1
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Pham DL, Gillette AA, Riendeau J, Wiech K, Guzman EC, Datta R, Skala MC. Perspectives on label-free microscopy of heterogeneous and dynamic biological systems. JOURNAL OF BIOMEDICAL OPTICS 2025; 29:S22702. [PMID: 38434231 PMCID: PMC10903072 DOI: 10.1117/1.jbo.29.s2.s22702] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Revised: 11/22/2023] [Accepted: 12/14/2023] [Indexed: 03/05/2024]
Abstract
Significance Advancements in label-free microscopy could provide real-time, non-invasive imaging with unique sources of contrast and automated standardized analysis to characterize heterogeneous and dynamic biological processes. These tools would overcome challenges with widely used methods that are destructive (e.g., histology, flow cytometry) or lack cellular resolution (e.g., plate-based assays, whole animal bioluminescence imaging). Aim This perspective aims to (1) justify the need for label-free microscopy to track heterogeneous cellular functions over time and space within unperturbed systems and (2) recommend improvements regarding instrumentation, image analysis, and image interpretation to address these needs. Approach Three key research areas (cancer research, autoimmune disease, and tissue and cell engineering) are considered to support the need for label-free microscopy to characterize heterogeneity and dynamics within biological systems. Based on the strengths (e.g., multiple sources of molecular contrast, non-invasive monitoring) and weaknesses (e.g., imaging depth, image interpretation) of several label-free microscopy modalities, improvements for future imaging systems are recommended. Conclusion Improvements in instrumentation including strategies that increase resolution and imaging speed, standardization and centralization of image analysis tools, and robust data validation and interpretation will expand the applications of label-free microscopy to study heterogeneous and dynamic biological systems.
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Affiliation(s)
- Dan L. Pham
- University of Wisconsin—Madison, Department of Biomedical Engineering, Madison, Wisconsin, United States
| | | | | | - Kasia Wiech
- University of Wisconsin—Madison, Department of Biomedical Engineering, Madison, Wisconsin, United States
| | | | - Rupsa Datta
- Morgridge Institute for Research, Madison, Wisconsin, United States
| | - Melissa C. Skala
- University of Wisconsin—Madison, Department of Biomedical Engineering, Madison, Wisconsin, United States
- Morgridge Institute for Research, Madison, Wisconsin, United States
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2
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Karnachoriti M, Kouri MA, Spyratou E, Danias N, Arkadopoulos N, Efstathopoulos EP, Seimenis I, Raptis YS, Kontos AG. Raman spectroscopy for colorectal tumor margin assessment: A promising tool for real-time surgical delimitation. Talanta 2025; 290:127787. [PMID: 40010115 DOI: 10.1016/j.talanta.2025.127787] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2024] [Revised: 02/17/2025] [Accepted: 02/20/2025] [Indexed: 02/28/2025]
Abstract
Raman spectroscopy is a promising non-invasive technique not only for the rapid and accurate detection of colorectal cancer (CRC) but also for the identification of positive surgical margins. In this study, micro-Raman spectroscopy was used to explore biochemical differences in surgically resected intestinal segments, with a focus on boundary tumor zone. Spectral and statistical analyses, including Partial least squares discriminant analysis (PLS-DA), were performed to identify significant molecular signatures and distinguish different tissue types. Our findings suggest that boundary tumor zone contain a mix of cancerous and normal cells, complicating the discrimination of these regions. Despite this challenge, we achieved a classification accuracy of 82 % for tumor margin differentiation from normal tissue along with identifying several biochemically significant spectroscopic differences. Rapid Raman measurements using a portable system, taken from resected tissues immediately after surgery, further demonstrated the technique's ability to differentiate cancerous from healthy tissues with 97 % accuracy, 98 % sensitivity, and 96 % specificity, underscoring the potential of Raman spectroscopy for real-time clinical applications in CRC surgery.
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Affiliation(s)
- Maria Karnachoriti
- Physics Department, School of Applied Mathematical and Physical Sciences, National Technical University of Athens, Iroon Politechniou 9, 15772, Athens, Greece.
| | - Maria Anthi Kouri
- 2nd Department of Radiology, Medical School, National and Kapodistrian University of Athens, 11527, Athens, Greece.
| | - Ellas Spyratou
- 2nd Department of Radiology, Medical School, National and Kapodistrian University of Athens, 11527, Athens, Greece.
| | - Nikolaos Danias
- 4th Department of Surgery, School of Medicine, Attikon University Hospital, University of Athens, 1 Rimini Street, 12462, Athens, Greece.
| | - Nikolaos Arkadopoulos
- 4th Department of Surgery, School of Medicine, Attikon University Hospital, University of Athens, 1 Rimini Street, 12462, Athens, Greece.
| | - Efstathios P Efstathopoulos
- 2nd Department of Radiology, Medical School, National and Kapodistrian University of Athens, 11527, Athens, Greece.
| | - Ioannis Seimenis
- Medical School, National and Kapodistrian University of Athens, 75 Mikras Assias str., 11527, Athens, Greece.
| | - Yiannis S Raptis
- Physics Department, School of Applied Mathematical and Physical Sciences, National Technical University of Athens, Iroon Politechniou 9, 15772, Athens, Greece.
| | - Athanassios G Kontos
- Physics Department, School of Applied Mathematical and Physical Sciences, National Technical University of Athens, Iroon Politechniou 9, 15772, Athens, Greece.
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3
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Sultan MH, Zhan Q, Wang Y, Xia Y, Jia X. Precision oncolytic viral therapy in colorectal cancer: Genetic targeting and immune modulation for personalized treatment (Review). Int J Mol Med 2025; 56:104. [PMID: 40342021 PMCID: PMC12081034 DOI: 10.3892/ijmm.2025.5545] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2024] [Accepted: 04/09/2025] [Indexed: 05/11/2025] Open
Abstract
Colorectal cancer (CRC) is a leading health issue and treatments to eradicate it, such as conventional chemotherapy, are non‑selective and come with a number of complications. The present review focuses on the relatively new area of precision oncolytic viral therapy (OVT), with genetic targeting and immune modifications that offer a new future for CRC treatment. In the present review, an overview of the selection factors that are considered optimal for an oncolytic virus, mechanisms of oncolysis and immunomodulation applied to the OVT, as well as new strategies to improve the efficacy of this method are described. Additionally, cause‑and‑effect relationships are examined for OVT efficacy, mediated by the tumor microenvironment, and directions for genetic manipulation of viral specificity are explored. The possibility of synergy between OVT and immune checkpoint inhibitors and other treatment approaches are demonstrated. Incorporating the details of the present review, biomarker‑guided combination therapies in precision OVT for individualized CRC care, significant issues and future trends in this required area of medicine are highlighted. Increasingly, OVT is leaving the experimental stage and may become routine practice; it provides a new perspective on overcoming CRC and highlights the importance of further research and clinical work.
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Affiliation(s)
- Muhammad Haris Sultan
- College of Life Sciences and Medicine, Xinyuan Institute of Medicine and Biotechnology, Zhejiang Sci-Tech University, Hangzhou, Zhejiang 310018, P.R. China
- Center for Translational Medicine and Precision Medicine, Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, Zhejiang 325000, P.R. China
| | - Qi Zhan
- College of Life Sciences and Medicine, Xinyuan Institute of Medicine and Biotechnology, Zhejiang Sci-Tech University, Hangzhou, Zhejiang 310018, P.R. China
| | - Yigang Wang
- College of Life Sciences and Medicine, Xinyuan Institute of Medicine and Biotechnology, Zhejiang Sci-Tech University, Hangzhou, Zhejiang 310018, P.R. China
| | - Yulong Xia
- Center for Translational Medicine and Precision Medicine, Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, Zhejiang 325000, P.R. China
| | - Xiaoyuan Jia
- College of Life Sciences and Medicine, Xinyuan Institute of Medicine and Biotechnology, Zhejiang Sci-Tech University, Hangzhou, Zhejiang 310018, P.R. China
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4
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Zhou Y, Chen T, Pan Y, Liu J. Exploring the mechanism of fibronectin extra domain B in the tumor microenvironment and implications for targeted immunotherapy and diagnostics (Review). Mol Med Rep 2025; 31:160. [PMID: 40211711 PMCID: PMC12015389 DOI: 10.3892/mmr.2025.13525] [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: 11/05/2024] [Accepted: 01/17/2025] [Indexed: 04/25/2025] Open
Abstract
Fibronectin extra domain B (FN‑EDB) is a unique domain of FN), whose expression is significantly upregulated in the tumor microenvironment (TME). FN‑EDB plays a key role in tumor cell adhesion, angiogenesis and invasion, and is closely related to tumor malignancy and poor prognosis. Moreover, the high expression of FN‑EDB in multiple cancer types makes it a potential therapeutic target. However, comprehensive studies of the mechanism of FN‑EDB in different cancer types and its potential as therapeutic targets are lacking. The present study aimed to explore the general role of FN‑EDB in multiple types of cancer and to integrate the knowledge of cell biology, molecular biology and immunology, so as to give a comprehensive understanding of the role of FN‑EDB in TME. Furthermore, by focusing on the use of FN‑EDB in clinical diagnosis and treatment, the potential of targeting FN‑EDB as a diagnostic and therapeutic target was evaluated and the progress in clinical trials of these drugs was discussed. By searching web sites such as PubMed and web of science, various high‑quality studies including RNA sequencing, drug experiments, cell experiments, animal models, clinical randomized controlled experiments and large‑scale cohort studies were collected, with sufficient evidence to support a comprehensive evaluation of the function and potential application of FN‑EDB. The present study revealed the general role of FN‑EDB in multiple types of cancer and evaluated its potential as a diagnostic and therapeutic target. It also provided a basis for future development of more effective and precise cancer therapies.
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Affiliation(s)
- Yuan Zhou
- Department of General Surgery, Sixth Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang Uyghur Autonomous Region 830000, P.R. China
| | - Tao Chen
- Department of Vascular Surgery, Jining Medical College, Jining, Shandong 272000, P.R. China
| | - Yawen Pan
- Department of Geriatric Medicine, Sixth Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang Uyghur Autonomous Region 830000, P.R. China
| | - Jing Liu
- Department of General Surgery, Sixth Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang Uyghur Autonomous Region 830000, P.R. China
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5
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Saeed Issa B, Adhab AH, Salih Mahdi M, Kyada A, Ganesan S, Bhanot D, Naidu KS, Kaur S, Mansoor AS, Radi UK, Saadoun Abd N, Kariem M. Decoding the complex web: cellular and molecular interactions in the lung tumour microenvironment. J Drug Target 2025; 33:666-690. [PMID: 39707828 DOI: 10.1080/1061186x.2024.2445772] [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: 10/11/2024] [Revised: 12/10/2024] [Accepted: 12/15/2024] [Indexed: 12/23/2024]
Abstract
The lung tumour microenvironment (TME) or stroma is a dynamic space of numerous cells and their released molecules. This complicated web regulates tumour progression and resistance to different modalities. Lung cancer cells in conjunction with their stroma liberate a wide range of factors that dampen antitumor attacks by innate immunity cells like natural killer (NK) cells and also adaptive responses by effector T cells. These factors include numerous growth factors, exosomes and epigenetic regulators, and also anti-inflammatory cytokines. Understanding the intricate interactions between tumour cells and various elements within the lung TME, such as immune and stromal cells can help provide novel strategies for better management and treatment of lung malignancies. The current article discusses the complex network of cells and signalling molecules, which mediate communications in lung TME. By elucidating these multifaceted interactions, we aim to provide insights into potential therapeutic targets and strategies for lung cancer treatment.
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Affiliation(s)
| | | | | | - Ashishkumar Kyada
- Marwadi University Research Center, Department of Pharmaceutical Sciences, Faculty of Health Sciences, Marwadi University, Rajkot, Gujarat, India
| | - Subbulakshmi Ganesan
- Department of Chemistry and Biochemistry, School of Sciences, JAIN (Deemed to be University), Bangalore, Karnataka, India
| | - Deepak Bhanot
- Centre for Research Impact & Outcome, Chitkara University Institute of Engineering and Technology, Chitkara University, Rajpura, Punjab, India
| | - K Satyam Naidu
- Department of Chemistry, Raghu Engineering College, Visakhapatnam, Andhra Pradesh, India
| | - Sharnjeet Kaur
- Department of Applied Sciences, Chandigarh Engineering College, Chandigarh Group of Colleges-Jhanjeri, Mohali, Punjab, India
| | | | - Usama Kadem Radi
- Collage of Pharmacy, National University of Science and Technology, Dhi Qar, Iraq
| | - Nasr Saadoun Abd
- Medical Technical College, Al-Farahidi University, Baghdad, Iraq
| | - Muthena Kariem
- Department of Medical Analysis, Medical Laboratory Technique College, The Islamic University, Najaf, Iraq
- Department of Medical Analysis, Medical Laboratory Technique College, The Islamic University of Al Diwaniyah, Al Diwaniyah, Iraq
- Department of Medical Analysis, Medical Laboratory Technique College, The Islamic University of Babylon, Babylon, Iraq
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6
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Shi W, Tang H, Tan S, Wang L, Yu Z, Gao S, Zhou J. MMA-induced LOXL2 + PSCs promote linear ECM alignment in the aging pancreas leading to pancreatic cancer progression. Cell Death Dis 2025; 16:419. [PMID: 40425551 PMCID: PMC12116754 DOI: 10.1038/s41419-025-07751-5] [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: 12/21/2024] [Revised: 05/02/2025] [Accepted: 05/21/2025] [Indexed: 05/29/2025]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an age-associated malignancy closely linked to the extracellular matrix (ECM). However, the impact of age-related ECM changes in the normal pancreas on PDAC progression remains unclear. Here, we find that increased linear ECM alignment in normal pancreatic tissues from aged PDAC patients is associated with PDAC progression and worse outcomes. Furthermore, serum methylmalonic acid (MMA) levels are elevated in aged PDAC patients and associated with increased linear ECM alignment in normal pancreatic tissues of PDAC patients. Functionally, MMA promotes LOXL2 expression in pancreatic stellate cells (PSCs), increases linear ECM alignment in normal pancreatic tissues, and facilitates tumor progression. Mechanistically, MMA upregulates KLF10, which forms a transcriptional complex with SP1 to enhance LOXL2 expression in PSCs. Our study demonstrates the role of MMA-induced LOXL2+PSCs in ECM remodeling, thus serving as a potential therapeutic target to mitigate PDAC progression in aged patients. Schematic diagram showing the molecular mechanism by which MMA-induced LOXL+PSCs promote PDAC progression in the aging pancreas. In aged individuals, elevated levels of MMA in the blood induce the activation of the KLF10/SP1‒LOXL2 axis in PSCs to increase linear ECM alignment. Following the initiation of pancreatic cancer, this increased linear ECM alignment leads to increased tumor invasion into surrounding tissues, resulting in a greater proportion of stage T3/T4 tumors and a greater incidence of LVI and PNI in aged patients, ultimately leading to poorer outcomes (This schematic was created with www.figdraw.com ,export id: PRPRS4e268).
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Affiliation(s)
- Wenyuan Shi
- Department of Hepato-Pancreatico-Biliary Surgery, Zhongda Hospital Southeast University, Nanjing, China
- Department of Surgery, School of Medicine, Southeast University, Nanjing, China
| | - Haodong Tang
- Department of Hepato-Pancreatico-Biliary Surgery, Zhongda Hospital Southeast University, Nanjing, China
- Department of Surgery, School of Medicine, Southeast University, Nanjing, China
| | - Siyuan Tan
- Department of Hepato-Pancreatico-Biliary Surgery, Zhongda Hospital Southeast University, Nanjing, China
- Department of Surgery, School of Medicine, Southeast University, Nanjing, China
| | - Lishan Wang
- Department of Hepato-Pancreatico-Biliary Surgery, Zhongda Hospital Southeast University, Nanjing, China
- Department of Surgery, School of Medicine, Southeast University, Nanjing, China
| | - Zeqian Yu
- Department of Hepato-Pancreatico-Biliary Surgery, Zhongda Hospital Southeast University, Nanjing, China
- Department of Surgery, School of Medicine, Southeast University, Nanjing, China
| | - Shan Gao
- Zhongda Hospital, School of Life Sciences and Technology, Advanced Institute for Life and Health, Southeast University, Nanjing, China
| | - Jiahua Zhou
- Department of Hepato-Pancreatico-Biliary Surgery, Zhongda Hospital Southeast University, Nanjing, China.
- Department of Surgery, School of Medicine, Southeast University, Nanjing, China.
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7
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Lee JJ, Ng KY, Bakhtiar A. Extracellular matrix: unlocking new avenues in cancer treatment. Biomark Res 2025; 13:78. [PMID: 40426238 PMCID: PMC12117852 DOI: 10.1186/s40364-025-00757-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2024] [Accepted: 03/05/2025] [Indexed: 05/29/2025] Open
Abstract
The extracellular matrix (ECM) plays a critical role in cancer progression by influencing tumor growth, invasion, and metastasis. This review explores the emerging therapeutic strategies that target the ECM as a novel approach in cancer treatment. By disrupting the structural and biochemical interactions within the tumor microenvironment, ECM-targeted therapies aim to inhibit cancer progression and overcome therapeutic resistance. We examine the current state of ECM research, focusing on key components such as collagen, laminin, fibronectin, periostin, and hyaluronic acid, and their roles in tumor biology. Additionally, we discuss the challenges associated with ECM-targeted therapies, including drug delivery, specificity, and potential side effects, while highlighting recent advancements and future directions. This review underscores the potential of ECM-focused strategies to enhance the efficacy of existing treatments and contribute to more effective cancer therapies.
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Affiliation(s)
- Jia Jing Lee
- School of Pharmacy, Monash University Malaysia, Jalan Lagoon Selatan, Bandar Sunway, 47500, Selangor, Malaysia
| | - Khuen Yen Ng
- School of Pharmacy, Monash University Malaysia, Jalan Lagoon Selatan, Bandar Sunway, 47500, Selangor, Malaysia
| | - Athirah Bakhtiar
- School of Pharmacy, Monash University Malaysia, Jalan Lagoon Selatan, Bandar Sunway, 47500, Selangor, Malaysia.
