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Jin L, Qin Y, Zhao Y, Zhou X, Zeng Y. Endothelial cytoskeleton in mechanotransduction and vascular diseases. J Biomech 2025; 182:112579. [PMID: 39938443 DOI: 10.1016/j.jbiomech.2025.112579] [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: 11/27/2024] [Revised: 02/04/2025] [Accepted: 02/05/2025] [Indexed: 02/14/2025]
Abstract
The cytoskeleton is an important structural component that regulates various aspects of cell morphology, movement, and intracellular signaling. It plays a pivotal role in the cellular response to biomechanical stimuli, particularly in endothelial cells, which are critical for vascular homeostasis and the pathogenesis of cardiovascular diseases. Mechanical forces, such as shear and tension, activate intracellular signaling cascades that regulate transcription, translation, and cellular behaviors. Despite extensive research into cytoskeletal functions, the precise mechanisms by which the cytoskeleton transduces mechanical signals remain incompletely understood. This review focuses on the role of cytoskeletal components in membrane, cytoplasm, and nucleus in mechanotransduction, with an emphasis on their structure, mechanical and biological behaviors, dynamic interactions, and response to mechanical forces. The collaboration between membrane cytoskeleton, cytoplasmic cytoskeleton, and nucleoskeleton is indispensable for endothelial cells to respond to mechanical stimuli. Understanding their mechanoresponsive mechanisms is essential for advancing therapeutic strategies for cardiovascular diseases.
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Affiliation(s)
- Linlu Jin
- Institute of Biomedical Engineering, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu 610041 Sichuan, China
| | - Yixue Qin
- Institute of Biomedical Engineering, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu 610041 Sichuan, China
| | - Yunran Zhao
- Institute of Biomedical Engineering, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu 610041 Sichuan, China
| | - Xintong Zhou
- Institute of Biomedical Engineering, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu 610041 Sichuan, China
| | - Ye Zeng
- Institute of Biomedical Engineering, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu 610041 Sichuan, China.
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2
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Woo W, Park B, Ahadi A, Chung LIY, Jung CM, Bharat A, Chae YK. The Role of Pulmonary Metastasectomy for Non-Primary Lung Cancer: Umbrella Review of Meta-Analyses. J Surg Oncol 2024. [PMID: 39674949 DOI: 10.1002/jso.28033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2024] [Accepted: 11/16/2024] [Indexed: 12/17/2024]
Abstract
BACKGROUND AND OBJECTIVES Due to heterogeneous characteristics of primary cancers, the efficacy of pulmonary metastasectomy (PM) in nonprimary lung cancers has not been investigated. This study aims to investigate the clinical outcomes of PM for non-primary lung cancer. METHODS A systematic search for meta-analyses on PM for nonprimary lung cancers was conducted, encompassing publications up to January 3, 2024. This included seven primary cancers: renal cell, breast, adrenocortical, head and neck cancers, melanoma, germ cell tumors, and sarcoma. Overall survival and recurrence rates post-PM were assessed using random-effect models. RESULTS This study included 16 systematic-review articles and 101 individual studies, involving 10 277 patients who underwent PM for nonprimary lung cancer. About half of the patients (47.1%) presented with multiple metastasis, and complete resection achieved in 87.2% [95% CI: 83.0-90.8]. The pooled 5-year overall survival rate post-PM was 41.2% [95%CI: 37.1%-45.4%]. Patients with germ cell tumors demonstrated higher survival rate (p < 0.05), while melanoma exhibited the worst outcome (p < 0.05). During follow-up, 57.6% [95% CI: 46.4-68.1] had recurrence; 48% of them had intrathoracic-only recurrence. CONCLUSION This study underscores the survival benefits associated with PM. Overall survival rates following PM did not differ based on primary cancer types. These findings highlight the importance of recognizing and incorporating PM into clinical practice when appropriate.
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Affiliation(s)
- Wongi Woo
- Department of Internal Medicine, Dignity Health St. Joseph Medical Center Stockton, Stockton, California, USA
| | - Brandon Park
- University of Missouri-Kansas City School of Medicine, Kansas City, Missouri, USA
| | - Awranoos Ahadi
- Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Liam Il-Young Chung
- Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Chan Mi Jung
- Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Ankit Bharat
- Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Young Kwang Chae
- Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
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3
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Dupas A, Goetz JG, Osmani N. Extravasation of immune and tumor cells from an endothelial perspective. J Cell Sci 2024; 137:jcs262066. [PMID: 39530179 DOI: 10.1242/jcs.262066] [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] [Indexed: 11/16/2024] Open
Abstract
Crossing the vascular endothelium is a necessary stage for circulating cells aiming to reach distant organs. Leukocyte passage through the endothelium, known as transmigration, is a multistep process during which immune cells adhere to the vascular wall, migrate and crawl along the endothelium until they reach their exit site. Similarly, circulating tumor cells (CTCs), which originate from the primary tumor or reseed from early metastatic sites, disseminate using the blood circulation and also must cross the endothelial barrier to set new colonies in distant organs. CTCs are thought to mimic arrest and extravasation utilized by leukocytes; however, their extravasation also requires processes that, from an endothelial perspective, are specific to cancer cells. Although leukocyte extravasation relies on maintaining endothelial impermeability, it appears that cancer cells can indoctrinate endothelial cells into promoting their extravasation independently of their normal functions. In this Review, we summarize the common and divergent mechanisms of endothelial responses during extravasation of leukocytes (in inflammation) and CTCs (in metastasis), and highlight how these might be leveraged in the development of anti-metastatic treatments.
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Affiliation(s)
- Amandine Dupas
- Tumor Biomechanics lab, INSERM UMR_S 1109, CRBS, 1 rue Eugène Boeckel, CS 60026, 67084 Strasbourg Cedex, France
- Université de Strasbourg, Strasbourg, F-67000, France
- Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, F-67000, France
- Equipe Labellisée Ligue Contre le Cancer, France
| | - Jacky G Goetz
- Tumor Biomechanics lab, INSERM UMR_S 1109, CRBS, 1 rue Eugène Boeckel, CS 60026, 67084 Strasbourg Cedex, France
- Université de Strasbourg, Strasbourg, F-67000, France
- Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, F-67000, France
- Equipe Labellisée Ligue Contre le Cancer, France
| | - Naël Osmani
- Tumor Biomechanics lab, INSERM UMR_S 1109, CRBS, 1 rue Eugène Boeckel, CS 60026, 67084 Strasbourg Cedex, France
- Université de Strasbourg, Strasbourg, F-67000, France
- Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, F-67000, France
- Equipe Labellisée Ligue Contre le Cancer, France
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Zhan L, Edd J, Mishra A, Toner M. Label-Free Microfluidic Apheresis of Circulating Tumor Cell Clusters. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2405853. [PMID: 39199012 PMCID: PMC11515904 DOI: 10.1002/advs.202405853] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Revised: 07/17/2024] [Indexed: 09/01/2024]
Abstract
Screening liters of blood (i.e., apheresis) represents a generalized approach to promote the reliable access to circulating tumor cell clusters (CTCCs), which are known to be highly metastasis-competent, yet ultrarare. However, no existing CTCC sorting technology has demonstrated high throughput, high yield, low shear stress, and minimal blood dilution simultaneously as required in apheresis. Here, a label-free method is introduced termed Precision Apheresis for Non-invasive Debulking of cell Aggregates (PANDA) to continuously isolate CTCCs from undiluted blood to clean buffer through size sorting, processing 1.4 billion cells per second. The cell focusing is optimized within whole blood leveraging secondary transverse flow and margination. The PANDA chip recovers >90% of spiked ≈24 rare HeLa cell clusters from 100 mL undiluted blood samples (equivalent to ≈500 billion blood cells) at 1 L h-1 throughput, with ≤20s device residence time, ≤15 Pa shear stress, and >99.9% return of blood components. The technology lays the groundwork for future routine isolation to increase the recovery of these ultrarare yet clinically significant tumor cell populations from large volumes of blood to advance cancer research, early detection, and treatment.
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Affiliation(s)
- Li Zhan
- Center for Engineering in Medicine and SurgeryMassachusetts General HospitalBostonMA02129USA
- Harvard Medical SchoolBostonMA02115USA
| | - Jon Edd
- Center for Engineering in Medicine and SurgeryMassachusetts General HospitalBostonMA02129USA
- Cancer CenterMassachusetts General HospitalBostonMA12129USA
| | - Avanish Mishra
- Center for Engineering in Medicine and SurgeryMassachusetts General HospitalBostonMA02129USA
- Harvard Medical SchoolBostonMA02115USA
- Cancer CenterMassachusetts General HospitalBostonMA12129USA
| | - Mehmet Toner
- Center for Engineering in Medicine and SurgeryMassachusetts General HospitalBostonMA02129USA
- Harvard Medical SchoolBostonMA02115USA
- Shriners Hospitals for ChildrenBostonMA02114USA
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5
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Perea Paizal J, Au SH, Bakal C. Nuclear rupture induced by capillary constriction forces promotes differential effects on metastatic and normal breast cells. Sci Rep 2024; 14:14793. [PMID: 38926422 PMCID: PMC11208511 DOI: 10.1038/s41598-024-64733-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: 10/26/2023] [Accepted: 06/12/2024] [Indexed: 06/28/2024] Open
Abstract
During metastatic dissemination, circulating tumour cells (CTCs) enter capillary beds, where they experience mechanical constriction forces. The transient and persistent effects of these forces on CTCs behaviour remain poorly understood. Here, we developed a high-throughput microfluidic platform mimicking human capillaries to investigate the impact of mechanical constriction forces on malignant and normal breast cell lines. We observed that capillary constrictions induced nuclear envelope rupture in both cancer and normal cells, leading to transient changes in nuclear and cytoplasmic area. Constriction forces transiently activated cGAS/STING and pathways involved in inflammation (NF-κB, STAT and IRF3), especially in the non-malignant cell line. Furthermore, the non-malignant cell line experienced transcriptional changes, particularly downregulation of epithelial markers, while the metastatic cell lines showed minimal alterations. These findings suggest that mechanical constriction forces within capillaries may promote differential effects in malignant and normal cell lines.
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Affiliation(s)
- Julia Perea Paizal
- Department of Bioengineering, Imperial College London, London, SW7 2AZ, UK.
- Division of Cancer Biology, Chester Beatty Laboratories, Institute of Cancer Research, 237 Fulham Road, London, SW6 6JB, UK.
- Cancer Research UK Convergence Science Centre, Roderic Hill Building, Imperial College London, London, SW7 2BB, UK.
| | - Sam H Au
- Department of Bioengineering, Imperial College London, London, SW7 2AZ, UK
- Cancer Research UK Convergence Science Centre, Roderic Hill Building, Imperial College London, London, SW7 2BB, UK
| | - Chris Bakal
- Division of Cancer Biology, Chester Beatty Laboratories, Institute of Cancer Research, 237 Fulham Road, London, SW6 6JB, UK
- Cancer Research UK Convergence Science Centre, Roderic Hill Building, Imperial College London, London, SW7 2BB, UK
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Pan Y, Cheng J, Zhu Y, Zhang J, Fan W, Chen X. Immunological nanomaterials to combat cancer metastasis. Chem Soc Rev 2024; 53:6399-6444. [PMID: 38745455 DOI: 10.1039/d2cs00968d] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/16/2024]
Abstract
Metastasis causes greater than 90% of cancer-associated deaths, presenting huge challenges for detection and efficient treatment of cancer due to its high heterogeneity and widespread dissemination to various organs. Therefore, it is imperative to combat cancer metastasis, which is the key to achieving complete cancer eradication. Immunotherapy as a systemic approach has shown promising potential to combat metastasis. However, current clinical immunotherapies are not effective for all patients or all types of cancer metastases owing to insufficient immune responses. In recent years, immunological nanomaterials with intrinsic immunogenicity or immunomodulatory agents with efficient loading have been shown to enhance immune responses to eliminate metastasis. In this review, we would like to summarize various types of immunological nanomaterials against metastasis. Moreover, this review will summarize a series of immunological nanomaterial-mediated immunotherapy strategies to combat metastasis, including immunogenic cell death, regulation of chemokines and cytokines, improving the immunosuppressive tumour microenvironment, activation of the STING pathway, enhancing cytotoxic natural killer cell activity, enhancing antigen presentation of dendritic cells, and enhancing chimeric antigen receptor T cell therapy. Furthermore, the synergistic anti-metastasis strategies based on the combinational use of immunotherapy and other therapeutic modalities will also be introduced. In addition, the nanomaterial-mediated imaging techniques (e.g., optical imaging, magnetic resonance imaging, computed tomography, photoacoustic imaging, surface-enhanced Raman scattering, radionuclide imaging, etc.) for detecting metastasis and monitoring anti-metastasis efficacy are also summarized. Finally, the current challenges and future prospects of immunological nanomaterial-based anti-metastasis are also elucidated with the intention to accelerate its clinical translation.
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Affiliation(s)
- Yuanbo Pan
- Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009, China.
- Key Laboratory of Precise Treatment and Clinical Translational Research of Neurological Diseases, Hangzhou, 310009, Zhejiang, China
- Clinical Research Center for Neurological Diseases of Zhejiang Province, Hangzhou, 310009, China
- Departments of Diagnostic Radiology, Surgery, Chemical and Biomolecular Engineering, and Biomedical Engineering, Yong Loo Lin School of Medicine and College of Design and Engineering, National University of Singapore, Singapore 119074, Singapore.
- Nanomedicine Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore
| | - Junjie Cheng
- Department of Radiology, Zhongda Hospital, Medical School, Southeast University, Nanjing, 210009, China
- Departments of Diagnostic Radiology, Surgery, Chemical and Biomolecular Engineering, and Biomedical Engineering, Yong Loo Lin School of Medicine and College of Design and Engineering, National University of Singapore, Singapore 119074, Singapore.
- Nanomedicine Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore
| | - Yang Zhu
- Department of Neurosurgery, Neurosurgery Research Institute, The First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, Fujian, China.
- Departments of Diagnostic Radiology, Surgery, Chemical and Biomolecular Engineering, and Biomedical Engineering, Yong Loo Lin School of Medicine and College of Design and Engineering, National University of Singapore, Singapore 119074, Singapore.
