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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. Interactions and communications in lung tumour microenvironment: chemo/radiotherapy resistance mechanisms and therapeutic targets. J Drug Target 2025; 33:817-836. [PMID: 39815747 DOI: 10.1080/1061186x.2025.2453730] [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: 11/17/2024] [Revised: 12/28/2024] [Accepted: 01/08/2025] [Indexed: 01/18/2025]
Abstract
The lung tumour microenvironment (TME) is composed of various cell types, including cancer cells, stromal and immune cells, as well as extracellular matrix (ECM). These cells and surrounding ECM create a stiff, hypoxic, acidic and immunosuppressive microenvironment that can augment the resistance of lung tumours to different forms of cell death and facilitate invasion and metastasis. This environment can induce chemo/radiotherapy resistance by inducing anti-apoptosis mediators such as phosphoinositide 3-kinase (PI3K)/Akt, signal transducer and activator of transcription 3 (STAT3) and nuclear factor kappa B (NF-κB), leading to the exhaustion of antitumor immunity and further resistance to chemo/radiotherapy. In addition, lung tumour cells can resist chemo/radiotherapy by boosting multidrug resistance mechanisms and antioxidant defence systems within cancer cells and other TME components. In this review, we discuss the interactions and communications between these different components of the lung TME and also the effects of hypoxia, immune evasion and ECM remodelling on lung cancer resistance. Finally, we review the current strategies in preclinical and clinical studies, including the inhibition of checkpoint molecules, chemoattractants, cytokines, growth factors and immunosuppressive mediators such as programmed death 1 (PD-1), insulin-like growth factor 2 (IGF-2) for targeting the lung TME to overcome resistance to chemotherapy and radiotherapy.
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Affiliation(s)
- Yuan Feng
- Guangxi University of Chinese Medicine, Nanning, China
| | - Ying Jiang
- Department of Neurology, Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine, Nanning, China
| | - Lin Yang
- Guangxi University of Chinese Medicine, Nanning, China
| | - Danni Lu
- Guangxi University of Chinese Medicine, Nanning, China
| | - Ning Li
- Guangxi University of Chinese Medicine, Nanning, China
| | - Qun Zhang
- Guangxi University of Chinese Medicine, Nanning, China
| | - Haiyan Yang
- Guangxi University of Chinese Medicine, Nanning, China
| | - Huiyuan Qin
- Guangxi University of Chinese Medicine, Nanning, China
| | - Jiaxin Zhang
- Guangxi University of Chinese Medicine, Nanning, China
| | - Xinyun Gou
- Guangxi University of Chinese Medicine, Nanning, China
| | - Feng Jiang
- Science and Technology Department, Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine, Nanning, China
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Deng S, Wang J, Zou F, Cheng D, Chen M, Gu J, Shi J, Yang J, Xue Y, Jiang Z, Qin L, Mao F, Chang X, Nie X, Liu L, Cao Y, Cai K. Palmitic Acid Accumulation Activates Fibroblasts and Promotes Matrix Stiffness in Colorectal Cancer. Cancer Res 2025; 85:1784-1802. [PMID: 39992719 PMCID: PMC12079102 DOI: 10.1158/0008-5472.can-24-2892] [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: 08/12/2024] [Revised: 11/27/2024] [Accepted: 02/17/2025] [Indexed: 02/26/2025]
Abstract
Obstructions can occur during any stage of colorectal cancer and correspond with poor prognosis. Obstructive colorectal cancer (OCRC) is harder and exhibits increased tumor budding and proliferation of myofibroblasts compared with nonobstructive colorectal cancer, suggesting that the occurrence of obstruction may be related to extracellular matrix (ECM) remodeling. In this study, we found that colorectal cancer and OCRC samples differed substantially in ECM composition, specifically in collagen (newly formed and mature) and proteoglycans (including glycosaminoglycan, hyaluronic acid, and chondroitin sulfate). OCRC also exhibited considerable changes in ECM biomechanics and collagen arrangement. Interestingly, OCRC samples presented a notable increase in matrix cancer-associated fibroblasts (mCAF). The abundance of mCAFs correlated with the accumulation of palmitic acid (PA), and high concentrations of PA increased the secretion of ECM-related proteins by mCAFs. Additionally, PA did not directly affect normal fibroblasts but rather activated the NF-κB pathway in tumor cells to stimulate secretion of CSF1, TGFβ1, and CXCL8, which promoted the activation of normal fibroblasts into mCAFs and exacerbated ECM stiffening. Drug screening with a natural compound library identified vanillylacetone as a potential inhibitor of PA-induced cytokine secretion and ECM stiffening. These findings highlight intratumoral PA accumulation as a key mechanism driving ECM alterations and OCRC progression and suggest that targeting this axis may be useful for treating patients with colorectal cancer with risk of obstruction. Significance: Palmitic acid accumulation activates the NF-κB pathway in colorectal cancer cells to promote cytokine secretion that facilitates the generation of matrix cancer-associated fibroblasts, driving extracellular matrix remodeling and development of obstructions.
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Affiliation(s)
- Shenghe Deng
- Department of General Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jun Wang
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Falong Zou
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Denglong Cheng
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Mian Chen
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Junnan Gu
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jianguo Shi
- Department of Gastrointestinal Surgery, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jia Yang
- Department of Gastrointestinal Surgery, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yifan Xue
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhenxin Jiang
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Le Qin
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Fuwei Mao
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaona Chang
- Department of Pathology, Union Hospital, Tongji Medical, Huazhong University of Science and Technology, Wuhan, China
| | - Xiu Nie
- Department of Pathology, Union Hospital, Tongji Medical, Huazhong University of Science and Technology, Wuhan, China
| | - Li Liu
- Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yinghao Cao
- Department of Digestive Surgical Oncology, Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Clinical Imaging Research Centre, Centre for Translational Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Kailin Cai
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Li Y, Peng S, Xu J, Liu W, Luo Q. Integrin signaling in tumor biology: mechanisms of intercellular crosstalk and emerging targeted therapies. PeerJ 2025; 13:e19328. [PMID: 40352270 PMCID: PMC12065456 DOI: 10.7717/peerj.19328] [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: 12/11/2024] [Accepted: 03/25/2025] [Indexed: 05/14/2025] Open
Abstract
Integrins, a family of transmembrane cell adhesion receptors, mediate intercellular and cell-extracellular matrix crosstalk via outside-in and inside-out signaling pathways. Integrins, categorized into 24 distinct combinations of α and β subunits, exhibit tissue-specific expression and perform unique or overlapping roles in physiological and pathophysiological processes. These roles encompass embryonic angiogenesis, tissue repair, and the modulation of tumor cell angiogenesis, progression, invasion, and metastasis. Notably, integrins are significant contributors to tumor development, offering valuable insights into the potential of integrin-targeted diagnostics and therapeutics. Currently, there are various preclinical and clinical trials aiming to harness integrin antagonists that are safe, efficacious, and exhibit low toxicity. Owing to the functional redundancy across integrin types and the complexity of the mechanisms of integrin-mediated multiple key processes associated with tumor biology, challenges exist that impede advancements in integrin-targeted therapy. Nevertheless, innovative strategies focused on integrin modulation represent significant breakthroughs for improving patient care and promoting comprehensive insights into the underlying mechanisms of tumor biology. This review elucidates the impact of integrins on three distinct cell types in multiple key processes associated with tumor biology and explores the emerging integrin-targeted therapeutic approaches for the treatment of tumors, which will provide ideas for optimal therapeutic approaches in the future.
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Affiliation(s)
- Yifan Li
- Queen Mary School, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Shantong Peng
- Queen Mary School, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Jiatong Xu
- Queen Mary School, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Wenjie Liu
- The First Clinical College, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Qi Luo
- College of Basic Medical Sciences, Nanchang University, Nanchang, Jiangxi, China
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Finger AM, Hendley AM, Figueroa D, Gonzalez H, Weaver VM. Tissue mechanics in tumor heterogeneity and aggression. Trends Cancer 2025:S2405-8033(25)00096-2. [PMID: 40307158 DOI: 10.1016/j.trecan.2025.04.004] [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: 08/27/2024] [Revised: 03/10/2025] [Accepted: 04/04/2025] [Indexed: 05/02/2025]
Abstract
Tumorigenesis ensues within a heterogeneous tissue microenvironment that promotes malignant transformation, metastasis and treatment resistance. A major feature of the tumor microenvironment is the heterogeneous population of cancer-associated fibroblasts and myeloid cells that stiffen the extracellular matrix. The heterogeneously stiffened extracellular matrix in turn activates cellular mechanotransduction and creates a hypoxic and metabolically hostile microenvironment. The stiffened extracellular matrix and elevated mechanosignaling also drive tumor aggression by fostering tumor cell growth, survival, and invasion, compromising antitumor immunity, expanding cancer stem cell frequency, and increasing mutational burden, which promote intratumor heterogeneity. Delineating the molecular mechanisms whereby tissue mechanics regulate these phenotypes should help to clarify the basis for tumor heterogeneity and cancer aggression and identify novel therapeutic targets that could improve patient outcome. Here, we discuss the role of the extracellular matrix in driving cancer aggression through its impact on tumor heterogeneity.
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Affiliation(s)
- Anna-Marie Finger
- Department of Anatomy, University of California, San Francisco, San Francisco, CA, USA 94143; Current address: Liver Disease Research, Global Drug Discovery, Novo Nordisk A/S, Malov, Denmark
| | - Audrey Marie Hendley
- Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California, San Francisco, San Francisco, CA, USA 94143
| | - Diego Figueroa
- Department of Radiation Oncology, Department of Bioengineering and Therapeutic Sciences, Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA 94143, USA
| | - Hugo Gonzalez
- Department of Anatomy, University of California, San Francisco, San Francisco, CA, USA 94143; Current address: Laboratory of Tumor Microenvironment and Metastasis, Centro Ciencia & Vida, Santiago, Chile
| | - Valerie Marie Weaver
- Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California, San Francisco, San Francisco, CA, USA 94143; Department of Radiation Oncology, Department of Bioengineering and Therapeutic Sciences, Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA 94143, USA.
