|
1
|
Feng CZ, Zhong SQ, Ye SW, Zheng Z, Sun H, Zhou SH. Tumor-derived exosomal miR-425-5p and miR-135b-3p enhance colorectal cancer progression through immune suppression and vascular permeability promotion. World J Gastrointest Oncol 2025; 17:106161. [DOI: 10.4251/wjgo.v17.i6.106161] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2025] [Revised: 03/24/2025] [Accepted: 04/22/2025] [Indexed: 06/13/2025] Open
Abstract
BACKGROUND Colorectal cancer (CRC) is a leading cause of cancer-related morbidity and mortality globally. Exosomal microRNAs (miRNAs) are known to modulate tumor progression by influencing immune responses and vascular dynamics. However, the roles of specific exosomal miRNAs, such as miR-425-5p and miR-135b-3p, in CRC remain unclear.
AIM To explore the specific roles and underlying mechanisms of exosomal miR-425-5p and miR-135b-3p in CRC progression.
METHODS Differentially expressed miRNAs were identified through microarray analysis of exosomes isolated from CRC tissues and adjacent normal mucosa. Functional roles of miR-425-5p and miR-135b-3p were evaluated in vitro using macrophage polarization, T cell differentiation, and vascular permeability assays, as well as in vivo tumor formation and metastasis experiments in nude mice. Validation experiments were performed using CRC cell lines (HCT116 and SW620).
RESULTS Exosomal miR-425-5p and miR-135b-3p were significantly upregulated in CRC compared to normal tissues. Functional studies revealed that miR-425-5p promotes macrophage M2-like polarization and suppresses T cell proinflammatory responses, while miR-135b-3p enhances vascular permeability and angiogenesis. Inhibition of these miRNAs in CRC cell-derived exosomes significantly suppressed tumor growth and metastasis in nude mice, reprogramming the tumor microenvironment toward reduced angiogenesis and enhanced immune activation. Combined inhibition of both miRNAs resulted in the most pronounced effects.
CONCLUSION Exosomal miR-425-5p and miR-135b-3p drive CRC progression by promoting immune suppression and vascular permeability. Their inhibition offers a promising strategy for modulating the tumor microenvironment and limiting CRC metastasis.
Collapse
Affiliation(s)
- Chun-Zai Feng
- Department of Tumor Surgery, Zhongshan City People’s Hospital, Zhongshan 528403, Guangdong Province, China
| | - Si-Quan Zhong
- Department of Tumor Surgery, Zhongshan City People’s Hospital, Zhongshan 528403, Guangdong Province, China
| | - Shao-Wei Ye
- Department of Tumor Surgery, Zhongshan City People’s Hospital, Zhongshan 528403, Guangdong Province, China
| | - Zheng Zheng
- Department of Tumor Surgery, Zhongshan City People’s Hospital, Zhongshan 528403, Guangdong Province, China
| | - Hao Sun
- Department of Tumor Surgery, Zhongshan City People’s Hospital, Zhongshan 528403, Guangdong Province, China
| | - Shi-Hai Zhou
- Department of Tumor Surgery, Zhongshan City People’s Hospital, Zhongshan 528403, Guangdong Province, China
| |
Collapse
|
|
2
|
Tu X, Lin W, Zhai X, Liang S, Huang G, Wang J, Jia W, Li S, Li B, Cheng B. Oleanolic acid inhibits M2 macrophage polarization and potentiates anti-PD-1 therapy in hepatocellular carcinoma by targeting miR-130b-3p-PTEN-PI3K-Akt signaling and glycolysis. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2025; 141:156750. [PMID: 40250003 DOI: 10.1016/j.phymed.2025.156750] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/12/2025] [Revised: 03/26/2025] [Accepted: 04/08/2025] [Indexed: 04/20/2025]
Abstract
BACKGROUND Hypoxia promotes M2 polarization of macrophages and the formation of the immunosuppressive tumor microenvironment (TME) in hepatocellular carcinoma (HCC). Oleanolic acid (OA) has shown great potential in the treatment of HCC. However, the mechanisms of macrophage M2 polarization in hypoxic tumor TME and the regulating effect of OA is still unclear. OBJECTIVE To investigate the mechanisms of macrophage M2 polarization induced by hypoxic HCC cells-derived exosomes and examine the efficacy of OA in remedying the immunosuppressive TME and the anti-PD1 therapy potential. METHODS Hypoxic and normoxic HCC-derived exosomes (H-Exo and N-Exo) were collected by centrifugation. The microRNAs (miRNA) carried by the exosomes were sequenced and then screened to identify the functional miRNA. THP-1-induced macrophages were treated with exosomes or miRNAs to induce the M2 polarization of macrophages. Real-time RT-PCR and Western blotting were used to identify the direct target of miR-130b-3p and its downstream molecules. Hepa1-6 hepatoma-bearing mice were subjected to determine the efficacy of OA in regulating the TME and the anti-PD1 therapy potential. RESULTS H-Exo promotes macrophage M2 polarization, and thereby accelerates the migration and epithelial-mesenchymal transition (EMT) of HCC cells. Exosomal miRNA sequencing and subsequent functional validation showed that miR-130b-3p was the mediator of H-Exo-induced macrophage M2 polarization. PTEN was identified as the target of miR-130b-3p, and downregulation of PTEN by miR-130b-3p led to the activation of PI3K/Akt signaling and macrophage M2 polarization. In addition, miR-130b-3p also enhanced the glycolysis. OA suppressed H-Exo and miR-130b-3p-induced macrophage M2 polarization, also inhibited miR-130b-3p-induced glycolysis. In vivo, OA treatment enhanced the efficacy of anti-PD1 antibody by decreasing the number of M2 macrophages and increasing the number of CD8+ T cells. CONCLUSION Our findings uncover a new mechanism of hypoxic HCC cells-induced M2 polarization of macrophages through exosomal miR-130b-3p-PTEN-PI3K-Akt signaling. The combination therapy of OA with anti-PD1 antibody may lead to substantial improvements of the immunotherapy efficacy and expand the beneficiaries.
Collapse
Affiliation(s)
- Xiaoyu Tu
- Faculty of Traditional Chinese Medicine, Naval Medical University (Second Military Medical University), Shanghai 200433, China; Department of Rehabilitation Medicine and Physiotherapy, the First Affiliated Hospital of Naval Medical University (Second Military Medical University), Shanghai 200433, China
| | - Wanfu Lin
- Faculty of Traditional Chinese Medicine, Naval Medical University (Second Military Medical University), Shanghai 200433, China; Oncology Department of Traditional Chinese Medicine, the First Affiliated Hospital of Naval Medical University (Second Military Medical University), Shanghai 200433, China
| | - Xiaofeng Zhai
- Faculty of Traditional Chinese Medicine, Naval Medical University (Second Military Medical University), Shanghai 200433, China; Oncology Department of Traditional Chinese Medicine, the First Affiliated Hospital of Naval Medical University (Second Military Medical University), Shanghai 200433, China
| | - Shufang Liang
- Faculty of Traditional Chinese Medicine, Naval Medical University (Second Military Medical University), Shanghai 200433, China; Oncology Department of Traditional Chinese Medicine, the First Affiliated Hospital of Naval Medical University (Second Military Medical University), Shanghai 200433, China
| | - Guokai Huang
- Faculty of Traditional Chinese Medicine, Naval Medical University (Second Military Medical University), Shanghai 200433, China; Oncology Department of Traditional Chinese Medicine, the First Affiliated Hospital of Naval Medical University (Second Military Medical University), Shanghai 200433, China
| | - Jingfang Wang
- Faculty of Traditional Chinese Medicine, Naval Medical University (Second Military Medical University), Shanghai 200433, China; Oncology Department of Traditional Chinese Medicine, the First Affiliated Hospital of Naval Medical University (Second Military Medical University), Shanghai 200433, China
| | - Wentao Jia
- Faculty of Traditional Chinese Medicine, Naval Medical University (Second Military Medical University), Shanghai 200433, China; Oncology Department of Traditional Chinese Medicine, the First Affiliated Hospital of Naval Medical University (Second Military Medical University), Shanghai 200433, China
| | - Shu Li
- Department of Gastroenterology, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200071, China.
| | - Bai Li
- Department of Rehabilitation Medicine and Physiotherapy, the First Affiliated Hospital of Naval Medical University (Second Military Medical University), Shanghai 200433, China.
| | - Binbin Cheng
- Faculty of Traditional Chinese Medicine, Naval Medical University (Second Military Medical University), Shanghai 200433, China; Oncology Department of Traditional Chinese Medicine, the First Affiliated Hospital of Naval Medical University (Second Military Medical University), Shanghai 200433, China.
