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Bai H, Feng L, Schmid F. Macrophage-based cancer immunotherapy: Challenges and opportunities. Exp Cell Res 2024; 442:114198. [PMID: 39103071 DOI: 10.1016/j.yexcr.2024.114198] [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: 05/25/2024] [Revised: 08/02/2024] [Accepted: 08/03/2024] [Indexed: 08/07/2024]
Abstract
Macrophages play crucial roles in the tumor microenvironment (TME), exerting diverse functions ranging from promoting tumor growth and metastasis to orchestrating anti-tumor immune responses. Their plasticity allows them to adopt distinct activation states, often called M1-like (pro-inflammatory) and M2-like (anti-inflammatory or pro-tumoral), significantly influencing tumor progression and response to therapy. Harnessing the potential of macrophages in cancer immunotherapy has emerged as a promising strategy, with increasing interest in targeting these cells directly or modulating their functions within the TME. This review explores the intricate interplay between macrophages, the TME, and immunotherapeutic approaches. We discuss the dynamic phenotypic and functional heterogeneity of tumor-associated macrophages (TAMs), their impact on disease progression, and the mechanisms underlying their response to immunotherapy. Furthermore, we highlight recent advancements in macrophage-based immunotherapeutic strategies, including macrophage-targeting agents, adoptive cell transfer, and engineering approaches. Understanding the complex crosstalk between macrophages and the TME is essential for developing effective immunotherapeutic interventions that exploit the immunomodulatory functions of macrophages to enhance anti-tumor immunity and improve clinical outcomes for cancer patients.
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Affiliation(s)
- Haotian Bai
- Division of Natural and Applied Sciences, Duke Kunshan University, Kunshan, Jiangsu, 215316, China; Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, 21205, USA.
| | - Li Feng
- Emergency Department, People's Hospital Affiliated to Shandong First Medical University, Jinan, 271100, Shandong Province, China.
| | - Felix Schmid
- School of Biomedical Sciences, Carleton University, Ottawa, Canada.
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Panda VK, Mishra B, Nath AN, Butti R, Yadav AS, Malhotra D, Khanra S, Mahapatra S, Mishra P, Swain B, Majhi S, Kumari K, Radharani NNV, Kundu GC. Osteopontin: A Key Multifaceted Regulator in Tumor Progression and Immunomodulation. Biomedicines 2024; 12:1527. [PMID: 39062100 PMCID: PMC11274826 DOI: 10.3390/biomedicines12071527] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2024] [Revised: 06/22/2024] [Accepted: 06/25/2024] [Indexed: 07/28/2024] Open
Abstract
The tumor microenvironment (TME) is composed of various cellular components such as tumor cells, stromal cells including fibroblasts, adipocytes, mast cells, lymphatic vascular cells and infiltrating immune cells, macrophages, dendritic cells and lymphocytes. The intricate interplay between these cells influences tumor growth, metastasis and therapy failure. Significant advancements in breast cancer therapy have resulted in a substantial decrease in mortality. However, existing cancer treatments frequently result in toxicity and nonspecific side effects. Therefore, improving targeted drug delivery and increasing the efficacy of drugs is crucial for enhancing treatment outcome and reducing the burden of toxicity. In this review, we have provided an overview of how tumor and stroma-derived osteopontin (OPN) plays a key role in regulating the oncogenic potential of various cancers including breast. Next, we dissected the signaling network by which OPN regulates tumor progression through interaction with selective integrins and CD44 receptors. This review addresses the latest advancements in the roles of splice variants of OPN in cancer progression and OPN-mediated tumor-stromal interaction, EMT, CSC enhancement, immunomodulation, metastasis, chemoresistance and metabolic reprogramming, and further suggests that OPN might be a potential therapeutic target and prognostic biomarker for the evolving landscape of cancer management.
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Affiliation(s)
- Venketesh K. Panda
- School of Biotechnology, KIIT Deemed to be University, Bhubaneswar 751024, India; (V.K.P.); (B.M.); (A.N.N.); (D.M.); (S.K.); (S.M.); (P.M.); (B.S.); (S.M.); (K.K.)
| | - Barnalee Mishra
- School of Biotechnology, KIIT Deemed to be University, Bhubaneswar 751024, India; (V.K.P.); (B.M.); (A.N.N.); (D.M.); (S.K.); (S.M.); (P.M.); (B.S.); (S.M.); (K.K.)
| | - Angitha N. Nath
- School of Biotechnology, KIIT Deemed to be University, Bhubaneswar 751024, India; (V.K.P.); (B.M.); (A.N.N.); (D.M.); (S.K.); (S.M.); (P.M.); (B.S.); (S.M.); (K.K.)
| | - Ramesh Butti
- Division of Hematology and Oncology, Department of Internal Medicine, Southwestern Medical Center, University of Texas, Dallas, TX 75235, USA;
| | - Amit Singh Yadav
- Biomedical Centre, Faculty of Medicine, Lund University, 223 62 Lund, Sweden; (A.S.Y.); (N.N.V.R.)
| | - Diksha Malhotra
- School of Biotechnology, KIIT Deemed to be University, Bhubaneswar 751024, India; (V.K.P.); (B.M.); (A.N.N.); (D.M.); (S.K.); (S.M.); (P.M.); (B.S.); (S.M.); (K.K.)
| | - Sinjan Khanra
- School of Biotechnology, KIIT Deemed to be University, Bhubaneswar 751024, India; (V.K.P.); (B.M.); (A.N.N.); (D.M.); (S.K.); (S.M.); (P.M.); (B.S.); (S.M.); (K.K.)
| | - Samikshya Mahapatra
- School of Biotechnology, KIIT Deemed to be University, Bhubaneswar 751024, India; (V.K.P.); (B.M.); (A.N.N.); (D.M.); (S.K.); (S.M.); (P.M.); (B.S.); (S.M.); (K.K.)
| | - Priyanka Mishra
- School of Biotechnology, KIIT Deemed to be University, Bhubaneswar 751024, India; (V.K.P.); (B.M.); (A.N.N.); (D.M.); (S.K.); (S.M.); (P.M.); (B.S.); (S.M.); (K.K.)
| | - Biswajit Swain
- School of Biotechnology, KIIT Deemed to be University, Bhubaneswar 751024, India; (V.K.P.); (B.M.); (A.N.N.); (D.M.); (S.K.); (S.M.); (P.M.); (B.S.); (S.M.); (K.K.)
| | - Sambhunath Majhi
- School of Biotechnology, KIIT Deemed to be University, Bhubaneswar 751024, India; (V.K.P.); (B.M.); (A.N.N.); (D.M.); (S.K.); (S.M.); (P.M.); (B.S.); (S.M.); (K.K.)
| | - Kavita Kumari
- School of Biotechnology, KIIT Deemed to be University, Bhubaneswar 751024, India; (V.K.P.); (B.M.); (A.N.N.); (D.M.); (S.K.); (S.M.); (P.M.); (B.S.); (S.M.); (K.K.)
| | - N. N. V. Radharani
- Biomedical Centre, Faculty of Medicine, Lund University, 223 62 Lund, Sweden; (A.S.Y.); (N.N.V.R.)
| | - Gopal C. Kundu
- School of Biotechnology, KIIT Deemed to be University, Bhubaneswar 751024, India; (V.K.P.); (B.M.); (A.N.N.); (D.M.); (S.K.); (S.M.); (P.M.); (B.S.); (S.M.); (K.K.)
- Kalinga Institute of Medical Sciences (KIMS), KIIT Deemed to be University, Bhubaneswar 751024, India
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Yang K, Yi T. Tumor cell stemness in gastrointestinal cancer: regulation and targeted therapy. Front Mol Biosci 2024; 10:1297611. [PMID: 38455361 PMCID: PMC10918437 DOI: 10.3389/fmolb.2023.1297611] [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: 09/20/2023] [Accepted: 11/14/2023] [Indexed: 03/09/2024] Open
Abstract
The cancer stem cells are a rare group of self-renewable cancer cells capable of the initiation, progression, metastasis and recurrence of tumors, and also a key contributor to the therapeutic resistance. Thus, understanding the molecular mechanism of tumor stemness regulation, especially in the gastrointestinal (GI) cancers, is of great importance for targeting CSC and designing novel therapeutic strategies. This review aims to elucidate current advancements in the understanding of CSC regulation, including CSC biomarkers, signaling pathways, and non-coding RNAs. We will also provide a comprehensive view on how the tumor microenvironment (TME) display an overall tumor-promoting effect, including the recruitment and impact of cancer-associated fibroblasts (CAFs), the establishment of an immunosuppressive milieu, and the induction of angiogenesis and hypoxia. Lastly, this review consolidates mainstream novel therapeutic interventions targeting CSC stemness regulation.
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Affiliation(s)
- Kangqi Yang
- School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Tuo Yi
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
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Chen CW, Wang HC, Tsai IM, Chen IS, Chen CJ, Hou YC, Shan YS. CD204-positive M2-like tumor-associated macrophages increase migration of gastric cancer cells by upregulating miR-210 to reduce NTN4 expression. Cancer Immunol Immunother 2024; 73:1. [PMID: 38175202 PMCID: PMC10766795 DOI: 10.1007/s00262-023-03601-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2023] [Accepted: 11/09/2023] [Indexed: 01/05/2024]
Abstract
BACKGROUND Tumor-associated macrophages (TAMs) are the predominant immune cells in the tumor microenvironment and portend poor prognosis. However, the molecular mechanisms underlying the tumor promotion of TAMs have not been fully elucidated. METHODS Coculture of gastric cancer cells with U937 cells was performed to investigate the impact of TAMs on cancer cell behavior. MicroRNA (miRNA) microarray and bioinformatics were applied to identify the involved miRNAs and the functional target genes. The regulation of the miRNA on its target gene was studied using anti-miRNA and miRNA mimic. RESULTS Coculture with CD204+ M2-like TAMs increased proliferation, migration, and epithelial-mesenchymal transition of gastric cancer cells. MiR-210 was the most upregulated miRNA in cancer cells identified by miRNA microarray after coculture. In gastric cancer tissues, miR-210 expression was positively correlated with CD204+ M2-like TAM infiltration. Inactivation of miR-210 by antimir attenuated CD204+ M2-like TAMs-induced cancer cell migration. Using pharmacological inhibitors and neutralizing antibodies, CD204+ M2-like TAMs-secreted TNFα was found to upregulate miR-210 through NF-κB/HIF-1α signaling. Bioinformatics analysis showed netrin-4 (NTN4) as a potential target of miR-210 to suppress gastric cancer cell migration. We also found an inverse expression between miR-210 and NTN4 in cancer cells after coculture or in tumor xenografts. Anti-miR-210 increased NTN4 expression, while miR-210 mimics downregulated NTN4 in cancer cells. Reporter luciferase assays showed that MiR-210 mimics suppressed NTN4 3' untranslated region-driven luciferase activity in cancer cells, but this effect was blocked after mutating miR-210 binding site. CONCLUSIONS CD204+ M2-like TAMs can utilize the TNF-α/NF-κB/HIF-1α/miR-210/NTN4 pathway to facilitate gastric cancer progression.
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Affiliation(s)
- Chin-Wang Chen
- Department of Surgery, Kaohsiung Veterans General Hospital Tainan Branch, Tainan, Taiwan
| | - Hao-Chen Wang
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Medical Imaging Center, Innovation Headquarters, National Cheng Kung University, Tainan, Taiwan
| | - I-Min Tsai
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - I-Shu Chen
- Department of Surgery, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
| | - Chang-Jung Chen
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Ya-Chin Hou
- Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, 138, Sheng-Li Road, Tainan, 70428, Taiwan
| | - Yan-Shen Shan
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
- Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, 138, Sheng-Li Road, Tainan, 70428, Taiwan.
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Urakami S, Koma YI, Tsukamoto S, Azumi Y, Miyako S, Kitamura Y, Kodama T, Nishio M, Shigeoka M, Abe H, Usami Y, Kodama Y, Yokozaki H. Biological and clinical significance of the YKL-40/osteopontin-integrin β4-p70S6K axis induced by macrophages in early oesophageal squamous cell carcinoma. J Pathol 2023; 261:55-70. [PMID: 37436683 DOI: 10.1002/path.6148] [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] [Received: 11/14/2022] [Revised: 05/12/2023] [Accepted: 05/27/2023] [Indexed: 07/13/2023]
Abstract
M2 macrophages contribute to the progression of oesophageal squamous cell carcinoma (ESCC); however, the roles of M2 macrophages in early ESCC remain unclear. To clarify the biological mechanisms underlying the interaction between M2 macrophages and oesophageal epithelial cells in early-stage ESCC, in vitro co-culture assays between the immortalised oesophageal epithelial cell line Het-1A and cytokine-defined M2 macrophages were established. Co-culture with M2 macrophages promoted the proliferation and migration of Het-1A cells via the mTOR-p70S6K signalling pathway activated by YKL-40, also known as chitinase 3-like 1, and osteopontin (OPN) that were hypersecreted in the co-culture supernatants. YKL-40 and OPN promoted the above phenotypes of Het-1A by making a complex with integrin β4 (β4). Furthermore, YKL-40 and OPN promoted M2 polarisation, proliferation, and migration of macrophages. To validate the pathological and clinical significances of in vitro experimental results, immunohistochemistry of human early ESCC tissues obtained by endoscopic submucosal dissection (ESD) was performed, confirming the activation of the YKL-40/OPN-β4-p70S6K axis in the tumour area. Moreover, epithelial expression of β4 and the number of epithelial and stromal infiltrating YKL-40- and OPN-positive cells correlated with the Lugol-voiding lesions (LVLs), a well-known predictor of the incidence of metachronous ESCC. Furthermore, the combination of high expression of β4 and LVLs or high numbers of epithelial and stromal infiltrating YKL-40- and OPN-positive immune cells could more clearly detect the incidence of metachronous ESCC than each of the parameters alone. Our results demonstrated that the YKL-40/OPN-β4-p70S6K axis played important roles in early-stage ESCC, and the high expression levels of β4 and high numbers of infiltrating YKL-40- and OPN-positive immune cells could be useful predictive parameters for the incidence of metachronous ESCC after ESD. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
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Affiliation(s)
- Satoshi Urakami
- Division of Pathology, Department of Pathology, Kobe University Graduate School of Medicine, Kobe, Japan
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Yu-Ichiro Koma
- Division of Pathology, Department of Pathology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Shuichi Tsukamoto
- Division of Pathology, Department of Pathology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Yuki Azumi
- Division of Pathology, Department of Pathology, Kobe University Graduate School of Medicine, Kobe, Japan
- Division of Gastro-intestinal Surgery, Department of Surgery, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Shoji Miyako
- Division of Pathology, Department of Pathology, Kobe University Graduate School of Medicine, Kobe, Japan
- Division of Gastro-intestinal Surgery, Department of Surgery, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Yu Kitamura
- Division of Pathology, Department of Pathology, Kobe University Graduate School of Medicine, Kobe, Japan
- Division of Gastro-intestinal Surgery, Department of Surgery, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Takayuki Kodama
- Division of Pathology, Department of Pathology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Mari Nishio
- Division of Pathology, Department of Pathology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Manabu Shigeoka
- Division of Pathology, Department of Pathology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Hirofumi Abe
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Yu Usami
- Department of Oral and Maxillofacial Pathology, Osaka University Graduate School of Dentistry, Osaka, Japan
| | - Yuzo Kodama
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Hiroshi Yokozaki
- Division of Pathology, Department of Pathology, Kobe University Graduate School of Medicine, Kobe, Japan
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Shen Y, Chen JX, Li M, Xiang Z, Wu J, Wang YJ. Role of tumor-associated macrophages in common digestive system malignant tumors. World J Gastrointest Oncol 2023; 15:596-616. [PMID: 37123058 PMCID: PMC10134211 DOI: 10.4251/wjgo.v15.i4.596] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2022] [Revised: 02/12/2023] [Accepted: 03/30/2023] [Indexed: 04/12/2023] Open
Abstract
Many digestive system malignant tumors are characterized by high incidence and mortality rate. Increasing evidence has revealed that the tumor microenvironment (TME) is involved in cancer initiation and tumor progression. Tumor-associated macrophages (TAMs) are a predominant constituent of the TME, and participate in the regulation of various biological behaviors and influence the prognosis of digestive system cancer. TAMs can be mainly classified into the antitumor M1 phenotype and protumor M2 phenotype. The latter especially are crucial drivers of tumor invasion, growth, angiogenesis, metastasis, immunosuppression, and resistance to therapy. TAMs are of importance in the occurrence, development, diagnosis, prognosis, and treatment of common digestive system malignant tumors. In this review, we summarize the role of TAMs in common digestive system malignant tumors, including esophageal, gastric, colorectal, pancreatic and liver cancers. How TAMs promote the development of tumors, and how they act as potential therapeutic targets and their clinical applications are also described.