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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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Kent O, Casey ER, Brown M, Bell S, Ehrman MC, Flagler MJ, Määttä A, Benham AM, Hawkins TJ. New imaging tools reveal live cellular collagen secretion, fibril dynamics and network organisation. Sci Rep 2025; 15:13764. [PMID: 40258849 PMCID: PMC12012225 DOI: 10.1038/s41598-025-96280-4] [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: 08/15/2024] [Accepted: 03/27/2025] [Indexed: 04/23/2025] Open
Abstract
Although light microscopy has been used to examine the early trafficking of collagen within the cell, much of our understanding of the detailed organisation of cell deposited collagen is from static electron microscopy studies. To understand the dynamics of live cell collagen deposition and fibril organisation, we generated a bright photostable mNGCol1α2 fusion protein and employed a range of microscopy techniques to follow its intracellular transport and elucidate extracellular fibril formation. Our findings reveal the dynamics of fibril growth and the dynamic nature of collagen network interactions at the cellular level. Notably we observed molecular events that build network organisation, including fibril bundling, bifurcation, directionality along existing fibrils, and looping/intertwining behaviours. Strikingly, mNGCol1α2 fluorescence intensity maxima can mark a fibril before another growing collagen fibril intersects at this location. Real-time, high-resolution imaging of collagen has enabled fibrillogenesis and organisational dynamics to be visualised together in an actively secreting cellular system. We also show that the N-terminal protease site is not an absolute requirement for collagen fibril incorporation. This approach paves the way for assessing the dynamic organisation and assembly of collagen into the extracellular matrix in skin models and other tissues during health, ageing and disease.
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Affiliation(s)
- Olivia Kent
- Department of Biosciences, Durham University, South Road, Durham, DH1 3LE, UK
| | - Eleanor R Casey
- Department of Biosciences, Durham University, South Road, Durham, DH1 3LE, UK
| | - Max Brown
- The Procter & Gamble Company, Newcastle Innovation Centre, Newcastle-Upon-Tyne, NE12 9TS, UK
| | - Steven Bell
- Department of Biosciences, Durham University, South Road, Durham, DH1 3LE, UK
| | - Matthew C Ehrman
- Procter & Gamble International Operations SA SG Branch, 70 Biopolis Street, Singapore, 138547, Singapore
| | | | - Arto Määttä
- Department of Biosciences, Durham University, South Road, Durham, DH1 3LE, UK
| | - Adam M Benham
- Department of Biosciences, Durham University, South Road, Durham, DH1 3LE, UK
| | - Timothy J Hawkins
- Department of Biosciences, Durham University, South Road, Durham, DH1 3LE, UK.
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Lan X, Li W, Zhao K, Wang J, Li S, Zhao H. Revisiting the role of cancer-associated fibroblasts in tumor microenvironment. Front Immunol 2025; 16:1582532. [PMID: 40313969 PMCID: PMC12043473 DOI: 10.3389/fimmu.2025.1582532] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2025] [Accepted: 03/31/2025] [Indexed: 05/03/2025] Open
Abstract
Cancer-associated fibroblasts (CAFs) are integral components of the tumor microenvironment playing key roles in tumor progression, metastasis, and therapeutic resistance. However, challenges persist in understanding their heterogeneity, origin, and functional diversity. One major obstacle is the lack of standardized naming conventions for CAF subpopulations, with current systems failing to capture their full complexity. Additionally, the identification of CAFs is hindered by the absence of specific biomarkers, limiting the precision of diagnostic and therapeutic strategies. In vitro culture conditions often fail to maintain the in vivo characteristics of CAFs, which complicates their study and the translation of findings to clinical practice. Although current detection methods, such as antibodies, mRNA probes, and single-cell transcriptomics, offer insights into CAF biology, they lack standardization and fail to provide reliable quantitative measures. Furthermore, the dynamic interactions between CAFs, tumor cells, and immune cells within the TME remain insufficiently understood, and the role of CAFs in immune evasion and therapy resistance is an area of ongoing research. Understanding how CAFs influence drug resistance and the immune response is essential for developing more effective cancer therapies. This review aims to provide an in-depth analysis of the challenges in CAF research, propose future research directions, and emphasize the need for improved CAF-targeted therapeutic strategies. By addressing these gaps, it seeks to highlight the potential of CAFs as targets for overcoming therapeutic resistance and enhancing the efficacy of cancer treatments.
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Affiliation(s)
| | | | | | | | | | - Hai Zhao
- Department of Neurosurgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
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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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Zhang J, Sun Z, Li G, Ding L, Wang Z, Liu M. Discovering biomarkers associated with infiltration of CD8 + T cells and tumor-associated fibrosis in colon adenocarcinoma using single-cell RNA sequencing and gene co-expression network. Front Immunol 2025; 16:1496640. [PMID: 40230854 PMCID: PMC11994618 DOI: 10.3389/fimmu.2025.1496640] [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: 09/23/2024] [Accepted: 03/11/2025] [Indexed: 04/16/2025] Open
Abstract
Background Colorectal adenocarcinoma (COAD) is a prevalent malignant tumor associated with a high mortality rate. Within the tumor microenvironment, CD8+ T cells play a pivotal role in the anti-tumor immune response within the human body. Fibrosis directly and indirectly affects the therapeutic response of tumor immunotherapy. However, the significance of regulatory genes associated with tumor-associated fibrosis and CD8+ T cell infiltration remains uncertain. Therefore, it is imperative to identify biomarkers with prognostic value and elucidate the precise role of CD8+ T cells and tumor-associated fibrosis. Methods We performed a single-cell transcriptome analysis of COAD samples from the GEO database. To evaluate immune infiltration in COAD samples, we utilized CIBERSORT and ESTIMATE. Furthermore, we analyzed the correlation between CD8+ T cells and immune infiltration. To analyze COAD expression's quantitative immune cell composition data, we conducted a Weighted Gene Correlation Network Analysis and utilized a deconvolution algorithm. The data for these analyses were obtained from the GEO database. We utilized univariate Cox regression and LASSO analysis to create a prognostic model. The predictive model was assessed through Kaplan-Meier analysis, and a survival prediction nomogram was created. Additionally, we analyzed the correlation between the prognostic model and chemotherapy drug sensitivity. To estimate the expression of hub genes, we employed immunohistochemistry, real-time PCR, and western blot techniques. Results Single-cell transcriptome analysis has indicated a higher prevalence of CD8+ T cells in COAD tumor samples. The connection between COAD and CD8+ T cells was further confirmed by WGCNA and deconvolution analysis using the GEO database. The Protein-Protein Interaction network analysis revealed three hub genes: LARS2, SEZ6L2, and SOX7. A predictive model was subsequently created using LASSO and univariate COX regression, which included these three genes. Two of these hub genes (LARS2 and SEZ6L2) were found to be upregulated in COAD cell lines and tissues, while SOX7 was observed to be downregulated. The prognostic model demonstrated a significant association with CD8+ T cells, suggesting that these genes could serve as potential biomarkers and targets for gene therapy in treating COAD. Conclusion This study has identified three key genes associated with CD8+ T cells and the prognosis of COAD, providing new prognostic biomarkers for diagnosing and treating COAD.
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Affiliation(s)
- Jinning Zhang
- Colorectal Cancer Surgery Department, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
- Future Medical Laboratory, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Ziquan Sun
- Department of General Surgery, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
- Heilongjiang Province Key Laboratory of Digestive Surgery and Nutrition & Metabolism, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Guodong Li
- Department of General Surgery, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
- Heilongjiang Province Key Laboratory of Digestive Surgery and Nutrition & Metabolism, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Lixian Ding
- Department of General Surgery, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Zitong Wang
- Colorectal Cancer Surgery Department, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Ming Liu
- Department of General Surgery, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
- Heilongjiang Province Key Laboratory of Digestive Surgery and Nutrition & Metabolism, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
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Basu R, Boguszewski CL, Kopchick JJ. Growth Hormone Action as a Target in Cancer: Significance, Mechanisms, and Possible Therapies. Endocr Rev 2025; 46:224-280. [PMID: 39657053 DOI: 10.1210/endrev/bnae030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2024] [Revised: 08/29/2024] [Accepted: 12/03/2024] [Indexed: 12/17/2024]
Abstract
Growth hormone (GH) is a pituitary-derived endocrine hormone required for normal postnatal growth and development. Hypo- or hypersecretion of endocrine GH results in 2 pathologic conditions, namely GH deficiency (GHD) and acromegaly. Additionally, GH is also produced in nonpituitary and tumoral tissues, where it acts rather as a cellular growth factor with an autocrine/paracrine mode of action. An increasingly persuasive and large body of evidence over the last 70 years concurs that GH action is implicit in escalating several cancer-associated events, locally and systemically. This pleiotropy of GH's effects is puzzling, but the association with cancer risk automatically raises a concern for patients with acromegaly and for individuals treated with GH. By careful assessment of the available knowledge on the fundamental concepts of cancer, suggestions from epidemiological and clinical studies, and the evidence from specific reports, in this review we aimed to help clarify the distinction of endocrine vs autocrine/paracrine GH in promoting cancer and to reconcile the discrepancies between experimental and clinical data. Along this discourse, we critically weigh the targetability of GH action in cancer-first by detailing the molecular mechanisms which posit GH as a critical node in tumor circuitry; and second, by enumerating the currently available therapeutic options targeting GH action. On the basis of our discussion, we infer that a targeted intervention on GH action in the appropriate patient population can benefit a sizable subset of current cancer prognoses.
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Affiliation(s)
- Reetobrata Basu
- Edison Biotechnology Institute, Ohio University, Athens, OH 45701, USA
- Department of Biomedical Sciences, Ohio University Heritage College of Osteopathic Medicine (OU-HCOM), Athens, OH 45701, USA
- Diabetes Institute, Ohio University Heritage College of Osteopathic Medicine (OU-HCOM), Athens, OH 45701, USA
| | - Cesar L Boguszewski
- SEMPR, Endocrine Division, Department of Internal Medicine, Federal University of Parana, Curitiba 80060-900, Brazil
| | - John J Kopchick
- Edison Biotechnology Institute, Ohio University, Athens, OH 45701, USA
- Department of Biomedical Sciences, Ohio University Heritage College of Osteopathic Medicine (OU-HCOM), Athens, OH 45701, USA
- Diabetes Institute, Ohio University Heritage College of Osteopathic Medicine (OU-HCOM), Athens, OH 45701, USA
- Molecular and Cellular Biology Program, Ohio University, Athens, OH 45701, USA
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Affὸ S, Sererols-Viñas L, Garcia-Vicién G, Cadamuro M, Chakraborty S, Sirica AE. Cancer-Associated Fibroblasts in Intrahepatic Cholangiocarcinoma: Insights into Origins, Heterogeneity, Lymphangiogenesis, and Peritoneal Metastasis. THE AMERICAN JOURNAL OF PATHOLOGY 2025; 195:378-396. [PMID: 39117110 DOI: 10.1016/j.ajpath.2024.07.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/08/2024] [Revised: 07/11/2024] [Accepted: 07/19/2024] [Indexed: 08/10/2024]
Abstract
Intrahepatic cholangiocarcinoma (iCCA) denotes a rare, highly malignant, and heterogeneous class of primary liver adenocarcinomas exhibiting phenotypic characteristics of cholangiocyte differentiation. Among the distinctive pathological features of iCCA, one that differentiates the most common macroscopic subtype (eg, mass-forming type) of this hepatic tumor from conventional hepatocellular carcinoma is a prominent desmoplastic reaction manifested as a dense fibro-collagenous-enriched tumor stroma. Cancer-associated fibroblasts (CAFs) represent the most abundant mesenchymal cell type in the desmoplastic reaction. Although the protumor effects of CAFs in iCCA have been increasingly recognized, more recent cell lineage tracing studies, advanced single-cell RNA sequencing, and expanded biomarker analyses have provided new awareness into their ontogeny, as well as underscored their biological complexity as reflected by the presence of multiple subtypes. In addition, evidence supports CAFs' potential to display cancer-restrictive roles, including immunosuppression. However, CAFs also play important roles in facilitating metastasis, as exemplified by lymph node metastasis and peritoneal carcinomatosis, which are common in iCCA. Herein, the authors provide a timely appraisal of the origins and phenotypic and functional complexity of CAFs in iCCA, together with providing mechanistic insights into lymphangiogenesis and peritoneal metastasis relevant to this lethal human cancer.