| |
Collapse
|
|
3
|
Xiang J, Yao L, Wang S, Zhao L, Yu J. Progress of exosomes in regulating tumor metastasis by remodeling the pre-metastatic immune microenvironment. Cell Immunol 2025; 413:104960. [PMID: 40367831 DOI: 10.1016/j.cellimm.2025.104960] [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: 02/21/2025] [Revised: 04/15/2025] [Accepted: 04/24/2025] [Indexed: 05/16/2025]
Abstract
Exosomes play an important role in the metastatic microenvironment, acting as a transmission belt that facilitates intercellular communication. By delivering proteins, nucleic acids, and other substances in the exosomes, they can change the function of the receptor target cells, change the microenvironment of the metastatic site, and promote the colonization of the tumor cells, thus promoting cancer metastasis. The interaction between tumor cells and the surrounding microenvironment is complex, with exosomes serving as key facilitators of crosstalk between the primary tumor microenvironment and the pre-metastasis microenvironment. Despite many current studies to explore exosomes, we still do not have a detailed understanding of the role and mechanism of exosomes in the pre-metastatic immune microenvironment, and there are many challenges in the clinical application of exosomes. In this paper, we summarize the role of exosomes in regulating the pre-metastatic immune microenvironment and its mechanism, focusing on how exosomes regulate the function of immune cells in the pre-metastatic microenvironment to promote tumor metastasis. In addition, the potential application of exosomes in tumor immunotherapy and strategies for targeting exosomes are discussed. This will contribute to the immunotherapy of cancer metastasis and promote the clinical application of exosomes.
Collapse
Affiliation(s)
- Jiangning Xiang
- Cancer Center, Beijing Friendship Hospital, Capital Medical University, No. 95 Yong an Road, Xi Cheng District, Beijing 100053, China
| | - Lin Yao
- Cancer Center, Beijing Friendship Hospital, Capital Medical University, No. 95 Yong an Road, Xi Cheng District, Beijing 100053, China
| | - Shan Wang
- Cancer Center, Beijing Friendship Hospital, Capital Medical University, No. 95 Yong an Road, Xi Cheng District, Beijing 100053, China
| | - Lei Zhao
- Cancer Center, Beijing Friendship Hospital, Capital Medical University, No. 95 Yong an Road, Xi Cheng District, Beijing 100053, China.
| | - Jing Yu
- Cancer Center, Beijing Friendship Hospital, Capital Medical University, No. 95 Yong an Road, Xi Cheng District, Beijing 100053, China.
| |
Collapse
|
|
4
|
Wan S, Liang C, Wu C, Wang S, Wang J, Xu L, Zhang X, Hou Y, Xia Y, Xu L, Huang X. Disulfidptosis in tumor progression. Cell Death Discov 2025; 11:205. [PMID: 40295497 PMCID: PMC12038022 DOI: 10.1038/s41420-025-02495-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2024] [Revised: 04/10/2025] [Accepted: 04/15/2025] [Indexed: 04/30/2025] Open
Abstract
Disulfidptosis, a regulated cell death modality driven by the cystine transporter solute carrier family 7 member 11 (SLC7A11), is characterized by actin cytoskeleton collapse under glucose starvation. This review systematically elucidates the pivotal role of disulfidptosis in tumor metabolic reprogramming, with a focus on its molecular mechanisms and distinctions from other cell death pathways. The core mechanisms include SLC7A11-mediated cystine overload and NRF2/c-Myc-regulated pentose phosphate pathway activation. By integrating multiomics data and single-cell transcriptomics, we comprehensively decipher the heterogeneous expression patterns of disulfidptosis-related genes (DRGs) and their dynamic interplay with immune microenvironment remodeling. Furthermore, the coexpression networks of DRGs and disulfidptosis-related long noncoding RNAs (DRLs) offer novel insights into tumor diagnosis, prognosis, and targeted therapy. Therapeutically, SLC7A11 inhibitors (e.g., HG106) and glucose transporter inhibitors (e.g., BAY-876) demonstrate efficacy by exploiting metabolic vulnerabilities, whereas natural compounds synergizing with immune checkpoint blockade provide strategies to counteract immunosuppressive microenvironments. Through interdisciplinary collaboration and clinical translation, disulfidptosis research holds transformative potential in redefining precision oncology.
Collapse
Affiliation(s)
- Senlin Wan
- Department of Gastrointestinal Surgery, The First Affiliated Hospital, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui, China
- Anhui Province Key Laboratory of Non-coding RNA Basic and Clinical Transformation, Wuhu, Anhui, China
| | - Changming Liang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui, China
- Anhui Province Key Laboratory of Non-coding RNA Basic and Clinical Transformation, Wuhu, Anhui, China
| | - Chengwei Wu
- Department of Gastrointestinal Surgery, The First Affiliated Hospital, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui, China
- Anhui Province Key Laboratory of Non-coding RNA Basic and Clinical Transformation, Wuhu, Anhui, China
| | - Song Wang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui, China
- Anhui Province Key Laboratory of Non-coding RNA Basic and Clinical Transformation, Wuhu, Anhui, China
| | - Jiawei Wang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui, China
- Anhui Province Key Laboratory of Non-coding RNA Basic and Clinical Transformation, Wuhu, Anhui, China
| | - Lishuai Xu
- Department of Gastrointestinal Surgery, The First Affiliated Hospital, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui, China
- Anhui Province Key Laboratory of Non-coding RNA Basic and Clinical Transformation, Wuhu, Anhui, China
| | - Xu Zhang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui, China
- Anhui Province Key Laboratory of Non-coding RNA Basic and Clinical Transformation, Wuhu, Anhui, China
| | - Yinfen Hou
- Department of Gastrointestinal Surgery, The First Affiliated Hospital, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui, China
- Anhui Province Key Laboratory of Non-coding RNA Basic and Clinical Transformation, Wuhu, Anhui, China
| | - Yabin Xia
- Department of Gastrointestinal Surgery, The First Affiliated Hospital, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui, China
- Anhui Province Key Laboratory of Non-coding RNA Basic and Clinical Transformation, Wuhu, Anhui, China
| | - Li Xu
- Department of Gastrointestinal Surgery, The First Affiliated Hospital, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui, China
- Anhui Province Key Laboratory of Non-coding RNA Basic and Clinical Transformation, Wuhu, Anhui, China
| | - Xiaoxu Huang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui, China.
- Anhui Province Key Laboratory of Non-coding RNA Basic and Clinical Transformation, Wuhu, Anhui, China.
| |
Collapse
|
|
5
|
Barjasteh AH, Jaseb Mazhar AleKassar R, Al-Asady AM, Latifi H, Avan A, Khazaei M, Ryzhikov M, Hassanian SM. Therapeutic Potentials of MiRNA for Colorectal Cancer Liver Metastasis Treatment: A Narrative Review. IRANIAN JOURNAL OF MEDICAL SCIENCES 2025; 50:202-219. [PMID: 40255223 PMCID: PMC12008659 DOI: 10.30476/ijms.2024.102910.3622] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Revised: 11/01/2024] [Accepted: 11/26/2024] [Indexed: 04/22/2025]
Abstract
Colorectal cancer (CRC) ranks among the most prevalent cancers worldwide and is the fourth leading cause of cancer-related deaths. Metastasis poses a significant obstacle in CRC treatment, as distant metastasis, particularly to the liver, remains the primary cause of mortality. Colorectal liver metastasis (CRLM) occurs frequently due to the liver's direct vascular connection to the colorectal region via the portal vein. Standard treatment approaches for CRLM are limited; only a few patients qualify for surgical intervention, resulting in a persistently low survival rate. Additionally, resistance to chemotherapy is common, emphasizing the need for more effective targeted therapies. Emerging evidence highlights the pivotal role of microRNAs (miRNAs) in modulating critical pathways associated with CRLM, including tumor invasion, epithelial-mesenchymal transition, and angiogenesis. MiRNAs exhibit dual functions as tumor suppressors and oncogenes by targeting multiple genes, thus playing a complex role in both the initiation and progression of metastasis. The regulatory mechanisms of miRNAs could help to identify novel biomarkers for early diagnosis and prognosis of CRLM, as well as promising therapeutic targets to overcome chemoresistance. Despite numerous studies on miRNA involvement in CRC metastasis, dedicated reviews focusing on miRNAs and CRLM remain scarce. This review aims to approach targeted therapies by examining the current understanding of miRNA involvement in CRLM and exploring their potential as diagnostic, prognostic, and therapeutic agents. Through an integrative approach, we aim to provide insights that could transform CRLM management and improve patient outcomes.
