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Aden D, Zaheer S, Sureka N, Trisal M, Chaurasia JK, Zaheer S. Exploring immune checkpoint inhibitors: Focus on PD-1/PD-L1 axis and beyond. Pathol Res Pract 2025; 269:155864. [PMID: 40068282 DOI: 10.1016/j.prp.2025.155864] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2024] [Revised: 01/20/2025] [Accepted: 02/25/2025] [Indexed: 04/19/2025]
Abstract
Immunotherapy emerges as a promising approach, marked by recent substantial progress in elucidating how the host immune response impacts tumor development and its sensitivity to various treatments. Immune checkpoint inhibitors have revolutionized cancer therapy by unleashing the power of the immune system to recognize and eradicate tumor cells. Among these, inhibitors targeting the programmed cell death protein 1 (PD-1) and its ligand (PD-L1) have garnered significant attention due to their remarkable clinical efficacy across various malignancies. This review delves into the mechanisms of action, clinical applications, and emerging therapeutic strategies surrounding PD-1/PD-L1 blockade. We explore the intricate interactions between PD-1/PD-L1 and other immune checkpoints, shedding light on combinatorial approaches to enhance treatment outcomes and overcome resistance mechanisms. Furthermore, we discuss the expanding landscape of immune checkpoint inhibitors beyond PD-1/PD-L1, including novel targets such as CTLA-4, LAG-3, TIM-3, and TIGIT. Through a comprehensive analysis of preclinical and clinical studies, we highlight the promise and challenges of immune checkpoint blockade in cancer immunotherapy, paving the way for future advancements in the field.
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Affiliation(s)
- Durre Aden
- Department of Pathology, Hamdard Institute of Medical science and research, Jamia Hamdard, New Delhi, India.
| | - Samreen Zaheer
- Department of Radiotherapy, Jawaharlal Nehru Medical College, AMU, Aligarh, India.
| | - Niti Sureka
- Department of Pathology, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi, India.
| | - Monal Trisal
- Department of Pathology, Hamdard Institute of Medical science and research, Jamia Hamdard, New Delhi, India.
| | | | - Sufian Zaheer
- Department of Pathology, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi, India.
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Ding X, Huang H, Fang Z, Jiang J. From Subtypes to Solutions: Integrating CMS Classification with Precision Therapeutics in Colorectal Cancer. Curr Treat Options Oncol 2024; 25:1580-1593. [PMID: 39589648 DOI: 10.1007/s11864-024-01282-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/11/2024] [Indexed: 11/27/2024]
Abstract
OPINION STATEMENT The biological heterogeneity of colorectal cancer makes its molecular characteristics essential for therapeutic decision-making and prognostic evaluation. Recent advancements in consensus molecular subtyping, based on gene expression profiling, have provided deeper insights into the heterogeneity of CRC. CMS1, known as the immune subtype, is characterized by robust immune activity and microsatellite instability. CMS2, the canonical subtype, exhibits significant activation of the WNT and MYC signaling pathways. CMS3, the metabolic subtype, features unique metabolic dysregulations. CMS4, the mesenchymal subtype, is recognized for its stromal invasion and angiogenesis, which are associated with a poorer prognosis. This review delivers a thorough analysis of the biological and clinical responses of each CMS subtype in colorectal cancer, highlighting their therapeutic vulnerabilities. It integrates data and clinical trial results to suggest potential new therapies for each subtype. The goal is to improve therapeutic efficacy, minimize treatment disparities, and offer CRC patients more precise treatment options.
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Affiliation(s)
- Xinyi Ding
- Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, Jiangsu Province, China
- Jiangsu Engineering Research Center for Tumor Immunotherapy, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, Jiangsu, China
- Institute of Cell Therapy, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, Jiangsu, China
| | - Hao Huang
- Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, Jiangsu Province, China
- Jiangsu Engineering Research Center for Tumor Immunotherapy, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, Jiangsu, China
- Institute of Cell Therapy, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, Jiangsu, China
| | - Zhang Fang
- Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, Jiangsu Province, China
- Jiangsu Engineering Research Center for Tumor Immunotherapy, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, Jiangsu, China
- Institute of Cell Therapy, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, Jiangsu, China
| | - Jingting Jiang
- Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, Jiangsu Province, China.
- Jiangsu Engineering Research Center for Tumor Immunotherapy, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, Jiangsu, China.
- Institute of Cell Therapy, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, Jiangsu, China.
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Lin X, Kang K, Chen P, Zeng Z, Li G, Xiong W, Yi M, Xiang B. Regulatory mechanisms of PD-1/PD-L1 in cancers. Mol Cancer 2024; 23:108. [PMID: 38762484 PMCID: PMC11102195 DOI: 10.1186/s12943-024-02023-w] [Citation(s) in RCA: 130] [Impact Index Per Article: 130.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Accepted: 05/10/2024] [Indexed: 05/20/2024] Open
Abstract
Immune evasion contributes to cancer growth and progression. Cancer cells have the ability to activate different immune checkpoint pathways that harbor immunosuppressive functions. The programmed death protein 1 (PD-1) and programmed cell death ligands (PD-Ls) are considered to be the major immune checkpoint molecules. The interaction of PD-1 and PD-L1 negatively regulates adaptive immune response mainly by inhibiting the activity of effector T cells while enhancing the function of immunosuppressive regulatory T cells (Tregs), largely contributing to the maintenance of immune homeostasis that prevents dysregulated immunity and harmful immune responses. However, cancer cells exploit the PD-1/PD-L1 axis to cause immune escape in cancer development and progression. Blockade of PD-1/PD-L1 by neutralizing antibodies restores T cells activity and enhances anti-tumor immunity, achieving remarkable success in cancer therapy. Therefore, the regulatory mechanisms of PD-1/PD-L1 in cancers have attracted an increasing attention. This article aims to provide a comprehensive review of the roles of the PD-1/PD-L1 signaling in human autoimmune diseases and cancers. We summarize all aspects of regulatory mechanisms underlying the expression and activity of PD-1 and PD-L1 in cancers, including genetic, epigenetic, post-transcriptional and post-translational regulatory mechanisms. In addition, we further summarize the progress in clinical research on the antitumor effects of targeting PD-1/PD-L1 antibodies alone and in combination with other therapeutic approaches, providing new strategies for finding new tumor markers and developing combined therapeutic approaches.
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Affiliation(s)
- Xin Lin
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, China
- FuRong Laboratory, Changsha, 410078, Hunan, China
- Cancer Research Institute, School of Basic Medical Sciences, Central South University, Changsha, 410008, Hunan, China
- The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Central South University, Changsha, 410078, Hunan, China
| | - Kuan Kang
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, China
- FuRong Laboratory, Changsha, 410078, Hunan, China
- Cancer Research Institute, School of Basic Medical Sciences, Central South University, Changsha, 410008, Hunan, China
- The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Central South University, Changsha, 410078, Hunan, China
| | - Pan Chen
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, China
| | - Zhaoyang Zeng
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, China
- FuRong Laboratory, Changsha, 410078, Hunan, China
- Cancer Research Institute, School of Basic Medical Sciences, Central South University, Changsha, 410008, Hunan, China
- The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Central South University, Changsha, 410078, Hunan, China
| | - Guiyuan Li
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, China
- FuRong Laboratory, Changsha, 410078, Hunan, China
- Cancer Research Institute, School of Basic Medical Sciences, Central South University, Changsha, 410008, Hunan, China
- The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Central South University, Changsha, 410078, Hunan, China
| | - Wei Xiong
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, China
- FuRong Laboratory, Changsha, 410078, Hunan, China
- Cancer Research Institute, School of Basic Medical Sciences, Central South University, Changsha, 410008, Hunan, China
- The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Central South University, Changsha, 410078, Hunan, China
| | - Mei Yi
- Department of Dermotology, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.
| | - Bo Xiang
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, China.
- FuRong Laboratory, Changsha, 410078, Hunan, China.
- Cancer Research Institute, School of Basic Medical Sciences, Central South University, Changsha, 410008, Hunan, China.
- The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Central South University, Changsha, 410078, Hunan, China.
- Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Tongzipo Road, Changsha, 410013, Hunan, China.
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Yu J, E T, Zhou M, Niu J, Wang J, Miao R, Dong C, Gao H, Jing C, Liang B. Integrin αvβ6 mediates the immune escape through regulation of PD-L1 and serves as a novel marker for immunotherapy of colon carcinoma. Am J Cancer Res 2024; 14:2608-2625. [PMID: 38859847 PMCID: PMC11162679 DOI: 10.62347/rhdb8792] [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: 12/19/2023] [Accepted: 05/15/2024] [Indexed: 06/12/2024] Open
Abstract
The immune escape of colon cancer and its role in the response to immunotherapies such as PD-1/PD-L1 checkpoint inhibitors have long been of great interest. The positive outcomes of immunotherapy are limited by the immunosuppressive nature of the tumor microenvironment. Integrin αvβ6, which can regulate the progression of colon cancer, was recently reported to be involved in the immune suppression of colon cancer. In the present study, we explored the correlation between αvβ6 and PD-L1 expression by immunohistochemistry of colon cancer tissues. Then, the regulation of PD-L1 signaling by αvβ6 in colon cancer cells was demonstrated. We constructed an in vivo model and performed immunophenotyping experiments to analyze further the regulation of the immune response by αvβ6. The role of αvβ6 in the response to anti-PD-1 therapy in colon cancer was also verified. αvβ6-positive tissues exhibited increased PD-L1 expression. Inhibition of αvβ6 not only downregulated constitutive PD-L1 expression but also decreased IFN-γ-induced PD-L1 expression. In addition, αvβ6-induced PD-L1 expression was suppressed by the ERK inhibitor PD98059, and knockdown of the β6-ERK2 binding site had the equivalent effect. αvβ6 decreased CD8+ T cell infiltration and granzyme B expression in CD8+ T cells in colon cancer patients. Furthermore, mice engrafted with αvβ6-expressing colon cancer cells exhibited an unsatisfactory response to anti-PD-1 therapy, and anti-PD-1-induced increases in CD4+ and CD8+ T cell infiltration could be inhibited by αvβ6. These results indicate that αvβ6 mediates immune escape in colon cancer by upregulating PD-L1 through the ERK/MAPK pathway. Moreover, αvβ6 could serve as a marker for the efficacy of anti-PD-1 therapy in colon cancer.