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Affiliation(s)
- Yue Shen
- Department of Dermatology, Suzhou Municipal Hospital, Suzhou 215008, Jiangsu Province, China
| | - Jia-Xi Chen
- School of Medicine, Zhejiang University, Hangzhou 310009, Zhejiang Province, China
| | - Ming Li
- Department of Pathology, Suzhou Municipal Hospital, Suzhou 215008, Jiangsu Province, China
| | - Ze Xiang
- School of Medicine, Zhejiang University, Hangzhou 310009, Zhejiang Province, China
| | - Jian Wu
- Department of Clinical Laboratory, Suzhou Municipal Hospital, Suzhou 215008, Jiangsu Province, China
| | - Yi-Jin Wang
- School of Medicine, Southern University of Science and Technology, Shenzhen 518055, Guangdong Province, China
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Wang S, Xu G, Li M, Zheng J, Wang Y, Feng X, Luo J, Wang S, Liu H, Duan W, Zhang H, Huang D, Zhao F, Nie Y, Yang J. M1 macrophage predicted efficacy of neoadjuvant camrelizumab combined with chemotherapy vs chemotherapy alone for locally advanced ESCC: A pilot study. Front Oncol 2023; 13:1139990. [PMID: 36969032 PMCID: PMC10038194 DOI: 10.3389/fonc.2023.1139990] [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: 01/08/2023] [Accepted: 02/20/2023] [Indexed: 03/12/2023] Open
Abstract
Introduction The efficacy and safety of immunotherapy have been widely recognized in gastrointestinal-related cancers. However, the efficacy of neoadjuvant camrelizumab for locally advanced esophageal squamous cell carcinoma (ESCC) has not been firmly established. This study compared the efficacy of camrelizumab in combination with neoadjuvant DCF (docetaxel, cisplatin and fluorouracil), with DCF alone for ESCC, and exploring biomarkers related to immune infiltration of the ESCC immunotherapy response. Methods We enrolled and randomly assigned patients with stage II-IVa ESCC to two study treatments: camrelizumab combined with docetaxel, cisplatin and fluorouracil (DCF) regimen and DCF regimen alone. The tissue for multiplex immunofluorescence (mIF) was obtained before and after neoadjuvant therapy. The Response Evaluation Criteria in Solid Tumors RECIST Version 1.1 (RECIST 1.1) and Tumor Regression Grade (TRG) was used to evaluate efficacy. Results A total of 30 patients were enrolled in the study. Following neoadjuvant camrelizumab, the objective response rate (ORR) and the disease control rate (DCR) were 46.7% (7/15) and 95.7% (14/15), respectively. No patients reported complete remission, while ORR and DCR in the chemotherapy group were 26.7% (4/15) and 86.7% (13/15), respectively. R0 resection after neoadjuvant treatment was achieved in 3 out of 15 patients in the combined group and in all patients (15/15) in the chemotherapy group. In the combined group, M1-type tumor-associated macrophages and CD56dim NK cells were more abundant in responders than in non-responders (p < 0.05). A higher M1/M2 ratio was observed in responders (p < 0.05). With respect to the NGS, among the copy number amplified genes, the 11q13 amplicon (CCND1/FGF19/FGF4/FGF3) showed the highest frequency (47%, 7/15). Conclusions Neoadjuvant camrelizumab combined with chemotherapy improved ORR in locally advanced ESCC. M1-type tumor-associated macrophages and CD56dim NK cells might be utilized to predict camrelizumab efficacy.
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Affiliation(s)
- Shu Wang
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xi-jing Hospital of Digestive Diseases, Fourth Military Medical University, Xi’an, China
- Department of Digestive Surgery, Xi Jing Hospital, The Fourth Military Medical University, Xi’an, China
| | - Guanghui Xu
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xi-jing Hospital of Digestive Diseases, Fourth Military Medical University, Xi’an, China
- Department of Digestive Surgery, Xi Jing Hospital, The Fourth Military Medical University, Xi’an, China
| | - Mengbin Li
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xi-jing Hospital of Digestive Diseases, Fourth Military Medical University, Xi’an, China
- Department of Digestive Surgery, Xi Jing Hospital, The Fourth Military Medical University, Xi’an, China
| | - Jiyang Zheng
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xi-jing Hospital of Digestive Diseases, Fourth Military Medical University, Xi’an, China
- Department of Digestive Surgery, Xi Jing Hospital, The Fourth Military Medical University, Xi’an, China
| | - Yuhao Wang
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xi-jing Hospital of Digestive Diseases, Fourth Military Medical University, Xi’an, China
- Department of Digestive Surgery, Xi Jing Hospital, The Fourth Military Medical University, Xi’an, China
| | - Xiangying Feng
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xi-jing Hospital of Digestive Diseases, Fourth Military Medical University, Xi’an, China
- Department of Digestive Surgery, Xi Jing Hospital, The Fourth Military Medical University, Xi’an, China
| | - Jialin Luo
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xi-jing Hospital of Digestive Diseases, Fourth Military Medical University, Xi’an, China
- Department of Digestive Surgery, Xi Jing Hospital, The Fourth Military Medical University, Xi’an, China
| | - Shibo Wang
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xi-jing Hospital of Digestive Diseases, Fourth Military Medical University, Xi’an, China
| | - Huan Liu
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xi-jing Hospital of Digestive Diseases, Fourth Military Medical University, Xi’an, China
| | - Weiming Duan
- The Medical Department, 3D Medicines Inc., Shanghai, China
| | - Hushan Zhang
- The Medical Department, 3D Medicines Inc., Shanghai, China
| | - Depei Huang
- The Medical Department, 3D Medicines Inc., Shanghai, China
| | - Feilong Zhao
- The Medical Department, 3D Medicines Inc., Shanghai, China
| | - Yongzhan Nie
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xi-jing Hospital of Digestive Diseases, Fourth Military Medical University, Xi’an, China
| | - Jianjun Yang
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xi-jing Hospital of Digestive Diseases, Fourth Military Medical University, Xi’an, China
- Department of Digestive Surgery, Xi Jing Hospital, The Fourth Military Medical University, Xi’an, China
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Kamran DES, Hussain M, Mirza T. Investigating In Situ Expression of c-MYC and Candidate Ubiquitin-Specific Proteases in DLBCL and Assessment for Peptidyl Disruptor Molecule against c-MYC-USP37 Complex. Molecules 2023; 28:molecules28062441. [PMID: 36985413 PMCID: PMC10058055 DOI: 10.3390/molecules28062441] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Revised: 03/02/2023] [Accepted: 03/05/2023] [Indexed: 03/30/2023] Open
Abstract
Diffuse Large B-Cell Lymphoma (DLBCL) is the most common form of non-Hodgkin's lymphoma (NHL). Elevated expression of c-MYC in DLBCL is associated with poor prognosis of the disease. In different cancers, c-MYC has been found regulated by different ubiquitin-specific proteases (USPs), but to date, the role of USPs in c-MYC regulation has not been investigated in DLBCL. In this study, in situ co expression of c-MYC and three candidates USPs, USP28, USP36 and USP37, have been investigated in both the ABC and GCB subtypes of DLBCL. This shows that USP37 expression is positively correlated with the c-MYC expression in the ABC subtype of DLBCL. Structurally, both c-MYC and USP37 has shown large proportion of intrinsically disordered regions, minimizing their chances for full structure crystallization. Peptide array and docking simulations has shown that N-terminal region of c-MYC interacts directly with residues within and in proximity of catalytically active C19 domain of the USP37. Given the structural properties of the interaction sites in the c-MYC-USP37 complex, a peptidyl inhibitor has been designed. Molecular docking has shown that the peptide fits well in the targeted site of c-MYC, masking most of its residues involved in the binding with USP37. The findings could further be exploited to develop therapeutic interventions against the ABC subtype of DLBCL.
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Affiliation(s)
- Durr E Sameen Kamran
- Department of Pathology, Dow Ishrat-ul-Ebad Khan Institute of Oral Health Sciences, Dow University of Health Sciences, Karachi 75330, Pakistan
- Bioinformatics and Molecular Medicine Research Group, Dow Research Institute of Biotechnology and Biomedical Sciences, Dow College of Biotechnology, Dow University of Health Sciences, Karachi 75330, Pakistan
| | - Mushtaq Hussain
- Bioinformatics and Molecular Medicine Research Group, Dow Research Institute of Biotechnology and Biomedical Sciences, Dow College of Biotechnology, Dow University of Health Sciences, Karachi 75330, Pakistan
| | - Talat Mirza
- Department of Research, Ziauddin University, Karachi 75000, Pakistan
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Chen X, Jiang J, Liu H, Li A, Wang W, Ni Z, Lin M. MSR1 characterized by chromatin accessibility mediates M2 macrophage polarization to promote gastric cancer progression. Int Immunopharmacol 2022; 112:109217. [PMID: 36095948 DOI: 10.1016/j.intimp.2022.109217] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Revised: 08/29/2022] [Accepted: 08/29/2022] [Indexed: 11/05/2022]
Abstract
BACKGROUND M2 macrophages play an important role in gastric cancer progression and metastasis, but the underlying tumor-promoting mechanisms are largely unknown. METHODS The TCIA database was used to identify the infiltration profile of macrophages. Integrated ATAC-seq, RNA-seq, and single-cell RNA sequencing (scRNA-seq) data from GC samples were used for the analysis. Using ATAC-seq profiles and RNA-seq datasets, combined with cox univariate survival analysis, we identified prognosis-related differentially expressed genes (DEGs) with chromatin accessibility, which were identified as hub genes. The CIBERSORTx algorithm was utilized to estimate the relative infiltration level of M2 macrophages, and Pearson correlation analysis was performed to investigate the relationship between hub genes and M2 macrophages. Multidimensional database validations were carried out to avoid biases. The expression level and function of hub genes in the clusters of macrophages were evaluated by using scRNA-seq data. The role of hub genes in the alternative activation of macrophages and gastric cancer malignant behaviors, as well as their potential regulatory mechanism in gastric cancer progression, were further explored. RESULTS 17,334 genes were acquired with chromatin accessibility in promoter regions by ATAC-seq. 2,714 genes were identified with both chromatin accessibility and differential expression based on the gene expression profiles (RNA-seq). By performing Cox univariate survival analysis, 171 survival-related DEGs with chromatin accessibility were identified as hub genes. Through the CIBERSORTx algorithm and Pearson correlation analysis, the gene MSR1 most associated with M2 macrophages was screened out. According to the scRNA-seq analysis, MSR1 was highly expressed in the clusters of macrophages and may be involved in regulating M2 macrophage polarization. In vitro experiments confirmed that M2 macrophage polarization and its induced malignant behavior of gastric cancer cells were inhibited by knockdown of MSR1. Furthermore, MSR1 mediated M2 macrophage polarization by regulating arginine and proline metabolism, thereby activating the AMPK/mTOR pathway to promote gastric cancer progression. CONCLUSION We identified a gene-MSR1-characterized by chromatin accessibility, associated with poor prognosis in gastric cancer. This gene dictates the progression of gastric cancer by facilitating M2 macrophage polarization.
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Affiliation(s)
- Xin Chen
- Department of General Surgery, Yangpu Hospital Affiliated to Tongji University, Tongji University School of Medicine, Shanghai 200090, China; Center for Clinical Research and Translational Medicine, Yangpu Hospital, Tongji University School of Medicine, Shanghai 200090, China; Institute of Gastrointestinal Surgery and Translational Medicine, Tongji University School of Medicine, Shanghai 200090, China
| | - Jiebang Jiang
- Center for Clinical Research and Translational Medicine, Yangpu Hospital, Tongji University School of Medicine, Shanghai 200090, China; Institute of Gastrointestinal Surgery and Translational Medicine, Tongji University School of Medicine, Shanghai 200090, China
| | - Hailong Liu
- Department of General Surgery, Yangpu Hospital Affiliated to Tongji University, Tongji University School of Medicine, Shanghai 200090, China
| | - Ajian Li
- Department of General Surgery, Yangpu Hospital Affiliated to Tongji University, Tongji University School of Medicine, Shanghai 200090, China
| | - Wenchao Wang
- Department of General Surgery, Yangpu Hospital Affiliated to Tongji University, Tongji University School of Medicine, Shanghai 200090, China
| | - Zhizhan Ni
- Department of General Surgery, Yangpu Hospital Affiliated to Tongji University, Tongji University School of Medicine, Shanghai 200090, China.
| | - Moubin Lin
- Department of General Surgery, Yangpu Hospital Affiliated to Tongji University, Tongji University School of Medicine, Shanghai 200090, China; Center for Clinical Research and Translational Medicine, Yangpu Hospital, Tongji University School of Medicine, Shanghai 200090, China; Institute of Gastrointestinal Surgery and Translational Medicine, Tongji University School of Medicine, Shanghai 200090, China.
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10
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Matsubara E, Komohara Y, Esumi S, Shinchi Y, Ishizuka S, Mito R, Pan C, Yano H, Kobayashi D, Fujiwara Y, Ikeda K, Sakagami T, Suzuki M. SPP1 Derived from Macrophages Is Associated with a Worse Clinical Course and Chemo-Resistance in Lung Adenocarcinoma. Cancers (Basel) 2022; 14:cancers14184374. [PMID: 36139536 PMCID: PMC9496817 DOI: 10.3390/cancers14184374] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Revised: 08/31/2022] [Accepted: 09/06/2022] [Indexed: 12/01/2022] Open
Abstract
Simple Summary Osteopontin, also called secreted phosphoprotein 1 (SPP1), is expressed by cancer cells and is known as a poor prognostic factor. Although the production of SPP1 by tumor-associated macrophages (TAMs) has been attracting much attention recently, there have been no studies distinguishing the SPP1 expression of cancer cells and TAMs. In the present study, we demonstrated the following points. (1) Increased SPP1 expression on TAMs is associated with a worse clinical course in EGFR-wild-type adenocarcinoma. (2) SPP1 expression on macrophages is dependent on GM-CSF-mediated macrophage differentiation. (3) Macrophage-derived SPP1 potentially contributed to chemoresistance in lung cancer. Abstract Osteopontin, also called secreted phosphoprotein 1 (SPP1), is a multifunctional secreted phosphorylated glycoprotein. SPP1 is also expressed in tumor cells, and many studies demonstrated that a high level of circulating SPP1 is correlated with a poor prognosis in various cancers. SPP1 is expressed not only by tumor cells but also by stromal cells, such as macrophages. However, there have been no studies distinguishing the SPP1 expression of cancer cells and tumor-associated macrophages (TAMs). Thus, in this study, we tried to accurately evaluate the SPP1 expression status on cancer cells and TAMs separately in patients with non-small cell lung cancer by using double immunohistochemistry. We demonstrated that high SPP1 expression on TAMs predicted a poor prognosis in lung adenocarcinoma patients. Additionally, we investigated the expression mechanisms related to SPP1 using human-monocyte-derived macrophages and revealed that the SPP1 expression level increased in macrophage differentiation mediated by granulocyte-macrophage colony-stimulating factor. Furthermore, SPP1 contributed to anti-cancer drug resistance in lung cancer cell lines. In conclusion, SPP1 production on TAMs predicted a poor prognosis in lung adenocarcinoma patients, and TAM-derived SPP1′s involvement in the chemo-resistance of cancer cells was suggested.
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Affiliation(s)
- Eri Matsubara
- Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan
- Department of Thoracic Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan
| | - Yoshihiro Komohara
- Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan
- Center for Metabolic Regulation of Healthy Aging, Kumamoto University, Kumamoto 860-8556, Japan
- Correspondence: ; Tel.: +81-96-373-5095
| | - Shigeyuki Esumi
- Department of Anatomy and Neurobiology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan
| | - Yusuke Shinchi
- Department of Thoracic Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan
| | - Shiho Ishizuka
- Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan
- Department of Respiratory Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan
| | - Remi Mito
- Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan
- Department of Respiratory Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan
| | - Cheng Pan
- Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan
| | - Hiromu Yano
- Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan
| | - Daiki Kobayashi
- Department of Omics and Systems Biology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8510, Japan
| | - Yukio Fujiwara
- Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan
| | - Koei Ikeda
- Department of Thoracic Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan
| | - Takuro Sakagami
- Department of Respiratory Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan
| | - Makoto Suzuki
- Department of Thoracic Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan
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Sukri A, Hanafiah A, Kosai NR. The Roles of Immune Cells in Gastric Cancer: Anti-Cancer or Pro-Cancer? Cancers (Basel) 2022; 14:cancers14163922. [PMID: 36010915 PMCID: PMC9406374 DOI: 10.3390/cancers14163922] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Revised: 08/05/2022] [Accepted: 08/07/2022] [Indexed: 12/03/2022] Open
Abstract
Simple Summary Gastric cancer is still one of the leading causes of death caused by cancer in developing countries. The emerging role of immunotherapy in cancer treatment has led to more research to elucidate the roles of essential immune cells in gastric cancer prognosis. We reviewed the roles of immune cells including T cells, B cells, dendritic cells, macrophages and natural killer cells in gastric cancer. Although the studies conducted on the roles of immune cells in gastric cancer pathogenesis produced conflicting results, understanding the roles of immune cells in gastric cancer will help us to harness them for application in immunotherapy for better prognosis and management of gastric cancer patients. Abstract Despite the fact that the incidence of gastric cancer has declined over the last decade, it is still the world’s leading cause of cancer-related death. The diagnosis of early gastric cancer is difficult, as symptoms of this cancer only manifest at a late stage of cancer progression. Thus, the prognosis of gastric cancer is poor, and the current treatment for improving patients’ outcomes involves the application of surgery and chemotherapy. Immunotherapy is one of the most recent therapies for gastric cancer, whereby the immune system of the host is programmed to combat cancer cells, and the therapy differs based upon the patient’s immune system. However, an understanding of the role of immune cells, namely the cell-mediated immune response and the humoral immune response, is pertinent for applications of immunotherapy. The roles of immune cells in the prognosis of gastric cancer have yielded conflicting results. This review discusses the roles of immune cells in gastric cancer pathogenesis, specifically, T cells, B cells, macrophages, natural killer cells, and dendritic cells, as well as the evidence presented thus far. Understanding how cancer cells interact with immune cells is of paramount importance in designing treatment options for gastric cancer immunotherapy.