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8
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Ke ZB, Chen JY, Xue YT, Lin B, Huang Q, Huang XY, Chen DN, Chen SH, Ye XJ, Zheng QS, Wei Y, Xue XY, Xu N. Mechanical signal modulates prostate cancer immune escape by USP8-mediated ubiquitination-dependent degradation of PD-L1 and MHC-1. Cell Death Dis 2025; 16:413. [PMID: 40410130 PMCID: PMC12102395 DOI: 10.1038/s41419-025-07736-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2024] [Revised: 04/30/2025] [Accepted: 05/13/2025] [Indexed: 05/25/2025]
Abstract
The tumor environment of prostate cancer (PCa) tissues of high Gleason score has been proved to be more immune suppressive and has higher extracellular matrix (ECM) stiffness, but whether ECM mechanical stiffness is the cause of higher ability of invasiveness and immune escape of PCa with high Gleason score remains uncertain. In this study, we showed that higher polyacrylamide hydrogels (PAAG) stiffness resulted in the progression and immune escape of PCa via integrin β1/FAK/YAP axis. The translocation of YAP into cell nucleus to bind to TEAD2 promoted the transcriptional activation of USP8. NBR1 could be ubiquitinated, and then degraded, via interacting with P62/SQSTM1 and through autophagy-lysosome pathway. Increased expression of USP8 promoted the abundance of NBR1 via K63-linked de-ubiquitination and PD-L1 via K48-linked de-ubiquitination in response to high PAAG stiffness. NBR1-mediated selective autophagy accelerated the degradation of MHC-1 of PCa. The USP8 inhibitor presented a potential application value in sensitizing immunotherapy of PCa. Taken together, we identified a USP8-mediated de-ubiquitination mechanism that involves in the process of high PAAG stiffness-mediated high expression of PD-L1 and low expression of MHC-1 of PCa cells, which provided a rationale of immunotherapy sensitization of PCa via USP8 inhibition.
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Affiliation(s)
- Zhi-Bin Ke
- Department of Urology, Urology Research Institute, the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, China
- Department of Urology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350212, China
| | - Jia-Yin Chen
- Department of Urology, Urology Research Institute, the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, China
- Department of Urology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350212, China
| | - Yu-Ting Xue
- Department of Urology, Urology Research Institute, the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, China
- Department of Urology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350212, China
| | - Bin Lin
- Department of Urology, Urology Research Institute, the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, China
- Department of Urology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350212, China
| | - Qi Huang
- Department of Urology, Urology Research Institute, the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, China
- Department of Urology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350212, China
| | - Xu-Yun Huang
- Department of Urology, Urology Research Institute, the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, China
- Department of Urology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350212, China
| | - Dong-Ning Chen
- Department of Urology, Urology Research Institute, the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, China
- Department of Urology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350212, China
| | - Shao-Hao Chen
- Department of Urology, Urology Research Institute, the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, China
- Department of Urology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350212, China
| | - Xiao-Jian Ye
- Department of Ultrasonography, the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, China
| | - Qing-Shui Zheng
- Department of Urology, Urology Research Institute, the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, China
- Department of Urology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350212, China
| | - Yong Wei
- Department of Urology, Urology Research Institute, the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, China
- Department of Urology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350212, China
| | - Xue-Yi Xue
- Department of Urology, Urology Research Institute, the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, China.
- Department of Urology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350212, China.
- Fujian Key Laboratory of Precision Medicine for Cancer, the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, China.
| | - Ning Xu
- Department of Urology, Urology Research Institute, the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, China.
- Department of Urology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350212, China.
- Fujian Key Laboratory of Precision Medicine for Cancer, the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, China.
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9
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Li Y, Tang T, Sun Y, Chen G, Yuan X, Cai D. The role of TLR-4 in chemoresistance of cancer. Discov Oncol 2025; 16:865. [PMID: 40404908 PMCID: PMC12098248 DOI: 10.1007/s12672-025-02509-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2025] [Accepted: 04/25/2025] [Indexed: 05/24/2025] Open
Abstract
Chemotherapy, which aims to eradicate tumor cells and enhance patient survival, is a prevalent approach for tumor treatment. Nevertheless, recurrence and drug resistance resulting from consecutive chemotherapy regimens have emerged as significant factors contributing to the high fatality rates among cancer patients. Numerous studies have revealed that chemicals discharged by injured and deceased cells can trigger the host repair program mediated by toll-like receptor-4 (TLR-4), enhancing tumor resistance. TLR-4 is not only expressed in immune cells but also in various malignant tumor cells, especially inflammation-associated tumor cells, and plays a crucial role in tumor formation, development, and chemoresistance. Endogenous ligands are released upon the killing of tumor cells by chemotherapy drugs, binding to and activating TLR-4, subsequently activating downstream NF-κB and other essential molecules, leading to the release of multiple factors associated with tumor proliferation and invasion, creating a microenvironment conducive to local recurrence and metastasis, and promoting tumor progression and drug resistance. This review assessed studies on the resistance of several tumor cells to commonly utilized anticancer treatments induced by TLR-4 to better comprehend the phenomena and mechanism of TLR-4-dependent resistance, as well as to put forward suggestions and insights for overcoming tumor resistance.
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Affiliation(s)
- Yuhua Li
- Department of Pharmacy, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, Guangdong, People's Republic of China
- Department of Pharmacy, The First Naval Force Hospital of Southern Theatre Command, Zhanjiang, 524005, Guangdong, People's Republic of China
| | - Tianle Tang
- Xijing Hospital, The Fourth Military Medical University, Xi'an, 710032, Shaanxi, People's Republic of China
| | - Yang Sun
- Key Laboratory of Gastrointestinal Pharmacology of Chinese Materia Medica of the State Administration of Traditional Chinese Medicine, Department of Pharmacology, School of Pharmacy, The Fourth Military Medical University, Xi'an, 710032, Shaanxi, People's Republic of China
| | - Gui'e Chen
- Department of Pharmacy, The First Naval Force Hospital of Southern Theatre Command, Zhanjiang, 524005, Guangdong, People's Republic of China
| | - Xinrong Yuan
- Department of Gynecology and Obstetrics, The First Naval Force Hospital of Southern Theatre Command, Zhanjiang, 524005, Guangdong, People's Republic of China.
| | - De Cai
- Department of Pharmacy, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, Guangdong, People's Republic of China.
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10
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Zhou M, Wu W, Wang Y, Zhang B, Zhao X, Zhou H, Cao Y, Wu P, Wang M, Wang J. Targeting COL5A1 enhances anoikis thus attenuating malignancy of glioblastoma via inhibiting the Wnt/β-catenin signaling pathway. J Neurooncol 2025:10.1007/s11060-025-05036-7. [PMID: 40402199 DOI: 10.1007/s11060-025-05036-7] [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: 02/25/2025] [Accepted: 04/03/2025] [Indexed: 05/23/2025]
Abstract
PURPOSE As one of the most prevalent primary brain tumors, glioblastoma (GBM) is characterized by its severe malignancy and extremely poor prognosis. Recent studies have demonstrated that targeting anoikis and malignancy showed impressed efficiency for treatment in a wide range of solid tumors, however, relevant research on GBM still remains unclarified. METHODS In this study, genes related with malignancy and anoikis of GBM were identified by utilizing the Cancer Genome Atlas (TCGA), the Chinese Glioma Genome Atlas (CGGA) and the Molecular Signatures Database (MSigDB). Subsequently, the role of the key gene was validated via proliferation, invasion and migration experiments both in conditions with and without attachment. Moreover, RNA sequencing analysis was employed to reveal further mechanisms. RESULTS Here, Type V collagen alpha 1 (COL5A1) was identified as a critical gene associated with anoikis and poor outcomes. Additionally, COL5A1 knockdown induced significant reduction in malignancy of GBM both in vitro and in vivo. Moreover, cell anoikis was remarkable enhanced by reduced expression of COL5A1 after low-attachment cell culture. Mechanically, RNA sequencing analysis revealed that the activity of the Wnt/β-catenin signaling pathway was diminished following COL5A1 knockdown, which indicated that COL5A1 reduced anoikis via regulating Wnt/β-catenin signaling pathway thus promoted malignancies of GBM cells. CONCLUSION These findings demonstrated the novel evidence that COL5A1 serves as an essential regulatory factor influencing both anoikis and malignancy of GBM cells by regulating Wnt/β-catenin signaling pathway, indicating that COL5A1 could be a novel prognosis-related biomarker and potential therapeutic target for GBM.
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Affiliation(s)
- Mingjing Zhou
- Department of Neurosurgery, The First Affiliated Hospital of Xi'an Jiaotong University, 277, Yanta West Road, Xi'an, Shaanxi, 710061, China
- Center of Brain Science, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China
| | - Wei Wu
- Department of Neurosurgery, The First Affiliated Hospital of Xi'an Jiaotong University, 277, Yanta West Road, Xi'an, Shaanxi, 710061, China
- Center of Brain Science, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China
| | - Yichang Wang
- Department of Neurosurgery, The First Affiliated Hospital of Xi'an Jiaotong University, 277, Yanta West Road, Xi'an, Shaanxi, 710061, China
- Center of Brain Science, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China
| | - Beichen Zhang
- Department of Neurosurgery, The First Affiliated Hospital of Xi'an Jiaotong University, 277, Yanta West Road, Xi'an, Shaanxi, 710061, China
- Center of Brain Science, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China
| | - Xuyan Zhao
- Comprehensive Breast Care Center, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710004, China
| | - Haoyu Zhou
- Department of Neurosurgery, The First Affiliated Hospital of Xi'an Jiaotong University, 277, Yanta West Road, Xi'an, Shaanxi, 710061, China
- Center of Brain Science, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China
| | - Yiyang Cao
- Department of Neurosurgery, The First Affiliated Hospital of Xi'an Jiaotong University, 277, Yanta West Road, Xi'an, Shaanxi, 710061, China
- Center of Brain Science, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China
| | - Pancheng Wu
- Department of Neurosurgery, The First Affiliated Hospital of Xi'an Jiaotong University, 277, Yanta West Road, Xi'an, Shaanxi, 710061, China
- Center of Brain Science, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China
| | - Maode Wang
- Department of Neurosurgery, The First Affiliated Hospital of Xi'an Jiaotong University, 277, Yanta West Road, Xi'an, Shaanxi, 710061, China.
- Center of Brain Science, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China.
| | - Jia Wang
- Department of Neurosurgery, The First Affiliated Hospital of Xi'an Jiaotong University, 277, Yanta West Road, Xi'an, Shaanxi, 710061, China.
- Center of Brain Science, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China.
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11
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Wu KZ, Ding RH, Zhao Z, Chong CYL, You R, Zhou H, Seah DH, Leow WQ, Lim HK, Shyamasundar S, Fernando K, Kuthubudeen FF, Ng G, Tay CY, Iyer NG, Ong CAJ, Fong ELS. Hydrogel-Mediated Preservation of Live Tumor Explants for Drug Development in Peritoneal Metastases. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2025:e2418647. [PMID: 40391640 DOI: 10.1002/adma.202418647] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/29/2024] [Revised: 04/17/2025] [Indexed: 05/22/2025]
Abstract
Clinically effective treatments for peritoneal metastases (PM) remain a significant unmet need. To expedite drug development in PM, hyaluronan (HA) hydrogel-supported PM patient-derived tumor explants (PDTE) that better preserve histological features, composition, and biological pathways of the original tumor, as compared to conventional PDTE culture methods are developed. Hydrogel modulation shows that stiffness, degradation, three-dimensional embedding, and HA itself are key parameters that enhance PDTE maintenance ex vivo. Further, HA hydrogels effectively preserve PDTE viability by disrupting myosin II-mediated tissue contraction, a phenomenon that occurs in the absence of hydrogel embedding. Lastly, the addition of ascites into PM PDTE not only recapitulates changes to the tumor microenvironment as observed in patients but also ascites-dependent drug efficacy, highlighting the importance of incorporating ascites into ex vivo PM models for accurate therapeutic evaluation. The bioengineered PM PDTE models in this study serve as a valuable platform for drug development and treatment personalization.
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Affiliation(s)
- Kenny Zhuoran Wu
- Department of Biomedical Engineering, National University of Singapore, 15 Kent Ridge Crescent, Singapore, 119276, Singapore
| | - Rockie Haiyao Ding
- Department of Biomedical Engineering, National University of Singapore, 15 Kent Ridge Crescent, Singapore, 119276, Singapore
| | - Zixuan Zhao
- The N.1 Institute for Health, National University of Singapore, 28 Medical Drive, Singapore, 117456, Singapore
| | - Clara Yieh Lin Chong
- Laboratory of Applied Human Genetics, Division of Medical Sciences, National Cancer Center Singapore, 30 Hospital Boulevard, Singapore, 168583, Singapore
- Department of Sarcoma, Peritoneal and Rare Tumors (SPRinT), Division of Surgery and Surgical Oncology, Singapore General Hospital, Outram Road, 169608 and National Cancer Center Singapore, 30 Hospital Boulevard, Singapore, 168583, Singapore
| | - Ruochii You
- Department of Biomedical Engineering, National University of Singapore, 15 Kent Ridge Crescent, Singapore, 119276, Singapore
| | - Hengjia Zhou
- Department of Biomedical Engineering, National University of Singapore, 15 Kent Ridge Crescent, Singapore, 119276, Singapore
| | - Dong Hua Seah
- Department of Biomedical Engineering, National University of Singapore, 15 Kent Ridge Crescent, Singapore, 119276, Singapore
| | - Wei Qiang Leow
- Department of Anatomical Pathology, Division of Pathology, Singapore General Hospital, 20 College Road, Singapore, 169856, Singapore
| | - Hong Kit Lim
- School of Materials Science and Engineering, Nanyang Technological University, 50 Nanyang Avenue, Singapore, 639798, Singapore
| | - Sukanya Shyamasundar
- Multiphoton Microscopy Core Facility, Yong Loo Lin School of Medicine, National University of Singapore, 4 Science Drive 2, Singapore, 117544, Singapore
| | - Kanishka Fernando
- Department of Biomedical Engineering, National University of Singapore, 15 Kent Ridge Crescent, Singapore, 119276, Singapore
| | - Fathima Farzana Kuthubudeen
- Department of Biomedical Engineering, National University of Singapore, 15 Kent Ridge Crescent, Singapore, 119276, Singapore
| | - Gillian Ng
- Laboratory of Applied Human Genetics, Division of Medical Sciences, National Cancer Center Singapore, 30 Hospital Boulevard, Singapore, 168583, Singapore
- Department of Sarcoma, Peritoneal and Rare Tumors (SPRinT), Division of Surgery and Surgical Oncology, Singapore General Hospital, Outram Road, 169608 and National Cancer Center Singapore, 30 Hospital Boulevard, Singapore, 168583, Singapore
| | - Chor Yong Tay
- School of Materials Science and Engineering, Nanyang Technological University, 50 Nanyang Avenue, Singapore, 639798, Singapore
| | - Narayanan Gopalakrishna Iyer
- Division of Surgical Oncology, National Cancer Center Singapore, 30 Hospital Boulevard, Singapore, 168583, Singapore
- Department of Head and Neck surgery, Singapore General Hospital, Outram Road, Singapore, 169608, Singapore
| | - Chin-Ann Johnny Ong
- Laboratory of Applied Human Genetics, Division of Medical Sciences, National Cancer Center Singapore, 30 Hospital Boulevard, Singapore, 168583, Singapore
- Department of Sarcoma, Peritoneal and Rare Tumors (SPRinT), Division of Surgery and Surgical Oncology, Singapore General Hospital, Outram Road, 169608 and National Cancer Center Singapore, 30 Hospital Boulevard, Singapore, 168583, Singapore
- SingHealth Duke-NUS Oncology Academic Clinical Program, Duke-NUS Medical School, 8 College Road, Singapore, 169857, Singapore
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Proteos, 138673, Singapore
| | - Eliza Li Shan Fong
- Department of Biomedical Engineering, National University of Singapore, 15 Kent Ridge Crescent, Singapore, 119276, Singapore
- The N.1 Institute for Health, National University of Singapore, 28 Medical Drive, Singapore, 117456, Singapore
- Cancer Science Institute, National University of Singapore, 14 Medical Drive, Singapore, 117599, Singapore
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12
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Xu DM, Chen LX, Xue T, Zhuang XY, Wei LC, Han H, Mo M. Decoding the impact of MMP1+ malignant subsets on tumor-immune interactions: insights from single-cell and spatial transcriptomics. Cell Death Discov 2025; 11:244. [PMID: 40394037 DOI: 10.1038/s41420-025-02503-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2024] [Revised: 04/15/2025] [Accepted: 04/23/2025] [Indexed: 05/22/2025] Open
Abstract
Matrix metalloproteinase 1 plays a pivotal role in tumor biology and immune modulation through its enzymatic remodeling of the extracellular matrix, facilitating tumor progression. In this study, we utilized large-scale single-cell RNA sequencing and spatial transcriptomics to investigate MMP1 expression, its cellular localization, and its impact on tumor progression and immune modulation. Our findings reveal that MMP1 expression is elevated in various tumor types and is strongly correlated with metastatic potential. High MMP1 expression was associated with increased activity in epithelial-mesenchymal transition signaling and TNFα/NF-κB pathways, which are known to promote tumor progression. Furthermore, MMP1+ malignant cells exhibited significant interactions with immune cells, particularly macrophages and CD8+ T cells. MMP1 expression correlated with enhanced macrophage infiltration and impaired CD8+ T-cell function, contributing to an immunosuppressive tumor microenvironment. Notably, the CXCL16-CXCR6 and ANXA1-FPR3 signaling axes were identified as key mediators of these interactions. Inhibition of MMP1 in vitro demonstrated reduced cell invasion, stemness, and proliferation, while increasing reactive oxygen species levels and promoting apoptosis. Our findings position MMP1 as a key player in the "tumor-immune" vicious cycle and a promising therapeutic target to enhance anti-tumor responses and improve patient outcomes.
