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Li H, Shan C, Zhu Y, Yao X, Lin L, Zhang X, Qian Y, Wang Y, Xu J, Zhang Y, Li H, Zhao L, Chen K. Helminth-induced immune modulation in colorectal cancer: exploring therapeutic applications. Front Immunol 2025; 16:1484686. [PMID: 40297577 PMCID: PMC12034720 DOI: 10.3389/fimmu.2025.1484686] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2024] [Accepted: 03/24/2025] [Indexed: 04/30/2025] Open
Abstract
Colorectal cancer is one of the most lethal tumors, posing a financial and healthcare burden. This study investigates how helminths and pre-existing diseases such as colitis, obesity, diabetes, and gut microbiota issues influence colon cancer development and prognosis. The immune system's protective immunosuppressive response to helminth invasion minimizes inflammation-induced cell damage and DNA mutations, lowering the risk of colorectal cancer precursor lesions. Helminth infection-mediated immunosuppression can hasten colorectal cancer growth and metastasis, which is detrimental to patient outcomes. Some helminth derivatives can activate immune cells to attack cancer cells, making them potentially useful as colorectal cancer vaccines or therapies. This review also covers gene editing approaches. We discovered that using CRISPR/Cas9 to inhibit live helminths modulates miRNA, which limits tumor growth. We propose more multicenter studies into helminth therapy's long-term effects and immune regulation pathways. We hope to treat colorectal cancer patients with helminth therapy and conventional cancer treatments in an integrative setting.
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Affiliation(s)
- Hongyu Li
- Key Laboratory of Artificial Organs and Computational Medicine of Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, Hangzhou, China
- Ocean College, Beibu Gulf University, Qinzhou, China
| | - Chaojun Shan
- Key Laboratory of Artificial Organs and Computational Medicine of Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, Hangzhou, China
| | - Yunhuan Zhu
- Key Laboratory of Artificial Organs and Computational Medicine of Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, Hangzhou, China
| | - Xiaodong Yao
- School of Marxism, Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Lijun Lin
- School of Basic Medicine and Forensic Medicine, Hangzhou Medical College, Hangzhou, China
| | - Xiaofen Zhang
- Key Laboratory of Artificial Organs and Computational Medicine of Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, Hangzhou, China
| | - Yuncheng Qian
- Key Laboratory of Artificial Organs and Computational Medicine of Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, Hangzhou, China
| | - Yuqing Wang
- Key Laboratory of Artificial Organs and Computational Medicine of Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, Hangzhou, China
| | - Jialu Xu
- Key Laboratory of Artificial Organs and Computational Medicine of Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, Hangzhou, China
| | - Yijie Zhang
- Key Laboratory of Artificial Organs and Computational Medicine of Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, Hangzhou, China
| | - Hairun Li
- Key Laboratory of Artificial Organs and Computational Medicine of Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, Hangzhou, China
| | - Ling Zhao
- Key Laboratory of Artificial Organs and Computational Medicine of Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, Hangzhou, China
| | - Keda Chen
- Key Laboratory of Artificial Organs and Computational Medicine of Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, Hangzhou, China
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Yari A, Hosseini SY, Asiyabi S, Hajiahmadi N, Farahmand M, Bamdad T. Oncolytic reovirus enhances the effect of CEA immunotherapy when combined with PD1-PDL1 inhibitor in a colorectal cancer model. Immunotherapy 2025; 17:425-435. [PMID: 40353308 DOI: 10.1080/1750743x.2025.2501926] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2024] [Accepted: 05/01/2025] [Indexed: 05/14/2025] Open
Abstract
AIM The effectiveness of immunotherapy with tumor associated antigen vaccines can be enhanced by combining oncolytic viruses with immune checkpoint inhibitors. This study evaluates the efficacy of oncolytic reovirus in combination with an adenovector expressing carcinoembryonic antigen (Ad-CEA) and a programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) inhibitor in a mouse model. METHODS Mice bearing CEA-expressing CT26 tumor cells were immunized with Ad-CEA along with a PD-1/PD-L1 inhibitor. Subsequently, three doses of reovirus were injected into the tumors. Tumor size, histopathological examination, CD8 and FOXP3 expression, the cytotoxicity of spleen T cell lymphocytes, and the secretion of Interferon-γ (IFN-γ) and Tumor necrosis factor- α (TNF-α) were examined. RESULTS The triple therapy used in this study resulted in the lowest tumor growth and the highest level of cytotoxic immunity. The Foxp3 levels in the tumor microenvironment and TNF-α secretion decreased compared to other control groups. Additionally, this group exhibited the lowest number of mitotic figures and the highest amount of tumor-infiltrating lymphocytes. CONCLUSION The combination of tumor vaccines with oncolytic viruses significantly improves treatment efficacy. Furthermore, inhibiting the PD-1/PD-L1 interaction during vaccination and also with virotherapy enhances immunovirotherapy by reducing immunosuppressive effects and stimulating the immune system, leading to improved therapeutic outcomes.
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Affiliation(s)
- Atefeh Yari
- Department of Virology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | | | - Sanaz Asiyabi
- Department of Virology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Nazila Hajiahmadi
- Department of Virology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Mohammad Farahmand
- Research Center for Emergency and Disaster Resilience, Red Crescent Society of the Islamic Republic of Iran, Tehran, Iran
| | - Taravat Bamdad
- Department of Virology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
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Zidlik V, Hurnik P, Vantuchova Y, Michalcova S, Skarda J, Hulinova T, Purova D, Ehrmann J. FOXP3, IL-35, and PD-L1 in intra- and peritumoral lymphocytic infiltrate of cutaneous melanomas as an important part of antitumor immunity. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2025. [PMID: 39865911 DOI: 10.5507/bp.2024.040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2025] Open
Abstract
BACKGROUND The tumor microenvironment is a significant mediator enabling tumor growth and progression. Tumor-infiltrating lymphocytes (TILs) are an important component of this but tumor cells develop mechanisms by which they can escape the action of the immune system. Immunosuppressive mechanisms cooperate with each other and involve cells of the immune system, the tumor microenvironment itself, chemokines and cytokines. In this study, we examined the FOXP3+, IL-35+, and PD-L1+ lymphocytes in tumor tissues as they are contributing to immunosuppression in some tumors, including melanoma. Such cells are also associated with tumor progression, early metastasis, and prognosis. METHODS AND RESULTS In this study, 95 cutaneous melanomas and 25 melanocytic nevi as a control group were examined by immunohistochemistry for FOXP3+, IL-35+, and PD-L1+ lymphocytes. Melanomas were divided into four groups according to the TNM classification: pT1 (35), pT2 (21), pT3 (21), and pT4 (18). PD-L1+ lymphocytes were enriched in pT3- and pT4-stage melanomas, especially in the periphery of the lesions (P<0.001). The number of FOXP3+ lymphocytes was positively correlated with the stage of the disease, especially in the center of the tumors (P<0.001). Likewise, IL-35+ lymphocytes (P<0.001) were enriched with the stage of the tumor. CONCLUSION This article demonstrates that the immunosuppressive environment develops in proportion to the stage of the melanoma. The most significant changes are found at the tumor periphery, confirming the heterogeneity of the tumor stroma which is more pronounced in more advanced tumors and which may contribute to the greater aggressiveness in these peripheral zones.
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Affiliation(s)
- Vladimir Zidlik
- Institute of Pathology and Molecular Genetics, Faculty Hospital Ostrava, Ostrava, Czech Republic
- Institute of Clinical and Molecular Pathology, Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic
| | - Pavel Hurnik
- Institute of Pathology and Molecular Genetics, Faculty Hospital Ostrava, Ostrava, Czech Republic
- Institute of Clinical and Molecular Pathology, Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic
| | - Yvetta Vantuchova
- Department of Dermatology, Faculty Hospital Ostrava, Ostrava, Czech Republic
| | - Simona Michalcova
- Department of Dermatology, Faculty Hospital Ostrava, Ostrava, Czech Republic
| | - Jozef Skarda
- Institute of Pathology and Molecular Genetics, Faculty Hospital Ostrava, Ostrava, Czech Republic
- Institute of Clinical and Molecular Pathology, Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic
- Department of Clinical and Molecular Pathology, Faculty of Medicine and Dentistry, Palacky University Olomouc, Olomouc, Czech Republic
| | - Tereza Hulinova
- Institute of Pathology and Molecular Genetics, Faculty Hospital Ostrava, Ostrava, Czech Republic
- Institute of Clinical and Molecular Pathology, Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic
| | - Dana Purova
- Social Health Institute, Palacky University Olomouc, Olomouc, Czech Republic
| | - Jiri Ehrmann
- Institute of Pathology and Molecular Genetics, Faculty Hospital Ostrava, Ostrava, Czech Republic
- Department of Clinical and Molecular Pathology, Faculty of Medicine and Dentistry, Palacky University Olomouc, Olomouc, Czech Republic
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Meyiah A, Elkord E. What is the relevance of FoxP3 in the tumor microenvironment and cancer outcomes? Expert Rev Clin Immunol 2024; 20:803-809. [PMID: 38512803 DOI: 10.1080/1744666x.2024.2334258] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2024] [Accepted: 03/20/2024] [Indexed: 03/23/2024]
Abstract
INTRODUCTION Forkhead box P3 (FoxP3) transcription factor plays critical roles in controlling immune responses and cancer progression in different cancers. FoxP3 expression within the tumor microenvironment (TME) may influence clinical outcomes negatively or positively, and it could play dual roles in cancer, either by promoting or inhibiting tumor development and progression. Some studies reported that high levels of FoxP3 could be associated with tumor progression and worse prognosis, while others reported contradictory results. AREAS COVERED In this special report, we present a brief account on the role and function of FoxP3 in the TME, and its contribution to the clinical outcomes of cancer patients. Importantly, we give insights on the potential factors that could contribute to different clinical outcomes in cancer patients. EXPERT OPINION Different studies showed that FoxP3 expression can be associated with bad prognoses in cancer patients. However, FoxP3 could have opposing roles by enhancing cancer progression or regression. Location and expression of FoxP3 in T cells or tumor cells can have different impacts on cancer prognoses. Different factors should be considered to establish FoxP3 as a more robust prognostic biomarker and a potential therapeutic target for enhancing anti-tumor immunity and improving clinical outcomes of cancer patients.
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Affiliation(s)
- Abdo Meyiah
- Department of Biological Sciences, School of Science, Xi'an Jiaotong-Liverpool University, Suzhou, China
| | - Eyad Elkord
- Department of Biological Sciences, School of Science, Xi'an Jiaotong-Liverpool University, Suzhou, China
- Biomedical Research Center, School of Science, Engineering and Environment, University of Salford, Manchester, UK
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Wang W, Ding M, Wang Q, Song Y, Huo K, Chen X, Xiang Z, Liu L. Advances in Foxp3+ regulatory T cells (Foxp3+ Treg) and key factors in digestive malignancies. Front Immunol 2024; 15:1404974. [PMID: 38919615 PMCID: PMC11196412 DOI: 10.3389/fimmu.2024.1404974] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2024] [Accepted: 05/24/2024] [Indexed: 06/27/2024] Open
Abstract
Foxp3+ regulatory T cells (Foxp3+ Treg) play a role in regulating various types of tumors, but uncertainty still exists regarding the exact mechanism underlying Foxp3+ Treg activation in gastrointestinal malignancies. As of now, research has shown that Foxp3+ Treg expression, altered glucose metabolism, or a hypoxic tumor microenvironment all affect Foxp3+ Treg function in the bodies of tumor patients. Furthermore, it has been demonstrated that post-translational modifications are essential for mature Foxp3 to function properly. Additionally, a considerable number of non-coding RNAs (ncRNAs) have been implicated in the activation of the Foxp3 signaling pathway. These mechanisms regulating Foxp3 may one day serve as potential therapeutic targets for gastrointestinal malignancies. This review primarily focuses on the properties and capabilities of Foxp3 and Foxp3+Treg. It emphasizes the advancement of research on the regulatory mechanisms of Foxp3 in different malignant tumors of the digestive system, providing new insights for the exploration of anticancer treatments.
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Affiliation(s)
- Wanyao Wang
- School of Basic Medicine, Mudanjiang Medical University, Mudanjiang, Heilongjiang, China
| | - Minglu Ding
- Mudanjiang Medical University, Mudanjiang, Heilongjiang, China
| | - Qiuhong Wang
- Mudanjiang Hospital for Cardiovascular Diseases, Department of Anesthesiology, Mudanjiang, Heilongjiang, China
| | - Yidan Song
- School of Basic Medicine, Mudanjiang Medical University, Mudanjiang, Heilongjiang, China
| | - Keyuan Huo
- School of Basic Medicine, Mudanjiang Medical University, Mudanjiang, Heilongjiang, China
| | - Xiaojie Chen
- School of Basic Medicine, Mudanjiang Medical University, Mudanjiang, Heilongjiang, China
| | - Zihan Xiang
- School of Basic Medicine, Mudanjiang Medical University, Mudanjiang, Heilongjiang, China
| | - Lantao Liu
- School of Basic Medicine, Mudanjiang Medical University, Mudanjiang, Heilongjiang, China
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Zhang X, Li J, Qin X, Li S, Liang D. The effect of FOXP3 genetic polymorphisms on correlations with hepatitis B virus-hepatocellular carcinoma: A case-control study. Heliyon 2024; 10:e23660. [PMID: 38173532 PMCID: PMC10761796 DOI: 10.1016/j.heliyon.2023.e23660] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Revised: 11/23/2023] [Accepted: 12/09/2023] [Indexed: 01/05/2024] Open
Abstract
Background Previous studies have reported that transcription factor forkhead box protein 3 (FOXP3) polymorphisms are correlated with the progress of some cancers, but the relationships between the FOXP3 polymorphisms and hepatocellular carcinoma (HCC) risk remain unclear. Method Genotypes were detected in156 hepatitis B virus (HBV)-HCC patients, 109 HBV-liver cirrhosis (LC) patients, 125 chronic hepatitis B (CHB) patients, and 188 healthy controls. The FOXP3 rs3761547 and rs3761548 polymorphisms were genotyped by polymerase chain reaction (PCR) combined with restriction fragment length polymorphism, and the rs2232365 polymorphism was genotyped using PCR with sequence-specific primers. Results We did not obtain any significant results with the FOXP3 rs3761547, rs3761548, and rs2232365 polymorphisms in groups of patients compared to healthy controls (all p > 0.05), no matter the overall group or subgroup. Conclusions Our findings suggest that the FOXP3 polymorphisms at rs3761547, rs3761548, and rs2232365 were not related to HBV-HCC risk in the Chinese population.
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Affiliation(s)
- Xiaolian Zhang
- Department of Clinical Laboratory, the First Affiliated Hospital of Guangxi Medical University, Key Laboratory of Clinical Laboratory Medicine of Guangxi Department of Education, Nanning, Guangxi, China
| | - Jinwan Li
- School of Basic Medical Sciences, Guangxi Medical University, Nanning, Guangxi, China
| | - Xue Qin
- Department of Clinical Laboratory, the First Affiliated Hospital of Guangxi Medical University, Key Laboratory of Clinical Laboratory Medicine of Guangxi Department of Education, Nanning, Guangxi, China
| | - Shan Li
- Department of Clinical Laboratory, the First Affiliated Hospital of Guangxi Medical University, Key Laboratory of Clinical Laboratory Medicine of Guangxi Department of Education, Nanning, Guangxi, China
| | - Dong Liang
- Medical Equipment Department, the First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
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Huang H, Liang X, Wu W, Yuan T, Chen Z, Wang L, Wu Z, Zhang T, Yang K, Wen K. FOXP3-regulated lncRNA NONHSAT136151 promotes colorectal cancer progression by disrupting QKI interaction with target mRNAs. J Cell Mol Med 2024; 28:e18068. [PMID: 38041531 PMCID: PMC10826441 DOI: 10.1111/jcmm.18068] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2023] [Revised: 11/16/2023] [Accepted: 11/22/2023] [Indexed: 12/03/2023] Open
Abstract
The role of lncRNAs in the pathogenesis of cancer, including colorectal cancer (CRC), has repeatedly been demonstrated. However, very few lncRNAs have been well annotated functionally. Our study identified a novel lncRNA upregulated in CRC, NONHSAT136151, which was correlated with clinical progression. In functional assays, NONHSAT136151 significantly enhanced CRC cell proliferation, migration and invasion. Mechanistically, NONHSAT136151 interacted with RNA-binding protein (RBP) QKI (Quaking) to interfere with QKI binding to target mRNAs and regulate their expression. As well, FOXP3 may be causally related to the dysregulation of NONHSAT136151 in CRC cells through its transcriptional activity. In conclusion, our findings identified a novel lncRNA regulated by FOXP3 participates in CRC progression through interacting with QKI, indicating a novel lncRNA-RBP interaction mechanism is involved in CRC pathogenesis.