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Affiliation(s)
- Jintao Yu
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical UniversityJinan, Shandong, China
| | - Tianyu E
- Shandong First Medical UniversityJinan, Shandong, China
| | - Mingliang Zhou
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical UniversityJinan, Shandong, China
| | - Jun Niu
- Department of Hepatobiliary Surgery, Qilu Hospital, Shandong UniversityJinan, Shandong, China
| | - Jinshen Wang
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical UniversityJinan, Shandong, China
| | - Ruizheng Miao
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical UniversityJinan, Shandong, China
| | - Cunjin Dong
- Department of Medical Affair, Heze Municipal HospitalHeze, Shandong, China
| | - Huijie Gao
- Department of Hepatobiliary Surgery, Qilu Hospital, Shandong UniversityJinan, Shandong, China
| | - Changqing Jing
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical UniversityJinan, Shandong, China
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital, Shandong UniversityJinan, Shandong, China
| | - Benjia Liang
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical UniversityJinan, Shandong, China
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Guo X, Huang S, Zhang Y, Wang H, Li L, Ran J, Chen D, Li X, Li J. Evodiamine inhibits growth of vemurafenib drug-resistant melanoma via suppressing IRS4/PI3K/AKT signaling pathway. J Nat Med 2024; 78:342-354. [PMID: 38324123 DOI: 10.1007/s11418-023-01769-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Accepted: 11/28/2023] [Indexed: 02/08/2024]
Abstract
Evodiamine, a novel alkaloid, was isolated from the fruit of tetradium. It exerts a diversity of pharmacological effects and has been used to treat gastropathy, hypertension, and eczema. Several studies reported that evodiamine has various biological effects, including anti-nociceptive, anti-bacterial, anti-obesity, and anti-cancer activities. However, there is no research regarding its effects on drug-resistant cancer. This study aimed to investigate the effect of evodiamine on human vemurafenib-resistant melanoma cells (A375/R cells) proliferation ability and its mechanism. Cell activity was assessed using the cell counting kit-8 (CCK-8) method. Flow cytometry assay was used to assess cell apoptosis and cell cycle. A xenograft model was used to analyze the inhibitory effects of evodiamine on tumor growth. Bioinformatics analyses, network pharmacology, and molecular docking were used to explore the potential mechanism of evodiamine in vemurafenib-resistant melanoma. RT-qPCR and Western blotting were performed to reveal the molecular mechanism. The alkaloid extract of the fruit of tetradium, evodiamine showed the strongest tumor inhibitory effect on vemurafenib-resistant melanoma cells compared to treatment with vemurafenib alone. Evodiamine inhibited vemurafenib-resistant melanoma cell growth, proliferation, and induced apoptosis, conforming to a dose-effect relationship and time-effect relationship. Results from network pharmacology and molecular docking suggested that evodiamine might interact with IRS4 to suppress growth of human vemurafenib-resistant melanoma cells. Interestingly, evodiamine suppressed IRS4 expression and then inhibited PI3K/AKT signaling pathway, and thus had the therapeutic action on vemurafenib-resistant melanoma.
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Affiliation(s)
- Xingxian Guo
- Centre for Lipid Research & Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Chongqing Medical University, Chongqing, China
| | - Shiying Huang
- Department of Clinical Laboratory, Zigong First People's Hospital, Zigong, China
| | - Yonghong Zhang
- Chongqing Engineering Research Center for Clinical Big-Data and Drug Evaluation Medical Data Science Academy, Chongqing Medical University, Chongqing, China
| | - Hong Wang
- Department of Pharmacy, Women and Children's Hospital of Chongqing Medical University, Department of Pharmacy, Chongqing Health Center for Women and Children), Chongqing, China
| | - Lisha Li
- Lab of Stem Cell and Tissue Engineering, Department of Histology and Embryology, Chongqing Medical University, Chongqing, 400010, China
| | - Jianhua Ran
- Neuroscience Research Center, College of Basic Medicine, Chongqing Medical University, Chongqing, China
| | - Dilong Chen
- Chongqing Key Laboratory of Development and Utilization of Genuine Medicinal Materials in Three Gorges Reservoir Area, Faculty of Basic Medical Sciences, Chongqing Three Gorges Medical College, Wanzhou, 404100, China
- NMPA Key Laboratory for Quality Monitoring of Narcotic Drugs and Psychotropic Substances, Chongqing Institute for Food and Drug Control, Chongqing, China
| | - Xiaopeng Li
- Chongqing Key Laboratory of Development and Utilization of Genuine Medicinal Materials in Three Gorges Reservoir Area, Faculty of Basic Medical Sciences, Chongqing Three Gorges Medical College, Wanzhou, 404100, China.
| | - Jing Li
- Lab of Stem Cell and Tissue Engineering, Department of Histology and Embryology, Chongqing Medical University, Chongqing, 400010, China.
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Hosseinkhani N, Hemmat N, Baghbani E, Baghbanzadeh A, Kazemi T, Mokhtarzadeh A, Jafarlou M, Amin Doustvandi M, Baradaran B. Dual silencing of tumor-intrinsic VISTA and CTLA-4 stimulates T-cell mediated immune responses and inhibits MCF7 breast cancer development. Gene 2024; 896:148043. [PMID: 38042220 DOI: 10.1016/j.gene.2023.148043] [Citation(s) in RCA: 11] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2023] [Revised: 11/16/2023] [Accepted: 11/28/2023] [Indexed: 12/04/2023]
Abstract
BACKGROUND As inhibitory immune checkpoint molecules, cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) and V-domain Ig suppressor of T-cell activation (VISTA) can be expressed in tumoral cells and facilitate immune evasion of tumoral cells. Herein, we studied the significance of tumor-intrinsic CTLA-4 and VISTA silencing in tumor development and inflammatory factors expression in a co-culture system with MCF7 and T-cells. METHODS MCF7 cells were transfected with 60 pmol of CTLA-siRNA, VISTA-siRNA, and dual VISTA-/CTLA-4-siRNA. The MTT assay was performed to study the effect of CTLA-4 and VISTA knockdown on the viability of MCF7 cells. Colony formation and wound-healing assays were performed to investigate the effect of CTLA-4 and VISTA silencing on the clonogenicity and migration of MCF7 cells. Flow cytometry was used to study the significance of CTLA-4 and VISTA knockdown on the apoptosis and cell cycle of MCF7 cells. Also, a co-culture system with MCF7 and T-cells was developed to study the expression levels of IL-2, IFN-γ, TNF-α, TGF-β, and IL-10 following CTLA-4 and VISTA knockdown. The expression levels of caspase3, Bax, Bcl2, and MMP-9 were also investigated using quantitative real-time PCR. Finally, the TCGA Breast Cancer and GSE45827 datasets were analyzed to study the potential prognostic values of VISTA and CTLA-4, their expression difference in luminal A breast cancer and non-tumoral tissues, and their correlation in luminal A breast cancer tissues. RESULTS Combined knockdown of tumor-intrinsic VISTA and CTLA-4 is superior in upregulating IL-2, IFN-γ, and TNF-α, downregulating TGF-β and IL-10 in T lymphocytes. Also, the combined silencing arrests the cell cycle at the sub-G1 phase, decreases migration, inhibits clonogenicity, and reduces cell viability of MCF7 cells. This combined treatment upregulates caspase 9 and BAX and downregulates MMP-9 in MCF7 cells. Our in-silico results have demonstrated a significant positive correlation between CTLA-4 and VISTA in luminal A breast cancer. CONCLUSION The additive effect of the combined knockdown of tumor-intrinsic VISTA and CTLA-4 can substantially upregulate pro-inflammatory factors, downregulate anti-inflammatory factors, and inhibit tumor development in MCF7 cells. The significant positive correlation between VISTA and CTLA-4 in luminal A breast cancer might support the idea that a network of inhibitory immune checkpoint molecules regulates anti-tumoral immune responses; thus, combinational immune checkpoint molecules blockade can be suggested.
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Affiliation(s)
- Negar Hosseinkhani
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Nima Hemmat
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Elham Baghbani
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Amir Baghbanzadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Tohid Kazemi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ahad Mokhtarzadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mahdi Jafarlou
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
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Zhao Q, Li H, Li W, Guo Z, Jia W, Xu S, Chen S, Shen X, Wang C. Identification and verification of a prognostic signature based on a miRNA-mRNA interaction pattern in colon adenocarcinoma. Front Cell Dev Biol 2023; 11:1161667. [PMID: 37745305 PMCID: PMC10511881 DOI: 10.3389/fcell.2023.1161667] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Accepted: 08/04/2023] [Indexed: 09/26/2023] Open
Abstract
The expression characteristics of non-coding RNA (ncRNA) in colon adenocarcinoma (COAD) are involved in regulating various biological processes. To achieve these functions, ncRNA and a member of the Argonaute protein family form an RNA-induced silencing complex (RISC). The RISC is directed by ncRNA, especially microRNA (miRNA), to bind the target complementary mRNAs and regulate their expression by interfering with mRNA cleavage, degradation, or translation. However, how to identify potential miRNA biomarkers and therapeutic targets remains unclear. Here, we performed differential gene screening based on The Cancer Genome Atlas dataset and annotated meaningful differential genes to enrich related biological processes and regulatory cancer pathways. According to the overlap between the screened differential mRNAs and differential miRNAs, a prognosis model based on a least absolute shrinkage and selection operator-based Cox proportional hazards regression analysis can be established to obtain better prognosis characteristics. To further explore the therapeutic potential of miRNA as a target of mRNA intervention, we conducted an immunohistochemical analysis and evaluated the expression level in the tissue microarray of 100 colorectal cancer patients. The results demonstrated that the expression level of POU4F1, DNASE1L2, and WDR72 in the signature was significantly upregulated in COAD and correlated with poor prognosis. Establishing a prognostic signature based on miRNA target genes will help elucidate the molecular pathogenesis of COAD and provide novel potential targets for RNA therapy.
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Affiliation(s)
- Qiwu Zhao
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Haosheng Li
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Wenchang Li
- Department of Interventional Radiography, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zichao Guo
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Wenqing Jia
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Shuiyu Xu
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Sixia Chen
- Tongji Hospital, Tongji University School of Medicine, Tongji University, Shanghai, China
| | - Xiaonan Shen
- Department of Gastroenterology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Changgang Wang
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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8
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Comprehensive characterization of B7 family members in NSCLC and identification of its regulatory network. Sci Rep 2023; 13:4311. [PMID: 36922519 PMCID: PMC10017798 DOI: 10.1038/s41598-022-26776-w] [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: 12/06/2021] [Accepted: 12/20/2022] [Indexed: 03/17/2023] Open
Abstract
B7 family members act as co-stimulatory or co-inhibitory molecules in the adaptive immune system. Thisstudy aimed to investigate the dysregulation, prognostic value and regulatory network of B7 family members in non-small cell lung cancer (NSCLC). Data for lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) patients were extracted from public databases. Patient prognosis was determined by Kaplan-Meier analysis. The downstream signaling pathways of B7 family were identified via GO and KEGG analysis. The key B7 related genes were selected by network, correlation and functional annotation analysis. Most B7 family members were dysregulated in LUAD and LUSC. The expression of B7-1/2/H3 and B7-H5 were significantly associated with overall survival in LUAD and LUSC, respectively. The major pathway affected by B7 family was the EGFR tyrosine kinase inhibitor resistance and ErbB signaling pathway. MAPK1, MAPK3 and MAP2K1 were pivotal B7 related genes in both LUAD and LUSC. This study reveals an overall dysregulation of B7 family members in NSCLC and highlights the potential of combination use of tyrosine kinase inhibitors or MEK/ERK inhibitors with B7 member blockade for NSCLC treatment.
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Influence of location-dependent sex difference on PD-L1, MMR/MSI, and EGFR in colorectal carcinogenesis. PLoS One 2023; 18:e0282017. [PMID: 36802389 PMCID: PMC9942979 DOI: 10.1371/journal.pone.0282017] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Accepted: 02/06/2023] [Indexed: 02/23/2023] Open
Abstract
BACKGROUND The incidence and mortality rates of colorectal cancer (CRC) has been reported to be strongly associated to sex/gender difference. CRC shows sexual dimorphism, and sex hormones have been shown to affect the tumor immune microenvironment. This study aimed to investigate location-dependent sex differences in tumorigenic molecular characteristics in patients with colorectal tumors, including adenoma and CRC. METHODS A total of 231 participants, including 138 patients with CRC, 55 patients with colorectal adenoma, and 38 healthy controls, were recruited between 2015 and 2021 at Seoul National University Bundang Hospital. All patients underwent colonoscopy and acquired tumor lesion samples were further analyzed for programmed death-ligand 1 (PD-L1), epidermal growth factor receptor (EGFR) expression, deficient mismatch repair (dMMR), and microsatellite instability (MSI) status. This study was registered with ClinicalTrial.gov, number NCT05638542. RESULTS The average of combined positive score (CPS) was higher in serrated lesions and polyps (lesions/polyps) compared to conventional adenomas (5.73 and 1.41, respectively, P < 0.001). No significant correlation was found between sex and PD-L1 expression within the groups, regardless of histopathological diagnosis. In multivariate analysis where each sex was further stratified by tumor location due to their interaction in CRC, PD-L1 expression was inversely correlated with males having proximal CRC with a CPS cutoff of 1 (Odds ratio (OR) 0.28, P = 0.034). Females with proximal CRC showed a significant association with dMMR/MSI-high (OR 14.93, P = 0.032) and high EGFR expression (OR 4.17, P = 0.017). CONCLUSION Sex and tumor location influenced molecular features such as PD-L1, MMR/MSI status and EGFR expression in CRC, suggesting a possible underlying mechanism of sex-specific colorectal carcinogenesis.