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Affiliation(s)
- Da-Ming Xu
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, P. R. China
- Department of Urology, Sun Yat-sen University Cancer Center, Guangzhou, P.R. China
| | - Ling-Xiao Chen
- Department of Urology, Xiangya Hospital, Central South University, Changsha, P.R. China
| | - Ting Xue
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, P. R. China
- Department of Urology, Sun Yat-sen University Cancer Center, Guangzhou, P.R. China
| | - Xiao-Yu Zhuang
- Department of Anesthesiology, Second Affiliated Hospital of Shantou University Medical College, Shantou, P. R. China
| | - Li-Chao Wei
- Department of Organ Transplantation, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, P.R. China
| | - Hui Han
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, P. R. China.
- Department of Urology, Sun Yat-sen University Cancer Center, Guangzhou, P.R. China.
| | - Miao Mo
- Department of Urology, Xiangya Hospital, Central South University, Changsha, P.R. China.
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13
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Baldassarre G, L de la Serna I, Vallette FM. Death-ision: the link between cellular resilience and cancer resistance to treatments. Mol Cancer 2025; 24:144. [PMID: 40375296 PMCID: PMC12080166 DOI: 10.1186/s12943-025-02339-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2025] [Accepted: 04/22/2025] [Indexed: 05/18/2025] Open
Abstract
One of the key challenges in defeating advanced tumors is the ability of cancer cells to evade the selective pressure imposed by chemotherapy, targeted therapies, immunotherapy and cellular therapies. Both genetic and epigenetic alterations contribute to the development of resistance, allowing cancer cells to survive initially effective treatments. In this narration, we explore how genetic and epigenetic regulatory mechanisms influence the state of tumor cells and their responsiveness to different therapeutic strategies. We further propose that an altered balance between cell growth and cell death is a fundamental driver of drug resistance. Cell death programs exist in various forms, shaped by cell type, triggering factors, and microenvironmental conditions. These processes are governed by temporal and spatial constraints and appear to be more heterogeneous than previously understood. To capture the intricate interplay between death-inducing signals and survival mechanisms, we introduce the concept of Death-ision. This framework highlights the dynamic nature of cell death regulation, determining whether specific cancer cell clones evade or succumb to therapy. Building on this understanding offers promising strategies to counteract resistant clones and enhance therapeutic efficacy. For instance, combining DNMT inhibitors with immune checkpoint blockade may counteract YAP1-driven resistance or the use of transcriptional CDK inhibitors could prevent or overcome chemotherapy resistance. Death-ision aims to provide a deeper understanding of the diversity and evolution of cell death programs, not only at diagnosis but also throughout disease progression and treatment adaptation.
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Affiliation(s)
- Gustavo Baldassarre
- Division of Molecular Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, National Cancer Institute, Aviano, 33081, Italy.
| | - Ivana L de la Serna
- Department of Cell and Cancer Biology, University of Toledo College of Medicine and Life Sciences, Toledo, OH, 43614, USA.
| | - François M Vallette
- Centre de Recherche en Cancérologie et Immunologie Intégrées Nantes Angers (CRCI2 NA), INSERM UMR1307/CNRS UMR 6075/Nantes Université/Univ. Angers. Nantes, 44007, Nantes, France.
- Institut de Cancérologie de L'Ouest (ICO), 44085, Saint-Herblain, France.
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14
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Deng H, Xiao Q, Xu X, Zhang L, Zhang Y. Quercetin Inhibits Gastric Cancer Progression via FAM198B/MAPK Pathway Modulation. Pharmgenomics Pers Med 2025; 18:115-141. [PMID: 40390771 PMCID: PMC12087595 DOI: 10.2147/pgpm.s511324] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2025] [Accepted: 05/07/2025] [Indexed: 05/21/2025] Open
Abstract
Background The family with the sequence similarity 198 member B (FAM198B) has been found to contribute to the progression of gastric cancer (GC). However, the role and molecular mechanism of FAM198B in GC remains poorly understood. This work found a link between FAM198B and quercetin, and the regulatory effect of FAM198B on the MAPK pathway of GC. Methods FAM198B expression was identified through multiple public data sets and verified in clinical tissue samples. The associations between FAM198B and the prognosis of patients with GC were analyzed via the Kaplan‒Meier plotter and Cox regression analysis. Gene set enrichment analysis, coexpressed genes, and RNA sequencing were used to explore the related functions and signaling pathways of FAM198B in GC. In vitro assays assessed the effects of FAM198B knockdown on GC cells. FAM198B was found as a quercetin target by the HERB database and in vitro assays. Results FAM198B was highly expressed in tissues from GC patients (p<0.001) and was positively associated with poor prognosis (p<0.001) and immune cell infiltration in GC patients. FAM198B knockdown inhibited the proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) of GC cells (all p<0.05). In addition, FAM198B knockdown decreased the phosphorylation of p-Erk1/2 and p-p38 in GC cells (all p<0.01). Quercetin inhibited FAM198B expression and the phosphorylation of p-Erk1/2 and p-p38 in GC cells (all p<0.05). Conclusion Quercetin inhibits the proliferation, migration, invasion, and EMT of GC cells by inhibiting the FAM198B/MAPK signaling pathway. These discoveries lay the groundwork for developing the treatment of GC by quercetin and targeting FAM198B. In the future, more preclinical and clinical studies are needed to confirm the efficacy and safety of quercetin and target FAM198B in GC.
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Affiliation(s)
- Hongyang Deng
- Department of General Surgery, Hepatic-Biliary-Pancreatic Institute, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, Gansu, People’s Republic of China
| | - Qi Xiao
- Department of General Surgery, Hepatic-Biliary-Pancreatic Institute, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, Gansu, People’s Republic of China
| | - Xiaodong Xu
- Department of General Surgery, Hepatic-Biliary-Pancreatic Institute, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, Gansu, People’s Republic of China
| | - Lingyi Zhang
- Department of Liver Disease, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, Gansu, People’s Republic of China
| | - Youcheng Zhang
- Department of General Surgery, Hepatic-Biliary-Pancreatic Institute, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, Gansu, People’s Republic of China
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15
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Larrea Murillo L, Green M, Mahon N, Saiani A, Tsigkou O. Modelling Cancer Pathophysiology: Mechanisms and Changes in the Extracellular Matrix During Cancer Initiation and Early Tumour Growth. Cancers (Basel) 2025; 17:1675. [PMID: 40427172 PMCID: PMC12110603 DOI: 10.3390/cancers17101675] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2025] [Revised: 05/05/2025] [Accepted: 05/09/2025] [Indexed: 05/29/2025] Open
Abstract
Cancer initiation and early tumour growth are complex processes influenced by multiple cellular and microenvironmental factors. A critical aspect of tumour progression is the dynamic interplay between cancer cells and the extracellular matrix (ECM), which undergoes significant alterations to support malignancy. The loss of cell polarity is an early hallmark of tumour progression, disrupting normal tissue architecture and fostering cancerous transformation. Circumstantially, cancer-associated microRNAs (miRNAs) regulate key oncogenic processes, including ECM remodelling, epithelial-to-mesenchymal transition (EMT), and tumorigenic vascular development, further driving tumour growth. ECM alterations, particularly changes in stiffness and mechanotransduction signals, create a supportive niche for cancer cells, enhancing their survival, proliferation, and invasion. EMT and its subtype, epithelial-to-endothelial transition (EET), contribute to tumour plasticity, promote the generation of cancer stem cells (CSCs), and support tumour vascularisation. Furthermore, processes of vascular development like vasculogenesis and angiogenesis are critical for sustaining early tumour growth, supplying oxygen and nutrients to hypoxic malignant cells within the evolving cancerous microenvironments. This review explores key mechanisms underlying these changes in tumorigenic microenvironments, with an emphasis on their collective role for tumour initiation and early tumour growth. It will further delve into present in vitro modelling strategies developed to closely mimic early cancer pathophysiology. Understanding these processes is crucial for developing targeted therapies aimed at disrupting key cancer-promoting pathways and improving clinical outcomes.
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Affiliation(s)
- Luis Larrea Murillo
- Department of Materials, School of Natural Sciences, Faculty of Science and Engineering, The University of Manchester, Manchester M13 9PL, UK; (M.G.)
- The Henry Royce Institute, Royce Hub Building, Manchester M13 9PL, UK
| | - Megan Green
- Department of Materials, School of Natural Sciences, Faculty of Science and Engineering, The University of Manchester, Manchester M13 9PL, UK; (M.G.)
- The Henry Royce Institute, Royce Hub Building, Manchester M13 9PL, UK
- Manchester Institute of Biotechnology (MIB), The University of Manchester, Manchester M1 7DN, UK
| | - Niall Mahon
- Department of Materials, School of Natural Sciences, Faculty of Science and Engineering, The University of Manchester, Manchester M13 9PL, UK; (M.G.)
- The Henry Royce Institute, Royce Hub Building, Manchester M13 9PL, UK
- Manchester Institute of Biotechnology (MIB), The University of Manchester, Manchester M1 7DN, UK
| | - Alberto Saiani
- Department of Materials, School of Natural Sciences, Faculty of Science and Engineering, The University of Manchester, Manchester M13 9PL, UK; (M.G.)
- Manchester Institute of Biotechnology (MIB), The University of Manchester, Manchester M1 7DN, UK
| | - Olga Tsigkou
- Department of Materials, School of Natural Sciences, Faculty of Science and Engineering, The University of Manchester, Manchester M13 9PL, UK; (M.G.)
- The Henry Royce Institute, Royce Hub Building, Manchester M13 9PL, UK
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16
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Wang Y, Zhu N, Liu J, Chen F, Song Y, Ma Y, Yang Z, Wang D. Role of tumor microenvironment in ovarian cancer metastasis and clinical advancements. J Transl Med 2025; 23:539. [PMID: 40369674 PMCID: PMC12079989 DOI: 10.1186/s12967-025-06508-0] [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: 01/13/2025] [Accepted: 04/16/2025] [Indexed: 05/16/2025] Open
Abstract
Ovarian cancer (OC) is the most lethal gynecological malignancy worldwide, characterized by heterogeneity at the molecular, cellular and anatomical levels. Most patients are diagnosed at an advanced stage, characterized by widespread peritoneal metastasis. Despite optimal cytoreductive surgery and platinum-based chemotherapy, peritoneal spread and recurrence of OC are common, resulting in poor prognoses. The overall survival of patients with OC has not substantially improved over the past few decades, highlighting the urgent necessity of new treatment options. Unlike the classical lymphatic and hematogenous metastasis observed in other malignancies, OC primarily metastasizes through widespread peritoneal seeding. Tumor cells (the "seeds") exhibit specific affinities for certain organ microenvironments (the "soil"), and metastatic foci can only form when there is compatibility between the "seeds" and "soil." Recent studies have highlighted the tumor microenvironment (TME) as a critical factor influencing the interactions between the "seeds" and "soil," with ascites and the local peritoneal microenvironment playing pivotal roles in the initiation and progression of OC. Prior to metastasis, the interplay among tumor cells, immunosuppressive cells, and stromal cells leads to the formation of an immunosuppressive pre-metastatic niche in specific sites. This includes characteristic alterations in tumor cells, recruitment and functional anomalies of immune cells, and dysregulation of stromal cell distribution and function. TME-mediated crosstalk between cancer and stromal cells drives tumor progression, therapy resistance, and metastasis. In this review, we summarize the current knowledge on the onset and metastatic progression of OC. We provide a comprehensive discussion of the characteristics and functions of TME related to OC metastasis, as well as its association with peritoneal spread. We also outline ongoing relevant clinical trials, aiming to offer new insights for identifying potential effective biomarkers and therapeutic targets in future clinical practice.
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Affiliation(s)
- Yang Wang
- Department of Gynecology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Cancer Hospital of Dalian University of Technology, No.44 Xiaoheyan Road, Dadong District, Shenyang, Liaoning Province, 110042, People's Republic of China
| | - Na Zhu
- Department of Gynecology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Cancer Hospital of Dalian University of Technology, No.44 Xiaoheyan Road, Dadong District, Shenyang, Liaoning Province, 110042, People's Republic of China
| | - Jing Liu
- Department of Gynecology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Cancer Hospital of Dalian University of Technology, No.44 Xiaoheyan Road, Dadong District, Shenyang, Liaoning Province, 110042, People's Republic of China
| | - Fang Chen
- Department of Gynecology, People's Hospital of Liaoning Province, Shenyang, Liaoning Province, 110016, People's Republic of China
| | - Yang Song
- Department of Gynecology and Obstetrics, Shengjing Hospital of China Medical University, No.36, Sanhao Street, Heping District, Shenyang, Liaoning, 110004, People's Republic of China
| | - Yue Ma
- Department of Gynecology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Cancer Hospital of Dalian University of Technology, No.44 Xiaoheyan Road, Dadong District, Shenyang, Liaoning Province, 110042, People's Republic of China.
| | - Zhuo Yang
- Department of Gynecology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Cancer Hospital of Dalian University of Technology, No.44 Xiaoheyan Road, Dadong District, Shenyang, Liaoning Province, 110042, People's Republic of China.
| | - Danbo Wang
- Department of Gynecology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Cancer Hospital of Dalian University of Technology, No.44 Xiaoheyan Road, Dadong District, Shenyang, Liaoning Province, 110042, People's Republic of China.
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17
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Feng Y, Jiang Y, Yang L, Lu D, Li N, Zhang Q, Yang H, Qin H, Zhang J, Gou X, Jiang F. Targeting CAFs and extracellular matrix (ECM) in lung cancer: Potential of adjuvants and nanoparticles. Bioorg Chem 2025; 162:108586. [PMID: 40398184 DOI: 10.1016/j.bioorg.2025.108586] [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: 04/04/2025] [Revised: 05/09/2025] [Accepted: 05/11/2025] [Indexed: 05/23/2025]
Abstract
Cancer-associated fibroblasts (CAFs) are prominent components of the lung tumor stroma and are known to foster tumor growth, invasion, and metastasis through extracellular matrix (ECM) and tumor stroma remodeling. The interactions of CAFs with cancer cells and other stromal components contribute significantly to the aggressive nature of lung cancer and pose challenges to conventional treatment approaches. Simultaneously, the ECM, which contains numerous proteins and other molecules surrounding cancer cells, serves as more than just a structural scaffold. In lung cancer, alterations in ECM composition and organization not only promote tumor cell proliferation and survival but also impact drug penetration, immune cell infiltration, and therapeutic resistance. Targeting the intricate interplay between CAFs and the dynamic ECM in lung cancer represents a crucial frontier in oncology research. This review aims to delve deeply into the pivotal roles of CAFs and the ECM in the tumorigenesis and progression of lung cancer. Then, the potential of utilizing adjuvants, phytochemicals, and nanoparticles to modulate the functions of CAFs and remodel the ECM in the lung tumor will be reviewed.
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Affiliation(s)
- Yuan Feng
- Doctoral student of Guangxi University of Chinese Medicine in grade 2022, Nanning, Guangxi 530200, China
| | - Ying Jiang
- Department of Neurology, Ruikang Hospital affiliated to Guangxi University of Chinese Medicine, Nanning, Guangxi 530011, China
| | - Lin Yang
- Master student of Guangxi University of Chinese Medicine in 2022, Nanning, Guangxi 530200, China
| | - Danni Lu
- Master student of Guangxi University of Chinese Medicine in 2022, Nanning, Guangxi 530200, China
| | - Ning Li
- Master student of Guangxi University of Chinese Medicine in 2023, Nanning, Guangxi 530200, China
| | - Qun Zhang
- Master student of Guangxi University of Chinese Medicine in 2023, Nanning, Guangxi 530200, China
| | - Haiyan Yang
- Master student of Guangxi University of Chinese Medicine in 2023, Nanning, Guangxi 530200, China
| | - Huiyuan Qin
- Master student of Guangxi University of Chinese Medicine in 2024, Nanning, Guangxi 530200, China
| | - Jiaxin Zhang
- Master student of Guangxi University of Chinese Medicine in 2024, Nanning, Guangxi 530200, China
| | - Xinyun Gou
- Master student of Guangxi University of Chinese Medicine in 2024, Nanning, Guangxi 530200, China
| | - Feng Jiang
- Science and Technology Department of Ruikang Hospital affiliated to Guangxi University of Chinese Medicine, 530011, China.
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18
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Wang H, Zhu YN, Zhang S, Liu K, Huang R, Li Z, Mei L, Li Y. Transcriptome-wide analysis reveals potential roles of CFD and ANGPTL4 in fibroblasts regulating B cell lineage for extracellular matrix-driven clustering and novel avenues for immunotherapy in breast cancer. Mol Med 2025; 31:179. [PMID: 40340806 PMCID: PMC12063413 DOI: 10.1186/s10020-025-01237-y] [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: 12/02/2024] [Accepted: 04/28/2025] [Indexed: 05/10/2025] Open
Abstract
BACKGROUND The remodeling of the extracellular matrix (ECM) plays a pivotal role in tumor progression and drug resistance. However, the compositional patterns of ECM in breast cancer and their underlying biological functions remain elusive. METHODS Transcriptome and genome data of breast cancer patients from TCGA database was downloaded. Patients were classified into different clusters by using non-negative matrix factorization (NMF) based on signatures of ECM components and regulators. Weighted Gene Co-expression Network Analysis (WGCNA) was used to identify core genes related to ECM clusters. Additional 10 independent public cohorts including Metabric, SCAN_B, GSE12276, GSE16446, GSE19615, GSE20685, GSE21653, GSE58644, GSE58812, and GSE88770 were collected to construct Training or Testing cohort, following machine learning calculating ECM correlated index (ECI) for survival analysis. Pathway enrichment and correlation analysis were used to explore the relationship among ECM clusters, ECI and TME. Single-cell transcriptome data from GSE161529 was processed for uncovering the differences among ECM clusters. RESULTS Using NMF, we identified three ECM clusters in the TCGA database: C1 (Neuron), C2 (ECM), and C3 (Immune). Subsequently, WGCNA was employed to pinpoint cluster-specific genes and develop a prognostic model. This model demonstrated robust predictive power for breast cancer patient survival in both the Training cohort (n = 5,392, AUC = 0.861) and the Testing cohort (n = 1,344, AUC = 0.711). Upon analyzing the tumor microenvironment (TME), we discovered that fibroblasts and B cell lineage were the core cell types associated with the ECM cluster phenotypes. Single-cell RNA sequencing data further revealed that angiopoietin like 4 (ANGPTL4)+ fibroblasts were specifically linked to the C2 phenotype, while complement factor D (CFD)+ fibroblasts characterized the other ECM clusters. CellChat analysis indicated that ANGPTL4+ and CFD+ fibroblasts regulate B cell lineage via distinct signaling pathways. Additionally, analysis using the Kaplan-Meier Plotter website showed that CFD was favorable for immunotherapy response, whereas ANGPTL4 negatively impacted the outcomes of cancer patients receiving immunotherapy. CONCLUSION We identified distinct ECM clusters in breast cancer patients, irrespective of molecular subtypes. Additionally, we constructed an effective prognostic model based on these ECM clusters and recognized ANGPTL4+ and CFD+ fibroblasts as potential biomarkers for immunotherapy in breast cancer.