Collapse
Affiliation(s)
- Amir Hossein Barjasteh
- Metabolic Syndrome Research Center, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Rawa Jaseb Mazhar AleKassar
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Abdulridha Mohammed Al-Asady
- Department of Medical Sciences, Faculty of Nursing, Warith Al-Anbiyaa University, Iraq
- Department of Medical Sciences, Faculty of Dentistry, University of Kerbala, Iraq
- Department of Pharmacology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hanieh Latifi
- Metabolic Syndrome Research Center, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amir Avan
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Faculty of Health, School of Biomedical Sciences, Queensland University of Technology (QUT), Brisbane, QLD 4059, Australia
| | - Majid Khazaei
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Medical Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | | | - Seyed Mahdi Hassanian
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| |
Collapse
|
|
6
|
Li Y, Wang H, Mao D, Che X, Chen Y, Liu Y. Understanding pre-metastatic niche formation: implications for colorectal cancer liver metastasis. J Transl Med 2025; 23:340. [PMID: 40098140 PMCID: PMC11912654 DOI: 10.1186/s12967-025-06328-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2024] [Accepted: 03/01/2025] [Indexed: 03/19/2025] Open
Abstract
The liver is the most commonly metastasized organ in colorectal cancer (CRC), and distant metastasis is the primary cause of mortality from CRC. In recent years, researchers have discovered that tumor cells create a "pre-metastatic niche (PMN)" favorable to metastasis before reaching the metastatic location. This review discusses the many processes and mechanisms that lead to PMN formation in CRC, including gut microbiota, stem cell stimulation, immunocyte interactions, and the induction of extracellular vesicles that carry important information. It examines research methods and diagnostic and therapeutic approaches for treating metastatic CRC with PMN. The crucial significance of PMN formation in metastatic CRC is also highlighted.
Collapse
Affiliation(s)
- Yaqin Li
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210028, China
- Multi-Component of Traditional Chinese Medicine and MicroecologyResearch Center, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, 210028, China
| | - Hong Wang
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210028, China
- Multi-Component of Traditional Chinese Medicine and MicroecologyResearch Center, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, 210028, China
| | - Dengxuan Mao
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210028, China
- Multi-Component of Traditional Chinese Medicine and MicroecologyResearch Center, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, 210028, China
| | - Xiaoyu Che
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210028, China
- Multi-Component of Traditional Chinese Medicine and MicroecologyResearch Center, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, 210028, China
| | - Yan Chen
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210028, China.
- Multi-Component of Traditional Chinese Medicine and MicroecologyResearch Center, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, 210028, China.
- Jiangsu Clinical Innovation Center of Digestive Cancer of Traditional Chinese Medicine, Administration of Traditional Chinese Medicine of Jiangsu Province, Nanjing, China.
| | - Yuping Liu
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210028, China.
- Multi-Component of Traditional Chinese Medicine and MicroecologyResearch Center, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, 210028, China.
- Jiangsu Clinical Innovation Center of Digestive Cancer of Traditional Chinese Medicine, Administration of Traditional Chinese Medicine of Jiangsu Province, Nanjing, China.
| |
Collapse
|
|
7
|
Zhao W, Wu Y, Wang Y, Li T, Liu Q, Hou Z. Exosomal miR-92a-3p modulates M2 macrophage polarization in colorectal cancer: implications for tumor migration and angiogenesis. Med Oncol 2025; 42:96. [PMID: 40059261 DOI: 10.1007/s12032-025-02635-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2024] [Accepted: 02/13/2025] [Indexed: 03/29/2025]
Abstract
Colorectal cancer (CRC) is one of the most prevalent malignant neoplasms globally. Its development and metastasis are closely associated with the polarization of macrophages within the tumor microenvironment (TME). In particular, the polarization of M2-type macrophages has been demonstrated to be related to the promotion of tumor growth, migration, and angiogenesis. This study aims to investigate the role of miR-92a-3p in colon cancer-derived exosomes in regulating M2-type macrophage polarization by targeting EID2B and to elucidate the impact of this process on tumor migration and angiogenesis. MicroRNAs that were differentially expressed in plasma exosomes from CRC patients were initially identified through a search of the GEO database. The results were then verified by RT-qPCR using miR-92a-3p. The uptake of exosomes was observed via laser confocal microscopy, and the impact of miR-92a-3p on the polarization of exosomes and macrophages was examined through the use of RT-qPCR and WB. A bioinformatics analysis and a dual-luciferase reporter assay were employed to identify the downstream target of miR-92a-3p and to investigate its effect on the MAPK/ERK pathway. miR-92a-3p was upregulated in plasma exosomes of colon cancer patients and exhibited a positive correlation with lymph node metastasis. The results demonstrated that miR-92a-3p was capable of promoting M0 macrophage polarization toward the M2 phenotype, and of enhancing the migratory and invasive capacities of CRC cells, as well as their angiogenic potential in vitro. Bioinformatic analysis and experimental validation demonstrated that miR-92a-3p targeted EID2B and that this target gene was negatively correlated with M2-type macrophage polarization. The results demonstrated that miR-92a-3p promotes macrophage M2 polarization by activating the MAPK/ERK pathway. miR-92a-3p activates the MAPK/ERK pathway and induces macrophage M2 polarization by targeting EID2B, thereby promoting migration and angiogenesis in CRC. These findings offer new potential targets for the treatment of colon cancer.
Collapse
Affiliation(s)
- Wei Zhao
- School of Basic Medical Sciences, Chengde Medical University, Chengde, China
| | - Yudan Wu
- Affiliated Hospital of Chengde Medical University, Chengde, China
| | - Yixiao Wang
- School of Basic Medical Sciences, Chengde Medical University, Chengde, China
| | - Tongyi Li
- School of Basic Medical Sciences, Chengde Medical University, Chengde, China
| | - Qiuyan Liu
- Affiliated Hospital of Chengde Medical University, Chengde, China
| | - Zhiping Hou
- School of Basic Medical Sciences, Chengde Medical University, Chengde, China.
| |
Collapse
|
|
8
|
Yuan Q, Jia L, Yang J, Li W. The role of macrophages in liver metastasis: mechanisms and therapeutic prospects. Front Immunol 2025; 16:1542197. [PMID: 40034694 PMCID: PMC11872939 DOI: 10.3389/fimmu.2025.1542197] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2024] [Accepted: 01/21/2025] [Indexed: 03/05/2025] Open
Abstract
Metastasis is a hallmark of advanced cancer, and the liver is a common site for secondary metastasis of many tumor cells, including colorectal, pancreatic, gastric, and prostate cancers. Macrophages in the tumor microenvironment (TME) promote tumor cell metastasis through various mechanisms, including angiogenesis and immunosuppression, and play a unique role in the development of liver metastasis. Macrophages are affected by a variety of factors. Under conditions of hypoxia and increased acidity in the TME, more factors are now found to promote the polarization of macrophages to the M2 type, including exosomes and amino acids. M2-type macrophages promote tumor cell angiogenesis through a variety of mechanisms, including the secretion of factors such as VEGF, IL-1β, and TGF-β1. M2-type macrophages are subjected to multiple regulatory mechanisms. They also interact with various cells within the tumor microenvironment to co-regulate certain conditions, including the creation of an immunosuppressive microenvironment. This interaction promotes tumor cell metastasis, drug resistance, and immune escape. Based on the advent of single-cell sequencing technology, further insights into macrophage subpopulations in the tumor microenvironment may help in exploring new therapeutic targets in the future. In this paper, we will focus on how macrophages affect the TME, how tumor cells and macrophages as well as other immune cells interact with each other, and further investigate the mechanisms involved in liver metastasis of tumor cells and their potential as therapeutic targets.
Collapse
Affiliation(s)
| | | | | | - Wei Li
- *Correspondence: Jiahua Yang, ; Wei Li,
| |
Collapse
|
|
9
|
Liang C, Wang S, Wu C, Wang J, Xu L, Wan S, Zhang X, Hou Y, Xia Y, Xu L, Huang X, Xie H. Role of the AKT signaling pathway in regulating tumor-associated macrophage polarization and in the tumor microenvironment: A review. Medicine (Baltimore) 2025; 104:e41379. [PMID: 39889181 PMCID: PMC11789917 DOI: 10.1097/md.0000000000041379] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Revised: 01/02/2025] [Accepted: 01/10/2025] [Indexed: 02/02/2025] Open
Abstract
Tumor-associated macrophages (TAMs) are present in and are important components of the tumor microenvironment (TME). TAMs differentiate into 2 functionally distinct morphologies, classically activated (M1)-type TAMs and alternatively activated (M2)-type TAMs, when stimulated by different cytokines. The 2 types of TAMs exhibit distinct properties and functions. M1 TAMs secrete high levels of pro-inflammatory and chemotactic factors, exerting proinflammatory, antitumor effects. Conversely, M2 TAMs alter the extracellular matrix, facilitate cellular immune escape, and stimulate tumor angiogenesis, thereby promoting anti-inflammatory responses and tumor growth. The ratio of M1 TAMs to M2 TAMs in the TME is closely related to the prognosis of the tumor. Tumor cells and other cells in the TME can regulate the polarization of TAMs and thus promote tumor progression through the secretion of various substances; however, polarized TAMs can also act on various cells in the TME through the secretion of exosomes, thus forming a positive feedback loop. Therefore, modulating the phenotype of TAMs in the TME or blocking the polarization of M2 TAMs might be a new approach for cancer treatment. However, the intracellular signaling pathways involved in the polarization of TAMs are poorly understood. The AKT signaling pathway is an important signaling pathway involved in the polarization, growth, proliferation, recruitment, and apoptosis of TAMs, as well as the action of TAMs on other cells within the TME. This paper reviews the AKT signaling pathway in the polarization of TAMs and the regulation of the TME and provides new ideas for tumor immunotherapy.
