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Conte M, Tomaciello M, De Feo MS, Frantellizzi V, Marampon F, De Cristofaro F, De Vincentis G, Filippi L. The Tight Relationship Between the Tumoral Microenvironment and Radium-223. Biomedicines 2025; 13:456. [PMID: 40002869 PMCID: PMC11853176 DOI: 10.3390/biomedicines13020456] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2025] [Revised: 02/04/2025] [Accepted: 02/09/2025] [Indexed: 02/27/2025] Open
Abstract
Radium-223 (223Ra) was the first radioactive isotope approved for treating castration-resistant prostate cancer (CRPC) with symptomatic bone metastases without visceral metastatic disease. To better understand the action of 223Ra, its role in the tumor microenvironment represents a crucial aspect. A literature search was conducted using the PubMed/MEDLINE database and studies regarding the relationship between 223Ra and the tumoral microenvironment were considered. The tumoral microenvironment is a complex setting in which complex interactions between cells and molecules occur. Radium-223, as an alpha-emitter, induces double-stranded DNA breaks; to potentiate this effect, it could be used in patients with genetic instability but also in combination with therapies which inhibit DNA repair, modulate the immune response, or control tumor growth. In conclusion, a few studies have taken into consideration the tumoral microenvironment in association with 223Ra. However, its understanding is a priority to better comprehend how to effectively exploit 223Ra and its action mechanism.
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Affiliation(s)
- Miriam Conte
- Department of Radiological Sciences, Oncology and Anatomical Pathology, Sapienza, “Sapienza” University of Rome, 00161 Rome, Italy; (M.C.); (M.T.); (M.S.D.F.); (V.F.); (F.M.); (F.D.C.); (G.D.V.)
| | - Miriam Tomaciello
- Department of Radiological Sciences, Oncology and Anatomical Pathology, Sapienza, “Sapienza” University of Rome, 00161 Rome, Italy; (M.C.); (M.T.); (M.S.D.F.); (V.F.); (F.M.); (F.D.C.); (G.D.V.)
| | - Maria Silvia De Feo
- Department of Radiological Sciences, Oncology and Anatomical Pathology, Sapienza, “Sapienza” University of Rome, 00161 Rome, Italy; (M.C.); (M.T.); (M.S.D.F.); (V.F.); (F.M.); (F.D.C.); (G.D.V.)
| | - Viviana Frantellizzi
- Department of Radiological Sciences, Oncology and Anatomical Pathology, Sapienza, “Sapienza” University of Rome, 00161 Rome, Italy; (M.C.); (M.T.); (M.S.D.F.); (V.F.); (F.M.); (F.D.C.); (G.D.V.)
| | - Francesco Marampon
- Department of Radiological Sciences, Oncology and Anatomical Pathology, Sapienza, “Sapienza” University of Rome, 00161 Rome, Italy; (M.C.); (M.T.); (M.S.D.F.); (V.F.); (F.M.); (F.D.C.); (G.D.V.)
| | - Flaminia De Cristofaro
- Department of Radiological Sciences, Oncology and Anatomical Pathology, Sapienza, “Sapienza” University of Rome, 00161 Rome, Italy; (M.C.); (M.T.); (M.S.D.F.); (V.F.); (F.M.); (F.D.C.); (G.D.V.)
| | - Giuseppe De Vincentis
- Department of Radiological Sciences, Oncology and Anatomical Pathology, Sapienza, “Sapienza” University of Rome, 00161 Rome, Italy; (M.C.); (M.T.); (M.S.D.F.); (V.F.); (F.M.); (F.D.C.); (G.D.V.)
| | - Luca Filippi
- Department of Biomedicine and Prevention, University of Rome “Tor Vergata”, Via Montpellier 1, 00133 Rome, Italy
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Wei LY, Li ZZ, Xu ZY, Wang GR, Xiao Y, Liu B, Bu LL. The ending is not the end: Lymph node metastasis in oral squamous cell carcinoma. Int Immunopharmacol 2025; 146:113917. [PMID: 39721451 DOI: 10.1016/j.intimp.2024.113917] [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: 10/07/2024] [Revised: 12/18/2024] [Accepted: 12/18/2024] [Indexed: 12/28/2024]
Abstract
Lymph node metastasis is an important biological feature of oral squamous cell carcinoma, bearing poorly prognostic implications. However, the role of lymph node metastasis in cancer progression remains inconclusive. On the one hand, lymph nodes are pivotal sites for initiating specific immunity, which is crucial for maintaining antitumor immune response. On the other hand, they also serve as primary conduits for tumor metastasis, with lymph node colonization potentially inducing systemic immune dysfunction, thereby further promoting tumor progression. Considering this paradoxical role of lymph nodes, comprehending their impact on the primary tumor and immunity becomes paramount. Furthermore, leveraging these distinctive attributes of lymph nodes presents novel avenues for enhancing current therapeutic strategies against oral squamous cell carcinoma. This review summarizes the anatomical and molecular profiles of lymph node metastasis in oral squamous cell carcinoma, elucidating how lymphatic involvement compromises antitumor immunity, thus facilitating primary tumor and distant metastases. Additionally, it explores avenues for harnessing these mechanisms to optimize clinical interventions.
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Affiliation(s)
- Li-Ya Wei
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China
| | - Zi-Zhan Li
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China
| | - Zhen-Yu Xu
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China
| | - Guang-Rui Wang
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China
| | - Yao Xiao
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China
| | - Bing Liu
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China; Department of Oral & Maxillofacial - Head Neck Oncology, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China.
| | - Lin-Lin Bu
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China; Department of Oral & Maxillofacial - Head Neck Oncology, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China.
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James BL, Zaidi SN, Aiswarya RK, Shetty V, Vidya Bhushan R, Dokhe Y, Naveen BS, Pillai V, Dhar SK, Kuriakose MA, Suresh A. Modeling the lymph node stromal cells in oral squamous cell carcinoma: insights into the stromal cues in nodal metastasis. Hum Cell 2025; 38:41. [PMID: 39760828 DOI: 10.1007/s13577-024-01166-8] [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: 07/01/2024] [Accepted: 12/16/2024] [Indexed: 01/07/2025]
Abstract
The study explores the development and characterization of lymph node stromal cell cultures (LNSCs) from patients with oral squamous cell carcinoma (OSCC), highlighting the importance of understanding tumor-node cross-talk for effective prognostic and therapeutic interventions. Herein, we describe the development and characterization of primary lymph node stromal cells (LNSCs, N = 14) from nodes of metastatic and non-metastatic OSCC patients. Primary cultures were established by the explant method from positive (N + ; N = 2), and negative nodes (N0m; N = 4) of the metastatic patients (N = 3) as well as negative (N0nm; N = 8) nodes from non-metastatic (N = 4) patients. STR profiling confirmed the purity and novelty, while characterization by immunocytochemistry/flow cytometry revealed heterogeneous cell populations consisting of fibroblastic reticular cells (CD31-Gp38 +) and double negative cells (CD31-Gp38-). Transcriptomic profiling indicated molecular alterations in the cells based on the non-metastatic, the pre-metastatic or metastatic status of the nodes, pro-inflammatory, matrix remodeling, and immune evasion being the primary pathways. Assessment of the protein levels for five selected markers (MX1, ISG15, CPM, ITGB4 and FOS) in the cell lines revealed that CPM levels were significantly reduced in the N + and N0m nodes whereas ISG15 levels reduced in N0m. Significantly, the profiling also provided insights into possible glycosylation of CPM (N0nm) and ISGylation of ISG15 (N0m). Cytokine profiling indicated release of chemokines/anti-proliferative cytokines from the negative nodes, while angiogenic/pro-metastatic cytokines were released from the nodes of metastatic patients. The lymph node stromal cell models established in the study with distinctive transcriptomic/cytokine characteristics will be invaluable in delineating the processes underlying nodal metastasis.
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Affiliation(s)
- Bonney Lee James
- Integrated Head and Neck Oncology Program (DSRG-5), Mazumdar Shaw Medical Foundation, Narayana Health, Bangalore, India
- Manipal Academy of Higher Education (MAHE), Manipal, Karnataka, India
| | - Shaesta Naseem Zaidi
- Department of Pathology, Mazumdar Shaw Medical Centre, Narayana Health, Bangalore, India
| | - R K Aiswarya
- Integrated Head and Neck Oncology Program (DSRG-5), Mazumdar Shaw Medical Foundation, Narayana Health, Bangalore, India
| | - Vivek Shetty
- Head and Neck Oncology, Mazumdar Shaw Medical Centre, Narayana Health, Bangalore, India
| | - R Vidya Bhushan
- Head and Neck Oncology, Mazumdar Shaw Medical Centre, Narayana Health, Bangalore, India
| | - Yogesh Dokhe
- Head and Neck Oncology, Mazumdar Shaw Medical Centre, Narayana Health, Bangalore, India
| | - B S Naveen
- Head and Neck Oncology, Mazumdar Shaw Medical Centre, Narayana Health, Bangalore, India
| | - Vijay Pillai
- Head and Neck Oncology, Mazumdar Shaw Medical Centre, Narayana Health, Bangalore, India
| | - Sujan K Dhar
- Computational Biology, Mazumdar Shaw Medical Foundation, Narayana Health, Bangalore, India
| | - Moni Abraham Kuriakose
- Integrated Head and Neck Oncology Program (DSRG-5), Mazumdar Shaw Medical Foundation, Narayana Health, Bangalore, India
- Head and Neck Oncology, Mazumdar Shaw Medical Centre, Narayana Health, Bangalore, India
| | - Amritha Suresh
- Integrated Head and Neck Oncology Program (DSRG-5), Mazumdar Shaw Medical Foundation, Narayana Health, Bangalore, India.
- Manipal Academy of Higher Education (MAHE), Manipal, Karnataka, India.
- Head and Neck Oncology, Mazumdar Shaw Medical Centre, Narayana Health, Bangalore, India.
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Wang Y, Bai M, Peng Q, Li L, Tian F, Guo Y, Jing C. Angiogenesis, a key point in the association of gut microbiota and its metabolites with disease. Eur J Med Res 2024; 29:614. [PMID: 39710789 DOI: 10.1186/s40001-024-02224-5] [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: 10/09/2024] [Accepted: 12/15/2024] [Indexed: 12/24/2024] Open
Abstract
The gut microbiota is a complex and dynamic ecosystem that plays a crucial role in human health and disease, including obesity, diabetes, cardiovascular diseases, neurodegenerative diseases, inflammatory bowel disease, and cancer. Chronic inflammation is a common feature of these diseases and is closely related to angiogenesis (the process of forming new blood vessels), which is often dysregulated in pathological conditions. Inflammation potentially acts as a central mediator. This abstract aims to elucidate the connection between the gut microbiota and angiogenesis in various diseases. The gut microbiota influences angiogenesis through various mechanisms, including the production of metabolites that directly or indirectly affect vascularization. For example, short-chain fatty acids (SCFAs) such as butyrate, propionate, and acetate are known to regulate immune responses and inflammation, thereby affecting angiogenesis. In the context of cardiovascular diseases, the gut microbiota promotes atherosclerosis and vascular dysfunction by producing trimethylamine N-oxide (TMAO) and other metabolites that promote inflammation and endothelial dysfunction. Similarly, in neurodegenerative diseases, the gut microbiota may influence neuroinflammation and the integrity of the blood-brain barrier, thereby affecting angiogenesis. In cases of fractures and wound healing, the gut microbiota promotes angiogenesis by activating inflammatory responses and immune effects, facilitating the healing of tissue damage. In cancer, the gut microbiota can either inhibit or promote tumor growth and angiogenesis, depending on the specific bacterial composition and their metabolites. For instance, some bacteria can activate inflammasomes, leading to the production of inflammatory factors that alter the tumor immune microenvironment and activate angiogenesis-related signaling pathways, affecting tumor angiogenesis and metastasis. Some bacteria can directly interact with tumor cells, activating angiogenesis-related signaling pathways. Diet, as a modifiable factor, significantly influences angiogenesis through diet-derived microbial metabolites. Diet can rapidly alter the composition of the microbiota and its metabolic activity, thereby changing the concentration of microbial-derived metabolites and profoundly affecting the host's immune response and angiogenesis. For example, a high animal protein diet promotes the production of pro-atherogenic metabolites like TMAO, activating inflammatory pathways and interfering with platelet function, which is associated with the severity of coronary artery plaques, peripheral artery disease, and cardiovascular diseases. A diet rich in dietary fiber promotes the production of SCFAs, which act as ligands for cell surface or intracellular receptors, regulating various biological processes, including inflammation, tissue homeostasis, and immune responses, thereby influencing angiogenesis. In summary, the role of the gut microbiota in angiogenesis is multifaceted, playing an important role in disease progression by affecting various biological processes such as inflammation, immune responses, and multiple signaling pathways. Diet-derived microbial metabolites play a crucial role in linking the gut microbiota and angiogenesis. Understanding the complex interactions between diet, the gut microbiota, and angiogenesis has the potential to uncover novel therapeutic targets for managing these conditions. Therefore, interventions targeting the gut microbiota and its metabolites, such as through fecal microbiota transplantation (FMT) and the application of probiotics to alter the composition of the gut microbiota and enhance the production of beneficial metabolites, present a promising therapeutic strategy.
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Affiliation(s)
- Yan Wang
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital, Shandong University, Jinan, 250021, Shandong, China
| | - Mingshuai Bai
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital, Shandong University, Jinan, 250021, Shandong, China
| | - Qifan Peng
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital, Shandong University, Jinan, 250021, Shandong, China
| | - Leping Li
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital, Shandong University, Jinan, 250021, Shandong, China
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China
| | - Feng Tian
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital, Shandong University, Jinan, 250021, Shandong, China.
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China.
| | - Ying Guo
- Department of Breast and Thyroid Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China.
| | - Changqing Jing
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital, Shandong University, Jinan, 250021, Shandong, China.
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China.
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Li X, Tian M, Yu L, Qian J, Yang J, Wang X, Lu C, Xiao C, Liu Y. The role of ferroptosis resistance in lymph-associated tumour metastasis. Biochim Biophys Acta Rev Cancer 2024; 1879:189200. [PMID: 39426689 DOI: 10.1016/j.bbcan.2024.189200] [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: 05/30/2024] [Revised: 10/11/2024] [Accepted: 10/13/2024] [Indexed: 10/21/2024]
Abstract
Tumour metastasis is a crucial factor in determining clinically challenging tumours. In this respect, the lymphatic system may act as potential entry portals for tumour metastasis, whilst, clinical detection of tumour-infiltrated lymph nodes also indicates poorer prognosis and higher metastatic risk. Whether tumour cells gain ferroptosis resistance in lymph that make them exhibit a stronger propensity for lymphatic dissemination compared to hematogenous spread might be a breakthrough for elucidating lymph-associated tumour metastasis. This review discusses how the lymphatic system endows tumour cells with ferroptosis resistance character, which makes them more propensity for lymph node pre-metastasis and distant metastasis through lymphatic circulation. Comprehensively considering the distinct structure and property of lymph and the unique metabolic characteristics of tumours, all of the lymphatic vessels, intestinal lymph and lymph nodes collectively manipulate an intricate interaction with the hematogenous system and afford substances exchange with tumour cells and extracellular vesicles, upon which make a ferroptosis resistant microenvironment for subsequent metastasis in distant organs and lymph nodes.
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Affiliation(s)
- Xiaoyu Li
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Meng Tian
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Liuchunyang Yu
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100029, China
| | - JinXiu Qian
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Jue Yang
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Xiangpeng Wang
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Cheng Lu
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing 100700, China.
| | - Cheng Xiao
- Institute of Clinical Medicine, China-Japan Friendship Hospital, Beijing 100029, China.
| | - Yuanyan Liu
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100029, China.
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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: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2024] [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.
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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.
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García-Silva S, Peinado H. Mechanisms of lymph node metastasis: An extracellular vesicle perspective. Eur J Cell Biol 2024; 103:151447. [PMID: 39116620 DOI: 10.1016/j.ejcb.2024.151447] [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: 02/01/2024] [Revised: 07/12/2024] [Accepted: 07/25/2024] [Indexed: 08/10/2024] Open
Abstract
In several solid tumors such as breast cancer, prostate cancer, colorectal cancer or melanoma, tumor draining lymph nodes are the earliest tissues where colonization by tumor cells is detected. Lymph nodes act as sentinels of metastatic dissemination, the deadliest phase of tumor progression. Besides hematogenous dissemination, lymphatic spread of tumor cells has been demonstrated, adding more complexity to the mechanisms involved in metastasis. A network of blood and lymphatic vessels surrounds tumors providing routes for tumor soluble factors to mediate regional and long-distance effects. Additionally, extracellular vesicles (EVs), particularly small EVs/exosomes, have been shown to circulate through the blood and lymph, favoring the formation of pre-metastatic niches in the tumor-draining lymph nodes (TDLNs) and distant organs. In this review, we present an overview of the relevance of lymph node metastasis, the structural and immune changes occurring in TDLNs during tumor progression, and how extracellular vesicles contribute to modulating some of these alterations while promoting the formation of lymph node pre-metastatic niches.