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Affiliation(s)
- Hongwei Wang
- Department of Oncological Surgery, Harbin Medical University Cancer Hospital, Harbin, 150000, Heilongjiang Province, China
| | - Yu-Nan Zhu
- Department of Oncological Surgery, Harbin Medical University Cancer Hospital, Harbin, 150000, Heilongjiang Province, China
| | - Sifan Zhang
- Department of Neurobiology, Harbin Medical University, Harbin, 150081, Heilongjiang Province, China
| | - Kexin Liu
- Department of Oncological Surgery, Harbin Medical University Cancer Hospital, Harbin, 150000, Heilongjiang Province, China
| | - Rong Huang
- Department of Oncological Surgery, Harbin Medical University Cancer Hospital, Harbin, 150000, Heilongjiang Province, China
| | - Zhigao Li
- Department of Oncological Surgery, Harbin Medical University Cancer Hospital, Harbin, 150000, Heilongjiang Province, China.
| | - Lan Mei
- Department of Oncological Surgery, Harbin Medical University Cancer Hospital, Harbin, 150000, Heilongjiang Province, China.
| | - Yingpu Li
- Department of Oncological Surgery, Harbin Medical University Cancer Hospital, Harbin, 150000, Heilongjiang Province, China.
- NHC Key Laboratory of Cell Transplantation, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, Heilongjiang Province, China.
- Genomics Research Center (Key Laboratory of Gut Microbiota and Pharmacogenomics of Heilongjiang Province), College of Pharmacy, Harbin Medical University, Harbin, 150081, Heilongjiang Province, China.
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19
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Ghafoor S, Garcia E, Jay DJ, Persad S. Molecular Mechanisms Regulating Epithelial Mesenchymal Transition (EMT) to Promote Cancer Progression. Int J Mol Sci 2025; 26:4364. [PMID: 40362600 PMCID: PMC12072817 DOI: 10.3390/ijms26094364] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2025] [Revised: 04/27/2025] [Accepted: 04/29/2025] [Indexed: 05/15/2025] Open
Abstract
The process of epithelial-mesenchymal transition (EMT) is crucial in various physiological/pathological circumstances such as development, wound healing, stem cell behavior, and cancer progression. It involves the conversion of epithelial cells into a mesenchymal phenotype, which causes the cells to become highly motile. This reprogramming is initiated and controlled by various signaling pathways and governed by several key transcription factors, including Snail 1, Snail 2 (Slug), TWIST 1, TWIST2, ZEB1, ZEB2, PRRX1, GOOSECOID, E47, FOXC2, SOX4, SOX9, HAND1, and HAND2. The intracellular signaling pathways are activated/inactivated by signals received from the extracellular environment and the transcription factors are carefully regulated at the transcriptional, translational, and post-translational levels to maintain tight regulatory control of EMT. One of the most important pathways involved in this process is the transforming growth factor-β (TGFβ) family signaling pathway. This review will discuss the role of EMT in promoting epithelial cancer progression and the convergence/interplay of multiple signaling pathways and transcription factors that regulate this phenomenon.
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Affiliation(s)
| | | | | | - Sujata Persad
- Department of Pediatrics, Faculty of Medicine and Dentistry, 3020R Katz Group Centre for Pharmacy and Health Research, University of Alberta, Edmonton, AB T6G 2E1, Canada; (S.G.); (E.G.); (D.J.J.)
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20
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Aquino A, Franzese O. Reciprocal Modulation of Tumour and Immune Cell Motility: Uncovering Dynamic Interplays and Therapeutic Approaches. Cancers (Basel) 2025; 17:1547. [PMID: 40361472 PMCID: PMC12072109 DOI: 10.3390/cancers17091547] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2025] [Revised: 04/28/2025] [Accepted: 04/30/2025] [Indexed: 05/15/2025] Open
Abstract
Dysregulated cell movement is a hallmark of cancer progression and metastasis, the leading cause of cancer-related mortality. The metastatic cascade involves tumour cell migration, invasion, intravasation, dissemination, and colonisation of distant organs. These processes are influenced by reciprocal interactions between cancer cells and the tumour microenvironment (TME), including immune cells, stromal components, and extracellular matrix proteins. The epithelial-mesenchymal transition (EMT) plays a crucial role in providing cancer cells with invasive and stem-like properties, promoting dissemination and resistance to apoptosis. Conversely, the mesenchymal-epithelial transition (MET) facilitates metastatic colonisation and tumour re-initiation. Immune cells within the TME contribute to either anti-tumour response or immune evasion. These cells secrete cytokines, chemokines, and growth factors that shape the immune landscape and influence responses to immunotherapy. Notably, immune checkpoint blockade (ICB) has transformed cancer treatment, yet its efficacy is often dictated by the immune composition of the tumour site. Elucidating the molecular cross-talk between immune and cancer cells, identifying predictive biomarkers for ICB response, and developing strategies to convert cold tumours into immune-active environments is critical to overcoming resistance to immunotherapy and improving patient survival.
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Affiliation(s)
| | - Ornella Franzese
- Department of Systems Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy;
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21
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Young MJ, Huang YH, Hung JJ. The combination of USP24-i-101-Astemizole sensitizes the cytotoxicity of Taxol and Gefitinib in drug-resistant lung cancer. Biomed Pharmacother 2025; 186:118047. [PMID: 40233501 DOI: 10.1016/j.biopha.2025.118047] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2025] [Revised: 03/23/2025] [Accepted: 04/04/2025] [Indexed: 04/17/2025] Open
Abstract
In this study, we utilized the yeast two-hybrid system to screen for proteins interacting with USP24. Out of 250 such proteins, functional enrichment analysis using MetaCore™ indicated that 33 of them were involved in lung cancer progression. We then investigated gene expression and survival rates of these 33 proteins in lung cancer patients and cell lines through TCGA databases, Kaplan-Meier Plotter databases, and RNA-seq profile from A549/A549-T24 cells. By employing the patients' survival rate and gene expression profile of these 33 USP24-interacting proteins as gene signatures, we identified 10 potential drugs for inhibiting lung cancer progression or drug resistance via drug repurposing strategy using the Connectivity Map (CMap) database. Of these 10 drugs, six showed similar indicators in Clinical Trials, while the other four candidates (15-delta prostaglandin J2, Astemizole, Trifluoperazine, and 1,4-chrysenequinone) were chosen to evaluate their effect on re-sensitizing cytotoxicity of Taxol and Gefitinib in drug-resistant cancer cells. Experiments demonstrated that treatment with USP24-i-101 and Astemizole alone significantly inhibited drug resistance and re-sensitized the cytotoxicity of Taxol and Gefitinib in drug-resistant lung cancer cells. Notably, combination therapy with USP24-i-101and Astemizole re-sensitized the cytotoxicity of Taxol and Gefitinib in drug-resistant lung cancer, which could benefit in inhibiting drug resistance during cancer therapy.
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Affiliation(s)
- Ming-Jer Young
- Department of Biotechnology and Bioindustry Sciences, National Cheng Kung University, Tainan, Taiwan
| | - Yi-Han Huang
- Department of Biotechnology and Bioindustry Sciences, National Cheng Kung University, Tainan, Taiwan; Research Center for Neuroscience, Taipei Medical University, Taipei 110, Taiwan
| | - Jan-Jong Hung
- Department of Biotechnology and Bioindustry Sciences, National Cheng Kung University, Tainan, Taiwan.
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22
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Liu Z, Yang F, Hao Y, Jiang Q, Jiang Y, Zhang S, Zhang Y, Zheng Q, Niu Z, Zhu H, Zhou X, Lu J, Gao H. A nomogram for predicting the risk of liver metastasis in non-functional neuroendocrine neoplasms: A population-based study. EUROPEAN JOURNAL OF SURGICAL ONCOLOGY 2025; 51:109708. [PMID: 40024114 DOI: 10.1016/j.ejso.2025.109708] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2024] [Revised: 02/12/2025] [Accepted: 02/17/2025] [Indexed: 03/04/2025]
Abstract
BACKGROUND Non-functional gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are rare tumors, and liver metastasis is the leading cause of death in patients with GEP-NENs. Due to the difficulty in conducting large cohort studies, no reliable tool currently exists to predict the risk of liver metastasis in these patients. This study aimed to develop and validate a nomogram model based on large cohort clinical data to accurately predict the risk of liver metastasis in patients with non-functional GEP-NENs. METHODS A retrospective cohort study was conducted, encompassing 838 patients with non-functional GEP-NENs diagnosed between 2009 and 2023. Independent risk factors for liver metastasis were identified through univariate and multivariate logistic regression analyses. A nomogram was constructed based on significant predictors, including T stage, N stage, Ki-67 index, primary tumor site, and BMI. The model's performance was evaluated using the C-index, calibration curves, and decision curve analysis (DCA) for both training and validation cohorts. RESULTS The nomogram demonstrated excellent predictive performance, with C-index values of 0.839 and 0.823 for the training and validation sets, respectively. Risk stratification using the nomogram's total score effectively differentiated high-risk from low-risk patients. Kaplan-Meier survival analysis revealed significant survival differences between these groups (P < 0.0001). Moreover, the calibration curves indicated strong agreement between predicted and observed outcomes. CONCLUSIONS The developed nomogram is a reliable tool for predicting the risk of liver metastasis in non-functional GEP-NENs. It facilitates early identification of high-risk patients, thereby enabling personalized treatment and timely intervention. Future research should focus on multicenter validation and the integration of molecular markers to enhance the robustness and clinical applicability of the model.
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Affiliation(s)
- Zhipeng Liu
- Department of Hepatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, PR China
| | - Faji Yang
- Department of Hepatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, PR China
| | - Yijie Hao
- Department of Hepatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, PR China
| | - Qirong Jiang
- Department of Hepatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, PR China
| | - Yupeng Jiang
- Department of Hepatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, PR China
| | - Shizhe Zhang
- Department of Hepatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, PR China
| | - Yisu Zhang
- Department of Hepatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, PR China
| | - Qixuan Zheng
- Department of Hepatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, PR China
| | - Zheyu Niu
- Department of Hepatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, PR China
| | - Huaqiang Zhu
- Department of Hepatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, PR China
| | - Xu Zhou
- Department of Hepatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, PR China
| | - Jun Lu
- Department of Hepatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, PR China.
| | - Hengjun Gao
- Department of Hepatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, PR China.
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23
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Dong L, Zhang X, Yu X, Liu G, Yang L. Proteoglycan-degrading enzymes engineered for enhanced tumor microenvironment interaction in renal cell carcinoma. Int J Biol Macromol 2025; 307:140440. [PMID: 39884611 DOI: 10.1016/j.ijbiomac.2025.140440] [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: 10/15/2024] [Revised: 01/13/2025] [Accepted: 01/27/2025] [Indexed: 02/01/2025]
Abstract
This work optimized proteoglycan-degrading enzymes through targeted mutagenesis to enhance their interaction with the tumor microenvironment in Renal Cell Carcinoma (RCC). A comprehensive mutagenesis approach identified 60 key mutations significantly improving enzymatic activity, stability, and structural integrity. When compared to Wild Type (WT) enzyme, a remarkable increase in specific activity by 35 % (p < 0.001) and a considerable decrease in the Km values for hyaluronidases from 2.5 mM to 1.5 mM (p < 0.05), as a result of these modifications. Computational methods are then employed to analyze the active site of the enzymes to detect potential residues that may alter. These computational techniques include molecular docking and protein structure prediction. The structural models of the enzymes are created by utilizing homology modeling and crystallography. These models demonstrate the spatial arrangement of the amino acid enzymes. It also illustrated the specific mutations to improve the potential of enzymes to relate to the Extracellular Matrix (ECM) of tumors. The computational screening methods effectively predicted how the modifications impact enzyme catalytic efficiency and stability. The modified enzymes retained 85 % of the enzyme activity, while the WT retained 60 %. Thus, the modified enzymes demonstrated better thermal stability than WT. Vitro test analyses show that the proteoglycan breakdown was significantly reduced by 70 % (p < 0.001), and for effective proteoglycan breakdown, hyaluronidase concentration is needed. This work proposed a novel therapeutic approach called proteoglycan-degrading enzymes for the treatment of RCC. These proteoglycan-degrading enzymes are more stable and effective for treating RCC, as demonstrated in the outcomes. Customized proteoglycan-degrading enzymes make the therapy more effective. The effective breakdown of the tumor's ECM in RCC models establishes this customized proteoglycan-degrading enzyme. These enzymes are effective for this customized cancer treatment as they improve stability, activity, and interaction with the TME.
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Affiliation(s)
- Lingling Dong
- Second Department of Cardiovascular Medicine, Shengjing Hospital Affiliated to China Medical University, Shenyang, Liaoning Province, China
| | - Xiaoli Zhang
- Department of Critical Care Medicine, Shengjing Hospital of China Medical University, No. 36, Sanhao Street, Heping District, Shenyang 110004, PR China
| | - Xiaopeng Yu
- Oncology Department, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, China
| | - Gang Liu
- Department of Urology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Lina Yang
- Second Department of Cardiovascular Medicine, Shengjing Hospital Affiliated to China Medical University, No. 36, Sanhao Street, Heping District, Shenyang 110004, Liaoning Province, China.
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24
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Liu Y, Zhang X, Gu W, Su H, Wang X, Wang X, Zhang J, Xu M, Sheng W. Unlocking the crucial role of cancer-associated fibroblasts in tumor metastasis: Mechanisms and therapeutic prospects. J Adv Res 2025; 71:399-413. [PMID: 38825314 DOI: 10.1016/j.jare.2024.05.031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2024] [Revised: 04/13/2024] [Accepted: 05/29/2024] [Indexed: 06/04/2024] Open
Abstract
BACKGROUND Tumor metastasis represents a stepwise progression and stands as a principal determinant of unfavorable prognoses among cancer patients. Consequently, an in-depth exploration of its mechanisms holds paramount clinical significance. Cancer-associated fibroblasts (CAFs), constituting the most abundant stromal cell population within the tumor microenvironment (TME), have garnered robust evidence support for their pivotal regulatory roles in tumor metastasis. AIM OF REVIEW This review systematically explores the roles of CAFs at eight critical stages of tumorigenic dissemination: 1) extracellular matrix (ECM) remodeling, 2) epithelial-mesenchymal transition (EMT), 3) angiogenesis, 4) tumor metabolism, 5) perivascular migration, 6) immune escape, 7) dormancy, and 8) premetastatic niche (PMN) formation. Additionally, we provide a compendium of extant strategies aimed at targeting CAFs in cancer therapy. KEY SCIENTIFIC CONCEPTS OF REVIEW This review delineates a structured framework for the interplay between CAFs and tumor metastasis while furnishing insights for the potential therapeutic developments. It contributes to a deeper understanding of cancer metastasis within the TME, facilitating the utilization of CAF-targeting therapies in anti-metastatic approaches.
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Affiliation(s)
- Yingxue Liu
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Institute of Pathology, Fudan University, Shanghai 200032, China
| | - Xiaoyan Zhang
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Institute of Pathology, Fudan University, Shanghai 200032, China
| | - Wenchao Gu
- Department of Diagnostic and Interventional Radiology, University of Tsukuba, Ibaraki, Japan
| | - Hui Su
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Institute of Pathology, Fudan University, Shanghai 200032, China
| | - Xin Wang
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Institute of Pathology, Fudan University, Shanghai 200032, China
| | - Xu Wang
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Institute of Pathology, Fudan University, Shanghai 200032, China
| | - Jiayu Zhang
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Institute of Pathology, Fudan University, Shanghai 200032, China
| | - Midie Xu
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Institute of Pathology, Fudan University, Shanghai 200032, China.
| | - Weiqi Sheng
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Institute of Pathology, Fudan University, Shanghai 200032, China.
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25
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Yuan L, Zhong L, Krummenacher C, Zhao Q, Zhang X. Epstein-Barr virus-mediated immune evasion in tumor promotion. Trends Immunol 2025; 46:386-402. [PMID: 40240193 DOI: 10.1016/j.it.2025.03.007] [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: 10/31/2024] [Revised: 03/12/2025] [Accepted: 03/20/2025] [Indexed: 04/18/2025]
Abstract
Epstein-Barr virus (EBV) was the first DNA virus identified to be tightly associated with multiple human tumors. It promotes malignant progression of tumors - including related lymphomas, nasopharyngeal carcinoma, and gastric adenocarcinoma - in part by evading surveillance and attack by the host immune system. In this article we review the main molecular mechanisms by which EBV-encoded proteins and RNAs interact with key molecules of the host immune system to inhibit Toll-like receptor (TLR)-nuclear factor κB (NF-κB), retinoic acid-inducible gene I (RIG-I), and interferon (IFN) signaling pathways, affect antigen presentation, prevent the cytotoxic effects of CD8+ effector cells, regulate the tumor microenvironment (TME) and cell metastasis and invasion, and inhibit cell apoptosis. These interactions not only contribute to the persistence of the virus but also provide potential targets for developing new immunotherapy strategies.