Collapse
Affiliation(s)
- Changming Liang
- Department of Gastrointestinal Surgery, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui, China
- Anhui Province Key Laboratory of Non-coding RNA Basic and Clinical Transformation (Wannan Medical College), Wuhu, Anhui, China
| | - Song Wang
- Department of Gastrointestinal Surgery, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui, China
- Anhui Province Key Laboratory of Non-coding RNA Basic and Clinical Transformation (Wannan Medical College), Wuhu, Anhui, China
| | - Chengwei Wu
- Department of Gastrointestinal Surgery, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui, China
- Anhui Province Key Laboratory of Non-coding RNA Basic and Clinical Transformation (Wannan Medical College), Wuhu, Anhui, China
| | - Jiawei Wang
- Department of Gastrointestinal Surgery, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui, China
- Anhui Province Key Laboratory of Non-coding RNA Basic and Clinical Transformation (Wannan Medical College), Wuhu, Anhui, China
| | - Lishuai Xu
- Department of Gastrointestinal Surgery, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui, China
- Anhui Province Key Laboratory of Non-coding RNA Basic and Clinical Transformation (Wannan Medical College), Wuhu, Anhui, China
| | - Senlin Wan
- Department of Gastrointestinal Surgery, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui, China
- Anhui Province Key Laboratory of Non-coding RNA Basic and Clinical Transformation (Wannan Medical College), Wuhu, Anhui, China
| | - Xu Zhang
- Department of Gastrointestinal Surgery, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui, China
- Anhui Province Key Laboratory of Non-coding RNA Basic and Clinical Transformation (Wannan Medical College), Wuhu, Anhui, China
| | - Yinfen Hou
- Department of Gastrointestinal Surgery, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui, China
- Anhui Province Key Laboratory of Non-coding RNA Basic and Clinical Transformation (Wannan Medical College), Wuhu, Anhui, China
| | - Yabin Xia
- Department of Gastrointestinal Surgery, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui, China
- Anhui Province Key Laboratory of Non-coding RNA Basic and Clinical Transformation (Wannan Medical College), Wuhu, Anhui, China
| | - Li Xu
- Department of Gastrointestinal Surgery, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui, China
- Anhui Province Key Laboratory of Non-coding RNA Basic and Clinical Transformation (Wannan Medical College), Wuhu, Anhui, China
| | - Xiaoxu Huang
- Department of Gastrointestinal Surgery, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui, China
- Anhui Province Key Laboratory of Non-coding RNA Basic and Clinical Transformation (Wannan Medical College), Wuhu, Anhui, China
| | - Hao Xie
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Wannan Medical College, Wuhu, Anhui, China
- Anhui Province Key Laboratory of Non-coding RNA Basic and Clinical Transformation (Wannan Medical College), Wuhu, Anhui, China
| |
Collapse
|
|
10
|
Wu Y, Xiao Y, Ding Y, Ran R, Wei K, Tao S, Mao H, Wang J, Pang S, Shi J, Zhu C, Wan W, Yang Q, Chen C. Colorectal cancer cell-derived exosomal miRNA-372-5p induces immune escape from colorectal cancer via PTEN/AKT/NF-κB/PD-L1 pathway. Int Immunopharmacol 2024; 143:113261. [PMID: 39353381 DOI: 10.1016/j.intimp.2024.113261] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2024] [Revised: 09/22/2024] [Accepted: 09/23/2024] [Indexed: 10/04/2024]
Abstract
Tumor cells can escape immune surveillance by changing their own escape or expressing abnormal genes and proteins, resulting in unlimited proliferation and invasive growth of cells. These changes are related to microRNAs (miRNAs), which reduce the killing effect of immune cells, devastate the immune response, and interfere with apoptosis through the aberrant expression of relevant miRNAs. In the preliminary phase of this study, miRNAs in clinical plasma exosomes of colorectal cancer patients were differentially analyzed by RNA sequencing technology, and miR-372-5p derived from extracellular vesicles (sEVs) was found to be a key signaling molecule mediating the regulation of macrophages by colorectal cancer (CRC). miRNA-372-5p is upregulated in colorectal cancer patient tissues and serum, as well as colorectal cancer cell lines and their exosomes. Subsequently, we found that macrophages could take up sEV secreted by colorectal cancer cells HCT116, affecting the expression of the immune checkpoint PD-L1, resulting in the generation of a tumor-immunosuppressive microenvironment and suppression of T cell activation in CRC. Gene enrichment mapping and database revealed that miR-372-5p regulates PD-L1 expression in colorectal cancer through the homologous phosphatase-tensin (PTEN)-phosphatidylinositol 3-kinase-protein kinase B (AKT)-nuclear factor-κB (NF-κB) pathway. Further studies confirmed that miRNA-372-5p-treated macrophages co-cultured with T cells affected the regulation of PD-L1 expression through the PTEN/AKT/NF-κB signaling pathway, resulting in decreased CD3+CD8+ T cell activity, decreased cytokine IL-2 and increased IFN-γ. And miRNA-372-5p could down-regulate the expression of PD-L1 in HCT116 through the PTEN/AKT/NF-κB pathway, inhibit tumor cell proliferation and promote apoptosis. Conclusion: Colorectal cancer cell-derived exosome miR-372-5p can be phagocytosed by colorectal cancer and macrophage cells, regulate the expression of PD-L1 in colorectal cancer cells and macrophages by targeting the PTEN/AKT/NF-κB pathway, and induce the immunosuppressive microenvironment of CRC to promote CRC development. This suggests that inhibiting the secretion of HCT116-specific sEV-miR-372-5p or targeting PD-L1 in tumor-associated macrophages could be a novel approach for CRC treatment and possibly a sensitizing approach for CRC anti-PD-L1 therapy.
Collapse
Affiliation(s)
- Yulun Wu
- Anhui Provincial Key Laboratory of Tumor Evolution and Intelligent Diagnosis and Treatment, Bengbu medical university, 2600 Donghai Avenue, Bengbu, Anhui 233030, China; Department of Life Sciences, Bengbu Medical University, Anhui 233030, China.
| | - Yuhan Xiao
- Anhui Provincial Key Laboratory of Tumor Evolution and Intelligent Diagnosis and Treatment, Bengbu medical university, 2600 Donghai Avenue, Bengbu, Anhui 233030, China; School of Laboratory Medicine, Bengbu Medical University, Anhui 233030, China.
| | - Yongxing Ding
- The Third the Pople's Hospital of Bengbu, Anhui 233000, China.
| | - Ruorong Ran
- Anhui Provincial Key Laboratory of Tumor Evolution and Intelligent Diagnosis and Treatment, Bengbu medical university, 2600 Donghai Avenue, Bengbu, Anhui 233030, China.
| | - Ke Wei
- Anhui Provincial Key Laboratory of Tumor Evolution and Intelligent Diagnosis and Treatment, Bengbu medical university, 2600 Donghai Avenue, Bengbu, Anhui 233030, China.
| | - Shuang Tao
- Anhui Provincial Key Laboratory of Tumor Evolution and Intelligent Diagnosis and Treatment, Bengbu medical university, 2600 Donghai Avenue, Bengbu, Anhui 233030, China.
| | - Huilan Mao
- Anhui Provincial Key Laboratory of Tumor Evolution and Intelligent Diagnosis and Treatment, Bengbu medical university, 2600 Donghai Avenue, Bengbu, Anhui 233030, China.
| | - Jing Wang
- Anhui Provincial Key Laboratory of Tumor Evolution and Intelligent Diagnosis and Treatment, Bengbu medical university, 2600 Donghai Avenue, Bengbu, Anhui 233030, China.
| | - Siyan Pang
- Anhui Provincial Key Laboratory of Tumor Evolution and Intelligent Diagnosis and Treatment, Bengbu medical university, 2600 Donghai Avenue, Bengbu, Anhui 233030, China.
| | - Jiwen Shi
- Anhui Provincial Key Laboratory of Tumor Evolution and Intelligent Diagnosis and Treatment, Bengbu medical university, 2600 Donghai Avenue, Bengbu, Anhui 233030, China.
| | - Chengle Zhu
- Anhui Provincial Key Laboratory of Tumor Evolution and Intelligent Diagnosis and Treatment, Bengbu medical university, 2600 Donghai Avenue, Bengbu, Anhui 233030, China.