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Affiliation(s)
- Silvia Affὸ
- Tumor Microenvironment Plasticity and Heterogeneity Research Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
| | - Laura Sererols-Viñas
- Tumor Microenvironment Plasticity and Heterogeneity Research Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Gemma Garcia-Vicién
- Tumor Microenvironment Plasticity and Heterogeneity Research Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | | | - Sanjukta Chakraborty
- Department of Medical Physiology, School of Medicine, Texas A&M Health Science Center, Bryan, Texas
| | - Alphonse E Sirica
- Department of Pathology (Emeritus), Virginia Commonwealth University School of Medicine, Richmond, Virginia.
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12
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Ghannam SF, Rutland CS, Allegrucci C, Mather ML, Alsaleem M, Bateman‐Price TD, Patke R, Ball G, Mongan NP, Rakha E. Geometric characteristics of stromal collagen fibres in breast cancer using differential interference contrast microscopy. J Microsc 2025; 297:135-152. [PMID: 39359124 PMCID: PMC11733853 DOI: 10.1111/jmi.13361] [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: 02/20/2024] [Revised: 09/17/2024] [Accepted: 09/18/2024] [Indexed: 10/04/2024]
Abstract
Breast cancer (BC) is characterised by a high level of heterogeneity, which is influenced by the interaction of neoplastic cells with the tumour microenvironment. The diagnostic and prognostic role of the tumour stroma in BC remains to be defined. Differential interference contrast (DIC) microscopy is a label-free imaging technique well suited to visualise weak optical phase objects such as cells and tissue. This study aims to compare stromal collagen fibre characteristics between in situ and invasive breast tumours using DIC microscopy and investigate the prognostic value of collagen parameters in BC. A tissue microarray was generated from 200 cases, comprising ductal carcinoma in situ (DCIS; n = 100) and invasive tumours (n = 100) with an extra 50 (25 invasive BC and 25 DCIS) cases for validation was utilised. Two sections per case were used: one stained with haematoxylin and eosin (H&E) stain for histological review and one unstained for examination using DIC microscopy. Collagen fibre parameters including orientation angle, fibre alignment, fibre density, fibre width, fibre length and fibre straightness were measured. Collagen fibre density was higher in the stroma of invasive BC (161.68 ± 11.2 fibre/µm2) compared to DCIS (p < 0.0001). The collagen fibres were thinner (13.78 ± 1.08 µm), straighter (0.96 ± 0.006, on a scale of 0-1), more disorganised (95.07° ± 11.39°) and less aligned (0.20 ± 0.09, on a 0-1 scale) in the invasive BC compared to DCIS (all p < 0.0001). A model considering these features was developed that could distinguish between DCIS and invasive tumours with 94% accuracy. There were strong correlations between fibre characteristics and clinicopathological parameters in both groups. A statistically significant association between fibre characteristics and patients' outcomes (breast cancer specific survival, and recurrence free survival) was observed in the invasive group but not in DCIS. Although invasive BC and DCIS were both associated with stromal reaction, the structural features of collagen fibres were significantly different in the two disease stages. Analysis of the stroma fibre characteristics in the preoperative core biopsy specimen may help to differentiate pure DCIS from those associated with invasion.
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Affiliation(s)
- Suzan F. Ghannam
- Academic Unit for Translational Medical SciencesSchool of MedicineUniversity of NottinghamNottinghamUK
- Faculty of MedicineDepartment of Histology and Cell BiologySuez Canal UniversityIsmailiaEgypt
- Nottingham Breast Cancer Research CentreBiodiscovery InstituteUniversity of NottinghamNottinghamUK
| | - Catrin Sian Rutland
- Nottingham Breast Cancer Research CentreBiodiscovery InstituteUniversity of NottinghamNottinghamUK
- School of Veterinary Medicine and ScienceUniversity of NottinghamNottinghamUK
| | - Cinzia Allegrucci
- Nottingham Breast Cancer Research CentreBiodiscovery InstituteUniversity of NottinghamNottinghamUK
- School of Veterinary Medicine and ScienceUniversity of NottinghamNottinghamUK
| | - Melissa L. Mather
- Optics and Photonics Research GroupFaculty of EngineeringUniversity of NottinghamNottinghamUK
| | - Mansour Alsaleem
- Department of Applied Medical ScienceApplied CollegeQassim UniversityQassimSaudi Arabia
| | - Thomas D. Bateman‐Price
- Optics and Photonics Research GroupFaculty of EngineeringUniversity of NottinghamNottinghamUK
| | - Rodhan Patke
- School of Veterinary Medicine and ScienceUniversity of NottinghamNottinghamUK
- Biodiscovery InstituteUniversity of NottinghamUniversity ParkNottinghamUK
| | - Graham Ball
- Medical Technology Research CentreAnglia Ruskin UniversityChelmsfordUK
| | - Nigel P. Mongan
- School of Veterinary Medicine and ScienceUniversity of NottinghamNottinghamUK
- Department of PharmacologyWeill Cornell MedicineNew YorkNew YorkUSA
| | - Emad Rakha
- Academic Unit for Translational Medical SciencesSchool of MedicineUniversity of NottinghamNottinghamUK
- Nottingham Breast Cancer Research CentreBiodiscovery InstituteUniversity of NottinghamNottinghamUK
- Cellular Pathology DepartmentNottingham University Hospitals NHS TrustNottinghamUK
- Pathology DepartmentHamad Medical CorporationDohaQatar
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13
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Shu Y, Li J. Disulfidptosis as a key regulator of glioblastoma progression and immune cell impairment. Front Immunol 2025; 16:1526296. [PMID: 39949776 PMCID: PMC11821639 DOI: 10.3389/fimmu.2025.1526296] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2024] [Accepted: 01/13/2025] [Indexed: 02/16/2025] Open
Abstract
Background Glioblastoma, associated with poor prognosis and impaired immune function, shows potential interactions between newly identified disulfidptosis mechanisms and T cell exhaustion, yet these remain understudied. Methods Key genes were identified using Lasso regression, followed by multivariate analysis to develop a prognostic model. Single-cell pseudotemporal analysis explored disulfidptosis T-cell exhaustion (Tex) signaling in cell differentiation. Immune infiltration was assessed via ssGSEA, while transwell assays and immunofluorescence examined the effects of disulfidptosis-Tex genes on glioma cell behavior and immune response. Results Eleven disulfidptosis-Tex genes were found critical for glioblastoma survival outcomes. This gene set underpinned a model predicting patient prognosis. Single-cell analysis showed high disulfidptosis-Tex activity in endothelial cells. Memory T cell populations were linked to these genes. SMC4 inhibition reduced LN299 cell migration and increased chemotherapy sensitivity, decreasing CD4 and CD8 T cell activation. Conclusions Disulfidptosis-Tex genes are pivotal in glioblastoma progression and immune interactions, offering new avenues for improving anti-glioblastoma therapies through modulation of T cell exhaustion.
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Zhang X, Zhang M, Sun H, Wang X, Wang X, Sheng W, Xu M. The role of transcription factors in the crosstalk between cancer-associated fibroblasts and tumor cells. J Adv Res 2025; 67:121-132. [PMID: 38309692 PMCID: PMC11725164 DOI: 10.1016/j.jare.2024.01.033] [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: 11/29/2023] [Revised: 01/27/2024] [Accepted: 01/29/2024] [Indexed: 02/05/2024] Open
Abstract
BACKGROUND Transcription factors (TFs) fulfill a critical role in the formation and maintenance of different cell types during the developmental process as well as disease. It is believed that cancer-associated fibroblasts (CAFs) are activation status of tissue-resident fibroblasts or derived from form other cell types via transdifferentiation or dedifferentiation. Despite a subgroup of CAFs exhibit anti-cancer effects, most of them are reported to exert effects on tumor progression, further indicating their heterogeneous origin. AIM OF REVIEW This review aimed to summarize and review the roles of TFs in the reciprocal crosstalk between CAFs and tumor cells, discuss the emerging mechanisms, and their roles in cell-fate decision, cellular reprogramming and advancing our understanding of the gene regulatory networks over the period of cancer initiation and progression. KEY SCIENTIFIC CONCEPTS OF REVIEW This manuscript delves into the key contributory factors of TFs that are involved in activating CAFs and maintaining their unique states. Additionally, it explores how TFs play a pivotal and multifaceted role in the reciprocal crosstalk between CAFs and tumor cells. This includes their involvement in processes such as epithelial-mesenchymal transition (EMT), proliferation, invasion, and metastasis, as well as metabolic reprogramming. TFs also have a role in constructing an immunosuppressive microenvironment, inducing resistance to radiation and chemotherapy, facilitating angiogenesis, and even 'educating' CAFs to support the malignancies of tumor cells. Furthermore, this manuscript delves into the current status of TF-targeted therapy and considers the future directions of TFs in conjunction with anti-CAFs therapies to address the challenges in clinical cancer treatment.
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Affiliation(s)
- 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
| | - Meng 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
| | - Hui Sun
- 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
| | - 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
| | - 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.
| | - 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.