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Affiliation(s)
- Lie Yuan
- College of Pharmacy, Chongqing Medical University, Chongqing, China
| | - Ling Zhong
- College of Pharmacy, Chongqing Medical University, Chongqing, China
| | - Claude Krummenacher
- Department of Biological and Biomedical Sciences, Rowan University, Glassboro, NJ, USA.
| | - Qinjian Zhao
- College of Pharmacy, Chongqing Medical University, Chongqing, China.
| | - Xiao Zhang
- College of Pharmacy, Chongqing Medical University, Chongqing, China.
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26
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Chen R, Zhang R, Ke F, Guo X, Zeng F, Liu Q. Mechanisms of breast cancer metastasis: the role of extracellular matrix. Mol Cell Biochem 2025; 480:2771-2796. [PMID: 39652293 DOI: 10.1007/s11010-024-05175-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2024] [Accepted: 11/23/2024] [Indexed: 05/03/2025]
Abstract
The components of the extracellular matrix (ECM) are dynamic, and they mediate mechanical signals that modulate cellular behaviors. Disruption of the ECM can induce the migration and invasion of cancer cells via specific signaling pathways and cytokines. Metastasis is a leading cause of high mortality in malignancies, and early intervention can improve survival rates. However, breast cancer is frequently diagnosed subsequent to metastasis, resulting in poor prognosis and distant metastasis poses substantial hurdles in therapy. In breast cancer, there is notable tissue remodeling of ECM proteins, with several identified as essential components for metastasis. Moreover, specific ECM molecules, receptors, enzymes, and various signaling pathways play crucial roles in breast cancer metastasis, drug treatment, and resistance. The in-depth consideration of these elements could provide potential therapeutic targets to enhance the survival rates and quality of life for breast cancer patients. This review explores the mechanisms by which alterations in the ECM contribute to breast cancer metastasis and discusses current clinical applications targeting ECM in breast cancer treatment, offering valuable perspectives for future ECM-based therapies.
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Affiliation(s)
- Rui Chen
- School of Pharmacy, Southwest Medical University, Luzhou, 646000, China
- Laboratory of Biochemistry and Molecular Biology, School of Basic Medical Science, Southwest Medical University, Luzhou, 646000, China
| | - Ranqi Zhang
- School of Pharmacy, Southwest Medical University, Luzhou, 646000, China
- Laboratory of Biochemistry and Molecular Biology, School of Basic Medical Science, Southwest Medical University, Luzhou, 646000, China
| | - Famin Ke
- School of Pharmacy, Southwest Medical University, Luzhou, 646000, China
| | - Xiurong Guo
- School of Pharmacy, Southwest Medical University, Luzhou, 646000, China
| | - Fancai Zeng
- Laboratory of Biochemistry and Molecular Biology, School of Basic Medical Science, Southwest Medical University, Luzhou, 646000, China.
| | - Qiuyu Liu
- School of Pharmacy, Southwest Medical University, Luzhou, 646000, China.
- Laboratory of Biochemistry and Molecular Biology, School of Basic Medical Science, Southwest Medical University, Luzhou, 646000, China.
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27
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Metzker-Pinto T, Tran YTH, Buzzatto-Leite I, Lok L, Sampar JF, Carvalho HF, Del Monte-Nieto G, Alvares LE. The chicken embryo brings new insights into the evolutionary role of WFDC1 during amniote development. Dev Biol 2025; 521:96-107. [PMID: 39947419 DOI: 10.1016/j.ydbio.2025.02.008] [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: 10/02/2024] [Revised: 02/05/2025] [Accepted: 02/08/2025] [Indexed: 02/19/2025]
Abstract
WFDC1 encodes an extracellular matrix protein involved in cell proliferation, migration, and epithelial-mesenchymal transition in disease conditions. Despite this, Wfdc1-null mice display no discernible malformations while cattle bearing a WFDC1 mutation present multiple ocular defects, leaving the role of WFDC1 during embryonic development unclear. To address this, we used the chicken embryo as a model to investigate WFDC1 developmental roles in amniotes. We performed a comparative expression analysis during chicken and mouse development, which revealed expression in ectodermal and mesodermal derivatives, with both conserved and species-specific domains. Conserved expression was observed in the eye, otic vesicle, central and peripheral nervous systems, and neural crest cells. Chicken-specific expression was identified in mesodermal structures, including the notochord, limbs and heart. However, even in the conserved sites like the eyes, WFDC1 localizes to different retinal layers, indicating potential divergence roles in retinal development and function across species. In contrast, WFDC1 expression in the limb buds is specific to chicken, encompassing the distal mesenchyme, interdigital membranes, and blastemas. Functional enrichment analysis links WFDC1 to limb patterning, morphogenesis, and Wnt signaling. The species-specific differences likely stem from evolutionary changes in gene regulation, supported by differences in proximal cis-regulatory elements of the WFDC1 loci between chicken and mouse. The complexity of WFDC1 expression in the chicken embryo, along with WFDC1 regulatory conservation within birds, indicates that this gene may play specific roles in avian development, possibly contributing to features specific to this lineage. Future studies using the chicken model will be valuable in further uncovering the specific roles of WFDC1.
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Affiliation(s)
- Thaís Metzker-Pinto
- Department of Biochemistry and Tissue Biology, University of Campinas (UNICAMP), Campinas, SP, Brazil
| | - Yen T H Tran
- Australian Regenerative Medicine Institute, Monash University, Melbourne, Victoria, Australia
| | - Igor Buzzatto-Leite
- Department of Biochemistry and Tissue Biology, University of Campinas (UNICAMP), Campinas, SP, Brazil
| | - Lloyd Lok
- Australian Regenerative Medicine Institute, Monash University, Melbourne, Victoria, Australia
| | - Jórdan F Sampar
- Department of Biochemistry and Tissue Biology, University of Campinas (UNICAMP), Campinas, SP, Brazil
| | - Hernandes F Carvalho
- Department of Structural and Functional Biology, University of Campinas (UNICAMP), Campinas, SP, Brazil
| | - Gonzalo Del Monte-Nieto
- Australian Regenerative Medicine Institute, Monash University, Melbourne, Victoria, Australia.
| | - Lúcia E Alvares
- Department of Biochemistry and Tissue Biology, University of Campinas (UNICAMP), Campinas, SP, Brazil.
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Chen Y, Yan Z, Li L, Liang Y, Wei X, Zhao Y, Cao Y, Zhang H, Tang L. Identification and validation of a 9-RBPs-related gene signature associated with prognosis and immune infiltration in bladder cancer based on bioinformatics analysis and machine learning. Transl Androl Urol 2025; 14:1066-1081. [PMID: 40376515 PMCID: PMC12076236 DOI: 10.21037/tau-2024-688] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2024] [Accepted: 03/24/2025] [Indexed: 05/18/2025] Open
Abstract
Background Bladder cancer (BLCA) is the most common type of malignancy affecting the urinary tract, characterized by high recurrence rates, propensity for progression, metastatic potential, and multidrug resistance, all of which ultimately contribute to an unfavorable prognosis. RNA-binding proteins (RBPs) play a critical role in cancer development and have been associated with the progression and prognosis of the disease. However, comprehensive investigations into the biological functions and molecular mechanisms of RBPs in BLCA remain limited. The study aims to explore the relationship between RBPs and prognosis in BLCA, and to develop and validate an RBPs-based prognostic signature, providing new insights for the diagnosis and treatment of BLCA. Methods Clinical data and RBPs expression profiles of BLCA patients were sourced from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). A systematic bioinformatics analysis was conducted to identify differentially expressed RBPs and assess their prognostic significance. The optimal predictive model was selected by integrating multiple machine learning algorithms, enabling the identification of hub genes associated with BLCA prognosis and developing an RBP-related gene signature. To evaluate the prognostic signature's efficacy, survival curves and receiver operating characteristic (ROC) curves were generated. A nomogram was constructed and validated to predict the survival of BLCA patients at 1, 3, and 5 years. Furthermore, analyses of immune infiltration and gene set enrichment analysis (GSEA) were conducted to explore the roles of RBPs in immune cell interactions and elucidate underlying biological pathways. Results A prognostic signature was effectively developed using nine RBPs (OAS1, MTG1, DUS4L, IGF2BP3, NOL12, PABPC1L, ZC3HAV1L, TRMT2A and TRMU), represented as risk score, through the integration of 13 combinatorial machine learning algorithms. Kaplan-Meier analysis revealed that the high-risk group exhibited a significantly poorer overall survival (OS) probability compared to the low-risk group. The areas under the ROC curves for the risk score model at 1, 3, and 5 years were 0.661, 0.655, and 0.676, respectively. The nomogram, which integrated clinical characteristics and risk scores, demonstrated robust prognostic accuracy. Furthermore, single-sample gene set enrichment analysis (ssGSEA) demonstrated significant correlations between both the risk score model and hub RBPs with the immune status of BLCA patients. GSEA indicated that major signaling pathways enriched in the high-risk group included extracellular matrix (ECM) components and interaction, as well as cytokine and receptor interaction. Conclusions This study successfully identified and developed a prognostic signature based on nine RBPs, accompanied by a nomogram for predicting survival probability in BLCA patients. Our findings demonstrate that these nine RBPs function as significant biomarkers for forecasting the prognosis and immune status in BLCA, suggesting their potential as therapeutic targets for BLCA.
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Affiliation(s)
- Yan Chen
- Wound Ostomy Clinic, the 1st Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China
- School of Nursing, Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Zhijie Yan
- Wound Ostomy Clinic, the 1st Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China
- School of Nursing, Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Lusi Li
- Department of Nursing, the 1st Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Yixing Liang
- Wound Ostomy Clinic, the 1st Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China
- School of Nursing, Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Xueyan Wei
- Wound Ostomy Clinic, the 1st Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China
- School of Nursing, Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Yinian Zhao
- Wound Ostomy Clinic, the 1st Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China
- School of Nursing, Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Ying Cao
- Department of Nursing, the 1st Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Huaxiu Zhang
- Department of Clinic, the 1st Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Liping Tang
- Wound Ostomy Clinic, the 1st Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China
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Yoon ML, Kim SY, Chun H, Park J, Seo WJ, Lee JY, Yoon JH. Diagnostic accuracy of serum biomarkers MMP11 and SPP1 in non-small cell lung cancer: an analysis of sensitivity, specificity, and area under the curve. Transl Lung Cancer Res 2025; 14:1197-1211. [PMID: 40386736 PMCID: PMC12082244 DOI: 10.21037/tlcr-2024-1068] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2024] [Accepted: 03/05/2025] [Indexed: 05/20/2025]
Abstract
Background Non-small cell lung cancer (NSCLC) represents the vast majority of lung cancer cases, comprising 80-85% of all diagnoses, and continues to be a primary contributor to cancer-related deaths. Early detection is essential for improving patient outcomes, yet current diagnostic markers lack both sensitivity and specificity. This study aims to identify novel biomarkers that could enhance early diagnosis. Methods We conducted a comprehensive gene expression analysis of three NSCLC datasets (GSE33479, GSE18842, and GSE32863) and identified seven genes with relevance to the extracellular region and space: MMP11, SPP1, ERO1L, CTHRC1, SPINK1, LAD1, and SFN. We further assessed these markers through serum protein analysis involving 200 NSCLC patients and 200 healthy controls, employing receiver operating characteristic (ROC) curve analysis to evaluate their diagnostic efficacy. Results Among the identified genes, MMP11 and SPP1 exhibited significant upregulation and strong discriminatory power in NSCLC tissues, achieving area under the curve (AUC) values exceeding 0.9. Serum protein levels of MMP11 and SPP1 were significantly higher in NSCLC patients compared to healthy controls. ROC curve analysis confirmed the diagnostic potential of MMP11 (AUC: 0.9896) and SPP1 (AUC: 0.9053), both outperforming the existing marker carcinoembryonic antigen (CEA) (AUC: 0.7109). MMP11 demonstrated sensitivity of 94.53% and specificity of 94.97%, while SPP1 showed sensitivity of 83.17% and specificity of 83.84%. In contrast, CEA exhibited a sensitivity of 66.83% and specificity of 67.69%. Conclusions The results indicate that MMP11 and SPP1, detectable in serum, may serve as valuable non-invasive biomarkers for the early diagnosis of NSCLC, particularly within health screening contexts. However, further research within larger and more diverse cohorts is imperative to validate these biomarkers and investigate the mechanisms underlying MMP11 and SPP1 expression in NSCLC. This study highlights the potential of these biomarkers to enhance diagnostic accuracy and improve patient outcomes in NSCLC.
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Affiliation(s)
- Minha Lea Yoon
- Clinical Trial Center, Gangnam St. Peter’s Hospital, Gangnam-gu, Seoul, Republic of Korea
| | - Sang Yean Kim
- Department of Pathology, College of Medicine, The Catholic University of Korea, Seocho-gu, Seoul, Republic of Korea
| | - Hyelim Chun
- Clinical Trial Center, Gangnam St. Peter’s Hospital, Gangnam-gu, Seoul, Republic of Korea
| | - Jina Park
- Clinical Trial Center, Gangnam St. Peter’s Hospital, Gangnam-gu, Seoul, Republic of Korea
| | - Woo-Jeong Seo
- Clinical Trial Center, Gangnam St. Peter’s Hospital, Gangnam-gu, Seoul, Republic of Korea
| | - Jung Young Lee
- Clinical Trial Center, Gangnam St. Peter’s Hospital, Gangnam-gu, Seoul, Republic of Korea
| | - Jung Hwan Yoon
- Department of Pathology, College of Medicine, The Catholic University of Korea, Seocho-gu, Seoul, Republic of Korea
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Chen J, Wang S, Ding Y, Xu D, Zheng S. Radiotherapy-induced alterations in tumor microenvironment: metabolism and immunity. Front Cell Dev Biol 2025; 13:1568634. [PMID: 40356601 PMCID: PMC12066526 DOI: 10.3389/fcell.2025.1568634] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2025] [Accepted: 04/16/2025] [Indexed: 05/15/2025] Open
Abstract
Tumor metabolism plays a pivotal role in shaping immune responses within the tumor microenvironment influencing tumor progression, immune evasion, and the efficacy of cancer therapies. Radiotherapy has been shown to impact both tumor metabolism and immune modulation, often inducing immune activation through damage-associated molecular patterns and the STING pathway. In this study, we analyse the particular characteristics of the tumour metabolic microenvironment and its effect on the immune microenvironment. We also review the changes in the metabolic and immune microenvironment that are induced by radiotherapy, with a focus on metabolic sensitisation to the effects of radiotherapy. Our aim is to contribute to the development of research ideas in the field of radiotherapy metabolic-immunological studies.
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Affiliation(s)
- Jinpeng Chen
- Department of General Surgery, Zhongda Hospital Southeast University, Nanjing, Jiangsu, China
- Southeast University Medical School, Nanjing, Jiangsu, China
| | - Sheng Wang
- Department of Radiation Oncology, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, Nanjing, Jiangsu, China
| | - Yue Ding
- Department of General Surgery, Zhongda Hospital Southeast University, Nanjing, Jiangsu, China
- Southeast University Medical School, Nanjing, Jiangsu, China
| | - Duo Xu
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Shiya Zheng
- Southeast University Medical School, Nanjing, Jiangsu, China
- Department of Oncology, Southeast University, Zhongda Hospital Southeast University, Nanjing, Jiangsu, China
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Ding X, Liang Y, Zhou S, Wu Y, Sałata P, Mikolajczk-Martinez A, Khosrawipour V, Zhang Z. Targeting tumor extracellular matrix with nanoparticles to circumvent therapeutic resistance. J Control Release 2025; 383:113786. [PMID: 40306575 DOI: 10.1016/j.jconrel.2025.113786] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2025] [Revised: 04/21/2025] [Accepted: 04/25/2025] [Indexed: 05/02/2025]
Abstract
Each stage of tumor development is intrinsically linked to the tumor microenvironment (TME), wherein the extracellular matrix (ECM) serves as a vital and abundant component in tumor tissues. The ECM is a non-cellular, three-dimensional macromolecular network scaffold that provides structural support to cells, stores bioactive molecules, and mediates signaling pathways through specific binding to cell surface receptors. Moreover, the ECM in tumor tissues plays a crucial role in impeding drug diffusion and resisting apoptosis induced by conventional anti-cancer therapies that primarily target cancer cells. Therefore, directing attentions towards the tumor ECM can facilitate the identification of novel targets and the development of new therapies. This review aims to summarize the composition, structure, remodeling, and function of tumor ECM, its association with drug resistance, and current targeting strategies, with a specific emphasis on nanoparticles (NPs).
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Affiliation(s)
- Xinyue Ding
- School of Pharmacy, Key laboratory of smart drug delivery (Ministry of Education) & National key laboratory of complex drug formulations for overcoming delivery barriers, Fudan University, Shanghai 201203, China
| | - Yiyu Liang
- School of Pharmacy, Key laboratory of smart drug delivery (Ministry of Education) & National key laboratory of complex drug formulations for overcoming delivery barriers, Fudan University, Shanghai 201203, China
| | - Siyuan Zhou
- School of Pharmacy, Key laboratory of smart drug delivery (Ministry of Education) & National key laboratory of complex drug formulations for overcoming delivery barriers, Fudan University, Shanghai 201203, China
| | - Yao Wu
- School of Pharmacy, Key laboratory of smart drug delivery (Ministry of Education) & National key laboratory of complex drug formulations for overcoming delivery barriers, Fudan University, Shanghai 201203, China
| | - Patricia Sałata
- Wrocław University of Environmental and Life Sciences, Wrocław, Poland
| | | | | | - Zhiwen Zhang
- School of Pharmacy, Key laboratory of smart drug delivery (Ministry of Education) & National key laboratory of complex drug formulations for overcoming delivery barriers, Fudan University, Shanghai 201203, China.