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Affiliation(s)
- Susana García-Silva
- Microenvironment and Metastasis Laboratory, Molecular Oncology Programme, Spanish National Cancer Research Center (CNIO), Madrid, Spain.
| | - Héctor Peinado
- Microenvironment and Metastasis Laboratory, Molecular Oncology Programme, Spanish National Cancer Research Center (CNIO), Madrid, Spain
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Maeshima Y, Kataoka TR, Vandenbon A, Hirata M, Takeuchi Y, Suzuki Y, Fukui Y, Kawashima M, Takada M, Ibi Y, Haga H, Morita S, Toi M, Kawaoka S, Kawaguchi K. Intra-patient spatial comparison of non-metastatic and metastatic lymph nodes reveals the reduction of CD169 + macrophages by metastatic breast cancers. EBioMedicine 2024; 107:105271. [PMID: 39173531 PMCID: PMC11382037 DOI: 10.1016/j.ebiom.2024.105271] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Revised: 06/06/2024] [Accepted: 07/25/2024] [Indexed: 08/24/2024] Open
Abstract
BACKGROUND Breast cancer cells suppress the host immune system to efficiently invade the lymph nodes; however, the underlying mechanism remains incompletely understood. Here, we aimed to comprehensively characterise the effects of breast cancers on immune cells in the lymph nodes. METHODS We collected non-metastatic and metastatic lymph node samples from 6 patients with breast cancer with lymph node metastasis. We performed bulk transcriptomics, spatial transcriptomics, and imaging mass cytometry to analyse the obtained lymph nodes. Furthermore, we conducted histological analyses against a larger patient cohort (474 slices from 58 patients). FINDINGS The comparison between paired lymph nodes with and without metastasis from the same patients demonstrated that the number of CD169+ lymph node sinus macrophages, an initiator of anti-cancer immunity, was reduced in metastatic lymph nodes (36.7 ± 21.1 vs 7.3 ± 7.0 cells/mm2, p = 0.0087), whereas the numbers of other major immune cell types were unaltered. We also detected that the infiltration of CD169+ macrophages into metastasised cancer tissues differed by section location within tumours, suggesting that CD169+ macrophages were gradually decreased after anti-cancer reactions. Furthermore, CD169+ macrophage elimination was prevalent in major breast cancer subtypes and correlated with breast cancer staging (p = 0.022). INTERPRETATION We concluded that lymph nodes with breast cancer metastases have fewer CD169+ macrophages, which may be detrimental to the activity of anti-cancer immunity. FUNDING JSPS KAKENHI (16H06279, 20H03451, 20H04842, 22H04925, 19K16770, and 21K15530, 24K02236), JSPS Fellows (JP22KJ1822), AMED (JP21ck0106698), JST FOREST (JPMJFR2062), Caravel, Co., Ltd, Japan Foundation for Applied Enzymology, and Sumitomo Pharma Co., Ltd. under SKIPS.
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Affiliation(s)
- Yurina Maeshima
- Department of Breast Surgery, Kyoto University Hospital, Graduate School of Medicine, Shogoin Sakyo-ku, Kyoto 606-8507, Japan; Inter-Organ Communication Research Team, Institute for Frontier Life and Medical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8507, Japan
| | - Tatsuki R Kataoka
- Department of Pathology, Iwate Medical University, Yahaba-cho, Shiwa-gun, Iwate Prefecture 028-3694, Japan
| | - Alexis Vandenbon
- Laboratory of Tissue Homeostasis, Institute for Life and Medical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8507, Japan; Institute for Liberal Arts and Sciences, Kyoto University, Kyoto 606-8507, Japan
| | - Masahiro Hirata
- Department of Diagnostic Pathology, Kyoto University, Shogoin Sakyo-ku, Kyoto 606-8507, Japan
| | - Yasuhide Takeuchi
- Department of Diagnostic Pathology, Kyoto University, Shogoin Sakyo-ku, Kyoto 606-8507, Japan
| | - Yutaka Suzuki
- Graduate School of Frontier Science, The University of Tokyo, Chiba 277-8562, Japan
| | - Yukiko Fukui
- Department of Breast Surgery, Kyoto University Hospital, Graduate School of Medicine, Shogoin Sakyo-ku, Kyoto 606-8507, Japan
| | - Masahiro Kawashima
- Department of Breast Surgery, Kyoto University Hospital, Graduate School of Medicine, Shogoin Sakyo-ku, Kyoto 606-8507, Japan
| | - Masahiro Takada
- Department of Breast Surgery, Kyoto University Hospital, Graduate School of Medicine, Shogoin Sakyo-ku, Kyoto 606-8507, Japan
| | - Yumiko Ibi
- Department of Biomedical Statistics and Bioinformatics, Kyoto University Graduate School of Medicine, Shogoin Sakyo-ku, Kyoto 606-8507, Japan
| | - Hironori Haga
- Department of Diagnostic Pathology, Kyoto University, Shogoin Sakyo-ku, Kyoto 606-8507, Japan
| | - Satoshi Morita
- Department of Biomedical Statistics and Bioinformatics, Kyoto University Graduate School of Medicine, Shogoin Sakyo-ku, Kyoto 606-8507, Japan
| | - Masakazu Toi
- Department of Breast Surgery, Kyoto University Hospital, Graduate School of Medicine, Shogoin Sakyo-ku, Kyoto 606-8507, Japan; Tokyo Metropolitan Cancer and Infectious Disease Center, Komagome Hospital, Honkomagome, Bunkyo-ku, Tokyo 113-8677, Japan
| | - Shinpei Kawaoka
- Inter-Organ Communication Research Team, Institute for Frontier Life and Medical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8507, Japan; Department of Integrative Bioanalytics, Institute of Development, Aging and Cancer, Tohoku University, Sendai 980-8575, Japan.
| | - Kosuke Kawaguchi
- Department of Breast Surgery, Kyoto University Hospital, Graduate School of Medicine, Shogoin Sakyo-ku, Kyoto 606-8507, Japan; Department of Breast Surgery, Breast Center, Mie University, Mie 514-0102, Japan.
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Leong SP. Immune responses and immunotherapeutic approaches in the treatment against cancer. Clin Exp Metastasis 2024; 41:473-493. [PMID: 39155358 PMCID: PMC11374840 DOI: 10.1007/s10585-024-10300-7] [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: 03/04/2024] [Accepted: 06/15/2024] [Indexed: 08/20/2024]
Abstract
Cancer cells within a population are heterogeneous due to genomic mutations or epigenetic changes. The immune response to cancer especially the T cell repertoire within the cancer microenvionment is important to the control and growth of cancer cells. When a cancer clone breaks through the surveillance of the immune system, it wins the battle to overcome the host's immune system. In this review, the complicated profile of the cancer microenvironment is emphasized. The molecular evidence of immune responses to cancer has been recently established. Based on these molecular mechanisms of immune interactions with cancer, clinical trials based on checkpoint inhibition therapy against CTLA-4 and/or PD-1 versus PD-L1 have been successful in the treatment of melanoma, lung cancer and other types of cancer. The diversity of the T cell repertoire is described and the tumor infiltrating lymphocytes within the cancer may be expanded ex vivo and infused back to the patient as a treatment modality for adoptive immunotherapy.
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Affiliation(s)
- Stanley P Leong
- California Pacific Medical Center and Research Institute, University of California School of Medicine, San Francisco, USA.
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10
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Dong L, Hu C, Ma Z, Huang Y, Shelley G, Kuczler MD, Kim CJ, Witwer KW, Keller ET, Amend SR, Xue W, Pienta KJ. Urinary extracellular vesicle-derived miR-126-3p predicts lymph node invasion in patients with high-risk prostate cancer. Med Oncol 2024; 41:169. [PMID: 38839666 PMCID: PMC11153291 DOI: 10.1007/s12032-024-02400-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: 03/25/2024] [Accepted: 04/28/2024] [Indexed: 06/07/2024]
Abstract
To investigate extracellular vesicles (EVs), biomarkers for predicting lymph node invasion (LNI) in patients with high-risk prostate cancer (HRPCa), plasma, and/or urine samples were prospectively collected from 45 patients with prostate cancer (PCa) and five with benign prostatic hyperplasia (BPH). Small RNA sequencing was performed to identify miRNAs in the EVs. All patients with PCa underwent radical prostatectomy and extended pelvic lymph node dissection. Differentially expressed miRNAs were identified in patients with and without pathologically-verified LNI. The candidate miRNAs were validated in low-risk prostate cancer (LRPCa) and BPH. Four miRNA species (e.g., miR-126-3p) and three miRNA species (e.g., miR-27a-3p) were more abundant in urinary and plasma EVs, respectively, of patients with PCa. None of these miRNA species were shared between urinary and plasma EVs. miR-126-3p was significantly more abundant in patients with HR PCa with LNI than in those without (P = 0.018). miR-126-3p was significantly more abundant in the urinary EVs of patients with HRPCa than in those with LRPCa (P = 0.017) and BPH (P = 0.011). In conclusion, urinary EVs-derived miR-126-3p may serve as a good biomarker for predicting LNI in patients with HRPCa.
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Affiliation(s)
- Liang Dong
- Department of Urology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China
- The Brady Urological Institute, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Baltimore, MD, 21287, USA
| | - Cong Hu
- Department of Urology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China
| | - Zehua Ma
- Department of Urology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China
- Department of Urology, Guizhou Provincial People's Hospital, Guiyang, 550001, China
| | - Yiyao Huang
- Department of Laboratory Medicine & Guangdong Engineering and Technology Research Center for Rapid Diagnostic Biosensors, Nanfang Hospital Southern Medical University, Guangzhou, 510515, China
- Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA
| | - Greg Shelley
- Biointerfaces Institute, University of Michigan, Ann Arbor, MI, 48109, USA
- Department of Urology, University of Michigan, Ann Arbor, MI, 48109, USA
| | - Morgan D Kuczler
- The Brady Urological Institute, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Baltimore, MD, 21287, USA
| | - Chi-Ju Kim
- The Brady Urological Institute, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Baltimore, MD, 21287, USA
| | - Kenneth W Witwer
- Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA
| | - Evan T Keller
- Biointerfaces Institute, University of Michigan, Ann Arbor, MI, 48109, USA
- Department of Urology, University of Michigan, Ann Arbor, MI, 48109, USA
| | - Sarah R Amend
- The Brady Urological Institute, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Baltimore, MD, 21287, USA
| | - Wei Xue
- Department of Urology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China.
- Department of Urology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, 160 Pujian Road, Pudong New Area, Shanghai, 200127, China.
| | - Kenneth J Pienta
- The Brady Urological Institute, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Baltimore, MD, 21287, USA.
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11
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Dong L, Hu C, Ma Z, Huang Y, Shelley G, Kuczler MD, Kim CJ, Witwer KW, Keller ET, Amend SR, Xue W, Pienta KJ. Urinary extracellular vesicle-derived miR-126-3p predicts lymph node invasion in patients with high-risk prostate cancer. RESEARCH SQUARE 2024:rs.3.rs-4164213. [PMID: 38585988 PMCID: PMC10996795 DOI: 10.21203/rs.3.rs-4164213/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/09/2024]
Abstract
To investigate extracellular vesicles (EVs) biomarkers for predicting lymph node invasion (LNI) in patients with high-risk prostate cancer (HRPCa), plasma and/or urine samples were prospectively collected from 45 patients with prostate cancer (PCa) and five with benign prostatic hyperplasia (BPH). Small RNA sequencing was performed to identify miRNAs in the EVs. All patients with PCa underwent radical prostatectomy and extended pelvic lymph node dissection. Differentially-expressed miRNAs were identified in patients with and without pathologically-verified LNI. The candidate miRNAs were validated in low-risk prostate cancer (LRPCa) and BPH. Four miRNA species (e.g. miR-126-3p) and three miRNA species (e.g. miR-27a-3p) were more abundant in urinary and plasma EVs, respectively, of patients with PCa. None of these miRNA species were shared between urinary and plasma EVs. miR-126-3p was significantly more abundant in patients with HR PCa with LNI than in those without (P = 0.018). miR-126-3p was significantly more abundant in the urinary EVs of patients with HRPCa than in those with LRPCa (P = 0.017) and BPH (P = 0.011). In conclusion, urinary EVs-derived miR-126-3p may serve as a good biomarker for predicting LNI in patients with HRPCa.
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Affiliation(s)
- Liang Dong
- Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine
| | - Cong Hu
- Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine
| | - Zehua Ma
- Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine
| | - Yiyao Huang
- Nanfang Hospital Southern Medical University
| | | | - Morgan D Kuczler
- The Brady Urological Institute, Johns Hopkins University School of Medicine
| | - Chi-Ju Kim
- The Brady Urological Institute, Johns Hopkins University School of Medicine
| | | | | | - Sarah R Amend
- The Brady Urological Institute, Johns Hopkins University School of Medicine
| | - Wei Xue
- Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine
| | - Kenneth J Pienta
- The Brady Urological Institute, Johns Hopkins University School of Medicine
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12
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Zhan Q, Liu B, Situ X, Luo Y, Fu T, Wang Y, Xie Z, Ren L, Zhu Y, He W, Ke Z. New insights into the correlations between circulating tumor cells and target organ metastasis. Signal Transduct Target Ther 2023; 8:465. [PMID: 38129401 PMCID: PMC10739776 DOI: 10.1038/s41392-023-01725-9] [Citation(s) in RCA: 31] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Revised: 12/07/2023] [Accepted: 12/08/2023] [Indexed: 12/23/2023] Open
Abstract
Organ-specific metastasis is the primary cause of cancer patient death. The distant metastasis of tumor cells to specific organs depends on both the intrinsic characteristics of the tumor cells and extrinsic factors in their microenvironment. During an intermediate stage of metastasis, circulating tumor cells (CTCs) are released into the bloodstream from primary and metastatic tumors. CTCs harboring aggressive or metastatic features can extravasate to remote sites for continuous colonizing growth, leading to further lesions. In the past decade, numerous studies demonstrated that CTCs exhibited huge clinical value including predicting distant metastasis, assessing prognosis and monitoring treatment response et al. Furthermore, increasingly numerous experiments are dedicated to identifying the key molecules on or inside CTCs and exploring how they mediate CTC-related organ-specific metastasis. Based on the above molecules, more and more inhibitors are being developed to target CTCs and being utilized to completely clean CTCs, which should provide promising prospects to administer advanced tumor. Recently, the application of various nanomaterials and microfluidic technologies in CTCs enrichment technology has assisted to improve our deep insights into the phenotypic characteristics and biological functions of CTCs as a potential therapy target, which may pave the way for us to make practical clinical strategies. In the present review, we mainly focus on the role of CTCs being involved in targeted organ metastasis, especially the latest molecular mechanism research and clinical intervention strategies related to CTCs.
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Affiliation(s)
- Qinru Zhan
- Department of Pathology, The First Affiliated Hospital of Sun Yat-sen University, 510000, Guangzhou, Guangdong, P.R. China
| | - Bixia Liu
- Department of Pathology, The First Affiliated Hospital of Sun Yat-sen University, 510000, Guangzhou, Guangdong, P.R. China
| | - Xiaohua Situ
- Department of Pathology, The First Affiliated Hospital of Sun Yat-sen University, 510000, Guangzhou, Guangdong, P.R. China
| | - Yuting Luo
- Department of Pathology, The First Affiliated Hospital of Sun Yat-sen University, 510000, Guangzhou, Guangdong, P.R. China
| | - Tongze Fu
- Department of Pathology, The First Affiliated Hospital of Sun Yat-sen University, 510000, Guangzhou, Guangdong, P.R. China
- Institute of Precision Medicine, The First Affiliated Hospital of Sun Yat-sen University, 510000, Guangzhou, Guangdong, P.R. China
| | - Yanxia Wang
- Zhongshan School of Medicine, Sun Yat-sen University, 510000, Guangzhou, Guangdong, P.R. China
| | - Zhongpeng Xie
- Zhongshan School of Medicine, Sun Yat-sen University, 510000, Guangzhou, Guangdong, P.R. China
| | - Lijuan Ren
- Department of Pathology, The First Affiliated Hospital of Sun Yat-sen University, 510000, Guangzhou, Guangdong, P.R. China
| | - Ying Zhu
- Department of Radiology, The First Affiliated Hospital of Sun Yat-sen University, 510000, Guangzhou, Guangdong, P.R. China.
| | - Weiling He
- Department of Microbiology and Immunology, Weill Cornell Medicine, New York, NY, 10065, USA.
- School of Medicine, Xiang'an Hospital of Xiamen University, Xiamen University, 361000, Xiamen, Fujian, P.R. China.
| | - Zunfu Ke
- Department of Pathology, The First Affiliated Hospital of Sun Yat-sen University, 510000, Guangzhou, Guangdong, P.R. China.