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15
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Wu C, Von Schalscha T, Sansanwal D, Qian C, Jiang Q, Shepard RM, Wettersten HI, McCormack SJ, Weis SM, Cheresh DA. Targeting Pancreatic Cancer Cell Stemness by Blocking Fibronectin-Binding Integrins on Cancer-Associated Fibroblasts. CANCER RESEARCH COMMUNICATIONS 2025; 5:195-208. [PMID: 39785683 PMCID: PMC11783622 DOI: 10.1158/2767-9764.crc-24-0491] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/18/2024] [Revised: 12/06/2024] [Accepted: 01/07/2025] [Indexed: 01/12/2025]
Abstract
SIGNIFICANCE Simultaneous targeting of two integrins that function as receptors for FN, a protumor ECM protein, can prevent fibroblasts from supporting the malignant behavior of pancreatic cancer cells.
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Affiliation(s)
- Chengsheng Wu
- Department of Pathology, Moores Cancer Center, Sanford Consortium for Regenerative Medicine at the University of California, San Diego, La Jolla, California
| | - Tami Von Schalscha
- Department of Pathology, Moores Cancer Center, Sanford Consortium for Regenerative Medicine at the University of California, San Diego, La Jolla, California
| | - Diva Sansanwal
- Department of Pathology, Moores Cancer Center, Sanford Consortium for Regenerative Medicine at the University of California, San Diego, La Jolla, California
| | - Chen Qian
- Department of Pathology, Moores Cancer Center, Sanford Consortium for Regenerative Medicine at the University of California, San Diego, La Jolla, California
| | - Qinlin Jiang
- Department of Pathology, Moores Cancer Center, Sanford Consortium for Regenerative Medicine at the University of California, San Diego, La Jolla, California
| | - Ryan M. Shepard
- Department of Pathology, Moores Cancer Center, Sanford Consortium for Regenerative Medicine at the University of California, San Diego, La Jolla, California
| | - Hiromi I. Wettersten
- Department of Pathology, Moores Cancer Center, Sanford Consortium for Regenerative Medicine at the University of California, San Diego, La Jolla, California
| | | | - Sara M. Weis
- Department of Pathology, Moores Cancer Center, Sanford Consortium for Regenerative Medicine at the University of California, San Diego, La Jolla, California
| | - David A. Cheresh
- Department of Pathology, Moores Cancer Center, Sanford Consortium for Regenerative Medicine at the University of California, San Diego, La Jolla, California
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16
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Kumar S, Ranga A. Role of miRNAs in breast cancer development and progression: Current research. Biofactors 2025; 51:e2146. [PMID: 39601401 DOI: 10.1002/biof.2146] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2024] [Accepted: 10/16/2024] [Indexed: 11/29/2024]
Abstract
Breast cancer, a complex and heterogeneous ailment impacting numerous women worldwide, persists as a prominent cause of cancer-related fatalities. MicroRNAs (miRNAs), small non-coding RNAs, have garnered significant attention for their involvement in breast cancer's progression. These molecules post-transcriptionally regulate gene expression, influencing crucial cellular processes including proliferation, differentiation, and apoptosis. This review provides an overview of the current research on the role of miRNAs in breast cancer. It discusses the role of miRNAs in breast cancer, including the different subtypes of breast cancer, their molecular characteristics, and the mechanisms by which miRNAs regulate gene expression in breast cancer cells. Additionally, the review highlights recent studies identifying specific miRNAs that are dysregulated in breast cancer and their potential use as diagnostic and prognostic biomarkers. Furthermore, the review explores the therapeutic potential of miRNAs in breast cancer treatment. Preclinical studies have shown the effectiveness of miRNA-based therapies, such as antagomir and miRNA mimic therapies, in inhibiting tumor growth and metastasis. Emerging areas, including the application of artificial intelligence (AI) to advance miRNA research and the "One Health" approach that integrates human and animal cancer insights, are also discussed. However, challenges remain before these therapies can be fully translated into clinical practice. In conclusion, this review emphasizes the significance of miRNAs in breast cancer research and their potential as innovative diagnostic and therapeutic tools. A deeper understanding of miRNA dysregulation in breast cancer is essential for their successful application in clinical settings. With continued research, miRNA-based approaches hold promise for improving patient outcomes in this devastating disease.
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Affiliation(s)
- Sachin Kumar
- Department of Pharmacology, DIPSAR, Delhi Pharmaceutical Sciences and Research University, New Delhi, India
| | - Abhishek Ranga
- Department of Pharmacology, DIPSAR, Delhi Pharmaceutical Sciences and Research University, New Delhi, India
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17
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Taeb S, Rostamzadeh D, Amini SM, Rahmati M, Golshekan M, Abedinzade M, Ahmadi E, Neha S, Najafi M. Revolutionizing Cancer Treatment: Harnessing the Power of Mesenchymal Stem Cells for Precise Targeted Therapy in the Tumor Microenvironment. Curr Top Med Chem 2025; 25:243-262. [PMID: 38797895 DOI: 10.2174/0115680266299112240514103048] [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: 12/17/2023] [Revised: 04/03/2024] [Accepted: 04/16/2024] [Indexed: 05/29/2024]
Abstract
In recent years, mesenchymal stem cells (MSCs) have emerged as promising anti-- cancer mediators with the potential to treat several cancers. MSCs have been modified to produce anti-proliferative, pro-apoptotic, and anti-angiogenic molecules that could be effective against a variety of malignancies. Additionally, customizing MSCs with cytokines that stimulate pro-tumorigenic immunity or using them as vehicles for traditional chemical molecules with anti-cancer characteristics. Even though the specific function of MSCs in tumors is still challenged, promising outcomes from preclinical investigations of MSC-based gene therapy for a variety of cancers inspire the beginning of clinical trials. In addition, the tumor microenvironment (TME) could have a substantial influence on normal tissue stem cells, which can affect the treatment outcomes. To overcome the complications of TME in cancer development, MSCs could provide some signs of hope for converting TME into unequivocal therapeutic tools. Hence, this review focuses on engineered MSCs (En-MSCs) as a promising approach to overcoming the complications of TME.
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Affiliation(s)
- Shahram Taeb
- Department of Radiology, School of Paramedical Sciences, Guilan University of Medical Sciences, Rasht, Iran
| | - Davoud Rostamzadeh
- Department of Immunology, University of Connecticut Health Center, Farmington, CT 06030, Connecticut, USA
| | - Seyed Mohammad Amini
- Radiation Biology Research center, Iran University of Medical Sciences, Tehran, Iran
| | - Mohammad Rahmati
- Department of Medical Biotechnology, Faculty of Paramedicine, Guilan University of Medical Sciences, Rasht, Iran
| | - Mostafa Golshekan
- Guilan Road Trauma Research Center, Guilan University of Medical Sciences, Rasht, Iran
| | - Mahmoud Abedinzade
- Department of Medical Physiology, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran
| | - Elham Ahmadi
- Department of Immunology, University of Connecticut Health Center, Farmington, CT 06030, Connecticut, USA
| | - Singh Neha
- Department of Immunology, University of Connecticut Health Center, Farmington, CT 06030, Connecticut, USA
| | - Masoud Najafi
- Medical Technology Research Center, Institute of Health Technology, Kermanshah University of Medical Sciences, Kermanshah, Iran
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18
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Pan L, Zhang C, Ma R, Fan L. Case report: Esophageal bulge with white patch: endoscopic removal of leiomyoma and high-grade intraepithelial neoplasia. Front Oncol 2024; 14:1515288. [PMID: 39711950 PMCID: PMC11659137 DOI: 10.3389/fonc.2024.1515288] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2024] [Accepted: 11/18/2024] [Indexed: 12/24/2024] Open
Abstract
Esophageal leiomyoma is the most common benign intramural tumor of the esophagus. Despite being the most common benign tumor in its category, esophageal leiomyomas constitute only 1.2% of all esophageal tumors. While esophageal leiomyoma itself is uncommon, the occurrence of multiple esophageal leiomyomas is even rarer, and the coexistence of high-grade squamous intraepithelial neoplasia (HGIN), involving both epithelial and mesenchymal tissues, is exceedingly rare. This case report describes a patient with multiple esophageal leiomyomas and localized HGIN, diagnosed using endoscopic ultrasonography, which identified a submucosal lesion within the muscularis mucosae. The lesion was successfully treated using endoscopic high-frequency electrocoagulation resection. This minimally invasive approach proved to be precise, safe, and effective, offering therapeutic outcomes comparable to those of traditional surgical resection, as confirmed by postoperative pathological analysis. As a primary goal, the abstract should render the general significance and conceptual advance of the work clearly accessible to a broad readership. References should not be cited in the abstract. Leave the Abstract empty if your article does not require one - please see the "Article types" on every Frontiers journal page for full details.
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Affiliation(s)
- Lili Pan
- Department of Gastroenterology, Jining First People’s Hospital, Jining, China
| | - Chong Zhang
- Department of Pathology, Jining First People’s Hospital, Jining, China
| | - Ran Ma
- Department of Gastroenterology, Jining First People’s Hospital, Jining, China
| | - Lijuan Fan
- Department of Gastroenterology, Jining First People’s Hospital, Jining, China
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Zhang X, Ren X, Zhang S, Wang Y. Overexpression of ELF1 combined with MMP9 is associated with prognosis and tumor microenvironment in gastric cancer. Exp Ther Med 2024; 28:441. [PMID: 39583246 PMCID: PMC11582528 DOI: 10.3892/etm.2024.12730] [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: 04/11/2024] [Accepted: 07/26/2024] [Indexed: 11/26/2024] Open
Abstract
Gastric cancer (GC) is a prevalent malignancy of the digestive system. E74-like factor 1 (ELF1) is a transcription factor that is specific to T cells and belongs to the Ets family. They are typically expressed in numerous tumor cells, such as pancreatic cancer, oral squamous cell, endometrial carcinoma, nasopharyngeal carcinoma and prostate and colorectal cancer, where they can promote cell invasion and migration. MMP9 is an important protease of the MMP family, since it serves a vital role in tumor progression and prognostic evaluation in colorectal cancer, uveal melanoma and clear cell renal cell carcinoma. The present study aimed to investigate the expression, correlation with MMP9 and clinical significance of ELF1 in GC. In addition, it aimed to explore the possible mechanisms. The ELF1 mRNA expression profile was first assessed using the GEPIA database and R4.2.1 software (Limma package). Reverse transcription-quantitative PCR (RT-qPCR) was used then to validate ELF1 mRNA expression levels in fresh GC samples from 40 patients. The clinical diagnostic value of ELF1 was also assessed using RT-qPCR. Tissue microarray immunohistochemistry (TMA-IHC) was utilized to examine the expression levels of ELF1 and MMP9 proteins in 355 paraffin-embedded GC samples. Subsequently, the present study further investigated the relationship between ELF1 and MMP9 and their possible effects on the clinicopathological features and prognosis of patients with GC. Gene correlation analysis was conducted using the GEPIA database and complemented with Tumor Immune Estimation Resource (TIMER) and CIBERSORT analyses to explore associations with immune infiltration. A significantly higher expression of ELF1 mRNA was found in GC tissues compared with that in adjacent normal tissues (P<0.05). High ELF1 expression in GC tumor cells was found to distinguish GC tissues from adjacent normal tissues with a sensitivity of 87.5% and specificity of 77.5%. ELF1 and MMP9 proteins also showed higher expression in 355 GC compared with adjacent normal tissues, where they were significantly positively correlated (P<0.001). The two were closely associated with various clinicopathological features, including infiltration depth, lymph node involvement, metastasis, TNM staging, microscopic venous invasion, lymphatic invasion and blood serum carcinoembryonic antigen levels in GC. Furthermore, ELF1 and MMP9 expression levels were negatively associated with the overall survival of patients with GC. Prognostic analysis using the Cox proportional hazards model identified high ELF1 expression [hazards ratio (HR), 2.555; 95% CI, 1.546-4.224; P=0.002], high MMP9 expression (HR, 3.813; 95% CI, 2.406-6.041; P<0.001), advanced TNM stage (P=0.001) and advanced N stage (P=0.011) to be independent prognostic factors for patients with GC. Correlation analysis results from the GEPIA database indicated significant associations of ELF1 expression with various GC-related genes, including MutL homolog 1, erythroblastic leukemia viral oncogene homolog 2, PI3K catalytic subunit α, and tumor suppressor protein 53, MMP-9, Cadherin 1, TIMP1, growth factor A and kinase insert domain receptor. In addition, immune infiltration correlation analysis on TIMER and CIBERSORT revealed ELF1 positive relationship with specific infiltrating immune cell types, including naive B, memory-activated CD4+ and gamma delta T cells, and activated NK cells (P<0.05). This observation was further confirmed using immunohistochemistry, showing that ELF1 was associated with CD19 (B-cells) (P<0.001) and CD4 (CD4+ T cells, P=0.002). In conclusion, results from the present study suggest that ELF1 is overexpressed in GC. ELF1 combined with MMP9 can serve as a predictor of malignant biological behavior in GC and therefore a prognostic indicator for patients, due to its association with the tumor microenvironment.