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Affiliation(s)
- Asif Sukri
- Integrative Pharmacogenomics Institute (iPROMISE), Universiti Teknologi MARA (UiTM), Bandar Puncak Alam, Shah Alam 43200, Malaysia
| | - Alfizah Hanafiah
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Cheras, Kuala Lumpur 56000, Malaysia
- Correspondence:
| | - Nik Ritza Kosai
- Department of Surgery, Faculty of Medicine, Universiti Kebangsaan Malaysia, Cheras, Kuala Lumpur 56000, Malaysia
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12
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Tan Y, Zhao L, Yang YG, Liu W. The Role of Osteopontin in Tumor Progression Through Tumor-Associated Macrophages. Front Oncol 2022; 12:953283. [PMID: 35898884 PMCID: PMC9309262 DOI: 10.3389/fonc.2022.953283] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Accepted: 06/15/2022] [Indexed: 11/18/2022] Open
Abstract
Osteopontin (OPN) is a multifunctional phosphorylated protein. It is widely involved in solid tumor progression, such as intensification of macrophage recruitment, inhibition of T-cell activity, aggravation of tumor interstitial fibrosis, promotion of tumor metastasis, chemotherapy resistance, and angiogenesis. Most of these pathologies are affected by tumor-associated macrophages (TAMs), an important component of the tumor microenvironment (TME). TAMs have been extensively characterized, including their subsets, phenotypes, activation status, and functions, and are considered a promising therapeutic target for cancer treatment. This review focuses on the interaction between OPN and TAMs in mediating tumor progression. We discuss the strategies for targeting OPN and TAMs to treat cancer and factors that may affect the therapeutic outcomes of blocking OPN or depleting TAMs. We also discuss the role of cancer cell- vs. TAM-derived OPN in tumorigenesis, the mechanisms of how OPN affects TAM recruitment and polarization, and why OPN could mediate anti-tumor and pro-tumor effects, as well as previously reported discrepancies.
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Affiliation(s)
- Yuying Tan
- Key Laboratory of Organ Regeneration & Transplantation of the Ministry of Education, The First Hospital of Jilin University, Changchun, China
- National–Local Joint Engineering Laboratory of Animal Models for Human Diseases, Jilin University, Changchun, China
| | - Lei Zhao
- Key Laboratory of Organ Regeneration & Transplantation of the Ministry of Education, The First Hospital of Jilin University, Changchun, China
- National–Local Joint Engineering Laboratory of Animal Models for Human Diseases, Jilin University, Changchun, China
| | - Yong-Guang Yang
- Key Laboratory of Organ Regeneration & Transplantation of the Ministry of Education, The First Hospital of Jilin University, Changchun, China
- National–Local Joint Engineering Laboratory of Animal Models for Human Diseases, Jilin University, Changchun, China
- International Center of Future Science, Jilin University, Changchun, China
- *Correspondence: Yong-Guang Yang, ; Wentao Liu,
| | - Wentao Liu
- Key Laboratory of Organ Regeneration & Transplantation of the Ministry of Education, The First Hospital of Jilin University, Changchun, China
- National–Local Joint Engineering Laboratory of Animal Models for Human Diseases, Jilin University, Changchun, China
- *Correspondence: Yong-Guang Yang, ; Wentao Liu,
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13
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Svensson MC, Svensson M, Nodin B, Borg D, Hedner C, Hjalmarsson C, Leandersson K, Jirström K. High Infiltration of CD68+/CD163- Macrophages Is an Adverse Prognostic Factor after Neoadjuvant Chemotherapy in Esophageal and Gastric Adenocarcinoma. J Innate Immun 2022; 14:615-628. [PMID: 35504250 PMCID: PMC9801256 DOI: 10.1159/000524434] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Accepted: 02/19/2022] [Indexed: 01/03/2023] Open
Abstract
Tumor-associated macrophages (TAMs) have emerged as key players in tumor immunology but demonstrate a continuum of functional states being either tumor suppressive or promoting. Moreover, chemotherapeutic agents have been shown to alter the tumor microenvironment. Perioperative chemotherapy is a standard treatment option for resectable esophageal and gastric (EG) adenocarcinoma. The aim of this study was to investigate the influence of neoadjuvant chemotherapy (NAC) on TAMs to improve the prognostication and treatment course for these patients. The study cohort comprised 148 patients, all of whom were diagnosed with resectable EG adenocarcinoma and treated with NAC. Immunohistochemistry was applied to assess the total infiltration and infiltration into tumor nests (TN) of CD68+/CD163-, CD68+/CD163+, and MARCO+ TAMs, on paired biopsies from primary tumors (PT) pre-NAC, and resected PT and lymph node metastases post-NAC. In pre-NAC specimens, high CD68+/CD163+ infiltration into TN was an unfavorable prognostic factor. No association was found between TAM density in PT pre-NAC and histopathological regression. The density of CD68+/CD163+ TAMs was increased in PT post-NAC, while the density of MARCO+ TAMs was decreased. CD68+/CD163- TAM density was not altered. In post-NAC specimens, higher total as well as TN infiltration of CD68+/CD163- TAMs were adverse prognostic factors. In conclusion, these results suggest that NAC may alter certain TAM subsets in EG adenocarcinoma, along with their functional properties and thus their prognostic value.
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Affiliation(s)
- Maria C. Svensson
- Department of Clinical Sciences Lund, Oncology and Therapeutic Pathology, Lund University, Lund, Sweden
| | - Maja Svensson
- Department of Clinical Sciences Lund, Oncology and Therapeutic Pathology, Lund University, Lund, Sweden,*Maria C. Svensson,
| | - Björn Nodin
- Department of Clinical Sciences Lund, Oncology and Therapeutic Pathology, Lund University, Lund, Sweden
| | - David Borg
- Department of Clinical Sciences Lund, Oncology and Therapeutic Pathology, Lund University, Lund, Sweden
| | - Charlotta Hedner
- Department of Clinical Sciences Lund, Oncology and Therapeutic Pathology, Lund University, Lund, Sweden
| | - Claes Hjalmarsson
- Department of Clinical Sciences Lund, Oncology, Lund University, Lund, Sweden
| | - Karin Leandersson
- Cancer Immunology, Department of Translational Medicine, Lund University, Malmö, Sweden
| | - Karin Jirström
- Department of Clinical Sciences Lund, Oncology and Therapeutic Pathology, Lund University, Lund, Sweden
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14
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Diffuse gastric cancer: Emerging mechanisms of tumor initiation and progression. Biochim Biophys Acta Rev Cancer 2022; 1877:188719. [PMID: 35307354 DOI: 10.1016/j.bbcan.2022.188719] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Revised: 03/10/2022] [Accepted: 03/11/2022] [Indexed: 02/07/2023]
Abstract
Gastric cancer is globally the fourth leading cause of cancer-related deaths. Patients with diffuse-type gastric cancer (DGC) particularly have a poor prognosis that only marginally improved over the last decades, as conventional chemotherapies are frequently ineffective and specific therapies are unavailable. Early-stage DGC is characterized by intramucosal lesions of discohesive cells, which can be present for many years before the emergence of advanced DGC consisting of highly proliferative and invasive cells. The mechanisms underlying the key steps of DGC development and transition to aggressive tumors are starting to emerge. Novel mouse- and organoid models for DGC, together with multi-omic analyses of DGC tumors, revealed contributions of both tumor cell-intrinsic alterations and gradual changes in the tumor microenvironment to DGC progression. In this review, we will discuss how these recent findings are leading towards an understanding of the cellular and molecular mechanisms responsible for DGC initiation and malignancy, which may provide opportunities for targeted therapies.
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15
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Na HY, Park Y, Nam SK, Koh J, Kwak Y, Ahn SH, Park DJ, Kim HH, Lee KS, Lee HS. Prognostic significance of natural killer cell-associated markers in gastric cancer: quantitative analysis using multiplex immunohistochemistry. J Transl Med 2021; 19:529. [PMID: 34952595 PMCID: PMC8710020 DOI: 10.1186/s12967-021-03203-8] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Accepted: 12/16/2021] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND Natural killer (NK) cells mediate the anti-tumoral immune response as an important component of innate immunity. The aim of this study was to investigate the prognostic significance and functional implication of NK cell-associated surface receptors in gastric cancer (GC) by using multiplex immunohistochemistry (mIHC). METHODS We performed an mIHC on tissue microarray slides, including 55 GC tissue samples. A total of 11 antibodies including CD57, NKG2A, CD16, HLA-E, CD3, CD20, CD45, CD68, CK, SMA, and ki-67 were used. CD45 + CD3-CD57 + cells were considered as CD57 + NK cells. RESULTS Among CD45 + immune cells, the proportion of CD57 + NK cell was the lowest (3.8%), whereas that of CD57 + and CD57- T cells (65.5%) was the highest, followed by macrophages (25.4%), and B cells (5.3%). CD57 + NK cells constituted 20% of CD45 + CD57 + immune cells while the remaining 80% were CD57 + T cells. The expression of HLA-E in tumor cells correlated with that in tumoral T cells, B cells, and macrophages, but not CD57 + NK cells. The higher density of tumoral CD57 + NK cells and tumoral CD57 + NKG2A + NK cells was associated with inferior survival. CONCLUSIONS Although the number of CD57 + NK cells was lower than that of other immune cells, CD57 + NK cells and CD57 + NKG2A + NK cells were significantly associated with poor outcomes, suggesting that NK cell subsets play a critical role in GC progression. NK cells and their inhibitory receptor, NKG2A, may be potential targets in GC.
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Affiliation(s)
- Hee Young Na
- Department of Pathology, Seoul National University Bundang Hospital, 173-82 Gumi-ro, Bundang-gu, Seongnam-si, Gyeonggi-do, 13620, Republic of Korea
- Department of Pathology, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea
| | - Yujun Park
- Department of Pathology, Seoul National University Bundang Hospital, 173-82 Gumi-ro, Bundang-gu, Seongnam-si, Gyeonggi-do, 13620, Republic of Korea
- Department of Pathology, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea
| | - Soo Kyung Nam
- Department of Pathology, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea
| | - Jiwon Koh
- Department of Pathology, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea
- Department of Pathology, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea
| | - Yoonjin Kwak
- Department of Pathology, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea
- Department of Pathology, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea
| | - Sang-Hoon Ahn
- Department of Surgery, Seoul National University Bundang Hospital, 173-82 Gumi-ro, Bundang-gu, Seongnam-si, Gyeonggi-do, 13620, Republic of Korea
| | - Do Joong Park
- Department of Surgery, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea
| | - Hyung-Ho Kim
- Department of Surgery, Seoul National University Bundang Hospital, 173-82 Gumi-ro, Bundang-gu, Seongnam-si, Gyeonggi-do, 13620, Republic of Korea
- Department of Surgery, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea
| | - Kyu Sang Lee
- Department of Pathology, Seoul National University Bundang Hospital, 173-82 Gumi-ro, Bundang-gu, Seongnam-si, Gyeonggi-do, 13620, Republic of Korea.
- Department of Pathology, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea.
| | - Hye Seung Lee
- Department of Pathology, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea.
- Department of Pathology, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea.
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Liu M, Zhang L, Zhou Q, Wang Y, Sun Q, Ren X. The Distinct Impact of TAM Infiltration on the Prognosis of Patients With Cardia and Non-Cardia Gastric Cancer and Its Association With H. pylori Infection. Front Oncol 2021; 11:737061. [PMID: 34926251 PMCID: PMC8677656 DOI: 10.3389/fonc.2021.737061] [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: 07/06/2021] [Accepted: 11/12/2021] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND In stage III gastric cancer (GC), the role of tumor-associated macrophages (TAMs) and Helicobacter pylori (H. pylori) infection impact tumor progression; however, the specific mechanisms remain controversial. We speculated whether this controversy is caused by differences in the location of TAM infiltration (in the core (CT) and invasive margin (MI) of primary tumors) and the topographical subsites of GC (cardia and non-cardia). Therefore, in this study, we investigated TAMs in different locations and H. pylori infection status as prognostic biomarkers for GC. METHODS Immunohistochemical staining for CD68 (pan-macrophage), CD163 (M2-like macrophage), and H. pylori in 200 samples (100 cases of cardia-GC [CGC] and 100 cases of non-cardia GC [NCGC]) was performed. We compared the number of CD68+ and CD163+ macrophages that infiltrated the CT and MI in patients with the prognosis of CGC and NCGC, respectively. In addition, we analyzed the relationship between H. pylori status and the prognosis of patients with GC in different locations, as well as the correlation with TAM infiltration. RESULTS The distribution of TAMs had distinct characteristics in CGC and NCGC, especially differences between CT and MI subtype. A Kaplan-Meier analysis showed that a high number of CD68+ macrophages that infiltrated the CT in CGC was associated with a better prognosis, whereas infiltration at the MI in NCGC indicated a poor prognosis. Furthermore, a high number of CD163+ macrophages infiltrating the MI resulted in a poor prognosis in CGC and NCGC cohorts. Considering the larger differences in the relationship between the infiltration of CD68+ macrophages at different locations and prognosis, we divided the GC cases into marginal and central GC, based on this difference. This resulted in an accurate estimation of the prognosis. Moreover, positive H. pylori status in central GC was significantly associated with a better prognosis and TAM infiltration. CONCLUSION TAMs in different locations and H. pylori status were identified as independent prognostic markers, with an obvious correlation between them. Therefore, it is important to clarify the impact of TAM location on the prognosis of patients with GC, which contributes to the development of potential therapeutic strategies.
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Affiliation(s)
| | | | | | | | - Qian Sun
- Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin’s Clinical Research Center for Cancer, Tianjin, China
| | - Xiubao Ren
- Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin’s Clinical Research Center for Cancer, Tianjin, China
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Liang YL, Lin CN, Tsai HF, Wu PY, Lin SH, Hong TM, Hsu KF. Omental Macrophagic "Crown-like Structures" Are Associated with Poor Prognosis in Advanced-Stage Serous Ovarian Cancer. ACTA ACUST UNITED AC 2021; 28:4234-4246. [PMID: 34677277 PMCID: PMC8534828 DOI: 10.3390/curroncol28050359] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2021] [Revised: 09/29/2021] [Accepted: 10/16/2021] [Indexed: 12/11/2022]
Abstract
The tumor microenvironment is a well-recognized framework in which immune cells present in the tumor microenvironment promote or inhibit cancer formation and development. A crown-like structure (CLS) has been reported as a dying or dead adipocyte surrounded by a 'crown' of macrophages within adipose tissue, which is a histologic hallmark of the inflammatory process in this tissue. CLSs have also been found to be related to formation, progression and prognosis of some types of cancer. However, the presence of CLSs in the omentum of advanced-stage high-grade serous ovarian carcinoma (HGSOC) has not been thoroughly investigated. By using CD68, a pan-macrophage marker, and CD163, an M2-like polarization macrophage marker, immunohistochemistry (IHC) was performed to identify tumor-associated macrophages (TAMs) and CLSs. This retrospective study analyzed 116 patients with advanced-stage HGSOC who received complete treatment and had available clinical data from July 2008 through December 2016 at National Cheng Kung University Hospital (NCKUH) (Tainan, Taiwan). Based on multivariate Cox regression analysis, patients with omental CD68+ CLSs had poor OS (median survival: 24 vs. 38 months, p = 0.001, hazard ratio (HR): 2.26, 95% confidence interval (CI): 1.41-3.61); patients with omental CD163+ CLSs also had poor OS (median survival: 22 vs. 36 months, HR: 2.14, 95%CI: 1.33-3.44, p = 0.002). Additionally, patients with omental CD68+ or CD163+ CLSs showed poor PFS (median survival: 11 vs. 15 months, HR: 2.28, 95%CI: 1.43-3.64, p = 0.001; median survival: 11 vs. 15 months, HR: 2.17, 95%CI: 1.35-3.47, respectively, p = 0.001). Conversely, the density of CD68+ or CD163+ TAMs in ovarian tumors was not associated with patient prognosis in advanced-stage HGSOC in our cohort. In conclusion, we, for the first time, demonstrate that the presence of omental CLSs is associated with poor prognosis in advanced-stage HGSOC.