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Jeong KY. Challenges to addressing the unmet medical needs for immunotherapy targeting cold colorectal cancer. World J Gastrointest Oncol 2023; 15:215-224. [PMID: 36908316 PMCID: PMC9994045 DOI: 10.4251/wjgo.v15.i2.215] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Revised: 12/18/2022] [Accepted: 01/09/2023] [Indexed: 02/14/2023] Open
Abstract
With the establishment of the immune surveillance mechanism since the 1950s, attempts have been made to activate the immune system for cancer treatment through the discovery of various cytokines or the development of antibodies up to now. The fruits of these efforts have contributed to the recognition of the 3rd generation of anticancer immunotherapy as the mainstream of cancer treatment. However, the limitations of cancer immunotherapy are also being recognized through the conceptual establishment of cold tumors recently, and colorectal cancer (CRC) has become a major issue from this therapeutic point of view. Here, it is emphasized that non-clinical strategies to overcome the immunosuppressive environment and clinical trials based on these basic investigations are being made on the journey to achieve better treatment outcomes for the treatment of cold CRC.
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Affiliation(s)
- Keun-Yeong Jeong
- Research and Development Center, PearlsinMires, Seoul 03690, South Korea
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11
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Andrade-Meza A, Arias-Romero LE, Armas-López L, Ávila-Moreno F, Chirino YI, Delgado-Buenrostro NL, García-Castillo V, Gutiérrez-Cirlos EB, Juárez-Avelar I, Leon-Cabrera S, Mendoza-Rodríguez MG, Olguín JE, Perez-Lopez A, Pérez-Plasencia C, Reyes JL, Sánchez-Pérez Y, Terrazas LI, Vaca-Paniagua F, Villamar-Cruz O, Rodríguez-Sosa M. Mexican Colorectal Cancer Research Consortium (MEX-CCRC): Etiology, Diagnosis/Prognosis, and Innovative Therapies. Int J Mol Sci 2023; 24:ijms24032115. [PMID: 36768437 PMCID: PMC9917340 DOI: 10.3390/ijms24032115] [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: 11/02/2022] [Revised: 12/22/2022] [Accepted: 12/22/2022] [Indexed: 01/25/2023] Open
Abstract
In 2013, recognizing that Colorectal Cancer (CRC) is the second leading cause of death by cancer worldwide and that it was a neglected disease increasing rapidly in Mexico, the community of researchers at the Biomedicine Research Unit of the Facultad de Estudios Superiores Iztacala from the Universidad Nacional Autónoma de México (UNAM) established an intramural consortium that involves a multidisciplinary group of researchers, technicians, and postgraduate students to contribute to the understanding of this pathology in Mexico. This article is about the work developed by the Mexican Colorectal Cancer Research Consortium (MEX-CCRC): how the Consortium was created, its members, and its short- and long-term goals. Moreover, it is a narrative of the accomplishments of this project. Finally, we reflect on possible strategies against CRC in Mexico and contrast all the data presented with another international strategy to prevent and treat CRC. We believe that the Consortium's characteristics must be maintained to initiate a national strategy, and the reported data could be useful to establish future collaborations with other countries in Latin America and the world.
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Affiliation(s)
- Antonio Andrade-Meza
- Unidad de Investigación en Biomedicina, Facultad de Estudios Superiores-Iztacala (FES-I), Universidad Nacional Autónoma de México (UNAM), Tlalnepantla 54090, Mexico
- Programa de Doctorado en Ciencias Biomédicas, Universidad Nacional Autónoma de México (UNAM), Ciudad de México 04510, Mexico
| | - Luis E. Arias-Romero
- Unidad de Investigación en Biomedicina, Facultad de Estudios Superiores-Iztacala (FES-I), Universidad Nacional Autónoma de México (UNAM), Tlalnepantla 54090, Mexico
| | - Leonel Armas-López
- Unidad de Investigación en Biomedicina, Facultad de Estudios Superiores-Iztacala (FES-I), Universidad Nacional Autónoma de México (UNAM), Tlalnepantla 54090, Mexico
| | - Federico Ávila-Moreno
- Unidad de Investigación en Biomedicina, Facultad de Estudios Superiores-Iztacala (FES-I), Universidad Nacional Autónoma de México (UNAM), Tlalnepantla 54090, Mexico
| | - Yolanda I. Chirino
- Unidad de Investigación en Biomedicina, Facultad de Estudios Superiores-Iztacala (FES-I), Universidad Nacional Autónoma de México (UNAM), Tlalnepantla 54090, Mexico
| | - Norma L. Delgado-Buenrostro
- Unidad de Investigación en Biomedicina, Facultad de Estudios Superiores-Iztacala (FES-I), Universidad Nacional Autónoma de México (UNAM), Tlalnepantla 54090, Mexico
| | - Verónica García-Castillo
- Unidad de Investigación en Biomedicina, Facultad de Estudios Superiores-Iztacala (FES-I), Universidad Nacional Autónoma de México (UNAM), Tlalnepantla 54090, Mexico
| | - Emma B. Gutiérrez-Cirlos
- Unidad de Investigación en Biomedicina, Facultad de Estudios Superiores-Iztacala (FES-I), Universidad Nacional Autónoma de México (UNAM), Tlalnepantla 54090, Mexico
| | - Imelda Juárez-Avelar
- Unidad de Investigación en Biomedicina, Facultad de Estudios Superiores-Iztacala (FES-I), Universidad Nacional Autónoma de México (UNAM), Tlalnepantla 54090, Mexico
- Programa de Doctorado en Ciencias Biológicas, Universidad Nacional Autónoma de México (UNAM), Ciudad de México 04510, Mexico
| | - Sonia Leon-Cabrera
- Unidad de Investigación en Biomedicina, Facultad de Estudios Superiores-Iztacala (FES-I), Universidad Nacional Autónoma de México (UNAM), Tlalnepantla 54090, Mexico
- Carrera de Médico Cirujano, Facultad de Estudios Superiores-Iztacala (FES-I), Universidad Nacional Autónoma de México (UNAM), Tlalnepantla 54090, Mexico
| | - Mónica G. Mendoza-Rodríguez
- Unidad de Investigación en Biomedicina, Facultad de Estudios Superiores-Iztacala (FES-I), Universidad Nacional Autónoma de México (UNAM), Tlalnepantla 54090, Mexico
| | - Jonadab E. Olguín
- Laboratorio Nacional en Salud: Diagnóstico Molecular y Efecto Ambiental en Enfermedades Crónico-Degenerativas, Facultad de Estudios Superiores-Iztacala (FES-I), Universidad Nacional Autónoma de México (UNAM), Tlalnepantla 54090, Mexico
| | - Araceli Perez-Lopez
- Unidad de Investigación en Biomedicina, Facultad de Estudios Superiores-Iztacala (FES-I), Universidad Nacional Autónoma de México (UNAM), Tlalnepantla 54090, Mexico
| | - Carlos Pérez-Plasencia
- Unidad de Investigación en Biomedicina, Facultad de Estudios Superiores-Iztacala (FES-I), Universidad Nacional Autónoma de México (UNAM), Tlalnepantla 54090, Mexico
- Subdirección de Investigación Básica, Instituto Nacional de Cancerología, Ciudad de México 14080, Mexico
| | - José L. Reyes
- Unidad de Investigación en Biomedicina, Facultad de Estudios Superiores-Iztacala (FES-I), Universidad Nacional Autónoma de México (UNAM), Tlalnepantla 54090, Mexico
| | - Yesennia Sánchez-Pérez
- Subdirección de Investigación Básica, Instituto Nacional de Cancerología, Ciudad de México 14080, Mexico
| | - Luis I. Terrazas
- Unidad de Investigación en Biomedicina, Facultad de Estudios Superiores-Iztacala (FES-I), Universidad Nacional Autónoma de México (UNAM), Tlalnepantla 54090, Mexico
- Laboratorio Nacional en Salud: Diagnóstico Molecular y Efecto Ambiental en Enfermedades Crónico-Degenerativas, Facultad de Estudios Superiores-Iztacala (FES-I), Universidad Nacional Autónoma de México (UNAM), Tlalnepantla 54090, Mexico
| | - Felipe Vaca-Paniagua
- Unidad de Investigación en Biomedicina, Facultad de Estudios Superiores-Iztacala (FES-I), Universidad Nacional Autónoma de México (UNAM), Tlalnepantla 54090, Mexico
- Laboratorio Nacional en Salud: Diagnóstico Molecular y Efecto Ambiental en Enfermedades Crónico-Degenerativas, Facultad de Estudios Superiores-Iztacala (FES-I), Universidad Nacional Autónoma de México (UNAM), Tlalnepantla 54090, Mexico
- Subdirección de Investigación Básica, Instituto Nacional de Cancerología, Ciudad de México 14080, Mexico
| | - Olga Villamar-Cruz
- Unidad de Investigación en Biomedicina, Facultad de Estudios Superiores-Iztacala (FES-I), Universidad Nacional Autónoma de México (UNAM), Tlalnepantla 54090, Mexico
| | - Miriam Rodríguez-Sosa
- Unidad de Investigación en Biomedicina, Facultad de Estudios Superiores-Iztacala (FES-I), Universidad Nacional Autónoma de México (UNAM), Tlalnepantla 54090, Mexico
- Correspondence: ; Tel.: +52-55-5623-1333
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12
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Yasudome R, Seki N, Asai S, Goto Y, Kita Y, Hozaka Y, Wada M, Tanabe K, Idichi T, Mori S, Ohtsuka T. Molecular Pathogenesis of Colorectal Cancer: Impact of Oncogenic Targets Regulated by Tumor Suppressive miR-139-3p. Int J Mol Sci 2022; 23:ijms231911616. [PMID: 36232922 PMCID: PMC9569794 DOI: 10.3390/ijms231911616] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2022] [Revised: 09/14/2022] [Accepted: 09/27/2022] [Indexed: 11/09/2022] Open
Abstract
We recently determined the RNA sequencing-based microRNA (miRNA) expression signature of colorectal cancer (CRC). Analysis of the signature showed that the expression of both strands of pre-miR-139 (miR-139-5p, the guide strand, and miR-139-3p, the passenger strand) was significantly reduced in CRC tissues. Transient transfection assays revealed that expression of miR-139-3p blocked cancer cell malignant transformation (e.g., cell proliferation, migration, and invasion). Notably, expression of miR-139-3p markedly blocked RAC-alpha serine/threonine-protein kinase (AKT) phosphorylation in CRC cells. A combination of in silico database and gene expression analyses of miR-139-3p-transfected cells revealed 29 putative targets regulated by miR-139-3p in CRC cells. RNA immunoprecipitation analysis using an Argonaute2 (AGO2) antibody revealed that KRT80 was efficiently incorporated into the RNA-induced silencing complex. Aberrant expression of Keratin 80 (KRT80) was detected in CRC clinical specimens by immunostaining. A knockdown assay using small interfering RNA (siRNA) targeting KRT80 showed that reducing KRT80 expression suppressed the malignant transformation (cancer cell migration and invasion) of CRC cells. Importantly, inhibiting KRT80 expression reduced AKT phosphorylation in CRC cells. Moreover, hexokinase-2 (HK2) expression was reduced in cells transfected with the KRT80 siRNAs or miR-139-3p. The involvement of miRNA passenger strands (e.g., miR-139-3p) in CRC cells is a new concept in miRNA studies. Our tumor-suppressive miRNA-based approach helps elucidate the molecular pathogenesis of CRC.