| | - Wenrui Wan
- Department of Biotechnology, Bengbu Medical University, Anhui 233030, China.
| | - Qingling Yang
- Department of Biochemistry and Molecular Biology, Bengbu Medical University, Anhui 233030, China.
| | - Changjie Chen
- Department of Biochemistry and Molecular Biology, Bengbu Medical University, Anhui 233030, China.
| |
Collapse
|
|
11
|
Mao H, Ye R, Tang G, Tao S, Wei K, Wu Y, Pang S, Wang J, Shi J, Ji Y, Xiao Y, Geng C, Wang W, Chen C, Yang Q. Drug-resistant exosome miR-99b-3p induces macrophage polarization and confers chemoresistance on sensitive cells by targeting PPP2CA. Int Immunopharmacol 2024; 142:113168. [PMID: 39298813 DOI: 10.1016/j.intimp.2024.113168] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2024] [Revised: 09/11/2024] [Accepted: 09/11/2024] [Indexed: 09/22/2024]
Abstract
The most frequent cancer in women to be diagnosed is breast cancer, and chemotherapy's ability to be effective is still significantly hampered by drug resistance. Tumor-derived exosomes play a significant role in drug resistance, immunological modulation, metastasis, and tumor proliferation. In this work, the differential miRNAs in the exosomes of drug-resistant and susceptible breast cancer cell lines were screened using miRNA-seq. It was demonstrated that drug-resistant human breast cancer cells and their exosomes expressed more miR-99b-3p than did susceptible cells and their exosomes. While drug-resistant cells' migration and paclitaxel resistance can be inhibited by driving down the expression of miR-99b-3p in those cells, exosomes containing miR-99b-3p from those cells can help susceptible cells migrate and become resistant. miR-99b-3p affects cell migration and paclitaxel resistance by targeting PPP2CA to promote AKT/mTOR phosphorylation. The drug-resistant cell exosome miR-99b-3p can be taken up by macrophages and affect the drug resistance and migration ability of sensitive cells by promoting the M2 polarization of macrophages. Downregulating miR-99b-3p has been shown in vivo to reverse macrophage M2 polarization, suppress tumor development, and prevent treatment resistance. The present study shows that drug-resistant cell exosomes miR-99b-3p can directly influence the migration, proliferation, and paclitaxel sensitivity of sensitive cells via PPP2CA. Additionally, the exosomes from drug-resistant cells can influence the polarization of macrophage M2 in the tumor microenvironment, which can also have an impact on the proliferation, migration, and paclitaxel sensitivity of sensitive cells.
Collapse
Affiliation(s)
- Huilan Mao
- Anhui Province Key Laboratory of Cancer Translational Medicine (Bengbu Medical University), Anhui 233030, China; Department of Life Sciences, Bengbu Medical University, Anhui 233030, China
| | - Ruyin Ye
- Anhui Province Key Laboratory of Cancer Translational Medicine (Bengbu Medical University), Anhui 233030, China; Department of Life Sciences, Bengbu Medical University, Anhui 233030, China
| | - Guohui Tang
- Anhui Province Key Laboratory of Cancer Translational Medicine (Bengbu Medical University), Anhui 233030, China
| | - Shuang Tao
- Anhui Province Key Laboratory of Cancer Translational Medicine (Bengbu Medical University), Anhui 233030, China
| | - Ke Wei
- Anhui Province Key Laboratory of Cancer Translational Medicine (Bengbu Medical University), Anhui 233030, China
| | - Yulun Wu
- Anhui Province Key Laboratory of Cancer Translational Medicine (Bengbu Medical University), Anhui 233030, China
| | - Siyan Pang
- Anhui Province Key Laboratory of Cancer Translational Medicine (Bengbu Medical University), Anhui 233030, China
| | - Jing Wang
- Anhui Province Key Laboratory of Cancer Translational Medicine (Bengbu Medical University), Anhui 233030, China
| | - Jiwen Shi
- Anhui Province Key Laboratory of Cancer Translational Medicine (Bengbu Medical University), Anhui 233030, China
| | - Yuxin Ji
- Anhui Province Key Laboratory of Cancer Translational Medicine (Bengbu Medical University), Anhui 233030, China
| | - Yuhan Xiao
- Anhui Province Key Laboratory of Cancer Translational Medicine (Bengbu Medical University), Anhui 233030, China
| | - Chenchen Geng
- Anhui Province Key Laboratory of Cancer Translational Medicine (Bengbu Medical University), Anhui 233030, China
| | - Wenrui Wang
- Department of Life Sciences, Bengbu Medical University, Anhui 233030, China.
| | - Changjie Chen
- Department of Biochemistry and Molecular Biology, Bengbu Medical University, Anhui 233030, China.
| | - Qingling Yang
- Department of Biochemistry and Molecular Biology, Bengbu Medical University, Anhui 233030, China; Institute of Health and Medicine, Hefei Comprehensive National Science Center, Hefei, Anhui 230000, China.
| |
Collapse
|
|
12
|
Li S, Hao L, Hu X. Biological Roles and Clinical Therapeutic Applications of Tumor-Associated Macrophages in Colorectal Liver Metastasis. J Inflamm Res 2024; 17:8429-8443. [PMID: 39529996 PMCID: PMC11552512 DOI: 10.2147/jir.s493656] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2024] [Accepted: 10/28/2024] [Indexed: 11/16/2024] Open
Abstract
Colorectal cancer (CRC) commonly metastasizes to the liver, and this poses a significant clinical challenge. Tumor-associated macrophages (TAMs), key players within the TME, play a significant role in promoting CRC metastasis by secreting various chemokines, growth factors, and cytokines. This review not only aims to enhance our knowledge of TAMs' functions in CRC progression and metastasis but also examines innovative therapeutic strategies to address the clinical problem of colorectal liver metastasis (CLM). By targeting TAMs, we may be able to develop more effective treatments and offer hope to patients suffering from this devastating disease.
Collapse
Affiliation(s)
- Shenghao Li
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, People’s Republic of China
- Department of Infectious Diseases, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, People’s Republic of China
| | - Liyuan Hao
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, People’s Republic of China
- Department of Infectious Diseases, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, People’s Republic of China
| | - Xiaoyu Hu
- Department of Infectious Diseases, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, People’s Republic of China
| |
Collapse
|
|
13
|
Fan Q, Fu ZW, Xu M, Lv F, Shi JS, Zeng QQ, Xiong DH. Research progress of tumor-associated macrophages in immune checkpoint inhibitor tolerance in colorectal cancer. World J Gastrointest Oncol 2024; 16:4064-4079. [DOI: 10.4251/wjgo.v16.i10.4064] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2024] [Revised: 08/03/2024] [Accepted: 08/16/2024] [Indexed: 09/26/2024] Open
Abstract
The relevant mechanism of tumor-associated macrophages (TAMs) in the treatment of colorectal cancer patients with immune checkpoint inhibitors (ICIs) is discussed, and the application prospects of TAMs in reversing the treatment tolerance of ICIs are discussed to provide a reference for related studies. As a class of drugs widely used in clinical tumor immunotherapy, ICIs can act on regulatory molecules on cells that play an inhibitory role-immune checkpoints-and kill tumors in the form of an immune response by activating a variety of immune cells in the immune system. The sensitivity of patients with different types of colorectal cancer to ICI treatment varies greatly. The phenotype and function of TAMs in the colorectal cancer microenvironment are closely related to the efficacy of ICIs. ICIs can regulate the phenotypic function of TAMs, and TAMs can also affect the tolerance of colorectal cancer to ICI therapy. TAMs play an important role in ICI resistance, and making full use of this target as a therapeutic strategy is expected to improve the immunotherapy efficacy and prognosis of patients with colorectal cancer.