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Affiliation(s)
- Yu-Ling Liang
- Department of Obstetrics and Gynecology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan; (Y.-L.L.); (C.-N.L.); (H.-F.T.); (P.-Y.W.)
| | - Chang-Ni Lin
- Department of Obstetrics and Gynecology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan; (Y.-L.L.); (C.-N.L.); (H.-F.T.); (P.-Y.W.)
| | - Hsing-Fen Tsai
- Department of Obstetrics and Gynecology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan; (Y.-L.L.); (C.-N.L.); (H.-F.T.); (P.-Y.W.)
| | - Pei-Ying Wu
- Department of Obstetrics and Gynecology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan; (Y.-L.L.); (C.-N.L.); (H.-F.T.); (P.-Y.W.)
| | - Sheng-Hsiang Lin
- Graduate Institute of Clinical Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan;
| | - Tse-Ming Hong
- Graduate Institute of Clinical Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan;
- Correspondence: (T.-M.H.); (K.-F.H.); Tel.: +886-6-2353535 (ext. 4259) (T.-M.H.); +886-6-2353535 (ext. 5263) (K.-F.H.); Fax: +886-6-2359885 (T.-M.H.); +886-6-2766185 (K.-F.H.)
| | - Keng-Fu Hsu
- Department of Obstetrics and Gynecology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan; (Y.-L.L.); (C.-N.L.); (H.-F.T.); (P.-Y.W.)
- Graduate Institute of Clinical Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan;
- Correspondence: (T.-M.H.); (K.-F.H.); Tel.: +886-6-2353535 (ext. 4259) (T.-M.H.); +886-6-2353535 (ext. 5263) (K.-F.H.); Fax: +886-6-2359885 (T.-M.H.); +886-6-2766185 (K.-F.H.)
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Hu J, Ma Y, Ma J, Yang Y, Ning Y, Zhu J, Wang P, Chen G, Liu Y. M2 Macrophage-Based Prognostic Nomogram for Gastric Cancer After Surgical Resection. Front Oncol 2021; 11:690037. [PMID: 34458140 PMCID: PMC8397443 DOI: 10.3389/fonc.2021.690037] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Accepted: 06/29/2021] [Indexed: 12/24/2022] Open
Abstract
A good prediction model is useful to accurately predict patient prognosis. Tumor-node-metastasis (TNM) staging often cannot accurately predict prognosis when used alone. Some researchers have shown that the infiltration of M2 macrophages in many tumors indicates poor prognosis. This approach has the potential to predict prognosis more accurately when used in combination with TNM staging, but there is less research in gastric cancer. A multivariate analysis demonstrated that CD163 expression, TNM staging, age, and gender were independent risk factors for overall survival. Thus, these parameters were assessed to develop the nomogram in the training data set, which was tested in the validation and whole data sets. The model showed a high degree of discrimination, calibration, and good clinical benefit in the training, validation, and whole data sets. In conclusion, we combined CD163 expression in macrophages, TNM staging, age, and gender to develop a nomogram to predict 3- and 5-year overall survivals after curative resection for gastric cancer. This model has the potential to provide further diagnostic and prognostic value for patients with gastric cancer.
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Affiliation(s)
- Jianwen Hu
- Department of General Surgery, Peking University First Hospital, Beijing, China
| | - Yongchen Ma
- Endoscopy Center, Peking University First Hospital, Beijing, China
| | - Ju Ma
- Department of General Surgery, Peking University First Hospital, Beijing, China
| | - Yanpeng Yang
- Department of General Surgery, Peking University First Hospital, Beijing, China
| | - Yingze Ning
- Department of General Surgery, Peking University First Hospital, Beijing, China
| | - Jing Zhu
- Department of General Surgery, Peking University First Hospital, Beijing, China
| | - Pengyuan Wang
- Department of General Surgery, Peking University First Hospital, Beijing, China
| | - Guowei Chen
- Department of General Surgery, Peking University First Hospital, Beijing, China
| | - Yucun Liu
- Department of General Surgery, Peking University First Hospital, Beijing, China
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Moeini P, Niedźwiedzka-Rystwej P. Tumor-Associated Macrophages: Combination of Therapies, the Approach to Improve Cancer Treatment. Int J Mol Sci 2021; 22:ijms22137239. [PMID: 34281293 PMCID: PMC8269174 DOI: 10.3390/ijms22137239] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2021] [Revised: 06/25/2021] [Accepted: 06/30/2021] [Indexed: 02/07/2023] Open
Abstract
Macrophages are one of the most important cells of the innate immune system and are known for their ability to engulf and digest foreign substances, including cellular debris and tumor cells. They can convert into tumor-associated macrophages (TAMs) when mature macrophages are recruited into the tumor microenvironment. Their role in cancer progression, metastasis, and therapy failure is of special note. The aim of this review is to understand how the presence of TAMs are both advantageous and disadvantageous in the immune system.
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Affiliation(s)
- Pedram Moeini
- Plant Virology Research Center, Shiraz University, Shiraz 71441-65186, Iran;
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20
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Sadasivan SM, Chen Y, Gupta NS, Han X, Bobbitt KR, Chitale DA, Williamson SR, Rundle AG, Tang D, Rybicki BA. The interplay of growth differentiation factor 15 (GDF15) expression and M2 macrophages during prostate carcinogenesis. Carcinogenesis 2021; 41:1074-1082. [PMID: 32614434 DOI: 10.1093/carcin/bgaa065] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Revised: 06/05/2020] [Accepted: 06/22/2020] [Indexed: 01/08/2023] Open
Abstract
M2 (tumor-supportive) macrophages may upregulate growth differentiation factor 15 (GDF15), which is highly expressed in prostate tumors, but the combined utility of these markers as prognostic biomarkers are unclear. We retrospectively studied 90 prostate cancer cases that underwent radical prostatectomy as their primary treatment and were followed for biochemical recurrence (BCR). These cases also had a benign prostate biopsy at least 1 year or more before their prostate cancer surgery. Using computer algorithms to analyze digitalized immunohistochemically stained slides, GDF15 expression and the presence of M2 macrophages based on the relative density of CD204- and CD68-positive macrophages were measured in prostate: (i) benign biopsy, (ii) cancer and (iii) tumor-adjacent benign (TAB) tissue. Both M2 macrophages (P = 0.0004) and GDF15 (P < 0.0001) showed significant inter-region expression differences. Based on a Cox proportional hazards model, GDF15 expression was not associated with BCR but, in men where GDF15 expression differences between cancer and TAB were highest, the risk of BCR was significantly reduced (hazard ratio = 0.26; 95% confidence interval = 0.09-0.94). In addition, cases with high levels of M2 macrophages in prostate cancer had almost a 5-fold increased risk of BCR (P = 0.01). Expression of GDF15 in prostate TAB was associated with M2 macrophage levels in both prostate cancer and TAB and appeared to moderate M2-macrophage-associated BCR risk. In summary, the relationship of GDF15 expression and CD204-positive M2 macrophage levels is different in a prostate tumor environment compared with an earlier benign biopsy and, collectively, these markers may predict aggressive disease.
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Affiliation(s)
| | - Yalei Chen
- Department of Public Health Sciences, Detroit, MI, USA
| | | | - Xiaoxia Han
- Department of Public Health Sciences, Detroit, MI, USA
| | | | | | | | - Andrew G Rundle
- Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA
| | - Deliang Tang
- Environmental Heath Sciences, Mailman School of Public Health, Columbia University, New York, NY, USA
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21
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Positron Emission Tomography Imaging of Macrophages in Cancer. Cancers (Basel) 2021; 13:cancers13081921. [PMID: 33923410 PMCID: PMC8072570 DOI: 10.3390/cancers13081921] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Revised: 04/13/2021] [Accepted: 04/13/2021] [Indexed: 12/14/2022] Open
Abstract
Macrophages are large phagocytic cells that can be classified as a type of white blood cell and may be either mobile or stationary in tissues. The presence of macrophages in essentially every major disease makes them attractive candidates to serve as therapeutic targets and diagnostic biomarkers. Macrophages that are found in the microenvironment of solid tumors are referred to as tumor-associated macrophages (TAMs) and have been shown to influence chemoresistance, immune regulation, tumor initiation and tumor growth. The imaging of TAMs through Positron Emission Tomography (PET) has the potential to provide valuable information on cancer biology, tumor progression, and response to therapy. This review will highlight the versatility of macrophage imaging in cancer through the use of PET.
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22
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Jing Y, Xu F, Liang W, Liu J, Zhang L. Role of regulatory B cells in gastric cancer: Latest evidence and therapeutics strategies. Int Immunopharmacol 2021; 96:107581. [PMID: 33812259 DOI: 10.1016/j.intimp.2021.107581] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2021] [Revised: 03/07/2021] [Accepted: 03/09/2021] [Indexed: 12/16/2022]
Abstract
Gastric cancer (GC) is the second most common cancer globally and kills about 700,000 people annually. Today's knowledge clearly shows a close and complicated relationship between the tumor microenvironment (TME) and the immune system. The immune system components can both stimulate tumor growth and inhibit tumor cells. However, numerous of these mechanisms are not yet fully understood. As an essential immune cell in humoral immunity, B lymphocytes can play a dual role during various pathologic states, including infections, autoimmune diseases, and cancer, depending on their phenotype and environmental signals. Inherently, B cells can inhibit tumor growth by producing antibodies as well as the presentation of tumor antigens. However, evidence suggests that a subset of these cells termed regulatory B cells (Bregs) with an inhibitory phenotype can suppress anti-tumor responses and support the tumor growth by producing anti-inflammatory cytokines and the expression of inhibitory molecules. Therefore, in this review, the role of Bregs in the microenvironment of GC and treatment strategies based on targeting this subset of B cells have been investigated.
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Affiliation(s)
- Yuanming Jing
- Department of Gastrointestinal Surgery, Shaoxing People's Hospital, Shaoxing Hospital, The First Affiliated Hospital of Shaoxing University, Shaoxing 312000, Zhejiang Province, PR China.
| | - Fangming Xu
- Department of Orthopedics, Zhoushan Hospital of Traditional Chinese Medicine Affiliated to Zhejiang Chinese Medical University, 355 Xinqiao Road, Dinghai District, Zhoushan 316000, Zhejiang Province, PR China
| | - Wenqing Liang
- Department of Orthopedics, Zhoushan Hospital of Traditional Chinese Medicine Affiliated to Zhejiang Chinese Medical University, 355 Xinqiao Road, Dinghai District, Zhoushan 316000, Zhejiang Province, PR China
| | - Jian Liu
- Department of Hepatobiliary Surgery, Shanghai Oriental Hepatobiliary Hospital, Shanghai 200438, PR China
| | - Lin Zhang
- Department of Pharmacy, Shaoxing People's Hospital, Shaoxing Hospital, The First Affiliated Hospital of Shaoxing University, Shaoxing 312000, Zhejiang Province, PR China.
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23
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Chen YC, Lai YS, Hsuuw YD, Chang KT. Withholding of M-CSF Supplement Reprograms Macrophages to M2-Like via Endogenous CSF-1 Activation. Int J Mol Sci 2021; 22:3532. [PMID: 33805444 PMCID: PMC8037162 DOI: 10.3390/ijms22073532] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 03/13/2021] [Accepted: 03/25/2021] [Indexed: 12/17/2022] Open
Abstract
Macrophage colony-stimulating factor (M-CSF or CSF-1) is known to have a broad range of actions on myeloid cells maturation, including the regulation of macrophage differentiation, proliferation and survival. Macrophages generated by M-CSF stimulus have been proposed to be alternatively activated or M2 phenotype. M-CSF is commonly overexpressed by tumors and is also known to enhance tumor growth and aggressiveness via stimulating pro-tumor activities of tumor-associated macrophages (TAMs). Currently, inhibition of CSF-1/CSF-1R interaction by therapeutic antibody to deplete TAMs and their pro-tumor functions is becoming a prevalent strategy in cancer therapy. However, its antitumor activity shows a limited single-agent effect. Therefore, macrophages in response to M-CSF interruption are pending for further investigation. To achieve this study, bone marrow derived macrophages were generated in vitro by M-CSF stimulation for 7 days and then continuously grown until day 21 in M-CSF absence. A selective pressure for cell survival was initiated after withdrawal of M-CSF. The surviving cells were more prone to M2-like phenotype, even after receiving interleukin-4 (IL-4) stimulation. The transcriptome analysis unveiled that endogenous CSF-1 level was dramatically up-regulated and numerous genes downstream to CSF-1 covering tumor necrosis factor (TNF), ras-related protein 1 (Rap1) and phosphatidylinositol 3-kinase (PI3K)-protein kinase B (AKT) signaling pathway were significantly modulated, especially for proliferation, migration and adhesion. Moreover, the phenomenal increase of miR-21-5p and genes related to pro-tumor activity were observed in parallel. In summary, withholding of CSF-1/CSF-1R interaction would rather augment than suspend the M-CSF-driven pro-tumor activities of M2 macrophages in a long run.
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Affiliation(s)
- Yu-Chih Chen
- Graduate Institute of Bioresources, National Pingtung University of Science and Technology, Pingtung 91201, Taiwan; christian--
| | - Yin-Siew Lai
- Research Center for Animal Biologics, National Pingtung University of Science and Technology, Pingtung 91201, Taiwan;
| | - Yan-Der Hsuuw
- Department of Tropical Agriculture and International Cooperation, Pingtung 91201, Taiwan;
| | - Ko-Tung Chang
- Research Center for Animal Biologics, National Pingtung University of Science and Technology, Pingtung 91201, Taiwan;
- Flow Cytometry Center, Precision Instruments Center, National Pingtung University of Science and Technology, Pingtung 91201, Taiwan
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24
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Klement JD, Poschel DB, Lu C, Merting AD, Yang D, Redd PS, Liu K. Osteopontin Blockade Immunotherapy Increases Cytotoxic T Lymphocyte Lytic Activity and Suppresses Colon Tumor Progression. Cancers (Basel) 2021; 13:cancers13051006. [PMID: 33670921 PMCID: PMC7957528 DOI: 10.3390/cancers13051006] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Revised: 02/18/2021] [Accepted: 02/19/2021] [Indexed: 12/16/2022] Open
Abstract
Simple Summary Despite the breakthrough in human cancer immunotherapy, colorectal cancer, except for the small subset of microsatellite instable colorectal cancer (MSI, ~4% total cases), is one of the few human cancers that does not respond to current immune checkpoint inhibitor (ICI) immunotherapy. CTLs are present in both MSI and microsatellite stable (MSS) human colon carcinoma, suggesting that PD-L1-independent mechanisms may exist and suppress CTL activation in the colon tumor microenvironment. We determined that osteopontin (OPN) inhibits tumor-specific cytotoxic T lymphocyte (CTL) lytic activity to promote colon tumor growth in vivo. Accordingly, OPN blockade immunotherapy using OPN neutralization monoclonal antibodies 100D3 and 103D6 suppressed colon tumor growth in vivo. Our findings indicate that 100D3 and 103D6 has the potential to be further developed for colorectal cancer immunotherapy. Abstract Human colorectal cancers are mostly microsatellite-stable with no response to anti-PD-1 blockade immunotherapy, necessitating the development of a new immunotherapy. Osteopontin (OPN) is elevated in human colorectal cancer and may function as an immune checkpoint. We aimed at elucidating the mechanism of action of OPN and determining the efficacy of OPN blockade immunotherapy in suppression of colon cancer. We report here that OPN is primarily expressed in tumor cells, myeloid cells, and innate lymphoid cells in human colorectal carcinoma. Spp1 knock out mice exhibit a high incidence and fast growth rate of carcinogen-induced tumors. Knocking out Spp1 in colon tumor cells increased tumor-specific CTL cytotoxicity in vitro and resulted in decreased tumor growth in vivo. The OPN protein level is elevated in the peripheral blood of tumor-bearing mice. We developed four OPN neutralization monoclonal antibodies based on their efficacy in blocking OPN inhibition of T cell activation. OPN clones 100D3 and 103D6 increased the efficacy of tumor-specific CTLs in killing colon tumor cells in vitro and suppressed colon tumor growth in tumor-bearing mice in vivo. Our data indicate that OPN blockade immunotherapy with 100D3 and 103D6 has great potential to be further developed for colorectal cancer immunotherapy and for rendering a colorectal cancer response to anti-PD-1 immunotherapy.