- Institute of Precision Medicine, The First Affiliated Hospital of Sun Yat-sen University, 510000, Guangzhou, Guangdong, P.R. China.
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13
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Lu C, Xie L, Qiu S, Jiang T, Wang L, Chen Z, Xia Y, Lv J, Li Y, Li B, Gu C, Xu Z. Small Extracellular Vesicles Derived from Helicobacter Pylori-Infected Gastric Cancer Cells Induce Lymphangiogenesis and Lymphatic Remodeling via Transfer of miR-1246. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2023:e2308688. [PMID: 37946695 DOI: 10.1002/smll.202308688] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/28/2023] [Indexed: 11/12/2023]
Abstract
Lymph node metastasis (LNM) is a significant barrier to the prognosis of patients with gastric cancer (GC). Helicobacter pylori (H. pylori)-positive GC patients experience a higher rate of LNM than H. pylori-negative GC patients. However, the underlying mechanism remains unclear. Based on the findings of this study, H. pylori-positive GC patients have greater lymphangiogenesis and lymph node immunosuppression than H. pylori-negative GC patients. In addition, miR-1246 is overexpressed in the plasma small extracellular vesicles (sEVs) of H. pylori-positive GC patients, indicating a poor prognosis. Functionally, sEVs derived from GC cells infected with H. pylori deliver miR-1246 to lymphatic endothelial cells (LECs) and promote lymphangiogenesis and lymphatic remodeling. Mechanistically, miR-1246 suppresses GSK3β expression and promotes β-Catenin and downstream MMP7 expression in LECs. miR-1246 also stabilizes programmed death ligand-1 (PD-L1) by suppressing GSK3β and induces the apoptosis of CD8+ T cells. Overall, miR-1246 in plasma sEVs may be a novel biomarker and therapeutic target in GC-LNM.
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Affiliation(s)
- Chen Lu
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, 210000, China
- The First Clinical Medical College of Nanjing Medical University, Nanjing, Jiangsu, 210000, China
| | - Li Xie
- Department of General Surgery, Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu, 212000, China
| | - Shengkui Qiu
- Department of General Surgery, The Second Affiliated Hospital of Nantong University, Nantong, Jiangsu, 226001, China
| | - Tianlu Jiang
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, 210000, China
- The First Clinical Medical College of Nanjing Medical University, Nanjing, Jiangsu, 210000, China
| | - Luyao Wang
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, 210000, China
- The First Clinical Medical College of Nanjing Medical University, Nanjing, Jiangsu, 210000, China
| | - Zetian Chen
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, 210000, China
- The First Clinical Medical College of Nanjing Medical University, Nanjing, Jiangsu, 210000, China
| | - Yiwen Xia
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, 210000, China
- The First Clinical Medical College of Nanjing Medical University, Nanjing, Jiangsu, 210000, China
| | - Jialun Lv
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, 210000, China
- The First Clinical Medical College of Nanjing Medical University, Nanjing, Jiangsu, 210000, China
| | - Ying Li
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, 210000, China
- The First Clinical Medical College of Nanjing Medical University, Nanjing, Jiangsu, 210000, China
| | - Bowen Li
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, 210000, China
| | - Chao Gu
- Department of General Surgery, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, Jiangsu, 215000, China
| | - Zekuan Xu
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, 210000, China
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, Jiangsu, 210000, China
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14
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Wang M, Deng C, Yang C, Yan M, Lu H, Zhang Y, Liu H, Tong Z, Ma J, Wang J, Zhang Y, Wang J, Xuan Y, Cheng H, Zhao K, Zhang J, Chai C, Li M, Yu Z. Unraveling temporal and spatial biomarkers of epithelial-mesenchymal transition in colorectal cancer: insights into the crucial role of immunosuppressive cells. J Transl Med 2023; 21:794. [PMID: 37940972 PMCID: PMC10633927 DOI: 10.1186/s12967-023-04600-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2023] [Accepted: 10/06/2023] [Indexed: 11/10/2023] Open
Abstract
The occurrence and progression of tumors can be established through a complex interplay among tumor cells undergoing epithelial-mesenchymal transition (EMT), invasive factors and immune cells. In this study, we employed single-cell RNA sequencing (scRNA-seq) and spatially resolved transcriptomics (ST) to evaluate the pseudotime trajectory and spatial interactive relationship between EMT-invasive malignant tumors and immune cells in primary colorectal cancer (CRC) tissues at different stages (stage I/II and stage III with tumor deposit). Our research characterized the spatiotemporal relationship among different invasive tumor programs by constructing pseudotime endpoint-EMT-invasion tumor programs (EMTPs) located at the edge of ST, utilizing evolution trajectory analysis integrated with EMT-invasion genes. Strikingly, the invasive and expansive process of tumors undergoes remarkable spatial reprogramming of regulatory and immunosuppressive cells, such as myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs), regulatory T cells (Treg), and exhausted T cells (Tex). These EMTP-adjacent cell are linked to EMT-related invasion genes, especially the C-X-C motif ligand 1 (CXCL1) and CXCL8 genes that are important for CRC prognosis. Interestingly, the EMTPs in stage I mainly produce an inflammatory margin invasive niche, while the EMTPs in stage III tissues likely produce a hypoxic pre-invasive niche. Our data demonstrate the crucial role of regulatory and immunosuppressive cells in tumor formation and progression of CRC. This study provides a framework to delineate the spatiotemporal invasive niche in CRC samples.
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Affiliation(s)
- Muhong Wang
- Department of Colorectal Surgery, Harbin Medical University Cancer Hospital, Harbin, 150086, China
| | - Chunyu Deng
- School of Life Science and Technology, Harbin Institute of Technology, Harbin, 150080, China
| | - Cheng Yang
- Department of Colorectal Surgery, Harbin Medical University Cancer Hospital, Harbin, 150086, China
| | - Mingze Yan
- Department of Colorectal Surgery, Harbin Medical University Cancer Hospital, Harbin, 150086, China
| | - Haibo Lu
- Department of Colorectal Surgery, Harbin Medical University Cancer Hospital, Harbin, 150086, China
| | - Yan Zhang
- School of Life Science and Technology, Harbin Institute of Technology, Harbin, 150080, China
| | - Honghao Liu
- School of Life Science and Technology, Harbin Institute of Technology, Harbin, 150080, China
| | - Zhekuan Tong
- Department of Colorectal Surgery, Harbin Medical University Cancer Hospital, Harbin, 150086, China
| | - Jiaao Ma
- Department of Colorectal Surgery, Harbin Medical University Cancer Hospital, Harbin, 150086, China
| | - Jiaming Wang
- Department of Colorectal Surgery, Harbin Medical University Cancer Hospital, Harbin, 150086, China
| | - Yan Zhang
- Department of Colorectal Surgery, Harbin Medical University Cancer Hospital, Harbin, 150086, China
| | - Jiahao Wang
- Department of Colorectal Surgery, Harbin Medical University Cancer Hospital, Harbin, 150086, China
| | - Yuhong Xuan
- Department of Colorectal Surgery, Harbin Medical University Cancer Hospital, Harbin, 150086, China
| | - Haiyue Cheng
- Department of Colorectal Surgery, Harbin Medical University Cancer Hospital, Harbin, 150086, China
| | - Kai Zhao
- Department of Colorectal Surgery, Harbin Medical University Cancer Hospital, Harbin, 150086, China
| | - Jiaqi Zhang
- Department of Colorectal Surgery, Harbin Medical University Cancer Hospital, Harbin, 150086, China
| | - Cuicui Chai
- Digestive Disease Center, The Seventh Affiliated Hospital Sun Yat-Sen University, Shenzhen, 518107, China
| | - Mingzhe Li
- Digestive Disease Center, The Seventh Affiliated Hospital Sun Yat-Sen University, Shenzhen, 518107, China.
| | - Zhiwei Yu
- Department of Colorectal Surgery, Harbin Medical University Cancer Hospital, Harbin, 150086, China.
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15
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Viúdez-Pareja C, Kreft E, García-Caballero M. Immunomodulatory properties of the lymphatic endothelium in the tumor microenvironment. Front Immunol 2023; 14:1235812. [PMID: 37744339 PMCID: PMC10512957 DOI: 10.3389/fimmu.2023.1235812] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2023] [Accepted: 08/08/2023] [Indexed: 09/26/2023] Open
Abstract
The tumor microenvironment (TME) is an intricate complex and dynamic structure composed of various cell types, including tumor, stromal and immune cells. Within this complex network, lymphatic endothelial cells (LECs) play a crucial role in regulating immune responses and influencing tumor progression and metastatic dissemination to lymph node and distant organs. Interestingly, LECs possess unique immunomodulatory properties that can either promote or inhibit anti-tumor immune responses. In fact, tumor-associated lymphangiogenesis can facilitate tumor cell dissemination and metastasis supporting immunoevasion, but also, different molecular mechanisms involved in LEC-mediated anti-tumor immunity have been already described. In this context, the crosstalk between cancer cells, LECs and immune cells and how this communication can shape the immune landscape in the TME is gaining increased interest in recent years. In this review, we present a comprehensive and updated report about the immunomodulatory properties of the lymphatic endothelium within the TME, with special focus on primary tumors and tumor-draining lymph nodes. Furthermore, we outline emerging research investigating the potential therapeutic strategies targeting the lymphatic endothelium to enhance anti-tumor immune responses. Understanding the intricate mechanisms involved in LEC-mediated immune modulation in the TME opens up new possibilities for the development of innovative approaches to fight cancer.
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Affiliation(s)
- Cristina Viúdez-Pareja
- Department of Molecular Biology and Biochemistry, Faculty of Sciences, Andalucía Tech, University of Málaga, Málaga, Spain
- IBIMA (Biomedical Research Institute of Málaga)-Plataforma BIONAND, Málaga, Spain
| | - Ewa Kreft
- Department of Molecular Biology and Biochemistry, Faculty of Sciences, Andalucía Tech, University of Málaga, Málaga, Spain
- IBIMA (Biomedical Research Institute of Málaga)-Plataforma BIONAND, Málaga, Spain
| | - Melissa García-Caballero
- Department of Molecular Biology and Biochemistry, Faculty of Sciences, Andalucía Tech, University of Málaga, Málaga, Spain
- IBIMA (Biomedical Research Institute of Málaga)-Plataforma BIONAND, Málaga, Spain
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16
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Cruz-Burgos M, Cortés-Ramírez SA, Losada-García A, Morales-Pacheco M, Martínez-Martínez E, Morales-Montor JG, Servín-Haddad A, Izquierdo-Luna JS, Rodríguez-Martínez G, Ramos-Godínez MDP, González-Covarrubias V, Cañavera-Constantino A, González-Ramírez I, Su B, Leong HS, Rodríguez-Dorantes M. Unraveling the Role of EV-Derived miR-150-5p in Prostate Cancer Metastasis and Its Association with High-Grade Gleason Scores: Implications for Diagnosis. Cancers (Basel) 2023; 15:4148. [PMID: 37627176 PMCID: PMC10453180 DOI: 10.3390/cancers15164148] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2023] [Revised: 08/05/2023] [Accepted: 08/14/2023] [Indexed: 08/27/2023] Open
Abstract
Metastasis remains the leading cause of mortality in prostate cancer patients. The presence of tumor cells in lymph nodes is an established prognostic indicator for several cancer types, such as melanoma, breast, oral, pancreatic, and cervical cancers. Emerging evidence highlights the role of microRNAs enclosed within extracellular vesicles as facilitators of molecular communication between tumors and metastatic sites in the lymph nodes. This study aims to investigate the potential diagnostic utility of EV-derived microRNAs in liquid biopsies for prostate cancer. By employing microarrays on paraffin-embedded samples, we characterized the microRNA expression profiles in metastatic lymph nodes, non-metastatic lymph nodes, and primary tumor tissues of prostate cancer. Differential expression of microRNAs was observed in metastatic lymph nodes compared to prostate tumors and non-metastatic lymph node tissues. Three microRNAs (miR-140-3p, miR-150-5p, and miR-23b-3p) were identified as differentially expressed between tissue and plasma samples. Furthermore, we evaluated the expression of these microRNAs in exosomes derived from prostate cancer cells and plasma samples. Intriguingly, high Gleason score samples exhibited the lowest expression of miR-150-5p compared to control samples. Pathway analysis suggested a potential regulatory role for miR-150-5p in the Wnt pathway and bone metastasis. Our findings suggest EV-derived miR-150-5p as a promising diagnostic marker for identifying patients with high-grade Gleason scores and detecting metastasis at an early stage.
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Affiliation(s)
- Marian Cruz-Burgos
- Laboratorio de Oncogenómica, Instituto Nacional de Medicina Genómica (INMEGEN), Mexico City 14610, Mexico; (M.C.-B.)
| | - Sergio A. Cortés-Ramírez
- Laboratorio de Oncogenómica, Instituto Nacional de Medicina Genómica (INMEGEN), Mexico City 14610, Mexico; (M.C.-B.)
| | - Alberto Losada-García
- Laboratorio de Oncogenómica, Instituto Nacional de Medicina Genómica (INMEGEN), Mexico City 14610, Mexico; (M.C.-B.)
| | - Miguel Morales-Pacheco
- Laboratorio de Oncogenómica, Instituto Nacional de Medicina Genómica (INMEGEN), Mexico City 14610, Mexico; (M.C.-B.)
| | - Eduardo Martínez-Martínez
- Laboratory of Cell Communication and Extracellular Vesicles, Instituto Nacional de Medicina Genómica (INMEGEN), Mexico City 14610, Mexico
| | | | - Alejandro Servín-Haddad
- Urology Department, Hospital General Dr. Manuel Gea Gonzalez, Mexico City 14080, Mexico; (J.G.M.-M.); (A.S.-H.)
| | | | - Griselda Rodríguez-Martínez
- Laboratorio de Oncogenómica, Instituto Nacional de Medicina Genómica (INMEGEN), Mexico City 14610, Mexico; (M.C.-B.)
| | | | | | | | - Imelda González-Ramírez
- Departamento de Atención a la Salud, Universidad Autónoma Metropolitana, Mexico City 14387, Mexico
| | - Boyang Su
- Department of Medical Biophysics, Temerty Faculty of Medicine, University of Toronto, Toronto, ON M5G 1L7, Canada
- Biological Sciences Platform, Sunybrook Research Institute, Toronto, ON M4N 3M5, Canada
| | - Hon S. Leong
- Department of Medical Biophysics, Temerty Faculty of Medicine, University of Toronto, Toronto, ON M5G 1L7, Canada
- Biological Sciences Platform, Sunybrook Research Institute, Toronto, ON M4N 3M5, Canada
| | - Mauricio Rodríguez-Dorantes
- Laboratorio de Oncogenómica, Instituto Nacional de Medicina Genómica (INMEGEN), Mexico City 14610, Mexico; (M.C.-B.)
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17
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Xu Y, Yao Y, Yu L, Zhang X, Mao X, Tey SK, Wong SWK, Yeung CLS, Ng TH, Wong MYM, Che C, Lee TKW, Gao Y, Cui Y, Yam JWP. Clathrin light chain A-enriched small extracellular vesicles remodel microvascular niche to induce hepatocellular carcinoma metastasis. J Extracell Vesicles 2023; 12:e12359. [PMID: 37606345 PMCID: PMC10443339 DOI: 10.1002/jev2.12359] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2023] [Revised: 07/22/2023] [Accepted: 08/07/2023] [Indexed: 08/23/2023] Open
Abstract
Small extracellular vesicles (sEVs) play a key role in exchanging cargoes between cells in tumour microenvironment. This study aimed to elucidate the functions and mechanisms of hepatocellular carcinoma (HCC) derived sEV-clathrin light chain A (CLTA) in remodelling microvascular niche. CLTA level in the circulating sEVs of HCC patients was analysed by enzyme-linked immunosorbent assay (ELISA). The functions of sEV-CLTA in affecting HCC cancerous properties were examined by multiple functional assays. Mass spectrometry was used to identify downstream effectors of sEV-CLTA in human umbilical vein endothelial cells (HUVECs). Tube formation, sprouting, trans-endothelial invasion and vascular leakiness assays were performed to determine the functions of sEV-CLTA and its effector, basigin (BSG) in HUVECs. BSG inhibitor, SP-8356, was tested in a mouse model of patient-derived xenografts (PDXs). Circulating sEVs of HCC patients had markedly enhanced CLTA levels than control individuals and were reduced in patients after surgery. HCC derived sEV-CLTA enhanced HCC cancerous properties, disrupted endothelial integrity and induced angiogenesis. Mechanistically, CLTA remodels microvascular niche by stabilizing and upregulating BSG. Last, SP-8356 alone or in combination with sorafenib attenuated PDXs growth. The study reveals the role of HCC derived sEV-CLTA in microvascular niche formation. Inhibition of CLTA and its mediated pathway may illuminate a new therapeutic strategy for HCC patients.
