy that targets IL-8 to manage CRC worldwide incidence and survival rate, more precisely.
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Affiliation(s)
- Soroush Najdaghi
- Cancer Immunology Project (CIP), Universal Scientific Education and Research Network (USERN), Tehran, Iran; Isfahan Neurosciences Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Sepideh Razi
- Cancer Immunology Project (CIP), Universal Scientific Education and Research Network (USERN), Tehran, Iran; Student Research Committee, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Nima Rezaei
- Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran; Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Cancer Immunology Project (CIP), Universal Scientific Education and Research Network (USERN), Sheffield, UK.
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Marques P, Grossman AB, Korbonits M. The tumour microenvironment of pituitary neuroendocrine tumours. Front Neuroendocrinol 2020; 58:100852. [PMID: 32553750 DOI: 10.1016/j.yfrne.2020.100852] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Revised: 05/26/2020] [Accepted: 06/02/2020] [Indexed: 02/06/2023]
Abstract
The tumour microenvironment (TME) includes a variety of non-neoplastic cells and non-cellular elements such as cytokines, growth factors and enzymes surrounding tumour cells. The TME emerged as a key modulator of tumour initiation, progression and invasion, with extensive data available in many cancers, but little is known in pituitary tumours. However, the understanding of the TME of pituitary tumours has advanced thanks to active research in this field over the last decade. Different immune and stromal cell subpopulations, and several cytokines, growth factors and matrix remodelling enzymes, have been characterised in pituitary tumours. Studying the TME in pituitary tumours may lead to a better understanding of tumourigenic mechanisms, identification of biomarkers useful to predict aggressive disease, and development of novel therapies. This review summarises the current knowledge on the different TME cellular/non-cellular elements in pituitary tumours and provides an overview of their role in tumourigenesis, biological behaviour and clinical outcomes.
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Affiliation(s)
- Pedro Marques
- Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
| | - Ashley B Grossman
- Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
| | - Márta Korbonits
- Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
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Kuai Y, Liu H, Liu D, Liu Y, Sun Y, Xie J, Sun J, Fang Y, Pan H, Han W. An ultralow dose of the NADPH oxidase inhibitor diphenyleneiodonium (DPI) is an economical and effective therapeutic agent for the treatment of colitis-associated colorectal cancer. Am J Cancer Res 2020; 10:6743-6757. [PMID: 32550901 PMCID: PMC7295061 DOI: 10.7150/thno.43938] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2020] [Accepted: 05/11/2020] [Indexed: 12/31/2022] Open
Abstract
Long-term inflammatory stimulation is considered one of the most important causes of colorectal cancer. Diphenyleneiodonium (DPI), an NADPH oxidase inhibitor, can inhibit a variety of inflammatory responses. However, the systemic toxicity of DPI limits its clinical application. Whether DPI can inhibit colitis-associated colorectal cancer (CAC) at ultralow concentrations remains unknown. Methods: CAC was induced by azoxymethane (AOM) injection followed by treatment with dextran sulfate sodium (DSS), and DPI was intraperitoneally injected (i.p.) in the first cycle for 21 days. Colon tissue was collected and analyzed by western blotting. Immune cell infiltration and macrophage polarization were examined by immunohistochemistry, immunofluorescence, or real-time polymerase-chain reaction (PCR). Reactive oxygen species (ROS) production was measured by flow cytometry. Results: Ultralow dose DPI significantly ameliorated the DSS-induced colitis and attenuated the colon tumorigenesis in the mouse model of AOM/ DSS-induced CAC. Mechanistically, an ultralow dose of DPI inhibited the production of pro-inflammatory cytokines, (tumor necrosis factor (TNF)-α and interleukin (IL)-6), reduced the macrophage infiltration and classical polarization, and induced the ROS generation. These effects were found to be related to the inhibition of the phosphorylation of signal transducer and activator of transcription 3 (STAT3), mitogen-activated protein kinase (MAPK), and nuclear factor kappa B (NF -κB). Conclusion: The present study revealed that an ultralow dose of DPI, with no significant systemic toxicity involved, may be an effective way to prevent the occurrence and development of CAC.