- Nanomedicine Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore
| | - Jianmin Zhang
- Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009, China.
- Key Laboratory of Precise Treatment and Clinical Translational Research of Neurological Diseases, Hangzhou, 310009, Zhejiang, China
- Clinical Research Center for Neurological Diseases of Zhejiang Province, Hangzhou, 310009, China
| | - Wenpei Fan
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, China Pharmaceutical University, Nanjing, 211198, China.
| | - Xiaoyuan Chen
- Departments of Diagnostic Radiology, Surgery, Chemical and Biomolecular Engineering, and Biomedical Engineering, Yong Loo Lin School of Medicine and College of Design and Engineering, National University of Singapore, Singapore 119074, Singapore.
- Clinical Imaging Research Centre, Centre for Translational Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117599, Singapore
- Nanomedicine Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore
- Institute of Molecular and Cell Biology, Agency for Science, Technology, and Research (A*STAR), 61 Biopolis Drive, Proteos, Singapore, 138673, Singapore
- Theranostics Center of Excellence (TCE), Yong Loo Lin School of Medicine, National University of Singapore, 11 Biopolis Way, Helios, Singapore 138667, Singapore
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Wei YJ, Wei X, Zhang X, Wu CX, Cai JY, Chen ML, Wang JH. A hydrodynamic-based dual-function microfluidic chip for high throughput discriminating tumor cells. Talanta 2024; 273:125884. [PMID: 38508128 DOI: 10.1016/j.talanta.2024.125884] [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: 10/25/2023] [Revised: 02/26/2024] [Accepted: 03/06/2024] [Indexed: 03/22/2024]
Abstract
A hydrodynamic-based microfluidic chip consisted of two function units that could not only separate tumor cells (TCs) from whole blood but also remove residual blood cells was designed. The separation of TCs was achieved by a straight contraction-expansion array (CEA) microchannel on the front end of the chip. The addition of contractive structure brought a micro-vortex like Dean vortex that promoted cell focusing in the channel, while when cells entered the dilated region, the wall-induced lift force generated by the channel wall gave cells a push away from the wall. As the wall-induced lift force is proportional to the third power of the cell diameter, TCs with larger diameter will have a larger lateral migration under the wall-induced lift force, realizing the separation of TCs from blood sample. Fluorescent particles with diameters of 19.3 μm and 4.5 μm were used to simulate TCs and red blood cells, respectively, to verify the separation capacity of the proposed CEA microchannel for particles with different diameter. And a separation efficiency 98.7% for 19.3 μm particles and a removal rate 96.2% for 4.5 μm particles was observed at sample flow rate of 10 μL min-1 and sheath flow rate of 190 μL min-1. In addition, a separation efficiency about 96.1% for MCF-7 cells (stained with DiI) and removal rates of 96.2% for red blood cells (RBCs) and 98.7% for white blood cells (WBCs) were also obtained under the same condition. However, on account of the large number of blood cells in the blood, there will be a large number of blood cells remained in the isolated TCs, so a purification unit based on hydrodynamic filtration (HDF) was added after the separation microchannel. The purification channel is a size-dictated cell filter that can remove residual blood cells but retain TCs, thus achieving the purification of TCs. Combined the CEA microchannel and the purifier, the microchip facilitates sorting of MCF-7 cells from whole blood with a separation rate about 95.3% and a removal rate over 99.99% for blood cells at a sample flow rate of 10 μL min-1, sheath flow rate of 190 μL min-1 and washing flow rate of 63 μL min-1.
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Affiliation(s)
- Yu-Jia Wei
- Research Center for Analytical Sciences, Department of Chemistry, College of Sciences, Northeastern University, Box 332, Shenyang, 110819, China
| | - Xing Wei
- Research Center for Analytical Sciences, Department of Chemistry, College of Sciences, Northeastern University, Box 332, Shenyang, 110819, China
| | - Xuan Zhang
- Research Center for Analytical Sciences, Department of Chemistry, College of Sciences, Northeastern University, Box 332, Shenyang, 110819, China
| | - Cheng-Xing Wu
- Research Center for Analytical Sciences, Department of Chemistry, College of Sciences, Northeastern University, Box 332, Shenyang, 110819, China
| | - Ji-Ying Cai
- Research Center for Analytical Sciences, Department of Chemistry, College of Sciences, Northeastern University, Box 332, Shenyang, 110819, China
| | - Ming-Li Chen
- Research Center for Analytical Sciences, Department of Chemistry, College of Sciences, Northeastern University, Box 332, Shenyang, 110819, China.
| | - Jian-Hua Wang
- Research Center for Analytical Sciences, Department of Chemistry, College of Sciences, Northeastern University, Box 332, Shenyang, 110819, China.
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8
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Jakab M, Lee KH, Uvarovskii A, Ovchinnikova S, Kulkarni SR, Jakab S, Rostalski T, Spegg C, Anders S, Augustin HG. Lung endothelium exploits susceptible tumor cell states to instruct metastatic latency. NATURE CANCER 2024; 5:716-730. [PMID: 38308117 PMCID: PMC11136671 DOI: 10.1038/s43018-023-00716-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Accepted: 12/15/2023] [Indexed: 02/04/2024]
Abstract
In metastasis, cancer cells travel around the circulation to colonize distant sites. Due to the rarity of these events, the immediate fates of metastasizing tumor cells (mTCs) are poorly understood while the role of the endothelium as a dissemination interface remains elusive. Using a newly developed combinatorial mTC enrichment approach, we provide a transcriptional blueprint of the early colonization process. Following their arrest at the metastatic site, mTCs were found to either proliferate intravascularly or extravasate, thereby establishing metastatic latency. Endothelial-derived angiocrine Wnt factors drive this bifurcation, instructing mTCs to follow the extravasation-latency route. Surprisingly, mTC responsiveness towards niche-derived Wnt was established at the epigenetic level, which predetermined tumor cell behavior. Whereas hypomethylation enabled high Wnt activity leading to metastatic latency, methylated mTCs exhibited low activity and proliferated intravascularly. Collectively the data identify the predetermined methylation status of disseminated tumor cells as a key regulator of mTC behavior in the metastatic niche.
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Affiliation(s)
- Moritz Jakab
- European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany.
- Division of Vascular Oncology and Metastasis, German Cancer Research Center Heidelberg (DKFZ-ZMBH Alliance), Heidelberg, Germany.
- Faculty of Biosciences, Heidelberg University, Heidelberg, Germany.
| | - Ki Hong Lee
- European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany
- Division of Vascular Oncology and Metastasis, German Cancer Research Center Heidelberg (DKFZ-ZMBH Alliance), Heidelberg, Germany
- Faculty of Biosciences, Heidelberg University, Heidelberg, Germany
| | - Alexey Uvarovskii
- Center for Molecular Biology, Heidelberg University, Heidelberg, Germany
- Evotec SE, Göttingen, Germany
| | - Svetlana Ovchinnikova
- Center for Molecular Biology, Heidelberg University, Heidelberg, Germany
- Bioquant Center, Heidelberg University, Heidelberg, Germany
| | - Shubhada R Kulkarni
- European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany
- Division of Vascular Oncology and Metastasis, German Cancer Research Center Heidelberg (DKFZ-ZMBH Alliance), Heidelberg, Germany
| | - Sevinç Jakab
- Faculty of Biosciences, Heidelberg University, Heidelberg, Germany
| | - Till Rostalski
- European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany
- Division of Vascular Oncology and Metastasis, German Cancer Research Center Heidelberg (DKFZ-ZMBH Alliance), Heidelberg, Germany
| | - Carleen Spegg
- Division of Vascular Oncology and Metastasis, German Cancer Research Center Heidelberg (DKFZ-ZMBH Alliance), Heidelberg, Germany
| | - Simon Anders
- Center for Molecular Biology, Heidelberg University, Heidelberg, Germany
- Bioquant Center, Heidelberg University, Heidelberg, Germany
| | - Hellmut G Augustin
- European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany.
- Division of Vascular Oncology and Metastasis, German Cancer Research Center Heidelberg (DKFZ-ZMBH Alliance), Heidelberg, Germany.
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9
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Guerra A, Betancourt-Mar JA, Llanos-Pérez JA, Mansilla R, Nieto-Villar JM. Metastasis Models: Thermodynamics and Complexity. Methods Mol Biol 2024; 2745:45-75. [PMID: 38060179 DOI: 10.1007/978-1-0716-3577-3_4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/08/2023]
Abstract
The thermodynamic formalism of nonequilibrium systems together with the theory of complex systems and systems biology offer an appropriate theoretical framework to explain the complexity observed at the macroscopic level in physiological phenomena. In turn, they allow the establishment of an appropriate conceptual and operational framework to address the study of phenomena such as the emergence and evolution of cancer.This chapter is organized as follows: In Subheading 1, an integrated vision of these disciplines is offered for the characterization of the emergence and evolution of cancer, seen as a nonlinear dynamic system, temporally and spatially self-organized out of thermodynamic equilibrium. The development of the various mathematical models and different techniques and approaches used in the characterization of cancer metastasis is presented in Subheading 2. Subheading 3 is devoted to the time course of cancer metastasis, with particular emphasis on the epithelial-mesenchymal transition (EMT henceforth) as well as chronotherapeutic treatments. In Subheading 4, models of the spatial evolution of cancer metastasis are presented. Finally, in Subheading 5, some conclusions and remarks are presented.
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Affiliation(s)
- A Guerra
- Department of Chemical-Physics, A. Alzola Group of Thermodynamics of Complex Systems M.V. Lomonosov Chair, Faculty of Chemistry, University of Havana, Havana, Cuba
| | | | | | - R Mansilla
- Centro Peninsular en Humanidades y Ciencias Sociales (CEPHCIS), National Autonomous University of Mexico (UNAM), Mérida, Mexico
| | - J M Nieto-Villar
- Department of Chemical-Physics, A. Alzola Group of Thermodynamics of Complex Systems M.V. Lomonosov Chair, Faculty of Chemistry, University of Havana, Havana, Cuba.
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10
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Muthusamy S. Quantifying Adhesion of Inflammatory Cells to the Endothelium In Vitro. Methods Mol Biol 2024; 2711:225-233. [PMID: 37776461 DOI: 10.1007/978-1-0716-3429-5_18] [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] [Indexed: 10/02/2023]
Abstract
We present a simple and quantitative assay system that accurately models human endothelium by use of primary human umbilical vein endothelial cells (HUVECs) in cell culture plates coated with gelatin, a matrix that mimics basal lamina, the matrix that is tightly associated with the vascular endothelium and is critical for its proper function. We describe using this system to quantitatively measure adhesion of the inflammatory cells - monocytic THP-1 cell line to the HUVEC monolayer. The THP-1 cells are fluorescently labeled which allows to quantify the number of the fluorescent THP-1 cells adhering to the endothelium under a microscope and the level of florescence - a quantitative measure of the number of adhering fluorescent THP-1 cells using a fluorescent plate reader. After optimization, we were able to detect increased adhesion of the THP-1 cells to the endothelium in response to the inflammatory cytokine TNFα in a dose-dependent manner like what has been observed in vivo.
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11
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Schito L, Rey-Keim S. Hypoxia signaling and metastatic progression. Semin Cancer Biol 2023; 97:42-49. [PMID: 37926346 DOI: 10.1016/j.semcancer.2023.11.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2023] [Revised: 10/30/2023] [Accepted: 11/01/2023] [Indexed: 11/07/2023]
Abstract
Disruption of oxygen homeostasis, resulting from an imbalance between O2 supply and demand during malignant proliferation, leads to the development of hypoxic tumor microenvironments that promote the acquisition of aggressive cancer cell phenotypes linked to metastasis and patient mortality. In this review, the mechanistic links between tumor hypoxia and metastatic progression are presented. Current status and perspectives of targeting hypoxia signaling pathways as a strategy to halt cancer cell metastatic activities are emphasized.
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Affiliation(s)
- Luana Schito
- UCD School of Medicine, Belfield, Dublin D04 C7X2, Ireland; UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin D04 C7X2, Ireland.
| | - Sergio Rey-Keim
- UCD School of Medicine, Belfield, Dublin D04 C7X2, Ireland; UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin D04 C7X2, Ireland.
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12
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Ni Y, Liang Y, Li M, Lin Y, Zou X, Han F, Cao J, Li L. The updates on metastatic mechanism and treatment of colorectal cancer. Pathol Res Pract 2023; 251:154837. [PMID: 37806170 DOI: 10.1016/j.prp.2023.154837] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Revised: 09/20/2023] [Accepted: 09/30/2023] [Indexed: 10/10/2023]
Abstract
Colorectal cancer (CRC) is a main cause of cancer death worldwide. Metastasis is a major cause of cancer-related death in CRC. The treatment of metastatic CRC has progressed minimally. However, the potential molecular mechanisms involved in CRC metastasis have remained to be comprehensively clarified. An improved understanding of the CRC mechanistic determinants is needed to better prevent and treat metastatic cancer. In this review, based on evidence from a growing body of research in metastatic cancers, we discuss the cellular and molecular mechanisms involved in CRC metastasis. This review reveals both the molecular mechanisms of metastases and identifies new opportunities for developing more effective strategies to target metastatic relapse and improve CRC patient outcomes.
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Affiliation(s)
- Yunfei Ni
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China; Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China; Guangdong Provincial Key Laboratory of Molecular Tumor Pathology, Guangzhou, Guangdong, China
| | - You Liang
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China; Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Mingzhou Li
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China; Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China; Guangdong Provincial Key Laboratory of Molecular Tumor Pathology, Guangzhou, Guangdong, China
| | - Yang Lin
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China; Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China; Guangdong Provincial Key Laboratory of Molecular Tumor Pathology, Guangzhou, Guangdong, China
| | - Xin Zou
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China; Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China; Guangdong Provincial Key Laboratory of Molecular Tumor Pathology, Guangzhou, Guangdong, China
| | - Fangyi Han
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China; Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China; Guangdong Provincial Key Laboratory of Molecular Tumor Pathology, Guangzhou, Guangdong, China
| | - Jianing Cao
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China; Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China; Guangdong Provincial Key Laboratory of Molecular Tumor Pathology, Guangzhou, Guangdong, China
| | - Liang Li
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China; Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China; Guangdong Provincial Key Laboratory of Molecular Tumor Pathology, Guangzhou, Guangdong, China.