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Affiliation(s)
- Yi Xu
- Department of Pathology, School of Clinical Medicine, Li Ka Shing Faculty of MedicineThe University of Hong KongHong Kong
- Department of Hepatopancreatobiliary SurgerySecond Affiliated Hospital of Harbin Medical UniversityHarbinHeilongjiangP. R. China
| | - Yue Yao
- Department of Pathology, School of Clinical Medicine, Li Ka Shing Faculty of MedicineThe University of Hong KongHong Kong
- Department of Endocrinology and MetabolismSecond Affiliated Hospital of Harbin Medical UniversityHarbinHeilongjiangP. R. China
| | - Liang Yu
- Department of Pathology, School of Clinical Medicine, Li Ka Shing Faculty of MedicineThe University of Hong KongHong Kong
- Department of Hepatopancreatobiliary SurgerySecond Affiliated Hospital of Harbin Medical UniversityHarbinHeilongjiangP. R. China
| | - Xiaoxin Zhang
- Department of Pathology, School of Clinical Medicine, Li Ka Shing Faculty of MedicineThe University of Hong KongHong Kong
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of MedicineJiangsu UniversityZhenjiangJiangsuP. R. China
| | - Xiaowen Mao
- Department of Pathology, School of Clinical Medicine, Li Ka Shing Faculty of MedicineThe University of Hong KongHong Kong
- State Key Laboratory of Liver Research (The University of Hong Kong)Hong Kong
| | - Sze Keong Tey
- Department of Surgery, School of Clinical Medicine, Li Ka Shing Faculty of MedicineThe University of Hong KongHong Kong
| | - Samuel Wan Ki Wong
- Department of Pathology, School of Clinical Medicine, Li Ka Shing Faculty of MedicineThe University of Hong KongHong Kong
| | - Cherlie Lot Sum Yeung
- Department of Pathology, School of Clinical Medicine, Li Ka Shing Faculty of MedicineThe University of Hong KongHong Kong
| | - Tung Him Ng
- Department of Pathology, School of Clinical Medicine, Li Ka Shing Faculty of MedicineThe University of Hong KongHong Kong
| | - Melody YM Wong
- Laboratory for Synthetic Chemistry and Chemical Biology LimitedHong Kong
| | - Chi‐Ming Che
- Laboratory for Synthetic Chemistry and Chemical Biology LimitedHong Kong
- State Key Laboratory of Synthetic Chemistry, and Department of ChemistryThe University of Hong KongHong Kong
| | - Terence Kin Wah Lee
- Department of Applied Biology and Chemical TechnologyThe Hong Kong Polytechnic UniversityHong Kong
| | - Yi Gao
- Department of Hepatobiliary Surgery IIZhuJiang Hospital, Southern Medical UniversityGuangzhouGuangdongP. R. China
| | - Yunfu Cui
- Department of Hepatopancreatobiliary SurgerySecond Affiliated Hospital of Harbin Medical UniversityHarbinHeilongjiangP. R. China
| | - Judy Wai Ping Yam
- Department of Pathology, School of Clinical Medicine, Li Ka Shing Faculty of MedicineThe University of Hong KongHong Kong
- State Key Laboratory of Liver Research (The University of Hong Kong)Hong Kong
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Wu K, Han N, Mao Y, Li Y. Increased levels of PD1 and glycolysis in CD4 + T cells are positively associated with lymph node metastasis in OSCC. BMC Oral Health 2023; 23:356. [PMID: 37270478 DOI: 10.1186/s12903-023-03043-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2023] [Accepted: 05/14/2023] [Indexed: 06/05/2023] Open
Abstract
BACKGROUND Cervical lymph node metastasis is one of the poorest prognostic factors in oral squamous cell carcinoma (OSCC). Activated immune cells generally have metabolic abnormalities in the tumour microenvironment. However, it is unknown whether abnormal glycolysis in T cells could facilitate metastatic lymph nodes in OSCC patients. The aim of this study was to investigate the effects of immune checkpoints in metastatic lymph nodes and determine the correlation between glycolysis and immune checkpoint expression in CD4+ T cells. METHODS Flow cytometry and immunofluorescence staining were used to analyse the differences in CD4+ PD1+ T cells between metastatic lymph nodes (LN+) and negative lymph nodes (LN-). RT‒PCR was performed to detail the expression of immune checkpoints and glycolysis-related enzymes in LN+ and LN-. RESULTS The frequency of CD4+ T cells decreased in LN+ patients (p = 0.0019). The PD1 expression of LN+ increased markedly compared to that of LN- (p = 0.0205). Similarly, the PD1 of CD4+ T cells in LN+ increased significantly compared to that of LN-. Additionally, glycolysis-related enzyme levels in CD4+ T cells from LN+ patients were dramatically higher than those in LN- patients. PD1 and Hk2 expression in CD4+ T cells was also increased in LN+ OSCC patients with prior surgical treatment compared to those without. CONCLUSIONS These findings suggest that lymph node metastasis and recurrence in OSCC are associated with increases in PD1 and glycolysis in CD4+ T cells; this response may serve as a potential regulator of OSCC progression.
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Affiliation(s)
- Kun Wu
- Department of Oral and Maxillofacial Surgery, Second Xiangya Hospital of Central South University, Changsha, China
- Department of Oral and Maxillofacial-Head and Neck Oncology, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Nannan Han
- Department of Oral and Maxillofacial-Head and Neck Oncology, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yuanyuan Mao
- Department of Oral and Maxillofacial Surgery, Second Xiangya Hospital of Central South University, Changsha, China.
- Department of Anesthesiology, Second Xiangya Hospital of Central South University, Renmin road, No. 139, Changsha, Hunan, 410011, China.
| | - Yan Li
- Department of Oral and Maxillofacial-Head and Neck Oncology, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
- Precision Research Center for Refractory Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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Pierrard J, Van Ooteghem G, Van den Eynde M. Implications of the Organ-Specific Immune Environment for Immune Priming Effect of Radiotherapy in Metastatic Setting. Biomolecules 2023; 13:689. [PMID: 37189436 PMCID: PMC10136331 DOI: 10.3390/biom13040689] [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: 02/21/2023] [Revised: 04/07/2023] [Accepted: 04/17/2023] [Indexed: 05/17/2023] Open
Abstract
With the development of immune checkpoint inhibitors (ICIs), the tumour immune microenvironment (TIME) has been increasingly considered to improve cancer management. The TIME of metastatic lesions is strongly influenced by the underlying immune contexture of the organ in which they are located. The metastatic location itself appears to be an important prognostic factor in predicting outcomes after ICI treatment in cancer patients. Patients with liver metastases are less likely to respond to ICIs than patients with metastases in other organs, likely due to variations in the metastatic TIME. Combining additional treatment modalities is an option to overcome this resistance. Radiotherapy (RT) and ICIs have been investigated together as an option to treat various metastatic cancers. RT can induce a local and systemic immune reaction, which can promote the patient's response to ICIs. Here, we review the differential impact of the TIME according to metastatic location. We also explore how RT-induced TIME modifications could be modulated to improve outcomes of RT-ICI combinations.
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Affiliation(s)
- Julien Pierrard
- UCLouvain, Center of Molecular Imaging, Radiotherapy and Oncology (MIRO), Institute de Recherche Experimentale et Clinique (IREC), 1200 Brussels, Belgium
- Radiation Oncology Department, Cliniques Universitaires Saint-Luc, 1200 Brussels, Belgium
| | - Geneviève Van Ooteghem
- UCLouvain, Center of Molecular Imaging, Radiotherapy and Oncology (MIRO), Institute de Recherche Experimentale et Clinique (IREC), 1200 Brussels, Belgium
- Radiation Oncology Department, Cliniques Universitaires Saint-Luc, 1200 Brussels, Belgium
| | - Marc Van den Eynde
- UCLouvain, Center of Molecular Imaging, Radiotherapy and Oncology (MIRO), Institute de Recherche Experimentale et Clinique (IREC), 1200 Brussels, Belgium
- Medical Oncology Department, Cliniques Universitaires Saint-Luc, 1200 Brussels, Belgium
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20
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Wang X, Dai G, Jiang G, Zhang D, Wang L, Zhang W, Chen H, Cheng T, Zhou Y, Wei X, Li F, Ma D, Tan S, Wei R, Xi L. A TMVP1-modified near-infrared nanoprobe: molecular imaging for tumor metastasis in sentinel lymph node and targeted enhanced photothermal therapy. J Nanobiotechnology 2023; 21:130. [PMID: 37069646 PMCID: PMC10108508 DOI: 10.1186/s12951-023-01883-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Accepted: 04/06/2023] [Indexed: 04/19/2023] Open
Abstract
BACKGROUND TMVP1 is a novel tumor targeting polypeptide screened by our laboratory with a core sequence of five amino acids LARGR. It specially binds to vascular endothelial growth factor receptor-3 (VEGFR-3), which is mainly expressed on neo-lymphatic vessels in sentinel lymph node (SLN) with tumor metastasis in adults. Here, we prepared a targeted nanoprobe using TMVP1-modified nanomaterials for tumor metastasis SLN imaging. RESULTS In this study, TMVP1-modified polymer nanomaterials were loaded with the near-infrared (NIR) fluorescent dye, indocyanine green (ICG), to prepare a molecular imaging TMVP1-ICG nanoparticles (NPs) to identify tumor metastasis in SLN at molecular level. TMVP1-ICG-NPs were successfully prepared using the nano-precipitation method. The particle diameter, morphology, drug encapsulation efficiency, UV absorption spectrum, cytotoxicity, safety, and pharmacokinetic properties were determined. The TMVP1-ICG-NPs had a diameter of approximately 130 nm and an ICG loading rate of 70%. In vitro cell experiments and in vivo mouse experiments confirmed that TMVP1-ICG-NPs have good targeting ability to tumors in situ and to SLN with tumor metastasis by binding to VEGFR-3. Effective photothermal therapy (PTT) with TMVP1-ICG-NPs was confirmed in vitro and in vivo. As expected, TMVP1-ICG-NPs improved ICG blood stability, targeted tumor metastasis to SLN, and enhanced PTT/photodynamic (PDT) therapy, without obvious cytotoxicity, making it a promising theranostic nanomedicine. CONCLUSION TMVP1-ICG-NPs identified SLN with tumor metastasis and were used to perform imaging-guided PTT, which makes it a promising strategy for providing real-time NIR fluorescence imaging and intraoperative PTT for patients with SLN metastasis.
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Affiliation(s)
- Xueqian Wang
- Department of Gynecological Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, China
- National Clinical Research Center for Obstetrics and Gynecology, Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, China
| | - Geyang Dai
- Department of Gynecological Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, China
- National Clinical Research Center for Obstetrics and Gynecology, Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, China
| | - Guiying Jiang
- Department of Gynecology, West China Second University Hospital, Chengdu, 610000, China
| | - Danya Zhang
- Department of Gynecological Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, China
- National Clinical Research Center for Obstetrics and Gynecology, Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, China
| | - Ling Wang
- Department of Gynecological Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, China
- National Clinical Research Center for Obstetrics and Gynecology, Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, China
| | - Wen Zhang
- Hubei University of Medicine, Shiyan, 442000, China
| | - Huang Chen
- School of Medicine, Jianghan University, Wuhan, 430000, China
| | - Teng Cheng
- Department of Thyroid and Breast Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Ying Zhou
- Department of Gynecological Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, China
- National Clinical Research Center for Obstetrics and Gynecology, Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, China
| | - Xiao Wei
- Department of Gynecological Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, China
- National Clinical Research Center for Obstetrics and Gynecology, Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, China
| | - Fei Li
- Department of Gynecological Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, China
- National Clinical Research Center for Obstetrics and Gynecology, Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, China
| | - Ding Ma
- Department of Gynecological Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, China
- National Clinical Research Center for Obstetrics and Gynecology, Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, China
| | - Songwei Tan
- Tongji School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, China
| | - Rui Wei
- Department of Gynecological Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, China.
- National Clinical Research Center for Obstetrics and Gynecology, Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, China.
| | - Ling Xi
- Department of Gynecological Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, China.
- National Clinical Research Center for Obstetrics and Gynecology, Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, China.
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Zeng Y, Chen LC, Ye ZS, Deng JY. Examined lymph node count for gastric cancer patients after curative surgery. World J Clin Cases 2023; 11:1930-1938. [PMID: 36998963 PMCID: PMC10044965 DOI: 10.12998/wjcc.v11.i9.1930] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Revised: 01/29/2023] [Accepted: 02/21/2023] [Indexed: 03/16/2023] Open
Abstract
Lymph node (LN) metastasis is the most common form of metastasis in gastric cancer (GC). The status and stage of LN metastasis are important indicators that reflect the progress of GC. The number of LN metastases is still the most effective index to evaluate the prognosis of patients in all stages of LN metastasis. Examined LN (ELN) count refers to the number of LNs harvested from specimens by curative gastrectomy for pathological examination. This review summarizes the factors that influence ELN count, including individual and tumor factors, intraoperative dissection factors, postoperative sorting factors, and pathological examination factors. Different ELN counts will lead to prognosis-related stage migration. Fine LN sorting and regional LN sorting are the two most important LN sorting technologies. The most direct and effective way to harvest a large number of LNs is for surgeons to perform in vitro fine LN sorting.
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Affiliation(s)
- Yi Zeng
- Department of Gastrointestinal Surgical Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou 350014, Fujian Province, China
| | - Lu-Chuan Chen
- Department of Gastrointestinal Surgical Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou 350014, Fujian Province, China
| | - Zai-Sheng Ye
- Department of Gastrointestinal Surgical Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou 350014, Fujian Province, China
| | - Jing-Yu Deng
- Department of Gastric Surgery, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300202, China
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22
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Zhang J, Cui J, Gao J, Zhang D, Lin D, Lin J. Polysaccharides of Plantago asiatica enhance antitumor activity via regulating macrophages to M1-like phenotype. Biomed Pharmacother 2023; 159:114246. [PMID: 36652734 DOI: 10.1016/j.biopha.2023.114246] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Revised: 01/04/2023] [Accepted: 01/12/2023] [Indexed: 01/18/2023] Open
Abstract
Monocyte-derived macrophages can be polarized into antitumor M1 phenotype, which inhibited the growth of tumors, and immune-suppressive M2 phenotype, which promoted the development and metastasis of tumors. Plantain polysaccharide (PLP), extracted from the Plantago asiatica, has shown its various biological activities. However, the ability of PLP involved in immune regulation was still obscure. Accordingly, we aimed to investigate whether PLP could polarize macrophages and further inhibit 4T1 tumor cells in vivo and in vitro. In this research, in vitro results showed that PLP displayed the potential in polarizing RAW264.7 macrophages into M1 phenotype and indirect inhibiting migratory effect on 4T1 cells. Furthermore, the phagocytosis and the release of reactive oxygen species (ROS) of macrophages were enhanced. In vivo anti-tumor results demonstrated that PLP could effectively inhibit the growth of 4T1 breast tumors by promoting accumulation of macrophages and T cells in the spleen and lymph node. In conclusion, these findings indicated that PLP inhibited the proliferation and progression of breast tumors by accumulating CD4+, CD8+ T cells and M1-like macrophages in lymph node and spleen, and therefore provided an experimental basis for PLP as a potential antitumor adjunctive therapy in preclinical and clinical trials.
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Affiliation(s)
- Jiatong Zhang
- The Clinical Department, College of Veterinary Medicine, China Agricultural University, Beijing, China
| | - Jingwen Cui
- The Clinical Department, College of Veterinary Medicine, China Agricultural University, Beijing, China
| | - Jiafeng Gao
- The Clinical Department, College of Veterinary Medicine, China Agricultural University, Beijing, China
| | - Di Zhang
- The Clinical Department, College of Veterinary Medicine, China Agricultural University, Beijing, China
| | - Degui Lin
- The Clinical Department, College of Veterinary Medicine, China Agricultural University, Beijing, China.
| | - Jiahao Lin
- The Clinical Department, College of Veterinary Medicine, China Agricultural University, Beijing, China; Center of Research and Innovation of Chinese Traditional Veterinary Medicine, China Agricultural University, Beijing, China.
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Benito-Martín A, Jasiulionis MG, García-Silva S. Extracellular vesicles and melanoma: New perspectives on tumor microenvironment and metastasis. Front Cell Dev Biol 2023; 10:1061982. [PMID: 36704194 PMCID: PMC9871288 DOI: 10.3389/fcell.2022.1061982] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2022] [Accepted: 12/27/2022] [Indexed: 01/11/2023] Open
Abstract
Secreted extracellular vesicles (EVs) are lipid bilayer particles without functional nucleus naturally released from cells which constitute an intercellular communication system. There is a broad spectrum of vesicles shed by cells based on their physical properties such as size (small EVs and large EVs), biogenesis, cargo and functions, which provide an increasingly heterogenous landscape. In addition, they are involved in multiple physiological and pathological processes. In cancer, EV release is opted by tumor cells as a beneficial process for tumor progression. Cutaneous melanoma is a cancer that originates from the melanocyte lineage and shows a favorable prognosis at early stages. However, when melanoma cells acquire invasive capacity, it constitutes the most aggressive and deadly skin cancer. In this context, extracellular vesicles have been shown their relevance in facilitating melanoma progression through the modulation of the microenvironment and metastatic spreading. In agreement with the melanosome secretory capacity of melanocytes, melanoma cells display an enhanced EV shedding activity that has contributed to the utility of melanoma models for unravelling EV cargo and functions within a cancer scenario. In this review, we provide an in-depth overview of the characteristics of melanoma-derived EVs and their role in melanoma progression highlighting key advances and remaining open questions in the field.