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Affiliation(s)
- Handong Huang
- Soochow University Medical CollegeSuzhouJiangsuChina
- Department of General SurgeryAffiliated Hospital of Zunyi Medical UniversityZunyiGuizhouChina
| | - Xiaoxiang Liang
- Department of General SurgeryAffiliated Hospital of Zunyi Medical UniversityZunyiGuizhouChina
| | - Weizheng Wu
- Department of General SurgeryAffiliated Hospital of Zunyi Medical UniversityZunyiGuizhouChina
| | - Tao Yuan
- Department of General SurgeryAffiliated Hospital of Zunyi Medical UniversityZunyiGuizhouChina
| | - Zhengquan Chen
- Department of General SurgeryAffiliated Hospital of Zunyi Medical UniversityZunyiGuizhouChina
| | - Lin Wang
- Department of General SurgeryAffiliated Hospital of Zunyi Medical UniversityZunyiGuizhouChina
| | - Zhenyu Wu
- Department of General SurgeryAffiliated Hospital of Zunyi Medical UniversityZunyiGuizhouChina
| | - Tao Zhang
- Department of General SurgeryAffiliated Hospital of Zunyi Medical UniversityZunyiGuizhouChina
| | - Kai Yang
- Department of General SurgeryAffiliated Hospital of Zunyi Medical UniversityZunyiGuizhouChina
| | - Kunming Wen
- Soochow University Medical CollegeSuzhouJiangsuChina
- Department of General SurgeryAffiliated Hospital of Zunyi Medical UniversityZunyiGuizhouChina
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Fang L, Yao Y, Guan X, Liao Y, Wang B, Cui L, Han S, Zou H, Su D, Ma Y, Liu B, Wang Y, Huang R, Ruan Y, Yu X, Yao Y, Liu C, Zhang Y. China special issue on gastrointestinal tumors-Regulatory-immunoscore-A novel indicator to guide precision adjuvant chemotherapy in colorectal cancer. Int J Cancer 2023; 153:1904-1915. [PMID: 37085990 DOI: 10.1002/ijc.34539] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Revised: 03/08/2023] [Accepted: 03/10/2023] [Indexed: 04/23/2023]
Abstract
Novel biomarkers are essential to improve the treatment efficacy and overall survival of stage II and III colorectal cancer (CRC), allowing for personalized treatment decisions. Here, the densities of CD8+ and FOXP3+ T cells in the tumor and invasive margin were processed by immunohistochemistry and digital pathology to form a scoring system named regulatory-Immunoscore (RIS). Cox proportional hazards regression models were used to determine the risk factors associated with time to recurrence. Harrell's concordance index and the time-dependent area under the curve were used to assess model performance. A total of 1213 stage I-III DNA mismatch repair-proficient colorectal cancer (pMMR CRC) patients were randomly assigned to a training set (n = 642) and a validation set (n = 571). From the Cox multivariable analysis, the association of RIS with survival was independent of patient age, sex and anatomy-based tumor risk parameters (P < .0001). For stage II patients, chemotherapy was significantly associated with better recurrence time in patients with low (95% confidence interval [CI]: 0.11-0.54, P = .001) and intermediate (95% CI = 0.25-0.57, P < .001) RIS values. In stage III patients treated with adjuvant chemotherapy, a treatment duration of 6 or more months was significantly associated with better recurrence time in patients with intermediate RIS values (95% CI = 0.38-0.90, P = .016) when compared with duration under 6 months. Therefore, these findings suggest that RIS is reliable for predicting recurrence risk and treatment responsiveness for patients with stage I-III pMMR CRC.
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Affiliation(s)
- Lin Fang
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
- Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin, China
- Key Laboratory of Tumor Immunology in Heilongjiang, Harbin, China
| | - Yang Yao
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
- Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin, China
- Clinical Research Center for Colorectal Cancer in Heilongjiang, Harbin, China
| | - Xin Guan
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
- Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin, China
- Clinical Research Center for Colorectal Cancer in Heilongjiang, Harbin, China
| | - Yuanyu Liao
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
- Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin, China
| | - Bojun Wang
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
- Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin, China
- Key Laboratory of Tumor Immunology in Heilongjiang, Harbin, China
| | - Luying Cui
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
- Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin, China
| | - Shuling Han
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
- Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin, China
| | - Haoyi Zou
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Dan Su
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
- Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin, China
| | - Yue Ma
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
- Key Laboratory of Tumor Immunology in Heilongjiang, Harbin, China
| | - Biao Liu
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
- Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin, China
| | - Yao Wang
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
- Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin, China
| | - Rui Huang
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
- Key Laboratory of Tumor Immunology in Heilongjiang, Harbin, China
| | - Yuli Ruan
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
- Clinical Research Center for Colorectal Cancer in Heilongjiang, Harbin, China
| | - Xuefan Yu
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
- Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin, China
| | - Yuanfei Yao
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
- Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin, China
- Clinical Research Center for Colorectal Cancer in Heilongjiang, Harbin, China
| | - Chao Liu
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
- Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin, China
- Key Laboratory of Tumor Immunology in Heilongjiang, Harbin, China
| | - Yanqiao Zhang
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
- Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin, China
- Key Laboratory of Tumor Immunology in Heilongjiang, Harbin, China
- Clinical Research Center for Colorectal Cancer in Heilongjiang, Harbin, China
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Tamari H, Kitadai Y, Takigawa H, Yuge R, Urabe Y, Shimamoto F, Oka S. Investigating the Role of Tumor-Infiltrating Lymphocytes as Predictors of Lymph Node Metastasis in Deep Submucosal Invasive Colorectal Cancer: A Retrospective Cross-Sectional Study. Cancers (Basel) 2023; 15:5238. [PMID: 37958412 PMCID: PMC10649548 DOI: 10.3390/cancers15215238] [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: 08/18/2023] [Revised: 09/25/2023] [Accepted: 10/30/2023] [Indexed: 11/15/2023] Open
Abstract
The role of tumor-infiltrating T cells (TILs) in colorectal cancer (CRC) and their significance in early-stage CRC remain unknown. We investigated the role of TILs in early-stage CRC, particularly in deep submucosal invasive (T1b) CRC. Sixty patients with CRC (20 each with intramucosal [IM group], submucosal invasive [SM group], and advanced cancer [AD group]) were randomly selected. We examined changes in TILs with tumor invasion and the relationship between TILs and LN metastasis risk. Eighty-four patients with T1b CRC who underwent initial surgical resection with LN dissection or additional surgical resection with LN dissection after endoscopic resection were then selected. TIL phenotype and number were evaluated using triple immunofluorescence for CD4, CD8, and Foxp3. All subtypes were more numerous according to the degree of CRC invasion and more abundant at the invasive front of the tumor (IF) than in the center of the tumor (CT) in the SM and AD groups. The increased Foxp3 cells at the IF and high ratios of Foxp3/CD4 and Foxp3/CD8 positively correlated with LN metastasis. In conclusion, tumor invasion positively correlated with the number of TILs in CRC. The number and ratio of Foxp3 cells at the IF may predict LN metastasis in T1b CRC.
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Affiliation(s)
- Hirosato Tamari
- Department of Gastroenterology, Hiroshima University Hospital, Hiroshima 734-8551, Japan; (H.T.); (H.T.); (R.Y.); (S.O.)
| | - Yasuhiko Kitadai
- Department of Health Sciences, Faculty of Human Culture and Science, Prefectural University of Hiroshima, Hiroshima 734-8558, Japan
| | - Hidehiko Takigawa
- Department of Gastroenterology, Hiroshima University Hospital, Hiroshima 734-8551, Japan; (H.T.); (H.T.); (R.Y.); (S.O.)
| | - Ryo Yuge
- Department of Gastroenterology, Hiroshima University Hospital, Hiroshima 734-8551, Japan; (H.T.); (H.T.); (R.Y.); (S.O.)
| | - Yuji Urabe
- Department of Gastrointestinal Endoscopy and Medicine, Hiroshima University Hospital, Hiroshima 734-8551, Japan;
| | - Fumio Shimamoto
- Faculty of Health Sciences, Hiroshima Cosmopolitan University, Hiroshima 734-0014, Japan;
| | - Shiro Oka
- Department of Gastroenterology, Hiroshima University Hospital, Hiroshima 734-8551, Japan; (H.T.); (H.T.); (R.Y.); (S.O.)
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Maryam S, Krukiewicz K, Haq IU, Khan AA, Yahya G, Cavalu S. Interleukins (Cytokines) as Biomarkers in Colorectal Cancer: Progression, Detection, and Monitoring. J Clin Med 2023; 12:jcm12093127. [PMID: 37176567 PMCID: PMC10179696 DOI: 10.3390/jcm12093127] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2023] [Revised: 04/18/2023] [Accepted: 04/20/2023] [Indexed: 05/15/2023] Open
Abstract
Cancer is the primary cause of death in economically developed countries and the second leading cause in developing countries. Colorectal cancer (CRC) is the third most common cause of cancer-related deaths worldwide. Risk factors for CRC include obesity, a diet low in fruits and vegetables, physical inactivity, and smoking. CRC has a poor prognosis, and there is a critical need for new diagnostic and prognostic biomarkers to reduce related deaths. Recently, studies have focused more on molecular testing to guide targeted treatments for CRC patients. The most crucial feature of activated immune cells is the production and release of growth factors and cytokines that modulate the inflammatory conditions in tumor tissues. The cytokine network is valuable for the prognosis and pathogenesis of colorectal cancer as they can aid in the cost-effective and non-invasive detection of cancer. A large number of interleukins (IL) released by the immune system at various stages of CRC can act as "biomarkers". They play diverse functions in colorectal cancer, and include IL-4, IL-6, IL-8, IL-11, IL-17A, IL-22, IL-23, IL-33, TNF, TGF-β, and vascular endothelial growth factor (VEGF), which are pro-tumorigenic genes. However, there are an inadequate number of studies in this area considering its correlation with cytokine profiles that are clinically useful in diagnosing cancer. A better understanding of cytokine levels to establish diagnostic pathways entails an understanding of cytokine interactions and the regulation of their various biochemical signaling pathways in healthy individuals. This review provides a comprehensive summary of some interleukins as immunological biomarkers of CRC.
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Affiliation(s)
- Sajida Maryam
- Department of Biosciences, COMSATS University Islamabad (CUI), Islamabad 44000, Pakistan
| | - Katarzyna Krukiewicz
- Department of Physical Chemistry and Technology of Polymers, Silesian University of Technology, M. Strzody 9, 44-100 Gliwice, Poland
- Centre for Organic and Nanohybrid Electronics, Silesian University of Technology, Konarskiego 22B, 44-100 Gliwice, Poland
| | - Ihtisham Ul Haq
- Department of Biosciences, COMSATS University Islamabad (CUI), Islamabad 44000, Pakistan
- Department of Physical Chemistry and Technology of Polymers, Silesian University of Technology, M. Strzody 9, 44-100 Gliwice, Poland
- Joint Doctoral School, Silesian University of Technology, Akademicka 2A, 44-100 Gliwice, Poland
| | - Awal Ayaz Khan
- Department of Biosciences, COMSATS University Islamabad (CUI), Islamabad 44000, Pakistan
| | - Galal Yahya
- Department of Microbiology and Immunology, Faculty of Pharmacy, Zagazig University, Zagazig 44519, Al Sharqia, Egypt
- Department of Molecular Genetics, Faculty of Biology, Technical University of Kaiserslautern, Paul-Ehrlich Str. 24, 67663 Kaiserslautern, Germany
| | - Simona Cavalu
- Faculty of Medicine and Pharmacy, University of Oradea, P-ta 1 Decembrie 10, 410087 Oradea, Romania
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11
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Garcia-Becerra N, Aguila-Estrada MU, Palafox-Mariscal LA, Hernandez-Flores G, Aguilar-Lemarroy A, Jave-Suarez LF. FOXP3 Isoforms Expression in Cervical Cancer: Evidence about the Cancer-Related Properties of FOXP3Δ2Δ7 in Keratinocytes. Cancers (Basel) 2023; 15:cancers15020347. [PMID: 36672296 PMCID: PMC9856939 DOI: 10.3390/cancers15020347] [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: 12/17/2022] [Revised: 01/03/2023] [Accepted: 01/03/2023] [Indexed: 01/06/2023] Open
Abstract
Cervical cancer (CC) is the fourth most common type of cancer among women; the main predisposing factor is persistent infection by high-risk human papillomavirus (hr-HPV), mainly the 16 or 18 genotypes. Both hr-HPVs are known to manipulate the cellular machinery and the immune system to favor cell transformation. FOXP3, a critical transcription factor involved in the biology of regulatory T cells, has been detected as highly expressed in the tumor cells of CC patients. However, its biological role in CC, particularly in the keratinocytes, remained unclarified. Therefore, this work aimed to uncover the effect of FOXP3 on the biology of the tumoral cells. First, public databases were analyzed to identify the FOXP3 expression levels and the transcribed isoforms in CC and normal tissue samples. The study's findings demonstrated an increased expression of FOXP3 in HPV16+ CC samples. Additionally, the FOXP3Δ2 variant was detected as the most frequent splicing isoform in tumoral cells, with a high differential expression level in metastatic samples. However, the analysis of FOXP3 expression in different CC cell lines, HPV+ and HPV-, suggests no relationship between the presence of HPV and FOXP3 expression. Since the variant FOXP3Δ2Δ7 was found highly expressed in the HPV16+ SiHa cell line, a model with constitutive expression of FOXP3Δ2Δ7 was established to evaluate its role in proliferation, migration, and cell division. Finally, RNAseq was performed to identify differentially expressed genes and enriched pathways modulated by FOXP3Δ2Δ7. The exogenous expression of FOXP3Δ2Δ7 promotes cell division, proliferation, and migration. The transcriptomic analyses highlight the upregulation of multiple genes with protumor activities. Moreover, immunological and oncogenic pathways were detected as highly enriched. These data support the hypothesis that FOXP3Δ2Δ7 in epithelial cells induces cancer-related hallmarks and provides information about the molecular events triggered by this isoform, which could be important for developing CC.
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Affiliation(s)
- Natalia Garcia-Becerra
- Programa de Doctorado en Ciencias Biomédicas, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Mexico
- División de Inmunología, Centro de Investigación Biomédica de Occidente (CIBO), Instituto Mexicano del Seguro Social (IMSS), Guadalajara 44340, Mexico
| | - Marco Ulises Aguila-Estrada
- División de Inmunología, Centro de Investigación Biomédica de Occidente (CIBO), Instituto Mexicano del Seguro Social (IMSS), Guadalajara 44340, Mexico
| | - Luis Arturo Palafox-Mariscal
- Programa de Doctorado en Ciencias Biomédicas, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Mexico
- División de Inmunología, Centro de Investigación Biomédica de Occidente (CIBO), Instituto Mexicano del Seguro Social (IMSS), Guadalajara 44340, Mexico
| | - Georgina Hernandez-Flores
- División de Inmunología, Centro de Investigación Biomédica de Occidente (CIBO), Instituto Mexicano del Seguro Social (IMSS), Guadalajara 44340, Mexico
| | - Adriana Aguilar-Lemarroy
- División de Inmunología, Centro de Investigación Biomédica de Occidente (CIBO), Instituto Mexicano del Seguro Social (IMSS), Guadalajara 44340, Mexico
- Correspondence: (A.A.-L.); (L.F.J.-S.)
| | - Luis Felipe Jave-Suarez
- División de Inmunología, Centro de Investigación Biomédica de Occidente (CIBO), Instituto Mexicano del Seguro Social (IMSS), Guadalajara 44340, Mexico
- Correspondence: (A.A.-L.); (L.F.J.-S.)