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Yang J, Han J. Comprehensive analysis based on IFN-γ and SASP related genes, bulk RNA and single-cell sequencing to evaluate the prognosis and immune landscape of stomach adenocarcinoma. Genes Genomics 2025:10.1007/s13258-025-01646-7. [PMID: 40293675 DOI: 10.1007/s13258-025-01646-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2024] [Accepted: 04/15/2025] [Indexed: 04/30/2025]
Abstract
BACKGROUND Stomach adenocarcinoma (STAD) represents the predominant subtype of gastric cancer, known for its drug resistance, unfavorable prognosis, and low cure rates. IFN-γ serves as a cytokine generated by immune cells, instrumental in tumor immune clearance and essential to the tumor microenvironment. The aging-associated secretory phenotype (SASP) can modify the local tissue environment, facilitating gastric cancer progression and chemotherapy resistance. OBJECTIVE This study intends to identify STAD subtypes based on IFN-γ and SASP-related genes and to develop a risk prognostic model for predicting patient survival, tumor immune microenvironment, and responses to drug treatment. METHODS The genomic and clinical datasets originate from the Cancer Genome Atlas (TCGA) database, while the genes associated with IFN-γ and SASP come from pertinent scholarly articles. We discovered the prognostic genes linked to IFN-γ and SASP in STAD using Cox regression analysis. Next, we applied non-negative matrix factorization (NMF) to categorize LIHC into distinct molecular subtypes, identifying differentially expressed genes across these subtypes. Following this, we developed a predictive model using Cox and LASSO regression analyses to stratify patients into specific risk categories, validating the model to assess the prognostic significance of the identified signatures. Lastly, we integrated single-cell data to elucidate the immune landscape of STAD and identified potential drugs along with their sensitivity profiles. RESULTS We identified 17 prognostic genes related to IFN-γ and SASP, successfully classifying patients into two distinct molecular subtypes. These subtypes exhibited notable differences in immune profiles and prognostic outcomes. We pinpointed three differentially expressed genes to establish risk characteristics and created a prognostic model capable of accurately predicting patient outcomes. Our findings revealed a strong association between STAD and the extracellular matrix, low-risk group exhibited favorable prognosis, and may derive greater benefits from immunotherapy. CONCLUSION We developed a risk model using IFN-γ and SASP-associated genes to predict the prognosis of STAD patients more accurately. Additionally, we assessed the immune landscape of STAD by integrating bulk RNA and single-cell sequencing analyses. This approach may yield valuable insights for clinical decision-making and immunotherapy strategies in STAD.
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Affiliation(s)
- Jie Yang
- Department of Gastrointestinal Surgery, Xi'an Daxing Hospital, No.353 North Labor Road, Xi'an, 710016, Shanxi, China
| | - Junwei Han
- Department of Gastrointestinal Surgery, Xi'an Daxing Hospital, No.353 North Labor Road, Xi'an, 710016, Shanxi, China.
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Mariano NC, Marotti JD, Chen Y, Karakyriakou B, Salgado R, Christensen BC, Miller TW, Kettenbach AN. Quantitative proteomics analysis of triple-negative breast cancers. NPJ Precis Oncol 2025; 9:117. [PMID: 40269124 PMCID: PMC12019170 DOI: 10.1038/s41698-025-00907-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2024] [Accepted: 04/05/2025] [Indexed: 04/25/2025] Open
Abstract
Triple-negative breast cancer (TNBC) accounts for approximately 15% of all Breast Cancer (BC) cases with poorer prognosis and clinical outcomes compared to other BC subtypes due to greater tumor heterogeneity and few therapeutically targetable oncogenic drivers. To reveal actionable pathways for anti-cancer treatment, we use a proteomic approach to quantitatively compare the abundances of 6306 proteins across 55 formalin-fixed and paraffin-embedded (FFPE) TNBC tumors. We identified four major TNBC clusters by unsupervised clustering analysis of protein abundances. Analyses of clinicopathological characteristics revealed associations between the proteomic profiles and clinical phenotypes exhibited by each subtype. We validate the findings by inferring immune and stromal cell type composition from genome-wide DNA methylation profiles. Finally, quantitative proteomics on TNBC cell lines was conducted to identify in vitro models for each subtype. Collectively, our data provide subtype-specific insights into molecular drivers, clinicopathological phenotypes, tumor microenvironment (TME) compositions, and potential pharmacologic vulnerabilities for further investigations.
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Affiliation(s)
| | - Jonathan D Marotti
- Department of Pathology and Laboratory Medicine, Lebanon, NH, USA
- Dartmouth Cancer Center, Lebanon, NH, USA
| | | | | | - Roberto Salgado
- Department of Pathology, GZA-ZNA Hospitals, Antwerp, Belgium
- Division of Research, Peter MacCallum Cancer Centre, Melbourne, Australia
| | - Brock C Christensen
- Department of Pathology and Laboratory Medicine, Lebanon, NH, USA
- Dartmouth Cancer Center, Lebanon, NH, USA
- Department of Molecular and Systems Biology, Lebanon, NH, USA
- Department of Epidemiology, Lebanon, NH, USA
- Department of Community and Family Medicine, Lebanon, NH, USA
| | - Todd W Miller
- Dartmouth Cancer Center, Lebanon, NH, USA
- Department of Molecular and Systems Biology, Lebanon, NH, USA
- Department of Pharmacology & Toxicology, Medical College of Wisconsin, Milwaukee, WI, USA
- Department of Pathology, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Arminja N Kettenbach
- Department of Biochemistry and Cell Biology, Hanover, NH, USA.
- Dartmouth Cancer Center, Lebanon, NH, USA.
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Li S, Wang H, Xu XQ, Li WM, You H, Jia JD, He YW, Kong YY. Association of pre-diagnosis plasma proteomic contexture with overall survival of early- and late-stage colon cancer patients. BMC Cancer 2025; 25:744. [PMID: 40259320 PMCID: PMC12012972 DOI: 10.1186/s12885-025-14099-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2024] [Accepted: 04/07/2025] [Indexed: 04/23/2025] Open
Abstract
BACKGROUND The pre-diagnosis plasma proteomic contexture of colon cancer patients may reflect host immune and biological conditions and potentially associate with survival outcomes. We aimed to characterize pre-diagnosis proteomic contextures in colon cancer patients and determine potential association with overall survival of the patients. METHODS Baseline plasma samples collected at an average of 7.90 years before diagnosis from colon cancer patients in the UK Biobank cohort were analyzed using Olink proteomics technology. Cox-regression analysis was applied to identify distinct pre-diagnosis proteomic contextures and determine their association with survival outcomes. RESULTS In early-stage colon cancer, a 10-protein pre-diagnosis profile was identified, involving biological processes of extracellular matrix remodeling and immune evasion through deregulation of innate immune activation. Increased activity in these pathways before diagnosis was associated with poor survival outcomes. In late-stage cases, an 8-protein pre-diagnosis profile was linked to pathways involving in cell adhesion, angiogenesis, and pro-inflammatory response. Similarly, heightened activity in these pathways prior to diagnosis correlated with worse survival. When combined with two demographic factors age and sex, these proteomic profiles demonstrated strong predictive associations with survival outcomes at multiple time points post-diagnosis. The area under the receiver operating characteristic curve values were 0.85, 0.82, and 0.89 for early-stage cancer at 1, 5, and 10 years, respectively, and 0.71, 0.72, and 0.79 for late-stage cancer over the same periods. CONCLUSIONS Biological processes like extracellular matrix remodeling and pro-inflammatory response are active well before diagnosis and may play a critical role in shaping colon cancer progression.
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Affiliation(s)
- Shun Li
- National Clinical Research Center for Digestive Diseases, State Key Lab of Digestive Health, Beijing Friendship Hospital, Capital Medical University, Beijing, China
- Clinical Epidemiology and EBM Unit, Beijing Clinical Research Institute, Beijing, China
| | - Hao Wang
- National Clinical Research Center for Digestive Diseases, State Key Lab of Digestive Health, Beijing Friendship Hospital, Capital Medical University, Beijing, China
- Clinical Epidemiology and EBM Unit, Beijing Clinical Research Institute, Beijing, China
| | - Xiao-Qian Xu
- National Clinical Research Center for Digestive Diseases, State Key Lab of Digestive Health, Beijing Friendship Hospital, Capital Medical University, Beijing, China
- Clinical Epidemiology and EBM Unit, Beijing Clinical Research Institute, Beijing, China
| | - Wei-Ming Li
- National Clinical Research Center for Digestive Diseases, State Key Lab of Digestive Health, Beijing Friendship Hospital, Capital Medical University, Beijing, China
- Clinical Epidemiology and EBM Unit, Beijing Clinical Research Institute, Beijing, China
| | - Hong You
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Ji-Dong Jia
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - You-Wen He
- Department of Integrative Immunobiology, Duke University School of Medicine, Durham, NC, 27710, USA
| | - Yuan-Yuan Kong
- National Clinical Research Center for Digestive Diseases, State Key Lab of Digestive Health, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
- Clinical Epidemiology and EBM Unit, Beijing Clinical Research Institute, Beijing, China.
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Gao P, Tian H, Ge K, Wang F, Zhao Y, Sun J, Zhang Q. P4HA1 is highly expressed in gastric cancer and promotes proliferation and metastasis of gastric cancer cells. Discov Oncol 2025; 16:575. [PMID: 40253309 PMCID: PMC12009265 DOI: 10.1007/s12672-025-02337-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2024] [Accepted: 04/08/2025] [Indexed: 04/21/2025] Open
Abstract
BACKGROUND Gastric cancer (GC), a prevalent aggressive form of tumor, imposes a significant burden in terms of morbidity and mortality. Prolyl 4-hydroxylase, alpha polypeptide I (P4HA1), a key enzyme in collagen synthesis, comprises two identical alpha subunits and two beta subunits. Studies on the expression and impact of P4HA1 in GC cells are limited. METHODS The expression and prognosis of P4HA1 in GC were analyzed using bioinformatics. To confirm the P4HA1 level in GC tissues and cells, Western blot (WB) and RT-qPCR experiments were conducted. The signaling pathways related to P4HA1 in GC were examined using the DAVID database. Moreover, the expression of P4HA1 was downregulated by transfecting GC cell lines (HGC-27 and SGC-7901) with siRNA technology. Furthermore, GC proliferation, migration, and invasion were detected via plate cloning, CCK-8, and Transwell assays. The epithelial-mesenchymal transition (EMT) genes (E-cadherin, N-cadherin, Vimentin) and the stemness marker CD44 protein expression in GC cells were detected using WB. The sphere-forming ability of GC cells was analyzed using a sphere-forming assay to determine the effect of P4HA1. RESULTS Bioinformatics and experimental analyses demonstrated that P4HA1 expression was extensively detected in GC tissues and cells, and strongly related to a poor prognosis for GC. In vitro studies demonstrated that P4HA1 suppression hindered the proliferation, migration, and invasion of GC cells and suppressed EMT characteristics. Both sphere-forming and WB assays revealed that the sphere-forming potential of GC cells and the level of CD44 protein decreased after knocking down the expression of P4HA1, indicating that suppression of P4HA1 could inhibit the stemness of GC cells. CONCLUSION The study concluded that P4HA1 has the potential to be expressed substantially in GC tissues and cells and is capable of enhancing the proliferation, metastasis, and stemness of GC.
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Affiliation(s)
- PeiYao Gao
- Department of Blood Transfusion, Fuyang Women and Children's Hospital, Fuyang, 236000, China
- Department of Clinical Laboratory, The First Affiliated Hospital of Bengbu Medical University, Bengbu, 233004, China
| | - HengJin Tian
- Department of Clinical Laboratory, The First Affiliated Hospital of Bengbu Medical University, Bengbu, 233004, China
- Key Laboratory of Cancer Research and Clinical Laboratory Diagnosis, Bengbu Medical University, Bengbu, 233030, China
| | - KunPeng Ge
- Department of Clinical Laboratory, The First Affiliated Hospital of Bengbu Medical University, Bengbu, 233004, China
- Key Laboratory of Cancer Research and Clinical Laboratory Diagnosis, Bengbu Medical University, Bengbu, 233030, China
| | - FeiFan Wang
- Department of Blood Transfusion, The First Affiliated Hospital of Naval Medical University, Shanghai, 200433, China
| | - YanMing Zhao
- Department of Clinical Laboratory, the Second People's Hospital of Bengbu, Bengbu, 233000, China
| | - JiWen Sun
- Department of Blood Transfusion, Fuyang Women and Children's Hospital, Fuyang, 236000, China.
- Department of Clinical Laboratory, The First Affiliated Hospital of Bengbu Medical University, Bengbu, 233004, China.
| | - Qiang Zhang
- Department of Clinical Laboratory, The First Affiliated Hospital of Bengbu Medical University, Bengbu, 233004, China.
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Hitpass Romero K, Stevenson TJ, Smyth LCD, Watkin B, McCullough SJC, Vinnell L, Smith AM, Schweder P, Correia JA, Kipnis J, Dragunow M, Rustenhoven J. Age-related meningeal extracellular matrix remodeling compromises CNS lymphatic function. J Neuroinflammation 2025; 22:109. [PMID: 40247257 PMCID: PMC12007191 DOI: 10.1186/s12974-025-03436-0] [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: 03/09/2025] [Accepted: 04/01/2025] [Indexed: 04/19/2025] Open
Abstract
Efficient clearance of central nervous system (CNS) waste proteins and appropriate immune surveillance is essential for brain health. These processes are facilitated by lymphatic networks present in the meninges that drain cerebrospinal fluid (CSF). Age-related impairments to meningeal lymphatic drainage contribute to CNS waste accumulation and immune dysfunction, yet the underlying mechanisms remain poorly understood. Here, we identify extracellular matrix (ECM) remodeling in the aged dura as a key driver of CSF clearance deficits, demonstrating that peri-lymphatic collagen accumulation disrupts lymphatic function. Exploring immune-derived factors contributing to this ECM remodeling, we identify transforming growth factor beta 1 (TGFβ1) as a major regulator using primary human dural fibroblasts. Using a novel mouse model with constitutively active TGFβ receptor 1 (TGFβR1) signaling in dural fibroblasts, we show that excessive peri-lymphatic collagen deposition impairs meningeal lymphatic drainage and alters meningeal immunity. Mechanistically, we reveal that ECM-associated matrix stiffness disrupts lymphatic junction integrity and impairs lymphangiogenesis in human lymphatic endothelial cells. These findings establish dural immune cell and fibroblast-mediated ECM remodeling as a critical regulator of CSF clearance and highlight it as a potential therapeutic target for restoring brain waste clearance in aging.
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Affiliation(s)
- Kate Hitpass Romero
- Department of Pharmacology and Clinical Pharmacology, The University of Auckland, Auckland, New Zealand
- Centre for Brain Research, The University of Auckland, Auckland, New Zealand
| | - Taylor J Stevenson
- Department of Pharmacology and Clinical Pharmacology, The University of Auckland, Auckland, New Zealand
- Centre for Brain Research, The University of Auckland, Auckland, New Zealand
| | - Leon C D Smyth
- Brain Immunology and Glia Center, School of Medicine, Washington University in St. Louis, St. Louis, MO, USA
- Department of Pathology and Immunology, School of Medicine, Washington University in St. Louis, St. Louis, MO, USA
- Immunology Graduate Program, School of Medicine, Washington University in St. Louis, St. Louis, MO, USA
| | - Ben Watkin
- Department of Pharmacology and Clinical Pharmacology, The University of Auckland, Auckland, New Zealand
- Centre for Brain Research, The University of Auckland, Auckland, New Zealand
| | - Samuel J C McCullough
- Department of Pharmacology and Clinical Pharmacology, The University of Auckland, Auckland, New Zealand
- Centre for Brain Research, The University of Auckland, Auckland, New Zealand
| | - Luca Vinnell
- Department of Pharmacology and Clinical Pharmacology, The University of Auckland, Auckland, New Zealand
- Centre for Brain Research, The University of Auckland, Auckland, New Zealand
| | - Amy M Smith
- Department of Pharmacology and Clinical Pharmacology, The University of Auckland, Auckland, New Zealand
- Centre for Brain Research, The University of Auckland, Auckland, New Zealand
| | - Patrick Schweder
- Centre for Brain Research, The University of Auckland, Auckland, New Zealand
- Auckland City Hospital, Auckland, 1023, New Zealand
| | - Jason A Correia
- Centre for Brain Research, The University of Auckland, Auckland, New Zealand
- Auckland City Hospital, Auckland, 1023, New Zealand
| | - Jonathan Kipnis
- Brain Immunology and Glia Center, School of Medicine, Washington University in St. Louis, St. Louis, MO, USA
- Department of Pathology and Immunology, School of Medicine, Washington University in St. Louis, St. Louis, MO, USA
- Immunology Graduate Program, School of Medicine, Washington University in St. Louis, St. Louis, MO, USA
| | - Mike Dragunow
- Department of Pharmacology and Clinical Pharmacology, The University of Auckland, Auckland, New Zealand
- Centre for Brain Research, The University of Auckland, Auckland, New Zealand
| | - Justin Rustenhoven
- Department of Pharmacology and Clinical Pharmacology, The University of Auckland, Auckland, New Zealand.
- Centre for Brain Research, The University of Auckland, Auckland, New Zealand.
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Aitchison EE, Dimesa AM, Shoari A. Matrix Metalloproteinases in Glioma: Drivers of Invasion and Therapeutic Targets. BIOTECH 2025; 14:28. [PMID: 40265458 PMCID: PMC12015896 DOI: 10.3390/biotech14020028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2025] [Revised: 04/08/2025] [Accepted: 04/15/2025] [Indexed: 04/24/2025] Open
Abstract
Matrix metalloproteinases (MMPs) are a family of zinc-dependent proteolytic enzymes that are crucial for the remodeling of the extracellular matrix, a process that is often co-opted by cancers, including brain tumors, to facilitate growth, invasion, and metastasis. In gliomas, MMPs contribute to a complex interplay involving tumor proliferation, angiogenesis, and immune modulation, thereby influencing tumor progression and patient prognosis. This review provides a comprehensive analysis of the roles of various MMPs in different types of gliomas, from highly malignant gliomas to metastatic lesions. Emphasis is placed on how the dysregulation of MMPs impacts tumor behavior, the association between specific MMPs and the tumor grade, and their potential as biomarkers for diagnosis and prognosis. Additionally, the current therapeutic approaches targeting MMP activity are discussed, exploring both their challenges and future potential. By synthesizing recent findings, this paper aims to clarify the broad significance of MMPs in gliomas and propose avenues for translational research that could enhance treatment strategies and clinical outcomes.