Collapse
Affiliation(s)
- Qi Fan
- Intestinal Center, Chongqing University Three Gorges Hospital, Chongqing 404000, China
| | - Zheng-Wei Fu
- Intestinal Center, Chongqing University Three Gorges Hospital, Chongqing 404000, China
| | - Ming Xu
- Intestinal Center, Chongqing University Three Gorges Hospital, Chongqing 404000, China
| | - Feng Lv
- Intestinal Center, Chongqing University Three Gorges Hospital, Chongqing 404000, China
| | - Jia-Song Shi
- Intestinal Center, Chongqing University Three Gorges Hospital, Chongqing 404000, China
| | - Qi-Qi Zeng
- Department of Gastroenterology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, Jiangsu Province, China
| | - De-Hai Xiong
- Intestinal Center, Chongqing University Three Gorges Hospital, Chongqing 404000, China
| |
Collapse
|
|
14
|
Wang Y, Jia J, Wang F, Fang Y, Yang Y, Zhou Q, Yuan W, Gu X, Hu J, Yang S. Pre-metastatic niche: formation, characteristics and therapeutic implication. Signal Transduct Target Ther 2024; 9:236. [PMID: 39317708 PMCID: PMC11422510 DOI: 10.1038/s41392-024-01937-7] [Citation(s) in RCA: 27] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Revised: 06/29/2024] [Accepted: 07/23/2024] [Indexed: 09/26/2024] Open
Abstract
Distant metastasis is a primary cause of mortality and contributes to poor surgical outcomes in cancer patients. Before the development of organ-specific metastasis, the formation of a pre-metastatic niche is pivotal in promoting the spread of cancer cells. This review delves into the intricate landscape of the pre-metastatic niche, focusing on the roles of tumor-derived secreted factors, extracellular vesicles, and circulating tumor cells in shaping the metastatic niche. The discussion encompasses cellular elements such as macrophages, neutrophils, bone marrow-derived suppressive cells, and T/B cells, in addition to molecular factors like secreted substances from tumors and extracellular vesicles, within the framework of pre-metastatic niche formation. Insights into the temporal mechanisms of pre-metastatic niche formation such as epithelial-mesenchymal transition, immunosuppression, extracellular matrix remodeling, metabolic reprogramming, vascular permeability and angiogenesis are provided. Furthermore, the landscape of pre-metastatic niche in different metastatic organs like lymph nodes, lungs, liver, brain, and bones is elucidated. Therapeutic approaches targeting the cellular and molecular components of pre-metastatic niche, as well as interventions targeting signaling pathways such as the TGF-β, VEGF, and MET pathways, are highlighted. This review aims to enhance our understanding of pre-metastatic niche dynamics and provide insights for developing effective therapeutic strategies to combat tumor metastasis.
Collapse
Affiliation(s)
- Yuhang Wang
- Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, 1 East Jianshe Road, Zhengzhou, 450000, China
| | - Jiachi Jia
- College of Medicine, Zhengzhou University, Zhengzhou, 450001, China
| | - Fuqi Wang
- Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, 1 East Jianshe Road, Zhengzhou, 450000, China
| | - Yingshuai Fang
- College of Medicine, Zhengzhou University, Zhengzhou, 450001, China
| | - Yabing Yang
- College of Medicine, Zhengzhou University, Zhengzhou, 450001, China
| | - Quanbo Zhou
- Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, 1 East Jianshe Road, Zhengzhou, 450000, China
| | - Weitang Yuan
- Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, 1 East Jianshe Road, Zhengzhou, 450000, China
| | - Xiaoming Gu
- Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, 1 East Jianshe Road, Zhengzhou, 450000, China.
| | - Junhong Hu
- Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, 1 East Jianshe Road, Zhengzhou, 450000, China.
| | - Shuaixi Yang
- Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, 1 East Jianshe Road, Zhengzhou, 450000, China.
| |
Collapse
|
|
15
|
Yang X, Fan L, Huang J, Li Y. Plasma Exosome miR-203a-3p is a Potential Liquid Biopsy Marker for Assessing Tumor Progression in Breast Cancer Patients. BREAST CANCER (DOVE MEDICAL PRESS) 2024; 16:631-643. [PMID: 39310782 PMCID: PMC11416789 DOI: 10.2147/bctt.s478328] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/15/2024] [Accepted: 09/06/2024] [Indexed: 09/25/2024]
Abstract
Background Timely detection of tumor progression in breast cancer (BC) patients is critical for therapeutic management and prognosis. Plasma exosomal miRNAs are potential liquid biopsy markers for monitoring tumor progression, but their roles in BC remain unclear. Methods In the TCGA database, we first screened for miRNAs significantly associated with BC progression by comparing miRNA expression in para-carcinoma tissues, stage I BC tissues, and stage II-III BC tissues (n = 1026). Cox regression analyses and survival analyses were performed on candidate miRNAs to explore their prognostic value (n = 848). KEGG, GO, and PPI analyses were used to identify enriched pathways associated with cancer. Finally, the potential of candidate miRNAs as liquid biopsy markers was evaluated by sequencing and analyzing plasma exosomal miRNAs from our collection of 45 BC patients (14 in stage I, 31 in stage II-III) and 5 healthy controls, combined with qRT-PCR analysis to assess the correlation of candidate gene expression in plasma exosomes and BC tissues. Results We found that only miR-203a-3p was progressively elevated with BC progression and was associated with poor prognosis in the TCGA dataset. Its potential target genes were enriched in pathways related to tumor progression, and the downregulation of 48 of these genes was associated with poor prognosis. More importantly, plasma exosomal miR-203a-3p was also found to gradually increase with BC progression, and its expression was positively correlated with miR-203a-3p in BC tissues. This result suggests that plasma exosomal miR-203a-3p may reflect the expression of miR-203a-3p in tumor tissues and serve as a potential liquid biopsy marker for monitoring BC progressions. Conclusion We found for the first time that elevated miR-203a-3p was associated with BC progression and poor prognosis. Our findings suggested that plasma exosomal miR-203a-3p could hold potential as a liquid biopsy marker for evaluating BC progression in patients.
Collapse
Affiliation(s)
- Xin Yang
- Peking University Fifth School of Clinical Medicine, Beijing, People’s Republic of China
| | - Lei Fan
- Breast Center, Department of Thyroid-Breast-Hernia Surgery, Department of General Surgery, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, People’s Republic of China
| | - Jicheng Huang
- Breast Center, Department of Thyroid-Breast-Hernia Surgery, Department of General Surgery, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, People’s Republic of China
| | - Yongjun Li
- Peking University Fifth School of Clinical Medicine, Beijing, People’s Republic of China
| |
Collapse
|
|
16
|
Bayat M, Sadri Nahand J. Exosomal miRNAs: the tumor's trojan horse in selective metastasis. Mol Cancer 2024; 23:167. [PMID: 39164756 PMCID: PMC11334467 DOI: 10.1186/s12943-024-02081-0] [Citation(s) in RCA: 20] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2024] [Accepted: 08/12/2024] [Indexed: 08/22/2024] Open
Abstract
Organs of future metastasis are not passive receivers of circulating tumor cells, but are instead selectively and actively modified by the primary tumor before metastatic spread has even occurred. Tumors orchestrate a pre-metastatic program by conditioning distant organs to create microenvironments that foster the survival and proliferation of tumor cells before their arrival, thereby establishing pre-metastatic niches. Primary tumor-derived exosomes modulate these pre-metastatic niches, generating a permissive environment that facilitates the homing and expansion of tumor cells. Moreover, microRNAs have emerged as a key component of exosomal cargo, serving not only to induce the formation of pre-metastatic niches but also to prime these sites for the arrival and colonization of specific secondary tumor populations. Against this backdrop, this review endeavors to elucidate the impact of tumor-derived exosomal microRNAs on the genesis of their individualized pre-metastatic niches, with a view towards identifying novel means of specifying cancer metastasis and exploiting this phenomenon for cancer immunotherapy.
Collapse
Affiliation(s)
- Mobina Bayat
- Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, 15731, Iran
| | - Javid Sadri Nahand
- Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, 15731, Iran.
| |
Collapse
|
|
17
|
Lin H, Zhou J, Ding T, Zhu Y, Wang L, Zhong T, Wang X. Therapeutic potential of extracellular vesicles from diverse sources in cancer treatment. Eur J Med Res 2024; 29:350. [PMID: 38943222 PMCID: PMC11212438 DOI: 10.1186/s40001-024-01937-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2024] [Accepted: 06/11/2024] [Indexed: 07/01/2024] Open
Abstract
Cancer, a prevalent and complex disease, presents a significant challenge to the medical community. It is characterized by irregular cell differentiation, excessive proliferation, uncontrolled growth, invasion of nearby tissues, and spread to distant organs. Its progression involves a complex interplay of several elements and processes. Extracellular vesicles (EVs) serve as critical intermediaries in intercellular communication, transporting critical molecules such as lipids, RNA, membrane, and cytoplasmic proteins between cells. They significantly contribute to the progression, development, and dissemination of primary tumors by facilitating the exchange of information and transmitting signals that regulate tumor growth and metastasis. However, EVs do not have a singular impact on cancer; instead, they play a multifaceted dual role. Under specific circumstances, they can impede tumor growth and influence cancer by delivering oncogenic factors or triggering an immune response. Furthermore, EVs from different sources demonstrate distinct advantages in inhibiting cancer. This research examines the biological characteristics of EVs and their involvement in cancer development to establish a theoretical foundation for better understanding the connection between EVs and cancer. Here, we discuss the potential of EVs from various sources in cancer therapy, as well as the current status and future prospects of engineered EVs in developing more effective cancer treatments.