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12
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Gulubova MV, Chonov DC, Ivanova KV, Hristova MK, Krasimirova-Ignatova MM, Vlaykova TI. Intratumoural expression of IL-6/STAT3, IL-17 and FOXP3 immune cells in the immunosuppressive tumour microenvironment of colorectal cancer Immune cells-positive for IL-6, STAT3, IL-17 and FOXP3 and colorectal cancer development. BIOTECHNOL BIOTEC EQ 2022. [DOI: 10.1080/13102818.2022.2072765] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Affiliation(s)
| | - Dimitur Chavdarov Chonov
- Department of General and Operative Surgery, Trakia University, Medical Faculty, Stara Zagora Bulgaria
- Ward of Operative Surgery, University Hospital “Prof. D-r Stoyan Kirkovich”, Stara Zagora, Bulgaria
| | - Koni Vancho Ivanova
- Department of Pathology, Trakia University, Medical Faculty, Stara Zagora, Bulgaria
| | | | | | - Tatyana Ivanova Vlaykova
- Department of Chemistry and Biochemistry, Medical Faculty, Trakia University, Stara Zagora, Bulgaria
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13
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Kuol N, Davidson M, Karakkat J, Filippone RT, Veale M, Luwor R, Fraser S, Apostolopoulos V, Nurgali K. Blocking Muscarinic Receptor 3 Attenuates Tumor Growth and Decreases Immunosuppressive and Cholinergic Markers in an Orthotopic Mouse Model of Colorectal Cancer. Int J Mol Sci 2022; 24:596. [PMID: 36614038 PMCID: PMC9820315 DOI: 10.3390/ijms24010596] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Revised: 12/22/2022] [Accepted: 12/23/2022] [Indexed: 12/31/2022] Open
Abstract
Tumor cells have evolved to express immunosuppressive molecules allowing their evasion from the host's immune system. These molecules include programmed death ligands 1 and 2 (PD-L1 and PD-L2). Cancer cells can also produce acetylcholine (ACh), which plays a role in tumor development. Moreover, tumor innervation can stimulate vascularization leading to tumor growth and metastasis. The effects of atropine and muscarinic receptor 3 (M3R) blocker, 1,1-dimethyl-4-diphenylacetoxypiperidinium iodide (4-DAMP), on cancer growth and spread were evaluated in vitro using murine colon cancer cell line, CT-26, and in vivo in an orthotopic mouse model of colorectal cancer. In the in vitro model, atropine and 4-DAMP significantly inhibited CT-26 cell proliferation in a dose dependent manner and induced apoptosis. Atropine attenuated immunosuppressive markers and M3R via inhibition of EGFR/AKT/ERK signaling pathways. However, 4-DAMP showed no effect on the expression of PD-L1, PD-L2, and choline acetyltransferase (ChAT) on CT-26 cells but attenuated M3R by suppressing the phosphorylation of AKT and ERK. Blocking of M3R in vivo decreased tumor growth and expression of immunosuppressive, cholinergic, and angiogenic markers through inhibition of AKT and ERK, leading to an improved immune response against cancer. The expression of immunosuppressive and cholinergic markers may hold potential in determining prognosis and treatment regimens for colorectal cancer patients. This study's results demonstrate that blocking M3R has pronounced antitumor effects via several mechanisms, including inhibition of immunosuppressive molecules, enhancement of antitumor immune response, and suppression of tumor angiogenesis via suppression of the AKT/ERK signaling pathway. These findings suggest a crosstalk between the cholinergic and immune systems during cancer development. In addition, the cholinergic system influences cancer evasion from the host's immunity.
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Affiliation(s)
- Nyanbol Kuol
- Institute for Health and Sport, Victoria University, Melbourne 3011, Australia
- Department of Physiology and Cell Biology, University of Nevada, Reno, NV 89557, USA
| | - Majid Davidson
- Institute for Health and Sport, Victoria University, Melbourne 3011, Australia
| | - Jimsheena Karakkat
- Institute for Health and Sport, Victoria University, Melbourne 3011, Australia
| | | | - Margaret Veale
- La Trobe Institute of Molecule Science, La Trobe University, Melbourne 3086, Australia
| | - Rodney Luwor
- Royal Melbourne Hospital, University of Melbourne, Melbourne 3010, Australia
| | - Sarah Fraser
- Institute for Health and Sport, Victoria University, Melbourne 3011, Australia
| | - Vasso Apostolopoulos
- Institute for Health and Sport, Victoria University, Melbourne 3011, Australia
- Immunology Program, Australian Institute of Musculoskeletal Sciences, Melbourne 3021, Australia
| | - Kulmira Nurgali
- Institute for Health and Sport, Victoria University, Melbourne 3011, Australia
- Department of Medicine Western Health, University of Melbourne, Melbourne 3010, Australia
- Regenerative Medicine and Stem Cells Program, Australian Institute of Musculoskeletal Sciences, Melbourne 3021, Australia
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14
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Zhang Y, Tian X, Bai Y, Liu X, Zhu J, Zhang L, Wang J. WTAP mediates FOXP3 mRNA stability to promote SMARCE1 expression and augment glycolysis in colon adenocarcinoma. Mamm Genome 2022; 33:654-671. [PMID: 36173464 DOI: 10.1007/s00335-022-09962-z] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Accepted: 09/12/2022] [Indexed: 11/28/2022]
Abstract
N6-methyladenosine (m6A) is the most abundant mRNA internal modification and has reportedly been linked to aerobic glycolysis, a hallmark event in tumor development. This work focuses on the role of the m6A methyltransferase WT1-associated protein (WTAP) in metabolic reprogramming and development of colon adenocarcinoma (COAD) and the molecules involved. The WTAP expression in COAD tissues and cells was detected. WTAP was knocked down in two COAD cell lines to figure out its role in the glycolytic activity and malignant phenotype of cancer cells. Cancer cells were further injected into nude mice subcutaneously or via tail vein to evaluate tumor growth and metastasis. The downstream molecules involved were explored using bioinformatics tools, and the molecular interactions were confirmed by immunoprecipitation, luciferase assays, and rescue experiments. WTAP was abundantly expressed in COAD samples. Knockdown of WTAP suppressed glucose consumption, lactate production, and glycolysis, which consequently suppressed cancer cell growth and dissemination in vitro and in vivo. WTAP promoted m6A methylation and stabilized forkhead box P3 (FOXP3) mRNA with the participation of the m6A "reader" YTHDF1. FOXP3 could further bind to SMARCE1 promoter for transcriptional activation. Rescue experiments showed that upregulation of FOXP3 or SMARCE1 restored the glycolytic activity in COAD cells and augmented the growth and mobility of cells both in vitro and in vivo. This study demonstrates that WTAP grants glycolytic activity to COAD and promotes tumor malignant development via the m6A modification of FOXP3 mRNA and the upregulation of SMARCE1.
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Affiliation(s)
- Yu Zhang
- Department of Gastroenterology, The First Affiliated Hospital of Henan University of Science and Technology, No. 24, Jinghua Road Jianxi District, Luoyang, 471003, Henan, People's Republic of China
| | - Xiaoxiao Tian
- Department of Gastroenterology, The First Affiliated Hospital of Henan University of Science and Technology, No. 24, Jinghua Road Jianxi District, Luoyang, 471003, Henan, People's Republic of China
| | - Yanli Bai
- Department of Gastroenterology, The First Affiliated Hospital of Henan University of Science and Technology, No. 24, Jinghua Road Jianxi District, Luoyang, 471003, Henan, People's Republic of China
| | - Xianmin Liu
- Department of Gastroenterology, The First Affiliated Hospital of Henan University of Science and Technology, No. 24, Jinghua Road Jianxi District, Luoyang, 471003, Henan, People's Republic of China
| | - Jingjing Zhu
- Department of Gastroenterology, The First Affiliated Hospital of Henan University of Science and Technology, No. 24, Jinghua Road Jianxi District, Luoyang, 471003, Henan, People's Republic of China
| | - Lamei Zhang
- Department of Gastroenterology, The First Affiliated Hospital of Henan University of Science and Technology, No. 24, Jinghua Road Jianxi District, Luoyang, 471003, Henan, People's Republic of China
| | - Jinliang Wang
- Department of Gastroenterology, The First Affiliated Hospital of Henan University of Science and Technology, No. 24, Jinghua Road Jianxi District, Luoyang, 471003, Henan, People's Republic of China.
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15
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Wozniakova M, Skarda J, Raska M. The Role of Tumor Microenvironment and Immune Response in Colorectal Cancer Development and Prognosis. Pathol Oncol Res 2022; 28:1610502. [PMID: 35936516 PMCID: PMC9350736 DOI: 10.3389/pore.2022.1610502] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Accepted: 06/28/2022] [Indexed: 11/13/2022]
Abstract
Colorectal cancer (CRC) is one of the most common cancers worldwide. The patient’s prognosis largely depends on the tumor stage at diagnosis. The pathological TNM Classification of Malignant Tumors (pTNM) staging of surgically resected cancers represents the main prognostic factor and guidance for decision-making in CRC patients. However, this approach alone is insufficient as a prognostic predictor because clinical outcomes in patients at the same histological tumor stage can still differ. Recently, significant progress in the treatment of CRC has been made due to improvements in both chemotherapy and surgical management. Immunotherapy-based approaches are one of the most rapidly developing areas of tumor therapy. This review summarizes the current knowledge about the tumor microenvironment (TME), immune response and its interactions with CRC development, immunotherapy and prognosis.
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Affiliation(s)
- Maria Wozniakova
- Institute of Pathology and Molecular Genetics, University Hospital Ostrava, Ostrava, Czechia
- Department of Clinical and Molecular Pathology, Faculty of Medicine and Dentistry, Palacký University Olomouc, Olomouc, Czechia
- *Correspondence: Maria Wozniakova,
| | - Jozef Skarda
- Institute of Pathology and Molecular Genetics, University Hospital Ostrava, Ostrava, Czechia
- Department of Clinical and Molecular Pathology, Faculty of Medicine and Dentistry, Palacký University Olomouc, Olomouc, Czechia
| | - Milan Raska
- Department of Immunology, Faculty of Medicine and Dentistry, Palacký University Olomouc, Olomouc, Czechia
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16
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Context-Dependent Effects Explain Divergent Prognostic Roles of Tregs in Cancer. Cancers (Basel) 2022; 14:cancers14122991. [PMID: 35740658 PMCID: PMC9221270 DOI: 10.3390/cancers14122991] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Revised: 06/02/2022] [Accepted: 06/14/2022] [Indexed: 02/04/2023] Open
Abstract
Simple Summary Immune cells play an important role in cancer, with regard to classification, diagnostic or prognostic matters. In particular, we focused on the prognostic value of Tregs in this meta-analysis. We took into account the local context and their heterogeneity in order to solve their apparent ambiguous role. We used three proxies to recapitulate the complexity of the context: the neighboring cell, the tissue and the quantification method; and we carefully dissected the regulatory population into existing subsets. We showed that CD45RO+ Tregs had a reproducible negative prognostic value across all five cancer types studied (breast, colorectal, gastric, lung and ovarian). It suggests that Tregs from an homogeneous context have a consistent prognostic role across cancer types. Abstract Assessing cancer prognosis is a challenging task, given the heterogeneity of the disease. Multiple features (clinical, environmental, genetic) have been used for such assessments. The tumor immune microenvironment (TIME) is a key feature, and describing the impact of its many components on cancer prognosis is an active field of research. The complexity of the tumor microenvironment context makes it difficult to use the TIME to assess prognosis, as demonstrated by the example of regulatory T cells (Tregs). The effect of Tregs on prognosis is ambiguous, with different studies considering them to be negative, positive or neutral. We focused on five different cancer types (breast, colorectal, gastric, lung and ovarian). We clarified the definition of Tregs and their utility for assessing cancer prognosis by taking the context into account via the following parameters: the Treg subset, the anatomical location of these cells, and the neighboring cells. With a meta-analysis on these three parameters, we were able to clarify the prognostic role of Tregs. We found that CD45RO+ Tregs had a reproducible negative effect on prognosis across cancer types, and we gained insight into the contributions of the anatomical location of Tregs and of their neighboring cells on their prognostic value. Our results suggest that Tregs play a similar prognostic role in all cancer types. We also establish guidelines for improving the design of future studies addressing the pathophysiological role of Tregs in cancer.
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Ay EN, Demirkol Ş, Hakan MT, Horozoğlu C, Arıkan S, Doğan MB, Akyüz F, Hepokur CÖ, Yaylım İ. Investigation of possible associations between tryptophan/kynurenine status and FOXP3 expression in colorectal cancer. Scandinavian Journal of Clinical and Laboratory Investigation 2022; 82:185-191. [PMID: 35452343 DOI: 10.1080/00365513.2022.2040050] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
Tryptophan metabolism in the tumor microenvironment exerts immunosuppressive effects by affecting the anti-tumor functions of immune cells. The immunosuppressive roles of tryptophan and tryptophan metabolites and their effects on the FOXP3 gene, highly expressed in regulatory T cells (Tregs), are remarkable. Our study aimed to investigate the relation between tryptophan metabolism and the transcription factor FOXP3 gene in colorectal cancer (CRC). Patients with CRC (n = 159) and controls (n = 112) were included in the study. The FOXP3 rs3761548 variant genotyping from the isolated genomic DNA was performed by PCR-RFLP. FOXP3 gene expression was determined by Q-PCR in RNAs isolated from resected tissues at the same time. Serum tryptophan, kynurenine, kynurenic acid levels of the cases were determined by HPLC. In serum samples with CRC, tryptophan level was 14.32 ± 1.09 μmol/L, kynurenine level was 1.33 ± 0.02 μmol/L, and the kynurenic acid level was 0.01 ± 0.001 μmol/L. The level of tryptophan was found to be low in CRC compared to control (p < .001). In cases with CRC, CC genotype (p = .048) and C allele (p = .012) frequency for FOXP3 rs3761548 were higher than the control group. It was found that the expression level of the FOXP3 gene was approximately 44 times higher in the advanced tumor stage (T3 + T4) than in the early tumor stage (T1 + T2) (p = .021).We suggest that there may be a possible relationship among serum TRP, TRP metabolites (KYN, KYNA) levels, FOXP3 gene expression, and FOXP3 gene variants in CRC pathogenesis.
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Affiliation(s)
- Ebru Nur Ay
- Department of Molecular Medicine, Istanbul University, Aziz Sancar Institute of Experimental Medicine, Istanbul, Turkey.,Department of Medical Services and Techniques, Vocational School of Health Services, Istinye University, Istanbul, Turkey
| | - Şeyda Demirkol
- Department of Molecular Medicine, Istanbul University, Aziz Sancar Institute of Experimental Medicine, Istanbul, Turkey.,Department of Molecular Biology and Genetics, Biruni University, Istanbul, Turkey
| | - Mehmet Tolgahan Hakan
- Department of Molecular Medicine, Istanbul University, Aziz Sancar Institute of Experimental Medicine, Istanbul, Turkey
| | - Cem Horozoğlu
- Department of Biochemistry, Biruni University Medical Faculty, İstanbul, Turkey
| | - Soykan Arıkan
- General Surgery Clinic, Cam and Sakura City Hospital, Istanbul, Turkey
| | - Mehmet Baki Doğan
- General Surgery Clinic, Istanbul Training and Research Hospital, Istanbul, Turkey
| | - Filiz Akyüz
- Department of Gastroenterology, Istanbul Faculty of Medicine, Istanbul, Turkey
| | - Ceylan Özsoy Hepokur
- Department of Biochemistry, Faculty of Pharmacy, Sivas Cumhuriyet University, Sivas, Turkey
| | - İlhan Yaylım
- Department of Molecular Medicine, Istanbul University, Aziz Sancar Institute of Experimental Medicine, Istanbul, Turkey
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18
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Oshi M, Sarkar J, Wu R, Tokumaru Y, Yan L, Nakagawa K, Ishibe A, Matsuyama R, Endo I, Takabe K. Intratumoral density of regulatory T cells is a predictor of host immune response and chemotherapy response in colorectal cancer. Am J Cancer Res 2022; 12:490-503. [PMID: 35261782 PMCID: PMC8899991] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Accepted: 01/03/2022] [Indexed: 06/14/2023] Open
Abstract
Regulatory T cells (Tregs) are a subset of CD4+ T lymphocytes known to dampen the host immune response against cancer cells. Within the tumor microenvironment, Tregs are potent facilitators of immune tolerance, and a higher proportion of Tregs compared to cytotoxic T cells predicts a worse outcome in most solid tumors. We studied the association between Treg density, and cancer biology and clinical outcome in colorectal cancer (CRC). We used xCell to estimate intratumoral Tregs in total of 898 CRC patients in the Cancer Genome Atlas (TCGA) and GCE39582 cohorts. High-Treg CRCs enriched immune response-related gene sets; inflammatory response, IFN-γ and IFN-α response, IL2/IL6 signaling, and allograft rejection, and had significantly high infiltration of CD8, CD4, M1 and M2 macrophage, and dendritic cells in both cohorts. While high-Treg CRCs enriched multiple pro-cancer signaling pathways compared to low-Treg CRCs, such as Epithelial Mesenchymal Transition, K-ras, Hypoxia, TGF-β, TNF-α, and angiogenesis, Treg infiltration was surprisingly associated with earlier CRC stage in TCGA. Notably, in two separate cohorts a higher proportion of Tregs predicted an improved response to chemotherapy. In the GSE28702 cohort, metastatic CRCs with more Tregs showed a significantly better response to mFOLFOX6 versus low-Treg CRC metastases (88.9% response vs. 16.7%, P<0.001). In the GSE72970 cohort, high-Treg CRCs were found to have a 68.8% response to FOLFOX/FOLFIRI without bevacizumab, compared to 44% response in the low-Treg CRCs. Additionally, high-Treg CRCs were associated with increased expression of immune checkpoint molecules PD-L1/PD-L2, CTLA4, TIGIT and BTLA, implying susceptibility to immunotherapy. We also found that CRCs with higher proportions of Tregs were associated with lower amounts of three microorganisms in the tumor: Lachnoclostridium, flavivirus, and Ornithobacterium. In conclusion, we show that amount of Treg in the tumor is a predictor of host immune response and chemotherapy response in CRC.