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Hannan CJ, Lewis D, O'Leary C, Donofrio CA, Evans DG, Roncaroli F, Brough D, King AT, Coope D, Pathmanaban ON. The inflammatory microenvironment in vestibular schwannoma. Neurooncol Adv 2020; 2:vdaa023. [PMID: 32642684 PMCID: PMC7212860 DOI: 10.1093/noajnl/vdaa023] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Vestibular schwannomas are tumors arising from the vestibulocochlear nerve at the cerebellopontine angle. Their proximity to eloquent brainstem structures means that the pathology itself and the treatment thereof can be associated with significant morbidity. The vast majority of these tumors are sporadic, with the remainder arising as a result of the genetic syndrome Neurofibromatosis Type 2 or, more rarely, LZTR1-related schwannomatosis. The natural history of these tumors is extremely variable, with some tumors not displaying any evidence of growth, others demonstrating early, persistent growth and a small number growing following an extended period of indolence. Emerging evidence now suggests that far from representing Schwann cell proliferation only, the tumor microenvironment is complex, with inflammation proposed to play a key role in their growth. In this review, we provide an overview of this new evidence, including the role played by immune cell infiltration, the underlying molecular pathways involved, and biomarkers for detecting this inflammation in vivo. Given the limitations of current treatments, there is a pressing need for novel therapies to aid in the management of this condition, and we conclude by proposing areas for future research that could lead to the development of therapies targeted toward inflammation in vestibular schwannoma.
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Affiliation(s)
- Cathal John Hannan
- Manchester Centre for Clinical Neurosciences, Salford Royal Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.,Division of Evolution & Genomic Sciences, School of Biological Sciences, Faculty of Biology Medicine and Health, University of Manchester, Manchester, UK.,Division of Cardiovascular Sciences, School of Medical Sciences, Faculty of Biology Medicine and Health, University of Manchester, Manchester, UK
| | - Daniel Lewis
- Manchester Centre for Clinical Neurosciences, Salford Royal Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK
| | - Claire O'Leary
- Manchester Centre for Clinical Neurosciences, Salford Royal Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.,Division of Neuroscience & Experimental Psychology, School of Biological Sciences, Faculty of Biology Medicine and Health, University of Manchester, Manchester, UK
| | - Carmine A Donofrio
- Manchester Centre for Clinical Neurosciences, Salford Royal Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK
| | - Dafydd Gareth Evans
- Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University Hospitals National Health Service Foundation Trust, Manchester, UK.,Division of Evolution & Genomic Sciences, School of Biological Sciences, Faculty of Biology Medicine and Health, University of Manchester, Manchester, UK
| | - Federico Roncaroli
- Manchester Centre for Clinical Neurosciences, Salford Royal Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.,Division of Neuroscience & Experimental Psychology, School of Biological Sciences, Faculty of Biology Medicine and Health, University of Manchester, Manchester, UK
| | - David Brough
- Division of Neuroscience & Experimental Psychology, School of Biological Sciences, Faculty of Biology Medicine and Health, University of Manchester, Manchester, UK
| | - Andrew Thomas King
- Manchester Centre for Clinical Neurosciences, Salford Royal Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.,Division of Cardiovascular Sciences, School of Medical Sciences, Faculty of Biology Medicine and Health, University of Manchester, Manchester, UK
| | - David Coope
- Manchester Centre for Clinical Neurosciences, Salford Royal Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.,Division of Neuroscience & Experimental Psychology, School of Biological Sciences, Faculty of Biology Medicine and Health, University of Manchester, Manchester, UK
| | - Omar Nathan Pathmanaban
- Manchester Centre for Clinical Neurosciences, Salford Royal Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.,Division of Cell Matrix Biology & Regenerative Medicine, School of Biological Sciences, Faculty of Biology Medicine and Health, University of Manchester, Manchester, UK