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Affiliation(s)
- Ryutaro Yasudome
- Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8520, Japan
| | - Naohiko Seki
- Department of Functional Genomics, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan
- Correspondence: ; Tel.: +81-43-226-2971
| | - Shunichi Asai
- Department of Functional Genomics, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan
| | - Yusuke Goto
- Department of Functional Genomics, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan
| | - Yoshiaki Kita
- Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8520, Japan
| | - Yuto Hozaka
- Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8520, Japan
| | - Masumi Wada
- Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8520, Japan
| | - Kan Tanabe
- Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8520, Japan
| | - Tetsuya Idichi
- Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8520, Japan
| | - Shinichiro Mori
- Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8520, Japan
| | - Takao Ohtsuka
- Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8520, Japan
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13
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Dai W, Wang Z, Liang X, Wang M, Ni W, Yang Y, Zang YS. Circulating lncRNA EGFR-AS1 as a diagnostic biomarker of colorectal cancer and an indicator of tumor burden. J Gastrointest Oncol 2022; 13:2439-2446. [PMID: 36388668 PMCID: PMC9660029 DOI: 10.21037/jgo-22-968] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Accepted: 10/18/2022] [Indexed: 01/24/2023] Open
Abstract
BACKGROUND Colorectal cancer (CRC) is one of the most common malignancies. Although CRC treatment has been significantly improved, patient survival remains low because most patients already have advanced disease at diagnosis. Early screening and diagnosis of tumors is critical; however, the current tissue biopsy and radiological evaluation methods have very limited effectiveness. Therefore, establishing new convenient and non-invasive biomarkers is urgently needed for timely detection, therapeutic assessment, and prognostic prediction. At present, non-coding RNAs (ncRNAs) have attracted research attention owing to their potential oncological applications. METHODS The long ncRNA epidermal growth factor receptor antisense RNA 1 (EGFR-AS1) is overexpressed in multiple malignancies including CRC. The present study examined the circulating EGFR-AS1 level in CRC, and the results showed that EGFR-AS1 could be considered an indicator of tumor burden. RESULTS Elevated circulating EGFR-AS1 levels were detected in CRC cases (n=128) compared with control cases comprising endoscopy confirmed CRC-free individuals [n=64, median expression normalized to glyceraldehyde-3-phosphate dehydrogenase (GAPDH), 1.578 vs. 0.780, P<0.001]. Individuals with larger tumors (≥5 cm) had elevated circulating EGFR-AS1 levels compared to those with smaller tumors (<5 cm, 1.739 vs. 1.290, P<0.001). The expression of serum EGFR-AS1 in stage III/IV CRC was higher than that in stage I/II CRC (1.691 vs. 1.412, P<0.05). Plasma EGFR-AS1 levels were markedly reduced following surgical resection of colorectal lesions in a subset of patients [n=32, 1.192 (pre-surgery) vs. 0.692, P<0.001]. Furthermore, the expression of EGFR-AS1 in resected CRC tissues was significantly higher than that in paracancerous tissues (n=32, 1.336 vs. 0.487, P<0.001). CONCLUSIONS These results highlight the potential of EGFR-AS1 as a diagnostic biomarker in CRC.
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Affiliation(s)
- Weiping Dai
- Department of Oncology, Second Affiliated Hospital of Navy Medical University, Shanghai, China
| | - Zhan Wang
- Department of Oncology, Second Affiliated Hospital of Navy Medical University, Shanghai, China
| | - Xiaoben Liang
- E.N.T. Department, Children’s Hospital of Shanghai, Shanghai Jiao Tong University, Shanghai, China
| | - Miaomiao Wang
- Department of Oncology, Second Affiliated Hospital of Navy Medical University, Shanghai, China
| | - Wanliu Ni
- Department of Gastroenterology, Beizhan Hospital of Shanghai, Shanghai, China
| | - Ye Yang
- Department of Gastroenterology, Beizhan Hospital of Shanghai, Shanghai, China
| | - Yuan-Sheng Zang
- Department of Oncology, Second Affiliated Hospital of Navy Medical University, Shanghai, China
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14
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Heteronemin and Tetrac Induce Anti-Proliferation by Blocking EGFR-Mediated Signaling in Colorectal Cancer Cells. Mar Drugs 2022; 20:md20080482. [PMID: 36005485 PMCID: PMC9410344 DOI: 10.3390/md20080482] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Revised: 07/21/2022] [Accepted: 07/24/2022] [Indexed: 02/04/2023] Open
Abstract
Overexpressed EGFR and mutant K-Ras play vital roles in therapeutic resistance in colorectal cancer patients. To search for an effective therapeutic protocol is an urgent task. A secondary metabolite in the sponge Hippospongia sp., Heteronemin, has been shown to induce anti-proliferation in several types of cancers. A thyroxine-deaminated analogue, tetrac, binds to integrin αvβ3 to induce anti-proliferation in different cancers. Heteronemin- and in combination with tetrac-induced antiproliferative effects were evaluated. Tetrac enhanced heteronemin-induced anti-proliferation in HT-29 cells (KRAS WT CRC) and HCT-116 cells (KRAS MT CRC). Heteronemin and tetrac arrested cell cycle in different phases. Combined treatment increased the cell accumulation in sub-G1 and S phases. The combined treatment also induced the inactivation of EGFR signaling and downregulated the phosphorylated ERK1/2 protein in both cell lines. Heteronemin and the combination showed the downregulation of the phosphorylated and total PI3K protein in HT-29 cells (KRAS WT CRC). Results by NanoString technology and RT-qPCR revealed that heteronemin and combined treatment suppressed the expression of EGFR and downstream genes in HCT-116 cells (KRAS MT CRC). Heteronemin or combined treatment downregulated genes associated with cancer progression and decreased cell motility. Heteronemin or the combined treatment suppressed PD-L1 expression in both cancer cell lines. However, only tetrac and the combined treatment inhibited PD-L1 protein accumulation in HT-29 cells (KRAS WT CRC) and HCT-116 cells (KRAS MT CRC), respectively. In summary, heteronemin induced anti-proliferation in colorectal cancer cells by blocking the EGFR-dependent signal transduction pathway. The combined treatment further enhanced the anti-proliferative effect via PD-L1 suppression. It can be an alternative strategy to suppress mutant KRAS resistance for anti-EGFR therapy.
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15
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Drug Resistance in Colorectal Cancer: From Mechanism to Clinic. Cancers (Basel) 2022; 14:cancers14122928. [PMID: 35740594 PMCID: PMC9221177 DOI: 10.3390/cancers14122928] [Citation(s) in RCA: 52] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Revised: 06/03/2022] [Accepted: 06/07/2022] [Indexed: 12/11/2022] Open
Abstract
Colorectal cancer (CRC) is one of the leading causes of death worldwide. The 5-year survival rate is 90% for patients with early CRC, 70% for patients with locally advanced CRC, and 15% for patients with metastatic CRC (mCRC). In fact, most CRC patients are at an advanced stage at the time of diagnosis. Although chemotherapy, molecularly targeted therapy and immunotherapy have significantly improved patient survival, some patients are initially insensitive to these drugs or initially sensitive but quickly become insensitive, and the emergence of such primary and secondary drug resistance is a significant clinical challenge. The most direct cause of resistance is the aberrant anti-tumor drug metabolism, transportation or target. With more in-depth research, it is found that cell death pathways, carcinogenic signals, compensation feedback loop signal pathways and tumor immune microenvironment also play essential roles in the drug resistance mechanism. Here, we assess the current major mechanisms of CRC resistance and describe potential therapeutic interventions.
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16
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Tang C, Zhou Y, Sun W, Hu H, Liu Y, Chen L, Ou F, Zeng S, Lin N, Yu L. Oncopeptide MBOP Encoded by LINC01234 Promotes Colorectal Cancer through MAPK Signaling Pathway. Cancers (Basel) 2022; 14:cancers14092338. [PMID: 35565466 PMCID: PMC9100262 DOI: 10.3390/cancers14092338] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Revised: 04/15/2022] [Accepted: 04/27/2022] [Indexed: 12/12/2022] Open
Abstract
Colorectal cancer (CRC) ranks third in incidence rate and second in mortality rate of malignancy worldwide, and the diagnosis and therapeutics of it remain to be further studied. With the emergence of noncoding RNAs (ncRNAs) and potential peptides derived from ncRNAs across various biological processes, we here aimed to identify a ncRNA-derived peptide possible for revealing the oncogenesis of CRC. Through combined predictive analysis of the coding potential of a batch of long noncoding RNAs (lncRNAs), the existence of an 85 amino-acid-peptide, named MEK1-binding oncopeptide (MBOP) and encoded from LINC01234 was confirmed. Mass spectrometry and Western blot assays indicated the overexpression of MBOP in CRC tissues and cell lines compared to adjacent noncancerous tissues and the normal colonic epithelial cell line. In vivo and in vitro migration and proliferation assays defined MBOP as an oncogenic peptide. Immunoprecipitation trials showed that MEK1 was the key interacting protein of MBOP, and MBOP promoted the MEK1/pERK/MMP2/MMP9 axis in CRC. Two E3-ligase enzymes MAEA and RMND5A mediated the ubiquitin-protease-system-related degradation of MBOP. This study indicates that MBOP might be a candidate prognostic indicator and a potential target for clinical therapy of CRC.
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Affiliation(s)
- Chunyuan Tang
- Institute of Drug Metabolism and Pharmaceutical Analysis, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China; (C.T.); (Y.Z.); (W.S.); (H.H.); (Y.L.); (F.O.); (S.Z.)
| | - Ying Zhou
- Institute of Drug Metabolism and Pharmaceutical Analysis, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China; (C.T.); (Y.Z.); (W.S.); (H.H.); (Y.L.); (F.O.); (S.Z.)
| | - Wen Sun
- Institute of Drug Metabolism and Pharmaceutical Analysis, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China; (C.T.); (Y.Z.); (W.S.); (H.H.); (Y.L.); (F.O.); (S.Z.)
| | - Haihong Hu
- Institute of Drug Metabolism and Pharmaceutical Analysis, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China; (C.T.); (Y.Z.); (W.S.); (H.H.); (Y.L.); (F.O.); (S.Z.)
| | - Yuxi Liu
- Institute of Drug Metabolism and Pharmaceutical Analysis, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China; (C.T.); (Y.Z.); (W.S.); (H.H.); (Y.L.); (F.O.); (S.Z.)
| | - Lu Chen
- Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Department of Clinical Pharmacy, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; (L.C.); (N.L.)