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Affiliation(s)
- Masanori Oshi
- Department of Surgical Oncology, Roswell Park Cancer InstituteBuffalo, NY, USA
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of MedicineYokohama, Kanagawa, Japan
| | - Joy Sarkar
- Department of Surgical Oncology, Roswell Park Cancer InstituteBuffalo, NY, USA
| | - Rongrong Wu
- Department of Surgical Oncology, Roswell Park Cancer InstituteBuffalo, NY, USA
| | - Yoshihisa Tokumaru
- Department of Surgical Oncology, Roswell Park Cancer InstituteBuffalo, NY, USA
- Department of Surgery, Jacobs School of Medicine and Biomedical Sciences, State University of New YorkBuffalo, NY, USA
| | - Li Yan
- Department of Surgical Oncology, Graduate School of Medicine, Gifu UniversityGifu, Japan
| | - Kazuya Nakagawa
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of MedicineYokohama, Kanagawa, Japan
| | - Atsushi Ishibe
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of MedicineYokohama, Kanagawa, Japan
| | - Ryusei Matsuyama
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of MedicineYokohama, Kanagawa, Japan
| | - Itaru Endo
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of MedicineYokohama, Kanagawa, Japan
| | - Kazuaki Takabe
- Department of Surgical Oncology, Roswell Park Cancer InstituteBuffalo, NY, USA
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of MedicineYokohama, Kanagawa, Japan
- Department of Surgery, Jacobs School of Medicine and Biomedical Sciences, State University of New YorkBuffalo, NY, USA
- Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental SciencesNiigata, Japan
- Department of Breast Surgery, Fukushima Medical University School of MedicineFukushima, Japan
- Department of Breast Surgery and Oncology, Tokyo Medical UniversityTokyo, Japan
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19
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Brunty S, Clower L, Mitchell B, Fleshman T, Zgheib NB, Santanam N. Peritoneal Modulators of Endometriosis-Associated Ovarian Cancer. Front Oncol 2021; 11:793297. [PMID: 34900746 PMCID: PMC8655857 DOI: 10.3389/fonc.2021.793297] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Accepted: 11/04/2021] [Indexed: 12/13/2022] Open
Abstract
Ovarian cancer is the 4th largest cause of cancer death in women. Approximately 10-15% of women of childbearing age suffer from endometriosis. Endometriosis is defined by the growth and presence of endometrial tissue (lesions) outside of the uterus. The women with endometriosis also have an increased presence of peritoneal fluid (PF) that comprises of inflammatory cells, growth factors, cytokines/chemokines, etc. Epidemiological studies have shown that >3% of women with endometriosis develop ovarian cancer (low-grade serous or endometrioid types). Our hypothesis is that the PF from women with endometriosis induces transformative changes in the ovarian cells, leading to ovarian cancer development. PF from women with and without endometriosis was collected after IRB approval and patient consent. IOSE (human normal ovarian epithelial cells) and TOV-21G cells (human ovarian clear cell carcinoma cell line) were treated with various volumes of PF (no endometriosis or endometriosis) for 48 or 96 h and proliferation measured. Expression levels of epigenetic regulators and FoxP3, an inflammatory tumor suppressor, were determined. A Human Cancer Inflammation and Immunity Crosstalk RT2 Profiler PCR array was used to measure changes in cancer related genes in treated cells. Results showed increased growth of TOV-21G cells treated with PF from women with endometriosis versus without endometriosis and compared to IOSE cells. Endo PF treatment induced EZH2, H3K27me3, and FoxP3. The RT2 PCR array of TOV-21G cells treated with endo PF showed upregulation of various inflammatory genes (TLRs, Myd88, etc.). These studies indicate that PF from women with endometriosis can both proliferate and transform ovarian cells and hence this microenvironment plays a major mechanistic role in the progression of endometriosis to ovarian cancer.
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Affiliation(s)
- Sarah Brunty
- Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV, United States
| | - Lauren Clower
- Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV, United States
| | - Brenda Mitchell
- Department of Obstetrics & Gynecology, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV, United States
| | - Taylor Fleshman
- Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV, United States
| | - Nadim Bou Zgheib
- Department of Obstetrics & Gynecology, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV, United States
| | - Nalini Santanam
- Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV, United States
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Li L, Xu XT, Wang LL, Qin SB, Zhou JY. Expression and clinicopathological significance of Foxp3 and VISTA in cervical cancer. Am J Transl Res 2021; 13:10428-10438. [PMID: 34650712 PMCID: PMC8507058] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Accepted: 01/27/2021] [Indexed: 06/13/2023]
Abstract
OBJECTIVE To detect the expression differences of Foxp3 and VISTA in chronic cervical inflammation, cervical intraepithelial neoplasia, and cervical cancer, and to explore the role of Foxp3 and VISTA in the development of cervical cancer and the effect of Foxp3 and VISTA on the prognosis of cervical cancer, to provide a theoretical basis for clinical immunotherapy of cervical cancer. METHODS We collected 130 paraffin specimens of cervical tissue, which included 70 cases of cervical cancer tissue, 40 cases of cervical intraepithelial neoplasia tissues and 20 cases of chronic cervicitis. The expression of Foxp3 and VISTA in each group was detected, and the study was conducted based on the clinicopathological characteristics of the patients. The patients were followed up and the prognosis was statistically analyzed. RESULT 1. The expression of Foxp3 and VISTA was statistically different between the cervical cancer group and other groups. 2. Expressions of Foxp3 and VISTA were significantly correlated. 3. In 70 cases of cervical cancer, the expression of Foxp3 and VISTA was related to the clinical stage. 4. The 3-year survival rate of 70 patients with cervical cancer was 72.9%, and there were no factors affecting 3-year OS found. The expression of Foxp3 and VISTA was significantly correlated with the prognosis of cervical cancer. Foxp3 and VISTA double positive expression group had the worst prognosis. CONCLUSION 1. In cervical cancer, the expression of Foxp3 and VISTA was significantly higher than that of cervical intraepithelial neoplasia and chronic cervicitis, which suggested that they were closely related to the occurrence and growth of cervical cancer. 2. The expression of Foxp3 and VISTA was significantly related. 3. The positive expression of Foxp3 and VISTA could be used as independent prognostic factors for cervical cancer prognosis providing a strong basis for cervical cancer immunotherapy.
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Affiliation(s)
- Li Li
- Department of Radiation Oncology, The First Affiliated Hospital of Soochow University Suzhou 215006, China
| | - Xiao-Ting Xu
- Department of Radiation Oncology, The First Affiliated Hospital of Soochow University Suzhou 215006, China
| | - Li-Li Wang
- Department of Radiation Oncology, The First Affiliated Hospital of Soochow University Suzhou 215006, China
| | - Song-Bing Qin
- Department of Radiation Oncology, The First Affiliated Hospital of Soochow University Suzhou 215006, China
| | - Ju-Ying Zhou
- Department of Radiation Oncology, The First Affiliated Hospital of Soochow University Suzhou 215006, China
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21
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The association of immunosurveillance and distant metastases in colorectal cancer. J Cancer Res Clin Oncol 2021; 147:3333-3341. [PMID: 34476575 PMCID: PMC8484134 DOI: 10.1007/s00432-021-03753-w] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Accepted: 07/31/2021] [Indexed: 11/24/2022]
Abstract
Background Colorectal cancer (CRC) is the third most common malignancy worldwide, but the key driver to distant metastases is still unknown. This study aimed to elucidate the link between immunosurveillance and organotropism of metastases in CRC by evaluating different gene signatures and pathways. Material and methods CRC patients undergoing surgery at the Department of General, Visceral and Transplantation Surgery at the Ludwig-Maximilian University Hospital Munich (Munich, Germany) were screened and categorized into M0 (no distant metastases), HEP (liver metastases) and PER (peritoneal carcinomatosis) after a 5-year follow-up. Six patients of each group were randomly selected to conduct a NanoString analysis, which includes 770 genes. Subsequently, all genes were further analyzed by gene set enrichment analysis (GSEA) based on seven main cancer-associated databases. Results Comparing HEP vs. M0, the gene set associated with the Toll-like receptor (TLR) cascade defined by the Reactome database was significantly overrepresented in HEP. HSP90B1, MAPKAPK3, PPP2CB, PPP2R1A were identified as the core enrichment genes. The immunologic signature pathway GSE6875_TCONV_VS_FOXP3_KO_TREG_DN with FOXP3 as downstream target was significantly overexpressed in M0. RB1, TMEM 100, CFP, ZKSCAN5, DDX50 were the core enrichment genes. Comparing PER vs. M0 no significantly differentially expressed gene signatures were identified. Conclusion Chronic inflammation might enhance local tumor growth. This is the first study identifying immune related gene sets differentially expressed between patients with either liver or peritoneal metastases. The present findings suggest that the formation of liver metastases might be associated with TLR-associated pathways. In M0, a high expression of FOXP3 + tumor infiltrating lymphocytes (TILs) seemed to prevent at least in part metastases. Thus, these correlative findings lay the cornerstone to further studies elucidating the underlying mechanisms of organotropism of metastases.
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22
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Li C, Wang H, Fang H, He C, Pei Y, Gai X. FOXP3 facilitates the invasion and metastasis of non-small cell lung cancer cells through regulating VEGF, EMT and the Notch1/Hes1 pathway. Exp Ther Med 2021; 22:958. [PMID: 34335900 PMCID: PMC8290412 DOI: 10.3892/etm.2021.10390] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Accepted: 03/08/2021] [Indexed: 12/13/2022] Open
Abstract
Forkhead box P3 (FOXP3) is a specific marker of regulatory T cells (Tregs) that is also expressed in tumour cells. Previous studies have revealed that FOXP3 can promote metastasis in several types of cancer, including non-small cell lung cancer (NSCLC); however, the underlying mechanism of FOXP3 remains unclear. The aim of the present study was to investigate the effect of FOXP3 on vascular endothelial growth factor (VEGF), epithelial-to-mesenchymal transition (EMT) and the Notch1/Hes1 pathway in NSCLC. After FOXP3 small interfering RNA (siRNAs) were transfected into A549 cells, the expression of FOXP3 mRNA and protein was determined by reverse transcription-quantitative PCR and western blotting. Cell migration and invasion were analyzed by Transwell assays. The concentrations of matrix metalloproteinase (MMP)-2, MMP-9 and VEGF in the cell supernatant were evaluated by ELISA. The expression of relevant proteins involved in EMT and Notch1/Hes1 pathway were assessed via western blotting. Additionally, the expression of FOXP3, CD31 and E-cadherin was detected by immunohistochemical (IHC) staining of 55 human NSCLC tissue samples. The results demonstrated that FOXP3 knockdown significantly inhibited the cell migratory and invasive abilities, decreased the concentrations of MMP-2, MMP-9 and VEGF, downregulated the protein expression of vimentin, N-cadherin, Notch1 and Hes family BHLH transcription factor 1 (Hes1), and upregulated the protein expression of E-cadherin. Furthermore, FOXP3 expression was positively associated with CD31+ vascular endothelial cells and negatively correlated with E-cadherin in NSCLC tissues. In addition, the Notch1/Hes1 pathway inhibitor DAPT significantly downregulated the expression of FOXP3 in a dose-dependent manner. Taken together, these findings demonstrated that FOXP3 may facilitate the invasive and migratory abilities of NSCLC cells via regulating the angiogenic factor VEGF, the EMT and the Notch1/Hes1 pathway.
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Affiliation(s)
- Chun Li
- Department of Immunology, School of Basic Medical Sciences, Beihua University, Jilin, Jilin 132013, P.R. China
| | - Hefei Wang
- Department of Gynecology, The Third Affiliated Hospital of Xiang Ya School of Medicine, Central South University, Changsha, Hunan 410013, P.R. China
| | - Hui Fang
- Department of Immunology, School of Basic Medical Sciences, Beihua University, Jilin, Jilin 132013, P.R. China.,Department of Laboratory, Chifeng Clinical Medical School, Inner Mongolia Medical University, Chifeng, Inner Mongolia 024000, P.R. China
| | - Chengyuan He
- Department of Immunology, School of Basic Medical Sciences, Beihua University, Jilin, Jilin 132013, P.R. China
| | - Yijie Pei
- Department of Immunology, School of Basic Medical Sciences, Beihua University, Jilin, Jilin 132013, P.R. China
| | - Xiaodong Gai
- Department of Immunology, School of Basic Medical Sciences, Beihua University, Jilin, Jilin 132013, P.R. China
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23
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Seki-Soda M, Sano T, Ogawa M, Yokoo S, Oyama T. CD15 + tumor infiltrating granulocytic cells can predict recurrence and their depletion is accompanied by good responses to S-1 with oral cancer. Head Neck 2021; 43:2457-2467. [PMID: 33893751 DOI: 10.1002/hed.26712] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Revised: 03/18/2021] [Accepted: 04/08/2021] [Indexed: 12/28/2022] Open
Abstract
BACKGROUND It has been reported in oral squamous cell carcinoma (OSCC) that myeloid-derived suppressor cells infiltrate tumor tissues. This study examined whether S-1 chemotherapy changes immune cell populations in the tumor microenvironment. METHODS We examined 71 patients with of OSCC, including 51 patients who received preoperative S-1 chemotherapy. Immunohistochemistry for PD-L1, CD8, forkhead box protein 3 (FOXP3), and CD15 was performed using biopsy and resected specimens. RESULTS The numbers of CD8+ , FOXP3+ , and CD15+ cells in resected specimens were significantly decreased by S-1 chemotherapy. The reduction of the proportion of CD15+ cells significantly differed between responders and nonresponders. Most responders were distributed into the group with low PD-L1 expression and a low density of CD8+ cells before chemotherapy. Furthermore, many patients with recurrence exhibited a high density of CD15+ cells in biopsy specimens. CONCLUSION Preoperative S-1 chemotherapy can potentially improve prognosis by reducing CD15+ cells in the tumor microenvironment.
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Affiliation(s)
- Mai Seki-Soda
- Department of Diagnostic Pathology, Gunma University Graduate School of Medicine, Maebashi, Japan.,Department of Oral and Maxillofacial Surgery and Plastic Surgery, Gunma University Graduate School of Medicine, Maebashi, Japan
| | - Takaaki Sano
- Department of Diagnostic Pathology, Gunma University Graduate School of Medicine, Maebashi, Japan
| | - Masaru Ogawa
- Department of Oral and Maxillofacial Surgery and Plastic Surgery, Gunma University Graduate School of Medicine, Maebashi, Japan
| | - Satoshi Yokoo
- Department of Oral and Maxillofacial Surgery and Plastic Surgery, Gunma University Graduate School of Medicine, Maebashi, Japan
| | - Tetsunari Oyama
- Department of Diagnostic Pathology, Gunma University Graduate School of Medicine, Maebashi, Japan
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24
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Neumeyer S, Hua X, Seibold P, Jansen L, Benner A, Burwinkel B, Halama N, Berndt SI, Phipps AI, Sakoda LC, Schoen RE, Slattery ML, Chan AT, Gala M, Joshi AD, Ogino S, Song M, Herpel E, Bläker H, Kloor M, Scherer D, Ulrich A, Ulrich CM, Win AK, Figueiredo JC, Hopper JL, Macrae F, Milne RL, Giles GG, Buchanan DD, Peters U, Hoffmeister M, Brenner H, Newcomb PA, Chang-Claude J. Genetic Variants in the Regulatory T cell-Related Pathway and Colorectal Cancer Prognosis. Cancer Epidemiol Biomarkers Prev 2020; 29:2719-2728. [PMID: 33008876 PMCID: PMC7976673 DOI: 10.1158/1055-9965.epi-20-0714] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Revised: 07/29/2020] [Accepted: 09/28/2020] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND High numbers of lymphocytes in tumor tissue, including T regulatory cells (Treg), have been associated with better colorectal cancer survival. Tregs, a subset of CD4+ T lymphocytes, are mediators of immunosuppression in cancer, and therefore variants in genes related to Treg differentiation and function could be associated with colorectal cancer prognosis. METHODS In a prospective German cohort of 3,593 colorectal cancer patients, we assessed the association of 771 single-nucleotide polymorphisms (SNP) in 58 Treg-related genes with overall and colorectal cancer-specific survival using Cox regression models. Effect modification by microsatellite instability (MSI) status was also investigated because tumors with MSI show greater lymphocytic infiltration and have been associated with better prognosis. Replication of significant results was attempted in 2,047 colorectal cancer patients of the International Survival Analysis in Colorectal Cancer Consortium (ISACC). RESULTS A significant association of the TGFBR3 SNP rs7524066 with more favorable colorectal cancer-specific survival [hazard ratio (HR) per minor allele: 0.83; 95% confidence interval (CI), 0.74-0.94; P value: 0.0033] was replicated in ISACC (HR: 0.82; 95% CI, 0.68-0.98; P value: 0.03). Suggestive evidence for association was found with two IL7 SNPs, rs16906568 and rs7845577. Thirteen SNPs with differential associations with overall survival according to MSI in the discovery analysis were not confirmed. CONCLUSIONS Common genetic variation in the Treg pathway implicating genes such as TGFBR3 and IL7 was shown to be associated with prognosis of colorectal cancer patients. IMPACT The implicated genes warrant further investigation.