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Yu Y, Ke L, Xia WX, Xiang Y, Lv X, Bu J. Elevated Levels of TNF-α and Decreased Levels of CD68-Positive Macrophages in Primary Tumor Tissues Are Unfavorable for the Survival of Patients With Nasopharyngeal Carcinoma. Technol Cancer Res Treat 2020; 18:1533033819874807. [PMID: 31522611 PMCID: PMC6747870 DOI: 10.1177/1533033819874807] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Due to the critical role of inflammation in nasopharyngeal carcinoma, we aim to investigate the correlation between nasopharyngeal carcinoma prognosis and the levels of tumor necrosis factor α and macrophages for the development of new prognostic models. The levels of tumor necrosis factor-α and CD68-positive macrophages were measured in 111 primary nasopharyngeal carcinoma specimens by immunohistochemistry. Kaplan-Meier analysis showed that, compared with nonelevated tumor necrosis factor-α levels, elevated tumor necrosis factor α levels were correlated with poorer 10-year distant metastasis-free survival (24.5% vs 5.2%, P = .004) and bone metastasis-free survival (17.0% vs 0.0%, P = .001). Multivariate analysis revealed that tumor necrosis factor α level was an independent prognostic factor for distant metastasis-free survival (hazard ratio = 16.765, P = .001), while the level of CD68-positive macrophages was a favorable independent prognostic factor for cancer-specific survival (hazard ratio = 0.481, P = .023) and disease-free survival (hazard ratio = 0.403, P = .010). Additionally, several prognostic models that considered tumor-node-metastasis stage alone or in combination with tumor necrosis factor α and/or CD68-positive macrophage levels were compared by receiver operating characteristic curve analysis. Interestingly, the T_score model, which considered the tumor necrosis factor α level alone, could better predict the distant metastasis-free survival and bone metastasis-free survival, whereas the MT model, which considered the combination of T stage and CD68-positive macrophage level, could better predict the cancer-specific survival and disease-free survival of patients with nasopharyngeal carcinoma. Elevated tumor necrosis factor-α levels and decreased CD68-positive macrophage levels in primary nasopharyngeal carcinoma tissues are unfavorable prognostic indicators in nasopharyngeal carcinoma. The T_score model or the MT model could be better prognostic models than those currently available for nasopharyngeal carcinoma and could be used to select high-risk patients and aid in the design of individualized immunotherapy.
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Affiliation(s)
- Yahui Yu
- Department of Radiation Oncology, Oncology Center, Zhujiang Hospital, Southern Medical University, Zhujiang Hospital, Guangzhou, China.,Yahui Yu, Liangru Ke, Weixiong Xia contributed equally to this work
| | - Liangru Ke
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, China.,Yahui Yu, Liangru Ke, Weixiong Xia contributed equally to this work
| | - Wei-Xiong Xia
- Department of Nasopharyngeal Carcinoma, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, China.,Yahui Yu, Liangru Ke, Weixiong Xia contributed equally to this work
| | - Yanqun Xiang
- Department of Diagnostic Radiology, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Xing Lv
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, China
| | - Junguo Bu
- Department of Radiation Oncology, Oncology Center, Zhujiang Hospital, Southern Medical University, Zhujiang Hospital, Guangzhou, China
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Khandia R, Munjal A. Interplay between inflammation and cancer. ADVANCES IN PROTEIN CHEMISTRY AND STRUCTURAL BIOLOGY 2020; 119:199-245. [DOI: 10.1016/bs.apcsb.2019.09.004] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
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45
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Xue D, Tabib T, Morse C, Lafyatis R. Transcriptome landscape of myeloid cells in human skin reveals diversity, rare populations and putative DC progenitors. J Dermatol Sci 2019; 97:41-49. [PMID: 31836271 DOI: 10.1016/j.jdermsci.2019.11.012] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2019] [Revised: 11/08/2019] [Accepted: 11/25/2019] [Indexed: 01/21/2023]
Abstract
BACKGROUND The heterogeneous functions of dermal myeloid cells in antigen presentation, and scavenging pathogens and cell debris places them centrally in cutaneous inflammation. Single cell transcriptomics can provide new understanding of the heterogeneity and function of yet incompletely understood human dermal myeloid cell subsets. OBJECTIVE Investigate the transcriptome landscape of myeloid cells in healthy human skin. METHODS Single cell RNA-sequencing was performed on skin biopsies from ten healthy donors and analyzed to identify myeloid cell populations. RESULTS One LIN- HLA-DR+ cluster with expression of myeloid-specific genes was identified as a cluster of myeloid cells. Upon reanalysis of this cluster, we identified three macrophage subsets, marked by high expression of CCR1, MARCO or TREM2; and six dendritic cell subsets, marked by high expression of CLEC9A, CXorf21, MCOLN2, LAMP3, KIAA0101 and Langerin, representing respectively cDC1, two subsets of cDC2, a novel DC type, a cluster of proliferating DC, and a Langerhans cell subset. GO term analysis indicated specialized functions for the discrete rare populations of myeloid cells: TREM2 Mφ in lipid metabolism and LAMP3 DC as a mature cDC. Proliferating DCs appeared to represent cDC2 progenitors. CONCLUSION The transcriptional landscape of myeloid cell populations in human skin indicates several, novel populations with specialized functions, as well as a rare proliferating DC population that likely accounts for local regeneration or expansion of dermal DCs. We provide robust gene expression markers for each of these populations that should permit better understandings of their roles in various homeostatic and pathologic immune processes in the skin.