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13
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Nowosad A, Marine JC, Karras P. Perivascular niches: critical hubs in cancer evolution. Trends Cancer 2023; 9:897-910. [PMID: 37453870 DOI: 10.1016/j.trecan.2023.06.010] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Revised: 06/15/2023] [Accepted: 06/19/2023] [Indexed: 07/18/2023]
Abstract
Tumors are heterogeneous ecosystems in which cancer cells coexist within a complex tumor immune microenvironment (TIME). The malignant, stromal, and immune cell compartments establish a plethora of bidirectional cell-cell communication crosstalks that influence tumor growth and metastatic dissemination, which we are only beginning to understand. Cancer cells either co-opt or promote the formation of new blood and lymphatic vessels to cope with their need for nutrients and oxygen. Recent studies have highlighted additional key roles for the tumor vasculature and have identified the perivascular niche as a cellular hub, where intricate and dynamic cellular interactions promote cancer stemness, immune evasion, dormancy, and metastatic spreading. Here, we review these findings, and discuss how they may be exploited therapeutically.
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Affiliation(s)
- Ada Nowosad
- Laboratory for Molecular Cancer Biology, VIB Center for Cancer Biology, KU Leuven, Leuven, Belgium; Department of Oncology, KU Leuven, Leuven, Belgium
| | - Jean-Christophe Marine
- Laboratory for Molecular Cancer Biology, VIB Center for Cancer Biology, KU Leuven, Leuven, Belgium; Department of Oncology, KU Leuven, Leuven, Belgium.
| | - Panagiotis Karras
- Laboratory for Molecular Cancer Biology, VIB Center for Cancer Biology, KU Leuven, Leuven, Belgium; Department of Oncology, KU Leuven, Leuven, Belgium.
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14
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Lahooti B, Akwii RG, Zahra FT, Sajib MS, Lamprou M, Alobaida A, Lionakis MS, Mattheolabakis G, Mikelis CM. Targeting endothelial permeability in the EPR effect. J Control Release 2023; 361:212-235. [PMID: 37517543 DOI: 10.1016/j.jconrel.2023.07.039] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2023] [Revised: 07/19/2023] [Accepted: 07/23/2023] [Indexed: 08/01/2023]
Abstract
The characteristics of the primary tumor blood vessels and the tumor microenvironment drive the enhanced permeability and retention (EPR) effect, which confers an advantage towards enhanced delivery of anti-cancer nanomedicine and has shown beneficial effects in preclinical models. Increased vascular permeability is a landmark feature of the tumor vessels and an important driver of the EPR. The main focus of this review is the endothelial regulation of vascular permeability. We discuss current challenges of targeting vascular permeability towards clinical translation and summarize the structural components and mechanisms of endothelial permeability, the principal mediators and signaling players, the targeted approaches that have been used and their outcomes to date. We also critically discuss the effects of the tumor-infiltrating immune cells, their interplay with the tumor vessels and the impact of immune responses on nanomedicine delivery, the impact of anti-angiogenic and tumor-stroma targeting approaches, and desirable nanoparticle design approaches for greater translational benefit.
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Affiliation(s)
- Behnaz Lahooti
- Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA
| | - Racheal G Akwii
- Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA
| | - Fatema Tuz Zahra
- Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA
| | - Md Sanaullah Sajib
- Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA
| | - Margarita Lamprou
- Laboratory of Molecular Pharmacology, Department of Pharmacy, University of Patras, Patras 26504, Greece
| | - Ahmed Alobaida
- Department of Pharmaceutics, College of Pharmacy, University of Ha'il, Ha'il 81442, Saudi Arabia
| | - Michail S Lionakis
- Fungal Pathogenesis Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - George Mattheolabakis
- School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana at Monroe, Monroe, LA 71201, USA.
| | - Constantinos M Mikelis
- Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA; Laboratory of Molecular Pharmacology, Department of Pharmacy, University of Patras, Patras 26504, Greece.
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15
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Zhang R, Chen J, Wang S, Zhang W, Zheng Q, Cai R. Ferroptosis in Cancer Progression. Cells 2023; 12:1820. [PMID: 37508485 PMCID: PMC10378139 DOI: 10.3390/cells12141820] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2023] [Revised: 07/01/2023] [Accepted: 07/08/2023] [Indexed: 07/30/2023] Open
Abstract
Ferroptosis is a newly discovered iron-dependent form of regulated cell death driven by phospholipid peroxidation and associated with processes including iron overload, lipid peroxidation, and dysfunction of cellular antioxidant systems. Ferroptosis is found to be closely related to many diseases, including cancer at every stage. Epithelial-mesenchymal transition (EMT) in malignant tumors that originate from epithelia promotes cancer-cell migration, invasion, and metastasis by disrupting cell-cell and cell-cell matrix junctions, cell polarity, etc. Recent studies have shown that ferroptosis appears to share multiple initiators and overlapping pathways with EMT in cancers and identify ferroptosis as a potential predictor of various cancer grades and prognoses. Cancer metastasis involves multiple steps, including local invasion of cancer cells, intravasation, survival in circulation, arrest at a distant organ site, extravasation and adaptation to foreign tissue microenvironments, angiogenesis, and the formation of "premetastatic niche". Numerous studies have revealed that ferroptosis is closely associated with cancer metastasis. From the cellular perspective, ferroptosis has been implicated in the regulation of cancer metastasis. From the molecular perspective, the signaling pathways activated during the two events interweave. This review briefly introduces the mechanisms of ferroptosis and discusses how ferroptosis is involved in cancer progression, including EMT, cancer angiogenesis, invasion, and metastasis.
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Affiliation(s)
- Rongyu Zhang
- Department of Biochemistry & Molecular Cell Biology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Jinghong Chen
- Department of Biochemistry & Molecular Cell Biology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Saiyang Wang
- Department of Biochemistry & Molecular Cell Biology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Wenlong Zhang
- Department of Biochemistry & Molecular Cell Biology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Quan Zheng
- Center for Singl-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Rong Cai
- Department of Biochemistry & Molecular Cell Biology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
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16
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Wang Y, Schneider SW, Gorzelanny C. Crosstalk between Circulating Tumor Cells and Plasma Proteins-Impact on Coagulation and Anticoagulation. Cancers (Basel) 2023; 15:cancers15113025. [PMID: 37296987 DOI: 10.3390/cancers15113025] [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: 04/04/2023] [Revised: 05/24/2023] [Accepted: 05/31/2023] [Indexed: 06/12/2023] Open
Abstract
Cancer metastasis is a complex process. After their intravasation into the circulation, the cancer cells are exposed to a harsh environment of physical and biochemical hazards. Whether circulating tumor cells (CTCs) survive and escape from blood flow defines their ability to metastasize. CTCs sense their environment with surface-exposed receptors. The recognition of corresponding ligands, e.g., fibrinogen, by integrins can induce intracellular signaling processes driving CTCs' survival. Other receptors, such as tissue factor (TF), enable CTCs to induce coagulation. Cancer-associated thrombosis (CAT) is adversely connected to patients' outcome. However, cancer cells have also the ability to inhibit coagulation, e.g., through expressing thrombomodulin (TM) or heparan sulfate (HS), an activator of antithrombin (AT). To that extent, individual CTCs can interact with plasma proteins, and whether these interactions are connected to metastasis or clinical symptoms such as CAT is largely unknown. In the present review, we discuss the biological and clinical relevance of cancer-cell-expressed surface molecules and their interaction with plasma proteins. We aim to encourage future research to expand our knowledge of the CTC interactome, as this may not only yield new molecular markers improving liquid-biopsy-based diagnostics but also additional targets for better cancer therapies.
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Affiliation(s)
- Yuanyuan Wang
- Department of Dermatology and Venereology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany
| | - Stefan W Schneider
- Department of Dermatology and Venereology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany
| | - Christian Gorzelanny
- Department of Dermatology and Venereology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany
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17
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Bozzuto G, Colone M, Toccacieli L, Molinari A, Calcabrini A, Stringaro A. Interaction of Drug-Sensitive and -Resistant Human Melanoma Cells with HUVEC Cells: A Label-Free Cell-Based Impedance Study. Biomedicines 2023; 11:1544. [PMID: 37371639 DOI: 10.3390/biomedicines11061544] [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: 04/24/2023] [Revised: 05/19/2023] [Accepted: 05/24/2023] [Indexed: 06/29/2023] Open
Abstract
Cancer cell extravasation is a crucial step in cancer metastasis. However, many of the mechanisms involved in this process are only now being elucidated. Thus, in the present study we analysed the trans-endothelial invasion of melanoma cells by a high throughput label-free cell impedance assay applied to transwell chamber invasion assay. This technique monitors and quantifies in real-time the invasion of endothelial cells by malignant tumour cells, for a long time, avoiding artefacts due to preparation of the end point measurements. Results obtained by impedance analysis were compared with endpoint measurements. In this study, we used human melanoma M14 wild type (WT) cells and their drug resistant counterparts, M14 multidrug resistant (ADR) melanoma cells, selected by prolonged exposure to doxorubicin (DOX). Tumour cells were co-cultured with monolayers of human umbilical vein endothelial cells (HUVEC). Results herein reported demonstrated that: (i) the trans-endothelial migration of resistant melanoma cells was faster than sensitive ones; (ii) the endothelial cells appeared to be strongly affected by the transmigration of melanoma cells which showed the ability to degrade their cytoplasm; (iii) resistant cells preferentially adopted the transcellular invasion vs. the paracellular one; (iv) the endothelial damage mediated by tumour metalloproteinases seemed to be reversible.
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Affiliation(s)
- Giuseppina Bozzuto
- National Center for Drug Research and Evaluation, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy
| | - Marisa Colone
- National Center for Drug Research and Evaluation, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy
| | - Laura Toccacieli
- National Center for Drug Research and Evaluation, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy
| | - Agnese Molinari
- National Center for Drug Research and Evaluation, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy
| | - Annarica Calcabrini
- National Center for Drug Research and Evaluation, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy
| | - Annarita Stringaro
- National Center for Drug Research and Evaluation, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy
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18
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Ahmed R, Anam K, Ahmed H. Development of Galectin-3 Targeting Drugs for Therapeutic Applications in Various Diseases. Int J Mol Sci 2023; 24:8116. [PMID: 37175823 PMCID: PMC10179732 DOI: 10.3390/ijms24098116] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Revised: 04/24/2023] [Accepted: 04/29/2023] [Indexed: 05/15/2023] Open
Abstract
Galectin-3 (Gal3) is one of the most studied members of the galectin family that mediate various biological processes such as growth regulation, immune function, cancer metastasis, and apoptosis. Since Gal3 is pro-inflammatory, it is involved in many diseases that are associated with chronic inflammation such as cancer, organ fibrosis, and type 2 diabetes. As a multifunctional protein involved in multiple pathways of many diseases, Gal3 has generated significant interest in pharmaceutical industries. As a result, several Gal3-targeting therapeutic drugs are being developed to address unmet medical needs. Based on the PubMed search of Gal3 to date (1987-2023), here, we briefly describe its structure, carbohydrate-binding properties, endogenous ligands, and roles in various diseases. We also discuss its potential antagonists that are currently being investigated clinically or pre-clinically by the public and private companies. The updated knowledge on Gal3 function in various diseases could initiate new clinical or pre-clinical investigations to test therapeutic strategies, and some of these strategies could be successful and recognized as novel therapeutics for unmet medical needs.
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Affiliation(s)
| | | | - Hafiz Ahmed
- GlycoMantra Inc., Biotechnology Center, University of Maryland Baltimore County, Baltimore, MD 21250, USA
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19
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Flores-Morales V, Villasana-Ruíz AP, Garza-Veloz I, González-Delgado S, Martinez-Fierro ML. Therapeutic Effects of Coumarins with Different Substitution Patterns. Molecules 2023; 28:2413. [PMID: 36903660 PMCID: PMC10005689 DOI: 10.3390/molecules28052413] [Citation(s) in RCA: 31] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Revised: 02/24/2023] [Accepted: 03/03/2023] [Indexed: 03/09/2023] Open
Abstract
The use of derivatives of natural and synthetic origin has gained attention because of their therapeutic effects against human diseases. Coumarins are one of the most common organic molecules and are used in medicine for their pharmacological and biological effects, such as anti-inflammatory, anticoagulant, antihypertensive, anticonvulsant, antioxidant, antimicrobial, and neuroprotective, among others. In addition, coumarin derivates can modulate signaling pathways that impact several cell processes. The objective of this review is to provide a narrative overview of the use of coumarin-derived compounds as potential therapeutic agents, as it has been shown that substituents on the basic core of coumarin have therapeutic effects against several human diseases and types of cancer, including breast, lung, colorectal, liver, and kidney cancer. In published studies, molecular docking has represented a powerful tool to evaluate and explain how these compounds selectively bind to proteins involved in various cellular processes, leading to specific interactions with a beneficial impact on human health. We also included studies that evaluated molecular interactions to identify potential biological targets with beneficial effects against human diseases.