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Affiliation(s)
- Sonja Neumeyer
- Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Institute of Translational Genomics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
| | - Xinwei Hua
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
- School of Public Health, University of Washington, Seattle, Washington
| | - Petra Seibold
- Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Lina Jansen
- Division of Clinical Epidemiology and Aging Research, DKFZ, Heidelberg, Germany
| | - Axel Benner
- Division of Biostatistics, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Barbara Burwinkel
- Division of Molecular Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Department of Gynecology and Obstetrics, Molecular Biology of Breast Cancer, University of Heidelberg, Heidelberg, Germany
| | - Niels Halama
- Department of Medical Oncology, National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany
- Tissue Imaging and Analysis Center, National Center for Tumor Diseases, BIOQUANT, University of Heidelberg, Heidelberg, Germany
- Institute for Immunology, University Hospital Heidelberg, Heidelberg, Germany
| | - Sonja I Berndt
- Division of Cancer Epidemiology and Genetics, NCI, NIH, Bethesda, Maryland
| | - Amanda I Phipps
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
- Epidemiology Department, University of Washington, Seattle, Washington
| | - Lori C Sakoda
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
- Division of Research, Kaiser Permanente Northern California, Oakland, California
| | - Robert E Schoen
- Department of Medicine and Epidemiology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Martha L Slattery
- Department of Internal Medicine, University of Utah, Salt Lake City, Utah
| | - Andrew T Chan
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
- Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Manish Gala
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Amit D Joshi
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts
| | - Shuji Ogino
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts
- Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
- Broad Institute of MIT and Harvard, Cambridge, Massachusetts
| | - Mingyang Song
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts
| | - Esther Herpel
- NCT Tissue Bank, National Center for Tumor Diseases (NCT), Heidelberg, Germany
- Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany
| | - Hendrik Bläker
- Institute of Pathology, Charité University Medicine, Berlin, Germany
| | - Matthias Kloor
- Department of Applied Tumor Biology, Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany
| | - Dominique Scherer
- Institute of Medical Biometry and Informatics, University Hospital Heidelberg, Heidelberg, Germany
| | - Alexis Ulrich
- Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, University of Heidelberg, Germany
| | - Cornelia M Ulrich
- Huntsman Cancer Institute, Population Sciences, Salt Lake City, Utah
- Department of Population Health Sciences, University of Utah, Salt Lake City, Utah
| | - Aung K Win
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, Melbourne, Australia
| | - Jane C Figueiredo
- Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles California
| | - John L Hopper
- Colorectal Medicine and Genetics, The Royal Melbourne Hospital, Victoria, Australia
| | - Finlay Macrae
- Colorectal Medicine and Genetics, The Royal Melbourne Hospital, Victoria, Australia
| | - Roger L Milne
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, Melbourne, Australia
- Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia
| | - Graham G Giles
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, Melbourne, Australia
- Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia
| | - Daniel D Buchanan
- Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, Victoria, Australia
- University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Parkville, Victoria, Australia
- Genomic Medicine and Family Cancer Clinic, Royal Melbourne Hospital, Parkville, Victoria, Australia
| | - Ulrike Peters
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
- Department of Epidemiology, University of Washington, Seattle, Washington
| | - Michael Hoffmeister
- Division of Clinical Epidemiology and Aging Research, DKFZ, Heidelberg, Germany
| | - Hermann Brenner
- Division of Clinical Epidemiology and Aging Research, DKFZ, Heidelberg, Germany
- Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany
- German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Polly A Newcomb
- Institute of Translational Genomics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Jenny Chang-Claude
- Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
- Cancer Epidemiology Group, University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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Yang G, Dong K, Zhang Z, Zhang E, Liang B, Chen X, Huang Z. EXO1 Plays a Carcinogenic Role in Hepatocellular Carcinoma and is related to the regulation of FOXP3. J Cancer 2020; 11:4917-4932. [PMID: 32626539 PMCID: PMC7330697 DOI: 10.7150/jca.40673] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2019] [Accepted: 05/29/2020] [Indexed: 12/21/2022] Open
Abstract
Exonuclease 1 (EXO1), a member of the RAD2 nuclease family, was first described as possessing 5' to 3' nuclease activity and 5' structure-specific endonuclease activity. Here, we show that EXO1 is significantly upregulated in HCC tumor tissues and that high EXO1 expression is significantly correlated with liver cirrhosis. We further demonstrate that EXO1 knockdown decreases proliferation and colony forming abilities of HCC cells in vitro and tumorigenicity in vivo, as well as decreases migration and invasive capabilities of HCC cells. Alternatively, EXO1 overexpression significantly increases the proliferation, colony forming ability, and migration and invasive capabilities of HCC cells in vitro. Additionally, we truncated a region upstream of the transcription start site (TSS) of EXO1 and used the region with the strongest transcriptional activity to predict that the transcription factor FOXP3 can bind to the EXO1 promoter. Bioinformatics analysis found that FOXP3 was positively correlated with EXO1 and luciferase reporter assays and RT-PCR confirmed that FOXP3 could enhance the transcriptional activity of EXO1. CCK-8 assays showed that depletion of FOXP3 further reduces cell proliferation ability after knocking down of EXO1 in vitro. Taken together, our findings indicate that EXO1 acts as an oncogene in HCC and its expression level is related to FOXP3 activity.
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Affiliation(s)
- Guang Yang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Keshuai Dong
- Department of Hepatobiliary and Laparoscopic Surgery, Renmin Hospital, Wuhan University, Hubei Key Laboratory of Digestive System Disease, Wuhan, China
| | - Zunyi Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Erlei Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Binyong Liang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaoping Chen
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhiyong Huang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Wang Z, Zhang J. FOXP3 promotes colorectal carcinoma liver metastases by evaluating MMP9 expression via regulating S-adenosylmethionine metabolism. ANNALS OF TRANSLATIONAL MEDICINE 2020; 8:592. [PMID: 32566619 PMCID: PMC7290543 DOI: 10.21037/atm-20-3287] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Background Growing evidence has proved that Forkhead box protein 3 (FOXP3), which is a master regulatory gene in the development and function of regulatory T-cells, is expressed in human cancer cells. This expression indicates the crucial role FOXP3 takes up as the disease progresses. However, its role in colorectal cancer (CRC) liver metastasis is still mostly unknown. This study set out to explore the molecular characteristics of FOXP3 in driving the liver metastasis within CRC. Methods We downloaded the RNA-seq data from the GSE50760. Weighted gene co-expression network analysis (WGCNA)WGCNA and RNA-Seq analysis were applied to find the key gene network associated with colorectal cancer liver metastasis. Then we performed pathway enrichment analysis on liver metastasis-associated gene set. Immunohistochemistry, in vitro and in vivo studies were conducted to test expression and function of FOXP3 in CRC tissues and liver metastasis tissues. Non-targeted metabolomics analysis was performed to identify the alteration of FOXP3 expression in metabolites of colorectal cancer liver metastasis. Western blot was performed to confirm changes of matrix metalloproteinase 9MMP9 expression were downstream events of S-adenosyl-methionine (SAM). Results We found that FOXP3 and MMP9 exhibited co-expression relationships and affected liver metastasis in CRC. Upregulation of FOXP3 promotes cell migration and invasion in CRC, which suggests a pro-cancer effect. Moreover, metabolomics analysis showed that knockdown of FOXP3 significantly reduced SAM levels, and changes of MMP9 expression were downstream events of SAM, which is concentration-dependent. Besides, The Kyoto Encyclopedia of Genes and Genomes (KEGG) and Western blot analysis confirmed that overexpression of FOXP3 activates the Wnt pathway to promote colon cancer metastasis. Conclusions Our results altogether suggested that FOXP3 expression inhibited the SAM cycle to reduce SAMe levels, resulting in altered MMP9 expression and helped CRC liver metastasis.
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Affiliation(s)
- Zhe Wang
- Medical Oncology Department of Gastrointestinal Cancer, Liaoning Cancer Hospital & Institute, Cancer Hospital of China Medical University, Shenyang 110042, China
| | - Jingdong Zhang
- Medical Oncology Department of Gastrointestinal Cancer, Liaoning Cancer Hospital & Institute, Cancer Hospital of China Medical University, Shenyang 110042, China
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27
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The Prognostic Implications of Tumor Infiltrating Lymphocytes in Colorectal Cancer: A Systematic Review and Meta-Analysis. Sci Rep 2020; 10:3360. [PMID: 32099066 PMCID: PMC7042281 DOI: 10.1038/s41598-020-60255-4] [Citation(s) in RCA: 190] [Impact Index Per Article: 38.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2019] [Accepted: 02/03/2020] [Indexed: 12/17/2022] Open
Abstract
Tumor-infiltrating lymphocytes (TILs) are an important histopathologic feature of colorectal cancer that confer prognostic information. Previous clinical and epidemiologic studies have found that the presence and quantification of tumor-infiltrating lymphocytes are significantly associated with disease-specific and overall survival in colorectal cancer. We performed a systematic review and meta-analysis, establishing pooled estimates for survival outcomes based on the presence of TILs in colon cancer. PubMed (Medline), Embase, Cochrane Library, Web of Science, and ClinicalTrials.gov were searched from inception to April 2017. Studies were included, in which the prognostic significance of intratumoral tumor infiltrating lymphocytes, as well as subsets of CD3, CD8, FOXP3, CD45R0 lymphocytes, were determined within the solid tumor center, the invasive margin, and tumor stroma. Random-effects models were calculated to estimated summary effects using hazard ratios. Forty-three relevant studies describing 21,015 patients were included in our meta-analysis. The results demonstrate that high levels of generalized TILS as compared to low levels had an improved overall survival (OS) with a HR of 0.65 (p = <0.01). In addition, histologically localized CD3+ T-cells at the tumor center were significantly associated with better disease-free survival (HR = 0.46, 95% CI 0.36–0.61, p = 0.05), and CD3 + cells at the invasive margin were associated with improved disease-free survival (HR = 0.57, 95% CI 0.38–0.86, p = 0.05). CD8+ T-cells at the tumor center had statistically significant prognostic value on cancer-specific survival and overall survival with HRs of 0.65 (p = 0.02) and 0.71 (p < 0.01), respectively. Lastly, FOXP3+ T-cells at the tumor center were associated with improved prognosis for cancer-specific survival (HR = 0.65, p < 0.01) and overall survival (HR = 0.70, p < 0.01). These findings suggest that TILs and specific TIL subsets serve as prognostic biomarkers for colorectal cancer.
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Wang Y, Zhang Q, Chen Y, Liang CL, Liu H, Qiu F, Dai Z. Antitumor effects of immunity-enhancing traditional Chinese medicine. Biomed Pharmacother 2020; 121:109570. [PMID: 31710893 DOI: 10.1016/j.biopha.2019.109570] [Citation(s) in RCA: 184] [Impact Index Per Article: 36.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2019] [Revised: 10/07/2019] [Accepted: 10/20/2019] [Indexed: 02/06/2023] Open
Abstract
Traditional Chinese Medicine (TCM) has been traditionally used to treat patients with cancers in China. It not only alleviates the symptoms of tumor patients and improves their quality of life, but also controls the size of tumors and prolongs the survival of tumor patients. While some herbs of TCM may exert therapeutic effects by directly targeting cancer cells or reducing side effects caused by antitumor drugs, others can control tumor growth and metastasis via enhancing antitumor immunity. In particular, TCM can exert antitumor effects by upregulating immune responses even in immunosuppressive tumor microenvironment. For instance, it reduces the number of M2-type macrophages and Treg cells in the tumor tissue. Although extensive reviews on directly killing cancer cells by TCM have been conducted, a review of anticancer activity of TCM solely based on its immunity-enhancing capacity is unusual. This review will summarize research progress of antitumor TCM that regulates the immune system, including both innate immunity, such as macrophages, dendritic cells, natural killer cells and MDSCs, and adaptive immunity, including CD4+/CD8+ T lymphocytes, regulatory T cells (Tregs) and B cells. As cancer immunotherapy has recently achieved certain success, it is expected that the clinical applications of immunity-enhancing TCM or traditional medicine for treating various cancer patients will be expanded. Further studies on the mechanisms by which TCM regulates immunity will provide new insights into how TCM controls tumor growth and metastasis, and may help improve its therapeutic effects on various cancers in clinic.
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Affiliation(s)
- Yeshu Wang
- Section of Immunology & Joint Immunology Program, the Second Clinical Medical College of Guangzhou University of Chinese Medicine, and Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, Guangdong 510006, China
| | - Qunfang Zhang
- Section of Immunology & Joint Immunology Program, the Second Clinical Medical College of Guangzhou University of Chinese Medicine, and Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, Guangdong 510006, China
| | - Yuchao Chen
- Section of Immunology & Joint Immunology Program, the Second Clinical Medical College of Guangzhou University of Chinese Medicine, and Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, Guangdong 510006, China
| | - Chun-Ling Liang
- Section of Immunology & Joint Immunology Program, the Second Clinical Medical College of Guangzhou University of Chinese Medicine, and Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, Guangdong 510006, China
| | - Huazhen Liu
- Section of Immunology & Joint Immunology Program, the Second Clinical Medical College of Guangzhou University of Chinese Medicine, and Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, Guangdong 510006, China
| | - Feifei Qiu
- Section of Immunology & Joint Immunology Program, the Second Clinical Medical College of Guangzhou University of Chinese Medicine, and Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, Guangdong 510006, China
| | - Zhenhua Dai
- Section of Immunology & Joint Immunology Program, the Second Clinical Medical College of Guangzhou University of Chinese Medicine, and Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, Guangdong 510006, China.
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Han L, Dai S, Li Z, Zhang C, Wei S, Zhao R, Zhang H, Zhao L, Shan B. Combination of the natural compound Periplocin and TRAIL induce esophageal squamous cell carcinoma apoptosis in vitro and in vivo: Implication in anticancer therapy. J Exp Clin Cancer Res 2019; 38:501. [PMID: 31864387 PMCID: PMC6925860 DOI: 10.1186/s13046-019-1498-z] [Citation(s) in RCA: 23] [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: 09/23/2019] [Accepted: 12/04/2019] [Indexed: 11/29/2022] Open
Abstract
BACKGROUND Esophageal cancer is one of the most common malignant tumors in the world. With currently available therapies, only 20% ~ 30% patients can survive this disease for more than 5 years. TRAIL, a natural ligand for death receptors that can induce the apoptosis of cancer cells, has been explored as a therapeutic agent for cancers, but it has been reported that many cancer cells are resistant to TRAIL, limiting the potential clinical use of TRAIL as a cancer therapy. Meanwhile, Periplocin (CPP), a natural compound from dry root of Periploca sepium Bge, has been studied for its anti-cancer activity in a variety of cancers. It is not clear whether CPP and TRAIL can have activity on esophageal squamous cell carcinoma (ESCC) cells, or whether the combination of these two agents can have synergistic activity. METHODS We used MTS assay, flow cytometry and TUNEL assay to detect the effects of CPP alone or in combination with TRAIL on ESCC cells. The mechanism of CPP enhances the activity of TRAIL was analyzed by western blot, dual luciferase reporter gene assay and chromatin immunoprecipitation (ChIP) assay. The anti-tumor effects and the potential toxic side effects of CPP alone or in combination with TRAIL were also evaluated in vivo. RESULTS In our studies, we found that CPP alone or in combination with TRAIL could inhibit the proliferation of ESCC cells and induce apoptosis, and we certificated that combination of two agents exert synergized functions. For the first time, we identified FoxP3 as a key transcriptional repressor for both DR4 and DR5. By down-regulating FoxP3, CPP increases the expression of DR4/DR5 and renders ESCC cells much more sensitive to TRAIL. We also showed that CPP reduced the expression of Survivin by inhibiting the activity of Wnt/β-catenin pathway. All these contributed to synergistic activity of CPP and TRAIL on ESCC cells in vitro and in vivo. CONCLUSION Our data suggest that CPP and TRAIL could be further explored as potential therapeutic approach for esophageal cancer.