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Affiliation(s)
- Dan Xue
- Division of Rheumatology and Clinical Rheumatology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA; The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Tracy Tabib
- Division of Rheumatology and Clinical Rheumatology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
| | - Christina Morse
- Division of Rheumatology and Clinical Rheumatology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
| | - Robert Lafyatis
- Division of Rheumatology and Clinical Rheumatology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
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Marques P, Barry S, Carlsen E, Collier D, Ronaldson A, Awad S, Dorward N, Grieve J, Mendoza N, Muquit S, Grossman AB, Balkwill F, Korbonits M. Chemokines modulate the tumour microenvironment in pituitary neuroendocrine tumours. Acta Neuropathol Commun 2019; 7:172. [PMID: 31703742 PMCID: PMC6839241 DOI: 10.1186/s40478-019-0830-3] [Citation(s) in RCA: 62] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2019] [Accepted: 10/13/2019] [Indexed: 02/06/2023] Open
Abstract
Non-tumoural cells within the tumour microenvironment (TME) influence tumour proliferation, invasiveness and angiogenesis. Little is known about TME in pituitary neuroendocrine tumours (PitNETs). We aimed to characterise the role of TME in the aggressive behaviour of PitNETs, focusing on immune cells and cytokines. The cytokine secretome of 16 clinically non-functioning PitNETs (NF-PitNETs) and 8 somatotropinomas was assessed in primary culture using an immunoassay panel with 42 cytokines. This was correlated with macrophage (CD68, HLA-DR, CD163), T-lymphocyte (CD8, CD4, FOXP3), B-lymphocyte (CD20), neutrophil (neutrophil elastase) and endothelial cells (CD31) content, compared to normal pituitaries (NPs, n = 5). In vitro tumour-macrophage interactions were assessed by conditioned medium (CM) of GH3 (pituitary tumour) and RAW264.7 (macrophage) cell lines on morphology, migration/invasion, epithelial-to-mesenchymal transition and cytokine secretion. IL-8, CCL2, CCL3, CCL4, CXCL10, CCL22 and CXCL1 are the main PitNET-derived cytokines. PitNETs with increased macrophage and neutrophil content had higher IL-8, CCL2, CCL3, CCL4 and CXCL1 levels. CD8+ T-lymphocytes were associated to higher CCL2, CCL4 and VEGF-A levels. PitNETs had more macrophages than NPs (p < 0.001), with a 3-fold increased CD163:HLA-DR macrophage ratio. PitNETs contained more CD4+ T-lymphocytes (p = 0.005), but fewer neutrophils (p = 0.047) with a 2-fold decreased CD8:CD4 ratio. NF-PitNETs secreted more cytokines and had 9 times more neutrophils than somatotropinomas (p = 0.002). PitNETs with higher Ki-67 had more FOXP3+ T cells, as well as lower CD68:FOXP3, CD8:CD4 and CD8:FOXP3 ratios. PitNETs with "deleterious immune phenotype" (CD68hiCD4hiFOXP3hiCD20hi) had a Ki-67 ≥ 3%. CD163:HLA-DR macrophage ratio was positively correlated with microvessel density (p = 0.015) and area (p < 0.001). GH3 cell-CM increased macrophage chemotaxis, while macrophage-CM changed morphology, invasion, epithelial-to-mesenchymal transition and secreted cytokines of GH3 cells. PitNETs are characterised by increased CD163:HLA-DR macrophage and reduced CD8:CD4 and CD8:FOXP3 T cell ratios. PitNET-derived chemokines facilitate macrophage, neutrophil and T cell recruitment into the tumours which can determine aggressive behaviour.