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Affiliation(s)
- Virginia Flores-Morales
- Asymmetric Synthesis and Bio-chemoinformatics Laboratory (LSAyB), Ingeniería Química (UACQ), Universidad Autónoma de Zacatecas, Carretera Zacatecas-Guadalajara Km.6. Ejido la Escondida, Zacatecas 98160, Mexico
| | - Ana P. Villasana-Ruíz
- Asymmetric Synthesis and Bio-chemoinformatics Laboratory (LSAyB), Ingeniería Química (UACQ), Universidad Autónoma de Zacatecas, Carretera Zacatecas-Guadalajara Km.6. Ejido la Escondida, Zacatecas 98160, Mexico
- Molecular Medicine Laboratory, Academic Unit of Human Medicine and Health Sciences, Universidad Autónoma de Zacatecas, Carretera Zacatecas-Guadalajara Km.6. Ejido La Escondida, Zacatecas 98160, Mexico
| | - Idalia Garza-Veloz
- Molecular Medicine Laboratory, Academic Unit of Human Medicine and Health Sciences, Universidad Autónoma de Zacatecas, Carretera Zacatecas-Guadalajara Km.6. Ejido La Escondida, Zacatecas 98160, Mexico
| | - Samantha González-Delgado
- Molecular Medicine Laboratory, Academic Unit of Human Medicine and Health Sciences, Universidad Autónoma de Zacatecas, Carretera Zacatecas-Guadalajara Km.6. Ejido La Escondida, Zacatecas 98160, Mexico
| | - Margarita L. Martinez-Fierro
- Molecular Medicine Laboratory, Academic Unit of Human Medicine and Health Sciences, Universidad Autónoma de Zacatecas, Carretera Zacatecas-Guadalajara Km.6. Ejido La Escondida, Zacatecas 98160, Mexico
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20
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Puente-Cobacho B, Varela-López A, Quiles JL, Vera-Ramirez L. Involvement of redox signalling in tumour cell dormancy and metastasis. Cancer Metastasis Rev 2023; 42:49-85. [PMID: 36701089 PMCID: PMC10014738 DOI: 10.1007/s10555-022-10077-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2022] [Accepted: 12/27/2022] [Indexed: 01/27/2023]
Abstract
Decades of research on oncogene-driven carcinogenesis and gene-expression regulatory networks only started to unveil the complexity of tumour cellular and molecular biology. This knowledge has been successfully implemented in the clinical practice to treat primary tumours. In contrast, much less progress has been made in the development of new therapies against metastasis, which are the main cause of cancer-related deaths. More recently, the role of epigenetic and microenviromental factors has been shown to play a key role in tumour progression. Free radicals are known to communicate the intracellular and extracellular compartments, acting as second messengers and exerting a decisive modulatory effect on tumour cell signalling. Depending on the cellular and molecular context, as well as the intracellular concentration of free radicals and the activation status of the antioxidant system of the cell, the signalling equilibrium can be tilted either towards tumour cell survival and progression or cell death. In this regard, recent advances in tumour cell biology and metastasis indicate that redox signalling is at the base of many cell-intrinsic and microenvironmental mechanisms that control disseminated tumour cell fate and metastasis. In this manuscript, we will review the current knowledge about redox signalling along the different phases of the metastatic cascade, including tumour cell dormancy, making emphasis on metabolism and the establishment of supportive microenvironmental connections, from a redox perspective.
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Affiliation(s)
- Beatriz Puente-Cobacho
- Department of Genomic Medicine, GENYO, Centre for Genomics and Oncology, Pfizer-University of Granada and Andalusian Regional Government, PTS, Granada, Spain
| | - Alfonso Varela-López
- Department of Physiology, Institute of Nutrition and Food Technology "José Mataix Verdú", Biomedical Research Center, University of Granada, Granada, Spain
| | - José L Quiles
- Department of Physiology, Institute of Nutrition and Food Technology "José Mataix Verdú", Biomedical Research Center, University of Granada, Granada, Spain
| | - Laura Vera-Ramirez
- Department of Genomic Medicine, GENYO, Centre for Genomics and Oncology, Pfizer-University of Granada and Andalusian Regional Government, PTS, Granada, Spain. .,Department of Physiology, Institute of Nutrition and Food Technology "José Mataix Verdú", Biomedical Research Center, University of Granada, Granada, Spain.
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21
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Mierke CT. The versatile roles of ADAM8 in cancer cell migration, mechanics, and extracellular matrix remodeling. Front Cell Dev Biol 2023; 11:1130823. [PMID: 36910158 PMCID: PMC9995898 DOI: 10.3389/fcell.2023.1130823] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Accepted: 02/15/2023] [Indexed: 02/25/2023] Open
Abstract
The posttranslational proteolytic cleavage is a unique and irreversible process that governs the function and half-life of numerous proteins. Thereby the role of the family of A disintegrin and metalloproteases (ADAMs) plays a leading part. A member of this family, ADAM8, has gained attention in regulating disorders, such as neurogenerative diseases, immune function and cancer, by attenuating the function of proteins nearby the extracellular membrane leaflet. This process of "ectodomain shedding" can alter the turnover rate of a number of transmembrane proteins that function in cell adhesion and receptor signal transduction. In the past, the major focus of research about ADAMs have been on neurogenerative diseases, such as Alzheimer, however, there seems to be evidence for a connection between ADAM8 and cancer. The role of ADAMs in the field of cancer research has gained recent attention, but it has been not yet been extensively addressed. Thus, this review article highlights the various roles of ADAM8 with particular emphasis on pathological conditions, such as cancer and malignant cancer progression. Here, the shedding function, direct and indirect matrix degradation, effects on cancer cell mobility and transmigration, and the interplay of ADAM8 with matrix-embedded neighboring cells are presented and discussed. Moreover, the most probable mechanical impact of ADAM8 on cancer cells and their matrix environment is addressed and debated. In summary, this review presents recent advances in substrates/ligands and functions of ADAM8 in its new role in cancer and its potential link to cell mechanical properties and discusses matrix mechanics modifying properties. A deeper comprehension of the regulatory mechanisms governing the expression, subcellular localization, and activity of ADAM8 is expected to reveal appropriate drug targets that will permit a more tailored and fine-tuned modification of its proteolytic activity in cancer development and metastasis.
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Affiliation(s)
- Claudia Tanja Mierke
- Faculty of Physics and Earth Science, Biological Physics Division, Peter Debye Institute of Soft Matter Physics, Leipzig University, Leipzig, Germany
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22
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Jeethy Ram T, Lekshmi A, Darvin P, Rajappan P, Jagathnath Krishna KM, Anoop TM, Augustine P, Mathew AP, Cherian K, Bhargavan RV, Somanathan T, Radhakrishna Pillai M, Santhosh Kumar TR, Sujathan K. Co-expression of galectin-3 and vimentin in triple negative breast cancer cells promotes tumor progression, metastasis and survival. Tumour Biol 2023; 45:31-54. [PMID: 37574746 DOI: 10.3233/tub-230002] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/15/2023] Open
Abstract
BACKGROUND Lack of druggable targets and complex expression heterogeneity of known targets is common among TNBC subtypes. An enhanced expression of galectin-3 in TNBCs has already been documented. We have observed a tumor progression-dependent galectin-3 expression in TNBCs compared to adjacent epithelium and non TNBCs. OBJECTIVE To unravel the association of galectin- 3 in tumor progression, aggressiveness and drug resistance in TNBC patients. METHODS Galectin-3 expression in 489 breast cancer tissues was correlated with clinicopathological features and the results were validated in cell lines and mouse model by silencing galectin-3 using shRNA and the proteins were profiled by western blot and qRT-PCR. Protein interaction was analyzed by GFP Trap and Mass spectrometry. RESULTS Galectin-3 expression correlated with tumor stage in TNBC and a lower galectin-3 expression was associated with poor patient survival. The positive correlation between galectin-3, vimentin and CD44 expression, pinpoints galectin-3 contribution to epithelial to mesenchymal transition, drug resistance and stemness. Vimentin was found as an interacting partner of galectin-3. Duplexing of galecin-3 and vimentin in patient samples revealed the presence of tumor cells co-expressing both galectin-3 and vimentin. In vitro studies also showed its role in tumor cell survival and metastatic potential, elementary for tumor progression. In vivo studies further confirmed its metastatic potential. CONCLUSIONS Tumor progression dependent expression pattern of galectin 3 was found to indicate prognosis. Co-expression of galectin-3 and vimentin in tumor cells promotes tumor dissemination, survival and its metastatic capability in TNBCs.
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Affiliation(s)
- T Jeethy Ram
- Division of Cancer Research, Regional Cancer Centre, Thiruvananthapuram, Kerala, India
- Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Asha Lekshmi
- Division of Cancer Research, Regional Cancer Centre, Thiruvananthapuram, Kerala, India
| | - Pramod Darvin
- Cancer Research, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, Kerala, India
| | - Prakash Rajappan
- Cancer Research, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, Kerala, India
| | | | - T M Anoop
- Medical Oncology, Regional Cancer Centre, Thiruvananthapuram, Kerala, India
| | - Paul Augustine
- Surgical Oncology, Regional Cancer Centre, Thiruvananthapuram, Kerala, India
| | - Arun Peter Mathew
- Surgical Oncology, Regional Cancer Centre, Thiruvananthapuram, Kerala, India
| | - Kurian Cherian
- Surgical Oncology, Regional Cancer Centre, Thiruvananthapuram, Kerala, India
| | - Rexeena V Bhargavan
- Surgical Oncology, Regional Cancer Centre, Thiruvananthapuram, Kerala, India
| | - Thara Somanathan
- Pathology, Regional Cancer Centre, Thiruvananthapuram, Kerala, India
| | - M Radhakrishna Pillai
- Cancer Research, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, Kerala, India
| | - T R Santhosh Kumar
- Cancer Research, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, Kerala, India
| | - K Sujathan
- Division of Cancer Research, Regional Cancer Centre, Thiruvananthapuram, Kerala, India
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Agboyibor C, Dong J, Effah CY, Drokow EK, Ampomah-Wireko M, Pervaiz W, Sangmor A, Ma X, Li J, Liu HM, Zhang P. Epigenetic compounds targeting pharmacological target lysine specific demethylase 1 and its impact on immunotherapy, chemotherapy and radiotherapy for treatment of tumor recurrence and resistance. Biomed Pharmacother 2023; 157:113934. [PMID: 36395607 DOI: 10.1016/j.biopha.2022.113934] [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: 09/17/2022] [Revised: 10/22/2022] [Accepted: 10/26/2022] [Indexed: 11/15/2022] Open
Abstract
It has been proven that metastatic recurrence and therapeutic resistance are linked. Due to the variability of individuals and tumors, as well as the tumor's versatility in avoiding therapies, therapy resistance is more difficult to treat. Therapy resistance has significantly restricted the clinical feasibility and efficacy of tumor therapy, despite the discovery of novel compounds and therapy combinations with increasing efficacy. In several tumors, lysine specific demethylase 1 (LSD1) has been associated to metastatic recurrence and therapeutic resistance. For researchers to better comprehend how LSD1-mediated tumor therapy resistance occurs and how to overcome it in various tumors, this study focused on the role of LSD1 in tumor recurrence and therapeutic resistance. The importance of therapeutically targeted LSD1 was also discussed. Most gene pathway signatures are related to LSD1 inhibitor sensitivity. However, some gene pathway signatures, especially in AML, negatively correlate with LSD1 inhibitor sensitivity, but targeting LSD1 makes the therapy-resistant tumor sensitive to physiological doses of conventional therapy. We propose that combining LSD1 inhibitor with traditional tumor therapy can help patients attain a complete response and prevent cancer relapse.
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Affiliation(s)
- Clement Agboyibor
- School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, PR China; Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Zhengzhou University, Zhengzhou 450001, PR China; Institute of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, PR China; Key Laboratory of Henan Province for Drug Quality Control and Evaluation, Zhengzhou University, Zhengzhou 450001, PR China; Collaborative Innovation Center of New Drug Research and Safety Evaluation of Henan Province; Zhengzhou University, Zhengzhou 450001, PR China; Institute of Drug Discovery and Development; Zhengzhou University, Zhengzhou 450001, PR China
| | - Jianshu Dong
- School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, PR China; Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Zhengzhou University, Zhengzhou 450001, PR China; Institute of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, PR China; Key Laboratory of Henan Province for Drug Quality Control and Evaluation, Zhengzhou University, Zhengzhou 450001, PR China; Collaborative Innovation Center of New Drug Research and Safety Evaluation of Henan Province; Zhengzhou University, Zhengzhou 450001, PR China
| | - Clement Yaw Effah
- College of Public Health, Zhengzhou University, Zhengzhou 450001, PR China
| | - Emmanuel Kwateng Drokow
- Department of Oncology, Zhengzhou University People's Hospital & Henan Provincial People's Hospital Henan, 450003, Zhengzhou, PR China
| | | | - Waqar Pervaiz
- School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, PR China; Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Zhengzhou University, Zhengzhou 450001, PR China; Institute of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, PR China; Key Laboratory of Henan Province for Drug Quality Control and Evaluation, Zhengzhou University, Zhengzhou 450001, PR China; Collaborative Innovation Center of New Drug Research and Safety Evaluation of Henan Province; Zhengzhou University, Zhengzhou 450001, PR China; Institute of Drug Discovery and Development; Zhengzhou University, Zhengzhou 450001, PR China
| | - Augustina Sangmor
- School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, PR China
| | - Xinli Ma
- China-US(Henan) Hormel Cancer Institute, No.127, Dongming Road, Jinshui District, Zhengzhou, Henan 450008, PR China
| | - Jian Li
- China-US(Henan) Hormel Cancer Institute, No.127, Dongming Road, Jinshui District, Zhengzhou, Henan 450008, PR China
| | - Hong-Min Liu
- School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, PR China; Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Zhengzhou University, Zhengzhou 450001, PR China; Institute of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, PR China; Key Laboratory of Henan Province for Drug Quality Control and Evaluation, Zhengzhou University, Zhengzhou 450001, PR China; Collaborative Innovation Center of New Drug Research and Safety Evaluation of Henan Province; Zhengzhou University, Zhengzhou 450001, PR China; Institute of Drug Discovery and Development; Zhengzhou University, Zhengzhou 450001, PR China.
| | - Peng Zhang
- Department of Bone and Soft Tissue Cancer, The Affiliated Cancer Hospital of Zhengzhou University (Henan Cancer Hospital), Zhengzhou, Henan province, PR China 450008.