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Affiliation(s)
- Xiaoxia Zhang
- Department of Pathology, Affiliated Maternal & Child Care Hospital of Nantong University, Nantong, Jiangsu 226018, P.R. China
| | - Xiaoyan Ren
- Department of Pathology, Affiliated Maternal & Child Care Hospital of Nantong University, Nantong, Jiangsu 226018, P.R. China
| | - Shu Zhang
- Department of Pathology, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China
| | - Yan Wang
- Department of Pathology, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China
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20
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Musiime M, Erusappan PM, Cukierman E, Chang J, Molven A, Hansen U, Zeltz C, Gullberg D. Fibroblast integrin α11β1 is a collagen assembly receptor in mechanoregulated fibrillar adhesions. Matrix Biol 2024; 134:144-161. [PMID: 39406317 DOI: 10.1016/j.matbio.2024.10.006] [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: 04/19/2024] [Revised: 10/12/2024] [Accepted: 10/12/2024] [Indexed: 11/25/2024]
Abstract
Solid epithelial cancers with significant desmoplasia are characterized by an excessive deposition of collagen-based matrix, which often supports tumor progression. However, the mechanism of how collagen receptors mediate collagen fibrillogenesis still remains mostly unclear. We show that the collagen-binding integrin α11β1 can co-localize with tensin-1 and deposited collagen I in human pancreatic ductal adenocarcinoma (PDAC) stroma. In addition to the canonical fibrillar adhesion integrin α5β1 expressed by human PDAC cancer-associated fibroblasts (CAFs), tensin-1-positive fibrillar adhesions contained α11β1 but lacked α1β1 and α2β1. CAFs lacking α5β1 expression displayed mechanoregulated and tensin-1 dependent α11β1 fibrillar adhesions, suggesting independent roles of the two integrins with regards to fibrillar adhesions-based de novo fibrillogenesis. Further, we demonstrate that cell surface-associated collagen I assembly necessitated α11β1, but not α5β1 expression. In summary, α11β1 integrin is a novel component of fibrillar adhesions, which is strategically positioned to mediate de novo collagen fibrillogenesis at the cell surface under pro-fibrotic conditions.
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Affiliation(s)
- Moses Musiime
- University of Bergen, Department of Biomedicine and Centre for Cancer Biomarkers, Jonas Lies vei 91, 5009 Bergen, Norway
| | - Pugazendhi Murugan Erusappan
- University of Bergen, Department of Biomedicine and Centre for Cancer Biomarkers, Jonas Lies vei 91, 5009 Bergen, Norway; Institute for Experimental Medical Research, Oslo university Hospital and university of Oslo, Kirkeveien 166, 0450, Oslo, Norway
| | - Edna Cukierman
- Cancer Signaling & Microenvironment Program, M&C Greenberg Pancreatic Cancer Institute, Fox Chase Cancer Center, Temple Health, Philadelphia, PA, 19111, USA
| | - Joan Chang
- Wellcome Centre for Cell-Matrix Research, Faculty of Biology, Medicine & Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, M13 9PT, UK
| | - Anders Molven
- Gade Laboratory for Pathology, Department of Clinical Medicine, University of Bergen, NO-5020 Bergen, Norway; Department of Pathology and Section for Cancer Genomics, Haukeland University Hospital, NO-5020 Bergen, Norway
| | - Uwe Hansen
- Institute for Musculoskeletal Medicine, University Hospital of Münster, Münster, Germany
| | - Cédric Zeltz
- University of Bergen, Department of Biomedicine and Centre for Cancer Biomarkers, Jonas Lies vei 91, 5009 Bergen, Norway.
| | - Donald Gullberg
- University of Bergen, Department of Biomedicine and Centre for Cancer Biomarkers, Jonas Lies vei 91, 5009 Bergen, Norway.
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Singh P, Jay DG. The Role of eHsp90 in Extracellular Matrix Remodeling, Tumor Invasiveness, and Metastasis. Cancers (Basel) 2024; 16:3873. [PMID: 39594828 PMCID: PMC11592750 DOI: 10.3390/cancers16223873] [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: 10/03/2024] [Revised: 11/01/2024] [Accepted: 11/01/2024] [Indexed: 11/28/2024] Open
Abstract
Identifying proteins that act in tumor invasiveness and metastasis remains a critical unmet need in our search for effective cancer therapy. Hsp90, an abundant intracellular chaperone protein, plays a key role in maintaining cell homeostasis, and its elevated activity is pivotal in cancer progression. Due to the reliance of cancer cells on Hsp90's chaperone function to sustain tumor growth and spread, Hsp90 inhibitors have been the subject of numerous clinical trials over the past two decades. However, these efforts have largely been unsuccessful, primarily due to the cellular toxicity caused by pan-Hsp90 inhibitors at doses required for anticancer efficacy. Therefore, novel approaches to target Hsp90 are necessary. An identified subpopulation of Hsp90 located outside cells (eHsp90) may offer a promising alternative as a therapeutic target against cancer. Studies including our own have shown that eHsp90 is released specifically by cancer cells, and eHsp90 has unique interactors and functions extracellularly to promote tumor invasiveness, the initial step in metastasis. Inhibition of eHsp90 has been shown to suppress metastasis in animal models, indicating its therapeutic potential, although the underlying mechanisms remain incompletely understood. Cancer cells modulate the tumor microenvironment (TME) during the invasion, especially the ECM proteins and the state of the ECM is a strong predictor of invasive and metastatic cancer. Given that most of the known eHsp90 clients are ECM proteins or are proteins involved in ECM modulation, ECM remodelling could be the key mechanism through which eHsp90 enhances invasiveness. This review will focus on ECM modulation by eHsp90 as a driver of cancer invasion and metastasis. We will also discuss the potency of inhibiting eHsp90 in inhibiting invasion and metastatic spread in preclinical models and the using circulating Hsp90 patient samples as a biomarker of cancer invasion and metastasis.
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Affiliation(s)
- Pragya Singh
- Graduate School of Biomedical Sciences, Department of Developmental, Molecular and Chemical Biology, Tufts University School of Medicine, Boston, MA 02111, USA
| | - Daniel G. Jay
- Graduate School of Biomedical Sciences, Department of Developmental, Molecular and Chemical Biology, Tufts University School of Medicine, Boston, MA 02111, USA
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22
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Rizvi SFA, Zhang H, Fang Q. Engineering peptide drug therapeutics through chemical conjugation and implication in clinics. Med Res Rev 2024; 44:2420-2471. [PMID: 38704826 DOI: 10.1002/med.22046] [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: 02/16/2023] [Revised: 03/21/2024] [Accepted: 04/21/2024] [Indexed: 05/07/2024]
Abstract
The development of peptide drugs has made tremendous progress in the past few decades because of the advancements in modification chemistry and analytical technologies. The novel-designed peptide drugs have been modified through various biochemical methods with improved diagnostic, therapeutic, and drug-delivery strategies. Researchers found it a helping hand to overcome the inherent limitations of peptides and bring continued advancements in their applications. Furthermore, the emergence of peptide-drug conjugates (PDCs)-utilizes target-oriented peptide moieties as a vehicle for cytotoxic payloads via conjugation with cleavable chemical agents, resulting in the key foundation of the new era of targeted peptide drugs. This review summarizes the various classifications of peptide drugs, suitable chemical modification strategies to improve the ADME (adsorption, distribution, metabolism, and excretion) features of peptide drugs, and recent (2015-early 2024) progress/achievements in peptide-based drug delivery systems as well as their fruitful implication in preclinical and clinical studies. Furthermore, we also summarized the brief description of other types of PDCs, including peptide-MOF conjugates and peptide-UCNP conjugates. The principal aim is to provide scattered and diversified knowledge in one place and to help researchers understand the pinching knots in the science of PDC development and progress toward a bright future of novel peptide drugs.