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Affiliation(s)
- John D. Klement
- Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, GA 30912, USA; (J.D.K.); (D.B.P.); (A.D.M.); (D.Y.); (P.S.R.)
- Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA
- Charlie Norwood VA Medical Center, Augusta, GA 30904, USA
| | - Dakota B. Poschel
- Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, GA 30912, USA; (J.D.K.); (D.B.P.); (A.D.M.); (D.Y.); (P.S.R.)
- Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA
- Charlie Norwood VA Medical Center, Augusta, GA 30904, USA
| | - Chunwan Lu
- School of Life Sciences, Tianjin University, Tianjin 300072, China;
| | - Alyssa D. Merting
- Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, GA 30912, USA; (J.D.K.); (D.B.P.); (A.D.M.); (D.Y.); (P.S.R.)
- Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA
- Charlie Norwood VA Medical Center, Augusta, GA 30904, USA
| | - Dafeng Yang
- Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, GA 30912, USA; (J.D.K.); (D.B.P.); (A.D.M.); (D.Y.); (P.S.R.)
- Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA
- Charlie Norwood VA Medical Center, Augusta, GA 30904, USA
| | - Priscilla S. Redd
- Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, GA 30912, USA; (J.D.K.); (D.B.P.); (A.D.M.); (D.Y.); (P.S.R.)
- Chemedimmune Inc., Augusta, GA 30912, USA
| | - Kebin Liu
- Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, GA 30912, USA; (J.D.K.); (D.B.P.); (A.D.M.); (D.Y.); (P.S.R.)
- Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA
- Charlie Norwood VA Medical Center, Augusta, GA 30904, USA
- Correspondence: ; Tel.: +1-706-721-9483
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Dennison L, Mohan AA, Yarchoan M. Tumor and Systemic Immunomodulatory Effects of MEK Inhibition. Curr Oncol Rep 2021; 23:23. [PMID: 33547983 PMCID: PMC8028056 DOI: 10.1007/s11912-020-01008-4] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/17/2020] [Indexed: 12/13/2022]
Abstract
PURPOSE OF REVIEW Mitogen-activated protein kinase (MAPK) kinase (MEK) is an integral component of the RAS signaling pathway, one of the most frequently mutated pathways in cancer biology. MEK inhibitors were initially developed to directly target oncogenic signaling, but are recognized to have pleiotropic effects on both tumor cells and lymphocytes. Here, we review the preclinical and clinical evidence that MEK inhibition is immunomodulatory and discuss the potential rationale for combining MEK inhibitors with systemic immunotherapies. RECENT FINDINGS MEK inhibition may modulate the tumor microenvironment (TME) through direct effects on both tumor cells and immune cells. Despite encouraging evidence that MEK inhibition can reprogram the tumor microenvironment (TME) and augment anti-tumor immunity regardless of KRAS/BRAF status, recent clinical outcome studies combining MEK inhibition with systemic immunotherapy have yielded mixed results. The combination of MEK inhibitors plus systemic immunotherapies has been tolerable, but has thus far failed to demonstrate clear evidence of synergistic clinical activity. These results underscore the need to understand the appropriate therapeutic context for this combination. MEK inhibitors have the potential to inhibit oncogenic signaling and reprogram the tumor immune microenvironment, representing an attractive therapy to combine with systemic immunotherapies. Ongoing preclinical and clinical studies will further clarify the immunomodulatory effects of MEK inhibitors to inform the design of rational therapeutic combinations.
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Affiliation(s)
- Lauren Dennison
- The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, 21231, USA
| | - Aditya A Mohan
- The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, 21231, USA
| | - Mark Yarchoan
- The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, 21231, USA.
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26
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Aramini B, Masciale V, Grisendi G, Banchelli F, D'Amico R, Maiorana A, Morandi U, Dominici M, Haider KH. Cancer stem cells and macrophages: molecular connections and future perspectives against cancer. Oncotarget 2021; 12:230-250. [PMID: 33613850 PMCID: PMC7869576 DOI: 10.18632/oncotarget.27870] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Accepted: 01/07/2021] [Indexed: 12/12/2022] Open
Abstract
Cancer stem cells (CSCs) have been considered the key drivers of cancer initiation and progression due to their unlimited self-renewal capacity and their ability to induce tumor formation. Macrophages, particularly tumor-associated macrophages (TAMs), establish a tumor microenvironment to protect and induce CSCs development and dissemination. Many studies in the past decade have been performed to understand the molecular mediators of CSCs and TAMs, and several studies have elucidated the complex crosstalk that occurs between these two cell types. The aim of this review is to define the complex crosstalk between these two cell types and to highlight potential future anti-cancer strategies.
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Affiliation(s)
- Beatrice Aramini
- Division of Thoracic Surgery, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Valentina Masciale
- Division of Thoracic Surgery, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Giulia Grisendi
- Division of Oncology, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Federico Banchelli
- Center of Statistic, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Roberto D'Amico
- Center of Statistic, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Antonino Maiorana
- Institute of Pathology, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Uliano Morandi
- Division of Thoracic Surgery, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Massimo Dominici
- Division of Oncology, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy
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27
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Stromal Protein-Mediated Immune Regulation in Digestive Cancers. Cancers (Basel) 2021; 13:cancers13010146. [PMID: 33466303 PMCID: PMC7795083 DOI: 10.3390/cancers13010146] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 12/21/2020] [Accepted: 12/24/2020] [Indexed: 12/13/2022] Open
Abstract
Simple Summary Solid cancers are surrounded by a network of non-cancerous cells comprising different cell types, including fibroblasts, and acellular protein structures. This entire network is called the tumor microenvironment (TME) and it provides a physical barrier to the tumor shielding it from infiltrating immune cells, such as lymphocytes, or therapeutic agents. In addition, the TME has been shown to dampen efficient immune responses of infiltrated immune cells, which are key in eliminating cancer cells from the organism. In this review, we will discuss how TME proteins in particular are involved in this dampening effect, known as immunosuppression. We will focus on three different types of digestive cancers: pancreatic cancer, colorectal cancer, and gastric cancer. Moreover, we will discuss current therapeutic approaches using TME proteins as targets to reverse their immunosuppressive effects. Abstract The stromal tumor microenvironment (TME) consists of immune cells, vascular and neural structures, cancer-associated fibroblasts (CAFs), as well as extracellular matrix (ECM), and favors immune escape mechanisms promoting the initiation and progression of digestive cancers. Numerous ECM proteins released by stromal and tumor cells are crucial in providing physical rigidity to the TME, though they are also key regulators of the immune response against cancer cells by interacting directly with immune cells or engaging with immune regulatory molecules. Here, we discuss current knowledge of stromal proteins in digestive cancers including pancreatic cancer, colorectal cancer, and gastric cancer, focusing on their functions in inhibiting tumor immunity and enabling drug resistance. Moreover, we will discuss the implication of stromal proteins as therapeutic targets to unleash efficient immunotherapy-based treatments.
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28
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Butti R, Kumar TVS, Nimma R, Banerjee P, Kundu IG, Kundu GC. Osteopontin Signaling in Shaping Tumor Microenvironment Conducive to Malignant Progression. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1329:419-441. [PMID: 34664250 DOI: 10.1007/978-3-030-73119-9_20] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Context-dependent reciprocal crosstalk between cancer and surrounding stromal cells in the tumor microenvironment is imperative for the regulation of various hallmarks of cancer. A myriad of growth factors, chemokines, and their receptors aids in the interaction between cancer cells and tumor microenvironmental components. Osteopontin is a chemokine-like protein, overexpressed in different types of cancers. Osteopontin plays a crucial role in orchestrating dialogue between cancer and stromal cells. Osteopontin, in tumor microenvironment, is produced in tumor as well as stromal cells. Tumor-derived osteopontin regulates proliferation, migration, activation, and differentiation of different types of stromal cells. Osteopontin secreted from tumor cells regulates the generation of cancer-associated fibroblasts from resident fibroblasts and mesenchymal stem cells. Osteopontin also shapes immunosuppressive tumor microenvironment by controlling regulatory T cells and tumor-associated macrophages. Moreover, secretion of osteopontin from tumor stroma has been highly documented. Stromal cell-derived osteopontin induces epithelial-to-mesenchymal transition, angiogenesis, metastasis, and cancer stem cell enrichment. Tumor- or stroma-derived osteopontin mainly functions through binding with cell surface receptors, integrins and CD44, and activates downstream signaling events like PI-3 kinase/Akt and MAPK pathways. Presumably, disrupting the communication between the tumor cells and surrounding microenvironment by targeting osteopontin-regulated signaling using specific antibodies, small-molecule inhibitors, and chemotherapeutic agents is a novel therapeutic strategy for clinical management of cancer.
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Affiliation(s)
- Ramesh Butti
- Laboratory of Tumor Biology, Angiogenesis and Nanomedicine Research, National Centre for Cell Science, SP Pune University Campus, Pune, India
| | - Totakura V S Kumar
- Laboratory of Tumor Biology, Angiogenesis and Nanomedicine Research, National Centre for Cell Science, SP Pune University Campus, Pune, India
| | - Ramakrishna Nimma
- Laboratory of Tumor Biology, Angiogenesis and Nanomedicine Research, National Centre for Cell Science, SP Pune University Campus, Pune, India
| | - Pinaki Banerjee
- Laboratory of Tumor Biology, Angiogenesis and Nanomedicine Research, National Centre for Cell Science, SP Pune University Campus, Pune, India
| | - Ipsita G Kundu
- Department of Pharmacy, Birla Institute of Technology and Science, Pilani, Hyderabad Campus, Institute of Eminence, Hyderabad, India
| | - Gopal C Kundu
- Laboratory of Tumor Biology, Angiogenesis and Nanomedicine Research, National Centre for Cell Science, SP Pune University Campus, Pune, India. .,School of Biotechnology and Kalinga Institute of Medical Sciences (KIMS), KIIT Deemed to be University, Institute of Eminence, Bhubaneswar, India.
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Calcitriol in the Presence of Conditioned Media from Metastatic Breast Cancer Cells Enhances Ex Vivo Polarization of M2 Alternative Murine Bone Marrow-Derived Macrophages. Cancers (Basel) 2020; 12:cancers12113485. [PMID: 33238581 PMCID: PMC7700498 DOI: 10.3390/cancers12113485] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Revised: 11/17/2020] [Accepted: 11/19/2020] [Indexed: 12/31/2022] Open
Abstract
Simple Summary In this study, we stimulated bone marrow-derived macrophages to M0, M1, and M2 subtypes, with or without calcitriol, or with or without 4T1 (metastatic), 67NR (non-metastatic), and Eph4-Ev (normal) cell culture supernatants (CMs) to test their effect on polarization. We showed that calcitriol increased the expression of Cd206 and Spp1 mRNA and CD36, CCL2, and arginase levels for M2 macrophages and decreased Cd80 and Spp1 mRNA and IL-1, IL-6, OPN, and iNOS for M1 macrophages. 4T1 CM influenced the expression of the studied genes and proteins to a greater extent than 67NR and Eph4; the strongest effect was noted for M2 macrophages. We show that calcitriol and 4T1 CM enhance the polarization of M2 macrophages and M2 macrophages differentiated with calcitriol-stimulated migration of 4T1 and 67NR cells. We indicate that the immunosuppressive properties of calcitriol may unfavorably affect the tumor microenvironment, and supplementation with vitamin D in oncological patients may not always bring benefits. Abstract In this study, we differentiated murine bone marrow-derived macrophages (BMDMs) into M0, M1, and M2 in the presence or absence of calcitriol. Real-time PCR analysis of gene expression, FACS analysis of surface markers, and chemokine/cytokine production assays were performed. In addition, the effect of the conditioned media (CM) from murine breast cancer 4T1 (metastatic) and 67NR (non-metastatic) and Eph4-Ev (normal) cells with and without calcitriol on the polarization of M1/M2 cells was determined. We found that calcitriol enhanced the differentiation of M2 macrophages, which was manifested by increased expression of Cd206 and Spp1 mRNA and CD36, Arg, and CCL2 in M2 BMDMs and by decreased expression of Cd80 and Spp1 mRNA and IL-1, IL-6, OPN, and iNOS in M1 BMDMs. 4T1 CM showed a higher effect on the gene and protein expression in macrophages than 67NR and Eph4-Ev, with the greatest effect observed on M2 macrophages which increased their differentiation and properties characteristic of alternative macrophages. Moreover, M2 macrophages differentiated with calcitriol-stimulated migration of 4T1 and 67NR cells through fibronectin and collagen type IV, respectively. Overall, our results indicated that vitamin D supplementation may not always be beneficial, especially in relation to cancers causing excessive, pathological activation of the immune system.
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Osteopontin: A Key Regulator of Tumor Progression and Immunomodulation. Cancers (Basel) 2020; 12:cancers12113379. [PMID: 33203146 PMCID: PMC7698217 DOI: 10.3390/cancers12113379] [Citation(s) in RCA: 83] [Impact Index Per Article: 16.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Revised: 11/09/2020] [Accepted: 11/10/2020] [Indexed: 02/06/2023] Open
Abstract
Simple Summary Anti-PD-1/PD-L1 and anti-CTLA-4-based immune checkpoint blockade (ICB) immunotherapy have recently emerged as a breakthrough in human cancer treatment. Durable efficacy has been achieved in many types of human cancers. However, not all human cancers respond to current ICB immunotherapy and only a fraction of the responsive cancers exhibit efficacy. Osteopontin (OPN) expression is highly elevated in human cancers and functions as a tumor promoter. Emerging data suggest that OPN may also regulate immune cell function in the tumor microenvironment. This review aims at OPN function in human cancer progression and new findings of OPN as a new immune checkpoint. We propose that OPN compensates PD-L1 function to promote tumor immune evasion, which may underlie human cancer non-response to current ICB immunotherapy. Abstract OPN is a multifunctional phosphoglycoprotein expressed in a wide range of cells, including osteoclasts, osteoblasts, neurons, epithelial cells, T, B, NK, NK T, myeloid, and innate lymphoid cells. OPN plays an important role in diverse biological processes and is implicated in multiple diseases such as cardiovascular, diabetes, kidney, proinflammatory, fibrosis, nephrolithiasis, wound healing, and cancer. In cancer patients, overexpressed OPN is often detected in the tumor microenvironment and elevated serum OPN level is correlated with poor prognosis. Initially identified in activated T cells and termed as early T cell activation gene, OPN links innate cells to adaptive cells in immune response to infection and cancer. Recent single cell RNA sequencing revealed that OPN is primarily expressed in tumor cells and tumor-infiltrating myeloid cells in human cancer patients. Emerging experimental data reveal a key role of OPN is tumor immune evasion through regulating macrophage polarization, recruitment, and inhibition of T cell activation in the tumor microenvironment. Therefore, in addition to its well-established direct tumor cell promotion function, OPN also acts as an immune checkpoint to negatively regulate T cell activation. The OPN protein level is highly elevated in peripheral blood of human cancer patients. OPN blockade immunotherapy with OPN neutralization monoclonal antibodies (mAbs) thus represents an attractive approach in human cancer immunotherapy.
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Tang X, Sui D, Liu M, Zhang H, Liu M, Wang S, Zhao D, Sun W, Liu M, Luo X, Lai X, Liu X, Deng Y, Song Y. Targeted delivery of zoledronic acid through the sialic acid - Siglec axis for killing and reversal of M2 phenotypic tumor-associated macrophages – A promising cancer immunotherapy. Int J Pharm 2020; 590:119929. [DOI: 10.1016/j.ijpharm.2020.119929] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Revised: 09/15/2020] [Accepted: 09/26/2020] [Indexed: 12/19/2022]
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Baj J, Brzozowska K, Forma A, Maani A, Sitarz E, Portincasa P. Immunological Aspects of the Tumor Microenvironment and Epithelial-Mesenchymal Transition in Gastric Carcinogenesis. Int J Mol Sci 2020; 21:2544. [PMID: 32268527 PMCID: PMC7177728 DOI: 10.3390/ijms21072544] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2020] [Revised: 03/30/2020] [Accepted: 04/02/2020] [Indexed: 12/11/2022] Open
Abstract
Infection with Helicobacter pylori, a Gram-negative, microaerophilic pathogen often results in gastric cancer in a subset of affected individuals. This explains why H. pylori is the only bacterium classified as a class I carcinogen by the World Health Organization. Several studies have pinpointed mechanisms by which H. pylori alters signaling pathways in the host cell to cause diseases. In this article, the authors have reviewed 234 studies conducted over a span of 18 years (2002-2020). The studies investigated the various mechanisms associated with gastric cancer induction. For the past 1.5 years, researchers have discovered new mechanisms contributing to gastric cancer linked to H. pylori etiology. Alongside alteration of the host signaling pathways using oncogenic CagA pathways, H. pylori induce DNA damage in the host and alter the methylation of DNA as a means of perturbing downstream signaling. Also, with H. pylori, several pathways in the host cell are activated, resulting in epithelial-to-mesenchymal transition (EMT), together with the induction of cell proliferation and survival. Studies have shown that H. pylori enhances gastric carcinogenesis via a multifactorial approach. What is intriguing is that most of the targeted mechanisms and pathways appear common with various forms of cancer.