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Affiliation(s)
- Alberto Benito-Martín
- Facultad de Medicina, Unidad de Investigación Biomédica, Universidad Alfonso X El Sabio (UAX), Villanueva de la Cañada, Spain,*Correspondence: Alberto Benito-Martín, ; Miriam Galvonas Jasiulionis, ; Susana García-Silva,
| | - Miriam Galvonas Jasiulionis
- Departamento de Farmacologia, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil,*Correspondence: Alberto Benito-Martín, ; Miriam Galvonas Jasiulionis, ; Susana García-Silva,
| | - Susana García-Silva
- Microenvironment and Metastasis Laboratory, Molecular Oncology Programme, Spanish National Cancer Research Center (CNIO), Madrid, Spain,*Correspondence: Alberto Benito-Martín, ; Miriam Galvonas Jasiulionis, ; Susana García-Silva,
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Priya B, Spadigam A, Dhupar A, Syed S. Tagging the pre-metastatic node in oral cancer: A cross-sectional study. J Cancer Res Ther 2023; 19:S645-S648. [PMID: 38384033 DOI: 10.4103/jcrt.jcrt_287_22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2022] [Accepted: 07/20/2022] [Indexed: 02/23/2024]
Abstract
INTRODUCTION Lymph node involvement is the first indication of spread of oral squamous cell carcinoma (OSCC) and it is also a most significant prognostic factor. Lymph nodes show various tumor-induced histological changes preceding actual metastasis, viz. increased vascularity, follicular hyperplasia and desmoplasia which leads to pre-metastatic niche formation. This pre-metastatic niche primarily provides a favorable microenvironment to for the survival and subsequent growth of cancer cells within the lymph node. AIM A retrospective study to evaluate carcinoma-induced changes in lymph nodes harvested from radical neck dissection in OSCC patients. OBJECTIVES 1) To evaluate cancer-induced histological changes in positive and negative lymph nodes in OSCC patients. 2) To look for common histopathological changes in both pre-metastatic and metastatic lymph nodes. MATERIALS AND METHODS Forty lymph nodes harvested from seven OSCC patients were sectioned and stained (Hematoxylin-Eosin) for documentation of histologically evident morphological and functional alterations. The Chi-square test was applied between the non-metastatic and metastatic lymph nodes findings and a statistically significant difference was seen. RESULTS Sections from 28 negative nodes showed changes associated with pre-metastatic niche conditioning whereas, 12 sections exhibit frank metastases. CONCLUSION The modified immunological responses and remodeling of the vasculature are the most common histologic tumor-induced pre-metastatic changes. This study reviewed and categorized these histological changes that point to pre-metastatic niche conditioning of lymph nodes.
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Affiliation(s)
- Bhanu Priya
- Department of Oral and Maxillofacial Pathology, Goa Dental College and Hospital, Bambolim, Goa, India
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Pontis F, Roz L, Fortunato O, Bertolini G. The metastatic niche formation: focus on extracellular vesicle-mediated dialogue between lung cancer cells and the microenvironment. Front Oncol 2023; 13:1116783. [PMID: 37207158 PMCID: PMC10189117 DOI: 10.3389/fonc.2023.1116783] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Accepted: 04/21/2023] [Indexed: 05/21/2023] Open
Abstract
Lung cancer is the deadliest cancer in the world, with the majority of patients presenting with advanced or metastatic disease at first diagnosis. The lungs are also one of the most common sites of metastasis from lung cancer and other tumors. Understanding the mechanisms that regulate metastasis formation from primary lung cancer and in the lungs is therefore fundamental unmet clinical need. One of the first steps during the establishment of lung cancer metastases includes the formation of the pre-metastatic niche (PMN) at distant organs, which may occur even during the early phases of cancer development. The PMN is established through intricate cross-talk between primary tumor-secreted factors and stromal components at distant sites. Mechanisms controlling primary tumor escape and seeding of distant organs rely on specific properties of tumor cells but are also tightly regulated by interactions with stromal cells at the metastatic niche that finally dictate the success of metastasis establishment. Here, we summarize the mechanisms underlying pre-metastatic niche formation starting from how lung primary tumor cells modulate distant sites through the release of several factors, focusing on Extracellular Vesicles (EVs). In this context, we highlight the role of lung cancer-derived EVs in the modulation of tumor immune escape. Then, we illustrate the complexity of Circulating Tumor Cells (CTCs) that represent the seeds of metastasis and how interactions with stromal and immune cells can help their metastatic dissemination. Finally, we evaluate the contribution of EVs in dictating metastasis development at the PMN through stimulation of proliferation and control of disseminated tumor cell dormancy. Overall, we present an overview of different steps in the lung cancer metastatic cascade, focusing on the EV-mediated interactions between tumor cells and stromal/immune cells.
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Naming the Barriers between Anti-CCR5 Therapy, Breast Cancer and Its Microenvironment. Int J Mol Sci 2022; 23:ijms232214159. [PMID: 36430633 PMCID: PMC9694078 DOI: 10.3390/ijms232214159] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Revised: 11/10/2022] [Accepted: 11/15/2022] [Indexed: 11/18/2022] Open
Abstract
Breast cancer represents the most common malignancy among women in the world. Although immuno-, chemo- and radiation therapy are widely recognized as the therapeutic trifecta, new strategies in the fight against breast cancer are continually explored. The local microenvironment around the tumor plays a great role in cancer progression and invasion, representing a promising therapeutic target. CCL5 is a potent chemokine with a physiological role of immune cell attraction and has gained particular attention in R&D for breast cancer treatment. Its receptor, CCR5, is a well-known co-factor for HIV entry through the cell membrane. Interestingly, biology research is unusually unified in describing CCL5 as a pro-oncogenic factor, especially in breast cancer. In silico, in vitro and in vivo studies blocking the CCL5/CCR5 axis show cancer cells become less invasive and less malignant, and the extracellular matrices produced are less oncogenic. At present, CCR5 blocking is a mainstay of HIV treatment, but despite its promising role in cancer treatment, CCR5 blocking in breast cancer remains unperformed. This review presents the role of the CCL5/CCR5 axis and its effector mechanisms, and names the most prominent hurdles for the clinical adoption of anti-CCR5 drugs in cancer.
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Li YL, Hung WC. Reprogramming of sentinel lymph node microenvironment during tumor metastasis. J Biomed Sci 2022; 29:84. [PMID: 36266717 PMCID: PMC9583492 DOI: 10.1186/s12929-022-00868-1] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Accepted: 10/15/2022] [Indexed: 11/10/2022] Open
Abstract
Metastasis is a major cause of death in patients with cancer. The two main routes for cancer cell dissemination are the blood and lymphatic systems. The underlying mechanism of hematogenous metastasis has been well characterized in the past few decades. However, our understanding of the molecular basis of lymphatic metastasis remains at a premature stage. Conceptually, cancer cells invade into lymphatic capillary, passively move to collecting lymphatic vessels, migrate into sentinel lymph node (SLN;, the first lymph node to which cancer cells spread from the primary tumor), and enter the blood circulatory system via the subclavian vein. Before arriving, cancer cells release specific soluble factors to modulate the microenvironment in SLN to establish a beachhead for successful colonization. After colonization, cancer cells inhibit anti-tumor immunity by inducing the recruitment of regulatory T cell and myeloid-derived suppressor cells, suppressing the function of dendritic cell and CD8+ T cell, and promoting the release of immunosuppressive cytokines. The development of novel strategies to reverse cancer cell-triggered SLN remodeling may re-activate immunity to reduce beachhead buildup and distant metastasis. In addition to being a microanatomic location for metastasis, the SLN is also an important site for immune modulation. Nanotechnology-based approaches to deliver lymph node-tropic antibodies or drug-conjugated nanoparticles to kill cancer cells on site are a new direction for cancer treatment. Conversely, the induction of stronger immunity by promoting antigen presentation in lymph nodes provides an alternate way to enhance the efficacy of immune checkpoint therapy and cancer vaccine. In this review article, we summarize recent findings on the reprogramming of SLN during lymphatic invasion and discuss the possibility of inhibiting tumor metastasis and eliciting anti-tumor immunity by targeting SLN.
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Affiliation(s)
- Yen-Liang Li
- National Institute of Cancer Research, National Health Research Institutes, Tainan, 704, Taiwan
| | - Wen-Chun Hung
- National Institute of Cancer Research, National Health Research Institutes, Tainan, 704, Taiwan. .,School of Pharmacy, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, 807, Taiwan.
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Li Z, Yu Q, Zhu Q, Yang X, Li Z, Fu J. Applications of machine learning in tumor-associated macrophages. Front Immunol 2022; 13:985863. [PMID: 36211379 PMCID: PMC9538115 DOI: 10.3389/fimmu.2022.985863] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Accepted: 09/07/2022] [Indexed: 11/29/2022] Open
Abstract
Evaluation of tumor-host interaction and intratumoral heterogeneity in the tumor microenvironment (TME) is gaining increasing attention in modern cancer therapies because it can reveal unique information about the tumor status. As tumor-associated macrophages (TAMs) are the major immune cells infiltrating in TME, a better understanding of TAMs could help us further elucidate the cellular and molecular mechanisms responsible for cancer development. However, the high-dimensional and heterogeneous data in biology limit the extensive integrative analysis of cancer research. Machine learning algorithms are particularly suitable for oncology data analysis due to their flexibility and scalability to analyze diverse data types and strong computation power to learn underlying patterns from massive data sets. With the application of machine learning in analyzing TME, especially TAM’s traceable status, we could better understand the role of TAMs in tumor biology. Furthermore, we envision that the promotion of machine learning in this field could revolutionize tumor diagnosis, treatment stratification, and survival predictions in cancer research. In this article, we described key terms and concepts of machine learning, reviewed the applications of common methods in TAMs, and highlighted the challenges and future direction for TAMs in machine learning.
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Affiliation(s)
- Zhen Li
- Radiation Oncology Department, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Qijun Yu
- Department of Pulmonary and Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University, Shanghai, China
- Institute of Respiratory Diseases, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Qingyuan Zhu
- Radiation Oncology Department, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Xiaojing Yang
- Radiation Oncology Department, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Zhaobin Li
- Radiation Oncology Department, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Jie Fu
- Radiation Oncology Department, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
- *Correspondence: Jie Fu,
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Abstract
The lymphatic system, composed of initial and collecting lymphatic vessels as well as lymph nodes that are present in almost every tissue of the human body, acts as an essential transport system for fluids, biomolecules and cells between peripheral tissues and the central circulation. Consequently, it is required for normal body physiology but is also involved in the pathogenesis of various diseases, most notably cancer. The important role of tumor-associated lymphatic vessels and lymphangiogenesis in the formation of lymph node metastasis has been elucidated during the last two decades, whereas the underlying mechanisms and the relation between lymphatic and peripheral organ dissemination of cancer cells are incompletely understood. Lymphatic vessels are also important for tumor-host communication, relaying molecular information from a primary or metastatic tumor to regional lymph nodes and the circulatory system. Beyond antigen transport, lymphatic endothelial cells, particularly those residing in lymph node sinuses, have recently been recognized as direct regulators of tumor immunity and immunotherapy responsiveness, presenting tumor antigens and expressing several immune-modulatory signals including PD-L1. In this review, we summarize recent discoveries in this rapidly evolving field and highlight strategies and challenges of therapeutic targeting of lymphatic vessels or specific lymphatic functions in cancer patients.
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Affiliation(s)
- Lothar C Dieterich
- Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology (ETH) Zurich, Zurich, Switzerland
| | - Carlotta Tacconi
- Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology (ETH) Zurich, Zurich, Switzerland.,Department of Biosciences, University of Milan, Milan, Italy
| | - Luca Ducoli
- Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology (ETH) Zurich, Zurich, Switzerland
| | - Michael Detmar
- Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology (ETH) Zurich, Zurich, Switzerland
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30
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Hu C, Huang Q, Sun Q. The Regulation of Lymph Node Pre-Metastatic Niche Formation in Head and Neck Squamous Cell Carcinoma. Front Oncol 2022; 12:852611. [PMID: 35574333 PMCID: PMC9094482 DOI: 10.3389/fonc.2022.852611] [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: 01/11/2022] [Accepted: 03/28/2022] [Indexed: 11/13/2022] Open
Abstract
In many distinct forms of malignancies, there is a close relationship between lymph node (LN) metastases and further dissemination to distant organs, and this is a critical prognostic factor. At the beginning of the process, the original tumor secretes soluble substances or releases extracellular vesicles (EVs) that are carried through lymphatic channels to draining (sentinel) LN. The tumor-derived factors then drive LN remodeling. These significant alterations occur prior to the emergence of the first metastatic cell, bringing about the development of a pre-metastatic niche that allows metastatic cells to survive and thrive. In this review, we discuss current information available about the regulation of lymph node pre-metastatic niche in head and neck squamous cell carcinoma (HNSCC), and the role of EVs in forming the pre-metastatic niche.
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Affiliation(s)
- Chen Hu
- Department of Otorhinolaryngology, QingPu Branch of Zhongshan Hospital Affiliated to Fudan University, Shanghai, China.,Department of Otorhinolaryngology, Eye & ENT Hospital, Fudan University, Shanghai, China
| | - Qiang Huang
- Department of Otorhinolaryngology, Eye & ENT Hospital, Fudan University, Shanghai, China
| | - Qing Sun
- Department of Otorhinolaryngology, QingPu Branch of Zhongshan Hospital Affiliated to Fudan University, Shanghai, China
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31
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Lu T, Zhang Z, Zhang J, Pan X, Zhu X, Wang X, Li Z, Ruan M, Li H, Chen W, Yan M. CD73 in small extracellular vesicles derived from HNSCC defines tumour-associated immunosuppression mediated by macrophages in the microenvironment. J Extracell Vesicles 2022; 11:e12218. [PMID: 35524455 PMCID: PMC9077142 DOI: 10.1002/jev2.12218] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Revised: 03/21/2022] [Accepted: 03/29/2022] [Indexed: 12/20/2022] Open
Abstract
Research on tumour cell‐derived small extracellular vesicles (sEVs) that regulate tumour microenvironment (TME) has provided strategies for targeted therapy of head and neck squamous cell carcinoma (HNSCC). Herein, we demonstrated that sEVs derived from HNSCC cancer cells carried CD73 (sEVsCD73), which promoted malignant progression and mediated immune evasion. The sEVsCD73 phagocytosed by tumour‐associated macrophages (TAMs) in the TME induced immunosuppression. Higher CD73high TAMs infiltration levels in the HNSCC microenvironment were correlated with poorer prognosis, while sEVsCD73 activated the NF‐κB pathway in TAMs, thereby inhibiting immune function by increasing cytokines secretion such as IL‐6, IL‐10, TNF‐α, and TGF‐β1. The absence of sEVsCD73 enhanced the sensitivity of anti‐PD‐1 therapy through reversed immunosuppression. Moreover, circulating sEVsCD73 increased the risk of lymph node metastasis and worse prognosis. Taken together, our study suggests that sEVsCD73 derived from tumour cells contributes to immunosuppression and is a potential predictor of anti‐PD‐1 responses for immune checkpoint therapy in HNSCC.