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Affiliation(s)
- Syed Faheem Askari Rizvi
- State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou, Gansu, China
- Key Laboratory of Preclinical Study for New Drugs of Gansu Province, Institute of Pathology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu, China
| | - Haixia Zhang
- State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou, Gansu, China
| | - Quan Fang
- Key Laboratory of Preclinical Study for New Drugs of Gansu Province, Institute of Pathology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu, China
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23
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Wang W, Ye L, Li H, Mao W, Xu X. Targeting esophageal carcinoma: molecular mechanisms and clinical studies. MedComm (Beijing) 2024; 5:e782. [PMID: 39415846 PMCID: PMC11480525 DOI: 10.1002/mco2.782] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Revised: 09/24/2024] [Accepted: 09/24/2024] [Indexed: 10/19/2024] Open
Abstract
Esophageal cancer (EC) is identified as a predominant health threat worldwide, with its highest incidence and mortality rates reported in China. The complex molecular mechanisms underlying EC, coupled with the differential incidence of esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC) across various regions, highlight the necessity for in-depth research targeting molecular pathogenesis and innovative treatment strategies. Despite recent progress in targeted therapy and immunotherapy, challenges such as drug resistance and the lack of effective biomarkers for patient selection persist, impeding the optimization of therapeutic outcomes. Our review delves into the molecular pathology of EC, emphasizing genetic and epigenetic alterations, aberrant signaling pathways, tumor microenvironment factors, and the mechanisms of metastasis and immune evasion. We further scrutinize the current landscape of targeted therapies, including the roles of EGFR, HER2, and VEGFR, alongside the transformative impact of ICIs. The discussion extends to evaluating combination therapies, spotlighting the synergy between targeted and immune-mediated treatments, and introduces the burgeoning domain of antibody-drug conjugates, bispecific antibodies, and multitarget-directed ligands. This review lies in its holistic synthesis of EC's molecular underpinnings and therapeutic interventions, fused with an outlook on future directions including overcoming resistance mechanisms, biomarker discovery, and the potential of novel drug formulations.
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Affiliation(s)
- Wenjing Wang
- Department of Medical Thoracic OncologyZhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of SciencesHangzhouZhejiangChina
- Postgraduate Training Base AllianceWenzhou Medical UniversityWenzhouZhejiangChina
| | - Lisha Ye
- Department of Medical Thoracic OncologyZhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of SciencesHangzhouZhejiangChina
- Postgraduate Training Base AllianceWenzhou Medical UniversityWenzhouZhejiangChina
| | - Huihui Li
- Department of Medical Thoracic OncologyZhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of SciencesHangzhouZhejiangChina
- Postgraduate Training Base AllianceWenzhou Medical UniversityWenzhouZhejiangChina
| | - Weimin Mao
- Postgraduate Training Base AllianceWenzhou Medical UniversityWenzhouZhejiangChina
- The Cancer Hospital of the University of Chinese Academy of Sciences, Institute of Basic Medicine and Cancer (IBMC)Chinese Academy of SciencesHangzhouZhejiangChina
| | - Xiaoling Xu
- Postgraduate Training Base AllianceWenzhou Medical UniversityWenzhouZhejiangChina
- Department of Radiation OncologyShanghai Pulmonary Hospital, Tongji University School of MedicineShanghaiChina
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24
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Musielak M, Graczyk K, Liszka M, Christou A, Rosochowicz MA, Lach MS, Adamczyk B, Suchorska WM, Piotrowski T, Stenerlöw B, Malicki J. Impact of Proton Irradiation Depending on Breast Cancer Subtype in Patient-Derived Cell Lines. Int J Mol Sci 2024; 25:10494. [PMID: 39408826 PMCID: PMC11477436 DOI: 10.3390/ijms251910494] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2024] [Revised: 09/26/2024] [Accepted: 09/27/2024] [Indexed: 10/20/2024] Open
Abstract
Research on different types of ionizing radiation's effects has been ongoing for years, revealing its efficacy in damaging cancer cells. Solid tumors comprise diverse cell types, each being able to respond differently to radiation. This study evaluated the radiobiological response of established (MDA-MB-231 (Triple negative breast cancer, TNBC), MCF-7 (Luminal A)) and patient-derived malignant cell lines, cancer-associated fibroblasts, and skin fibroblasts following proton IRR. All cell line types were irradiated with the proton dose of 2, 4, and 6 Gy. The radiobiological response was assessed using clonogenic assay, γH2AX, and p53 staining. It was noticeable that breast cancer lines of different molecular subtypes displayed no significant variations in their response to proton IRR. In terms of cancer-associated fibroblasts extracted from the tumor tissue, the line derived from a TNBC subtype tumor demonstrated higher resistance to ionizing radiation compared to lines isolated from luminal A tumors. Fibroblasts extracted from patients' skin responded identically to all doses of proton radiation. This study emphasizes that tumor response is not exclusively determined by the elimination of breast cancer cells, but also takes into account tumor microenvironmental variables and skin reactions.
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Affiliation(s)
- Marika Musielak
- Department of Electroradiology, Poznan University of Medical Sciences, 61-701 Poznan, Poland; (W.M.S.); (T.P.); (J.M.)
- Doctoral School, Poznan University of Medical Sciences, 61-701 Poznan, Poland;
- Radiobiology Laboratory, Department of Medical Physics, Greater Poland Cancer Centre, 61-866 Poznan, Poland;
| | - Kinga Graczyk
- Clinical Dosimetry, Department of Medical Physics, Greater Poland Cancer Centre, 61-866 Poznan, Poland;
- The Skandion Clinic, 751 23 Uppsala, Sweden; (M.L.); (A.C.)
| | | | | | - Monika A. Rosochowicz
- Doctoral School, Poznan University of Medical Sciences, 61-701 Poznan, Poland;
- Radiobiology Laboratory, Department of Medical Physics, Greater Poland Cancer Centre, 61-866 Poznan, Poland;
- Department of Orthopaedics and Traumatology, Poznan University of Medical Sciences, 61-701 Poznan, Poland
| | - Michał S. Lach
- Radiobiology Laboratory, Department of Medical Physics, Greater Poland Cancer Centre, 61-866 Poznan, Poland;
| | - Beata Adamczyk
- Breast Surgical Oncology Department, Greater Poland Cancer Centre, 61-866 Poznan, Poland;
| | - Wiktoria M. Suchorska
- Department of Electroradiology, Poznan University of Medical Sciences, 61-701 Poznan, Poland; (W.M.S.); (T.P.); (J.M.)
- Radiobiology Laboratory, Department of Medical Physics, Greater Poland Cancer Centre, 61-866 Poznan, Poland;
| | - Tomasz Piotrowski
- Department of Electroradiology, Poznan University of Medical Sciences, 61-701 Poznan, Poland; (W.M.S.); (T.P.); (J.M.)
- Department of Medical Physics, Greater Poland Cancer Centre, 61-866 Poznan, Poland
| | - Bo Stenerlöw
- Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, 753 10 Uppsala, Sweden;
| | - Julian Malicki
- Department of Electroradiology, Poznan University of Medical Sciences, 61-701 Poznan, Poland; (W.M.S.); (T.P.); (J.M.)
- Department of Medical Physics, Greater Poland Cancer Centre, 61-866 Poznan, Poland
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25
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Liu K, Gao Q, Jia Y, Wei J, Chaudhuri SM, Wang S, Tang A, Mani NL, Iyer R, Cheng Y, Gao B, Lu W, Sun Z, Zhang B, Liu H, Fang D. Ubiquitin-specific peptidase 22 controls integrin-dependent cancer cell stemness and metastasis. iScience 2024; 27:110592. [PMID: 39246448 PMCID: PMC11378969 DOI: 10.1016/j.isci.2024.110592] [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: 01/09/2024] [Revised: 04/28/2024] [Accepted: 07/24/2024] [Indexed: 09/10/2024] Open
Abstract
Integrins play critical roles in connecting the extracellular matrix and actin. While the upregulation of integrins is thought to promote cancer stemness and metastasis, the mechanisms underlying their upregulation in cancer stem cells (CSCs) remain poorly understood. Herein, we show that USP22 is essential in maintaining breast cancer cell stemness by promoting the transcription of integrin β1 (ITGB1). Both genetic and pharmacological inhibition of USP22 largely impaired breast CSCs self-renewal and prevented their metastasis. Reconstitution of integrin β1 partially rescued USP22-null breast cancer metastasis. USP22 functions as a bona fide deubiquitinase to protect the proteasomal degradation of the forkhead box M1 (FoxM1), a transcription factor for tumoral ITGB1 gene transcription. Immunohistochemistry staining detected a positive correlation among USP22, FoxM1, and integrin β1 in human breast cancers. Collectively, our study identifies the USP22-FoxM1-integrin β1 signaling axis as critical for cancer stemness and offers a potential target for antitumor therapy.
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Affiliation(s)
- Kun Liu
- Department of Pathology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Qiong Gao
- Department of Pathology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
- College of Basic Medical Sciences, Dalian Medical University, Dalian 116044, P.R. China
| | - Yuzhi Jia
- Department of Medicine, Hematology/Oncology Division, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Juncheng Wei
- Department of Pathology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Shuvam Mohan Chaudhuri
- Department of Pathology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Shengnan Wang
- Department of Pathology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Amy Tang
- Department of Pathology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Nikita Lavanya Mani
- Department of Pathology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Radhika Iyer
- Department of Pathology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Yang Cheng
- Department of Pathology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Beixue Gao
- Department of Pathology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Weiyuan Lu
- Department of Pathology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Zhaolin Sun
- College of Basic Medical Sciences, Dalian Medical University, Dalian 116044, P.R. China
| | - Bin Zhang
- Department of Medicine, Hematology/Oncology Division, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Huiping Liu
- Department of Pharmacology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Deyu Fang
- Department of Pathology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
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26
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Hsieh CH, Ho PS, Wang WL, Shih FH, Hong CT, Wang PW, Shieh DB, Chang WL, Wang YC. Decreased plasma gelsolin fosters a fibrotic tumor microenvironment and promotes chemoradiotherapy resistance in esophageal squamous cell carcinoma. J Biomed Sci 2024; 31:90. [PMID: 39261905 PMCID: PMC11389350 DOI: 10.1186/s12929-024-01078-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2024] [Accepted: 08/21/2024] [Indexed: 09/13/2024] Open
Abstract
BACKGROUND Stromal fibrosis is highly associated with therapeutic resistance and poor survival in esophageal squamous cell carcinoma (ESCC) patients. Low expression of plasma gelsolin (pGSN), a serum abundant protein, has been found to correlate with inflammation and fibrosis. Here, we evaluated pGSN expression in patients with different stages of cancer and therapeutic responses, and delineated the molecular mechanisms involved to gain insight into therapeutic strategies for ESCC. METHODS Circulating pGSN level in ESCC patients was determined by enzyme-linked immunosorbent assay analysis, and the tissue microarray of tumors was analyzed by immunohistochemistry staining. Cell-based studies were performed to investigate cancer behaviors and molecular mechanisms, and mouse models were used to examine the pGSN-induced tumor suppressive effects in vivo. RESULTS Circulating pGSN expression is distinctively decreased during ESCC progression, and low pGSN expression correlates with poor therapeutic responses and poor survival. Methylation-specific PCR analysis confirmed that decreased pGSN expression is partly attributed to the hypermethylation of the GSN promoter, the gene encoding pGSN. Importantly, cell-based immunoprecipitation and protein stability assays demonstrated that pGSN competes with oncogenic tenascin-C (TNC) for the binding and degradation of integrin αvβ3, revealing that decreased pGSN expression leads to the promotion of oncogenic signaling transduction in cancer cells and fibroblasts. Furthermore, overexpression of pGSN caused the attenuation of TNC expression and inactivation of cancer-associated fibroblast (CAF), thereby leading to tumor growth inhibition in mice. CONCLUSIONS Our results demonstrated that GSN methylation causes decreased secretion of pGSN, leading to integrin dysregulation, oncogenic TNC activation, and CAF formation. These findings highlight the role of pGSN in therapeutic resistance and the fibrotic tumor microenvironment of ESCC.