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24
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Taïeb HM, Herment G, Robinson T, Cipitria A. Effect of capillary fluid flow on single cancer cell cycle dynamics, motility, volume and morphology. LAB ON A CHIP 2022; 23:92-105. [PMID: 36448429 DOI: 10.1039/d2lc00322h] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/17/2023]
Abstract
From primary tumours and disseminating to secondary organs, cancer cells experience a wide variety of fluid flow profiles when passing through blood vessels or the lymphatic system before extravasation. Sinusoidal capillaries are a common site for extravasation. Therefore, we aim to investigate how metastatic cancer cells react to a biophysical cue such as capillary fluid flow by quantifying its effect on metastatic cell cycle progression, motility, cell and nuclear volume, and morphology. We use MDA-MB-231 breast cancer cells genetically modified with fluorescent ubiquitination-based cell cycle indicator 2 (FUCCI2) as a model system. Single cells are trapped using a microfluidic device and exposed to different laminar flows. Quantitative time-lapse imaging in both 2D epifluorescence and 3D confocal microscopy is performed using in-house software FUCCItrack. In addition, 3D time-lapse with cell and nuclear segmentation is performed with a deep learning approach to streamline the image processing of big datasets. We show that at a single cell level, faster fluid flow leads to a shorter S/G2/M phase and an overall shorter cell cycle, as well as increase in cell motility irrespective of the flow direction. 3D time-lapse confocal imaging of MDA-FUCCI2 single cells reveals the evolution of cell and nuclear volume and morphology as a function of a specific cell cycle phase. Both cell and nuclear volume increase linearly over time. Cell morphology elongates more strongly during the S/G2/M phase, whereas the nuclear shape remains constant. Under the highest flow conditions, only during the S/G2/M phase can we observe a more elongated nucleus, while the cell sphericity remains similar to the control. Collectively, this data, together with the deep learning approach, provides new insights into the potential impact of fluid flow at a single cell level.
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Affiliation(s)
- Hubert M Taïeb
- Department of Biomaterials, Max Planck Institute of Colloids and Interfaces, 14476 Potsdam, Germany.
| | - Guillaume Herment
- Department of Biomaterials, Max Planck Institute of Colloids and Interfaces, 14476 Potsdam, Germany.
| | - Tom Robinson
- Department of Theory and Bio-Systems, Max Planck Institute of Colloids and Interfaces, 14476 Potsdam, Germany.
| | - Amaia Cipitria
- Department of Biomaterials, Max Planck Institute of Colloids and Interfaces, 14476 Potsdam, Germany.
- Group of Bioengineering in Regeneration and Cancer, Biodonostia Health Research Institute, 20014 San Sebastian, Spain
- IKERBASQUE, Basque Foundation for Science, 48009 Bilbao, Spain
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25
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Noubissi Nzeteu GA, Geismann C, Arlt A, Hoogwater FJH, Nijkamp MW, Meyer NH, Bockhorn M. Role of Epithelial-to-Mesenchymal Transition for the Generation of Circulating Tumors Cells and Cancer Cell Dissemination. Cancers (Basel) 2022; 14:5483. [PMID: 36428576 PMCID: PMC9688619 DOI: 10.3390/cancers14225483] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Revised: 10/24/2022] [Accepted: 11/02/2022] [Indexed: 11/09/2022] Open
Abstract
Tumor-related death is primarily caused by metastasis; consequently, understanding, preventing, and treating metastasis is essential to improving clinical outcomes. Metastasis is mainly governed by the dissemination of tumor cells in the systemic circulation: so-called circulating tumor cells (CTCs). CTCs typically arise from epithelial tumor cells that undergo epithelial-to-mesenchymal transition (EMT), resulting in the loss of cell-cell adhesions and polarity, and the reorganization of the cytoskeleton. Various oncogenic factors can induce EMT, among them the transforming growth factor (TGF)-β, as well as Wnt and Notch signaling pathways. This entails the activation of numerous transcription factors, including ZEB, TWIST, and Snail proteins, acting as transcriptional repressors of epithelial markers, such as E-cadherin and inducers of mesenchymal markers such as vimentin. These genetic and phenotypic changes ultimately facilitate cancer cell migration. However, to successfully form distant metastases, CTCs must primarily withstand the hostile environment of circulation. This includes adaption to shear stress, avoiding being trapped by coagulation and surviving attacks of the immune system. Several applications of CTCs, from cancer diagnosis and screening to monitoring and even guided therapy, seek their way into clinical practice. This review describes the process leading to tumor metastasis, from the generation of CTCs in primary tumors to their dissemination into distant organs, as well as the importance of subtyping CTCs to improve personalized and targeted cancer therapy.
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Affiliation(s)
- Gaetan Aime Noubissi Nzeteu
- University Hospital of General and Visceral Surgery, Department of Human Medicine, University of Oldenburg and Klinikum Oldenburg, 26129 Oldenburg, Germany
| | - Claudia Geismann
- Laboratory of Molecular Gastroenterology & Hepatology, Department of Internal Medicine I, UKSH-Campus Kiel, 24118 Kiel, Germany
| | - Alexander Arlt
- Department for Gastroenterology and Hepatology, University Hospital Oldenburg, Klinikum Oldenburg AöR, European Medical School (EMS), 26133 Oldenburg, Germany
| | - Frederik J. H. Hoogwater
- Section of HPB Surgery & Liver Transplantation, Department of Surgery, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands
| | - Maarten W. Nijkamp
- Section of HPB Surgery & Liver Transplantation, Department of Surgery, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands
| | - N. Helge Meyer
- University Hospital of General and Visceral Surgery, Department of Human Medicine, University of Oldenburg and Klinikum Oldenburg, 26129 Oldenburg, Germany
| | - Maximilian Bockhorn
- University Hospital of General and Visceral Surgery, Department of Human Medicine, University of Oldenburg and Klinikum Oldenburg, 26129 Oldenburg, Germany
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26
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Fridrichova I, Kalinkova L, Ciernikova S. Clinical Relevancy of Circulating Tumor Cells in Breast Cancer: Epithelial or Mesenchymal Characteristics, Single Cells or Clusters? Int J Mol Sci 2022; 23:12141. [PMID: 36292996 PMCID: PMC9603393 DOI: 10.3390/ijms232012141] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Revised: 10/05/2022] [Accepted: 10/07/2022] [Indexed: 07/30/2023] Open
Abstract
Metastatic breast cancer (MBC) is typically an incurable disease with high mortality rates; thus, early identification of metastatic features and disease recurrence through precise biomarkers is crucial. Circulating tumor cells (CTCs) consisting of heterogeneous subpopulations with different morphology and genetic, epigenetic, and gene expression profiles represent promising candidate biomarkers for metastatic potential. The experimentally verified role of epithelial-to-mesenchymal transition in cancer dissemination has not been clearly described in BC patients, but the stemness features of CTCs strongly contributes to metastatic potency. Single CTCs have been shown to be protected in the bloodstream against recognition by the immune system through impaired interactions with T lymphocytes and NK cells, while associations of heterotypic CTC clusters with platelets, leucocytes, neutrophils, tumor-associated macrophages, and fibroblasts improve their tumorigenic behavior. In addition to single CTC and CTC cluster characteristics, we reviewed CTC evaluation methods and clinical studies in early and metastatic BCs. The variable CTC tests were developed based on specific principles and strategies. However, CTC count and the presence of CTC clusters were shown to be most clinically relevant in existing clinical trials. Despite the known progress in CTC research and sampling of BC patients, implementation of CTCs and CTC clusters in routine diagnostic and treatment strategies still requires improvement in detection sensitivity and precise molecular characterizations, focused predominantly on the role of CTC clusters for their higher metastatic potency.
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27
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Mukherjee A, Ha P, Wai KC, Naara S. The Role of ECM Remodeling, EMT, and Adhesion Molecules in Cancerous Neural Invasion: Changing Perspectives. Adv Biol (Weinh) 2022; 6:e2200039. [PMID: 35798312 DOI: 10.1002/adbi.202200039] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Revised: 05/05/2022] [Indexed: 01/28/2023]
Abstract
Perineural invasion (PNI) refers to the cancerous invasion of nerves. It provides an alternative route for metastatic invasion and can exist independently in the absence of lymphatic or vascular invasion. It is a prominent characteristic of specific aggressive malignancies where it correlates with poor prognosis. The clinical significance of PNI is widely recognized despite a lack of understanding of the molecular mechanisms underlying its pathogenesis. The interaction between the nerve and the cancer cells is the most pivotal PNI step which is mediated by the activation or inhibition of multiple signaling pathways that include chemokines, interleukins, nerve growth factors, and matrix metalloproteinases, to name a few. The nerve-cancer cell interaction brings about specific changes in the perineural niche, which not only affects the regular nerve functions, but also enhances the migratory, invasive, and adherent properties of the tumor cells. This review aims to elucidate the vital role of adhesion molecules, extracellular matrix, and epithelial-mesenchymal proteins that promote PNI, which may serve as therapeutic targets in the future.
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Affiliation(s)
- Abhishek Mukherjee
- Department of Genetics and Developmental BiologyRappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, 3525422, Israel
| | - Patrick Ha
- Department of Otolaryngology-Head and Neck Surgery, University of California-San Francisco, Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, 94158, USA
| | - Katherine C Wai
- Department of Otolaryngology-Head and Neck Surgery, University of California-San Francisco, Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, 94158, USA
| | - Shorook Naara
- Department of Genetics and Developmental BiologyRappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, 3525422, Israel.,Department of Otolaryngology-Head and Neck Surgery, University of California-San Francisco, Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, 94158, USA
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28
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Regev O, Kizner M, Roncato F, Dadiani M, Saini M, Castro-Giner F, Yajuk O, Kozlovski S, Levi N, Addadi Y, Golani O, Ben-Dor S, Granot Z, Aceto N, Alon R. ICAM-1 on Breast Cancer Cells Suppresses Lung Metastasis but Is Dispensable for Tumor Growth and Killing by Cytotoxic T Cells. Front Immunol 2022; 13:849701. [PMID: 35911772 PMCID: PMC9328178 DOI: 10.3389/fimmu.2022.849701] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Accepted: 06/13/2022] [Indexed: 11/13/2022] Open
Abstract
Breast tumors and their derived circulating cancer cells express the leukocyte β2 integrin ligand Intercellular adhesion molecule 1 (ICAM-1). We found that elevated ICAM-1 expression in breast cancer cells results in a favorable outcome and prolonged survival of breast cancer patients. We therefore assessed the direct in vivo contribution of ICAM-1 expressed by breast cancer cells to breast tumorigenesis and lung metastasis in syngeneic immunocompetent mice hosts using spontaneous and experimental models of the lung metastasis of the C57BL/6-derived E0771 cell line, a luminal B breast cancer subtype. Notably, the presence of ICAM-1 on E0771 did not alter tumor growth or the leukocyte composition in the tumor microenvironment. Interestingly, the elimination of Tregs led to the rapid killing of primary tumor cells independently of tumor ICAM-1 expression. The in vivo elimination of a primary E0771 tumor expressing the ovalbumin (OVA) model neoantigen by the OVA-specific OVA-tcr-I mice (OT-I) transgenic cytotoxic T lymphocytes (CTLs) also took place normally in the absence of ICAM-1 expression by E0771 breast cancer target cells. The whole lung imaging of these cells by light sheet microscopy (LSM) revealed that both Wild type (WT)- and ICAM-1-deficient E0771 cells were equally disseminated from resected tumors and accumulated inside the lung vasculature at similar magnitudes. ICAM-1-deficient breast cancer cells developed, however, much larger metastatic lesions than their control counterparts. Strikingly, the vast majority of these cells gave rise to intravascular tumor colonies both in spontaneous and experimental metastasis models. In the latter model, ICAM-1 expressing E0771- but not their ICAM-1-deficient counterparts were highly susceptible to elimination by neutrophils adoptively transferred from E0771 tumor-bearing donor mice. Ex vivo, neutrophils derived from tumor-bearing mice also killed cultured E0771 cells via ICAM-1-dependent interactions. Collectively, our results are a first indication that ICAM-1 expressed by metastatic breast cancer cells that expand inside the lung vasculature is involved in innate rather than in adaptive cancer cell killing. This is also a first indication that the breast tumor expression of ICAM-1 is not required for CTL-mediated killing but can function as a suppressor of intravascular breast cancer metastasis to lungs.
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Affiliation(s)
- Ofer Regev
- Department of Immunology, Weizmann Institute of Science, Rehovot, Israel
| | - Marina Kizner
- Department of Immunology, Weizmann Institute of Science, Rehovot, Israel
| | - Francesco Roncato
- Department of Immunology, Weizmann Institute of Science, Rehovot, Israel
| | - Maya Dadiani
- Cancer Research Center, Sheba Medical Center, Ramat-Gan, Israel
| | - Massimo Saini
- Department of Biology, Institute of Molecular Health Sciences, ETH Zurich, Zurich, Switzerland
| | - Francesc Castro-Giner
- Department of Biology, Institute of Molecular Health Sciences, ETH Zurich, Zurich, Switzerland
| | - Olga Yajuk
- Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, Hebrew University Medical School, Jerusalem, Israel
| | - Stav Kozlovski
- Department of Immunology, Weizmann Institute of Science, Rehovot, Israel
| | - Nehora Levi
- Department of Immunology, Weizmann Institute of Science, Rehovot, Israel
| | - Yoseph Addadi
- Life Sciences Core Facilities, Weizmann Institute of Science, Rehovot, Israel
| | - Ofra Golani
- Life Sciences Core Facilities, Weizmann Institute of Science, Rehovot, Israel
| | - Shifra Ben-Dor
- Life Sciences Core Facilities, Weizmann Institute of Science, Rehovot, Israel
| | - Zvi Granot
- Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, Hebrew University Medical School, Jerusalem, Israel
| | - Nicola Aceto
- Department of Biology, Institute of Molecular Health Sciences, ETH Zurich, Zurich, Switzerland
| | - Ronen Alon
- Department of Immunology, Weizmann Institute of Science, Rehovot, Israel
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29
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Zhong C, Lu Y, Li Y, Xie H, Zhou G, Jia L. Similarities and differences between embryonic implantation and CTC invasion: Exploring the roles of abortifacients in cancer metastasis chemoprevention. Eur J Med Chem 2022; 237:114416. [DOI: 10.1016/j.ejmech.2022.114416] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2022] [Revised: 04/18/2022] [Accepted: 04/24/2022] [Indexed: 11/03/2022]
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Dash SK, Patra B, Sharma V, Das SK, Verma RS. Fluid shear stress in a logarithmic microfluidic device enhances cancer cell stemness marker expression. LAB ON A CHIP 2022; 22:2200-2211. [PMID: 35544034 DOI: 10.1039/d1lc01139a] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
Fluid shear stress (FSS) is crucial in cancer cell survival and tumor development. Noteworthily, cancer cells are exposed to several degrees of FSS in the tumor microenvironment and during metastasis. Consequently, the stemness marker expression in cancer cells changes with the FSS signal, although it is unclear how it varies with different magnitudes and during metastasis. The current work explores the stemness and drug resistance characteristics of the cervical cancer cell line HeLa in a microfluidic device with a wide range of physiological FSS. Hence, the microfluidic device was designed to achieve a logarithmic flow distribution in four culture chambers, realizing four orders of biological shear stress on a single chip. The cell cycle analysis demonstrated altered cell proliferation and mitotic arrest after FSS treatment. In addition, EdU staining revealed increased cell proliferation with medium to low FSS, whereas high shear had a suppressing effect. FSS increased competence to withstand higher intracellular ROS and mitochondrial membrane potential in HeLa. Furthermore, stemness-related gene (Sox2, N-cadherin) and cell surface marker (CD44, CD33, CD117) expressions were enhanced by FSS mechanotransduction in a magnitude-dependent manner. In summary, these stemness-like properties were concurrent with the drug resistance capability of HeLa towards doxorubicin. Overall, our microfluidic device elucidates cancer cell survival and drug resistance mechanisms during metastasis and in cancer relapse patients.