- Westlake Laboratory of Life Sciences and Biomedicine of Zhejiang Province, Westlake University, Hangzhou 310024, China
| | - Fengting Ou
- Institute of Drug Metabolism and Pharmaceutical Analysis, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China; (C.T.); (Y.Z.); (W.S.); (H.H.); (Y.L.); (F.O.); (S.Z.)
| | - Su Zeng
- Institute of Drug Metabolism and Pharmaceutical Analysis, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China; (C.T.); (Y.Z.); (W.S.); (H.H.); (Y.L.); (F.O.); (S.Z.)
| | - Nengming Lin
- Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Department of Clinical Pharmacy, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; (L.C.); (N.L.)
- Westlake Laboratory of Life Sciences and Biomedicine of Zhejiang Province, Westlake University, Hangzhou 310024, China
| | - Lushan Yu
- Institute of Drug Metabolism and Pharmaceutical Analysis, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China; (C.T.); (Y.Z.); (W.S.); (H.H.); (Y.L.); (F.O.); (S.Z.)
- Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Department of Clinical Pharmacy, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; (L.C.); (N.L.)
- Correspondence: ; Tel.: +86-571-88208407
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17
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Andreuzzi E, Fejza A, Polano M, Poletto E, Camicia L, Carobolante G, Tarticchio G, Todaro F, Di Carlo E, Scarpa M, Scarpa M, Paulitti A, Capuano A, Canzonieri V, Maiero S, Fornasarig M, Cannizzaro R, Doliana R, Colombatti A, Spessotto P, Mongiat M. Colorectal cancer development is affected by the ECM molecule EMILIN-2 hinging on macrophage polarization via the TLR-4/MyD88 pathway. J Exp Clin Cancer Res 2022; 41:60. [PMID: 35148799 PMCID: PMC8840294 DOI: 10.1186/s13046-022-02271-y] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Accepted: 01/22/2022] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Colorectal cancer is one of the most frequent and deadly tumors. Among the key regulators of CRC growth and progression, the microenvironment has emerged as a crucial player and as a possible route for the development of new therapeutic opportunities. More specifically, the extracellular matrix acts directly on cancer cells and indirectly affecting the behavior of stromal and inflammatory cells, as well as the bioavailability of growth factors. Among the ECM molecules, EMILIN-2 is frequently down-regulated by methylation in CRC and the purpose of this study was to verify the impact of EMILIN-2 loss in CRC development and its possible value as a prognostic biomarker. METHODS The AOM/DSS CRC protocol was applied to Emilin-2 null and wild type mice. Tumor development was monitored by endoscopy, the molecular analyses performed by IHC, IF and WB and the immune subpopulations characterized by flow cytometry. Ex vivo cultures of monocyte/macrophages from the murine models were used to verify the molecular pathways. Publicly available datasets were exploited to determine the CRC patients' expression profile; Spearman's correlation analyses and Cox regression were applied to evaluate the association with the inflammatory response; the clinical outcome was predicted by Kaplan-Meier survival curves. Pearson correlation analyses were also applied to a cohort of patients enrolled in our Institute. RESULTS In preclinical settings, loss of EMILIN-2 associated with an increased number of tumor lesions upon AOM/DSS treatment. In addition, in the early stages of the disease, the Emilin-2 knockout mice displayed a myeloid-derived suppressor cells-rich infiltrate. Instead, in the late stages, lack of EMILIN-2 associated with a decreased number of M1 macrophages, resulting in a higher percentage of the tumor-promoting M2 macrophages. Mechanistically, EMILIN-2 triggered the activation of the Toll-like Receptor 4/MyD88/NF-κB pathway, instrumental for the polarization of macrophages towards the M1 phenotype. Accordingly, dataset and immunofluorescence analyses indicated that low EMILIN-2 expression levels correlated with an increased M2/M1 ratio and with poor CRC patients' prognosis. CONCLUSIONS These novel results indicate that EMILIN-2 is a key regulator of the tumor-associated inflammatory environment and may represent a promising prognostic biomarker for CRC patients.
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Affiliation(s)
- Eva Andreuzzi
- Department of Research and Diagnosis, Division of Molecular Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Italy.
| | - Albina Fejza
- Department of Research and Diagnosis, Division of Molecular Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Italy
| | - Maurizio Polano
- Experimental and Clinical Pharmacology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Italy
| | - Evelina Poletto
- Department of Research and Diagnosis, Division of Molecular Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Italy
| | - Lucrezia Camicia
- Department of Research and Diagnosis, Division of Molecular Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Italy
| | - Greta Carobolante
- Department of Research and Diagnosis, Division of Molecular Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Italy
| | - Giulia Tarticchio
- Department of Research and Diagnosis, Division of Molecular Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Italy
| | - Federico Todaro
- Department of Research and Diagnosis, Division of Molecular Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Italy
| | - Emma Di Carlo
- Department of Medicine and Sciences of Aging, "G. d'Annunzio" University of Chieti-Pescara, Chieti, Italy.,Anatomic Pathology and Immuno-Oncology Unit, Center for Advanced Studies and Technology (CAST), "G. d'Annunzio" University of Chieti-Pescara, Chieti, Italy
| | - Melania Scarpa
- Ricerca Traslazionale Avanzata, Istituto Oncologico Veneto IOV - IRCCS, Padua, Italy
| | - Marco Scarpa
- Clinica Chirurgica I- Azienda Ospedaliera di Padova, Padua, Italy
| | - Alice Paulitti
- Department of Research and Diagnosis, Division of Molecular Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Italy
| | - Alessandra Capuano
- Department of Research and Diagnosis, Division of Molecular Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Italy
| | - Vincenzo Canzonieri
- Pathology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Italy
| | - Stefania Maiero
- Division of Oncological Gastroenterology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Italy
| | - Mara Fornasarig
- Division of Oncological Gastroenterology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Italy
| | - Renato Cannizzaro
- Division of Oncological Gastroenterology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Italy
| | - Roberto Doliana
- Department of Research and Diagnosis, Division of Molecular Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Italy
| | - Alfonso Colombatti
- Department of Research and Diagnosis, Division of Molecular Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Italy
| | - Paola Spessotto
- Department of Research and Diagnosis, Division of Molecular Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Italy
| | - Maurizio Mongiat
- Department of Research and Diagnosis, Division of Molecular Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Italy.
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18
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Ma Y, Qu R, Zhang Y, Jiang C, Zhang Z, Fu W. Progress in the Study of Colorectal Cancer Caused by Altered Gut Microbiota After Cholecystectomy. Front Endocrinol (Lausanne) 2022; 13:815999. [PMID: 35282463 PMCID: PMC8907136 DOI: 10.3389/fendo.2022.815999] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Accepted: 02/01/2022] [Indexed: 12/26/2022] Open
Abstract
Epidemiological studies have found an increased incidence of colorectal cancer (CRC) in people who undergo cholecystectomy compared to healthy individuals. After cholecystectomy, bile enters the duodenum directly, unregulated by the timing of meals. Disruption of the balance of bile acid metabolism and increased production of primary bile acids, which in turn affects the composition and abundance of intestinal microorganisms. The link among cholecystectomy, the gut microbiota, and the occurrence and development of CRC is becoming clearer. However, due to the complexity of the microbial community, the mechanistic connections are less well understood. In this review, we summarize the changes of gut microbiota after cholecystectomy and illuminate the potential mechanisms on CRC, such as inflammation and immune regulation, production of genotoxins, metabolism of dietary ingredients, activation of signaling pathways, and so on. By reviewing these, we aimed to unravel the interactions between the gut microbiota and its host and be better positioned to develop treatments for CRC after cholecystectomy.
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Affiliation(s)
- Yanpeng Ma
- Department of General Surgery, Peking University Third Hospital, Beijing, China
- Cancer Center, Peking University Third Hospital, Beijing, China
| | - Ruize Qu
- Department of General Surgery, Peking University Third Hospital, Beijing, China
- Cancer Center, Peking University Third Hospital, Beijing, China
| | - Yi Zhang
- Department of General Surgery, Peking University Third Hospital, Beijing, China
- Cancer Center, Peking University Third Hospital, Beijing, China
| | - Changtao Jiang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing, China
- Key Laboratory of Molecular Cardiovascular Science (Peking University), Ministry of Education, Beijing, China
- Center of Basic Medical Research, Institute of Medical Innovation and Research, Third Hospital, Peking University, Beijing, China
- Center for Obesity and Metabolic Disease Research, School of Basic Medical Sciences, Peking University, Beijing, China
| | - Zhipeng Zhang
- Department of General Surgery, Peking University Third Hospital, Beijing, China
- Cancer Center, Peking University Third Hospital, Beijing, China
- *Correspondence: Zhipeng Zhang, ; Wei Fu,
| | - Wei Fu
- Department of General Surgery, Peking University Third Hospital, Beijing, China
- Cancer Center, Peking University Third Hospital, Beijing, China
- *Correspondence: Zhipeng Zhang, ; Wei Fu,
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19
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Emerging Therapeutic Agents for Colorectal Cancer. Molecules 2021; 26:molecules26247463. [PMID: 34946546 PMCID: PMC8707340 DOI: 10.3390/molecules26247463] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Revised: 12/03/2021] [Accepted: 12/06/2021] [Indexed: 02/07/2023] Open
Abstract
There are promising new therapeutic agents for CRC patients, including novel small-molecule inhibitors and immune checkpoint blockers. We focused on emerging CRC’s therapeutic agents that have shown the potential for progress in clinical practice. This review provides an overview of tyrosine kinase inhibitors targeting VEGF and KIT, BRAF and MEK inhibitors, TLR9 agonist, STAT3 inhibitors, and immune checkpoint blockers (PD1/PDL-1 inhibitors), for which recent advances have been reported. These new agents have the potential to provide benefits to CRC patients with unmet medical needs.
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20
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Shadbad MA, Asadzadeh Z, Derakhshani A, Hosseinkhani N, Mokhtarzadeh A, Baghbanzadeh A, Hajiasgharzadeh K, Brunetti O, Argentiero A, Racanelli V, Silvestris N, Baradaran B. A scoping review on the potentiality of PD-L1-inhibiting microRNAs in treating colorectal cancer: Toward single-cell sequencing-guided biocompatible-based delivery. Biomed Pharmacother 2021; 143:112213. [PMID: 34560556 DOI: 10.1016/j.biopha.2021.112213] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Revised: 09/13/2021] [Accepted: 09/15/2021] [Indexed: 12/15/2022] Open
Abstract
Tumoral programmed cell death ligand 1 (PD-L1) has been implicated in the immune evasion and development of colorectal cancer. Although monoclonal immune checkpoint inhibitors can exclusively improve the prognosis of patients with microsatellite instability-high (MSI-H) and tumor mutational burden-high (TMB-H) colorectal cancer, specific tumor-suppressive microRNAs (miRs) can regulate multiple oncogenic pathways and inhibit the de novo expression of oncoproteins, like PD-L1, both in microsatellite stable (MSS) and MSI-H colorectal cancer cells. This scoping review aimed to discuss the currently available evidence regarding the therapeutic potentiality of PD-L1-inhibiting miRs for colorectal cancer. For this purpose, the Web of Science, Scopus, and PubMed databases were systematically searched to obtain peer-reviewed studies published before 17 March 2021. We have found that miR-191-5p, miR-382-3p, miR-148a-3p, miR-93-5p, miR-200a-3p, miR-200c-3p, miR-138-5p, miR-140-3p, and miR-15b-5p can inhibit tumoral PD-L1 in colorectal cancer cells. Besides inhibiting PD-L1, miR-140-3p, miR-382-3p, miR-148a-3p, miR-93-5p, miR-200a-3p, miR-200c-3p, miR-138-5p, and miR-15b-5p can substantially reduce tumor migration, inhibit tumor development, stimulate anti-tumoral immune responses, decrease tumor viability, and enhance the chemosensitivity of colorectal cancer cells regardless of the microsatellite state. Concerning the specific, effective, and safe delivery of these miRs, the single-cell sequencing-guided biocompatible-based delivery of these miRs can increase the specificity of miR delivery, decrease the toxicity of traditional nanoparticles, transform the immunosuppressive tumor microenvironment into the proinflammatory one, suppress tumor development, decrease tumor migration, and enhance the chemosensitivity of tumoral cells regardless of the microsatellite state.