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Affiliation(s)
- Lujuan Han
- Research Centre, the Fourth Hospital of Hebei Medical University, 12# Jiankang Road, Shijiazhuang, 050011, Hebei, China
| | - Suli Dai
- Research Centre, the Fourth Hospital of Hebei Medical University, 12# Jiankang Road, Shijiazhuang, 050011, Hebei, China
| | - Zhirong Li
- Research Centre, the Fourth Hospital of Hebei Medical University, 12# Jiankang Road, Shijiazhuang, 050011, Hebei, China
| | - Cong Zhang
- Research Centre, the Fourth Hospital of Hebei Medical University, 12# Jiankang Road, Shijiazhuang, 050011, Hebei, China
| | - Sisi Wei
- Research Centre, the Fourth Hospital of Hebei Medical University, 12# Jiankang Road, Shijiazhuang, 050011, Hebei, China
| | - Ruinian Zhao
- Research Centre, the Fourth Hospital of Hebei Medical University, 12# Jiankang Road, Shijiazhuang, 050011, Hebei, China
| | - Hongtao Zhang
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Lianmei Zhao
- Research Centre, the Fourth Hospital of Hebei Medical University, 12# Jiankang Road, Shijiazhuang, 050011, Hebei, China.
| | - Baoen Shan
- Research Centre, the Fourth Hospital of Hebei Medical University, 12# Jiankang Road, Shijiazhuang, 050011, Hebei, China.
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Forkhead box P3 is selectively expressed in human trophoblasts and decreased in recurrent pregnancy loss. Placenta 2019; 81:1-8. [DOI: 10.1016/j.placenta.2019.04.003] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2019] [Revised: 03/21/2019] [Accepted: 04/09/2019] [Indexed: 12/31/2022]
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Yosudjai J, Wongkham S, Jirawatnotai S, Kaewkong W. Aberrant mRNA splicing generates oncogenic RNA isoforms and contributes to the development and progression of cholangiocarcinoma. Biomed Rep 2019; 10:147-155. [PMID: 30906543 PMCID: PMC6403481 DOI: 10.3892/br.2019.1188] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2018] [Accepted: 01/04/2019] [Indexed: 12/13/2022] Open
Abstract
Cholangiocarcinoma is a lethal biliary cancer, with an unclear molecular pathogenesis. Alternative splicing is a post-transcriptional modification that generates mature mRNAs, which are subsequently translated into proteins. Aberrant alternative splicing has been reported to serve a role in tumor initiation, maintenance and metastasis in several types of human cancer, including cholangiocarcinoma. In this review, the aberrant splicing of genes and the functional contributions of the spliced genes, in the carcinogenesis, progression and aggressiveness of cholangiocarcinoma are summarized. In addition, factors that influence this aberrant splicing that may be relevant as therapeutic targets or prognosis markers for cholangiocarcinoma are discussed.
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Affiliation(s)
- Juthamas Yosudjai
- Department of Biochemistry, Faculty of Medical Science, Naresuan University, Phitsanulok 65000, Thailand
| | - Sopit Wongkham
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Siwanon Jirawatnotai
- Siriraj Center for Research of Excellence (SiCORE) for System Pharmacology, Department of Pharmacology, Faculty of Medicine, Siriraj Medical School, Mahidol University, Bangkok 10700, Thailand
| | - Worasak Kaewkong
- Department of Biochemistry, Faculty of Medical Science, Naresuan University, Phitsanulok 65000, Thailand
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Chen YH, Zhou BY, Wu GC, Liao DQ, Li J, Liang SS, Wu XJ, Xu JF, Chen YH, Di XQ, Lin QY. Effects of exogenous IL-37 on the biological characteristics of human lung adenocarcinoma A549 cells and the chemotaxis of regulatory T cells. Cancer Biomark 2018; 21:661-673. [PMID: 29278881 DOI: 10.3233/cbm-170732] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND This study aims to investigate the effects of exogenous interleukin (IL)-37 on the biological characteristics of human lung adenocarcinoma A549 cells and the chemotaxis of regulatory T (Treg) cells. METHODS After isolating the CD4+ CD25+ Treg cells from the peripheral blood, flow cytometry was used to detect the purity of the Treg cells. A549 cells were divided into blank (no transfection), empty plasmid (transfection with pIRES2-EGFP empty plasmid) or IL-37 group (transfection with pIRES2-EGFP-IL-37 plasmid). RT-PCR was used to detect mRNA expression of IL-37 and ELISA to determine IL-37 and MMP-9 expressions. Western blotting was applied to detect the protein expressions of PCNA, Ki-67, Cyclin D1, CDK4, cleaved caspase-3 and cleaved caspase-9. MTT assay, flow cytometry, scratch test and transwell assay were performed to detect cell proliferation, cycle, apoptosis, migration and invasion. Effect of exogenous IL-37 on the chemotaxis of Treg cells was measured through transwell assay. Xenograft models in nude mice were eastablished to detect the impact of IL-37 on A549 cells. RESULTS The IL-37 group had a higher IL-37 expression, cell apoptosis in the early stage and percentage of cells in the G0/G1 phase than the blank and empty plasmid groups. The IL-37 group had a lower MMP-9 expression, optical density (OD), percentage of cells in the S and G2/M phases, migration, invasion and chemotaxis of CD4+CD25+ Foxp3+ Treg cells. The xenograft volume and weight of nude mice in the IL-37 group were lower than those in the blank and empty plasmid groups. Compared with the blank and empty plasmid groups, the IL-37 group had significantly reduced expression of PCNA, Ki-67, Cyclin D1 and CDK4 but elevated expression of cleaved caspase-3 and cleaved caspase-9. CONCLUSION Therefore, exogenous IL-37 inhibits the proliferation, migration and invasion of human lung adenocarcinoma A549 cells as well as the chemotaxis of Treg cells while promoting the apoptosis of A549 cells.
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Affiliation(s)
- Yu-Hua Chen
- Department of Clinical Laboratory, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524001, Guangdong, China
| | - Bi-Yun Zhou
- Department of Interventional Ward, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524001, Guangdong, China
| | - Guo-Cai Wu
- Department of Hematology, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524001, Guangdong, China
| | - De-Quan Liao
- Department of Clinical Laboratory, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524001, Guangdong, China
| | - Jing Li
- Department of Clinical Laboratory, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524001, Guangdong, China
| | - Si-Si Liang
- Department of Orthopedics, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524001, Guangdong, China
| | - Xian-Jin Wu
- Department of Clinical Laboratory, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524001, Guangdong, China
| | - Jun-Fa Xu
- Department of Clinical Immunology, Institute of Laboratory Medicine Guangdong Medical University, Dongguan 523808, Guangdong, China
| | - Yong-Hua Chen
- Department of Pathology, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524001, Guangdong, China
| | - Xiao-Qing Di
- Department of Pathology, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524001, Guangdong, China
| | - Qiong-Yan Lin
- Department of Pathology, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524001, Guangdong, China
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Stasikowska-Kanicka O, Wągrowska-Danilewicz M, Danilewicz M. Immunohistochemical Analysis of Foxp3 +, CD4 +, CD8 + Cell Infiltrates and PD-L1 in Oral Squamous Cell Carcinoma. Pathol Oncol Res 2018; 24:497-505. [PMID: 28669079 PMCID: PMC5972165 DOI: 10.1007/s12253-017-0270-y] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2016] [Accepted: 06/22/2017] [Indexed: 11/26/2022]
Abstract
The immunoexpression of the PD-L1 and the number of immune infiltrating cells have been shown to be a significant prognostic factors in various human cancers. Immunohistochemical method was used to examine the immunoexpression of PD-L1 and number of Foxp3+, CD4+, CD8+ cells in 78 cases of oral squamous cell carcinomas (OSCCs): with better prognosis - OSCCBP (n = 37), and with poorer prognosis - OSCCPP (n = 41), and 18 cases of normal mucosa as a control. The immunoexpression of PD-L1 and the mean number of Foxp3+ cells was significantly increased in OSCCPP group in comparison to OSCCBP and control groups. The mean number of CD4+ cells was significantly increased in OSCCPP group in comparison to OSCCBP and control groups. CD8+ cells were significantly more numerous in OSCCBP group in comparison to OSCCPP and control group. In both OSCCPP and OSCCBP groups there were positive significant correlations between number of Foxp3+ and CD4+ cells. We found positive correlations between the immunoexpression of PD-L1 and numbers of Foxp3+ cells, and negative correlation between the immunoexpression of PD-L1 and numbers of CD8+ cells in both OSCCPP and OSCCBP groups. We found also significant positive correlation between immunoexpression of PD-L1 and the number of CD4+ cells in OSCCPP group. In conclusion, our findings support the hypothesis of involvement of Tregs and PD-L1 in OSCC development and progression.
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Affiliation(s)
- Olga Stasikowska-Kanicka
- Department of Nephropathology, Medical University of Lodz, ul. Czechoslowacka 8/10, 92-216 Lodz, Poland
| | | | - Marian Danilewicz
- Department of Pathomorphology, Medical University of Lodz, Lodz, Poland
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Immuno-therapeutic potential of Schistosoma mansoni and Trichinella spiralis antigens in a murine model of colon cancer. Invest New Drugs 2018; 37:47-56. [PMID: 29808307 DOI: 10.1007/s10637-018-0609-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2018] [Accepted: 05/01/2018] [Indexed: 02/06/2023]
Abstract
Considerable evidence indicates a negative correlation between the prevalence of some parasitic infections and cancer and their interference with tumor growth. Therefore, parasitic antigens seem to be promising candidates for cancer immunotherapy. In this study, the therapeutic efficacy of autoclaved Schistosoma mansoni and Trichinella spiralis antigens against a colon cancer murine model was investigated. Both antigens showed immunomodulatory potential, as evidenced by a significant decrease in serum IL-17, a significant increase in serum IL-10, and the percentage of splenic CD4+T-cells and intestinal FoxP3+ Treg cells. However, treatment with S. mansoni antigen yielded protection against the deleterious effect of DMH-induced colon carcinogenesis only, with a significant decrease in the average lesion size and number of neoplasias per mouse. For the first time, we report an inhibitory effect of S. mansoni antigen on the progression of chemically induced colon carcinogenesis, but the exact mechanism has yet to be clarified. This anti-tumor strategy could introduce a new era of medicine in which a generation of anticancer vaccines of parasitic origin would boost the therapy for incurable cancers.
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Skarmoutsou E, Bevelacqua V, D' Amico F, Russo A, Spandidos DA, Scalisi A, Malaponte G, Guarneri C. FOXP3 expression is modulated by TGF‑β1/NOTCH1 pathway in human melanoma. Int J Mol Med 2018; 42:392-404. [PMID: 29620159 PMCID: PMC5979787 DOI: 10.3892/ijmm.2018.3618] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2018] [Accepted: 04/04/2018] [Indexed: 12/18/2022] Open
Abstract
Forkhead box protein 3 (FOXP3) transcription factor is expressed by immune cells and several human cancers and is associated with tumor aggressiveness and unfavorable clinical outcomes. NOTCH and transforming growth factor-β (TGF-β) protumorigenic effects are mediated by FOXP3 expression in several cancer models; however, their interaction and role in melanoma is unknown. We investigated TGF-β-induced FOXP3 gene expression during NOTCH1 signaling inactivation. Primary (WM35) and metastatic melanoma (A375 and A2058) cell lines and normal melanocytes (NHEM) were used. FOXP3 subcellular distribution was evaluated by immuno cytochemical analysis. Gene expression levels were assessed by reverse transcription-quantitative polymerase chain reaction. Protein levels were assessed by western blot analysis. The γ-secretase inhibitor (GSI) was used for NOTCH1 inhibition and recombinant human (rh)TGF-β was used for melanoma cell stimulation. Cell proliferation and viability were respectively assessed by MTT and Trypan blue dye assays. FOXP3 mRNA and protein levels were progressively higher in WM35, A375 and A2058 cell lines compared to NHEM and their levels were further increased after stimulation with rh-TGF-β. TGF-β-mediated FOXP3 expression was mediated by NOTCH1 signaling. Inhibition of NOTCH1 with concomitant rh-TGF-β stimulation determined the reduction in gene expression and protein level of FOXP3. Finally, melanoma cell line proliferation and viability were reduced by NOTCH1 inhibition. The results show that nn increase in FOXP3 expression in metastatic melanoma cell lines is a potential marker of tumor aggressiveness and metastasis. NOTCH1 is a central mediator of TGF-β-mediated FOXP3 expression and NOTCH1 inhibition produces a significant reduction of melanoma cell proliferation and viability.
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Affiliation(s)
- Eva Skarmoutsou
- Department of Biomedical and Biotechnological Science, University of Catania, 95124 Catania, Italy
| | - Valentina Bevelacqua
- Department of Biomedical and Biotechnological Science, University of Catania, 95124 Catania, Italy
| | - Fabio D' Amico
- Department of Biomedical and Biotechnological Science, University of Catania, 95124 Catania, Italy
| | - Angela Russo
- Department of Biomedical and Biotechnological Science, University of Catania, 95124 Catania, Italy
| | - Demetrios A Spandidos
- Laboratory of Clinical Virology, Medical School, University of Crete, 71003 Heraklion, Crete, Greece
| | - Aurora Scalisi
- Unit of Oncologic Diseases, ASP‑Catania, 95100 Catania, Italy
| | - Grazia Malaponte
- Research Unit of the Catania Section of the Italian League Against Cancer, 95122 Catania, Italy
| | - Claudio Guarneri
- Department of Clinical and Experimental Medicine, Section of Dermatology, University of Messina, 98122 Messina, Italy
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Therapeutic Antibodies in Cancer Therapy. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2017; 917:95-120. [PMID: 27236554 DOI: 10.1007/978-3-319-32805-8_6] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
The therapeutic arsenal in solid tumors comprises different anticancer strategies with diverse chemotherapeutic agents and a growing number of biological substances. Large clinical study-based chemotherapeutic protocols combined with biologicals have become an important component in (neo-) adjuvant therapy alongside surgery in solid cancers as well as radiation therapy in some instances. In recent years, monoclonal antibodies have entered the mainstream of cancer therapy. Their first use was as antagonists of oncogenic receptor tyrosine kinases, but today monoclonal antibodies have emerged as long-sought vehicles for the targeted delivery of potent chemotherapeutic agents and as powerful tools to manipulate anticancer immune responses. There is a growing number of FDA approved monoclonal antibodies and small molecules targeting specific types of cancer suggestive of the clinical relevance of this approach.Targeted cancer therapies , also referred to as personalized medicine, are being studied for use alone, in combination with other targeted therapies, and in combination with chemotherapy. The use of monoclonal antibodies in colorectal and gastric cancer for example have shown best outcome when combined with chemotherapy, even though single agent anti-EGFR antibodies seem to be active in particular setting of metastatic colorectal cancer patients. However, it is not well defined whether the addition of anti-VEGF - and anti-EGFR strategies to chemotherapy could improve outcome in those patients susceptible to colorectal cancer-related metastases resection. Among the most promising approaches to activating therapeutic antitumor immunity is the blockade of immune checkpoints, exemplified by the recently FDA-approved agent, Ipilimumab, an antibody that blocks the coinhibitory receptor CTLA-4. Capitalizing on the success of Ipilimumab, agents that target a second coinhibitory receptor, PD-1, or its ligand, PD-L1, are in clinical development. This section attempts to discuss recent progress of targeted agents and in tackling a more general target applicable to gastrointestinal cancer .
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Xu P, Fan W, Zhang Z, Wang J, Wang P, Li Y, Yu M. The Clinicopathological and Prognostic Implications of FoxP3 + Regulatory T Cells in Patients with Colorectal Cancer: A Meta-Analysis. Front Physiol 2017; 8:950. [PMID: 29209232 PMCID: PMC5702298 DOI: 10.3389/fphys.2017.00950] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2017] [Accepted: 11/08/2017] [Indexed: 12/11/2022] Open
Abstract
Background and Objective: Forkhead box P3 (FoxP3) is known as the specific marker for regulatory T lymphocytes (Tregs), which are responsible for self-tolerance and disturb the antitumor immunity. However, the prognostic implication of tumor-infiltrating FoxP3+ Tregs in patients with colorectal cancer (CRC) still remains controversial. The aim of this present study was to investigate the prognostic role of FoxP3+ Tregs in CRC through meta-analysis. Methods: PubMed, Embase and Web of Science were searched for relevant articles up to December 12, 2016. Pooled hazard ratio (HR) and 95% confidence interval (CI) were calculated to explore the prognostic value of FoxP3+ Tregs in CRC. Odds ratio (OR) was calculated to investigate the correlation between FoxP3+ Tregs and pathological parameters. Results: A total of 18 studies comprising 3,627 patients with CRC were enrolled in our meta-analysis. The combined HR for FoxP3+ Tregs on cancer-specific survival was 0.70 (95% CI = 0.62-0.80, P < 0.001). High FoxP3+ Tregs level was also associated with favorable prognosis on overall survival (HR = 0.76, 95% CI = 0.58-1.01, P = 0.058), with P-value very close to the statistical threshold. Yet, there was no correlation between FoxP3+ Tregs infiltration and disease-free survival (HR = 0.83, 95% CI = 0.63-1.09, P = 0.182). Moreover, FoxP3+ Tregs infiltration was significantly correlated with pT stage (OR = 0.50, 95% CI = 0.39-0.65, P < 0.001), tumor grade (OR = 0.77, 95% CI = 0.61-0.98, P = 0.032), lymphatic invasion (OR = 0.25, 95% CI = 0.07-0.89, P = 0.033) and vascular invasion (OR = 0.67, 95% CI = 0.52-0.86, P = 0.001). Conclusion: The present meta-analysis suggests that high FoxP3+ Tregs infiltration is inclined to indicate favorable prognosis and is associated with the pathogenesis of CRC. Immunotherapy targeting Tregs in patients with CRC should be further investigated.