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Affiliation(s)
- Sanat Kumar Dash
- Department of Mechanical Engineering, Indian Institute of Technology, Madras, Chennai, India
- Department of Biotechnology, Indian Institute of Technology, Madras, Room No. 201, Biotech Old Building, Chennai, India.
| | - Bamadeb Patra
- Department of Biotechnology, Indian Institute of Technology, Madras, Room No. 201, Biotech Old Building, Chennai, India.
| | - Vineeta Sharma
- Department of Biotechnology, Indian Institute of Technology, Madras, Room No. 201, Biotech Old Building, Chennai, India.
| | - Sarit K Das
- Department of Mechanical Engineering, Indian Institute of Technology, Madras, Chennai, India
| | - Rama Shanker Verma
- Department of Biotechnology, Indian Institute of Technology, Madras, Room No. 201, Biotech Old Building, Chennai, India.
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31
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Ronaldson-Bouchard K, Baldassarri I, Tavakol DN, Graney PL, Samaritano M, Cimetta E, Vunjak-Novakovic G. Engineering complexity in human tissue models of cancer. Adv Drug Deliv Rev 2022; 184:114181. [PMID: 35278521 PMCID: PMC9035134 DOI: 10.1016/j.addr.2022.114181] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Revised: 02/15/2022] [Accepted: 03/04/2022] [Indexed: 02/06/2023]
Abstract
Major progress in the understanding and treatment of cancer have tremendously improved our knowledge of this complex disease and improved the length and quality of patients' lives. Still, major challenges remain, in particular with respect to cancer metastasis which still escapes effective treatment and remains responsible for 90% of cancer related deaths. In recent years, the advances in cancer cell biology, oncology and tissue engineering converged into the engineered human tissue models of cancer that are increasingly recapitulating many aspects of cancer progression and response to drugs, in a patient-specific context. The complexity and biological fidelity of these models, as well as the specific questions they aim to investigate, vary in a very broad range. When selecting and designing these experimental models, the fundamental question is "how simple is complex enough" to accomplish a specific goal of cancer research. Here we review the state of the art in developing and using the human tissue models in cancer research and developmental drug screening. We describe the main classes of models providing different levels of biological fidelity and complexity, discuss their advantages and limitations, and propose a framework for designing an appropriate model for a given study. We close by outlining some of the current needs, opportunities and challenges in this rapidly evolving field.
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Affiliation(s)
- Kacey Ronaldson-Bouchard
- Department of Biomedical Engineering, Columbia University, 622 West 168th Street, VC12-234, New York, NY 10032, USA
| | - Ilaria Baldassarri
- Department of Biomedical Engineering, Columbia University, 622 West 168th Street, VC12-234, New York, NY 10032, USA
| | - Daniel Naveed Tavakol
- Department of Biomedical Engineering, Columbia University, 622 West 168th Street, VC12-234, New York, NY 10032, USA
| | - Pamela L Graney
- Department of Biomedical Engineering, Columbia University, 622 West 168th Street, VC12-234, New York, NY 10032, USA
| | - Maria Samaritano
- Department of Biomedical Engineering, Columbia University, 622 West 168th Street, VC12-234, New York, NY 10032, USA
| | - Elisa Cimetta
- Department of Industrial Engineering, University of Padua, Via Marzolo 9, 35131 Padova, Italy; Fondazione Istituto di Ricerca Pediatrica Città della Speranza, Corso Stati Uniti 4, 35127 Padova, Italy
| | - Gordana Vunjak-Novakovic
- Department of Biomedical Engineering, Columbia University, 622 West 168th Street, VC12-234, New York, NY 10032, USA; Department of Medicine, Columbia University, 622 West 168th Street, VC12-234, New York, NY 10032, USA; College of Dental Medicine, Columbia University, 622 West 168th Street, VC12-234, New York, NY 10032, USA.
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32
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Sadoughi F, Dana PM, Homayoonfal M, Sharifi M, Asemi Z. Molecular basis of melatonin protective effects in metastasis: A novel target of melatonin. Biochimie 2022; 202:15-25. [DOI: 10.1016/j.biochi.2022.05.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2022] [Revised: 05/19/2022] [Accepted: 05/19/2022] [Indexed: 11/16/2022]
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Value of 18F-FDG PET/CT Combined with Lung HRCT in Diagnosis of Solitary Pulmonary Intravascular Metastasis. CONTRAST MEDIA & MOLECULAR IMAGING 2022; 2022:8968855. [PMID: 35280706 PMCID: PMC8885262 DOI: 10.1155/2022/8968855] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/26/2021] [Accepted: 02/02/2022] [Indexed: 11/24/2022]
Abstract
Background Solitary pulmonary intravascular metastasis is a rare complication of malignant tumors, and accurate diagnosis can improve clinical decision-making, but diagnosing it effectively using conventional techniques is difficult. Purpose To explore the value of 18F-FDG PET/CT combined with lung high-resolution computed tomography (HRCT) in the diagnosis of solitary pulmonary intravascular metastasis. Methods 18F-FDG PET/CT, lung HRCT, and follow-up data of 18,143 cancer patients were retrospectively analyzed to select patients with pulmonary vessel involvement besides the primary tumor only. The histopathological or imaging follow-up results were used as the diagnostic criteria for pulmonary intravascular metastasis. Results A total of 13 patients with 17 pulmonary intravascular metastases were found, of which 9 patients had a single lesion and 4 had double. The SUVmax was 1.1–5.4 (average, 2.4 ± 1.4), and the length of hypermetabolic metastasis was 5.1–24.1 mm (average, 10.7 ± 6.5 mm). All the intravascular metastases were located in the terminal pulmonary vessels. Strip or branched pulmonary vessels enlargement with increased metabolism was the main imaging manifestation (15/17, 88.2%), while the other 2 cases only showed strip metabolic enhancement without abnormalities in pulmonary vessels (2/17, 11.8%). Four pulmonary intravascular metastases were confirmed by pathology, and the other 13 cases were diagnosed by imaging follow-up. Conclusion 18F-FDG PET/CT combined with lung HRCT is an effective technique for the diagnosis of solitary pulmonary intravascular metastasis. High-strip or branched FDG uptake in the distal pulmonary vessel accompanied by corresponding morphological changes in patients with malignant tumors can be used as a specific diagnostic indicator.
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Coagulation/fibrinolysis and circulating tumor cells in patients with advanced breast cancer. Breast Cancer Res Treat 2022; 192:583-591. [PMID: 35132503 PMCID: PMC8960658 DOI: 10.1007/s10549-021-06484-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Accepted: 12/03/2021] [Indexed: 11/18/2022]
Abstract
Purpose To evaluate the relationship between circulating tumor cells (CTCs) and standard coagulation tests in both a discovery and a validation cohort of patients with advanced breast cancer. Methods In a retrospective (n = 77) and a prospective (n = 92) study of patients with progressive advanced breast cancer, CTC count, platelet number, fibrinogen level, D-dimers, prothrombin time, and activated partial thromboplastin time were measured. The association between these coagulation studies and CTC count was analyzed. The impact of these measurements on overall survival (OS) was assessed. Results In both cohorts, results were similar; absolute CTC count was significantly associated to D-dimer level and inversely with platelet count. In the prospective cohort, quantification of tumor-derived extracellular vesicles (tdEVs) was associated with CTC count, and with coagulation abnormalities (low platelet count and increased D-dimers). tdEVs did not add to CTC count in predicting changes in platelets or D-dimers. In multivariate analysis only CTC ≥ 5 CTC/7.5 mL, ER status, HER2 status and lines of chemotherapy were associated with OS. In patients with terminally metastatic breast cancer, very high CTC counts are prevalent. Conclusion A significant association exists between increasing CTC number and increased D-dimers and decreased platelet counts, suggesting a potential role for CTCs as a direct contributor of intravascular coagulation activation. In patients with advanced and progressive breast cancer, abnormalities in routine coagulation tests is the rule. In patients with terminally advanced breast cancer a “leukemic” phase with high CTC count is prevalent.
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Borriello L, Coste A, Traub B, Sharma VP, Karagiannis GS, Lin Y, Wang Y, Ye X, Duran CL, Chen X, Friedman M, Sosa MS, Sun D, Dalla E, Singh DK, Oktay MH, Aguirre-Ghiso JA, Condeelis JS, Entenberg D. Primary tumor associated macrophages activate programs of invasion and dormancy in disseminating tumor cells. Nat Commun 2022; 13:626. [PMID: 35110548 PMCID: PMC8811052 DOI: 10.1038/s41467-022-28076-3] [Citation(s) in RCA: 80] [Impact Index Per Article: 26.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Accepted: 01/07/2022] [Indexed: 02/07/2023] Open
Abstract
Metastases are initiated by disseminated tumor cells (DTCs) that colonize distant organs. Growing evidence suggests that the microenvironment of the primary tumor primes DTCs for dormant or proliferative fates. However, the manner in which this occurs remains poorly understood. Here, using the Window for High-Resolution Intravital Imaging of the Lung (WHRIL), we study the live lung longitudinally and follow the fate of individual DTCs that spontaneously disseminate from orthotopic breast tumors. We find that spontaneously DTCs have increased levels of retention, increased speed of extravasation, and greater survival after extravasation, compared to experimentally metastasized tumor cells. Detailed analysis reveals that a subset of macrophages within the primary tumor induces a pro-dissemination and pro-dormancy DTC phenotype. Our work provides insight into how specific primary tumor microenvironments prime a subpopulation of cells for expression of proteins associated with dissemination and dormancy.
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Affiliation(s)
- Lucia Borriello
- Department of Anatomy and Structural Biology, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, USA
- Gruss-Lipper Biophotonics Center, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, USA
| | - Anouchka Coste
- Department of Anatomy and Structural Biology, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, USA
- Department of Surgery, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, USA
| | - Brian Traub
- Department of Anatomy and Structural Biology, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, USA
- Department of Surgery, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, USA
| | - Ved P Sharma
- Department of Anatomy and Structural Biology, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, USA
- Gruss-Lipper Biophotonics Center, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, USA
- Integrated Imaging Program, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, USA
| | - George S Karagiannis
- Gruss-Lipper Biophotonics Center, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, USA
- Department of Microbiology and Immunology, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, USA
- Cancer Dormancy and Tumor Microenvironment Institute and, Einstein Cancer Center, Albert Einstein College of Medicine/Montefiore Medical Center, 1300 Morris Park Avenue, Bronx, NY, 10461, USA
| | - Yu Lin
- Department of Anatomy and Structural Biology, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, USA
- Gruss-Lipper Biophotonics Center, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, USA
| | - Yarong Wang
- Department of Anatomy and Structural Biology, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, USA
- Gruss-Lipper Biophotonics Center, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, USA
| | - Xianjun Ye
- Department of Anatomy and Structural Biology, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, USA
- Gruss-Lipper Biophotonics Center, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, USA
- Integrated Imaging Program, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, USA
| | - Camille L Duran
- Department of Anatomy and Structural Biology, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, USA
- Gruss-Lipper Biophotonics Center, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, USA
| | - Xiaoming Chen
- Department of Anatomy and Structural Biology, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, USA
- Gruss-Lipper Biophotonics Center, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, USA
- Integrated Imaging Program, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, USA
| | - Madeline Friedman
- Department of Anatomy and Structural Biology, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, USA
| | - Maria Soledad Sosa
- Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Dan Sun
- Cancer Dormancy and Tumor Microenvironment Institute and, Einstein Cancer Center, Albert Einstein College of Medicine/Montefiore Medical Center, 1300 Morris Park Avenue, Bronx, NY, 10461, USA
- Department of Cell Biology, Albert Einstein College of Medicine/Montefiore Medical Center, 1300 Morris Park Avenue, Bronx, NY, 10461, USA
| | - Erica Dalla
- Division of Hematology and Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Deepak K Singh
- Cancer Dormancy and Tumor Microenvironment Institute and, Einstein Cancer Center, Albert Einstein College of Medicine/Montefiore Medical Center, 1300 Morris Park Avenue, Bronx, NY, 10461, USA
- Department of Cell Biology, Albert Einstein College of Medicine/Montefiore Medical Center, 1300 Morris Park Avenue, Bronx, NY, 10461, USA
| | - Maja H Oktay
- Department of Anatomy and Structural Biology, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, USA
- Gruss-Lipper Biophotonics Center, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, USA
- Integrated Imaging Program, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, USA
- Cancer Dormancy and Tumor Microenvironment Institute and, Einstein Cancer Center, Albert Einstein College of Medicine/Montefiore Medical Center, 1300 Morris Park Avenue, Bronx, NY, 10461, USA
- Department of Pathology, Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, USA
| | - Julio A Aguirre-Ghiso
- Gruss-Lipper Biophotonics Center, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, USA.
- Integrated Imaging Program, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, USA.