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Affiliation(s)
- Mahdi Abdoli Shadbad
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran; Immunology Research Center, Tabriz University of Medical Sciences, Iran
| | - Zahra Asadzadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Iran
| | - Afshin Derakhshani
- Laboratory of Experimental Pharmacology, IRCCS Istituto Tumori Giovanni Paolo II, Bari, Italy
| | | | - Ahad Mokhtarzadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Iran
| | - Amir Baghbanzadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Iran
| | | | - Oronzo Brunetti
- Istituto Tumori BariGiovanni Paolo II, Istituto Nazionale dei Tumori (IRCCS), Bari, Italy
| | - Antonella Argentiero
- Istituto Tumori BariGiovanni Paolo II, Istituto Nazionale dei Tumori (IRCCS), Bari, Italy
| | - Vito Racanelli
- Department of Biomedical Sciences and Human Oncology, School of Medicine, University of Bari Aldo Moro, Bari, Italy
| | - Nicola Silvestris
- Istituto Tumori BariGiovanni Paolo II, Istituto Nazionale dei Tumori (IRCCS), Bari, Italy; Department of Biomedical Sciences and Human Oncology, School of Medicine, University of Bari Aldo Moro, Bari, Italy.
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Iran; Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Iran.
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21
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Stefani C, Miricescu D, Stanescu-Spinu II, Nica RI, Greabu M, Totan AR, Jinga M. Growth Factors, PI3K/AKT/mTOR and MAPK Signaling Pathways in Colorectal Cancer Pathogenesis: Where Are We Now? Int J Mol Sci 2021; 22:10260. [PMID: 34638601 PMCID: PMC8508474 DOI: 10.3390/ijms221910260] [Citation(s) in RCA: 193] [Impact Index Per Article: 48.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Revised: 09/19/2021] [Accepted: 09/20/2021] [Indexed: 12/12/2022] Open
Abstract
Colorectal cancer (CRC) is a predominant malignancy worldwide, being the fourth most common cause of mortality and morbidity. The CRC incidence in adolescents, young adults, and adult populations is increasing every year. In the pathogenesis of CRC, various factors are involved including diet, sedentary life, smoking, excessive alcohol consumption, obesity, gut microbiota, diabetes, and genetic mutations. The CRC tumor microenvironment (TME) involves the complex cooperation between tumoral cells with stroma, immune, and endothelial cells. Cytokines and several growth factors (GFs) will sustain CRC cell proliferation, survival, motility, and invasion. Epidermal growth factor receptor (EGFR), Insulin-like growth factor -1 receptor (IGF-1R), and Vascular Endothelial Growth Factor -A (VEGF-A) are overexpressed in various human cancers including CRC. The phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) and all the three major subfamilies of the mitogen-activated protein kinase (MAPK) signaling pathways may be activated by GFs and will further play key roles in CRC development. The main aim of this review is to present the CRC incidence, risk factors, pathogenesis, and the impact of GFs during its development. Moreover, the article describes the relationship between EGF, IGF, VEGF, GFs inhibitors, PI3K/AKT/mTOR-MAPK signaling pathways, and CRC.
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Affiliation(s)
- Constantin Stefani
- Department of Family Medicine and Clinical Base, ‘‘Dr. Carol Davila’ Central Military Emergency University Hospital, 051075 Bucharest, Romania;
| | - Daniela Miricescu
- Department of Biochemistry, Faculty of Dental Medicine, Carol Davila University of Medicine and Pharmacy, 8 Eroii Sanitari Blvd, 050474 Bucharest, Romania; (I.-I.S.-S.); (A.R.T.)
| | - Iulia-Ioana Stanescu-Spinu
- Department of Biochemistry, Faculty of Dental Medicine, Carol Davila University of Medicine and Pharmacy, 8 Eroii Sanitari Blvd, 050474 Bucharest, Romania; (I.-I.S.-S.); (A.R.T.)
| | - Remus Iulian Nica
- Surgery 2, ‘Dr. Carol Davila’ Central Military Emergency University Hospital, 051075 Bucharest, Romania;
| | - Maria Greabu
- Department of Biochemistry, Faculty of Dental Medicine, Carol Davila University of Medicine and Pharmacy, 8 Eroii Sanitari Blvd, 050474 Bucharest, Romania; (I.-I.S.-S.); (A.R.T.)
| | - Alexandra Ripszky Totan
- Department of Biochemistry, Faculty of Dental Medicine, Carol Davila University of Medicine and Pharmacy, 8 Eroii Sanitari Blvd, 050474 Bucharest, Romania; (I.-I.S.-S.); (A.R.T.)
| | - Mariana Jinga
- Department of Gastroenterology, ‘Dr. Carol Davila’ Central Military Emergency University Hospital, 051075 Bucharest, Romania;
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22
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Galbraith NJ, Wood C, Steele CW. Targeting Metastatic Colorectal Cancer with Immune Oncological Therapies. Cancers (Basel) 2021; 13:3566. [PMID: 34298779 PMCID: PMC8307556 DOI: 10.3390/cancers13143566] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2021] [Revised: 07/08/2021] [Accepted: 07/11/2021] [Indexed: 02/07/2023] Open
Abstract
Metastatic colorectal cancer carries poor prognosis, and current therapeutic regimes convey limited improvements in survival and high rates of detrimental side effects in patients that may not stand to benefit. Immunotherapy has revolutionised cancer treatment by restoring antitumoural mechanisms. However, the efficacy in metastatic colorectal cancer, is limited. A literature search was performed using Pubmed (Medline), Web of Knowledge, and Embase. Search terms included combinations of immunotherapy and metastatic colorectal cancer, primarily focusing on clinical trials in humans. Analysis of these studies included status of MMR/MSS, presence of combination strategies, and disease control rate and median overall survival. Evidence shows that immune checkpoint inhibitors, such as anti-PD1 and anti-PD-L1, show efficacy in less than 10% of patients with microsatellite stable, MMR proficient colorectal cancer. In the small subset of patients with microsatellite unstable, MMR deficient cancers, response rates were 40-50%. Combination strategies with immunotherapy are under investigation but have not yet restored antitumoural mechanisms to permit durable disease regression. Immunotherapy provides the potential to offer additional strategies to established chemotherapeutic regimes in metastatic colorectal cancer. Further research needs to establish which adjuncts to immune checkpoint inhibition can unpick resistance, and better predict which patients are likely to respond to individualised therapies to not just improve response rates but to temper unwarranted side effects.
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Affiliation(s)
- Norman J. Galbraith
- Academic Department of Surgery, University of Glasgow, Level 2 New Lister Building, Glasgow Royal Infirmary, 10-16 Alexandra Parade, Glasgow G31 2ER, UK; (C.W.); (C.W.S.)
| | - Colin Wood
- Academic Department of Surgery, University of Glasgow, Level 2 New Lister Building, Glasgow Royal Infirmary, 10-16 Alexandra Parade, Glasgow G31 2ER, UK; (C.W.); (C.W.S.)
| | - Colin W. Steele
- Academic Department of Surgery, University of Glasgow, Level 2 New Lister Building, Glasgow Royal Infirmary, 10-16 Alexandra Parade, Glasgow G31 2ER, UK; (C.W.); (C.W.S.)
- Institute of Cancer Sciences, Beatson Institute, Garscube Campus, Switchback Road, Bearsden G61 1BD, UK
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23
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Fejza A, Polano M, Camicia L, Poletto E, Carobolante G, Toffoli G, Mongiat M, Andreuzzi E. The Efficacy of Anti-PD-L1 Treatment in Melanoma Is Associated with the Expression of the ECM Molecule EMILIN2. Int J Mol Sci 2021; 22:ijms22147511. [PMID: 34299131 PMCID: PMC8306837 DOI: 10.3390/ijms22147511] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2021] [Revised: 07/07/2021] [Accepted: 07/08/2021] [Indexed: 12/14/2022] Open
Abstract
The use of immune checkpoint inhibitors has revolutionized the treatment of melanoma patients, leading to remarkable improvements in the cure. However, to ensure a safe and effective treatment, there is the need to develop markers to identify the patients that would most likely respond to the therapies. The microenvironment is gaining attention in this context, since it can regulate both the immunotherapy efficacyand angiogenesis, which is known to be affected by treatment. Here, we investigated the putative role of the ECM molecule EMILIN-2, a tumor suppressive and pro-angiogenic molecule. We verified that the EMILIN2 expression is variable among melanoma patients and is associated with the response to PD-L1 inhibitors. Consistently, in preclinical settings, the absence of EMILIN-2 is associated with higher PD-L1 expression and increased immunotherapy efficacy. We verified that EMILIN-2 modulates PD-L1 expression in melanoma cells through indirect immune-dependent mechanisms. Notably, upon PD-L1 blockage, Emilin2−/− mice displayed improved intra-tumoral vessel normalization and decreased tumor hypoxia. Finally, we provide evidence indicating that the inclusion of EMILIN2 in a number of gene expression signatures improves their predictive potential, a further indication that the analysis of this molecule may be key for the development of new markers to predict immunotherapy efficacy.
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Affiliation(s)
- Albina Fejza
- Division of Molecular Oncology, Department of Research and Diagnosis, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, Italy; (A.F.); (L.C.); (E.P.); (G.C.)
| | - Maurizio Polano
- Experimental and Clinical Pharmacology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, Italy; (M.P.); (G.T.)
| | - Lucrezia Camicia
- Division of Molecular Oncology, Department of Research and Diagnosis, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, Italy; (A.F.); (L.C.); (E.P.); (G.C.)
| | - Evelina Poletto
- Division of Molecular Oncology, Department of Research and Diagnosis, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, Italy; (A.F.); (L.C.); (E.P.); (G.C.)
| | - Greta Carobolante
- Division of Molecular Oncology, Department of Research and Diagnosis, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, Italy; (A.F.); (L.C.); (E.P.); (G.C.)
| | - Giuseppe Toffoli
- Experimental and Clinical Pharmacology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, Italy; (M.P.); (G.T.)
| | - Maurizio Mongiat
- Division of Molecular Oncology, Department of Research and Diagnosis, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, Italy; (A.F.); (L.C.); (E.P.); (G.C.)
- Correspondence: (M.M.); (E.A.)
| | - Eva Andreuzzi
- Division of Molecular Oncology, Department of Research and Diagnosis, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, Italy; (A.F.); (L.C.); (E.P.); (G.C.)
- Correspondence: (M.M.); (E.A.)