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Affiliation(s)
- Peipei Xu
- Department of Clinical Laboratory, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Wei Fan
- Department of Clinical Laboratory, Zhongnan Hospital of Wuhan University, Wuhan, China.,Department of Pathology, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Zheng Zhang
- Department of Clinical Laboratory, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - June Wang
- Department of Clinical Laboratory, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Ping Wang
- Department of Clinical Laboratory, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Yirong Li
- Department of Clinical Laboratory, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Mingxia Yu
- Department of Clinical Laboratory, Zhongnan Hospital of Wuhan University, Wuhan, China
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Hu G, Li Z, Wang S. Tumor-infiltrating FoxP3 + Tregs predict favorable outcome in colorectal cancer patients: A meta-analysis. Oncotarget 2017; 8:75361-75371. [PMID: 29088871 PMCID: PMC5650426 DOI: 10.18632/oncotarget.17722] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2016] [Accepted: 04/11/2017] [Indexed: 02/06/2023] Open
Abstract
FoxP3+ regulatory T cells (FoxP3+ Tregs) are considered to be a key mediator in immune escape and tumor progression. However, the role of FoxP3+ Tregs in human colorectal cancer (CRC) remains controversial. Herein, we conducted a meta-analysis including 17 published studies with 3811 patients identified from PubMed and EBSCO to assess the prognostic impact of tumor-infiltrating FoxP3+ Tregs in human CRC. We found FoxP3+ Tregs infiltrating into both intraepithelium and stroma within tumor were significantly positively correlated with 1, 3, 5 and 10-year overall survival (OS), but not with 1, 3, 5-year disease-free survival (DFS) of patients. Interestingly, in stratified analyses by compartments within tumor FoxP3+ Tregs infiltrating into, FoxP3+ Tregs invading stromal compartment significantly improved 3 and 5-year OS, yet OS wasn't improved when FoxP3+ Tregs infiltrated into intraepithelium only. Furthermore, FoxP3+ Tregs invading both intraepithelium and stroma significantly inversely correlated with TNM stage of CRC. In conclusion, High density of FoxP3+ Tregs within tumor especially at stromal compartment leads to a favorable outcome in CRC, implicating FoxP3+ Tregs are one of valuable indexes for prognostic prediction in human CRC.
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Affiliation(s)
- Guoming Hu
- Department of General Surgery (Breast and Thyroid Surgery), Shaoxing People’s Hospital, Shaoxing Hospital of Zhejiang University, 312000, Shaoxing, China
| | - Zhi’an Li
- Department of Surgical Oncology, Shaoxing Second Hospital, 312000, Shaoxing, China
| | - Shimin Wang
- Department of Nephrology, Shaoxing People’s Hospital, Shaoxing Hospital of Zhejiang University, 312000, Shaoxing, China
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Tang J, Yang Z, Wang Z, Li Z, Li H, Yin J, Deng M, Zhu W, Zeng C. Foxp3 is correlated with VEGF-C expression and lymphangiogenesis in cervical cancer. World J Surg Oncol 2017; 15:173. [PMID: 28923073 PMCID: PMC5604510 DOI: 10.1186/s12957-017-1221-5] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2017] [Accepted: 08/07/2017] [Indexed: 01/11/2023] Open
Abstract
BACKGROUND Recent observations revealed Foxp3 participated in the development of cervical cancer. Furthermore, Foxp3 has a vital function in the lymphatic metastasis of cervical cancer. However, it is unclear whether Foxp3 is correlated with lymphangiogenesis of cervical cancer. METHODS In this experiment, expression of Foxp3 and VEGF-C was detected in 50 cervical cancer samples by immunohistochemistry. In addition, we evaluated the association between Foxp3 and VEGF-C expression and lymphangiogenesis of cervical cancer evaluated by lymphatic vessel density. RESULTS These data demonstrate Foxp3 is positively correlated with VEGF-C expression. Furthermore, Foxp3 is associated with lymphangiogenesis of cervical cancer. CONCLUSIONS These results revealed Foxp3 play an important role in lymphangiogenesis of cervical cancer. TRIAL REGISTRATION Gunagdong Medical University, PJ2013049.
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Affiliation(s)
- Jiabu Tang
- Department of Pathology, Guangdong Medical University, 1 Xincheng Road, Dongguan, 523808, China
| | - Zheng Yang
- Department of Pathology, The First Affiliated Hospital of Sun Yat-sen University, Zhongshan 2nd Road 74, Guangzhou, 510080, China
| | - Zhuo Wang
- Department of Pathology, The First Affiliated Hospital of Sun Yat-sen University, Zhongshan 2nd Road 74, Guangzhou, 510080, China
| | - Zhen Li
- Department of Pathology, Guangdong Medical University, 1 Xincheng Road, Dongguan, 523808, China
| | - Hongmei Li
- Department of Pathology, Guangdong Medical University, 1 Xincheng Road, Dongguan, 523808, China
| | - Jinbao Yin
- Department of Pathology, Guangdong Medical University, 1 Xincheng Road, Dongguan, 523808, China
| | - Min Deng
- Cancer Hospital and Cancer Research Institute, Guangzhou Medical University, Guangzhou, 510095, China.
| | - Wei Zhu
- Department of Pathology, Guangdong Medical University, 1 Xincheng Road, Dongguan, 523808, China.
| | - Chao Zeng
- Department of Pathology, Guangdong Medical University, 1 Xincheng Road, Dongguan, 523808, China.
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Shi JY, Ma LJ, Zhang JW, Duan M, Ding ZB, Yang LX, Cao Y, Zhou J, Fan J, Zhang X, Zhao YJ, Wang XY, Gao Q. FOXP3 Is a HCC suppressor gene and Acts through regulating the TGF-β/Smad2/3 signaling pathway. BMC Cancer 2017; 17:648. [PMID: 28903735 PMCID: PMC5598072 DOI: 10.1186/s12885-017-3633-6] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2017] [Accepted: 08/28/2017] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND FOXP3 has been discovered to be expressed in tumor cells and participate in the regulation of tumor behavior. Herein, we investigated the clinical relevance and biological significance of FOXP3 expression in human hepatocellular carcinoma (HCC). METHODS Expression profile of FOXP3 was analyzed using real-time RT-PCR, western blotting and immunofluorescence on HCC cell lines, and immunostaing of a tissue microarray containing of 240 primary HCC samples. The potential regulatory roles of FOXP3 were dissected by an integrated approach, combining biochemical assays, analysis of patient survival, genetic manipulation of HCC cell lines, mouse xenograft tumor models and chromatin immunoprecipitation (ChIP) sequencing. RESULTS FOXP3 was constitutively expressed in HCC cells with the existence of splice variants (especially exon 3 and 4 deleted, Δ3,4-FOXP3). High expression of FOXP3 significantly correlated with low serum α-fetoprotein (AFP) level, absence of vascular invasion and early TNM stage. Survival analyses revealed that increased FOXP3 expression was significantly associated with better survival and reduced recurrence, and served as an independent prognosticator for HCC patients. Furthermore, FOXP3 could potently suppress the proliferation and invasion of HCC cells in vitro and reduce tumor growth in vivo. However, Δ3,4-FOXP3 showed a significant reduction in the tumor-inhibiting effect. The inhibition of FOXP3 on HCC aggressiveness was acted probably by enhancing the TGF-β/Smad2/3 signaling pathway. CONCLUSION Our findings suggest that FOXP3 suppresses tumor progression in HCC via TGF-β/Smad2/3 signaling pathway, highlighting the role of FOXP3 as a prognostic factor and novel target for an optimal therapy against this fatal malignancy.
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Affiliation(s)
- Jie-Yi Shi
- Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, 180 Fenglin Road, Shanghai, 200032 People’s Republic of China
| | - Li-Jie Ma
- Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, 180 Fenglin Road, Shanghai, 200032 People’s Republic of China
| | - Ji-Wei Zhang
- Cancer Research Institute, Fudan University Shanghai Cancer Center, Shanghai, People’s Republic of China
| | - Meng Duan
- Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, 180 Fenglin Road, Shanghai, 200032 People’s Republic of China
| | - Zhen-Bin Ding
- Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, 180 Fenglin Road, Shanghai, 200032 People’s Republic of China
| | - Liu-Xiao Yang
- Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, 180 Fenglin Road, Shanghai, 200032 People’s Republic of China
| | - Ya Cao
- Cancer Research Institute, Xiangya School of Medicine, Central South University, Changsha, Hunan People’s Republic of China
| | - Jian Zhou
- Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, 180 Fenglin Road, Shanghai, 200032 People’s Republic of China
- Institute of Biomedical Sciences, Fudan University, Shanghai, People’s Republic of China
| | - Jia Fan
- Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, 180 Fenglin Road, Shanghai, 200032 People’s Republic of China
- Institute of Biomedical Sciences, Fudan University, Shanghai, People’s Republic of China
| | - Xiaoming Zhang
- Key Laboratory of Molecular Virology & Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, People’s Republic of China
| | - Ying-Jun Zhao
- Cancer Research Institute, Fudan University Shanghai Cancer Center, Shanghai, People’s Republic of China
| | - Xiao-Ying Wang
- Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, 180 Fenglin Road, Shanghai, 200032 People’s Republic of China
| | - Qiang Gao
- Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, 180 Fenglin Road, Shanghai, 200032 People’s Republic of China
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Li C, Sun L, Jiang R, Wang P, Xue H, Zhan Y, Gai X. Downregulation of FOXP3 inhibits cell proliferation and enhances chemosensitivity to cisplatin in human lung adenocarcinoma. Pathol Res Pract 2017; 213:1251-1256. [PMID: 28935177 DOI: 10.1016/j.prp.2017.09.004] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2017] [Revised: 08/12/2017] [Accepted: 09/05/2017] [Indexed: 01/09/2023]
Abstract
Our study aimed to investigate the biological role of FOXP3 expression in human lung adenocarcinoma (LAD) tissues and evaluate its involvement in cell proliferation and chemosensitivity to cisplatin in LAD cells. Paraffin-embedded tissues from 50 LAD patients were collected to detect FOXP3 and Ki-67 expression using immunohistochemistry (IHC). Downregulation of FOXP3 in A549 cells was performed using siRNA transfection. Real-time PCR or western blot assay was performed to analyze FOXP3 expression in A549 cells. Cell proliferation and cisplatin cytotoxicity test were assessed by CCK-8 assay. The expression of FOXP3 was significantly associated with lymph node metastasis and TNM stage of LAD patients. The FOXP3 expression was positively correlated with Ki-67 labelling index(LI)in LAD tissues. The downregulated expression of FOXP3 by siRNA transfection significantly inhibited cell proliferation and enhanced chemosensitivity to cisplatin in A549 cells. The expression of FOXP3 was significantly upregulated following cisplatin treatment in A549 cells. Our study indicates that FOXP3 may potentially be a novel molecular target in combating drug resistance in the chemotherapy of LAD.
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Affiliation(s)
- Chun Li
- Department of Immunology, School of Basic Medical Sciences, Beihua University, Jilin, Jilin 132013, People's Republic of China
| | - Liwei Sun
- Jilin Technology Innovation Center for Chinese Medicine Biotechnology, College of Biology and Chemistry, Beihua University, Jilin, Jilin 132013, People's Republic of China
| | - Rui Jiang
- Jilin Technology Innovation Center for Chinese Medicine Biotechnology, College of Biology and Chemistry, Beihua University, Jilin, Jilin 132013, People's Republic of China
| | - Peng Wang
- Department of Immunology, School of Basic Medical Sciences, Beihua University, Jilin, Jilin 132013, People's Republic of China
| | - Haogang Xue
- Department of Surgery, Affiliated Hospital of Beihua University, Jilin, Jilin 132013, People's Republic of China
| | - Yudong Zhan
- Department of Immunology, School of Basic Medical Sciences, Beihua University, Jilin, Jilin 132013, People's Republic of China
| | - Xiaodong Gai
- Department of Immunology, School of Basic Medical Sciences, Beihua University, Jilin, Jilin 132013, People's Republic of China.
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Miteva LD, Stanilov NS, Cirovski GМ, Stanilova SA. Upregulation of Treg-Related Genes in Addition with IL6 Showed the Significant Role for the Distant Metastasis in Colorectal Cancer. CANCER MICROENVIRONMENT 2017; 10:69-76. [PMID: 28868572 DOI: 10.1007/s12307-017-0198-5] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/05/2017] [Accepted: 08/29/2017] [Indexed: 12/20/2022]
Abstract
T helper 17 (Th17) and T regulatory (Treg) cytokines appear to be contributing greatly to colorectal cancer (CRC) development and progression. The aim of the current study was to investigate the expression of Foxp3; IL10; TGFB1; IL17A; IL6 and NOS2 genes in tumor tissue, regional positive lymph nodes and distant metastasis obtained from 26 patients with advanced CRC. Quantitative real-time polymerase chain reaction (qPCR) was performed for mRNA detection by TaqMan gene expression assay. In distant metastasis, IL6 was strongly expressed, over 7.5 fold, followed by Treg-related genes Foxp3; IL10 and TGFB1 in contrast to IL17A and NOS2. The similar pattern of expression was observed in positive regional lymph node in addition to significant down-regulation of NOS2 (RQ = 0.287; p = 0.011) and a trend for the elevation of IL17A. In tumor tissue, Fopx3 was significantly upregulated and Foxp3 mRNA positively correlated with TGFB1 in all investigated tissue types. In tumor tissue, expression of IL17A was correlated with NOS2 (r = 0.68; p = 0.005), while in distant metastasis IL10 was in strong relation with TGFB1 and IL6. In addition, a reverse correlation between IL6 and NOS2 (r = -0.66; p = 0.009), was observed in distant metastasis. The simultaneous expression of given Treg and Th17-related genes found both in the primary tumor and in the regional lymph nodes appears to provide suitable microenvironment sufficient for promoting metastatic growth. The upregulation of Foxp3; IL10, TGFB1 and IL6 might be a transcriptional profile hallmark for colorectal metastases.
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Affiliation(s)
- L D Miteva
- Department of Molecular Biology, Immunology and Medical Genetics, Medical Faculty, Trakia University, Stara Zagora, Bulgaria
| | - N S Stanilov
- Breast Oncoplastic Unit, University College London Hospital, London, UK
| | | | - Spaska Angelova Stanilova
- Department of Molecular Biology, Immunology and Medical Genetics, Medical Faculty, Trakia University, Stara Zagora, Bulgaria.
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Sun X, Feng Z, Wang Y, Qu Y, Gai Y. Expression of Foxp3 and its prognostic significance in colorectal cancer. Int J Immunopathol Pharmacol 2017; 30:201-206. [PMID: 28560891 PMCID: PMC5806801 DOI: 10.1177/0394632017710415] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
The aim of this study was to explore the expression and clinical significance of Foxp3 in colorectal tumor cells. An immunohistochemistry assay was used to detect the expression of Foxp3 in 173 cases of colorectal cancer. The relationship between the clinicopathological factors and the prognosis of colorectal cancer was analyzed. The rate of positive Foxp3 expression in tumor cells was 89.7%. There were no significant differences between cases with and without expression of Foxp3 with regard to sex, age, primary cancer sites, and distal metastasis. The expression of Foxp3 was negatively correlated with lymph node metastasis and pathological tumor, node, metastasis (pTNM) stage in tumor cells (P < 0.05), which reflects the depth of invasion. Foxp3 expression also had a positive correlation with the degree of differentiation (P < 0.01). A high level of Foxp3 expression was observed more often in tumor cells compared to tumor-surrounding tissues (P = 0.003). High expression of Foxp3 was also associated with longer overall and disease-free survival (P ⩽ 0.001). Foxp3 expression in colorectal cancer cells correlates with many clinicopathological characteristics; moreover, high expression of Foxp3 may be a promising potential prognostic factor for patients with colorectal cancer.