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Affiliation(s)
- Tingwei Lu
- Department of Oral and Maxillofacial-Head & Neck Oncology, Shanghai Ninth People's Hospital, College of Stomatology, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhen Zhang
- Department of Oral and Maxillofacial-Head & Neck Oncology, Shanghai Ninth People's Hospital, College of Stomatology, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jianjun Zhang
- Department of Oral and Maxillofacial-Head & Neck Oncology, Shanghai Ninth People's Hospital, College of Stomatology, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xinhua Pan
- Department of Oral and Maxillofacial-Head & Neck Oncology, Shanghai Ninth People's Hospital, College of Stomatology, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xueqin Zhu
- Department of Pediatric Dentistry, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xu Wang
- Department of Oral and Maxillofacial-Head & Neck Oncology, Shanghai Ninth People's Hospital, College of Stomatology, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhihui Li
- Department of Oral and Maxillofacial-Head & Neck Oncology, Shanghai Ninth People's Hospital, College of Stomatology, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Min Ruan
- Department of Oral and Maxillofacial-Head & Neck Oncology, Shanghai Ninth People's Hospital, College of Stomatology, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Huasheng Li
- Department of Oral and Maxillofacial-Head & Neck Oncology, Shanghai Ninth People's Hospital, College of Stomatology, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Wantao Chen
- Department of Oral and Maxillofacial-Head & Neck Oncology, Shanghai Ninth People's Hospital, College of Stomatology, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ming Yan
- Department of Oral and Maxillofacial-Head & Neck Oncology, Shanghai Ninth People's Hospital, College of Stomatology, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Hypoxia orchestrates the lymphovascular–immune ensemble in cancer. Trends Cancer 2022; 8:771-784. [DOI: 10.1016/j.trecan.2022.04.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Revised: 03/31/2022] [Accepted: 04/25/2022] [Indexed: 11/18/2022]
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Qian L, Zhang J, Lu S, He X, Feng J, Shi J, Liu Y. Potential key roles of tumour budding: a representative malignant pathological feature of non-small cell lung cancer and a sensitive indicator of prognosis. BMJ Open 2022; 12:e054009. [PMID: 35361643 PMCID: PMC8971788 DOI: 10.1136/bmjopen-2021-054009] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
OBJECTIVES To investigate the relationship between tumour budding, clinicopathological characteristics of patients and prognosis in non-small cell lung cancer. STUDY DESIGN A retrospective study was used. PARTICIPANTS We selected 532 patients with non-small cell lung cancer from China, including 380 patients with adenocarcinoma and 152 with squamous cell carcinoma. PRIMARY AND SECONDARY OUTCOME MEASURES Tumour budding was visible using H&E staining as well as pancytokeratin staining. The count data and measurement data were compared using the χ2 test and the t-test, respectively. The overall survival rate was the follow-up result. The survival curves were drawn using the Kaplan-Meier method, and the differences between groups were analysed using the log-rank method. The independent prognostic factor of patients with lung cancer was determined using a multivariate Cox proportional hazard model. RESULTS In patients with lung adenocarcinoma, there was a correlation between tumour budding and spread through air spaces (OR 36.698; 95% CI 13.925 to 96.715; p<0.001), and in patients with squamous cell carcinoma, tumour budding state was closely related to the peritumoural space (OR 11.667; 95% CI 4.041 to 33.683; p<0.001). On Cox regression analysis, multivariate analysis showed that tumour budding, pleural and vascular invasion, spread through air spaces, tumour size, lymph node metastasis, and tumour node metastasis stage were independent risk factors of prognosis for patients with non-small cell lung cancer. CONCLUSIONS As an effective and simple pathological diagnostic index, it is necessary to establish an effective grading system in the clinical diagnosis of lung cancer to verify the value of tumour budding as a prognostic indicator. We hope that this analysis of Chinese patients with non-small cell lung cancer can provide useful reference material for the continued study of tumour budding.
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Affiliation(s)
- Li Qian
- Pathology, Affiliated Hospital of Nantong University, Nantong, China
| | - Jianguo Zhang
- Pathology, Affiliated Hospital of Nantong University, Nantong, China
| | - Shumin Lu
- Oncology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Xin He
- Pathology, Affiliated Hospital of Nantong University, Nantong, China
| | - Jia Feng
- Pathology, Affiliated Hospital of Nantong University, Nantong, China
| | - Jiahai Shi
- Nantong Key Laboratory of Translational Medicine in Cardiothoracic Diseases, Affiliated Hospital of Nantong University, Nantong, China
| | - Yifei Liu
- Pathology, Affiliated Hospital of Nantong University, Nantong, China
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Rethacker L, Boy M, Bisio V, Roussin F, Denizeau J, Vincent-Salomon A, Borcoman E, Sedlik C, Piaggio E, Toubert A, Dulphy N, Caignard A. Innate lymphoid cells: NK and cytotoxic ILC3 subsets infiltrate metastatic breast cancer lymph nodes. Oncoimmunology 2022; 11:2057396. [PMID: 35371620 PMCID: PMC8973349 DOI: 10.1080/2162402x.2022.2057396] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
Innate lymphoid cells (ILCs) – which include cytotoxic Natural Killer (NK) cells and helper-type ILC – are important regulators of tissue immune homeostasis, with possible roles in tumor surveillance. We analyzed ILC and their functionality in human lymph nodes (LN). In LN, NK cells and ILC3 were the prominent subpopulations. Among the ILC3s, we identified a CD56+/ILC3 subset with a phenotype close to ILC3 but also expressing cytotoxicity genes shared with NK. In tumor-draining LNs (TD-LNs) and tumor samples from breast cancer (BC) patients, NK cells were prominent, and proportions of ILC3 subsets were low. In tumors and TD-LN, NK cells display reduced levels of NCR (Natural cytotoxicity receptors), despite high transcript levels and included a small subset CD127− CD56− NK cells with reduced function. Activated by cytokines CD56+/ILC3 cells from donor and patients LN acquired cytotoxic capacity and produced IFNg. In TD-LN, all cytokine activated ILC populations produced TNFα in response to BC cell line. Analyses of cytotoxic and helper ILC indicate a switch toward NK cells in TD-LN. The local tumor microenvironment inhibited NK cell functions through downregulation of NCR, but cytokine stimulation restored their functionality.
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Affiliation(s)
- Louise Rethacker
- INSERM U1160, Institut de Recherche Saint-Louis, Hôpital Saint Louis, Paris, France
| | - Maxime Boy
- INSERM U1160, Institut de Recherche Saint-Louis, Hôpital Saint Louis, Paris, France
| | - Valeria Bisio
- INSERM U1160, Institut de Recherche Saint-Louis, Hôpital Saint Louis, Paris, France
| | - France Roussin
- Service d’Anesthésie-Réanimation, AP-HP, Hôpital Saint-Louis, Paris, France
| | - Jordan Denizeau
- INSERM U932, Département de Recherche Translationelle, Institut Curie, Université de Recherche Paris Sciences & Lettres (PSL), Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France
| | - Anne Vincent-Salomon
- Diagnostic and Theranostic Medicine Division, Institut Curie, PSL Research University, Paris, France
| | - Edith Borcoman
- Department of Medical Oncology, Institut Curie, Paris, France
- Université Paris Diderot, Université de Paris, Paris, France
| | - Christine Sedlik
- INSERM U932, Département de Recherche Translationelle, Institut Curie, Université de Recherche Paris Sciences & Lettres (PSL), Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France
| | - Eliane Piaggio
- INSERM U932, Département de Recherche Translationelle, Institut Curie, Université de Recherche Paris Sciences & Lettres (PSL), Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France
| | - Antoine Toubert
- INSERM U1160, Institut de Recherche Saint-Louis, Hôpital Saint Louis, Paris, France
- Université Paris Diderot, Université de Paris, Paris, France
- Assistance Publique–Hôpitaux de Paris (AP–HP), Hôpital Saint-Louis, Laboratoire d’Immunologie et Histocompatibilité, Paris, France
| | - Nicolas Dulphy
- INSERM U1160, Institut de Recherche Saint-Louis, Hôpital Saint Louis, Paris, France
- Université Paris Diderot, Université de Paris, Paris, France
- Assistance Publique–Hôpitaux de Paris (AP–HP), Hôpital Saint-Louis, Laboratoire d’Immunologie et Histocompatibilité, Paris, France
| | - Anne Caignard
- INSERM U1160, Institut de Recherche Saint-Louis, Hôpital Saint Louis, Paris, France
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Bekisz S, Baudin L, Buntinx F, Noël A, Geris L. In Vitro, In Vivo, and In Silico Models of Lymphangiogenesis in Solid Malignancies. Cancers (Basel) 2022; 14:1525. [PMID: 35326676 PMCID: PMC8946816 DOI: 10.3390/cancers14061525] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Revised: 02/24/2022] [Accepted: 03/08/2022] [Indexed: 12/04/2022] Open
Abstract
Lymphangiogenesis (LA) is the formation of new lymphatic vessels by lymphatic endothelial cells (LECs) sprouting from pre-existing lymphatic vessels. It is increasingly recognized as being involved in many diseases, such as in cancer and secondary lymphedema, which most often results from cancer treatments. For some cancers, excessive LA is associated with cancer progression and metastatic dissemination to the lymph nodes (LNs) through lymphatic vessels. The study of LA through in vitro, in vivo, and, more recently, in silico models is of paramount importance in providing novel insights and identifying the key molecular actors in the biological dysregulation of this process under pathological conditions. In this review, the different biological (in vitro and in vivo) models of LA, especially in a cancer context, are explained and discussed, highlighting their principal modeled features as well as their advantages and drawbacks. Imaging techniques of the lymphatics, complementary or even essential to in vivo models, are also clarified and allow the establishment of the link with computational approaches. In silico models are introduced, theoretically described, and illustrated with examples specific to the lymphatic system and the LA. Together, these models constitute a toolbox allowing the LA research to be brought to the next level.
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Affiliation(s)
- Sophie Bekisz
- Biomechanics Research Unit, GIGA In silico Medicine, ULiège, 4000 Liège, Belgium;
| | - Louis Baudin
- Laboratory of Biology of Tumor and Development, GIGA Cancer, ULiège, 4000 Liège, Belgium; (L.B.); (F.B.); (A.N.)
| | - Florence Buntinx
- Laboratory of Biology of Tumor and Development, GIGA Cancer, ULiège, 4000 Liège, Belgium; (L.B.); (F.B.); (A.N.)
| | - Agnès Noël
- Laboratory of Biology of Tumor and Development, GIGA Cancer, ULiège, 4000 Liège, Belgium; (L.B.); (F.B.); (A.N.)
| | - Liesbet Geris
- Biomechanics Research Unit, GIGA In silico Medicine, ULiège, 4000 Liège, Belgium;
- Biomechanics Section, KU Leuven, 3000 Leuven, Belgium
- Skeletal Biology and Engineering Research Center, KU Leuven, 3000 Leuven, Belgium
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Habanjar O, Diab-Assaf M, Caldefie-Chezet F, Delort L. The Impact of Obesity, Adipose Tissue, and Tumor Microenvironment on Macrophage Polarization and Metastasis. BIOLOGY 2022; 11:339. [PMID: 35205204 PMCID: PMC8869089 DOI: 10.3390/biology11020339] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Revised: 01/19/2022] [Accepted: 02/15/2022] [Indexed: 12/11/2022]
Abstract
Tumor metastasis is a major cause of death in cancer patients. It involves not only the intrinsic alterations within tumor cells, but also crosstalk between these cells and components of the tumor microenvironment (TME). Tumorigenesis is a complex and dynamic process, involving the following three main stages: initiation, progression, and metastasis. The transition between these stages depends on the changes within the extracellular matrix (ECM), in which tumor and stromal cells reside. This matrix, under the effect of growth factors, cytokines, and adipokines, can be morphologically altered, degraded, or reorganized. Many cancers evolve to form an immunosuppressive TME locally and create a pre-metastatic niche in other tissue sites. TME and pre-metastatic niches include myofibroblasts, immuno-inflammatory cells (macrophages), adipocytes, blood, and lymphatic vascular networks. Several studies have highlighted the adipocyte-macrophage interaction as a key driver of cancer progression and dissemination. The following two main classes of macrophages are distinguished: M1 (pro-inflammatory/anti-tumor) and M2 (anti-inflammatory/pro-tumor). These cells exhibit distinct microenvironment-dependent phenotypes that can promote or inhibit metastasis. On the other hand, obesity in cancer patients has been linked to a poor prognosis. In this regard, tumor-associated adipocytes modulate TME through the secretion of inflammatory mediators, which modulate and recruit tumor-associated macrophages (TAM). Hereby, this review describes the cellular and molecular mechanisms that link inflammation, obesity, and cancer. It provides a comprehensive overview of adipocytes and macrophages in the ECM as they control cancer initiation, progression, and invasion. In addition, it addresses the mechanisms of tumor anchoring and recruitment for M1, M2, and TAM macrophages, specifically highlighting their origin, classification, polarization, and regulatory networks, as well as their roles in the regulation of angiogenesis, invasion, metastasis, and immunosuppression, specifically highlighting the role of adipocytes in this process.
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Affiliation(s)
- Ola Habanjar
- Université Clermont-Auvergne, INRAE, UNH, ECREIN, f-63000 Clermont-Ferrand, France; (O.H.); (F.C.-C.)
| | - Mona Diab-Assaf
- Equipe Tumorigénèse Pharmacologie moléculaire et anticancéreuse, Faculté des Sciences II, Université libanaise Fanar, Beyrouth 1500, Liban;
| | - Florence Caldefie-Chezet
- Université Clermont-Auvergne, INRAE, UNH, ECREIN, f-63000 Clermont-Ferrand, France; (O.H.); (F.C.-C.)
| | - Laetitia Delort
- Université Clermont-Auvergne, INRAE, UNH, ECREIN, f-63000 Clermont-Ferrand, France; (O.H.); (F.C.-C.)
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37
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Leary N, Walser S, He Y, Cousin N, Pereira P, Gallo A, Collado‐Diaz V, Halin C, Garcia‐Silva S, Peinado H, Dieterich LC. Melanoma-derived extracellular vesicles mediate lymphatic remodelling and impair tumour immunity in draining lymph nodes. J Extracell Vesicles 2022; 11:e12197. [PMID: 35188342 PMCID: PMC8859913 DOI: 10.1002/jev2.12197] [Citation(s) in RCA: 71] [Impact Index Per Article: 23.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Revised: 01/14/2022] [Accepted: 01/20/2022] [Indexed: 12/12/2022] Open
Abstract
Tumour-draining lymph nodes (LNs) undergo massive remodelling including expansion of the lymphatic sinuses, a process that has been linked to lymphatic metastasis by creation of a pre-metastatic niche. However, the signals leading to these changes have not been completely understood. Here, we found that extracellular vesicles (EVs) derived from melanoma cells are rapidly transported by lymphatic vessels to draining LNs, where they selectively interact with lymphatic endothelial cells (LECs) as well as medullary sinus macrophages. Interestingly, uptake of melanoma EVs by LN-resident LECs was partly dependent on lymphatic VCAM-1 expression, and induced transcriptional changes as well as proliferation of those cells. Furthermore, melanoma EVs shuttled tumour antigens to LN LECs for cross-presentation on MHC-I, resulting in apoptosis induction in antigen-specific CD8+ T cells. In conclusion, our data identify EV-mediated melanoma-LN LEC communication as a new pathway involved in tumour progression and tumour immune inhibition, suggesting that EV uptake or effector mechanisms in LECs might represent a new target for melanoma therapy.
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Affiliation(s)
- Noelle Leary
- Institute of Pharmaceutical SciencesSwiss Federal Institute of Technology (ETH) ZurichZurichSwitzerland
| | - Sarina Walser
- Institute of Pharmaceutical SciencesSwiss Federal Institute of Technology (ETH) ZurichZurichSwitzerland
| | - Yuliang He
- Institute of Pharmaceutical SciencesSwiss Federal Institute of Technology (ETH) ZurichZurichSwitzerland
| | - Nikola Cousin
- Institute of Pharmaceutical SciencesSwiss Federal Institute of Technology (ETH) ZurichZurichSwitzerland
| | - Paulo Pereira
- Institute of Pharmaceutical SciencesSwiss Federal Institute of Technology (ETH) ZurichZurichSwitzerland
| | - Alessandro Gallo
- Institute of Pharmaceutical SciencesSwiss Federal Institute of Technology (ETH) ZurichZurichSwitzerland
| | - Victor Collado‐Diaz
- Institute of Pharmaceutical SciencesSwiss Federal Institute of Technology (ETH) ZurichZurichSwitzerland
| | - Cornelia Halin
- Institute of Pharmaceutical SciencesSwiss Federal Institute of Technology (ETH) ZurichZurichSwitzerland
| | - Susana Garcia‐Silva
- Microenvironment and Metastasis LaboratorySpanish National Cancer Research CentreMadridSpain
| | - Hector Peinado
- Microenvironment and Metastasis LaboratorySpanish National Cancer Research CentreMadridSpain
| | - Lothar C. Dieterich
- Institute of Pharmaceutical SciencesSwiss Federal Institute of Technology (ETH) ZurichZurichSwitzerland
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García-Silva S, Benito-Martín A, Nogués L, Hernández-Barranco A, Mazariegos MS, Santos V, Hergueta-Redondo M, Ximénez-Embún P, Kataru RP, Lopez AA, Merino C, Sánchez-Redondo S, Graña-Castro O, Matei I, Nicolás-Avila JÁ, Torres-Ruiz R, Rodríguez-Perales S, Martínez L, Pérez-Martínez M, Mata G, Szumera-Ciećkiewicz A, Kalinowska I, Saltari A, Martínez-Gómez JM, Hogan SA, Saragovi HU, Ortega S, Garcia-Martin C, Boskovic J, Levesque MP, Rutkowski P, Hidalgo A, Muñoz J, Megías D, Mehrara BJ, Lyden D, Peinado H. Melanoma-derived small extracellular vesicles induce lymphangiogenesis and metastasis through an NGFR-dependent mechanism. NATURE CANCER 2021; 2:1387-1405. [PMID: 34957415 PMCID: PMC8697753 DOI: 10.1038/s43018-021-00272-y] [Citation(s) in RCA: 93] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/14/2023]
Abstract
Secreted extracellular vesicles (EVs) influence the tumor microenvironment and promote distal metastasis. Here, we analyzed the involvement of melanoma-secreted EVs in lymph node pre-metastatic niche formation in murine models. We found that small EVs (sEVs) derived from metastatic melanoma cell lines were enriched in nerve growth factor receptor (NGFR, p75NTR), spread through the lymphatic system and were taken up by lymphatic endothelial cells, reinforcing lymph node metastasis. Remarkably, sEVs enhanced lymphangiogenesis and tumor cell adhesion by inducing ERK kinase, nuclear factor (NF)-κB activation and intracellular adhesion molecule (ICAM)-1 expression in lymphatic endothelial cells. Importantly, ablation or inhibition of NGFR in sEVs reversed the lymphangiogenic phenotype, decreased lymph node metastasis and extended survival in pre-clinical models. Furthermore, NGFR expression was augmented in human lymph node metastases relative to that in matched primary tumors, and the frequency of NGFR+ metastatic melanoma cells in lymph nodes correlated with patient survival. In summary, we found that NGFR is secreted in melanoma-derived sEVs, reinforcing lymph node pre-metastatic niche formation and metastasis.