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Affiliation(s)
- Ella E. Aitchison
- Department of Cancer Biology, Mayo Clinic, Jacksonville, FL 32224, USA; (E.E.A.); (A.M.D.)
- School of Biological Sciences, Faculty of Biology Medicine and Health, University of Manchester, Manchester M13 9PT, UK
| | - Alexandra M. Dimesa
- Department of Cancer Biology, Mayo Clinic, Jacksonville, FL 32224, USA; (E.E.A.); (A.M.D.)
- Department of Biology, University of North Florida, Jacksonville, FL 32224, USA
| | - Alireza Shoari
- Department of Cancer Biology, Mayo Clinic, Jacksonville, FL 32224, USA; (E.E.A.); (A.M.D.)
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38
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Deng C, Xie C, Li Z, Mei J, Wang K. Multi-omics analysis identifies diagnostic circulating biomarkers and potential therapeutic targets, revealing IQGAP1 as an oncogene in gastric cancer. NPJ Precis Oncol 2025; 9:105. [PMID: 40229327 PMCID: PMC11997149 DOI: 10.1038/s41698-025-00895-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2024] [Accepted: 04/01/2025] [Indexed: 04/16/2025] Open
Abstract
This study employed a multi-omics integration approach to identify circulating biomarkers for gastric cancer (GC). We analyzed plasma and tumor tissue single-cell RNA sequencing data, along with gene and protein quantitative trait loci analyses. Leveraging data from UK Biobank and FinnGen, we investigated genetic associations with GC. Through colocalization, Mendelian Randomization, and various filtering analyses, we identified four genes (IQGAP1, KRTCAP2, PARP1, MLF2) and four proteins (EGFL9 [DLK2], ECM1, PDIA5, TIMP4) as potential GC biomarkers. These were selected based on significant genetic colocation probabilities and significant associations with GC. Seven of these biomarkers demonstrated predictive capability for GC occurrence, with AUC ranging from 0.61 to 0.99. Drug prediction analysis identified seven protein biomarkers as potential targets for immunotherapy, targeted therapies, and tumor chemotherapy. Further scRNA-seq analysis revealed significant expression differences between gastric tumor and normal tissues, particularly the upregulation of IQGAP1, which highlights its role in tumor growth.
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Affiliation(s)
- Chao Deng
- Institute of Integrated Traditional Chinese and Western Medicine, Affiliated Hospital of Jiangnan University, No. 1000, Hefeng Rd, Wuxi, 214122, China
- Wuxi School of Medicine, Jiangnan University, Wuxi, China
| | - Chenjun Xie
- Institute of Integrated Traditional Chinese and Western Medicine, Affiliated Hospital of Jiangnan University, No. 1000, Hefeng Rd, Wuxi, 214122, China
| | - Zixi Li
- Institute of Integrated Traditional Chinese and Western Medicine, Affiliated Hospital of Jiangnan University, No. 1000, Hefeng Rd, Wuxi, 214122, China
| | - Jie Mei
- The First Clinical Medicine College, Nanjing Medical University, Nanjing, 211166, China.
| | - Kewei Wang
- Institute of Integrated Traditional Chinese and Western Medicine, Affiliated Hospital of Jiangnan University, No. 1000, Hefeng Rd, Wuxi, 214122, China.
- Wuxi School of Medicine, Jiangnan University, Wuxi, China.
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Khalili-Tanha G, Radisky ES, Radisky DC, Shoari A. Matrix metalloproteinase-driven epithelial-mesenchymal transition: implications in health and disease. J Transl Med 2025; 23:436. [PMID: 40217300 PMCID: PMC11992850 DOI: 10.1186/s12967-025-06447-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2025] [Accepted: 03/30/2025] [Indexed: 04/14/2025] Open
Abstract
Epithelial-mesenchymal transition (EMT) is a process in which epithelial cells, defined by apical-basal polarity and tight intercellular junctions, acquire migratory and invasive properties characteristic of mesenchymal cells. Under normal conditions, EMT directs essential morphogenetic events in embryogenesis and supports tissue repair. When dysregulated, EMT contributes to pathological processes such as organ fibrosis, chronic inflammation, and cancer progression and metastasis. Matrix metalloproteinases (MMPs)-a family of zinc-dependent proteases that degrade structural components of the extracellular matrix-sit at the nexus of this transition by dismantling basement membranes, activating pro-EMT signaling pathways, and cleaving adhesion molecules. When normally regulated, MMPs promote balanced ECM turnover and support the cyclical remodeling necessary for proper development, wound healing, and tissue homeostasis. When abnormally regulated, MMPs drive excessive ECM turnover, thereby promoting EMT-related pathologies, including tumor progression and fibrotic disease. This review provides an integrated overview of the molecular mechanisms by which MMPs both initiate and sustain EMT under physiological and disease conditions. It discusses how MMPs can potentiate EMT through TGF-β and Wnt/β-catenin signaling, disrupt cell-cell junction proteins, and potentiate the action of hypoxia-inducible factors in the tumor microenvironment. It discusses how these pathologic processes remodel tissues during fibrosis, and fuel cancer cell invasion, metastasis, and resistance to therapy. Finally, the review explores emerging therapeutic strategies that selectively target MMPs and EMT, ranging from CRISPR/Cas-mediated interventions to engineered tissue inhibitors of metalloproteinases (TIMPs), and demonstrates how such approaches may suppress pathological EMT without compromising its indispensable roles in normal biology.
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Affiliation(s)
- Ghazaleh Khalili-Tanha
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Evette S Radisky
- Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, USA
| | - Derek C Radisky
- Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, USA
| | - Alireza Shoari
- Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, USA.
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Wang T, Liu H, Li M, Ji Z, Zhang X, Wang N, Chen Y, Sun J, Liu F. Microneedle-based nanodrugs for tumor immunotherapy. J Control Release 2025; 380:539-562. [PMID: 39923854 DOI: 10.1016/j.jconrel.2025.02.003] [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: 10/13/2024] [Revised: 01/08/2025] [Accepted: 02/02/2025] [Indexed: 02/11/2025]
Abstract
Microneedles have emerged as a promising and effective method for delivering therapeutic drugs and immunobiologics to treat various diseases. It is widely recognized that immune therapy has limited efficacy in solid tumors due to physical barriers and the immunosuppressive tumor microenvironment. Microneedle-based nanodrugs (NDMNs) offer a novel approach to overcome these limitations. These tiny needles are designed to load a variety of inorganic and organic nanoparticles, antigen vaccines, gene drugs, oncolytic viruses, and more. Utilizing microneedle arrays, NDMNs can effectively penetrate the skin barrier, delivering drugs precisely to the tumor site or immunoactive regions within the skin. Additionally, by designing and optimizing the microneedle structure, shape, and functionality, NDMNs enable precise drug release and efficient penetration, thereby enhancing the efficacy of tumor immunotherapy. In this review, we comprehensively discuss the pivotal role of NDMNs in cancer immunotherapy, summarizing innovative microneedle design strategies, mechanisms of immune activation, and delivery strategies of various nanodrugs. Furthermore, we explore the current clinical realities, limitations, and future prospects of NDMNs in tumor immunotherapy.
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Affiliation(s)
- Tianye Wang
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, Shenyang 110001, China; Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, China Medical University, Ministry of Education, Shenyang 110001, China; Department of General Surgery, The First Hospital of Dalian Medical University, Dalian 116000, China
| | - Hongyu Liu
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, Shenyang 110001, China; Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, China Medical University, Ministry of Education, Shenyang 110001, China
| | - Meng Li
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, Shenyang 110001, China; Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, China Medical University, Ministry of Education, Shenyang 110001, China
| | - Zao Ji
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, Shenyang 110001, China; Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, China Medical University, Ministry of Education, Shenyang 110001, China
| | - Xinyuan Zhang
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, Shenyang 110001, China; Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, China Medical University, Ministry of Education, Shenyang 110001, China
| | - Nan Wang
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, Shenyang 110001, China; Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, China Medical University, Ministry of Education, Shenyang 110001, China
| | - Ying Chen
- Department of Medical Oncology, the First Hospital of China Medical University, Shenyang 110001, China; Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, the First Hospital of China Medical University, Shenyang 110001, China; Liaoning Province Clinical Research Center for Cancer, Shenyang 110001, China; Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, Shenyang 110001, China.
| | - Jin Sun
- Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, China; Joint International Research Laboratory of Intelligent Drug Delivery Systems Ministry of Education, Shenyang 110016, China.
| | - Funan Liu
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, Shenyang 110001, China; Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, China Medical University, Ministry of Education, Shenyang 110001, China; Phase I Clinical Trails Center, The First Hospital, China Medical University, Shenyang 110001, China.
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Zhang M, Zhang B. Extracellular matrix stiffness: mechanisms in tumor progression and therapeutic potential in cancer. Exp Hematol Oncol 2025; 14:54. [PMID: 40211368 PMCID: PMC11984264 DOI: 10.1186/s40164-025-00647-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2025] [Accepted: 03/23/2025] [Indexed: 04/14/2025] Open
Abstract
Tumor microenvironment (TME) is a complex ecosystem composed of both cellular and non-cellular components that surround tumor tissue. The extracellular matrix (ECM) is a key component of the TME, performing multiple essential functions by providing mechanical support, shaping the TME, regulating metabolism and signaling, and modulating immune responses, all of which profoundly influence cell behavior. The quantity and cross-linking status of stromal components are primary determinants of tissue stiffness. During tumor development, ECM stiffness not only serves as a barrier to hinder drug delivery but also promotes cancer progression by inducing mechanical stimulation that activates cell membrane receptors and mechanical sensors. Thus, a comprehensive understanding of how ECM stiffness regulates tumor progression is crucial for identifying potential therapeutic targets for cancer. This review examines the effects of ECM stiffness on tumor progression, encompassing proliferation, migration, metastasis, drug resistance, angiogenesis, epithelial-mesenchymal transition (EMT), immune evasion, stemness, metabolic reprogramming, and genomic stability. Finally, we explore therapeutic strategies that target ECM stiffness and their implications for tumor progression.
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Affiliation(s)
- Meiling Zhang
- School of Basic Medicine, China Three Gorges University, 8 Daxue Road, Yichang, 443002, Hubei, China
- Central Laboratory, The First Affiliated Hospital of Jinan University, No. 613 Huangpu West Road, Tianhe District, Guangzhou, 510627, Guangdong, China
| | - Bin Zhang
- School of Basic Medicine, China Three Gorges University, 8 Daxue Road, Yichang, 443002, Hubei, China.
- Central Laboratory, The First Affiliated Hospital of Jinan University, No. 613 Huangpu West Road, Tianhe District, Guangzhou, 510627, Guangdong, China.
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42
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Choi SW, Kim JH, Hong J, Kwon M. Mapping immunotherapy potential: spatial transcriptomics in the unraveling of tumor-immune microenvironments in head and neck squamous cell carcinoma. Front Immunol 2025; 16:1568590. [PMID: 40264779 PMCID: PMC12011851 DOI: 10.3389/fimmu.2025.1568590] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2025] [Accepted: 03/25/2025] [Indexed: 04/24/2025] Open
Abstract
Head and neck squamous cell carcinoma (HNSCC) often exhibits poor response rates to immune checkpoint inhibitor (ICI) therapies, largely owing to the intricate composition and spatial organization of immune cells within the tumor-immune microenvironment (TIME). The diversity of immune cell populations, their spatial relationships, and dynamic interactions significantly influence the immunosuppressive nature of the TIME, thereby limiting the efficacy of immunotherapy. To address these challenges and enhance the therapeutic potential of ICIs in HNSCC, a comprehensive analysis of the TIME is essential. Spatial transcriptomics (ST), a cutting-edge technology, enables high-resolution mapping of gene expression within the spatial context of the tumor, providing critical insights into the functional roles and interactions of immune cells in the TIME. This review highlights the importance of ST in uncovering the complexities of the TIME in HNSCC and proposes strategies for leveraging these insights to develop more effective immunotherapeutic approaches. By integrating spatial and molecular information, this review aims to pave the way for personalized and precision-based treatments in HNSCC, ultimately improving patient outcomes.
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Affiliation(s)
| | | | | | - Minsu Kwon
- Department of Otolaryngology-Head and Neck Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
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Panigrahi A, Hunt AL, Assis D, Willetts M, Kallakury BV, Davidson B, Ahn J, Conrads TP, Goldman R. dia-PASEF Proteomics of Tumor and Stroma LMD Enriched from Archived HNSCC Samples. ACS OMEGA 2025; 10:13296-13302. [PMID: 40224439 PMCID: PMC11983184 DOI: 10.1021/acsomega.4c11051] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 12/06/2024] [Revised: 01/24/2025] [Accepted: 03/19/2025] [Indexed: 04/15/2025]
Abstract
We employed laser microdissection to selectively harvest histology-resolved tumors and stroma from formalin-fixed, paraffin-embedded head and neck squamous cell carcinoma (HNSCC) tissues. Peptide digests from the LMD-enriched HNSCC tissue were analyzed by quantitative mass-spectrometry-based proteomics using a data independent analysis approach. In paired samples, excellent proteome coverage was achieved, having quantified 6668 proteins with a median quantitative coefficient of variation under 10%. Significant differences in relevant functional pathways between the tumor and the stroma regions were observed. Extracellular matrix (ECM) was identified as a major component enriched in the stroma, including many cancer-associated fibroblast signature proteins in this compartment. We demonstrate the potential for comparative deep proteome analysis from a very low starting input in a scalable format. Correlating such results with clinical features or disease progression will likely enable the identification of novel targets for disease classification and interventions.
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Affiliation(s)
- Aswini Panigrahi
- Department
of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia 20057, United States
| | - Allison L. Hunt
- Women’s
Health Integrated Research Center, Women’s Service Line, Inova Health System, Annandale, Virginia 22003, United States
| | - Diego Assis
- Bruker
Scientific, Billerica, Massachusetts 01821, United States
| | - Matthew Willetts
- Bruker
Scientific, Billerica, Massachusetts 01821, United States
| | - Bhaskar V. Kallakury
- Department
of Pathology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia 20007, United States
| | - Bruce Davidson
- Department
of Otolaryngology-Head and Neck Surgery, Medstar Georgetown University Hospital, Washington, District of Columbia 20007, United States
| | - Jaeil Ahn
- Department
of Biostatistics, Bioinformatics and Biomathematics, Georgetown University, Washington, District of Columbia 20057, United States
| | - Thomas P. Conrads
- Women’s
Health Integrated Research Center, Women’s Service Line, Inova Health System, Annandale, Virginia 22003, United States
| | - Radoslav Goldman
- Department
of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia 20057, United States
- Department
of Biochemistry and Molecular & Cellular Biology, Georgetown University, Washington, District of Columbia 20057, United States
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44
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Fernández-Pérez AG, Herrera-González A, López-Naranjo EJ, Martínez-Álvarez IA, Uribe-Rodríguez D, Ramírez-Arreola DE, Sánchez-Peña MJ, Navarro-Partida J. Extracellular Vesicles from Different Mesenchymal Stem Cell Types Exhibit Distinctive Surface Protein Profiling and Molecular Characteristics: A Comparative Analysis. Int J Mol Sci 2025; 26:3393. [PMID: 40244251 PMCID: PMC11989379 DOI: 10.3390/ijms26073393] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2025] [Revised: 03/21/2025] [Accepted: 04/03/2025] [Indexed: 04/18/2025] Open
Abstract
The current medical need to respond to different diseases has sparked great interest in extracellular vesicles (EVs) derived from mesenchymal stem cells (MSCs) due to their great regenerative potential and as drug carriers by playing a critical role in cell-cell communication. However, due to their heterogeneity, there is no standardized universal method for their identification and characterization, which limits their clinical application. This study, following the recommendations and methodologies proposed by MISEV2023 for the characterization of EVs, shows for the first time a detailed morphological, protein, and biochemical comparison between EVs derived from three different MSCs sources (placenta, endometrium, and dental pulp). The information obtained from the different applied assays suggests that there are substantial differences between one EVs source and another. It also offers valuable insights that provide the guidelines to ease their profiling and therefore improve their selection, in order to speed up their use and clinical application; additionally, the knowledge obtained from each characterization test could facilitate new researchers in the field to choose a specific cell source to obtain EVs and select the appropriate methods that provide the necessary information according to their requirements.
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Affiliation(s)
- Atziri G. Fernández-Pérez
- Centro Universitario de Ciencias Exactas e Ingenierías (CUCEI), University of Guadalajara, Guadalajara 44430, Jalisco, Mexico; (A.G.F.-P.); (A.H.-G.); (E.J.L.-N.); (M.J.S.-P.)
| | - Azucena Herrera-González
- Centro Universitario de Ciencias Exactas e Ingenierías (CUCEI), University of Guadalajara, Guadalajara 44430, Jalisco, Mexico; (A.G.F.-P.); (A.H.-G.); (E.J.L.-N.); (M.J.S.-P.)
| | - Edgar J. López-Naranjo
- Centro Universitario de Ciencias Exactas e Ingenierías (CUCEI), University of Guadalajara, Guadalajara 44430, Jalisco, Mexico; (A.G.F.-P.); (A.H.-G.); (E.J.L.-N.); (M.J.S.-P.)
| | | | - David Uribe-Rodríguez
- Centro de Biotecnología Santer S.C., Guadalajara 45040, Jalisco, Mexico; (I.A.M.-Á.); (D.U.-R.)
| | - Daniel E. Ramírez-Arreola
- Centro Universitario de la Costa Sur (CUCSUR), University of Guadalajara, Autlan 48900, Jalisco, Mexico;
| | - María Judith Sánchez-Peña
- Centro Universitario de Ciencias Exactas e Ingenierías (CUCEI), University of Guadalajara, Guadalajara 44430, Jalisco, Mexico; (A.G.F.-P.); (A.H.-G.); (E.J.L.-N.); (M.J.S.-P.)
| | - Jose Navarro-Partida
- School of Medicine and Health Sciences, Monterrey Institute of Technology, Zapopan 45201, Jalisco, Mexico
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Caloian AD, Cristian M, Calin E, Pricop AR, Mociu SI, Seicaru L, Deacu S, Ciufu N, Suceveanu AI, Suceveanu AP, Mazilu L. Epigenetic Symphony in Diffuse Large B-Cell Lymphoma: Orchestrating the Tumor Microenvironment. Biomedicines 2025; 13:853. [PMID: 40299416 PMCID: PMC12024808 DOI: 10.3390/biomedicines13040853] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2025] [Revised: 03/18/2025] [Accepted: 03/21/2025] [Indexed: 04/30/2025] Open
Abstract
DLBCL is a testament to the complexity of nature. It is characterized by remarkable diversity in its molecular and pathological subtypes and clinical manifestations. Despite the strides made in DLBCL treatment and the introduction of innovative drugs, around one-third of patients face a relapse or develop refractory disease. Recent findings over the past ten years have highlighted the critical interplay between the evolution of DLBCL and various epigenetic mechanisms, including chromatin remodeling, DNA methylation, histone modifications, and the regulatory roles of non-coding RNAs. These epigenetic alterations are integral to the pathways of oncogenesis, tumor progression, and the development of therapeutic resistance. In the past decade, the identification of dysregulated epigenetic mechanisms in lymphomas has paved the way for an exciting field of epigenetic therapies. Crucially, these epigenetic transformations span beyond tumor cells to include the sophisticated network within the tumor microenvironment (TME). While the exploration of epigenetic dysregulation in lymphoma cells is thriving, the mechanisms affecting the functions of immune cells in the TME invite further investigation. This review is dedicated to weaving together the narrative of epigenetic alterations impacting both lymphoma cells with a focus on their infiltrating immune companions.