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24
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Ghidini M, Fusco N, Salati M, Khakoo S, Tomasello G, Petrelli F, Trapani D, Petrillo A. The Emergence of Immune-checkpoint Inhibitors in Colorectal Cancer Therapy. Curr Drug Targets 2021; 22:1021-1033. [PMID: 33563194 DOI: 10.2174/1389450122666210204204415] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Revised: 12/06/2020] [Accepted: 12/30/2020] [Indexed: 12/24/2022]
Abstract
Immunotherapy has revolutionized the treatment landscape in a number of solid tumors. In colorectal cancer, evidence suggests that microsatellite high (MSI-H) tumors are the most responsive to immune checkpoint blockade due to increased neo-antigen load and a favorable tumor microenvironment. Indeed, Pembrolizumab now represents a first-line option in such patients. However, MSI-H tumors represent the minority and a proportion of patients' progress despite initially responding. Trials are investigating different immunotherapy combinatorial strategies to enhance immune response in less immunogenic colorectal tumors. Such strategies include dual immune checkpoint blockade, combining immune checkpoint inhibitors with other treatment modalities such as radiotherapy, chemotherapy or other biological or targeted agents. Moreover, there is an increasing drive to identify biomarkers to better select patients most likely to respond to immunotherapy and understand intrinsic and acquired resistance mechanisms. Apart from MSI-H tumors, there is a strong rationale to suggest that tumors with alterations in DNA polymerase epsilon and DNA polymerase delta are also likely to respond to immunotherapy and trials in this subpopulation are underway. Other strategies such as priming O6-methylguanineDNA methyltransferase silenced tumors with alkylating agents to make them receptive to immune checkpoint blockade are also being investigated. Here we discuss different colorectal subpopulations together with their likelihood of response to immune checkpoint blockade and strategies to overcome barriers to a successful clinical outcome. We summarize evidence from published clinical trials and provide an overview of trials in progress whilst discussing newer immunotherapy strategies such as adoptive cell therapies and cancer vaccines.
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Affiliation(s)
- Michele Ghidini
- Medical Oncology Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy
| | - Nicola Fusco
- Department of Oncology and Hemato-Oncology, University of Milan, Italy
| | - Massimiliano Salati
- PhD Program, Clinical and Experimental Medicine, University of Modena and Reggio Emilia, Modena, Italy
| | - Shelize Khakoo
- Department of Medicine, The Royal Marsden Hospital NHS Foundation Trust, London and Surrey, United Kingdom
| | - Gianluca Tomasello
- Medical Oncology Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy
| | - Fausto Petrelli
- Medical Oncology Unit, Azienda Socio-Sanitaria Territoriale Bergamo Ovest, Treviglio, Bergamo, Italy
| | - Dario Trapani
- Division of Early Drug Development for Innovative Therapies, European Institute of Oncology IRCCS, Milan, Italy
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25
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Pramil E, Dillard C, Escargueil AE. Colorectal Cancer and Immunity: From the Wet Lab to Individuals. Cancers (Basel) 2021; 13:cancers13071713. [PMID: 33916641 PMCID: PMC8038567 DOI: 10.3390/cancers13071713] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 03/27/2021] [Accepted: 03/30/2021] [Indexed: 12/14/2022] Open
Abstract
Simple Summary Tackling the current dilemma of colorectal cancer resistance to immunotherapy is puzzling and requires novel therapeutic strategies to emerge. However, characterizing the intricate interactions between cancer and immune cells remains difficult because of the complexity and heterogeneity of both compartments. Developing rationales is intellectually feasible but testing them can be experimentally challenging and requires the development of innovative procedures and protocols. In this review, we delineated useful in vitro and in vivo models used for research in the field of immunotherapy that are or could be applied to colorectal cancer management and lead to major breakthroughs in the coming years. Abstract Immunotherapy is a very promising field of research and application for treating cancers, in particular for those that are resistant to chemotherapeutics. Immunotherapy aims at enhancing immune cell activation to increase tumor cells recognition and killing. However, some specific cancer types, such as colorectal cancer (CRC), are less responsive than others to the current immunotherapies. Intrinsic resistance can be mediated by the development of an immuno-suppressive environment in CRC. The mutational status of cancer cells also plays a role in this process. CRC can indeed be distinguished in two main subtypes. Microsatellite instable (MSI) tumors show a hyper-mutable phenotype caused by the deficiency of the DNA mismatch repair machinery (MMR) while microsatellite stable (MSS) tumors show a comparatively more “stable” mutational phenotype. Several studies demonstrated that MSI CRC generally display good prognoses for patients and immunotherapy is considered as a therapeutic option for this type of tumors. On the contrary, MSS metastatic CRC usually presents a worse prognosis and is not responsive to immunotherapy. According to this, developing new and innovative models for studying CRC response towards immune targeted therapies has become essential in the last years. Herein, we review the in vitro and in vivo models used for research in the field of immunotherapy applied to colorectal cancer.
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Affiliation(s)
- Elodie Pramil
- Sorbonne Université, INSERM U938, Centre de Recherche Saint-Antoine, F-75012 Paris, France; (E.P.); (C.D.)
- Alliance Pour la Recherche en Cancérologie—APREC, Tenon Hospital, F-75012 Paris, France
| | - Clémentine Dillard
- Sorbonne Université, INSERM U938, Centre de Recherche Saint-Antoine, F-75012 Paris, France; (E.P.); (C.D.)
- Alliance Pour la Recherche en Cancérologie—APREC, Tenon Hospital, F-75012 Paris, France
| | - Alexandre E. Escargueil
- Sorbonne Université, INSERM U938, Centre de Recherche Saint-Antoine, F-75012 Paris, France; (E.P.); (C.D.)
- Correspondence: ; Tel.: +33-(0)1-49-28-46-44
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26
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László L, Kurilla A, Takács T, Kudlik G, Koprivanacz K, Buday L, Vas V. Recent Updates on the Significance of KRAS Mutations in Colorectal Cancer Biology. Cells 2021; 10:667. [PMID: 33802849 PMCID: PMC8002639 DOI: 10.3390/cells10030667] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 03/03/2021] [Accepted: 03/10/2021] [Indexed: 12/17/2022] Open
Abstract
The most commonly mutated isoform of RAS among all cancer subtypes is KRAS. In this review, we focus on the special role of KRAS mutations in colorectal cancer (CRC), aiming to collect recent data on KRAS-driven enhanced cell signalling, in vitro and in vivo research models, and CRC development-related processes such as metastasis and cancer stem cell formation. We attempt to cover the diverse nature of the effects of KRAS mutations on age-related CRC development. As the incidence of CRC is rising in young adults, we have reviewed the driving forces of ageing-dependent CRC.
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Affiliation(s)
- Loretta László
- Research Centre for Natural Sciences, Institute of Enzymology, 1051 Budapest, Hungary; (L.L.); (A.K.); (T.T.); (G.K.); (K.K.); (L.B.)
| | - Anita Kurilla
- Research Centre for Natural Sciences, Institute of Enzymology, 1051 Budapest, Hungary; (L.L.); (A.K.); (T.T.); (G.K.); (K.K.); (L.B.)
| | - Tamás Takács
- Research Centre for Natural Sciences, Institute of Enzymology, 1051 Budapest, Hungary; (L.L.); (A.K.); (T.T.); (G.K.); (K.K.); (L.B.)
| | - Gyöngyi Kudlik
- Research Centre for Natural Sciences, Institute of Enzymology, 1051 Budapest, Hungary; (L.L.); (A.K.); (T.T.); (G.K.); (K.K.); (L.B.)
| | - Kitti Koprivanacz
- Research Centre for Natural Sciences, Institute of Enzymology, 1051 Budapest, Hungary; (L.L.); (A.K.); (T.T.); (G.K.); (K.K.); (L.B.)
| | - László Buday
- Research Centre for Natural Sciences, Institute of Enzymology, 1051 Budapest, Hungary; (L.L.); (A.K.); (T.T.); (G.K.); (K.K.); (L.B.)
- Department of Medical Chemistry, Semmelweis University Medical School, 1071 Budapest, Hungary
| | - Virag Vas
- Research Centre for Natural Sciences, Institute of Enzymology, 1051 Budapest, Hungary; (L.L.); (A.K.); (T.T.); (G.K.); (K.K.); (L.B.)
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Differential Effects of Gold Nanoparticles and Ionizing Radiation on Cell Motility between Primary Human Colonic and Melanocytic Cells and Their Cancerous Counterparts. Int J Mol Sci 2021; 22:ijms22031418. [PMID: 33572551 PMCID: PMC7866826 DOI: 10.3390/ijms22031418] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Revised: 01/27/2021] [Accepted: 01/28/2021] [Indexed: 02/07/2023] Open
Abstract
This study examined the effects of gold nanoparticles (AuNPs) and/or ionizing radiation (IR) on the viability and motility of human primary colon epithelial (CCD841) and colorectal adenocarcinoma (SW48) cells as well as human primary epidermal melanocytes (HEM) and melanoma (MM418-C1) cells. AuNPs up to 4 mM had no effect on the viability of these cell lines. The viability of the cancer cells was ~60% following exposure to 5 Gy. Exposure to 5 Gy X-rays or 1 mM AuNPs showed the migration of the cancer cells ~85% that of untreated controls, while co-treatment with AuNPs and IR decreased migration to ~60%. In the non-cancerous cell lines gap closure was enhanced by ~15% following 1 mM AuNPs or 5 Gy treatment, while for co-treatment it was ~22% greater than that for the untreated controls. AuNPs had no effect on cell re-adhesion, while IR enhanced only the re-adhesion of the cancer cell lines but not their non-cancerous counterparts. The addition of AuNPs did not enhance cell adherence. This different reaction to AuNPs and IR in the cancer and normal cells can be attributed to radiation-induced adhesiveness and metabolic differences between tumour cells and their non-cancerous counterparts.
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He J, Zhang W, Di T, Meng J, Qi Y, Li G, Zhang Y, Su H, Yan W. Water extract of sporoderm-broken spores of Ganoderma lucidum enhanced pd-l1 antibody efficiency through downregulation and relieved complications of pd-l1 monoclonal antibody. Biomed Pharmacother 2020; 131:110541. [PMID: 33152901 DOI: 10.1016/j.biopha.2020.110541] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2020] [Revised: 07/07/2020] [Accepted: 07/20/2020] [Indexed: 10/23/2022] Open
Abstract
PURPOSE Osteosarcoma is a malignant musculoskeletal tumor with early metastasis and a poor prognosis, especially in adolescents. Ganoderma lucidum (Leyss. Ex Fr.) Karst (G. lucidum), a traditional East Asian medicine, has been reported to play a critical role in antitumor and immunomodulatory activity. The aim of this study was to investigate the effects and molecular mechanisms of water extract of sporoderm-broken spores of G. lucidum (BSGWE) on osteosarcoma PD-L1 (programmed cell death-ligand 1) transcriptional regulation, efficacy enhancement, and side effect remission. METHODS The antitumor effects on cell proliferation of BSGWE in osteosarcoma cells were detected by apoptosis flow cytometry, and the migration ability of HOS and K7M2 cells were evaluated by cell scratch assay. Potential signaling regulation of PD-L1 was detected by western blotting. To confirm the signaling pathway of BSGWE-related PD-L1 downregulation, a pho-STAT3 turnover experiment was carried out. Colivelin was administered as a pho-STAT3 activator to rescue the BSGWE-induced PD-L1 inhibition. To further study in vivo signaling, in a Balb/c osteosarcoma allograft model, tumor volume was measured using an in vivo bioluminescence imaging system. The body weight curve and tumor volume curve were analyzed to reveal the remission effects of BSGWE on PD-L1 antibody-related body weight loss and its immunomodulatory effects on the osteosarcoma and spleen. The PD-L1 expression level and expression of related transcription-factor pho-STAT3 in tumor cells and spleens were assessed by IHC analysis. RESULTS BSGWE suppressed the proliferation and migration of osteosarcoma cells in vitro via induction of apoptosis. In addition, BSGWE downregulated PD-L1 expression and related STAT3 (signal transducers and activators of transcription) phosphorylation levels in a dose-dependent manner. Western blotting and qRT-PCR assay revealed that BSGWE downregulated PD-L1 expression by inhibiting STAT3 phosphorylation. A turnover experiment showed that colivelin administration could rescue PD-L1 inhibition via pho-STAT3 activation. BSGWE not only downregulated PD-L1 expression via the STAT3 pathway in an allograft Balb/c mouse model, but also relieved complications including weight loss and spleen atrophy in a mouse monoclonal antibody therapy model on the basis of its traditional advantages in immune enhancement. CONCLUSION BSGWE downregulated PD-L1 expression via pho-STAT3 inhibition of protein and RNA levels. BSGWE enhanced PD-L1 antibody efficacy via phosphorylated STAT3 downregulation in vitro and in vivo. BSGWE also relieved complications of weight loss and spleen atrophy in a murine allograft osteosarcoma immune checkpoint blockade therapy model.