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Affiliation(s)
- Susana García-Silva
- Microenvironment and Metastasis Laboratory, Molecular Oncology Programme, Spanish National Cancer Research Center (CNIO), Madrid, Spain
| | - Alberto Benito-Martín
- Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics and Cell and Developmental Biology, Weill Cornell Medical College, New York, NY, USA
| | - Laura Nogués
- Microenvironment and Metastasis Laboratory, Molecular Oncology Programme, Spanish National Cancer Research Center (CNIO), Madrid, Spain
| | - Alberto Hernández-Barranco
- Microenvironment and Metastasis Laboratory, Molecular Oncology Programme, Spanish National Cancer Research Center (CNIO), Madrid, Spain
| | - Marina S Mazariegos
- Microenvironment and Metastasis Laboratory, Molecular Oncology Programme, Spanish National Cancer Research Center (CNIO), Madrid, Spain
| | - Vanesa Santos
- Microenvironment and Metastasis Laboratory, Molecular Oncology Programme, Spanish National Cancer Research Center (CNIO), Madrid, Spain
| | - Marta Hergueta-Redondo
- Microenvironment and Metastasis Laboratory, Molecular Oncology Programme, Spanish National Cancer Research Center (CNIO), Madrid, Spain
| | - Pilar Ximénez-Embún
- Proteomics Unit, ProteoRed-ISCIII, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
| | - Raghu P Kataru
- Department of Surgery, Plastic and Reconstructive Surgery Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Ana Amor Lopez
- Microenvironment and Metastasis Laboratory, Molecular Oncology Programme, Spanish National Cancer Research Center (CNIO), Madrid, Spain
| | - Cristina Merino
- Microenvironment and Metastasis Laboratory, Molecular Oncology Programme, Spanish National Cancer Research Center (CNIO), Madrid, Spain
| | - Sara Sánchez-Redondo
- Microenvironment and Metastasis Laboratory, Molecular Oncology Programme, Spanish National Cancer Research Center (CNIO), Madrid, Spain
| | - Osvaldo Graña-Castro
- Bioinformatics Unit, Structural Biology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
| | - Irina Matei
- Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics and Cell and Developmental Biology, Weill Cornell Medical College, New York, NY, USA
| | - José Ángel Nicolás-Avila
- Area of Developmental and Cell Biology, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain
| | - Raúl Torres-Ruiz
- Molecular Cytogenetics Unit, Human Cancer Genetics Programme, Spanish National Cancer Research Center (CNIO), Madrid, Spain
| | - Sandra Rodríguez-Perales
- Molecular Cytogenetics Unit, Human Cancer Genetics Programme, Spanish National Cancer Research Center (CNIO), Madrid, Spain
| | - Lola Martínez
- Flow Cytometry Unit, Biotechnology Programme, Spanish National Cancer Research Center (CNIO), Madrid, Spain
| | - Manuel Pérez-Martínez
- Cofocal Microscopy Unit, Biotechnology Programme, Spanish National Cancer Research Center (CNIO), Madrid, Spain
| | - Gadea Mata
- Cofocal Microscopy Unit, Biotechnology Programme, Spanish National Cancer Research Center (CNIO), Madrid, Spain
| | - Anna Szumera-Ciećkiewicz
- Department of Pathology and Laboratory Medicine, Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland
- Diagnostic Hematology Department, Institute of Hematology and Transfusion Medicine, Warsaw, Poland
| | - Iwona Kalinowska
- Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland
| | - Annalisa Saltari
- Department of Dermatology, University of Zurich, University of Zurich Hospital, Zurich, Switzerland
| | - Julia M Martínez-Gómez
- Department of Dermatology, University of Zurich, University of Zurich Hospital, Zurich, Switzerland
| | - Sabrina A Hogan
- Department of Dermatology, University of Zurich, University of Zurich Hospital, Zurich, Switzerland
| | - H Uri Saragovi
- Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada
- Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada
| | - Sagrario Ortega
- Transgenic Mice Unit, Biotechnology Programme, Spanish National Cancer Research Center (CNIO), Madrid, Spain
| | - Carmen Garcia-Martin
- Electron Microscopy Unit, Spanish National Cancer Research Center (CNIO), Madrid, Spain
| | - Jasminka Boskovic
- Electron Microscopy Unit, Spanish National Cancer Research Center (CNIO), Madrid, Spain
| | - Mitchell P Levesque
- Department of Dermatology, University of Zurich, University of Zurich Hospital, Zurich, Switzerland
| | - Piotr Rutkowski
- Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland
| | - Andrés Hidalgo
- Area of Developmental and Cell Biology, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain
| | - Javier Muñoz
- Proteomics Unit, ProteoRed-ISCIII, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
| | - Diego Megías
- Cofocal Microscopy Unit, Biotechnology Programme, Spanish National Cancer Research Center (CNIO), Madrid, Spain
| | - Babak J Mehrara
- Department of Surgery, Plastic and Reconstructive Surgery Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
| | - David Lyden
- Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics and Cell and Developmental Biology, Weill Cornell Medical College, New York, NY, USA.
| | - Héctor Peinado
- Microenvironment and Metastasis Laboratory, Molecular Oncology Programme, Spanish National Cancer Research Center (CNIO), Madrid, Spain.
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Ding F, Huang C, Liang C, Wang C, Liu J, Tang D. 68Ga-FAPI-04 vs. 18F-FDG in a longitudinal preclinical PET imaging of metastatic breast cancer. Eur J Nucl Med Mol Imaging 2021; 49:290-300. [PMID: 34181060 DOI: 10.1007/s00259-021-05442-9] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2021] [Accepted: 05/31/2021] [Indexed: 01/10/2023]
Abstract
PURPOSE This longitudinal study aims to evaluate the performance of 68 Ga-FAPI-04 and 18F-FDG and to profile the dynamic process of tumor metastasis in a preclinical 4T1 breast cancer model. Although both of these two radioligands are wildly used in clinic, no study was reported on their performance in the longitudinal monitoring of tumor metastasis. Also, no correlation between the expression level of fibroblast activation protein (FAP) and the development of tumor metastasis has been elucidated previously. In this study, we evaluated the performance of 68 Ga-FAPI-04 and 18F-FDG PET during the entire process of tumor metastasis, and their potential for the early diagnosis of tumor metastasis. We also clarified the correlation of uptakes as well as the signal-to-background (S/B) ratios between these two probes at different stages of tumor metastasis. METHODS Forty 4T1 metastatic breast cancer murine models were established using female BALB/c mice, followed by the longitudinal imaging with 68 Ga-FAPI-04 and 18F-FDG once a week for up to 6 weeks. In vitro hematoxylin and eosin (H&E) and immunochemistry (IHE) staining were performed to evaluate FAP expression on the metastatic lesions. Further statistical analysis was performed to evaluate the correlation of 68 Ga-FAPI-04 and 18F-FDG uptake (%ID/cc) at different stages of the metastasis. RESULTS 68 Ga-FPAI-04 holds an advantage over 18F-FDG with higher sensitivity at the early stage of tumor metastasis. However, with the progress of tumor metastasis, uptake of 68 Ga-FAPI-04 decreases and becomes less sensitive than 18F-FDG. There is also no direct correlation between uptake or S/B ratios of 68 Ga-FAPI-04 and 18F-FDG during this dynamic process. CONCLUSION 68 Ga-FAPI-04 is more sensitive than 18F-FDG in detecting the early stage of tumor metastasis, but becomes less sensitive than 18F-FDG at the late stage of tumor metastasis. We envision this result would be meaningful for the explanation of the 68 Ga-FAPI-04 and 18F-FDG imaging both in the future clinic and preclinic studies.
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Affiliation(s)
- Fan Ding
- Department of Nuclear Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pu Jian Rd., Shanghai , 200127, China
| | - Chen Huang
- College of Medical Imaging, Shanghai University of Medicine & Healthy Science, Shanghai, 201318, China
- Jiading District Central Hospital, Shanghai University of Medicine & Healthy Science, No.1 Chengbei Rd., Jiading District, Shanghai, 201800, China
| | - Chenyi Liang
- Department of Nuclear Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pu Jian Rd., Shanghai , 200127, China
| | - Cheng Wang
- Department of Nuclear Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pu Jian Rd., Shanghai , 200127, China
| | - Jianjun Liu
- Department of Nuclear Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pu Jian Rd., Shanghai , 200127, China.
| | - Dewei Tang
- Department of Nuclear Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pu Jian Rd., Shanghai , 200127, China.
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40
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Ollivier L, Labbé M, Fradin D, Potiron V, Supiot S. Interaction Between Modern Radiotherapy and Immunotherapy for Metastatic Prostate Cancer. Front Oncol 2021; 11:744679. [PMID: 34595122 PMCID: PMC8477651 DOI: 10.3389/fonc.2021.744679] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Accepted: 08/24/2021] [Indexed: 12/23/2022] Open
Abstract
Prostate cancer is the most frequently diagnosed cancer in men and a leading cause of cancer-related death. In recent decades, the development of immunotherapies has resulted in great promise to cure metastatic disease. However, prostate cancer has failed to show any significant response, presumably due to its immunosuppressive microenvironment. There is therefore growing interest in combining immunotherapy with other therapies able to relieve the immunosuppressive microenvironment. Radiation therapy remains the mainstay treatment for prostate cancer patients, is known to exhibit immunomodulatory effects, depending on the dose, and is a potent inducer of immunogenic tumor cell death. Optimal doses of radiotherapy are thus expected to unleash the full potential of immunotherapy, improving primary target destruction with further hope of inducing immune-cell-mediated elimination of metastases at distance from the irradiated site. In this review, we summarize the current knowledge on both the tumor immune microenvironment in prostate cancer and the effects of radiotherapy on it, as well as on the use of immunotherapy. In addition, we discuss the utility to combine immunotherapy and radiotherapy to treat oligometastatic metastatic prostate cancer.
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Affiliation(s)
- Luc Ollivier
- Institut de Cancérologie de l'Ouest, Nantes, France.,Université de Nantes, CNRS, Inserm, CRCINA, Nantes, France
| | - Maureen Labbé
- Université de Nantes, CNRS, Inserm, CRCINA, Nantes, France
| | | | - Vincent Potiron
- Institut de Cancérologie de l'Ouest, Nantes, France.,Université de Nantes, CNRS, Inserm, CRCINA, Nantes, France
| | - Stéphane Supiot
- Institut de Cancérologie de l'Ouest, Nantes, France.,Université de Nantes, CNRS, Inserm, CRCINA, Nantes, France
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41
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da Costa VR, Araldi RP, Vigerelli H, D’Ámelio F, Mendes TB, Gonzaga V, Policíquio B, Colozza-Gama GA, Valverde CW, Kerkis I. Exosomes in the Tumor Microenvironment: From Biology to Clinical Applications. Cells 2021; 10:2617. [PMID: 34685596 PMCID: PMC8533895 DOI: 10.3390/cells10102617] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Revised: 08/25/2021] [Accepted: 08/26/2021] [Indexed: 12/12/2022] Open
Abstract
Cancer is one of the most important health problems and the second leading cause of death worldwide. Despite the advances in oncology, cancer heterogeneity remains challenging to therapeutics. This is because the exosome-mediated crosstalk between cancer and non-cancer cells within the tumor microenvironment (TME) contributes to the acquisition of all hallmarks of cancer and leads to the formation of cancer stem cells (CSCs), which exhibit resistance to a range of anticancer drugs. Thus, this review aims to summarize the role of TME-derived exosomes in cancer biology and explore the clinical potential of mesenchymal stem-cell-derived exosomes as a cancer treatment, discussing future prospects of cell-free therapy for cancer treatment and challenges to be overcome.
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Affiliation(s)
- Vitor Rodrigues da Costa
- Programa de Pós-Graduação em Biologia Estrutural e Funcional, Escola Paulista de Medicina (EPM), Federal University of São Paulo (UNIFES), São Paulo 04039-032, Brazil; (V.R.d.C.); (T.B.M.); (G.A.C.-G.)
- Genetics Laboratory, Instituto Butantan, São Paulo 05508-010, Brazil; (H.V.); (F.D.); (V.G.); (B.P.)
| | - Rodrigo Pinheiro Araldi
- Programa de Pós-Graduação em Biologia Estrutural e Funcional, Escola Paulista de Medicina (EPM), Federal University of São Paulo (UNIFES), São Paulo 04039-032, Brazil; (V.R.d.C.); (T.B.M.); (G.A.C.-G.)
- Genetics Laboratory, Instituto Butantan, São Paulo 05508-010, Brazil; (H.V.); (F.D.); (V.G.); (B.P.)
- Cellavita Pesquisas Científicas Ltd.a., Valinhos 13271-650, Brazil;
| | - Hugo Vigerelli
- Genetics Laboratory, Instituto Butantan, São Paulo 05508-010, Brazil; (H.V.); (F.D.); (V.G.); (B.P.)
| | - Fernanda D’Ámelio
- Genetics Laboratory, Instituto Butantan, São Paulo 05508-010, Brazil; (H.V.); (F.D.); (V.G.); (B.P.)
| | - Thais Biude Mendes
- Programa de Pós-Graduação em Biologia Estrutural e Funcional, Escola Paulista de Medicina (EPM), Federal University of São Paulo (UNIFES), São Paulo 04039-032, Brazil; (V.R.d.C.); (T.B.M.); (G.A.C.-G.)
- Genetics Laboratory, Instituto Butantan, São Paulo 05508-010, Brazil; (H.V.); (F.D.); (V.G.); (B.P.)
- Cellavita Pesquisas Científicas Ltd.a., Valinhos 13271-650, Brazil;
| | - Vivian Gonzaga
- Genetics Laboratory, Instituto Butantan, São Paulo 05508-010, Brazil; (H.V.); (F.D.); (V.G.); (B.P.)
- Cellavita Pesquisas Científicas Ltd.a., Valinhos 13271-650, Brazil;
| | - Bruna Policíquio
- Genetics Laboratory, Instituto Butantan, São Paulo 05508-010, Brazil; (H.V.); (F.D.); (V.G.); (B.P.)
- Cellavita Pesquisas Científicas Ltd.a., Valinhos 13271-650, Brazil;
| | - Gabriel Avelar Colozza-Gama
- Programa de Pós-Graduação em Biologia Estrutural e Funcional, Escola Paulista de Medicina (EPM), Federal University of São Paulo (UNIFES), São Paulo 04039-032, Brazil; (V.R.d.C.); (T.B.M.); (G.A.C.-G.)
- Genetic Bases of Thyroid Tumors Laboratory, Division of Genetics, Department of Morphology and Genetics, Federal University of São Paulo (UNIFESP), São Paulo 04039-032, Brazil
| | | | - Irina Kerkis
- Programa de Pós-Graduação em Biologia Estrutural e Funcional, Escola Paulista de Medicina (EPM), Federal University of São Paulo (UNIFES), São Paulo 04039-032, Brazil; (V.R.d.C.); (T.B.M.); (G.A.C.-G.)
- Genetics Laboratory, Instituto Butantan, São Paulo 05508-010, Brazil; (H.V.); (F.D.); (V.G.); (B.P.)