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Affiliation(s)
- Jacek Baj
- Chair and Department of Anatomy, Medical University of Lublin, 20-090 Lublin, Poland; (A.F.); (A.M.)
| | - Karolina Brzozowska
- Chair and Department of Forensic Medicine, Medical University of Lublin, 20-090 Lublin, Poland;
| | - Alicja Forma
- Chair and Department of Anatomy, Medical University of Lublin, 20-090 Lublin, Poland; (A.F.); (A.M.)
| | - Amr Maani
- Chair and Department of Anatomy, Medical University of Lublin, 20-090 Lublin, Poland; (A.F.); (A.M.)
| | - Elżbieta Sitarz
- Chair and 1st Department of Psychiatry, Psychotherapy and Early Intervention, Medical University of Lublin, Gluska Street 1, 20-439 Lublin, Poland;
| | - Piero Portincasa
- Clinica Medica “A. Murri”, Department of Biomedical Sciences and Human Oncology, University of Bari Aldo Moro, 70124 Bari, Italy;
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Rocha GA, de Melo FF, Cabral MMDA, de Brito BB, da Silva FAF, Queiroz DMM. Interleukin-27 is abrogated in gastric cancer, but highly expressed in other Helicobacter pylori-associated gastroduodenal diseases. Helicobacter 2020; 25:e12667. [PMID: 31702083 DOI: 10.1111/hel.12667] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2019] [Revised: 10/01/2019] [Accepted: 10/03/2019] [Indexed: 12/11/2022]
Abstract
BACKGROUND IL-27 has dual roles in the immune response either stimulating Th1 or inhibiting Th17 cells. Because there is a particular link of IL-23/Th17 axis in the development of cancer and IL-27 has been considered a potential treatment for cancer, we evaluated the gastric and serum concentrations of IL-27 in two mutually exclusive Helicobacter pylori-associated diseases, gastric cancer (GC) and duodenal ulcer (DU). MATERIAL AND METHODS We prospectively studied 110 H pylori-positive patients and 40 healthy blood donors. Serum and gastric concentrations of IL-27 and cytokines of the Th1/Th17 cells were assessed by ELISA. RESULTS IL-27 was not detected in GC patients, but the cytokine concentration was very high in the patients with DU. IL-27 was also detected in the gastritis patients and in the H pylori-positive blood donors. IL27RA mRNA expression in peripheral blood mononuclear cells, evaluated by rt-PCR, was stimulated by H pylori strains. The cytokine concentration positively correlated with the Th1 and negatively with Th17 cell representative cytokine levels. Gastric IL-27 concentrations were positively correlated with increased degree of mononuclear and polymorphonuclear cells on the antral gastric mucosa of DU patients in consonance with the DU gastritis pattern. IL-12p70 and IFN-γ gastric concentrations were significantly higher in DU than in GC. Conversely, gastric concentrations of Th17 cell-associated cytokines (IL-1β, IL-6, IL-17A, IL-23, and TGF-β) were significantly higher in GC than in DU patients. CONCLUSION Although H pylori infection is able to elicit IL-27 and IL-27Rα secretion, DU and GC have diametrically opposed cytokine patterns.
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Affiliation(s)
- Gifone A Rocha
- Laboratory of Research in Bacteriology, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Fabrício F de Melo
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Brazil
| | - Mônica M D A Cabral
- Department of Pathology, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Breno B de Brito
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Brazil
| | | | - Dulciene M M Queiroz
- Laboratory of Research in Bacteriology, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
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Jayasingam SD, Citartan M, Thang TH, Mat Zin AA, Ang KC, Ch'ng ES. Evaluating the Polarization of Tumor-Associated Macrophages Into M1 and M2 Phenotypes in Human Cancer Tissue: Technicalities and Challenges in Routine Clinical Practice. Front Oncol 2020; 9:1512. [PMID: 32039007 PMCID: PMC6992653 DOI: 10.3389/fonc.2019.01512] [Citation(s) in RCA: 421] [Impact Index Per Article: 84.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2019] [Accepted: 12/16/2019] [Indexed: 12/15/2022] Open
Abstract
Tumor-associated macrophages (TAMs) as immune cells within the tumor microenvironment have gained much interests as basic science regarding their roles in tumor progression unfolds. Better understanding of their polarization into pro-tumoral phenotype to promote tumor growth, tumor angiogenesis, immune evasion, and tumor metastasis has prompted various studies to investigate their clinical significance as a biomarker of predictive and prognostic value across different cancer types. Yet, the methodologies to investigate the polarization phenomena in solid tumor tissue vary. Nonetheless, quantifying the ratio of M1 to M2 TAMs has emerged to be a prevailing parameter to evaluate this polarization phenomena for clinical application. This mini-review focuses on recent studies exploring clinical significance of M1/M2 TAM ratio in human cancer tissue and critically evaluates the technicalities and challenges in quantifying this parameter for routine clinical practice. Immunohistochemistry appears to be the preferred methodology for M1/M2 TAM evaluation as it is readily available in clinical laboratories, albeit with certain limitations. Recommendations are made to standardize the quantification of TAMs for better transition into clinical practice and for better comparison among studies in various populations of patients and cancer types.
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Affiliation(s)
- Sharmilla Devi Jayasingam
- Oncological and Radiological Sciences Cluster, Advanced Medical and Dental Institute (AMDI), Universiti Sains Malaysia, Kepala Batas, Malaysia
| | - Marimuthu Citartan
- Infectious Disease Cluster, Advanced Medical and Dental Institute (AMDI), Universiti Sains Malaysia, Kepala Batas, Malaysia
| | - Thean Hock Thang
- Infectious Disease Cluster, Advanced Medical and Dental Institute (AMDI), Universiti Sains Malaysia, Kepala Batas, Malaysia
- Faculty of Applied Sciences, AIMST University, Kedah, Malaysia
| | - Anani Aila Mat Zin
- Department of Pathology, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, Malaysia
| | - Kai Cheen Ang
- Infectious Disease Cluster, Advanced Medical and Dental Institute (AMDI), Universiti Sains Malaysia, Kepala Batas, Malaysia
| | - Ewe Seng Ch'ng
- Oncological and Radiological Sciences Cluster, Advanced Medical and Dental Institute (AMDI), Universiti Sains Malaysia, Kepala Batas, Malaysia
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Zhuang H, Dai X, Zhang X, Mao Z, Huang H. Sophoridine suppresses macrophage-mediated immunosuppression through TLR4/IRF3 pathway and subsequently upregulates CD8 + T cytotoxic function against gastric cancer. Biomed Pharmacother 2019; 121:109636. [PMID: 31733580 DOI: 10.1016/j.biopha.2019.109636] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2019] [Revised: 11/01/2019] [Accepted: 11/01/2019] [Indexed: 01/19/2023] Open
Abstract
Gastric cancer is one of the most common and deadly neoplasms with limited effective treatments. The emergence of the immunotherapy has brought great expectations for cancer patients. Sophoridine is extracted from the seeds of sophora alopecuroides and has various pharmacological actions including anti-tumor, anti-inflammatory, anti- arrhythmia and anti-virus. However, the effect of Sophoridine on gastric cancer microenvironment immunity and its underling mechanism remains poorly known. This study was aimed to investigate the effect of Sophoridine on the polarization status of gastric tumor-associated macrophages (TAMs) and its underlying mechanism. We isolated primary bone marrow-derived macrophages (BMDMs) and primary CD8+ T cells to perform coculture assay. Sophoridine educated TAMs polarize to M1-TAMs and suppressed M2-TAMs polarization through TLR4/IRF3 axis. Sophoridine-treated TAMs exhibited stronger pro-inflammatory function through upregulation the expression of INOS, IFN-β and IL-12α, and downregulation the expression of Arg-1, CD206 and IL-10. Sophoridine -primed TAMs increased the proliferation and cytotoxic function of CD8+ T by upregulating the expression of Granzyme-B, TNF-α and Perforin, and downregulated the expression of CD8+ T cells function exhaustion markers PD-1, Tim-3 and Lag-3. Furthermore, Sophoridine inhibited the migration ability of macrophage by decrease the CCR2 expression. Thus, Sophoridine acted on macrophages and CD8+ T cells to reshape gastric cancer immune microenvironment. Our studies provided preclinical basis for clinical application of Sophoridine.
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Affiliation(s)
- Haiwen Zhuang
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou 215006, China; Division of Gastrointestinal Surgery, Department of General Surgery, Huai'an Second People's Hospital, The Affiliated Huai'an Hospital of Xuzhou Medical University, Huai'an, China
| | - Xudong Dai
- Department of General Surgery, Lianshui County People's Hospital, Lianshui people's hospital affiliated to kangda college of Nanjing medical university, Huai'an, China
| | - Xiaoyu Zhang
- Division of Gastrointestinal Surgery, Department of General Surgery, Huai'an Second People's Hospital, The Affiliated Huai'an Hospital of Xuzhou Medical University, Huai'an, China
| | - Zhongqi Mao
- Department of General Surgery, The First Affiliated Hospital of Soochow University, 899 Pinghai Road, Suzhou 215006, China.
| | - Haijin Huang
- Department of General Surgery, Hongze District People's Hospital, Hongze, China.
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Sharifi L, Nowroozi MR, Amini E, Arami MK, Ayati M, Mohsenzadegan M. A review on the role of M2 macrophages in bladder cancer; pathophysiology and targeting. Int Immunopharmacol 2019; 76:105880. [PMID: 31522016 DOI: 10.1016/j.intimp.2019.105880] [Citation(s) in RCA: 58] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2019] [Revised: 08/16/2019] [Accepted: 09/03/2019] [Indexed: 12/13/2022]
Abstract
Tumor-associated macrophages (TAMs) which are often referred to as immunosuppressive cells (M2 macrophage), constitute a subset of tumor microenvironment cells and affect tumor progression in solid tumors. Recently, these cells have gained remarkable importance as therapeutic candidates for solid tumors. In bladder cancer, major studies have focused on evaluating TAMs in response to Bacillus Calmette-Guerin (BCG) therapy. M2 macrophages may directly impact the BCG-induced immune responses against tumor in bladder cancer. They are the main inhibitors of the tumor microenvironment that promotes growth and metastasis of the tumor. However, the clinical significance of M2 macrophages in bladder cancer is controversial. In this review, we will discuss the clinical significance of M2 macrophages in prognosis of bladder cancer as well as worth of their potential targeting in bladder cancer treatment. In the following, we will introduce important factors resulting in M2 macrophage promotion and also experimental therapeutic agents that may cause the inhibition of bladder cancer tumor growth.
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Affiliation(s)
- Laleh Sharifi
- Uro-Oncology Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Erfan Amini
- Uro-Oncology Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Masoumeh Kourosh Arami
- Department of Basic Sciences, Faculty of Allied Medical Sciences, Iran University of Medical Sciences, Tehran, Iran
| | - Mohsen Ayati
- Uro-Oncology Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Monireh Mohsenzadegan
- Department of Medical Laboratory Science, Faculty of Allied Medical Sciences, Iran University of Medical Sciences, Tehran, Iran.
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Qiu Q, Li C, Song Y, Shi T, Luo X, Zhang H, Hu L, Yan X, Zheng H, Liu M, Liu M, Liu M, Yang S, Liu X, Chen G, Deng Y. Targeted delivery of ibrutinib to tumor-associated macrophages by sialic acid-stearic acid conjugate modified nanocomplexes for cancer immunotherapy. Acta Biomater 2019; 92:184-195. [PMID: 31108259 DOI: 10.1016/j.actbio.2019.05.030] [Citation(s) in RCA: 64] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2018] [Revised: 05/02/2019] [Accepted: 05/10/2019] [Indexed: 12/12/2022]
Abstract
Ibrutinib (IBR), an irreversible Bruton's tyrosine kinase (BTK) inhibitor, is expected to be a potent therapeutic modality, given that BTK is overexpressed in tumor-associated macrophages (TAMs) and participates in promoting tumor progression, angiogenesis, and immunosuppression. However, rapid clearance in vivo and low tumor accumulation have rendered effective uptake of IBR by TAMs challenge. Herein, we designed and synthesized a sialic acid (SA)-stearic acid conjugate modified on the surface of nanocomplexes to encapsulate IBR (SA/IBR/EPG) for targeted immunotherapy. Amphiphilic egg phosphatidylglycerol (EPG) structure and strong IBR-EPG interactions render these nanocomplexes high IBR loading capacity, prolonged blood circulation, and optimal particle sizes (∼30 nm), which can effectively deliver IBR to the tumor, followed by subsequent internalization of IBR by TAMs through SA-mediated active targeting. In vitro and in vivo tests showed that the prepared SA/IBR/EPG nanocomplexes could preferentially accumulate in TAMs and exert potent antitumor activity. Immunofluorescence staining analysis further confirmed that SA/IBR/EPG remarkably inhibited angiogenesis and tumorigenic cytokines released by TAM and eventually suppressed tumor progression, without eliciting any unwanted effect. Thus, SA-decorated IBR nanocomplexes present a promising strategy for cancer immunotherapy. STATEMENT OF SIGNIFICANCE: Ibrutinib (IBR), an irreversible Bruton's tyrosine kinase (BTK) inhibitor, is expected to be a potent therapeutic modality, given that BTK is overexpressed in tumor-associated macrophages (TAMs) and participates in promoting tumor progression, angiogenesis, and immunosuppression. However, rapid clearance in vivo and low tumor accumulation have rendered effective uptake of IBR by TAMs challenge. Herein, we designed and synthesized a sialic acid (SA)-stearic acid conjugate modified on the surface of nanocomplexes to encapsulate IBR (SA/IBR/EPG) for targeted delivery of IBR to TAMs. The developed SA/IBR/EPG nanocomplexes exhibited high efficiency in targeting TAMs and inhibiting BTK activation, consequently inhibiting Th2 tumorigenic cytokine release, reducing angiogenesis, and suppressing tumor growth. These results implied that the SA/IBR/EPG nanocomplex could be a promising strategy for TAM-targeting immunotherapy with minimal systemic side effects.
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Liu Q, Jiang S, Liu B, Yu Y, Zhao ZA, Wang C, Liu Z, Chen G, Chen H. Take Immune Cells Back on Track: Glycopolymer-Engineered Tumor Cells for Triggering Immune Response. ACS Macro Lett 2019; 8:337-344. [PMID: 35651134 DOI: 10.1021/acsmacrolett.9b00046] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The "self-homing" of cancer cells to primary or metastatic tumor sites indicates that they could serve as vehicles for self-targeted cancer therapy; this suggests a promising method for treating end-stage cancer. Inspired by this, we propose that engineering cancer cells to carry efficient "coup" molecules for in situ activation of immune cells in or near tumor sites to attack tumors is a promising strategy for cancer therapy. Therefore, herein we explored the potential of engineered tumor cells to enhance their anticancer activity by stimulating immune cells. We armed tumor cell surfaces with specific glycopolymer-ligands that bind to lectins on macrophages or dendritic cells by combining HaloTag protein (HTP) fusion technique with reversible addition-fragmentation chain transfer (RAFT) polymerization. We demonstrated that two synthetic well-defined glycopolymers containing, respectively, N-acetylglucosamine and N-acetylmannosamine units, were introduced and stably presented on the cell surfaces via the stable covalent binding of chloroalkane-terminated polymers with membrane-bound HTP. Furthermore, it was shown that the glycopolymer-engineered HeLa cells with HTP anchors increased expression of the typical marker for M1-type macrophages (CD86) and upregulated secretion of pro-inflammatory cytokines (IL-12p70, TNF-α, and iNOS), thereby accelerating HeLa cell lysis. The maturation of dendritic cells was also promoted. This study demonstrates the strong potential of glycopolymer-engineered tumor cells in cancer immunotherapy.