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Affiliation(s)
- Xiuwei Sun
- 1 Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Zhanjun Feng
- 1 Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Yunxuan Wang
- 1 Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Yao Qu
- 1 Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Yunzhu Gai
- 2 Department of Oncology, Guangzhou First People's Hospital, Guangzhou, China
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Lee JY, Seo EH, Oh CS, Paik JH, Hwang DY, Lee SH, Kim SH. Impact Of Circulating T Helper 1 And 17 Cells in the Blood on Regional Lymph Node Invasion in Colorectal Cancer. J Cancer 2017; 8:1249-1254. [PMID: 28607600 PMCID: PMC5463440 DOI: 10.7150/jca.18230] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2016] [Accepted: 03/05/2017] [Indexed: 01/14/2023] Open
Abstract
We hypothesised that the blood levels of immune cells would be related to the progression of colorectal cancer and regional lymph node metastasis. We investigated the association between the blood levels of immune cells and regional lymph node metastasis in colorectal cancer patients. Patients with American Joint Committee on Cancer (AJCC) stages 1 and 2 colorectal cancer were assigned to Early stage group and those with AJCC stages 3 and 4 were assigned to Late stage group. Blood levels of circulating immune cells, such as cluster of differentiation (CD)4+ including T helper 1 (Th1) and 17 (Th17) cells, regulatory T (Treg) cells, CD8+ T cells, and natural killer (NK) cells were assessed using fluorescence-activated cell sorting (FACS). The blood levels of CD4+ T, Treg, CD8+ T, and NK cells did not significantly differ between the two groups. However, the blood levels of Th1 and Th17 cells did significantly differ between the groups. Specifically, Late stage group had higher levels of Th1 and Th17 cells than Early stage group (Th1, 11.14±1.22% vs. 16.25±1.57%, p = 0.015; Th17, 3.32±0.05% vs. 1.11±0.15%, p < 0.01). In conclusion, the blood levels of Th1 and Th17 cells significantly increased as the N stage increased. The blood levels of Th1 and Th17 cells might be useful as predictive markers of lymph node invasion in colorectal cancer.
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Affiliation(s)
- Ji Yeon Lee
- Department of Microbiology, Konkuk University School of Medicine, Seoul, Korea
| | - Eun-Hye Seo
- Department of Microbiology, Konkuk University School of Medicine, Seoul, Korea
| | - Chung-Sik Oh
- Department of Anesthesiology and Pain medicine, Konkuk University Medical Center, Konkuk University School of Medicine, Seoul, Korea
| | - Jin-Hee Paik
- Department of Surgery, Konkuk University Medical Center, Konkuk University School of Medicine, Seoul, Korea
| | - Dae-Yong Hwang
- Department of Surgery, Konkuk University Medical Center, Konkuk University School of Medicine, Seoul, Korea
| | - Seung Hyun Lee
- Department of Microbiology, Konkuk University School of Medicine, Seoul, Korea
| | - Seong-Hyop Kim
- Department of Anesthesiology and Pain medicine, Konkuk University Medical Center, Konkuk University School of Medicine, Seoul, Korea.,Department of Medicine, Institute of Biomedical Science and Technology, Konkuk University School of Medicine, Seoul, Korea
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Tumor-Associated Macrophages and Regulatory T Cells Infiltration and the Clinical Outcome in Colorectal Cancer. Arch Immunol Ther Exp (Warsz) 2017; 65:445-454. [PMID: 28343267 PMCID: PMC5602054 DOI: 10.1007/s00005-017-0463-9] [Citation(s) in RCA: 147] [Impact Index Per Article: 18.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2016] [Accepted: 01/05/2017] [Indexed: 12/15/2022]
Abstract
The aim of the study is the assessment of the intensity of the infiltration of tumor-associated macrophages (TAMs) CD68+/iNOS− and Tregs CD8+/FoxP3+ in colorectal cancer (CRC) patients as prognostic factors with respect to disease-free survival (DFS) and overall survival (OS). In this retrospective study, tissue samples were obtained from 89 patients undergoing resection for CRC (stage IIA, pT3N0M0 and stages IIIB and IIIC, pT3N1-2M0). Recurrence was observed in 45 patients at the time of the follow-up (10 local recurrences, 35 distant metastases). In patients with recurrence the following were present: a tendency to an older average age at the time of diagnosis (p = 0.07), higher nodal involvement (p = 0.002) and more advanced clinical disease (p = 0.01). The analysis of the clinical data and immunohistochemical studies were performed with the methodology of identification of TAM and Treg subsets in histological sections, with the aim to use it in routine clinical management. Both DSF and OS were the clinical parameters assessed in the study. The presence of intense infiltration of TAMs in the tumor stroma was related to shorter DFS (p = 0.005) and OS (p = 0.006). The opposite tendency was observed in the tumor front (p = 0.061). The relative risks of recurrence and cancer-related death were more than twice higher in the group of patients with intense infiltration of TAMs in the tumor stroma (RR 2.05, 95% CI 1.33–3.14; p = 0.001 and RR 2.08, 95% CI 1.28–3.39; p = 0.003, respectively). Intense infiltration of Tregs in the tumor stroma was related to shorter DFS and OS (p < 0.0001). The relative risks of recurrence and death in a group of patients with intense infiltration of Tregs in the tumor stroma were more than 12 times higher than in patients with less intense infiltration (RR 12.3, 95% CI 5.44–27.9; p < 0.0001 and RR 12.5, 95% CI 4.9–32.4; p < 0.0001, respectively). Infiltration of TAMs CD68+/iNOS− and Tregs CD8+/FoxP3+ in the tumor stroma are negative prognostic factors with a positive correlation between them. Tregs may constitute an independent prognostic factor in patients with CRC.
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Chen YJ, Liu WH, Chang LS. Hydroquinone-induced FOXP3-ADAM17-Lyn-Akt-p21 signaling axis promotes malignant progression of human leukemia U937 cells. Arch Toxicol 2017; 91:983-997. [PMID: 27307158 DOI: 10.1007/s00204-016-1753-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2016] [Accepted: 06/08/2016] [Indexed: 12/17/2022]
Abstract
Hydroquinone (1,4-benzenediol; HQ), a major marrow metabolite of the leukemogen benzene, has been proven to evoke benzene-related hematological disorders and myelotoxicity in vitro and in vivo. The goal of the present study was to explore the role of FOXP3 in HQ-induced malignant progression of U937 human leukemia cells. U937 cells were treated with 5 μM HQ for 24 h, and the cells were re-suspended in serum-containing medium without HQ for 2 days. The same procedure was repeated three times, and the resulting U937/HQ cells were maintained in cultured medium containing 5 μM HQ. Proliferation and colony formation of U937/HQ cells were notably higher than those of U937 cells. Ten-eleven translocation methylcytosine dioxygenase-mediated demethylation of the Treg-specific demethylated region in FOXP3 gene resulted in higher FOXP3 expression in U937/HQ cells than in U937 cells. FOXP3-induced miR-183 expression reduced β-TrCP mRNA stability and suppressed β-TrCP-mediated Sp1 degradation, leading to up-regulation of Sp1 expression in U937/HQ cells. Sp1 up-regulation further increased ADAM17 and Lyn expression, and ADAM17 up-regulation stimulated Lyn activation in U937/HQ cells. Moreover, U937/HQ cells showed higher Lyn-mediated Akt activation and cytoplasmic p21 expression than U937 cells did. Abolishment of Akt activation decreased cytoplasmic p21 expression in U937/HQ cells. Suppression of FOXP3, ADAM17, and Lyn expression, as well as Akt inactivation, repressed proliferation and clonogenicity of U937/HQ cells. Together with the finding that cytoplasmic p21 shows anti-apoptotic and oncogenic activities in cancer cells, the present data suggest a role of FOXP3/ADAM17/Lyn/Akt/p21 signaling axis in HQ-induced hematological disorders.
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Affiliation(s)
- Ying-Jung Chen
- Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, 804, Taiwan
| | - Wen-Hsin Liu
- Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, 804, Taiwan
| | - Long-Sen Chang
- Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, 804, Taiwan.
- Department of Biotechnology, Kaohsiung Medical University, Kaohsiung, 807, Taiwan.
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Zhao M, Li Y, Wei X, Zhang Q, Jia H, Quan S, Cao D, Wang L, Yang T, Zhao J, Pei M, Tian S, Yu Y, Guo Y, Yang X. Negative immune factors might predominate local tumor immune status and promote carcinogenesis in cervical carcinoma. Virol J 2017; 14:5. [PMID: 28086903 PMCID: PMC5237320 DOI: 10.1186/s12985-016-0670-8] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2016] [Accepted: 12/09/2016] [Indexed: 02/06/2023] Open
Abstract
Background The disequilibrium of local immune microenvironment is an essential element during tumorigenesis. Method By conducting real-time polymerase chain reaction, we identified the mRNA level of immune factors, FoxP3 (forkhead box protein P3), CCL22/CCR4 (chemokine (C-C motif) ligand 22/CC chemokine receptor 4), OX40L/OX40 (tumor necrosis factor superfamily member 4/tumor necrosis factor receptor superfamily member 4) and Smad3 (SMAD family member 3) in neoplastic foci and its periphery tissues from 30 cases of squamous cervical carcinoma and 20 cases of normal cervix. Result The FoxP3, CCL22 and CCR4 mRNA level in local immune microenvironment of normal cervix was lower than that in cervical cancer. While OX40L, OX40 and Smad3 mRNA level profile in normal cervix was higher than that in cervical cancer. Beyond individual effect, the pairwise positive correlations were demonstrated among the mRNA level of FoxP3, CCL22 and CCR4. The mRNA level of OX40 negatively correlated with CCL22, but positively correlated with Smad3. Moreover, the mRNA level of FoxP3 and CCL22 was increased while Smad3 was decreased in cervical tissue with HPV (human papilloma virus) infection. Conclusion Our data yields insight into the roles of these immune factors in cervical carcinogenesis. It may therefore be that, in microenvironment of cervical squamous cell carcinoma, along with the context of HPV infection, negative immune regulators FoxP3, CCL22 and CCR4 might overwhelm positive immune factors OX40L, OX40 and Smad3, giving rise to an immunosuppressive status and promote the progression of cervical carcinogenesis. Trial registration Not applicable.
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Affiliation(s)
- Minyi Zhao
- Department of Obstetrics and Gynecology, First Affiliated Hospital of Xi'an Jiaotong University, 277 West Yanta Road, Xi'an, 710061, China
| | - Yang Li
- Department of Obstetrics and Gynecology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Xing Wei
- Department of Obstetrics and Gynecology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Qian Zhang
- Department of Obstetrics and Gynecology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Hongran Jia
- Department of Obstetrics and Gynecology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Shimin Quan
- Department of Obstetrics and Gynecology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Di Cao
- Department of Obstetrics and Gynecology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Li Wang
- Department of Obstetrics and Gynecology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Ting Yang
- Department of Obstetrics and Gynecology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Juan Zhao
- Department of Obstetrics and Gynecology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Meili Pei
- Department of Obstetrics and Gynecology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Sijuan Tian
- Department of Obstetrics and Gynecology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Yang Yu
- Department of Obstetrics and Gynecology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Yanping Guo
- Department of Obstetrics and Gynecology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Xiaofeng Yang
- Department of Obstetrics and Gynecology, First Affiliated Hospital of Xi'an Jiaotong University, 277 West Yanta Road, Xi'an, 710061, China.
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Zhu XW, Zhu HZ, Zhu YQ, Feng MH, Qi J, Chen ZF. Foxp3 expression in CD4+CD25+Foxp3+ regulatory T cells promotes development of colorectal cancer by inhibiting tumor immunity. ACTA ACUST UNITED AC 2016; 36:677-682. [PMID: 27752897 DOI: 10.1007/s11596-016-1644-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2016] [Revised: 08/30/2016] [Indexed: 12/11/2022]
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Yoshida N, Kinugasa T, Miyoshi H, Sato K, Yuge K, Ohchi T, Fujino S, Shiraiwa S, Katagiri M, Akagi Y, Ohshima K. A High RORγT/CD3 Ratio is a Strong Prognostic Factor for Postoperative Survival in Advanced Colorectal Cancer: Analysis of Helper T Cell Lymphocytes (Th1, Th2, Th17 and Regulatory T Cells). Ann Surg Oncol 2015; 23:919-27. [PMID: 26564244 DOI: 10.1245/s10434-015-4923-3] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2015] [Indexed: 12/19/2022]
Abstract
BACKGROUND Tumor-infiltrating lymphocytes (TILs), part of the host immune response, have been widely reported as influential factors in the tumor microenvironment for the clinical outcome of colorectal cancer (CRC). However, the network of helper T cells is very complex, and which T-cell subtypes affect the progression of CRC and postoperative prognosis remains unclear. This study investigated the expression of several subtypes of TILs including T helper type 1 (Th1), Th2, Th17, and regulatory T (Treg) cells to determine their correlation with clinicopathologic features and postoperative prognosis. METHODS The study investigated the expression of TILs using immunohistochemistry of tissue microarray samples for 199 CRC patients. The number of each T-cell subtype infiltrating tumors was counted using ImageJ software. The relationship between TIL marker expression, clinicopathologic features, and prognosis was analyzed. RESULTS A high RORγT/CD3 ratio (Th17 ratio) was significantly correlated with lymph node metastasis (p = 0.002), and a high of Foxp3/CD3 ratio (Treg ratio) was correlated with tumor location in the colon (p = 0.04), as shown by the Chi square test. In multivariate analysis, a high RORγT/CD3 ratio was the only independent prognostic factor for overall survival (p = 0.04; hazard ratio [HR], 1.84; 95% confidence interval [CI] 1.02-3.45). CONCLUSIONS This study confirmed a high RORγT/CD3 ratio as a strong prognostic marker for postoperative survival. The immunohistochemistry results suggest that Th17 may affect lymph node metastasis in CRC. If new immunotherapies reducing Th17 expression are established, they may improve the efficiency of cancer treatment and prolong the survival of patients with CRC.
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Affiliation(s)
- Naohiro Yoshida
- Department of Surgery, Kurume University School of Medicine, Kurume-shi, Fukuoka, Japan
| | - Tetsushi Kinugasa
- Department of Surgery, Kurume University School of Medicine, Kurume-shi, Fukuoka, Japan.
| | - Hiroaki Miyoshi
- Department of Pathology, Kurume University School of Medicine, Kurume, Fukuoka, Japan
| | - Kensaku Sato
- Department of Pathology, Kurume University School of Medicine, Kurume, Fukuoka, Japan
| | - Kotaro Yuge
- Department of Surgery, Kurume University School of Medicine, Kurume-shi, Fukuoka, Japan
| | - Takafumi Ohchi
- Department of Surgery, Kurume University School of Medicine, Kurume-shi, Fukuoka, Japan
| | - Shinya Fujino
- Department of Surgery, Kurume University School of Medicine, Kurume-shi, Fukuoka, Japan
| | - Sachiko Shiraiwa
- Department of Surgery, Kurume University School of Medicine, Kurume-shi, Fukuoka, Japan
| | - Mitsuhiro Katagiri
- Department of Surgery, Kurume University School of Medicine, Kurume-shi, Fukuoka, Japan
| | - Yoshito Akagi
- Department of Surgery, Kurume University School of Medicine, Kurume-shi, Fukuoka, Japan
| | - Koichi Ohshima
- Department of Pathology, Kurume University School of Medicine, Kurume, Fukuoka, Japan
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Chen L, Liu D, Zhang Y, Zhang H, Cheng H. Foxp3-dependent transformation of human primary CD4+ T lymphocytes by the retroviral protein tax. Biochem Biophys Res Commun 2015; 466:523-9. [PMID: 26381169 DOI: 10.1016/j.bbrc.2015.09.063] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2015] [Accepted: 09/11/2015] [Indexed: 12/31/2022]
Abstract
The retroviral Tax proteins of human T cell leukemia virus type 1 and 2 (HTLV-1 and -2) are highly homologous viral transactivators. Both viral proteins can immortalize human primary CD4+ memory T cells, but when expressed alone they rarely transform T cells. In the present study, we found that the Tax proteins displayed a differential ability to immortalize human CD4+Foxp3+ T cells with characteristic expression of CTLA-4 and GITR. Because epidermal growth factor receptor (EGFR) was reportedly expressed and activated in a subset of CD4+Foxp3+ T cells, we introduced an activated EGFR into Tax-immortalized CD4+Foxp3+ T cells. We observed that these modified cells were grown independently of exogenous IL-2, correlating with a T cell transformation phenotype. In Tax-immortalized CD4+Foxp3- T cells, ectopic expression of Foxp3 was a prerequisite for Tax transformation of T cells. Accordingly, treatment of the transformed T cells with erlotinib, a selective inhibitor of EGFR, induced degradation of EGFR in lysosome, consequently causing T cell growth inhibition. Further, we identified autophagy as a crucial cellular survival pathway for the transformed T cells. Silencing key autophagy molecules including Beclin1, Atg5 and PI3 kinase class III (PI3KC3) resulted in drastic impairment of T cell growth. Our data, therefore, unveiled a previously unidentified role of Foxp3 in T cell transformation, providing a molecular basis for HTLV-1 transformation of CD4+Foxp3+ T cells.
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Affiliation(s)
- Li Chen
- Pharmacy College, Fujian University of Traditional Chinese Medicine, Fuzhou, China; Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
| | - Dan Liu
- Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
| | - Yang Zhang
- Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
| | - Huan Zhang
- Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
| | - Hua Cheng
- Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201, USA; Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA; Departments of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA; Departments of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
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