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Lorenzo-Sanz L, Muñoz P. Tumor-Infiltrating Immunosuppressive Cells in Cancer-Cell Plasticity, Tumor Progression and Therapy Response. CANCER MICROENVIRONMENT 2019; 12:119-132. [PMID: 31583529 DOI: 10.1007/s12307-019-00232-2] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/11/2019] [Accepted: 09/01/2019] [Indexed: 12/16/2022]
Abstract
In most tumors, cancer cells show the ability to dynamically transit from a non-cancer stem-like cell to a cancer stem-like cell (CSC) state and vice versa. This cell plasticity has been associated with the epithelial-to-mesenchymal transition program (EMT) and can be regulated by tumor cell-intrinsic mechanisms and complex interactions with various tumor microenvironment (TME) components. These interactions favor the generation of a specific "CSC niche" that helps maintain the main properties, phenotypic plasticity and metastatic potential of this subset of tumor cells. For this reason, TME has been recognized as an important promoter of tumor progression and therapy resistance. Tumors have evolved a network of immunosuppressive mechanisms that limits the cytotoxic T cell response to cancer cells. Some key players in this network are tumor-associated macrophages, myeloid-derived suppressor cells and regulatory T cells, which not only favor a pro-tumoral and immunosuppressive environment that supports tumor growth and immune evasion, but also negatively influences immunotherapy. Here, we review the relevance of cytokines and growth factors provided by immunosuppressive immune cells in regulating cancer-cell plasticity. We also discuss how cancer cells remodel their own niche to promote proliferation, stemness and EMT, and escape immune surveillance. A better understanding of CSC-TME crosstalk signaling will enable the development of effective targeted or immune therapies that block tumor growth and metastasis.
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Affiliation(s)
- Laura Lorenzo-Sanz
- Aging and Cancer Group, Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), Av. Gran Vía de L'Hospitalet 199-203, 08908, Barcelona, Spain
| | - Purificación Muñoz
- Aging and Cancer Group, Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), Av. Gran Vía de L'Hospitalet 199-203, 08908, Barcelona, Spain.
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Sumitomo R, Hirai T, Fujita M, Murakami H, Otake Y, Huang CL. M2 tumor-associated macrophages promote tumor progression in non-small-cell lung cancer. Exp Ther Med 2019; 18:4490-4498. [PMID: 31777551 DOI: 10.3892/etm.2019.8068] [Citation(s) in RCA: 78] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2019] [Accepted: 08/19/2019] [Indexed: 12/24/2022] Open
Abstract
Tumor-associated macrophages (TAMs) are key components of the tumor microenvironment that can be polarized into different phenotypes, including tumor-inhibiting M1 macrophages and tumor-promoting M2 macrophages. To elucidate the biological and clinical significance of M2 TAMs in non-small-cell lung cancer (NSCLC), a comprehensive clinical assessment of the tissue distribution of M2 TAMs was performed. The tissue distribution of M2 TAMs was retrospectively analyzed using CD163 immunohistochemistry in 160 consecutive patients who underwent NSCLC resection. Tumor proliferation was evaluated via the Ki-67 proliferation index. The results revealed that the stromal density of M2 TAMs was significantly associated with the C-reactive protein (CRP) level (P=0.0250), the Ki-67 proliferation index (P=0.0090) and invasive size (P=0.0285). Furthermore, the stromal M2 TAM density was significantly associated with tumor differentiation (P=0.0018), lymph node metastasis (P=0.0347) and pathological stage (P=0.0412). The alveolar M2 TAM density was also significantly associated with the CRP level (P=0.0309), invasive size (P<0.0001), tumor differentiation (P=0.0192), tumor status (P=0.0108) and pathological stage (P=0.0110). By contrast, no association was observed between islet M2 TAM density and the aforementioned biological and clinical factors. In regards to prognosis, disease-free survival rate was significantly lower in patients with stromal M2 TAM-high tumors (P=0.0270) and in those with alveolar M2 TAM-high tumors (P=0.0283). Furthermore, the overall survival rate was also significantly lower in patients with stromal M2 TAM-high tumors (P=0.0162) and in those with alveolar M2 TAM-high tumors (P=0.0225). Therefore, during NSCLC progression, M2 TAMs may induce tumor cell aggressiveness and proliferation and increase metastatic potential, resulting in a poor prognosis in patients with NSCLC.