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Affiliation(s)
- Qi Liu
- State and Local Joint Engineering Laboratory for Novel Functional Polymeric Materials, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, 199 Ren’ai Road, Suzhou 215123, People’s Republic of China
- Center for Soft Condensed Matter Physics and Interdisciplinary Research, Soochow University, Suzhou 215006, People’s Republic of China
| | - Shuaibing Jiang
- State and Local Joint Engineering Laboratory for Novel Functional Polymeric Materials, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, 199 Ren’ai Road, Suzhou 215123, People’s Republic of China
| | - Bing Liu
- State and Local Joint Engineering Laboratory for Novel Functional Polymeric Materials, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, 199 Ren’ai Road, Suzhou 215123, People’s Republic of China
| | - You Yu
- Institute for Cardiovascular Science and Department of Cardiovascular Surgery of the First Affiliated Hospital, Soochow University, Suzhou 215000, People’s Republic of China
| | - Zhen-Ao Zhao
- Institute for Cardiovascular Science and Department of Cardiovascular Surgery of the First Affiliated Hospital, Soochow University, Suzhou 215000, People’s Republic of China
| | - Chao Wang
- Institute of Functional Nano and Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Soochow University, Suzhou, Jiangsu 215123, People’s Republic of China
| | - Zhuang Liu
- Institute of Functional Nano and Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Soochow University, Suzhou, Jiangsu 215123, People’s Republic of China
| | - Gaojian Chen
- State and Local Joint Engineering Laboratory for Novel Functional Polymeric Materials, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, 199 Ren’ai Road, Suzhou 215123, People’s Republic of China
- Center for Soft Condensed Matter Physics and Interdisciplinary Research, Soochow University, Suzhou 215006, People’s Republic of China
| | - Hong Chen
- State and Local Joint Engineering Laboratory for Novel Functional Polymeric Materials, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, 199 Ren’ai Road, Suzhou 215123, People’s Republic of China
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Umansky V, Adema GJ, Baran J, Brandau S, Van Ginderachter JA, Hu X, Jablonska J, Mojsilovic S, Papadaki HA, Pico de Coaña Y, Santegoets KCM, Santibanez JF, Serre K, Si Y, Sieminska I, Velegraki M, Fridlender ZG. Interactions among myeloid regulatory cells in cancer. Cancer Immunol Immunother 2019; 68:645-660. [PMID: 30003321 PMCID: PMC11028297 DOI: 10.1007/s00262-018-2200-6] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2018] [Accepted: 07/04/2018] [Indexed: 12/14/2022]
Abstract
Mounting evidence has accumulated on the critical role of the different myeloid cells in the regulation of the cancerous process, and in particular in the modulation of the immune reaction to cancer. Myeloid cells are a major component of host cells infiltrating tumors, interacting with each other, with tumor cells and other stromal cells, and demonstrating a prominent plasticity. We describe here various myeloid regulatory cells (MRCs) in mice and human as well as their relevant therapeutic targets. We first address the role of the monocytes and macrophages that can contribute to angiogenesis, immunosuppression and metastatic dissemination. Next, we discuss the differential role of neutrophil subsets in tumor development, enhancing the dual and sometimes contradicting role of these cells. A heterogeneous population of immature myeloid cells, MDSCs, was shown to be generated and accumulated during tumor progression as well as to be an important player in cancer-related immune suppression. Lastly, we discuss the role of myeloid DCs, which can either contribute to effective anti-tumor responses or play a more regulatory role. We believe that MRCs play a critical role in cancer-related immune regulation and suggest that future anti-cancer therapies will focus on these abundant cells.
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Affiliation(s)
- Viktor Umansky
- Skin Cancer Unit (G300), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.
- Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht Karl University of Heidelberg, Mannheim, Germany.
| | - Gosse J Adema
- Radiotherapy and OncoImmunology Laboratory, Department of Radiation Oncology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands
| | - Jaroslaw Baran
- Department of Clinical Immunology, Institute of Paediatrics, Jagiellonian University Medical College, Kraków, Poland
| | - Sven Brandau
- Department of Otorhinolaryngology, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Jo A Van Ginderachter
- Lab of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium
- Myeloid Cell Immunology Lab, VIB Center for Inflammation Research, Brussels, Belgium
| | - Xiaoying Hu
- Skin Cancer Unit (G300), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany
- Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht Karl University of Heidelberg, Mannheim, Germany
| | - Jadwiga Jablonska
- Department of Otorhinolaryngology, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Slavko Mojsilovic
- Laboratory for Experimental Hematology and Stem Cells, Institute for Medical Research, University of Belgrade, Belgrade, Republic of Serbia
| | - Helen A Papadaki
- Department of Hematology, School of Medicine, University of Crete, Heraklion, Greece
| | - Yago Pico de Coaña
- Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden
| | - Kim C M Santegoets
- Radiotherapy and OncoImmunology Laboratory, Department of Radiation Oncology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands
| | - Juan F Santibanez
- Department of Molecular Oncology, Institute for Medical Research, University of Belgrade, Belgrade, Republic of Serbia
- Centro Integrativo de Biología y Química Aplicada (CIBQA), Universidad Bernardo O'Higgins, Santiago, Chile
| | - Karine Serre
- Faculty of Medicine, Institute of Molecular Medicine (IMM)-João Lobo Antunes, University of Lisbon, Lisbon, Portugal
| | - Yu Si
- Department of Otorhinolaryngology, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Isabela Sieminska
- Department of Clinical Immunology, Institute of Paediatrics, Jagiellonian University Medical College, Kraków, Poland
| | - Maria Velegraki
- Department of Hematology, School of Medicine, University of Crete, Heraklion, Greece
| | - Zvi G Fridlender
- Institute of Pulmonary Medicine, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
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40
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Gimba E, Brum M, Nestal De Moraes G. Full-length osteopontin and its splice variants as modulators of chemoresistance and radioresistance (Review). Int J Oncol 2018; 54:420-430. [DOI: 10.3892/ijo.2018.4656] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2018] [Accepted: 10/25/2018] [Indexed: 11/06/2022] Open
Affiliation(s)
- Etel Gimba
- Program of Cellular and Molecular Oncobiology, National Cancer Institute, Rio de Janeiro 20231-050, Brazil
| | - Mariana Brum
- Program of Cellular and Molecular Oncobiology, National Cancer Institute, Rio de Janeiro 20231-050, Brazil
| | - Gabriela Nestal De Moraes
- Cellular and Molecular Hemato-Oncology Laboratory, Molecular Hemato-Oncology Program, National Cancer Institute, Rio de Janeiro 20230-130, Brazil
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41
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Räihä MR, Puolakkainen PA. Tumor-associated macrophages (TAMs) as biomarkers for gastric cancer: A review. Chronic Dis Transl Med 2018; 4:156-163. [PMID: 30276362 PMCID: PMC6160505 DOI: 10.1016/j.cdtm.2018.07.001] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2018] [Indexed: 02/07/2023] Open
Abstract
Gastric adenocarcinoma is one of the most common types of cancer worldwide, with an incidence of a million new cases annually. In addition to having a high mortality rate due to often delayed detection and its poor response to cancer therapy, it also spreads aggressively. Inflammation has been shown to play a role in carcinogenesis. Consequently, macrophages are important in phagocytosis, antigen presenting and producing cytokines and growth factors. As a response to microenvironmental signals, they may polarize into tumor resisting M1 or tumor promoting M2 macrophages. Recently, studies have indicated that M2-type macrophage resembling tumor-associated macrophages (TAMs) might be used as an independent prognostic factor for gastric cancer. This review will discuss the possible use of TAMs as prognostic tools for gastric cancer and whether they are suitable for use in clinical environment.
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Affiliation(s)
- Meri R Räihä
- Department of Surgery, Helsinki University Hospital and University of Helsinki, Helsinki 00014, Finland
| | - Pauli A Puolakkainen
- Department of Surgery, Helsinki University Hospital and University of Helsinki, Helsinki 00014, Finland
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42
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Chang J, Bhasin SS, Bielenberg DR, Sukhatme VP, Bhasin M, Huang S, Kieran MW, Panigrahy D. Chemotherapy-generated cell debris stimulates colon carcinoma tumor growth via osteopontin. FASEB J 2018; 33:114-125. [PMID: 29957058 PMCID: PMC6355061 DOI: 10.1096/fj.201800019rr] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
Colon cancer recurrence after therapy, such as 5-fluorouracil (5-FU), remains a challenge in the clinical setting. Chemotherapy reduces tumor burden by inducing cell death; however, the resulting dead tumor cells, or debris, may paradoxically stimulate angiogenesis, inflammation, and tumor growth. Here, we demonstrate that 5-FU–generated colon carcinoma debris stimulates the growth of a subthreshold inoculum of living tumor cells in subcutaneous and orthotopic models. Debris triggered the release of osteopontin (OPN) by tumor cells and host macrophages. Both coinjection of debris and systemic treatment with 5-FU increased plasma OPN levels in tumor-bearing mice. RNA expression levels of secreted phosphoprotein 1, the gene that encodes OPN, correlate with poor prognosis in patients with colorectal cancer and are elevated in chemotherapy-treated patients who experience tumor recurrence vs. no recurrence. Pharmacologic and genetic ablation of OPN inhibited debris-stimulated tumor growth. Systemic treatment with a combination of a neutralizing OPN antibody and 5-FU dramatically inhibited tumor growth. These results demonstrate a novel mechanism of tumor progression mediated by OPN released in response to chemotherapy-generated tumor cell debris. Neutralization of debris-stimulated OPN represents a potential therapeutic strategy to overcome the inherent limitation of cytotoxic therapies as a result of the generation of cell debris.—Chang, J., Bhasin, S. S., Bielenberg, D. R., Sukhatme, V. P., Bhasin, M., Huang, S., Kieran, M. W., Panigrahy, D. Chemotherapy-generated cell debris stimulates colon carcinoma tumor growth via osteopontin.
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Affiliation(s)
- Jaimie Chang
- Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.,Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.,Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Swati S Bhasin
- Division of Interdisciplinary Medicine and Biology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Diane R Bielenberg
- Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.,Department of Surgery, Harvard Medical School, Boston, Massachusetts, USA
| | - Vikas P Sukhatme
- Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.,Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Manoj Bhasin
- Division of Interdisciplinary Medicine and Biology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Sui Huang
- Institute for Systems Biology, Seattle, Washington, USA
| | - Mark W Kieran
- Division of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.,Department of Pediatric Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Dipak Panigrahy
- Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.,Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.,Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
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43
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Popēna I, Ābols A, Saulīte L, Pleiko K, Zandberga E, Jēkabsons K, Endzeliņš E, Llorente A, Linē A, Riekstiņa U. Effect of colorectal cancer-derived extracellular vesicles on the immunophenotype and cytokine secretion profile of monocytes and macrophages. Cell Commun Signal 2018; 16:17. [PMID: 29690889 PMCID: PMC5937830 DOI: 10.1186/s12964-018-0229-y] [Citation(s) in RCA: 81] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2017] [Accepted: 04/13/2018] [Indexed: 12/21/2022] Open
Abstract
Background Macrophages are one of the most important players in the tumor microenvironment. The polarization status of tumor associated macrophages into a pro-inflammatory type M1 or anti-inflammatory type M2 may influence cancer progression and patient survival. Extracellular vesicles (EVs) are membrane-bound vesicles containing different biomolecules that are involved in cell to cell signal transfer. Accumulating evidence suggests that cancer-derived EVs are taken up by macrophages and modulate their phenotype and cytokine profile. However, the interactions of cancer-derived EVs with monocytes and macrophages at various differentiation and polarization states are poorly understood. In the current study, we have analyzed the uptake and functional effects of primary (SW480) and metastatic (SW620) isogenic colorectal cancer (CRC) cell line-derived EVs on monocytes (M), inactive macrophages (M0) and M1 and M2 polarized macrophages. Methods THP-1 monocytes were differentiated into M0 macrophages by addition of phorbol-12-myristate-13-acetate. Then M0 macrophages were further polarized into M1 and M2 macrophages in the presence of LPS, IFN- γ, IL-4, and IL-13 respectively. Internalization of SW480 and SW620-derived EVs was analyzed by flow cytometry and fluorescence microscopy. Changes in monocyte and macrophage immunophenotype and secretory profile upon EV exposure were analyzed by flow cytometry, quantitative PCR and Luminex assays. Results THP-1 monocytes and M0 macrophages efficiently take up SW480 and SW620-derived EVs, and our results indicate that dynamin-dependent endocytic pathways may be implicated. Interestingly, SW480 and SW620-derived EVs increased CD14 expression in M0 macrophages whereas SW480-derived EVs decreased HLA-DR expression in M1 and M2 polarized macrophages. Moreover, SW480-derived EVs significantly increased CXCL10 expression in monocytes and M0 macrophages. In contrast, SW620-derived EVs induced secretion of IL-6, CXCL10, IL-23 and IL-10 in M0 macrophages. However, addition of CRC cell line-derived EVs together with LPS, IFN- γ (M1) and IL-4, IL-13 (M2) stimuli during macrophage polarization had no additional effect on cytokine expression in M1 and M2 macrophages. Conclusion Our results suggest that CRC cell line-derived EVs are internalized and reprogram the immunophenotype and secretory profile in monocytes and inactive macrophages inducing mixed M1 and M2 cytokine response. Although CRC EVs decreased HLA-DR expression in M1, M2 polarized macrophages, their effect on the secretory profile of M1 and M2 polarized macrophages was negligible. Electronic supplementary material The online version of this article (10.1186/s12964-018-0229-y) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Ineta Popēna
- Faculty of Medicine, University of Latvia, Raina blvd. 19, Riga, LV-1568, Latvia
| | - Artūrs Ābols
- Latvian Biomedical Research and Study Centre, Ratsupites iela 1, Riga, LV-1067, Latvia
| | - Līga Saulīte
- Faculty of Medicine, University of Latvia, Raina blvd. 19, Riga, LV-1568, Latvia
| | - Kārlis Pleiko
- Faculty of Medicine, University of Latvia, Raina blvd. 19, Riga, LV-1568, Latvia
| | - Elīna Zandberga
- Latvian Biomedical Research and Study Centre, Ratsupites iela 1, Riga, LV-1067, Latvia
| | - Kaspars Jēkabsons
- Faculty of Medicine, University of Latvia, Raina blvd. 19, Riga, LV-1568, Latvia
| | - Edgars Endzeliņš
- Latvian Biomedical Research and Study Centre, Ratsupites iela 1, Riga, LV-1067, Latvia
| | - Alicia Llorente
- Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital-The Norwegian Radium Hospital, 0379, Oslo, Norway
| | - Aija Linē
- Latvian Biomedical Research and Study Centre, Ratsupites iela 1, Riga, LV-1067, Latvia
| | - Una Riekstiņa
- Faculty of Medicine, University of Latvia, Raina blvd. 19, Riga, LV-1568, Latvia.
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Kobori T, Hamasaki S, Kitaura A, Yamazaki Y, Nishinaka T, Niwa A, Nakao S, Wake H, Mori S, Yoshino T, Nishibori M, Takahashi H. Interleukin-18 Amplifies Macrophage Polarization and Morphological Alteration, Leading to Excessive Angiogenesis. Front Immunol 2018; 9:334. [PMID: 29559970 PMCID: PMC5845536 DOI: 10.3389/fimmu.2018.00334] [Citation(s) in RCA: 52] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2017] [Accepted: 02/06/2018] [Indexed: 12/18/2022] Open
Abstract
M2 macrophage (Mφ) promotes pathologic angiogenesis through a release of pro-angiogenic mediators or the direct cell–cell interaction with endothelium in the micromilieu of several chronic inflammatory diseases, including rheumatoid arthritis and cancer, where interleukin (IL)-18 also contributes to excessive angiogenesis. However, the detailed mechanism remains unclear. The aim of this study is to investigate the mechanism by which M2 Mφs in the micromilieu containing IL-18 induce excessive angiogenesis in the in vitro experimental model using mouse Mφ-like cell line, RAW264.7 cells, and mouse endothelial cell line, b.End5 cells. We discovered that IL-18 acts synergistically with IL-10 to amplify the production of Mφ-derived mediators like osteopontin (OPN) and thrombin, yielding thrombin-cleaved form of OPN generation, which acts through integrins α4/α9, thereby augmenting M2 polarization of Mφ with characteristics of increasing surface CD163 expression in association with morphological alteration. Furthermore, the results of visualizing temporal behavior and morphological alteration of Mφs during angiogenesis demonstrated that M2-like Mφs induced excessive angiogenesis through the direct cell–cell interaction with endothelial cells, possibly mediated by CD163.