- Cancer Dormancy and Tumor Microenvironment Institute and, Einstein Cancer Center, Albert Einstein College of Medicine/Montefiore Medical Center, 1300 Morris Park Avenue, Bronx, NY, 10461, USA.
- Department of Cell Biology, Albert Einstein College of Medicine/Montefiore Medical Center, 1300 Morris Park Avenue, Bronx, NY, 10461, USA.
| | - John S Condeelis
- Department of Anatomy and Structural Biology, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, USA.
- Gruss-Lipper Biophotonics Center, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, USA.
- Department of Surgery, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, USA.
- Integrated Imaging Program, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, USA.
- Cancer Dormancy and Tumor Microenvironment Institute and, Einstein Cancer Center, Albert Einstein College of Medicine/Montefiore Medical Center, 1300 Morris Park Avenue, Bronx, NY, 10461, USA.
| | - David Entenberg
- Department of Anatomy and Structural Biology, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, USA.
- Gruss-Lipper Biophotonics Center, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, USA.
- Integrated Imaging Program, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, USA.
- Cancer Dormancy and Tumor Microenvironment Institute and, Einstein Cancer Center, Albert Einstein College of Medicine/Montefiore Medical Center, 1300 Morris Park Avenue, Bronx, NY, 10461, USA.
- Department of Pathology, Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, USA.
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Anti-Cancer Effects of α-Cubebenoate Derived from Schisandra chinensis in CT26 Colon Cancer Cells. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27030737. [PMID: 35164001 PMCID: PMC8839175 DOI: 10.3390/molecules27030737] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Revised: 01/18/2022] [Accepted: 01/20/2022] [Indexed: 11/26/2022]
Abstract
α-Cubebenoate derived from Schisandra chinensis has been reported to possess anti-allergic, anti-obesity, and anti-inflammatory effects and to exhibit anti-septic activity, but its anti-cancer effects have not been investigated. To examine the anti-cancer activity of α-cubebenoate, we investigated its effects on the proliferation, apoptosis, and metastasis of CT26 cells. The viabilities of CT26 cells (a murine colorectal carcinoma cell line) and HCT116 cells (a human colon cancer cell line) were remarkably and dose-dependently diminished by α-cubebenoate, whereas the viability of CCD-18Co cells (a normal human fibroblast cell line) were unaffected. Furthermore, α-cubebenoate treatment increased the number of apoptotic CT26 cells as compared with Vehicle-treated cells and increased Bax, Bcl-2, Cas-3, and Cleaved Cas-3 protein levels by activating the MAP kinase signaling pathway. α-Cubebenoate also suppressed CT26 migration by regulating the PI3K/AKT signaling pathway. Furthermore, similar reductions were observed in the expression levels of some migration-related proteins including VEGFA, MMP2, and MMP9. Furthermore, reduced VEGFA expression was found to be accompanied by the phosphorylations of FAK and MLC in the downstream signaling pathway of adhesion protein. The results of the present study provide novel evidence that α-cubebenoate can stimulate apoptosis and inhibit metastasis by regulating the MAPK, PI3K/AKT, and FAK/MLC signaling pathways.
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Pshennikova ES, Voronina AS. Dormancy: There and Back Again. Mol Biol 2022; 56:735-755. [PMID: 36217335 PMCID: PMC9534470 DOI: 10.1134/s0026893322050119] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Revised: 03/27/2022] [Accepted: 03/27/2022] [Indexed: 11/04/2022]
Abstract
Many cells are capable of maintaining viability in a non-dividing state with minimal metabolism under unfavorable conditions. These are germ cells, adult stem cells, and microorganisms. Unfortunately, a resting state, or dormancy, is possible for tuberculosis bacilli in a latent form of the disease and cancer cells, which may later form secondary tumors (metastases) in different parts of the body. These cells are resistant to therapy that can destroy intensely dividing cells and to the host immune system. A cascade of reactions that allows cells to enter and exit dormancy is triggered by regulatory factors from the microenvironment in niches that harbor the cells. A ratio of forbidding and permitting signals dictates whether the cells become dormant or start proliferation. The only difference between the cell dormancy regulation in normal and pathological conditions is that pathogens, mycobacteria, and cancer cells can influence their own fate by changing their microenvironment. Certain mechanisms of these processes are considered in the review.
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Affiliation(s)
- E. S. Pshennikova
- Bakh Institute of Biochemistry, Federal Research Center of Biotechnology, Russian Academy of Sciences, 119071 Moscow, Russia
| | - A. S. Voronina
- Bakh Institute of Biochemistry, Federal Research Center of Biotechnology, Russian Academy of Sciences, 119071 Moscow, Russia
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Akgol S, Kalkan BM, Yucel D, Kocabas F. SC1 limits tube formation, branching, migration, expansion and induce apoptosis of endothelial cells. Vascul Pharmacol 2021; 141:106903. [PMID: 34481979 DOI: 10.1016/j.vph.2021.106903] [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: 04/15/2021] [Revised: 07/02/2021] [Accepted: 08/27/2021] [Indexed: 11/30/2022]
Abstract
Endothelial cells (ECs) are essential in the growth and progression of the tumor cells by supplying nutrition and angiogenesis factors. Targeting ECs emerged as a major strategy to prevent the growth of tumors. Studies suggest that ERK1/2 signaling is important for endothelial cells, which could be specifically targeted by small molecule SC1. We aimed to study the effects of SC1 treatments on endothelial cell proliferation, angiogenesis, and death. To this end, we performed viability, apoptosis, cell cycle, gene expression, wound closure, tube formation, and western blot analysis in endothelial cells post SC1 treatments. Intriguingly, we found that SC1 has an antiangiogenic effect on endothelial cells, which limits the endothelial cell expansion, tube formation, branching, and migration. The proliferation is especially limited in dose dependent manner by SC1. In addition, we found that SC1 elevates the apoptosis of endothelial cells and associated pathways including BAK1, Stat1, Sox4, and Caspase1. We believe that these findings could contribute to the development of improved therapies based on the SC1 as an attractive candidate for anticancer clinical studies targeted to tumor angiogenesis.
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Affiliation(s)
- Sezer Akgol
- Department of Genetics and Bioengineering, Faculty of Engineering, Yeditepe University, Istanbul, Turkey
| | | | - Dogacan Yucel
- Department of Medicine, University of Minnesota, USA
| | - Fatih Kocabas
- Department of Genetics and Bioengineering, Faculty of Engineering, Yeditepe University, Istanbul, Turkey.
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Cencioni C, Comunanza V, Middonti E, Vallariello E, Bussolino F. The role of redox system in metastasis formation. Angiogenesis 2021; 24:435-450. [PMID: 33909153 PMCID: PMC8292271 DOI: 10.1007/s10456-021-09779-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Accepted: 03/02/2021] [Indexed: 01/02/2023]
Abstract
The metastatic cancer disease represents the real and urgent clinical need in oncology. Therefore, an understanding of the complex molecular mechanisms sustaining the metastatic cascade is critical to advance cancer therapies. Recent studies highlight how redox signaling influences the behavior of metastatic cancer cells, contributes to their travel in bloodstream from the primary tumor to the distant organs and conditions the progression of the micrometastases or their dormant state. Radical oxygen species not only regulate intracellular processes but participate to paracrine circuits by diffusion to nearby cells, thus assuming unpredicted roles in the communication between metastatic cancer cells, blood circulating cells, and stroma cells at site of colonization. Here, we review recent insights in the role of radical oxygen species in the metastasis formation with a special focus on extravasation at metastatic sites.
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Affiliation(s)
- Chiara Cencioni
- Institute for Systems Analysis and Computer Science "A. Ruberti", National Research Council (IASI-CNR), 00185, Rome, Italy
| | - Valentina Comunanza
- Department of Oncology, University of Torino, 10043, Orbassano, Italy
- Candiolo Cancer Institute - IRCCS-FPO, 10063, Candiolo, Italy
| | - Emanuele Middonti
- Department of Oncology, University of Torino, 10043, Orbassano, Italy
- Candiolo Cancer Institute - IRCCS-FPO, 10063, Candiolo, Italy
| | - Edoardo Vallariello
- Department of Oncology, University of Torino, 10043, Orbassano, Italy
- Candiolo Cancer Institute - IRCCS-FPO, 10063, Candiolo, Italy
| | - Federico Bussolino
- Department of Oncology, University of Torino, 10043, Orbassano, Italy.
- Candiolo Cancer Institute - IRCCS-FPO, 10063, Candiolo, Italy.
- , Strada Provinciale di Piobesi 142, Km 3.95, 10060, Candiolo, Italy.
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Bhattacharya A, Santhoshkumar A, Kurahara H, Harihar S. Metastasis Suppressor Genes in Pancreatic Cancer: An Update. Pancreas 2021; 50:923-932. [PMID: 34643607 DOI: 10.1097/mpa.0000000000001853] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
ABSTRACT Pancreatic cancer, especially pancreatic ductal adenocarcinoma (PDAC), has for long remained a deadly form of cancer characterized by high mortality rates resulting from metastasis to multiple organs. Several factors, including the late manifestation of the disease, partly amplified by lack of efficient screening methods, have hampered the drive to design an effective therapeutic strategy to treat this deadly cancer. Understanding the biology of PDAC progression and identifying critical genes regulating these processes are essential to overcome the barriers toward effective treatment. Metastasis suppressor genes have been shown to inhibit multiple steps in the metastatic cascade without affecting primary tumor formation and are considered to hold promise for treating metastatic cancers. In this review, we catalog the bona fide metastasis suppressor genes reported in PDAC and discuss their known mechanism of action.
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Affiliation(s)
- Arnav Bhattacharya
- From the Department of Genetic Engineering, SRM Institute of Science and Technology, Kattankulathur, India
| | - Anirudh Santhoshkumar
- From the Department of Genetic Engineering, SRM Institute of Science and Technology, Kattankulathur, India
| | - Hiroshi Kurahara
- Department of Digestive Surgery, Breast and Thyroid Surgery, Kagoshima University, Kagoshima, Japan
| | - Sitaram Harihar
- From the Department of Genetic Engineering, SRM Institute of Science and Technology, Kattankulathur, India
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Ahmad S, Abbas M, Ullah MF, Aziz MH, Beylerli O, Alam MA, Syed MA, Uddin S, Ahmad A. Long non-coding RNAs regulated NF-κB signaling in cancer metastasis: Micromanaging by not so small non-coding RNAs. Semin Cancer Biol 2021; 85:155-163. [PMID: 34314819 DOI: 10.1016/j.semcancer.2021.07.015] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Revised: 07/17/2021] [Accepted: 07/22/2021] [Indexed: 02/06/2023]
Abstract
Cancer metastasis is a major reason for the cancer-associated deaths and a role of long non-coding RNAs (lncRNAs) in cancer metastasis is increasingly being realized. Among the many oncogenic pathways, NF-κB signalling's involvement in cancer metastasis as a key inflammation-regulatory transcription factor has been a subject of interest for long time. Accumulating data from in vitro as well as in vivo studies along with analysis of clinical cancer tissues points to regulation of NF-κB signalling by lncRNAs with implications toward the onset of cancer metastasis. LncRNAs FOXD2-AS1, KRT19P3 and the NF-κB interacting lncRNA (NKILA) associate with lymph node metastasis and poor prognosis of individual cancers. The role of epithelial-mesenchymal transition (EMT) in cancer metastasis is well known. EMT is regulated by NF-κB and regulation of NF-κB/EMT-induced metastasis by lncRNAs remains a hot topic of research with indications for such roles of lncRNAs MALAT1, SNHG15, CRNDE and AC007271.3. Among the many lncRNAs, NKILA stands out as the most investigated lncRNA for its regulation of NF-κB. This tumor suppressive lncRNA has been reported downregulated in clinical samples representing different human cancers. Mechanistically, NKILA has been consistently shown to inhibit NF-κB activation via inhibition of IκBα phosphorylation and the resulting suppression of EMT. NKILA is also a target of natural anticancer compounds. Given the importance of NF-κB as a master regulatory transcription factor, lncRNAs, as the modulators of NF-κB signaling, can provide alternate targets for metastatic cancers with constitutively active NF-κB.
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Affiliation(s)
- Shaniya Ahmad
- Translational Research Lab, Department of Biotechnology, Jamia Millia Islamia, New Delhi, 110025, India
| | - Madiha Abbas
- School of Life Sciences, Jawaharlal Nehru University, New Delhi, 110067, India
| | - Mohammad Fahad Ullah
- Prince Fahd Research Chair, Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, University of Tabuk, Saudi Arabia
| | - Moammir H Aziz
- James H. Quillen VA Medical Center, Johnson City, TN, 37604, USA
| | - Ozal Beylerli
- Bashkir State Medical University, Ufa, Republic of Bashkortostan, 450008, Russia
| | - Majid Ali Alam
- Dermatology Institute and Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Mansoor Ali Syed
- Translational Research Lab, Department of Biotechnology, Jamia Millia Islamia, New Delhi, 110025, India
| | - Shahab Uddin
- Dermatology Institute and Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar; Laboratory of Animal Center, Qatar University, Doha, Qatar
| | - Aamir Ahmad
- Dermatology Institute and Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar.
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Disseminated Melanoma Cells Transdifferentiate into Endothelial Cells in Intravascular Niches at Metastatic Sites. Cell Rep 2021; 31:107765. [PMID: 32553158 DOI: 10.1016/j.celrep.2020.107765] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2018] [Revised: 12/24/2019] [Accepted: 05/21/2020] [Indexed: 12/15/2022] Open
Abstract
Tumor cell plasticity, including transdifferentiation, is thought to be a key driver of therapy failure, tumor dormancy, and metastatic dissemination. Although melanoma cells have been shown to adopt various phenotypic features in vitro, direct in vivo evidence of metastatic cell plasticity remains sparse. Here, we combine lineage tracing in a spontaneous metastatic mouse model of melanoma, advanced imaging, and single-cell RNA sequencing approaches to search for pathophysiologically relevant melanoma cellular states. We identify melanoma cells in intravascular niches of various metastatic organs. These cells are quiescent, are negative for characteristic melanoma markers, and acquire endothelial cell features. We replicate the endothelial transdifferentiation (EndT) finding in another mouse model and provide evidence of EndT in BRAFV600E-metastatic biopsies from human lung, brain, and small intestine, thus highlighting the clinical relevance of these findings. The tumor-vasculature pattern described herein may contribute to melanoma dormancy within metastatic organs and represent a putative target for therapies.