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Affiliation(s)
- Jiaming He
- The Second Affiliated Hospital Zhejiang University School of Medicine, Jiefang Campus, 88 Jiefang Road, Shangcheng District, Hangzhou, 310009, China; Zhejiang University School of Medicine, Zhejiang University Huajiachi Campus, 268 Kaixuan Road, Jianggan District, Hangzhou, 310029, China.
| | - Wenkan Zhang
- The Second Affiliated Hospital Zhejiang University School of Medicine, Jiefang Campus, 88 Jiefang Road, Shangcheng District, Hangzhou, 310009, China; Zhejiang University School of Medicine, Zhejiang University Huajiachi Campus, 268 Kaixuan Road, Jianggan District, Hangzhou, 310029, China.
| | - Tuoyu Di
- The Second Affiliated Hospital Zhejiang University School of Medicine, Jiefang Campus, 88 Jiefang Road, Shangcheng District, Hangzhou, 310009, China; Zhejiang University School of Medicine, Zhejiang University Huajiachi Campus, 268 Kaixuan Road, Jianggan District, Hangzhou, 310029, China.
| | - Jiahong Meng
- The Second Affiliated Hospital Zhejiang University School of Medicine, Jiefang Campus, 88 Jiefang Road, Shangcheng District, Hangzhou, 310009, China; Zhejiang University School of Medicine, Zhejiang University Huajiachi Campus, 268 Kaixuan Road, Jianggan District, Hangzhou, 310029, China.
| | - Yiying Qi
- The Second Affiliated Hospital Zhejiang University School of Medicine, Jiefang Campus, 88 Jiefang Road, Shangcheng District, Hangzhou, 310009, China; Zhejiang University School of Medicine, Zhejiang University Huajiachi Campus, 268 Kaixuan Road, Jianggan District, Hangzhou, 310029, China.
| | - Guoqi Li
- The Second Affiliated Hospital Zhejiang University School of Medicine, Jiefang Campus, 88 Jiefang Road, Shangcheng District, Hangzhou, 310009, China; Zhejiang University School of Medicine, Zhejiang University Huajiachi Campus, 268 Kaixuan Road, Jianggan District, Hangzhou, 310029, China.
| | - Yuxiang Zhang
- The Second Affiliated Hospital Zhejiang University School of Medicine, Jiefang Campus, 88 Jiefang Road, Shangcheng District, Hangzhou, 310009, China; Zhejiang University School of Medicine, Zhejiang University Huajiachi Campus, 268 Kaixuan Road, Jianggan District, Hangzhou, 310029, China.
| | - Hang Su
- The Second Affiliated Hospital Zhejiang University School of Medicine, Jiefang Campus, 88 Jiefang Road, Shangcheng District, Hangzhou, 310009, China; Zhejiang University School of Medicine, Zhejiang University Huajiachi Campus, 268 Kaixuan Road, Jianggan District, Hangzhou, 310029, China.
| | - Weiqi Yan
- The Second Affiliated Hospital Zhejiang University School of Medicine, Jiefang Campus, 88 Jiefang Road, Shangcheng District, Hangzhou, 310009, China; Zhejiang University School of Medicine, Zhejiang University Huajiachi Campus, 268 Kaixuan Road, Jianggan District, Hangzhou, 310029, China.
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Camorani S, Passariello M, Agnello L, Esposito S, Collina F, Cantile M, Di Bonito M, Ulasov IV, Fedele M, Zannetti A, De Lorenzo C, Cerchia L. Aptamer targeted therapy potentiates immune checkpoint blockade in triple-negative breast cancer. J Exp Clin Cancer Res 2020; 39:180. [PMID: 32892748 PMCID: PMC7487859 DOI: 10.1186/s13046-020-01694-9] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Accepted: 08/28/2020] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Triple-negative breast cancer (TNBC) is a uniquely aggressive cancer with high rates of relapse due to resistance to chemotherapy. TNBC expresses higher levels of programmed cell death-ligand 1 (PD-L1) compared to other breast cancers, providing the rationale for the recently approved immunotherapy with anti-PD-L1 monoclonal antibodies (mAbs). A huge effort is dedicated to identify actionable biomarkers allowing for combination therapies with immune-checkpoint blockade. Platelet-derived growth factor receptor β (PDGFRβ) is highly expressed in invasive TNBC, both on tumor cells and tumor microenvironment. We recently proved that tumor growth and lung metastases are impaired in mouse models of human TNBC by a high efficacious PDGFRβ aptamer. Hence, we aimed at investigating the effectiveness of a novel combination treatment with the PDGFRβ aptamer and anti-PD-L1 mAbs in TNBC. METHODS The targeting ability of the anti-human PDGFRβ aptamer toward the murine receptor was verified by streptavidin-biotin assays and confocal microscopy, and its inhibitory function by transwell migration assays. The anti-proliferative effects of the PDGFRβ aptamer/anti-PD-L1 mAbs combination was assessed in human MDA-MB-231 and murine 4 T1 TNBC cells, both grown as monolayer or co-cultured with lymphocytes. Tumor cell lysis and cytokines secretion by lymphocytes were analyzed by LDH quantification and ELISA, respectively. Orthotopic 4 T1 xenografts in syngeneic mice were used for dissecting the effect of aptamer/mAb combination on tumor growth, metastasis and lymphocytes infiltration. Ex vivo analyses through immunohistochemistry, RT-qPCR and immunoblotting were performed. RESULTS We show that the PDGFRβ aptamer potentiates the anti-proliferative activity of anti-PD-L1 mAbs on both human and murine TNBC cells, according to its human/mouse cross-reactivity. Further, by binding to activated human and mouse lymphocytes, the aptamer enhances the anti-PD-L1 mAb-induced cytotoxicity of lymphocytes against tumor cells. Importantly, the aptamer heightens the antibody efficacy in inhibiting tumor growth and lung metastases in mice. It acts on both tumor cells, inhibiting Akt and ERK1/2 signaling pathways, and immune populations, increasing intratumoral CD8 + T cells and reducing FOXP3 + Treg cells. CONCLUSION Co-treatment of PDGFRβ aptamer with anti-PD-L1 mAbs is a viable strategy, thus providing for the first time an evidence of the efficacy of PDGFRβ/PD-L1 co-targeting combination therapy in TNBC.
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Affiliation(s)
- Simona Camorani
- Institute of Experimental Endocrinology and Oncology "Gaetano Salvatore", CNR, Via S. Pansini 5, 80131, Naples, Italy
| | - Margherita Passariello
- Department of Molecular Medicine and Medical Biotechnology, University of Naples "Federico II", Via Pansini 5, 80131, Naples, Italy
- Ceinge-Biotecnologie Avanzate s.c.a.r.l., via Gaetano Salvatore 486, 80145, Naples, Italy
| | - Lisa Agnello
- Institute of Experimental Endocrinology and Oncology "Gaetano Salvatore", CNR, Via S. Pansini 5, 80131, Naples, Italy
| | - Silvia Esposito
- Ceinge-Biotecnologie Avanzate s.c.a.r.l., via Gaetano Salvatore 486, 80145, Naples, Italy
| | - Francesca Collina
- Pathology Unit, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, Naples, Italy
| | - Monica Cantile
- Pathology Unit, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, Naples, Italy
| | - Maurizio Di Bonito
- Pathology Unit, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, Naples, Italy
| | - Ilya V Ulasov
- Group of Experimental Biotherapy and Diagnostic, Institute for Regenerative Medicine, Sechenov First Moscow State Medical University, Moscow, 119991, Russia
| | - Monica Fedele
- Institute of Experimental Endocrinology and Oncology "Gaetano Salvatore", CNR, Via S. Pansini 5, 80131, Naples, Italy
| | - Antonella Zannetti
- Institute of Biostructure and Bioimaging, CNR, Via T. De Amicis 95, 80145, Naples, Italy
| | - Claudia De Lorenzo
- Department of Molecular Medicine and Medical Biotechnology, University of Naples "Federico II", Via Pansini 5, 80131, Naples, Italy.
- Ceinge-Biotecnologie Avanzate s.c.a.r.l., via Gaetano Salvatore 486, 80145, Naples, Italy.
| | - Laura Cerchia
- Institute of Experimental Endocrinology and Oncology "Gaetano Salvatore", CNR, Via S. Pansini 5, 80131, Naples, Italy.
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Yeon M, Kim Y, Jung HS, Jeoung D. Histone Deacetylase Inhibitors to Overcome Resistance to Targeted and Immuno Therapy in Metastatic Melanoma. Front Cell Dev Biol 2020; 8:486. [PMID: 32626712 PMCID: PMC7311641 DOI: 10.3389/fcell.2020.00486] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Accepted: 05/22/2020] [Indexed: 12/12/2022] Open
Abstract
Therapies that target oncogenes and immune checkpoint molecules constitute a major group of treatments for metastatic melanoma. A mutation in BRAF (BRAF V600E) affects various signaling pathways, including mitogen activated protein kinase (MAPK) and PI3K/AKT/mammalian target of rapamycin (mTOR) in melanoma. Target-specific agents, such as MAPK inhibitors improve progression-free survival. However, BRAFV600E mutant melanomas treated with BRAF kinase inhibitors develop resistance. Immune checkpoint molecules, such as programmed death-1 (PD-1) and programmed death ligand-1(PD-L1), induce immune evasion of cancer cells. MAPK inhibitor resistance results from the increased expression of PD-L1. Immune checkpoint inhibitors, such as anti-PD-L1 or anti-PD-1, are main players in immune therapies designed to target metastatic melanoma. However, melanoma patients show low response rate and resistance to these inhibitors develops within 6–8 months of treatment. Epigenetic reprogramming, such as DNA methylaion and histone modification, regulates the expression of genes involved in cellular proliferation, immune checkpoints and the response to anti-cancer drugs. Histone deacetylases (HDACs) remove acetyl groups from histone and non-histone proteins and act as transcriptional repressors. HDACs are often dysregulated in melanomas, and regulate MAPK signaling, cancer progression, and responses to various anti-cancer drugs. HDACs have been shown to regulate the expression of PD-1/PD-L1 and genes involved in immune evasion. These reports make HDACs ideal targets for the development of anti-melanoma therapeutics. We review the mechanisms of resistance to anti-melanoma therapies, including MAPK inhibitors and immune checkpoint inhibitors. We address the effects of HDAC inhibitors on the response to MAPK inhibitors and immune checkpoint inhibitors in melanoma. In addition, we discuss current progress in anti-melanoma therapies involving a combination of HDAC inhibitors, immune checkpoint inhibitors, and MAPK inhibitors.
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Affiliation(s)
- Minjeong Yeon
- Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chunchon, South Korea
| | - Youngmi Kim
- Institute of New Frontier Research, College of Medicine, Hallym University, Chunchon, South Korea
| | - Hyun Suk Jung
- Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chunchon, South Korea
| | - Dooil Jeoung
- Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chunchon, South Korea
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