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Affiliation(s)
- Ryota Sumitomo
- Department of Thoracic Surgery, Tazuke Kofukai Medical Research Institute, Kitano Hospital, Osaka 530-8480, Japan
| | - Tatsuya Hirai
- Department of Thoracic Surgery, Tazuke Kofukai Medical Research Institute, Kitano Hospital, Osaka 530-8480, Japan
| | - Masaaki Fujita
- Department of Clinical Immunology and Rheumatology, Tazuke Kofukai Medical Research Institute, Kitano Hospital, Osaka 530-8480, Japan
| | - Hiroaki Murakami
- Department of Thoracic Surgery, Tazuke Kofukai Medical Research Institute, Kitano Hospital, Osaka 530-8480, Japan
| | - Yosuke Otake
- Department of Thoracic Surgery, Tazuke Kofukai Medical Research Institute, Kitano Hospital, Osaka 530-8480, Japan
| | - Cheng-Long Huang
- Department of Thoracic Surgery, Tazuke Kofukai Medical Research Institute, Kitano Hospital, Osaka 530-8480, Japan
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Bai J, Kwok WC, Thiery JP. Traditional Chinese Medicine and regulatory roles on epithelial-mesenchymal transitions. Chin Med 2019; 14:34. [PMID: 31558913 PMCID: PMC6755703 DOI: 10.1186/s13020-019-0257-6] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2019] [Accepted: 09/11/2019] [Indexed: 02/06/2023] Open
Abstract
Epithelial–mesenchymal transition (EMT) is a critical biological process allowing epithelial cells to de-differentiate into mesenchymal cells. Orchestrated signaling pathways cooperatively induce EMT and effect physiological, sometimes pathological outcomes. Traditional Chinese Medicine (TCM) has been clinically prescribed for thousands of years and recent studies have found that TCM therapies can participate in EMT regulation. In this review, the historical discovery of EMT will be introduced, followed by a brief overview of its major roles in development and diseases. The second section will focus on EMT in organ fibrosis and tissue regeneration. The third section discusses EMT-induced cancer metastasis, and details how EMT contribute to distant dissemination. Finally, new EMT players are described, namely microRNA, epigenetic modifications, and alternative splicing. TCM drugs that affect EMT proven through an evidence-based research approach will be presented in each section.
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Affiliation(s)
- Jing Bai
- 1Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, USA
| | - Wee Chiew Kwok
- 2Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Jean-Paul Thiery
- Guangzhou Regenerative Medicine and Health, Guangdong Laboratory, Guangzhou, China
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Pan Z, Tian Y, Cao C, Niu G. The Emerging Role of YAP/TAZ in Tumor Immunity. Mol Cancer Res 2019; 17:1777-1786. [PMID: 31308148 DOI: 10.1158/1541-7786.mcr-19-0375] [Citation(s) in RCA: 67] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2019] [Revised: 06/03/2019] [Accepted: 07/10/2019] [Indexed: 11/16/2022]
Abstract
Yes-associated protein (YAP)/WW domain-containing transcription regulator 1 (TAZ) is an important transcriptional regulator and effector of the Hippo signaling pathway that has emerged as a critical determinant of malignancy in many human tumors. YAP/TAZ expression regulates the cross-talk between immune cells and tumor cells in the tumor microenvironment through its influence on T cells, myeloid-derived suppressor cells, and macrophages. However, the mechanisms underlying these effects are poorly understood. An improved understanding of the role of YAP/TAZ in tumor immunity is essential for exploring innovative tumor treatments and making further breakthroughs in antitumor immunotherapy. This review primarily focuses on the role of YAP/TAZ in immune cells, their interactions with tumor cells, and how this impacts on tumorigenesis, progression, and therapy resistance.
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Affiliation(s)
- Zhaoji Pan
- Xuzhou Central Hospital, The Affiliated XuZhou Hospital of Medical College of Southeast University, Xuzhou, Jiangsu, P.R. China
| | - Yiqing Tian
- Xinyi People's Hospital, Xinyi, Xuzhou, Jiangsu, P.R. China.
| | - Chengsong Cao
- Xuzhou Central Hospital, The Affiliated XuZhou Hospital of Medical College of Southeast University, Xuzhou, Jiangsu, P.R. China
| | - Guoping Niu
- Xuzhou Central Hospital, The Affiliated XuZhou Hospital of Medical College of Southeast University, Xuzhou, Jiangsu, P.R. China
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