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Affiliation(s)
- Chih-Hsiung Hsieh
- Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Pei-Shiuan Ho
- Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Wen-Lun Wang
- Department of Internal Medicine, E-Da Hospital, College of Medicine, I-Shou University, Kaohsiung, Taiwan
| | - Fu-Hsuan Shih
- Institute of Basic Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Chen-Tai Hong
- Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Pei-Wen Wang
- Institute of Oral Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Dar-Bin Shieh
- Institute of Oral Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Center of Applied Nanomedicine, National Cheng Kung University, Tainan, Taiwan
- Center for Micro/Nano Science and Technology, Advanced Optoelectronic Technology Center, Innovation Center for Advanced Medical Device Technology, National Cheng Kung University, Tainan, Taiwan
| | - Wei-Lun Chang
- Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
| | - Yi-Ching Wang
- Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
- Institute of Basic Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
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27
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Zhu S, Kubota N, Wang S, Wang T, Xiao G, Hoshida Y. STIE: Single-cell level deconvolution, convolution, and clustering in in situ capturing-based spatial transcriptomics. Nat Commun 2024; 15:7559. [PMID: 39214995 PMCID: PMC11364663 DOI: 10.1038/s41467-024-51728-5] [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: 03/19/2024] [Accepted: 08/14/2024] [Indexed: 09/04/2024] Open
Abstract
In in situ capturing-based spatial transcriptomics, spots of the same size and printed at fixed locations cannot precisely capture the randomly-located single cells, therefore inherently failing to profile transcriptome at the single-cell level. To this end, we present STIE, an Expectation Maximization algorithm that aligns the spatial transcriptome to its matched histology image-based nuclear morphology and recovers missing cells from ~70% gap area, thereby achieving the real single-cell level and whole-slide scale deconvolution, convolution, and clustering for both low- and high-resolution spots. STIE characterizes cell-type-specific gene expression and demonstrates outperforming concordance with true cell-type-specific transcriptomic signatures than the other spot- and subspot-level methods. Furthermore, STIE reveals the single-cell level insights, for instance, lower actual spot resolution than its reported spot size, unbiased evaluation of cell type colocalization, superior power of high-resolution spot in distinguishing nuanced cell types, and spatial cell-cell interactions at the single-cell level other than spot level.
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Affiliation(s)
- Shijia Zhu
- Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA.
- Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
| | - Naoto Kubota
- Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Shidan Wang
- Quantitative Biomedical Research Center, Department of Population and Data Sciences, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Tao Wang
- Quantitative Biomedical Research Center, Department of Population and Data Sciences, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Guanghua Xiao
- Quantitative Biomedical Research Center, Department of Population and Data Sciences, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Yujin Hoshida
- Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
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28
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Younesi FS, Miller AE, Barker TH, Rossi FMV, Hinz B. Fibroblast and myofibroblast activation in normal tissue repair and fibrosis. Nat Rev Mol Cell Biol 2024; 25:617-638. [PMID: 38589640 DOI: 10.1038/s41580-024-00716-0] [Citation(s) in RCA: 123] [Impact Index Per Article: 123.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/21/2024] [Indexed: 04/10/2024]
Abstract
The term 'fibroblast' often serves as a catch-all for a diverse array of mesenchymal cells, including perivascular cells, stromal progenitor cells and bona fide fibroblasts. Although phenotypically similar, these subpopulations are functionally distinct, maintaining tissue integrity and serving as local progenitor reservoirs. In response to tissue injury, these cells undergo a dynamic fibroblast-myofibroblast transition, marked by extracellular matrix secretion and contraction of actomyosin-based stress fibres. Importantly, whereas transient activation into myofibroblasts aids in tissue repair, persistent activation triggers pathological fibrosis. In this Review, we discuss the roles of mechanical cues, such as tissue stiffness and strain, alongside cell signalling pathways and extracellular matrix ligands in modulating myofibroblast activation and survival. We also highlight the role of epigenetic modifications and myofibroblast memory in physiological and pathological processes. Finally, we discuss potential strategies for therapeutically interfering with these factors and the associated signal transduction pathways to improve the outcome of dysregulated healing.
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Affiliation(s)
- Fereshteh Sadat Younesi
- Keenan Research Institute for Biomedical Science of the St. Michael's Hospital, Toronto, Ontario, Canada
- Faculty of Dentistry, University of Toronto, Toronto, Ontario, Canada
| | - Andrew E Miller
- Department of Biomedical Engineering, School of Engineering and Applied Science, University of Virginia, Charlottesville, VA, USA
| | - Thomas H Barker
- Department of Biomedical Engineering, School of Engineering and Applied Science, University of Virginia, Charlottesville, VA, USA
| | - Fabio M V Rossi
- School of Biomedical Engineering and Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada
| | - Boris Hinz
- Keenan Research Institute for Biomedical Science of the St. Michael's Hospital, Toronto, Ontario, Canada.
- Faculty of Dentistry, University of Toronto, Toronto, Ontario, Canada.
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29
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Sajjadi SF, Salehi N, Sadeghi M. Comprehensive integrated single-cell RNA sequencing analysis of brain metastasis and glioma microenvironment: Contrasting heterogeneity landscapes. PLoS One 2024; 19:e0306220. [PMID: 39058687 PMCID: PMC11280140 DOI: 10.1371/journal.pone.0306220] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Accepted: 06/12/2024] [Indexed: 07/28/2024] Open
Abstract
Understanding the specific type of brain malignancy, source of brain metastasis, and underlying transformation mechanisms can help provide better treatment and less harm to patients. The tumor microenvironment plays a fundamental role in cancer progression and affects both primary and metastatic cancers. The use of single-cell RNA sequencing to gain insights into the heterogeneity profiles in the microenvironment of brain malignancies is useful for guiding treatment decisions. To comprehensively investigate the heterogeneity in gliomas and brain metastasis originating from different sources (lung and breast), we integrated data from three groups of single-cell RNA-sequencing datasets obtained from GEO. We gathered and processed single-cell RNA sequencing data from 90,168 cells obtained from 17 patients. We then employed the R package Seurat for dataset integration. Next, we clustered the data within the UMAP space and acquired differentially expressed genes for cell categorization. Our results underscore the significance of macrophages as abundant and pivotal constituents of gliomas. In contrast, lung-to-brain metastases exhibit elevated numbers of AT2, cytotoxic CD4+ T, and exhausted CD8+ T cells. Conversely, breast-to-brain metastases are characterized by an abundance of epithelial and myCAF cells. Our study not only illuminates the variation in the TME between brain metastasis with different origins but also opens the door to utilizing established markers for these cell types to differentiate primary brain metastatic cancers.
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Affiliation(s)
- Seyedeh Fatemeh Sajjadi
- School of Biological Science, Institute for Research in Fundamental Sciences (IPM), Tehran, Iran
| | - Najmeh Salehi
- School of Biological Science, Institute for Research in Fundamental Sciences (IPM), Tehran, Iran
| | - Mehdi Sadeghi
- School of Biological Science, Institute for Research in Fundamental Sciences (IPM), Tehran, Iran
- National Institute of Genetic Engineering and Biotechnology (NIGEB), Tehran, Iran
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30
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Argentiero A, Andriano A, Caradonna IC, de Martino G, Desantis V. Decoding the Intricate Landscape of Pancreatic Cancer: Insights into Tumor Biology, Microenvironment, and Therapeutic Interventions. Cancers (Basel) 2024; 16:2438. [PMID: 39001498 PMCID: PMC11240778 DOI: 10.3390/cancers16132438] [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: 05/30/2024] [Revised: 06/24/2024] [Accepted: 06/28/2024] [Indexed: 07/16/2024] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) presents significant oncological challenges due to its aggressive nature and poor prognosis. The tumor microenvironment (TME) plays a critical role in progression and treatment resistance. Non-neoplastic cells, such as cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs), contribute to tumor growth, angiogenesis, and immune evasion. Although immune cells infiltrate TME, tumor cells evade immune responses by secreting chemokines and expressing immune checkpoint inhibitors (ICIs). Vascular components, like endothelial cells and pericytes, stimulate angiogenesis to support tumor growth, while adipocytes secrete factors that promote cell growth, invasion, and treatment resistance. Additionally, perineural invasion, a characteristic feature of PDAC, contributes to local recurrence and poor prognosis. Moreover, key signaling pathways including Kirsten rat sarcoma viral oncogene (KRAS), transforming growth factor beta (TGF-β), Notch, hypoxia-inducible factor (HIF), and Wnt/β-catenin drive tumor progression and resistance. Targeting the TME is crucial for developing effective therapies, including strategies like inhibiting CAFs, modulating immune response, disrupting angiogenesis, and blocking neural cell interactions. A recent multi-omic approach has identified signature genes associated with anoikis resistance, which could serve as prognostic biomarkers and targets for personalized therapy.