Collapse
Affiliation(s)
- Haihong Lin
- The First School of Clinical Medicine, Gannan Medical University, Ganzhou, 341000, China
- Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, 341000, China
| | - Jun Zhou
- Department of Laboratory Medicine, Beijing Jishuitan Hospital Guizhou Hospital, Guiyang, 550000, China
| | - Tao Ding
- Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, 341000, China
| | - Yifan Zhu
- The First School of Clinical Medicine, Gannan Medical University, Ganzhou, 341000, China
- Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, 341000, China
| | - Lijuan Wang
- The First School of Clinical Medicine, Gannan Medical University, Ganzhou, 341000, China
- Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, 341000, China
| | - Tianyu Zhong
- The First School of Clinical Medicine, Gannan Medical University, Ganzhou, 341000, China.
- Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, 341000, China.
| | - Xiaoling Wang
- The First School of Clinical Medicine, Gannan Medical University, Ganzhou, 341000, China.
- Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, 341000, China.
| |
Collapse
|
|
18
|
Yimin E, Lu C, Zhu K, Li W, Sun J, Ji P, Meng M, Liu Z, Yu C. Function and mechanism of exosomes derived from different cells as communication mediators in colorectal cancer metastasis. iScience 2024; 27:109350. [PMID: 38500820 PMCID: PMC10945197 DOI: 10.1016/j.isci.2024.109350] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/20/2024] Open
Abstract
Colorectal cancer (CRC) ranks as the second leading cause of cancer-related mortality, with metastasis being the primary determinant of poor prognosis in patients. Investigating the molecular mechanisms underlying CRC metastasis is currently a prominent and challenging area of research. Exosomes, as crucial intercellular communication mediators, facilitate the transfer of metabolic and genetic information from cells of origin to recipient cells. Their roles in mediating information exchange between CRC cells and immune cells, fibroblasts, and other cell types are pivotal in reshaping the tumor microenvironment, regulating key biological processes such as invasion, migration, and formation of pre-metastatic niche. This article comprehensively examines the communication function and mechanism of exosomes derived from different cells in cancer metastasis, while also presenting an outlook on current research advancements and future application prospects. The aim is to offer a distinctive perspective that contributes to accurate diagnosis and rational treatment strategies for CRC.
Collapse
Affiliation(s)
- Yimin E
- Department of General Surgery, The Second Affiliated Hospital of Nanjing Medical University, 121 Jiang Jia Yuan Road, Nanjing 210011, Jiangsu, China
| | - Chen Lu
- Department of General Surgery, Sir Run Run Hospital of Nanjing Medical University, Long Mian Avenue 109 Jiangning, Nanjing 211112, Jiangsu, China
| | - Kuixuan Zhu
- Department of Radiotherapy, The Third Affiliated Hospital of Kunming Medical University (Yunnan Cancer Hospital, Yunnan Cancer Center), Kunming 650100, Yunan, China
| | - Wenyuan Li
- Department of Anesthesiology, The Second Affiliated Hospital of Nanjing Medical University, 121 Jiang Jia Yuan Road, Nanjing 210011, Jiangsu, China
| | - Jing Sun
- Department of General Surgery, The Second Affiliated Hospital of Nanjing Medical University, 121 Jiang Jia Yuan Road, Nanjing 210011, Jiangsu, China
| | - Pengcheng Ji
- Department of General Surgery, Sir Run Run Hospital of Nanjing Medical University, Long Mian Avenue 109 Jiangning, Nanjing 211112, Jiangsu, China
| | - Minjie Meng
- Department of General Surgery, The Second Affiliated Hospital of Nanjing Medical University, 121 Jiang Jia Yuan Road, Nanjing 210011, Jiangsu, China
| | - Zhengxia Liu
- Department of Geriatrics, The Second Affiliated Hospital of Nanjing Medical University, 121 Jiang Jia Yuan Road, Nanjing 210011, Jiangsu, China
| | - Chunzhao Yu
- Department of General Surgery, Sir Run Run Hospital of Nanjing Medical University, Long Mian Avenue 109 Jiangning, Nanjing 211112, Jiangsu, China
- Department of General Surgery, The Second Affiliated Hospital of Nanjing Medical University, 121 Jiang Jia Yuan Road, Nanjing 210011, Jiangsu, China
| |
Collapse
|
|
19
|
Wang L, Wang W, Hu D, Liang Y, Liu Z, Zhong T, Wang X. Tumor-derived extracellular vesicles regulate macrophage polarization: role and therapeutic perspectives. Front Immunol 2024; 15:1346587. [PMID: 38690261 PMCID: PMC11058222 DOI: 10.3389/fimmu.2024.1346587] [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: 11/29/2023] [Accepted: 04/03/2024] [Indexed: 05/02/2024] Open
Abstract
Extracellular vesicles (EVs) are important cell-to-cell communication mediators. This paper focuses on the regulatory role of tumor-derived EVs on macrophages. It aims to investigate the causes of tumor progression and therapeutic directions. Tumor-derived EVs can cause macrophages to shift to M1 or M2 phenotypes. This indicates they can alter the M1/M2 cell ratio and have pro-tumor and anti-inflammatory effects. This paper discusses several key points: first, the factors that stimulate macrophage polarization and the cytokines released as a result; second, an overview of EVs and the methods used to isolate them; third, how EVs from various cancer cell sources, such as hepatocellular carcinoma, colorectal carcinoma, lung carcinoma, breast carcinoma, and glioblastoma cell sources carcinoma, promote tumor development by inducing M2 polarization in macrophages; and fourth, how EVs from breast carcinoma, pancreatic carcinoma, lungs carcinoma, and glioblastoma cell sources carcinoma also contribute to tumor development by promoting M2 polarization in macrophages. Modified or sourced EVs from breast, pancreatic, and colorectal cancer can repolarize M2 to M1 macrophages. This exhibits anti-tumor activities and offers novel approaches for tumor treatment. Therefore, we discovered that macrophage polarization to either M1 or M2 phenotypes can regulate tumor development. This is based on the description of altering macrophage phenotypes by vesicle contents.
Collapse
Affiliation(s)
- Lijuan Wang
- The First School of Clinical Medicine, Gannan Medical University, Ganzhou, China
- Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Weihua Wang
- Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Die Hu
- Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Yan Liang
- Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Zhanyu Liu
- Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Tianyu Zhong
- The First School of Clinical Medicine, Gannan Medical University, Ganzhou, China
- Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Xiaoling Wang
- The First School of Clinical Medicine, Gannan Medical University, Ganzhou, China
- Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| |
Collapse
|
|
20
|
Si G, Chen X, Li Y, Yuan X. Exosomes promote pre-metastatic niche formation in colorectal cancer. Heliyon 2024; 10:e27572. [PMID: 38509970 PMCID: PMC10950591 DOI: 10.1016/j.heliyon.2024.e27572] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2023] [Revised: 02/29/2024] [Accepted: 03/01/2024] [Indexed: 03/22/2024] Open
Abstract
It is well known that colorectal cancer (CRC) has a high morbidity rate, a poor prognosis when metastasized, and a greatly shortened 5-year survival rate. Therefore, understanding the mechanism of tumor metastasis is still important. Based on the "seed and soil" theory, the concept of " premetastatic niche (PMN)" was introduced by Kaplan et al. The complex interaction between primary tumors and the metastatic organ provides a beneficial microenvironment for tumor cells to colonize at a distance. With further exploration of the PMN, exosomes have gradually attracted interest from researchers. Exosomes are extracellular vesicles secreted from cells that include various biological information and are involved in communication between cells. As a key molecule in the PMN, exosomes are closely related to tumor metastasis. In this article, we obtained information by conducting a comprehensive search across academic databases including PubMed and Web of Science using relevant keywords. Only recent, peer-reviewed articles published in the English language were considered for inclusion. This study aims to explore in depth how exosomes promote the formation of pre-metastatic microenvironment (PMN) in colorectal cancer and its related mechanisms.