- Cellavita Pesquisas Científicas Ltd.a., Valinhos 13271-650, Brazil;
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Wang L, Li L, Zhu G. Role of Extracellular Vesicles on Cancer Lymphangiogenesis and Lymph Node Metastasis. Front Oncol 2021; 11:721785. [PMID: 34552874 PMCID: PMC8451414 DOI: 10.3389/fonc.2021.721785] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2021] [Accepted: 08/20/2021] [Indexed: 02/05/2023] Open
Abstract
Lymph node metastasis (LNM) of tumors is an established indicator of poor prognosis in patients. Tumor-associated lymphangiogenesis is a key step in LNM and has gained much attention. However, currently, there is no anti-tumor lymphangiogenesis drug used in clinical practice. Recently, studies on extracellular vesicles (EVs) have shown that different types of cells in the tumor microenvironment can release EVs that encapsulate a variety of molecules, including proteins, nucleic acids, and metabolites. Lymph endothelial cells (LECs) regulate tumor lymphangiogenesis through the uptake of EVs packed with different biologically active contents. In this review, we will discuss the possible mechanisms by which EVs participate in the regulation of tumor-associated lymphangiogenesis and LNM, summarize the potential value of EVs that can be used as biomarkers for the determination of tumor LNM, and indicate the potential anti-tumor lymphangiogenesis therapy.
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Affiliation(s)
- Linlin Wang
- Department of Stomatology, Sichuan Cancer Hospital, Sichuan Key Laboratory of Radiation Oncology, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Ling Li
- Department of Stomatology, Sichuan Cancer Hospital, Sichuan Key Laboratory of Radiation Oncology, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Guiquan Zhu
- State Key Laboratory of Oral Diseases, National Clinical Research Centre for Oral Diseases, Department of Head and Neck Oncology, West China Hospital of Stomatology, Sichuan University, Chengdu, China
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Müller CSL, Müller SG, Vogt T, Pföhler C. Current concepts of ectopic nodal inclusions with special emphasis on nodal nevi. J Dtsch Dermatol Ges 2021; 19:1145-1157. [PMID: 34390159 DOI: 10.1111/ddg.14521] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Accepted: 03/18/2021] [Indexed: 11/29/2022]
Abstract
Nodal inclusions of ectopic tissue within lymph nodes are seen comparatively often in dermatopathology and general pathology. Glandular and nonglandular epithelium, as well as melanocytic nevi can be observed within lymph nodes and represent mostly incidental findings without any relevance. The main challenge in reporting these morphologic features is to differentiate such benign inclusions from metastatic settlements of distinct organ tumors. As sentinel node biopsy and lymph node dissection have become standard procedure in clinical oncology and have an immense clinical impact, the correct evaluation of these nodal inclusions is indispensable to avoid undertreatment or overtreatment of patients. In addition, the genesis of these inclusions has not yet been satisfactorily clarified. Two concepts have been laid out: the theory of benign metastases and the migration arrest theory. However, neither theory has so far been able to answer the following questions: Why do we find more nodal nevi in patients with melanoma who had a sentinel node biopsy than in patients without melanoma, and why do we not find nodal nevi in deep visceral lymph nodes? We present a comprehensive review of the current knowledge on nodal inclusions, proposing a concept for the pathogenesis of nodal nevi, to answer these questions.
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Affiliation(s)
- Cornelia Sigrid Lissi Müller
- Medical supply center for Histology, Cytology, and Molecular diagnostics Trier GmbH, Wissenschaftspark Trier, TRIER, Germany
| | - Stephan G Müller
- Department of General-, Visceral-, Vascular- and Pediatric Surgery, Saarland University Medical Center, Homburg/Saar, Germany
| | - Thomas Vogt
- Department of Dermatology, Allergology, and Venerology, Saarland University Medical Center, Homburg/Saar, Germany
| | - Claudia Pföhler
- Department of Dermatology, Allergology, and Venerology, Saarland University Medical Center, Homburg/Saar, Germany
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Müller CSL, Müller SG, Vogt T, Pföhler C. Aktuelle Konzepte zu ektopen Lymphknoten‐Einschlüssen unter besonderer Berücksichtigung nodaler Nävi. J Dtsch Dermatol Ges 2021; 19:1145-1158. [PMID: 34390137 DOI: 10.1111/ddg.14521_g] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Accepted: 03/18/2021] [Indexed: 11/28/2022]
Affiliation(s)
| | - Stephan G Müller
- Klinik für allgemeine Chirurgie, Viszeral-, Gefäß- und Kinderchirurgie, Universitätsklinikum des Saarlandes, Homburg/Saar
| | - Thomas Vogt
- Klinik für Dermatologie, Allergologie und Venerologie, Universitätsklinikum des Saarlandes, Homburg/Saar
| | - Claudia Pföhler
- Klinik für Dermatologie, Allergologie und Venerologie, Universitätsklinikum des Saarlandes, Homburg/Saar
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45
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Olmeda D, Cerezo-Wallis D, Castellano-Sanz E, García-Silva S, Peinado H, Soengas MS. Physiological models for in vivo imaging and targeting the lymphatic system: Nanoparticles and extracellular vesicles. Adv Drug Deliv Rev 2021; 175:113833. [PMID: 34147531 DOI: 10.1016/j.addr.2021.113833] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Revised: 05/24/2021] [Accepted: 06/11/2021] [Indexed: 02/06/2023]
Abstract
Imaging of the lymphatic vasculature has gained great attention in various fields, not only because lymphatic vessels act as a key draining system in the body, but also for their implication in autoimmune diseases, organ transplant, inflammation and cancer. Thus, neolymphangiogenesis, or the generation of new lymphatics, is typically an early event in the development of multiple tumor types, particularly in aggressive ones such as malignant melanoma. Still, the understanding of how lymphatic endothelial cells get activated at distal (pre)metastatic niches and their impact on therapy is still unclear. Addressing these questions is of particular interest in the case of immune modulators, because endothelial cells may favor or halt inflammatory processes depending on the cellular context. Therefore, there is great interest in visualizing the lymphatic vasculature in vivo. Here, we review imaging tools and mouse models used to analyze the lymphatic vasculature during tumor progression. We also discuss therapeutic approaches based on nanomedicines to target the lymphatic system and the potential use of extracellular vesicles to track and target sentinel lymph nodes. Finally, we summarize main pre-clinical models developed to visualize the lymphatic vasculature in vivo, discussing their applications with a particular focus in metastatic melanoma.
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Affiliation(s)
- David Olmeda
- Melanoma Laboratory, Molecular Oncology Programme, Spanish National Cancer Research Center (CNIO), Madrid, Spain
| | - Daniela Cerezo-Wallis
- Melanoma Laboratory, Molecular Oncology Programme, Spanish National Cancer Research Center (CNIO), Madrid, Spain; Area of Cell & Developmental Biology, Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, 28029, Spain
| | - Elena Castellano-Sanz
- Microenvironment and Metastasis Laboratory, Molecular Oncology Programme, Spanish National Cancer Research Center (CNIO), Madrid, Spain
| | - Susana García-Silva
- Microenvironment and Metastasis Laboratory, Molecular Oncology Programme, Spanish National Cancer Research Center (CNIO), Madrid, Spain
| | - Héctor Peinado
- Microenvironment and Metastasis Laboratory, Molecular Oncology Programme, Spanish National Cancer Research Center (CNIO), Madrid, Spain.
| | - María S Soengas
- Melanoma Laboratory, Molecular Oncology Programme, Spanish National Cancer Research Center (CNIO), Madrid, Spain.
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Wutschka J, Kast B, Sator-Schmitt M, Appak-Baskoy S, Hess J, Sinn HP, Angel P, Schorpp-Kistner M. JUNB suppresses distant metastasis by influencing the initial metastatic stage. Clin Exp Metastasis 2021; 38:411-423. [PMID: 34282521 PMCID: PMC8318945 DOI: 10.1007/s10585-021-10108-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Accepted: 06/23/2021] [Indexed: 01/01/2023]
Abstract
The complex interactions between cells of the tumor microenvironment and cancer cells are considered a major determinant of cancer progression and metastasis. Yet, our understanding of the mechanisms of metastatic disease is not sufficient to successfully treat patients with advanced-stage cancer. JUNB is a member of the AP-1 transcription factor family shown to be frequently deregulated in human cancer and associated with invasion and metastasis. A strikingly high stromal JUNB expression in human breast cancer samples prompted us to functionally investigate the consequences of JUNB loss in cells of the tumor microenvironment on cancer progression and metastasis in mice. To adequately mimic the clinical situation, we applied a syngeneic spontaneous breast cancer metastasis model followed by primary tumor resection and identified stromal JUNB as a potent suppressor of distant metastasis. Comprehensive characterization of the JUNB-deficient tumor microenvironment revealed a strong influx of myeloid cells into primary breast tumors and lungs at early metastatic stage. In these infiltrating neutrophils, BV8 and MMP9, proteins promoting angiogenesis and tissue remodeling, were specifically upregulated in a JUNB-dependent manner. Taken together, we established stromal JUNB as a strong suppressor of distant metastasis. Consequently, therapeutic strategies targeting AP-1 should be carefully designed not to interfere with stromal JUNB expression as this may be detrimental for cancer patients.
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Affiliation(s)
- Juliane Wutschka
- Division of Signal Transduction and Growth Control, DKFZ-ZMBH Alliance, Im Neuenheimer Feld 280, 69120, Heidelberg, Germany
- Faculty of Biosciences, University Heidelberg, Heidelberg, Germany
| | - Bettina Kast
- Division of Signal Transduction and Growth Control, DKFZ-ZMBH Alliance, Im Neuenheimer Feld 280, 69120, Heidelberg, Germany
| | - Melanie Sator-Schmitt
- Division of Signal Transduction and Growth Control, DKFZ-ZMBH Alliance, Im Neuenheimer Feld 280, 69120, Heidelberg, Germany
| | - Sila Appak-Baskoy
- Division of Signal Transduction and Growth Control, DKFZ-ZMBH Alliance, Im Neuenheimer Feld 280, 69120, Heidelberg, Germany
- Department of Chemistry and Biology, Ryerson University, Toronto, ON, Canada
- iBEST (Institute of Biomedical Engineering, Science and Technology), Toronto, ON, Canada
| | - Jochen Hess
- Department of Otorhinolaryngology, Head and Neck Surgery, Heidelberg University Hospital, Heidelberg, Germany
- Research Group Molecular Mechanisms of Head and Neck Tumors, DKFZ, Heidelberg, Germany
| | - Hans-Peter Sinn
- Institute of Pathology, University of Heidelberg, Heidelberg, Germany
| | - Peter Angel
- Division of Signal Transduction and Growth Control, DKFZ-ZMBH Alliance, Im Neuenheimer Feld 280, 69120, Heidelberg, Germany
| | - Marina Schorpp-Kistner
- Division of Signal Transduction and Growth Control, DKFZ-ZMBH Alliance, Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.
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Tumor Immune Microenvironment Characterization of Primary Lung Adenocarcinoma and Lymph Node Metastases. BIOMED RESEARCH INTERNATIONAL 2021; 2021:5557649. [PMID: 34337026 PMCID: PMC8292094 DOI: 10.1155/2021/5557649] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Revised: 04/29/2021] [Accepted: 06/23/2021] [Indexed: 11/24/2022]
Abstract
Background The essential roles of the tumor microenvironment (TME) have been recognized during the initiation and progression of primary lung adenocarcinoma (LUAD). The aim of the present study was to delineate the immune landscape in both primary cancer and matched lymph node metastasis from a cohort of locally advanced stage LUAD patients with distinct outcomes. Methods Formalin-fixed, paraffin-embedded samples were collected from 36 locally advanced LUAD patients. Transcriptome data of the tumor immune microenvironment were resolved using an immune oncology panel RNA sequencing platform. Bioinformatics approaches were used to determine the differentially expressed genes (DEGs), dysregulated pathways, and immune cell fraction between patients with early recurrence (ER) and late recurrence (LR). Results Here, we showed that in primary cancer tissues, 23 DEGs were obtained between patients with ER and LR. Functional analysis revealed that the LR in LUAD patients may be associated with enriched gene sets belonging to the antigen presentation and MHC protein complex, innate immune response, and IFN-γ signaling pathways. Next, the transcriptome data were adopted to quantify immune cell fractions, indicating that high infiltration of mast cells and neutrophils was correlated with ER. Interestingly, similar findings were observed in metastatic lymph nodes from patients suffering from ER or LR. By analyzing the shared immune features of primary cancers and lymphatic metastases, we unraveled the prognostic value and joint utility of two DEGs, CORO1A and S100A8. Conclusions In LUAD, the enrichment in antigen presentation, MHC protein complex, and IFN-γ signaling, and low infiltration of neutrophils in primary or metastatic nodules may be indications for a favorable prognosis. Integrated with bioinformatics approaches, transcriptome data of immune-related genes from formalin-fixed, paraffin-embedded (FFPE) samples can effectively profile the landscape of the tumor immune microenvironment and help predict clinical outcomes.
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48
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Inactivation of EMILIN-1 by Proteolysis and Secretion in Small Extracellular Vesicles Favors Melanoma Progression and Metastasis. Int J Mol Sci 2021; 22:ijms22147406. [PMID: 34299025 PMCID: PMC8303474 DOI: 10.3390/ijms22147406] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Revised: 06/17/2021] [Accepted: 06/23/2021] [Indexed: 12/21/2022] Open
Abstract
Several studies have demonstrated that melanoma-derived extracellular vesicles (EVs) are involved in lymph node metastasis; however, the molecular mechanisms involved are not completely defined. Here, we found that EMILIN-1 is proteolyzed and secreted in small EVs (sEVs) as a novel mechanism to reduce its intracellular levels favoring metastasis in mouse melanoma lymph node metastatic cells. Interestingly, we observed that EMILIN-1 has intrinsic tumor and metastasis suppressive-like properties reducing effective migration, cell viability, primary tumor growth, and metastasis. Overall, our analysis suggests that the inactivation of EMILIN-1 by proteolysis and secretion in sEVs reduce its intrinsic tumor suppressive activities in melanoma favoring tumor progression and metastasis.
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Gillot L, Baudin L, Rouaud L, Kridelka F, Noël A. The pre-metastatic niche in lymph nodes: formation and characteristics. Cell Mol Life Sci 2021; 78:5987-6002. [PMID: 34241649 PMCID: PMC8316194 DOI: 10.1007/s00018-021-03873-z] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Revised: 05/10/2021] [Accepted: 06/05/2021] [Indexed: 02/06/2023]
Abstract
Lymph node metastasis is a crucial prognostic parameter in many different types of cancers and a gateway for further dissemination to distant organs. Prior to metastatic dissemination, the primary tumor prepares for the remodeling of the draining (sentinel) lymph node by secreting soluble factors or releasing extracellular vesicles that are transported by lymphatic vessels. These important changes occur before the appearance of the first metastatic cell and create what is known as a pre-metastatic niche giving rise to the subsequent survival and growth of metastatic cells. In this review, the lymph node structure, matrix composition and the emerging heterogeneity of cells forming it are described. Current knowledge of the major cellular and molecular processes associated with nodal pre-metastatic niche formation, including lymphangiogenesis, extracellular matrix remodeling, and immunosuppressive cell enlisting in lymph nodes are additionally summarized. Finally, future directions that research could possibly take and the clinical impact are discussed.
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Affiliation(s)
- Lionel Gillot
- Laboratory of Tumor and Development Biology, GIGA-Cancer, Liege University, Avenue Hippocrate 13, 4000 Liege, Belgium
| | - Louis Baudin
- Laboratory of Tumor and Development Biology, GIGA-Cancer, Liege University, Avenue Hippocrate 13, 4000 Liege, Belgium
| | - Loïc Rouaud
- Laboratory of Tumor and Development Biology, GIGA-Cancer, Liege University, Avenue Hippocrate 13, 4000 Liege, Belgium
| | - Frédéric Kridelka
- Department of Obstetrics and Gynecology, CHU of Liege, 4000 Liege, Belgium
| | - Agnès Noël
- Laboratory of Tumor and Development Biology, GIGA-Cancer, Liege University, Avenue Hippocrate 13, 4000 Liege, Belgium
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50
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Li M, Xian HC, Tang YJ, Liang XH, Tang YL. Fatty acid oxidation: driver of lymph node metastasis. Cancer Cell Int 2021; 21:339. [PMID: 34217300 PMCID: PMC8254237 DOI: 10.1186/s12935-021-02057-w] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Accepted: 06/27/2021] [Indexed: 02/08/2023] Open
Abstract
Fatty acid oxidation (FAO) is the emerging hallmark of cancer metabolism because certain tumor cells preferentially utilize fatty acids for energy. Lymph node metastasis, the most common way of tumor metastasis, is much indispensable for grasping tumor progression, formulating therapy measure and evaluating tumor prognosis. There is a plethora of studies showing different ways how tumor cells metastasize to the lymph nodes, but the role of FAO in lymph node metastasis remains largely unknown. Here, we summarize recent findings and update the current understanding that FAO may enable lymph node metastasis formation. Afterward, it will open innovative possibilities to present a distinct therapy of targeting FAO, the metabolic rewiring of cancer to terminal cancer patients.
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Affiliation(s)
- Mao Li
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, Department of Oral Pathology, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Hong-Chun Xian
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, Department of Oral Pathology, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Ya-Jie Tang
- State Key Laboratory of Microbial Technology, Shandong University, Qingdao, 266237, China.
| | - Xin-Hua Liang
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
| | - Ya-Ling Tang
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, Department of Oral Pathology, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
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