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Affiliation(s)
- Andreea-Daniela Caloian
- Faculty of Medicine, “Ovidius” University of Constanta, 900470 Constanta, Romania; (E.C.); (S.D.); (N.C.); (A.-I.S.); (A.-P.S.); (L.M.)
- Department of Hemato-Oncology, “Ovidius” Clinical Hospital, 900470 Constanta, Romania;
| | - Miruna Cristian
- Faculty of Medicine, “Ovidius” University of Constanta, 900470 Constanta, Romania; (E.C.); (S.D.); (N.C.); (A.-I.S.); (A.-P.S.); (L.M.)
- Center for Research and Development of the Morphological and Genetic Studies of Malignant Pathology-CEDMOG, “Ovidius” University of Constanta, 900470 Constanta, Romania
- Department of Forensic Medicine, “Sf. Apostol Andrei” Emergency County Hospital, 900439 Constanta, Romania
| | - Elena Calin
- Faculty of Medicine, “Ovidius” University of Constanta, 900470 Constanta, Romania; (E.C.); (S.D.); (N.C.); (A.-I.S.); (A.-P.S.); (L.M.)
- Department of Hemato-Oncology, “Ovidius” Clinical Hospital, 900470 Constanta, Romania;
| | - Andreea-Raluca Pricop
- Department of Dermatology, “Sf. Apostol Andrei” Emergency County Hospital, 900591 Constanta, Romania;
| | - Stelian-Ilie Mociu
- Department of Hemato-Oncology, “Ovidius” Clinical Hospital, 900470 Constanta, Romania;
| | - Liliana Seicaru
- Department of Clinical Patology, “Sf. Apostol Andrei” Emergency County Hospital, 900591 Constanta, Romania;
| | - Sorin Deacu
- Faculty of Medicine, “Ovidius” University of Constanta, 900470 Constanta, Romania; (E.C.); (S.D.); (N.C.); (A.-I.S.); (A.-P.S.); (L.M.)
- Department of Clinical Patology, “Sf. Apostol Andrei” Emergency County Hospital, 900591 Constanta, Romania;
| | - Nicolae Ciufu
- Faculty of Medicine, “Ovidius” University of Constanta, 900470 Constanta, Romania; (E.C.); (S.D.); (N.C.); (A.-I.S.); (A.-P.S.); (L.M.)
- Department of Hemato-Oncology, “Ovidius” Clinical Hospital, 900470 Constanta, Romania;
| | - Andra-Iulia Suceveanu
- Faculty of Medicine, “Ovidius” University of Constanta, 900470 Constanta, Romania; (E.C.); (S.D.); (N.C.); (A.-I.S.); (A.-P.S.); (L.M.)
- Department of Gastroenterology, “Sf. Apostol Andrei” Emergency County Hospital, 900591 Constanta, Romania
| | - Adrian-Paul Suceveanu
- Faculty of Medicine, “Ovidius” University of Constanta, 900470 Constanta, Romania; (E.C.); (S.D.); (N.C.); (A.-I.S.); (A.-P.S.); (L.M.)
- Department of Gastroenterology, “Sf. Apostol Andrei” Emergency County Hospital, 900591 Constanta, Romania
| | - Laura Mazilu
- Faculty of Medicine, “Ovidius” University of Constanta, 900470 Constanta, Romania; (E.C.); (S.D.); (N.C.); (A.-I.S.); (A.-P.S.); (L.M.)
- Department of Hemato-Oncology, “Ovidius” Clinical Hospital, 900470 Constanta, Romania;
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Konstantaraki M, Berdiaki A, Neagu M, Zurac S, Krasagakis K, Nikitovic D. Understanding Merkel Cell Carcinoma: Pathogenic Signaling, Extracellular Matrix Dynamics, and Novel Treatment Approaches. Cancers (Basel) 2025; 17:1212. [PMID: 40227764 PMCID: PMC11987840 DOI: 10.3390/cancers17071212] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2025] [Revised: 03/28/2025] [Accepted: 03/31/2025] [Indexed: 04/15/2025] Open
Abstract
Merkel cell carcinoma (MCC) is a rare but aggressive neuroendocrine skin cancer, driven by either Merkel cell polyomavirus (MCPyV) integration or ultraviolet (UV)-induced mutations. In MCPyV-positive tumors, viral T antigens inactivate tumor suppressors pRb and p53, while virus-negative MCCs harbor UV-induced mutations that activate similar oncogenic pathways. Key signaling cascades, including PI3K/AKT/mTOR and MAPK, support tumor proliferation, survival, and resistance to apoptosis. Histologically, MCC consists of small round blue cells with neuroendocrine features, high mitotic rate, and necrosis. The tumor microenvironment (TME) plays a central role in disease progression and immune escape. It comprises a mix of tumor-associated macrophages, regulatory and cytotoxic T cells, and elevated expression of immune checkpoint molecules such as PD-L1, contributing to an immunosuppressive niche. The extracellular matrix (ECM) within the TME is rich in proteoglycans, collagens, and matrix metalloproteinases (MMPs), facilitating tumor cell adhesion, invasion, and interaction with stromal and immune cells. ECM remodeling and integrin-mediated signaling further promote immune evasion and therapy resistance. Although immune checkpoint inhibitors targeting PD-1/PD-L1 have shown promise in treating MCC, resistance remains a major hurdle. Therapeutic strategies that concurrently target the TME-through inhibition of ECM components, MMPs, or integrin signaling-may enhance immune responses and improve clinical outcomes.
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Affiliation(s)
- Maria Konstantaraki
- Department of Histology-Embryology, Medical School, University of Crete, 71003 Heraklion, Greece; (M.K.); (A.B.)
- Dermatology Department, University Hospital of Heraklion, 71110 Heraklion, Greece;
| | - Aikaterini Berdiaki
- Department of Histology-Embryology, Medical School, University of Crete, 71003 Heraklion, Greece; (M.K.); (A.B.)
| | - Monica Neagu
- Immunology Laboratory, “Victor Babes” National Institute of Pathology, 99-101 Splaiul Independenței, 050096 Bucharest, Romania;
- Pathology Department, Colentina Clinical Hospital, 19-21 Sos Stefan Cel Mare, 020125 Bucharest, Romania;
| | - Sabina Zurac
- Pathology Department, Colentina Clinical Hospital, 19-21 Sos Stefan Cel Mare, 020125 Bucharest, Romania;
- Faculty of Dentistry, University of Medicine and Pharmacy, 8 Eroilor Sanitari Boulevard, 050474 Bucharest, Romania
| | | | - Dragana Nikitovic
- Department of Histology-Embryology, Medical School, University of Crete, 71003 Heraklion, Greece; (M.K.); (A.B.)
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Rasouli M, Safari F, Roudi R, Sobhani N. Investigation of mesenchymal stem cell secretome on breast cancer gene expression: A bioinformatic approach to identify differentially expressed genes, functional networks, and potential therapeutic targets. Comput Biol Chem 2025; 115:108331. [PMID: 39752852 DOI: 10.1016/j.compbiolchem.2024.108331] [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: 10/15/2024] [Revised: 12/11/2024] [Accepted: 12/24/2024] [Indexed: 02/26/2025]
Abstract
The mesenchymal stem cell (MSC) secretome plays a pivotal role in shaping the tumor microenvironment, influencing both cancer progression and potential therapeutic outcomes. In this research, by using publicly available dataset GSE196312, we investigated the role of MSC secretome on breast cancer cell gene expression. Our results raveled differentially expressed genes, including the upregulation of Phosphatidylinositol-3,4,5-Trisphosphate Dependent Rac Exchange Factor 1 (PREX1), C-C Motif Chemokine Ligand 28 (CCL28), and downregulation of Collagen Type I Alpha 1 Chain (COL1A1), Collagen Type I Alpha 3 Chain (COL1A3), Collagen Type III Alpha 1 Chain (COL3A1), which contributing to extra cellular matrix (ECM) weakening and promoting cell migration. Functional enrichment analyses also highlighted suppression of ECM remodeling pathways, and activation of calcium ion binding and Rap1 signaling pathway. We proposed that Ca2 + medicated activation of Ras-related protein 1 (Rap1) through its its downstream pathways such as Matrix Metalloprotease (MMP), PI3K/Akt, and MEK/ERK signaling pathway contribute to promotion of cell migration. However, the co-culture model by reducing Fibronectin 1 (FN1) and Secreted Protein Acidic and Cysteine Rich (SPARC) gene expression in cancer cells, emphasized on therapeutical aspects of MSC secretome. These findings emphasize on the dual edge sword nature of MSC secretome on cancer cell behaviors, while our major results emphasize on the cancer progression through ECM remodeling, the therapeutic aspects should not be underscored.
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Affiliation(s)
- Mohammad Rasouli
- Department of Biology, Faculty of Science, University of Guilan, Rasht, Iran
| | - Fatemeh Safari
- Department of Biology, Faculty of Science, University of Guilan, Rasht, Iran.
| | - Raheleh Roudi
- Molecular Imaging Program at Stanford (MIPS), Department of Radiology, Stanford University, Stanford, CA 94305, USA.
| | - Navid Sobhani
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
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Wang J, Wang Y, Zhou H, Yu G, Xu H, Gao D, Li M, Wang Y, Xu B. Identification of the specific characteristics of neuroendocrine prostate cancer: Immune status, hub genes and treatment. Transl Oncol 2025; 54:102320. [PMID: 39999729 PMCID: PMC11908612 DOI: 10.1016/j.tranon.2025.102320] [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: 11/23/2024] [Revised: 01/13/2025] [Accepted: 02/04/2025] [Indexed: 02/27/2025] Open
Abstract
Castration-resistant prostate cancer (CRPC) marks the advanced phase of prostate malignancy, manifested through two principal subtypes: castration-resistant adenocarcinoma (CRPC-adeno) and neuroendocrine prostate cancer (NEPC). This study aims to identify unique central regulatory genes, assess the immunological landscape, and explore potential therapeutic strategies specifically tailored to NEPC. We discovered 1444 differentially expressed genes (DEGs) distinguishing between the two cancer types and identified 12 critical hub genes. Notably, CHST1, MPPED2, and RIPPLY3 emerged as closely associated with the immune cell infiltration pattern, establishing them as top candidates. Prognostic analysis highlighted the potential critical roles of CHST1 and MPPED2 in prostate cancer development, findings corroborated through in vitro and in vivo assays. Moreover, we validated the functions and expression levels of CHST1, MPPED2, and RIPPLY3 in NEPC using cell lines, animal models and human tissues. In the final step, we found that imatinib might be the drug specific to NEPC, which was further confirmed by in vitro cell assay. Our results revealed the clinical characteristics, molecular features, immune cell infiltration pattern in CRPC-adeno and NEPC, and identified and confirmed CHST1, MPPED2, and RIPPLY3 as the critical genes in the development in prostate cancer and NEPC. We also predicted and validated imatinib as the potential specific drugs to NEPC.
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Affiliation(s)
- Jianqing Wang
- Department of Urology, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, China
| | - Yu Wang
- Vancouver Prostate Centre, Vancouver, BC, Canada; Department of Urologic Sciences, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada
| | - Huihui Zhou
- Department of Pathology, Affiliated Yuhuangding Hospital of Qingdao University, China
| | - Guopeng Yu
- Department of Urology, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, China
| | - Huan Xu
- Department of Urology, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, China
| | - Dajun Gao
- Department of Urology, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, China
| | - Minglun Li
- Urologic and Hematologic Oncology, Department of Radiation Oncology, LMU, University Hospital, Munich, Germany.
| | - Yuzhuo Wang
- Vancouver Prostate Centre, Vancouver, BC, Canada; Department of Urologic Sciences, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada.
| | - Bin Xu
- Department of Urology, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, China.
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Fatima S. Tumor Microenvironment: A Complex Landscape of Cancer Development and Drug Resistance. Cureus 2025; 17:e82090. [PMID: 40351953 PMCID: PMC12066109 DOI: 10.7759/cureus.82090] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/11/2025] [Indexed: 05/14/2025] Open
Abstract
Cancer is responsible for nearly one in six global fatalities, making it a major health issue worldwide. Despite advancements in early detection, surgery, and targeted therapies, effective treatment remains challenging due to the complexity and heterogeneity of the disease. A key factor in cancer progression and resistance to treatment is the tumor microenvironment (TME). It is a complex ecosystem comprising cancer cells, stromal cells, immune cells, extracellular matrix (ECM), and soluble factors like cytokines and chemokines. These components interact dynamically to influence tumor growth, metastasis, immune evasion, and treatment resistance. Cancer cells drive the formation of the TME by releasing signaling molecules, while stromal cells, such as fibroblasts and endothelial cells, support tumor metabolism, angiogenesis, and invasion. Immune cells within the TME can either suppress or promote tumor progression, depending on their activation state. Additionally, the TME can promote the growth of immunosuppressive cells that aid cancer cells in evading immune surveillance, such as regulatory T-cells and myeloid-derived suppressor cells. The TME also impedes drug delivery by creating defective blood vessels, contributing to drug resistance. Recent technological advancements have deepened our understanding of the TME, revealing its role in immune modulation, metabolism, and extracellular matrix remodeling. As a result, targeting the TME has become a promising strategy to overcome treatment resistance and improve cancer therapy outcomes.
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Affiliation(s)
- Sohaila Fatima
- Pathology, College of Medicine, King Khalid University, Abha, SAU
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50
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Chaulagain RP, Padder AM, Shrestha H, Gupta R, Bhandari R, Shrestha Y, Qasem Moqbel A, Gautam S, Lal N, Jin S. Deciphering the Matrisome: Extracellular Matrix Remodeling in Liver Cirrhosis and Hepatocellular Carcinoma. Cureus 2025; 17:e82171. [PMID: 40370880 PMCID: PMC12076258 DOI: 10.7759/cureus.82171] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/13/2025] [Indexed: 05/16/2025] Open
Abstract
Liver cirrhosis and hepatocellular carcinoma (HCC) are major public health concerns due to their high morbidity and mortality rates. The liver, a vital organ for metabolism, detoxification, and homeostasis, depends on the matrisome, a complex and dynamic network of extracellular matrix (ECM) components for maintaining structural and functional integrity. Chronic liver inflammation, induced by factors such as alcohol abuse, viral hepatitis, and non-alcoholic fatty liver disease, leads to fibrosis and cirrhosis, progressing to HCC. The matrisome, composed of ECM proteins including collagen, fibronectin, and laminin, plays a critical role in regulating tissue homeostasis, cell signaling, and tissue repair. Dysregulation of ECM components contributes to the pathogenesis of both liver cirrhosis and cancer. In cirrhosis, matrisome alterations are characterized by excessive ECM deposition and fibrosis, which disrupt the liver's architecture and impair its function. Activated hepatic stellate cells (HSCs) are the principal mediators of fibrosis, producing large quantities of ECM components. In liver cancer, matrisome remodeling facilitates tumorigenesis by promoting cancer cell proliferation, invasion, and metastasis. The tumor microenvironment, shaped by ECM alterations, further supports tumor growth and dissemination. Matrix metalloproteinases (MMPs) play a pivotal role in ECM degradation, fibrosis progression, and tumor invasion, while tissue inhibitors of metalloproteinases (TIMPs) modulate MMP activity. A comprehensive understanding of the molecular mechanisms that link matrisome alterations with the progression from cirrhosis to liver cancer is essential for identifying novel diagnostic and therapeutic targets. This review highlights the dynamic responses of the hepatic matrisome to both acute and chronic insults, emphasizing the complex interplay between ECM components, cellular behavior, and disease progression. Elucidating these interactions may inform strategies aimed at improving clinical outcomes for patients with liver cirrhosis and HCC.
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Affiliation(s)
- Ram Prasad Chaulagain
- Internal Medicine, Second Affiliated Hospital of Harbin Medical University, Harbin, CHN
| | - Aadil Mushtaq Padder
- Gastroenterology and Hepatology, Second Affiliated Hospital of Harbin Medical University, Harbin, CHN
| | | | - Radheshyam Gupta
- Urology Surgery, Cancer Hospital, Harbin Medical University, Harbin, CHN
| | - Rameshor Bhandari
- Surgical Gastroenterology, Grande International Hospital, Kathmandu, NPL
| | - Yelona Shrestha
- Dermatology, First Affiliated Hospital of Xinjiang Medical University, Xinxiang, CHN
| | | | - Smriti Gautam
- Dermatology, Kathmandu Medical College, Kathmandu, NPL
| | - Nand Lal
- Physiology, School of Biomedical Sciences, Harbin Medical University, Harbin, CHN
| | - Shizhu Jin
- Gastroenterology and Hepatology, Second Affiliated Hospital of Harbin Medical University, Harbin, CHN
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