Collapse
Affiliation(s)
- Guifei Si
- School of Clinical Medicine, Weifang Medical University, Weifang, Shandong, 261000, China
| | - Xuemei Chen
- School of Clinical Medicine, Weifang Medical University, Weifang, Shandong, 261000, China
| | - Yuquan Li
- School of Clinical Medicine, Weifang Medical University, Weifang, Shandong, 261000, China
| | - Xuemin Yuan
- Department of Gastroenterology, Linyi People's Hospital, Linyi, Shandong, 276000, China
| |
Collapse
|
|
21
|
Li Y, Liao W, Huang W, Liu F, Ma L, Qian X. Mechanism of gambogic acid repressing invasion and metastasis of colorectal cancer by regulating macrophage polarization via tumor cell-derived extracellular vesicle-shuttled miR-21. Drug Dev Res 2024; 85:e22141. [PMID: 38349264 DOI: 10.1002/ddr.22141] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2023] [Revised: 11/29/2023] [Accepted: 12/11/2023] [Indexed: 02/15/2024]
Abstract
Colorectal cancer (CRC) is a major cause of mortality and morbidity. Gambogic acid (GA) is a promising antitumor drug for treating CRC. We aimed to elucidate its mechanism in CRC invasion/metastasis via tumor cell-derived extracellular vesicle (EV)-carried miR-21. Nude mice peritoneal carcinomatosis (PC) model was subjected to GA treatment liver collection, followed by observation/counting of metastatic liver tissues/liver metastatic nodules by hematoxylin and eosin staining. miR-21 expression in metastatic liver tissues/CD68 + CD86, CD68 + CD206 cell percentages and M2 macrophage marker CD206 level in tumor tissues/interleukin (IL)-12 and IL-10 levels were determined by reverse transcription-quantitative polymerase chain reaction (RT-qPCR)/flow cytometry/enzyme-linked immunosorbent assay. HT-29 cells were treated with GA/miR-21 mimics/negative control for 48 h. miR-21 expression/cell proliferation/migration/invasion/apoptosis were assessed by RT-qPCR/cell counting kit-8/scratch assay/transwell assay/flow cytometry. EVs were extracted from HT-29 cells and identified by transmission electron microscope/nanoparticle tracking analysis/Western blot. IL-4/IL-13-induced macrophages/PC nude mice were treated with GA and EVs, with the internalization of EVs by macrophages assessed through the uptake test. After intraperitoneal injection of GA, PC nude mice exhibited decreased tumor cell density/irregular cell number/liver metastatic nodule number/miR-21 expression, and CRC cells manifested reduced CD68 + CD206 cells/IL-10/miR-21/proliferation/migration/invasion and increased CD68 + CD86 cells/IL-12/apoptosis, while these trends were opposite after miR-21 overexpression, implying that GA curbed CRC/cell invasion/metastasis and macrophage polarization by diminishing miR-21 levels. miR-21 was encapsulated in HT-29 cell-derived EVs. M2 polarization elevated CD206 cells/IL-10, which were decreased by simultaneous GA treatment. EVs could be uptaken by macrophages. CRC cell-EV-miR-21 annulled the suppression effects of GA on macrophage M2 polarization. GA suppressed macrophage M2 polarization by lessening tumor cell derived-EV-shuttled miR-21, thereby weakening CRC invasion/metastasis.
Collapse
Affiliation(s)
- You Li
- Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
- Department of Oncology, Xuzhou Citiy Hospital of TCM, Affiliated to Nanjing University of Chinese Medicine, Xuzhou, China
| | - Wenqi Liao
- Department of Cardiology, Xuzhou City Hospital of TCM, Affiliated to Nanjing University of Chinese Medicine, Xuzhou, China
| | - Wei Huang
- Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
- Department of Oncology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Fenglin Liu
- Department of Oncology, Xuzhou Citiy Hospital of TCM, Affiliated to Nanjing University of Chinese Medicine, Xuzhou, China
| | - Lin Ma
- Department of Oncology, Xuzhou Citiy Hospital of TCM, Affiliated to Nanjing University of Chinese Medicine, Xuzhou, China
| | - Xiaoping Qian
- Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
- Comprehensive Cancer Center, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| |
Collapse
|
|
22
|
Wu L, Xia W, Hua Y, Fan K, Lu Y, Wang M, Jin Y, Zhang W, Pan S. Cellular crosstalk of macrophages and therapeutic implications in non-small cell lung cancer revealed by integrative inference of single-cell transcriptomics. Front Pharmacol 2023; 14:1295442. [PMID: 38044943 PMCID: PMC10690610 DOI: 10.3389/fphar.2023.1295442] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2023] [Accepted: 11/02/2023] [Indexed: 12/05/2023] Open
Abstract
Introduction: Non-small cell lung cancer (NSCLC) exhibits heterogeneity with diverse immune cell infiltration patterns that can influence tumor cell behavior and immunotherapy. A comprehensive characterization of the tumor microenvironment can guide precision medicine. Methods: Here, we generated a single-cell atlas of 398170 cells from 52 NSCLC patients, and investigated the imprinted genes and cellular crosstalk for macrophages. Subsequently, we evaluated the effect of tumor cells on macrophages and verified the expression of marker genes using co-culture experiments, flow cytometry and RT-qPCR assays. Results: Remarkable macrophage adaptability to NSCLC environment was observed, which contributed to generating tumor-associated macrophages (TAMs). We identified 5 distinct functional TAM subtypes, of which the majority were SELENOP-positive macrophages, with high levels of SLC40A1 and CCL13. The TAMs were also involved in mediating CD8+ T cell activity and form intercellular interaction with cancer cells, as indicated by receptor-ligand binding. Indirect coculture of tumor cells SPC-A1 and THP-1 monocytes, produced M2-like TAMs that highly expressed several markers of SELENOP-positive macrophages. The abundance of this type TAMs seemed to be associated with poorer overall survival rates [hazard ratio (HR) = 1.34, 95% confidence interval (CI) = 0.98-1.83, p = 0.068] based on deconvolution of TCGA-LUAD dataset. Discussion: In summary, we provided a high-resolution molecular resource of TAMs, and displayed the acquired properties in the tumor microenvironment. Dynamic crosstalk between TAMs and tumor cells via multiple ligand-receptor pairs were revealed, emphasizing its role in sustaining the pro-tumoral microenvironment and its implications for cancer therapy.
Collapse
Affiliation(s)
- Lei Wu
- Department of Laboratory Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- Branch of National Clinical Research Center for Laboratory Medicine, Nanjing, China
| | - Wenying Xia
- Department of Laboratory Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- Branch of National Clinical Research Center for Laboratory Medicine, Nanjing, China
| | - Yiting Hua
- Department of Laboratory Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- Branch of National Clinical Research Center for Laboratory Medicine, Nanjing, China
| | - Kun Fan
- Department of Laboratory Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- Branch of National Clinical Research Center for Laboratory Medicine, Nanjing, China
| | - Yanfei Lu
- Department of Laboratory Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- Branch of National Clinical Research Center for Laboratory Medicine, Nanjing, China
| | - Min Wang
- Department of Laboratory Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- Branch of National Clinical Research Center for Laboratory Medicine, Nanjing, China
| | - Yuexinzi Jin
- Department of Laboratory Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- Branch of National Clinical Research Center for Laboratory Medicine, Nanjing, China
| | - Wei Zhang
- Department of Laboratory Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- Branch of National Clinical Research Center for Laboratory Medicine, Nanjing, China
| | - Shiyang Pan
- Department of Laboratory Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- Branch of National Clinical Research Center for Laboratory Medicine, Nanjing, China
| |
Collapse
|
|
23
|
Wu J, Dong W, Pan Y, Wang J, Wu M, Yu Y. Crosstalk between gut microbiota and metastasis in colorectal cancer: implication of neutrophil extracellular traps. Front Immunol 2023; 14:1296783. [PMID: 37936694 PMCID: PMC10626548 DOI: 10.3389/fimmu.2023.1296783] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Accepted: 10/10/2023] [Indexed: 11/09/2023] Open
Abstract
Primary colorectal cancer (CRC) often leads to liver metastasis, possibly due to the formation of pre-metastatic niche (PMN) in liver. Thus, unravelling the key modulator in metastasis is important for the development of clinical therapies. Gut microbiota dysregulation is a key event during CRC progression and metastasis. Numerous studies have elucidated the correlation between specific gut bacteria strains (e.g., pks + E. coli and Bacteroides fragilis) and CRC initiation, and gut bacteria translocation is commonly witnessed during CRC progression. Gut microbiota shapes tumor microenvironment (TME) through direct contact with immune cells or through its functional metabolites. However, how gut microbiota facilitates CRC metastasis remains controversial. Meanwhile, recent studies identify the dissemination of bacteria from gut lumen to liver, suggesting the role of gut microbiota in shaping tumor PMN. A pro-tumoral PMN is characterized by the infiltration of immunosuppressive cells and increased pro-inflammatory immune responses. Notably, neutrophils form web-like structures known as neutrophil extracellular traps (NETs) both in primary TME and metastatic sites, NETs are involved in cancer progression and metastasis. In this review, we focus on the role of gut microbiota in CRC progression and metastasis, highlight the multiple functions of different immune cell types in TME, especially neutrophils and NETs, discuss the possible mechanisms of gut microbiota in shaping PMN formation, and provide therapeutical indications in clinic.
Collapse
Affiliation(s)
- Jiawei Wu
- Department of General Surgery, Changhai Hospital, Naval Medical University, Shanghai, China
- Clinical Research and Lab Center, Affiliated Kunshan Hospital of Jiangsu University, Kunshan, China
| | - Wenyan Dong
- Department of General Surgery, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Yayun Pan
- Department of Anesthesiology, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Jingjing Wang
- Department of Burn and Plastic Surgery, Affiliated Kunshan Hospital of Jiangsu University, Kunshan, China
| | - Minliang Wu
- Department of Plastic Surgery, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Yue Yu
- Department of General Surgery, Changhai Hospital, Naval Medical University, Shanghai, China
| |
Collapse
|