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Khadge S, Cole K, Talmadge JE. Myeloid derived suppressor cells and the release of micro-metastases from dormancy. Clin Exp Metastasis 2021; 38:279-293. [PMID: 34014424 DOI: 10.1007/s10585-021-10098-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Accepted: 04/22/2021] [Indexed: 12/11/2022]
Abstract
Metastasis is the primary cause of cancer mortality and an improved understanding of its pathology is critical to the development of novel therapeutic approaches. Mechanism-based therapeutic strategies require insight into the timing of tumor cell dissemination, seeding of distant organs, formation of occult lesions and critically, their release from dormancy. Due to imaging limitations, primary tumors can only be detected when they reach a relatively large size (e.g. > 1 cm3), which, based on our understanding of tumor evolution, occurs approximately 10 years and about 30 doubling times following tumor initiation. Genomic profiling of paired primary tumors and metastases has suggested that tumor seeding at secondary sites occurs early during tumor progression and frequently, years prior to clinical diagnosis. Following seeding, tumor cells may enter into and remain in a dormant state, and if they survive and are released from dormancy, they can proliferate into an overt lesion. The timeline of tumor initiation and metastatic dormancy is regulated by tumor interactions with its microenvironment, angiogenesis, and tumor-specific cytotoxic T-lymphocyte (CTL) responses. Therefore, a better understanding of the cellular interactions responsible for immune evasion and/or tumor cell release from dormancy would facilitate the development of therapeutics targeted against this critical part of tumor progression. The immunosuppressive mechanisms mediated by myeloid-derived suppressor cells (MDSCs) contribute to tumor progression and, we posit, promote tumor cell escape from CTL-associated dormancy. Thus, while clinical and translational research has demonstrated a role for MDSCs in facilitating tumor progression and metastasis through tumor escape from adoptive and innate immune responses (T-, natural killer and B-cell responses), few studies have considered the role of MDSCs in tumor release from dormancy. In this review, we discuss MDSC expansion, driven by tumor burden associated growth factor secretion and their role in tumor cell escape from dormancy, resulting in manifest metastases. Thus, the therapeutic strategies to inhibit MDSC expansion and function may provide an approach to delay metastatic relapse and prolong the survival of patients with advanced malignancies.
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Affiliation(s)
- Saraswoti Khadge
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Kathryn Cole
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - James E Talmadge
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, 68198, USA. .,Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, 68198-5950, USA. .,Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, 68198-6495, USA.
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Plasmin and Plasminogen System in the Tumor Microenvironment: Implications for Cancer Diagnosis, Prognosis, and Therapy. Cancers (Basel) 2021; 13:cancers13081838. [PMID: 33921488 PMCID: PMC8070608 DOI: 10.3390/cancers13081838] [Citation(s) in RCA: 65] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2021] [Revised: 03/19/2021] [Accepted: 03/24/2021] [Indexed: 12/12/2022] Open
Abstract
Simple Summary In this review, we present a detailed discussion of how the plasminogen-activation system is utilized by tumor cells in their unrelenting attack on the tissues surrounding them. Plasmin is an enzyme which is responsible for digesting several proteins that hold the tissues surrounding solid tumors together. In this process tumor cells utilize the activity of plasmin to digest tissue barriers in order to leave the tumour site and spread to other parts of the body. We specifically focus on the role of plasminogen receptor—p11 which is an important regulatory protein that facilitates the conversion of plasminogen to plasmin and by this means promotes the attack by the tumour cells on their surrounding tissues. Abstract The tumor microenvironment (TME) is now being widely accepted as the key contributor to a range of processes involved in cancer progression from tumor growth to metastasis and chemoresistance. The extracellular matrix (ECM) and the proteases that mediate the remodeling of the ECM form an integral part of the TME. Plasmin is a broad-spectrum, highly potent, serine protease whose activation from its precursor plasminogen is tightly regulated by the activators (uPA, uPAR, and tPA), the inhibitors (PAI-1, PAI-2), and plasminogen receptors. Collectively, this system is called the plasminogen activation system. The expression of the components of the plasminogen activation system by malignant cells and the surrounding stromal cells modulates the TME resulting in sustained cancer progression signals. In this review, we provide a detailed discussion of the roles of plasminogen activation system in tumor growth, invasion, metastasis, and chemoresistance with specific emphasis on their role in the TME. We particularly review the recent highlights of the plasminogen receptor S100A10 (p11), which is a pivotal component of the plasminogen activation system.
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Sigdel I, Gupta N, Faizee F, Khare VM, Tiwari AK, Tang Y. Biomimetic Microfluidic Platforms for the Assessment of Breast Cancer Metastasis. Front Bioeng Biotechnol 2021; 9:633671. [PMID: 33777909 PMCID: PMC7992012 DOI: 10.3389/fbioe.2021.633671] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Accepted: 02/05/2021] [Indexed: 12/27/2022] Open
Abstract
Of around half a million women dying of breast cancer each year, more than 90% die due to metastasis. Models necessary to understand the metastatic process, particularly breast cancer cell extravasation and colonization, are currently limited and urgently needed to develop therapeutic interventions necessary to prevent breast cancer metastasis. Microfluidic approaches aim to reconstitute functional units of organs that cannot be modeled easily in traditional cell culture or animal studies by reproducing vascular networks and parenchyma on a chip in a three-dimensional, physiologically relevant in vitro system. In recent years, microfluidics models utilizing innovative biomaterials and micro-engineering technologies have shown great potential in our effort of mechanistic understanding of the breast cancer metastasis cascade by providing 3D constructs that can mimic in vivo cellular microenvironment and the ability to visualize and monitor cellular interactions in real-time. In this review, we will provide readers with a detailed discussion on the application of the most up-to-date, state-of-the-art microfluidics-based breast cancer models, with a special focus on their application in the engineering approaches to recapitulate the metastasis process, including invasion, intravasation, extravasation, breast cancer metastasis organotropism, and metastasis niche formation.
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Affiliation(s)
- Indira Sigdel
- Biofluidics Laboratory, Department of Bioengineering, College of Engineering, University of Toledo, Toledo, OH, United States
| | - Niraj Gupta
- Biofluidics Laboratory, Department of Bioengineering, College of Engineering, University of Toledo, Toledo, OH, United States
| | - Fairuz Faizee
- Biofluidics Laboratory, Department of Bioengineering, College of Engineering, University of Toledo, Toledo, OH, United States
| | - Vishwa M Khare
- Eurofins Lancaster Laboratories, Philadelphia, PA, United States
| | - Amit K Tiwari
- Department of Pharmacology and Experimental Therapeutics, College of Pharmacy & Pharmaceutical Sciences, University of Toledo, Toledo, OH, United States
| | - Yuan Tang
- Biofluidics Laboratory, Department of Bioengineering, College of Engineering, University of Toledo, Toledo, OH, United States
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Beato Merino M, Diago A, Fernandez-Flores A, Fraga J, García Herrera A, Garrido M, Idoate Gastearena M, Llamas-Velasco M, Monteagudo C, Onrubia J, Pérez-González Y, Pérez Muñoz N, Ríos-Martín J, Ríos-Viñuela E, Rodríguez Peralto J, Rozas Muñoz E, Sanmartín O, Santonja C, Santos-Briz A, Saus C, Suárez Peñaranda J, Velasco Benito V. Clinical and Histopathologic Characteristics of the Main Causes of Vascular Occusion — Part II: Coagulation Disorders, Emboli, and Other. ACTAS DERMO-SIFILIOGRAFICAS 2021. [DOI: 10.1016/j.adengl.2020.12.024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
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Liu J, Li X, Yue L, Lv H. Circ_0105346 Knockdown Inhibits Osteosarcoma Development via Regulating miR-1182/WNT7B Axis. Cancer Manag Res 2021; 13:521-535. [PMID: 33505171 PMCID: PMC7829129 DOI: 10.2147/cmar.s281430] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Accepted: 12/28/2020] [Indexed: 12/18/2022] Open
Abstract
Background Osteosarcoma (OS) is a common bone malignancy in children and adolescents. Circular RNAs (circRNAs) have been reported to affect OS progression. This paper mainly delineated the role of circRNA circ_0105346 in OS development and the potential mechanism. Methods Quantitative reverse transcription PCR (qRT-PCR) and Western blot assays were applied to detect the expression of circ_0105346, microRNA (miR)-1182 and wingless-type MMTV integration site family 7B (WNT7B). 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay was conducted to evaluate cell viability, and flow cytometry was performed to monitor cell apoptosis and cycle. In addition, cell migration and invasion were determined via transwell assay. Wound healing assay was also employed to evaluate the migrated capacity of OS cells. Western blot assay was also employed to examine the levels of protein markers. Additionally, the interaction between miR-1182 and circ_0105346 or WNT7B was confirmed by the dual-luciferase reporter, RNA immunoprecipitation (RIP) and pull-down assays. Mouse xenograft model was constructed to clarify the effect of circ_0105346 on tumor growth in vivo. Results Circ_0105346 and WNT7B were upregulated, while miR-1182 was downregulated in OS tissues and cells. Circ_0105346 knockdown suppressed OS cell proliferation, cell cycle, migration, invasion and glycolysis, as well as accelerated apoptosis, which was attenuated by miR-1182 inhibition. Interestingly, circ_0105346 targeted miR-1182, and miR-1182 interacted with WNT7B. Circ_0105346 could upregulate WNT7B by downregulating miR-1182 expression. Furthermore, circ_0105346 knockdown blocked tumor growth in vivo. Conclusion Circ_0105346 knockdown repressed OS progression by regulating miR-1182/WNT7B axis, at least in part.
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Affiliation(s)
- Jinbao Liu
- Department of Orthopaedics, The First Clinical Medical School, Shandong University of Traditional Chinese Medicine, Jinan 250011, People's Republic of China
| | - Xiaoyang Li
- Department of Orthopaedics, The First Clinical Medical School, Shandong University of Traditional Chinese Medicine, Jinan 250011, People's Republic of China
| | - Liang Yue
- Department of Pediatric Orthopaedics, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan 250011, People's Republic of China
| | - Hao Lv
- Department of Pediatric Orthopaedics, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan 250011, People's Republic of China
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The Diagnostic Value of FDG PET/CT and Thin-Slice High-Resolution Chest CT in Pulmonary Intravascular Metastasis. AJR Am J Roentgenol 2021; 216:769-775. [PMID: 33405948 DOI: 10.2214/ajr.20.23017] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
OBJECTIVE. Pulmonary intravascular metastasis is a special type of pulmonary metastasis of malignancies; however, few relevant studies have been performed. This study aimed to determine the characteristics of pulmonary intravascular metastasis and improve understanding of the disease by retrospective analysis of FDG PET/CT and thin-layer high-resolution CT (HRCT) imaging of the chest in patients with tumors. MATERIALS AND METHODS. We identified all patients who underwent FDG PET/CT at two hospitals between January 2016 and February 2019 and conducted a comparative analysis of HRCT and PET/CT images. In total, 84 patients (38 women and 46 men) ranging in age from 35 to 82 years old (mean age, 54.7 ± 14.5 [SD] years) participated in the study. Patient characteristics were summarized, and diagnosis was confirmed by chest CT or PET/CT follow-up. RESULTS. A total of 260 pulmonary intravascular metastases were found, which were classified as type I (no significant abnormality, n = 5), type II (abrupt and uneven thickening of the pulmonary vessel, n = 118), type III (simultaneous invasion of adjacent pulmonary vessel, n = 121), and type IV (large strip-shaped high-density mass, n = 16). The majority were located in peripheral pulmonary vessels (94.2% [245/260]). FDG up-take was increased in 252 lesions, and the mean SUVmax was 4.6 ± 2.5. CONCLUSION. The combination of PET/CT and chest HRCT is an effective approach for detecting pulmonary intravascular metastasis. The linear pattern of FDG uptake, abnormal pulmonary blood vessel morphology, and location (below the lung segment) are specific indicators for the diagnosis of pulmonary intravascular metastasis and should be recognized by clinicians and radiologists.
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Fang L, Xu Q, Qian J, Zhou JY. Aberrant Factors of Fibrinolysis and Coagulation in Pancreatic Cancer. Onco Targets Ther 2021; 14:53-65. [PMID: 33442266 PMCID: PMC7797325 DOI: 10.2147/ott.s281251] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Accepted: 12/11/2020] [Indexed: 12/13/2022] Open
Abstract
Aberrant factors associated with fibrinolysis and thrombosis are found in many cancer patients, which can promote metastasis and are associated with poor prognosis. The relationship between tumor-associated fibrinolysis and thrombosis is poorly understood in pancreatic cancer. This review provides a brief highlight of existing studies that the fibrinolysis and coagulation systems were activated in pancreatic cancer patients, along with aberrant high concentrations of tissue plasminogen activator (t-PA), urine plasminogen activator (u-PA), D-dimer, fibrinogen, or platelets. These factors cooperate with each other, propelling tumor cell shedding, localization, adhesion to distant metastasis. The relationship between thrombosis or fibrinolysis and cancer immune escape is also investigated. In addition, the potential prevention and therapy strategies of pancreatic cancer targeting factors in fibrinolysis and coagulation systems are also been discussed, in which we highlight two effective agents aspirin and low-molecular weight heparin (LMWH). Summarily, this review provides new directions for the research and treatment of pancreatic cancer.
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Affiliation(s)
- Lianghua Fang
- Department of Oncology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, People's Republic of China
| | - Qing Xu
- Women's Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, Nanjing 210029, People's Republic of China
| | - Jun Qian
- Department of Oncology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, People's Republic of China
| | - Jin-Yong Zhou
- Central Laboratory, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, People's Republic of China
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Nandi S, Ghosh S, Ranjan A, Sood RS, Pal JK, Hajela K, Gupta RK. Lectins in Health and Diseases: Galectins and Cancer. LECTINS 2021:215-271. [DOI: 10.1007/978-981-16-7462-4_11] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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