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Affiliation(s)
- Takuro Kobori
- Department of Pharmacology, Faculty of Medicine, Kindai University, Osaka-Sayama, Japan
| | - Shinichi Hamasaki
- Department of Anesthesiology, Faculty of Medicine, Kindai University, Osaka-Sayama, Japan
| | - Atsuhiro Kitaura
- Department of Anesthesiology, Faculty of Medicine, Kindai University, Osaka-Sayama, Japan
| | - Yui Yamazaki
- Department of Pharmacology, Faculty of Medicine, Kindai University, Osaka-Sayama, Japan
| | - Takashi Nishinaka
- Department of Pharmacology, Faculty of Medicine, Kindai University, Osaka-Sayama, Japan
| | - Atsuko Niwa
- Department of Pharmacology, Faculty of Medicine, Kindai University, Osaka-Sayama, Japan
| | - Shinichi Nakao
- Department of Anesthesiology, Faculty of Medicine, Kindai University, Osaka-Sayama, Japan
| | - Hidenori Wake
- Department of Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
| | - Shuji Mori
- Department of Pharmacology, School of Pharmacy, Shujitsu University, Okayama, Japan
| | - Tadashi Yoshino
- Department of Pathology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
| | - Masahiro Nishibori
- Department of Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
| | - Hideo Takahashi
- Department of Pharmacology, Faculty of Medicine, Kindai University, Osaka-Sayama, Japan
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45
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Gu X, Gao XS, Ma M, Qin S, Qi X, Li X, Sun S, Yu H, Wang W, Zhou D. Prognostic significance of osteopontin expression in gastric cancer: a meta-analysis. Oncotarget 2018; 7:69666-69673. [PMID: 27626167 PMCID: PMC5342506 DOI: 10.18632/oncotarget.11936] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2016] [Accepted: 09/02/2016] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Accumulated studies have exploited the association between osteopontin (OPN) expression and survival of patients with gastric cancer (GC), however, the results were controversial. Thus, we performed a meta-analysis, aiming to investigate the prognostic role of OPN for GC patients and to explore the association between OPN and clinicalpathological features of GC. RESULTS A total of ten studies involving 1775 patients were included in final meta-analysis. Of the included studies, nine were conducted on Asian patients and one was performed on Caucasian patients. Regarding OPN detection, immunohistochemistry (IHC) was used on tissue specimens in eight studies and enzyme linked immunosorbent assay (ELISA) was used on plasma specimens in two studies. The pooled data showed that high OPN expression was correlated with poor OS (HR = 1.59, 95% CI: 1.15-2.22, p = 0.006). Subgroup analyses demonstrated that OPN had enhanced prognostic value for Asian patients (HR = 1.64, 95% CI = 1.11-2.41, p = 0.012) and for patients receiving surgical resection (HR = 1.6, 95% CI = 1.04-2.48, p = 0.034). In addition, the results also showed that elevated OPN expression was associated with lymph node metastasis, TNM stage, depth of invasion, tumor size and distant metastasis in GC. METHODS Relevant studies were retrieved through PubMed, Embase and Web of Science. Combined hazard ratio (HR) and 95% confidence interval (CI) were calculated to assess the association between OPN and overall survival (OS). Subgroup analyses and publication bias were also conducted. CONCLUSIONS OPN overexpression was correlated with poor OS and clinical features reflecting high aggressiveness in patients with GC. OPN was a promising prognostic biomarker for GC.
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Affiliation(s)
- Xiaobin Gu
- Department of Radiation Oncology, Peking University First Hospital, Peking University, Beijing, China
| | - Xian-Shu Gao
- Department of Radiation Oncology, Peking University First Hospital, Peking University, Beijing, China
| | - Mingwei Ma
- Department of Radiation Oncology, Peking University First Hospital, Peking University, Beijing, China
| | - Shangbin Qin
- Department of Radiation Oncology, Peking University First Hospital, Peking University, Beijing, China
| | - Xin Qi
- Department of Radiation Oncology, Peking University First Hospital, Peking University, Beijing, China
| | - Xiaoying Li
- Department of Radiation Oncology, Peking University First Hospital, Peking University, Beijing, China
| | - Shaoqian Sun
- Department of Radiation Oncology, Peking University First Hospital, Peking University, Beijing, China
| | - Hao Yu
- Department of Radiation Oncology, Peking University First Hospital, Peking University, Beijing, China
| | - Wen Wang
- Department of Radiation Oncology, Peking University First Hospital, Peking University, Beijing, China
| | - Dong Zhou
- Department of Radiation Oncology, Peking University First Hospital, Peking University, Beijing, China
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Zhang LY, Ge XL, Li Z, Tang YJ, Xiong YY, Li XJ, Liu JF, Wanggou SY, Li CT, Yang K, Chen X, Hu ZL, Liu YS, Liu ZX. Fibroblasts play a potential role in bone destruction via osteopontin related caldesmon expression and polymerization in human non-functioning pituitary adenomas. Sci Rep 2017; 7:17523. [PMID: 29235490 PMCID: PMC5727473 DOI: 10.1038/s41598-017-17679-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2017] [Accepted: 11/23/2017] [Indexed: 12/14/2022] Open
Abstract
Non-functioning pituitary adenomas (NFPAs) are the most frequent pituitary tumors. The elucidation of the mechanisms of aggressive NFPAs in bone destruction is required in order to guide the clinical diagnosis and treatment of NFPAs. In the present study, we investigated the differential proteomics of fibroblasts isolated from clinical specimens of NFPAs with or without bone destruction. Proteomic analysis revealed a group of molecules associated with cytoskeleton organization, including caldesmon, were differentially expressed between fibroblasts isolated from bone destruction NFPAs (BD-NFPAs) and fibroblasts isolated from non-bone destruction NFPAs (NBD-NFPAs). The secreted proteins analysis found that osteopontin was significantly upregulated in BD-NFPAs fibroblasts. Furthermore, immunohistochemical staining of the NFPAs clinical samples showed that the expression of caldesmon in stromal cells and the expression of osteopontin in both tumor cells and stroma were significantly increased in BD-NFPAs. Taken together, our results indicate a possible way that osteopontin secreted from both NFPA cells and surrounding fibroblasts modify caldesmon expression and polymerization in fibroblasts, which may contribute to bone destruction in NFPA patients.
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Affiliation(s)
- Li-Yang Zhang
- Department of Neurosurgery, Xiangya Hospital, Central South University; 87 Xiangya Road, Changsha, Hunan, 410078, P.R. China.,Department of Medicine, University of Oklahoma Health Science Center; 975NE, 10th ST, Oklahoma City, Oklahoma, 73104, United States
| | - Xiao-Lu Ge
- High Resolution Mass Spectrometry Laboratory of Advanced Research Center, Central South University, Changsha, Hunan, 410008, P.R. China
| | - Zheng Li
- High Resolution Mass Spectrometry Laboratory of Advanced Research Center, Central South University, Changsha, Hunan, 410008, P.R. China
| | - Yong-Jian Tang
- Department of Neurosurgery, Xiangya Hospital, Central South University; 87 Xiangya Road, Changsha, Hunan, 410078, P.R. China
| | - Yuan-Yuan Xiong
- Department of Neurosurgery, Xiangya Hospital, Central South University; 87 Xiangya Road, Changsha, Hunan, 410078, P.R. China
| | - Xue-Jun Li
- Department of Neurosurgery, Xiangya Hospital, Central South University; 87 Xiangya Road, Changsha, Hunan, 410078, P.R. China
| | - Jin-Fang Liu
- Department of Neurosurgery, Xiangya Hospital, Central South University; 87 Xiangya Road, Changsha, Hunan, 410078, P.R. China
| | - Si-Yi Wanggou
- Department of Neurosurgery, Xiangya Hospital, Central South University; 87 Xiangya Road, Changsha, Hunan, 410078, P.R. China
| | - Chun-Tao Li
- Department of Neurosurgery, Xiangya Hospital, Central South University; 87 Xiangya Road, Changsha, Hunan, 410078, P.R. China
| | - Kui Yang
- Department of Neurosurgery, Xiangya Hospital, Central South University; 87 Xiangya Road, Changsha, Hunan, 410078, P.R. China
| | - Xin Chen
- Department of Neurosurgery, Xiangya Hospital, Central South University; 87 Xiangya Road, Changsha, Hunan, 410078, P.R. China
| | - Zhong-Liang Hu
- Department of Pathology, Xiangya Hospital, Central South University; 87 Xiangya Road, Changsha, Hunan, 410078, P.R. China
| | - Yun-Sheng Liu
- Department of Neurosurgery, Xiangya Hospital, Central South University; 87 Xiangya Road, Changsha, Hunan, 410078, P.R. China
| | - Zhi-Xiong Liu
- Department of Neurosurgery, Xiangya Hospital, Central South University; 87 Xiangya Road, Changsha, Hunan, 410078, P.R. China.
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Fu XL, Duan W, Su CY, Mao FY, Lv YP, Teng YS, Yu PW, Zhuang Y, Zhao YL. Interleukin 6 induces M2 macrophage differentiation by STAT3 activation that correlates with gastric cancer progression. Cancer Immunol Immunother 2017; 66:1597-1608. [PMID: 28828629 PMCID: PMC11028627 DOI: 10.1007/s00262-017-2052-5] [Citation(s) in RCA: 145] [Impact Index Per Article: 18.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2016] [Accepted: 08/11/2017] [Indexed: 02/07/2023]
Abstract
Interleukin 6 (IL-6) was abundant in the tumor microenvironment and played potential roles in tumor progression. In our study, the expression of IL-6 in tumor tissues from 36 gastric cancer (GC) patients was significantly higher than in non-tumor tissues. Moreover, the number of CD163+CD206+ M2 macrophages that infiltrated in tumor tissues was significantly greater than those infiltrated in non-tumor tissues. The frequencies of M2 macrophages were positively correlated with the IL-6 expression in GC tumors. We also found that IL-6 could induce normal macrophages to differentiate into M2 macrophages with higher IL-10 and TGF-β expression, and lower IL-12 expression, via activating STAT3 phosphorylation. Accordingly, knocking down STAT3 using small interfering RNA decreased the expression of M2 macrophages-related cytokines (IL-10 and TGF-β). Furthermore, supernatants from IL-6-induced M2 macrophages promote GC cell proliferation and migration. Moreover, IL-6 production and CD163+CD206+ M2 macrophage infiltration in tumors were associated with disease progression and reduced GC patient survival. In conclusion, our data indicate that IL-6 induces M2 macrophage differentiation (IL-10highTGF-βhighIL-12 p35low ) by activating STAT3 phosphorylation, and the IL-6-induced M2 macrophages exert a pro-tumor function by promoting GC cell proliferation and migration.
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Affiliation(s)
- Xiao-Long Fu
- Department of General Surgery and Center of Minimal Invasive Gastrointestinal Surgery, Southwest Hospital, Third Military Medical University, No. 30 Gaotanyan Street, Chongqing, 400038, People's Republic of China
| | - Wei Duan
- Department of General Surgery and Center of Minimal Invasive Gastrointestinal Surgery, Southwest Hospital, Third Military Medical University, No. 30 Gaotanyan Street, Chongqing, 400038, People's Republic of China
| | - Chong-Yu Su
- Department of General Surgery and Center of Minimal Invasive Gastrointestinal Surgery, Southwest Hospital, Third Military Medical University, No. 30 Gaotanyan Street, Chongqing, 400038, People's Republic of China
| | - Fang-Yuan Mao
- National Engineering Research Centre of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy, Third Military Medical University, No. 30 Gaotanyan Street, Chongqing, 400038, People's Republic of China
| | - Yi-Ping Lv
- National Engineering Research Centre of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy, Third Military Medical University, No. 30 Gaotanyan Street, Chongqing, 400038, People's Republic of China
| | - Yong-Sheng Teng
- National Engineering Research Centre of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy, Third Military Medical University, No. 30 Gaotanyan Street, Chongqing, 400038, People's Republic of China
| | - Pei-Wu Yu
- Department of General Surgery and Center of Minimal Invasive Gastrointestinal Surgery, Southwest Hospital, Third Military Medical University, No. 30 Gaotanyan Street, Chongqing, 400038, People's Republic of China
| | - Yuan Zhuang
- National Engineering Research Centre of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy, Third Military Medical University, No. 30 Gaotanyan Street, Chongqing, 400038, People's Republic of China.
| | - Yong-Liang Zhao
- Department of General Surgery and Center of Minimal Invasive Gastrointestinal Surgery, Southwest Hospital, Third Military Medical University, No. 30 Gaotanyan Street, Chongqing, 400038, People's Republic of China.
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Yamagata Y, Tomioka H, Sakamoto K, Sato K, Harada H, Ikeda T, Kayamori K. CD163-Positive Macrophages Within the Tumor Stroma Are Associated With Lymphangiogenesis and Lymph Node Metastasis in Oral Squamous Cell Carcinoma. J Oral Maxillofac Surg 2017; 75:2144-2153. [DOI: 10.1016/j.joms.2017.03.009] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2017] [Revised: 03/06/2017] [Accepted: 03/06/2017] [Indexed: 01/01/2023]
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49
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Antsiferova M, Piwko-Czuchra A, Cangkrama M, Wietecha M, Sahin D, Birkner K, Amann VC, Levesque M, Hohl D, Dummer R, Werner S. Activin promotes skin carcinogenesis by attraction and reprogramming of macrophages. EMBO Mol Med 2017; 9:27-45. [PMID: 27932444 PMCID: PMC5210090 DOI: 10.15252/emmm.201606493] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Activin has emerged as an important player in different types of cancer, but the underlying mechanisms are largely unknown. We show here that activin overexpression is an early event in murine and human skin tumorigenesis. This is functionally important, since activin promoted skin tumorigenesis in mice induced by the human papillomavirus 8 oncogenes. This was accompanied by depletion of epidermal γδ T cells and accumulation of regulatory T cells. Most importantly, activin increased the number of skin macrophages via attraction of blood monocytes, which was prevented by depletion of CCR2‐positive monocytes. Gene expression profiling of macrophages from pre‐tumorigenic skin and bioinformatics analysis demonstrated that activin induces a gene expression pattern in skin macrophages that resembles the phenotype of tumor‐associated macrophages in different malignancies, thereby promoting angiogenesis, cell migration and proteolysis. The functional relevance of this finding was demonstrated by antibody‐mediated depletion of macrophages, which strongly suppressed activin‐induced skin tumor formation. These results demonstrate that activin induces skin carcinogenesis via attraction and reprogramming of macrophages and identify novel activin targets involved in tumor formation.
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Affiliation(s)
- Maria Antsiferova
- Department of Biology, Institute of Molecular Health Sciences, ETH Zurich, Zurich, Switzerland
| | | | - Michael Cangkrama
- Department of Biology, Institute of Molecular Health Sciences, ETH Zurich, Zurich, Switzerland
| | - Mateusz Wietecha
- Department of Biology, Institute of Molecular Health Sciences, ETH Zurich, Zurich, Switzerland
| | - Dilara Sahin
- Department of Biology, Institute of Molecular Health Sciences, ETH Zurich, Zurich, Switzerland
| | - Katharina Birkner
- Department of Biology, Institute of Molecular Health Sciences, ETH Zurich, Zurich, Switzerland
| | - Valerie C Amann
- Department of Dermatology, University Hospital, Zurich, Switzerland
| | | | - Daniel Hohl
- Department of Dermatology, University of Lausanne, Lausanne, Switzerland
| | - Reinhard Dummer
- Department of Dermatology, University Hospital, Zurich, Switzerland
| | - Sabine Werner
- Department of Biology, Institute of Molecular Health Sciences, ETH Zurich, Zurich, Switzerland
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Jiang W, Liu K, Guo Q, Cheng J, Shen L, Cao Y, Wu J, Shi J, Cao H, Liu B, Tao K, Wang G, Cai K. Tumor-infiltrating immune cells and prognosis in gastric cancer: a systematic review and meta-analysis. Oncotarget 2017; 8:62312-62329. [PMID: 28977947 PMCID: PMC5617507 DOI: 10.18632/oncotarget.17602] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2016] [Accepted: 04/11/2017] [Indexed: 12/29/2022] Open
Abstract
Tumor-infiltrating immune cells are a pivotal component of the tumor microenvironment (TME), but their indicative role remains poorly defined. A meta-analysis was performed to reveal the prognostic efficiency of tumor-infiltrating immune cells in gastric cancer (GC). By searching PubMed and Embase, we identified a total of 35 eligible articles that involved 4888 patients. Random or fixed effect models were employed to extract pooled hazard ratios (HRs) with 95% confidence intervals (CIs). Our results indicated that high CD3+ lymphocyte infiltration in all the locations (AG), the tumor nest (TN), and the tumor stroma (TS) predicted better overall survival (OS) (HR=0.71, 95% CI=0.57-0.90; HR=0.58, 95% CI=0.42-0.80; and HR=0.50, 95% CI=0.37-0.68, respectively). CD8+ T cell infiltration in AG and FoxP3+ regulatory T cells (Tregs) in the tumor invasive margin (TM) were also associated with improved OS (HR=0.90, 95% CI=0.83-0.97; HR=0.65, 95% CI=0.48-0.87, respectively). However, contrasting results were found in the macrophage subset, with M2 in AG (HR=1.45, 95% CI=1.13-1.86) and the TN (HR=1.67, 95% CI=1.12-2.48) associated with worse OS. In summary, the combination of the densities and locations of tumor-infiltrating immune cells can be useful for predicting survival for GC patients, but additional research is needed to reinforce the reliability of this study's conclusions.
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Affiliation(s)
- Wen Jiang
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ke Liu
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qing Guo
- Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ji Cheng
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Liming Shen
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yinghao Cao
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jing Wu
- MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Department of Maternal and Child Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jianguo Shi
- Department of Gastrointestinal Surgery, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Heng Cao
- Department of Gastrointestinal Surgery, Xinyang Central Hospital, Xinyang, China
| | - Bo Liu
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Kaixiong Tao
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Guobin Wang
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Kailin Cai
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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