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Affiliation(s)
| | - Alessandro Andriano
- Department of Precision and Regenerative Medicine and Ionian Area, Pharmacology Section, Medical School, University of Bari Aldo Moro, 70124 Bari, Italy
| | - Ingrid Catalina Caradonna
- Department of Precision and Regenerative Medicine and Ionian Area, Pharmacology Section, Medical School, University of Bari Aldo Moro, 70124 Bari, Italy
| | - Giulia de Martino
- Department of Biosciences, Biotechnology and Environment, University of Bari Aldo Moro, 70121 Bari, Italy
| | - Vanessa Desantis
- Department of Precision and Regenerative Medicine and Ionian Area, Pharmacology Section, Medical School, University of Bari Aldo Moro, 70124 Bari, Italy
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31
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Damerau A, Rosenow E, Alkhoury D, Buttgereit F, Gaber T. Fibrotic pathways and fibroblast-like synoviocyte phenotypes in osteoarthritis. Front Immunol 2024; 15:1385006. [PMID: 38895122 PMCID: PMC11183113 DOI: 10.3389/fimmu.2024.1385006] [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: 02/11/2024] [Accepted: 05/14/2024] [Indexed: 06/21/2024] Open
Abstract
Osteoarthritis (OA) is the most common form of arthritis, characterized by osteophyte formation, cartilage degradation, and structural and cellular alterations of the synovial membrane. Activated fibroblast-like synoviocytes (FLS) of the synovial membrane have been identified as key drivers, secreting humoral mediators that maintain inflammatory processes, proteases that cause cartilage and bone destruction, and factors that drive fibrotic processes. In normal tissue repair, fibrotic processes are terminated after the damage has been repaired. In fibrosis, tissue remodeling and wound healing are exaggerated and prolonged. Various stressors, including aging, joint instability, and inflammation, lead to structural damage of the joint and micro lesions within the synovial tissue. One result is the reduced production of synovial fluid (lubricants), which reduces the lubricity of the cartilage areas, leading to cartilage damage. In the synovial tissue, a wound-healing cascade is initiated by activating macrophages, Th2 cells, and FLS. The latter can be divided into two major populations. The destructive thymocyte differentiation antigen (THY)1─ phenotype is restricted to the synovial lining layer. In contrast, the THY1+ phenotype of the sublining layer is classified as an invasive one with immune effector function driving synovitis. The exact mechanisms involved in the transition of fibroblasts into a myofibroblast-like phenotype that drives fibrosis remain unclear. The review provides an overview of the phenotypes and spatial distribution of FLS in the synovial membrane of OA, describes the mechanisms of fibroblast into myofibroblast activation, and the metabolic alterations of myofibroblast-like cells.
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Affiliation(s)
- Alexandra Damerau
- Department of Rheumatology and Clinical Immunology, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt Universität zu Berlin, Berlin, Germany
- German Rheumatism Research Center Berlin, a Leibniz Institute, Glucocorticoids - Bioenergetics - 3R Research Lab, Berlin, Germany
| | - Emely Rosenow
- Department of Rheumatology and Clinical Immunology, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt Universität zu Berlin, Berlin, Germany
| | - Dana Alkhoury
- Department of Rheumatology and Clinical Immunology, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt Universität zu Berlin, Berlin, Germany
| | - Frank Buttgereit
- Department of Rheumatology and Clinical Immunology, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt Universität zu Berlin, Berlin, Germany
- German Rheumatism Research Center Berlin, a Leibniz Institute, Glucocorticoids - Bioenergetics - 3R Research Lab, Berlin, Germany
| | - Timo Gaber
- Department of Rheumatology and Clinical Immunology, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt Universität zu Berlin, Berlin, Germany
- German Rheumatism Research Center Berlin, a Leibniz Institute, Glucocorticoids - Bioenergetics - 3R Research Lab, Berlin, Germany
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Röhrich M, Daum J, Gutjahr E, Spektor AM, Glatting FM, Sahin YA, Buchholz HG, Hoppner J, Schroeter C, Mavriopoulou E, Schlamp K, Grott M, Eichhorn F, Heußel CP, Kauczor HU, Kreuter M, Giesel F, Schreckenberger M, Winter H, Haberkorn U. Diagnostic Potential of Supplemental Static and Dynamic 68Ga-FAPI-46 PET for Primary 18F-FDG-Negative Pulmonary Lesions. J Nucl Med 2024; 65:872-879. [PMID: 38604763 PMCID: PMC11149599 DOI: 10.2967/jnumed.123.267103] [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: 11/24/2023] [Revised: 02/20/2024] [Indexed: 04/13/2024] Open
Abstract
PET using 68Ga-labeled fibroblast activation protein (FAP) inhibitors (FAPIs) holds high potential for diagnostic imaging of various malignancies, including lung cancer (LC). However, 18F-FDG PET is still the clinical gold standard for LC imaging. Several subtypes of LC, especially lepidic LC, are frequently 18F-FDG PET-negative, which markedly hampers the assessment of single pulmonary lesions suggestive of LC. Here, we evaluated the diagnostic potential of static and dynamic 68Ga-FAPI-46 PET in the 18F-FDG-negative pulmonary lesions of 19 patients who underwent surgery or biopsy for histologic diagnosis after PET imaging. For target validation, FAP expression in lepidic LC was confirmed by FAP immunohistochemistry. Methods: Hematoxylin and eosin staining and FAP immunohistochemistry of 24 tissue sections of lepidic LC from the local tissue bank were performed and analyzed visually. Clinically, 19 patients underwent static and dynamic 68Ga-FAPI-46 PET in addition to 18F-FDG PET based on individual clinical indications. Static PET data of both examinations were analyzed by determining SUVmax, SUVmean, and tumor-to-background ratio (TBR) against the blood pool, as well as relative parameters (68Ga-FAPI-46 in relation to18F-FDG), of histologically confirmed LC and benign lesions. Time-activity curves and dynamic parameters (time to peak, slope, k 1, k 2, k 3, and k 4) were extracted from dynamic 68Ga-FAPI-46 PET data. The sensitivity and specificity of all parameters were analyzed by calculating receiver-operating-characteristic curves. Results: FAP immunohistochemistry confirmed the presence of strongly FAP-positive cancer-associated fibroblasts in lepidic LC. LC showed markedly elevated 68Ga-FAPI-46 uptake, higher TBRs, and higher 68Ga-FAPI-46-to-18F-FDG ratios for all parameters than did benign pulmonary lesions. Dynamic imaging analysis revealed differential time-activity curves for LC and benign pulmonary lesions: initially increasing time-activity curves with a decent slope were typical of LC, and steadily decreasing time-activity curve indicated benign pulmonary lesions, as was reflected by a significantly increased time to peak and significantly smaller absolute values of the slope for LC. Relative 68Ga-FAPI-46-to-18F-FDG ratios regarding SUVmax and TBR showed the highest sensitivity and specificity for the discrimination of LC from benign pulmonary lesions. Conclusion: 68Ga-FAPI-46 PET is a powerful new tool for the assessment of single 18F-FDG-negative pulmonary lesions and may optimize patient stratification in this clinical setting.
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Affiliation(s)
- Manuel Röhrich
- Department of Nuclear Medicine, University Hospital Heidelberg, Heidelberg, Germany;
- Department of Nuclear Medicine, University Hospital Mainz, Mainz, Germany
- German Center of Lung Research, Heidelberg, Germany
| | - Johanna Daum
- Department of Nuclear Medicine, University Hospital Heidelberg, Heidelberg, Germany
- German Center of Lung Research, Heidelberg, Germany
| | - Ewgenija Gutjahr
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | - Anna-Maria Spektor
- Department of Nuclear Medicine, University Hospital Heidelberg, Heidelberg, Germany
- German Center of Lung Research, Heidelberg, Germany
| | - Frederik M Glatting
- Department of Nuclear Medicine, University Hospital Heidelberg, Heidelberg, Germany
- Clinical Cooperation Unit Molecular and Radiation Oncology, German Cancer Research Center, Heidelberg, Germany
- Department of Radiation Oncology, University Hospital Heidelberg, Heidelberg, Germany
| | | | | | - Jorge Hoppner
- Department of Nuclear Medicine, University Hospital Heidelberg, Heidelberg, Germany
- German Center of Lung Research, Heidelberg, Germany
| | - Cathrin Schroeter
- Department of Nuclear Medicine, University Hospital Heidelberg, Heidelberg, Germany
- German Center of Lung Research, Heidelberg, Germany
| | - Eleni Mavriopoulou
- Department of Nuclear Medicine, University Hospital Heidelberg, Heidelberg, Germany
- German Center of Lung Research, Heidelberg, Germany
| | - Kai Schlamp
- German Center of Lung Research, Heidelberg, Germany
- Department of Radiology, Thoraxklinik, University Hospital Heidelberg, Heidelberg, Germany
| | - Matthias Grott
- German Center of Lung Research, Heidelberg, Germany
- Department of Thoracic Surgery, Thoraxklinik, University Hospital Heidelberg, Heidelberg, Germany
| | - Florian Eichhorn
- German Center of Lung Research, Heidelberg, Germany
- Department of Thoracic Surgery, Thoraxklinik, University Hospital Heidelberg, Heidelberg, Germany
| | - Claus Peter Heußel
- German Center of Lung Research, Heidelberg, Germany
- Department of Radiology, Thoraxklinik, University Hospital Heidelberg, Heidelberg, Germany
| | - Hans Ulrich Kauczor
- German Center of Lung Research, Heidelberg, Germany
- Department of Diagnostic and Interventional Radiology, University Hospital Heidelberg, Heidelberg, Germany
- Center for Interstitial and Rare Lung Diseases, Pneumology, and Respiratory Critical Care Medicine, Thoraxklinik, University of Heidelberg, Heidelberg, Germany
| | - Michael Kreuter
- Department of Pneumology, Mainz Center for Pulmonary Medicine, Mainz University, Mainz, Germany
- Medical Center and Department of Pulmonary, Critical Care, and Sleep Medicine, Marienhaus Clinic Mainz, Mainz, Germany
| | - Frederik Giesel
- Department of Nuclear Medicine, University Hospital Heidelberg, Heidelberg, Germany
- German Center of Lung Research, Heidelberg, Germany
- Department of Nuclear Medicine, Medical Faculty, University Hospital Düsseldorf, Heinrich Heine University, Düsseldorf, Germany
- Institute for Radiation Sciences, Osaka University, Osaka, Japan
- German Cancer Consortium, Heidelberg, Germany; and
| | | | - Hauke Winter
- German Center of Lung Research, Heidelberg, Germany
- Department of Radiology, Thoraxklinik, University Hospital Heidelberg, Heidelberg, Germany
| | - Uwe Haberkorn
- Department of Nuclear Medicine, University Hospital Heidelberg, Heidelberg, Germany
- German Center of Lung Research, Heidelberg, Germany
- Department of Diagnostic and Interventional Radiology, University Hospital Heidelberg, Heidelberg, Germany
- Clinical Cooperation Unit Nuclear Medicine, German Cancer Research Center, Heidelberg, Germany
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Devarasou S, Kang M, Shin JH. Biophysical perspectives to understanding cancer-associated fibroblasts. APL Bioeng 2024; 8:021507. [PMID: 38855445 PMCID: PMC11161195 DOI: 10.1063/5.0199024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2024] [Accepted: 05/24/2024] [Indexed: 06/11/2024] Open
Abstract
The understanding of cancer has evolved significantly, with the tumor microenvironment (TME) now recognized as a critical factor influencing the onset and progression of the disease. This broader perspective challenges the traditional view that cancer is primarily caused by mutations, instead emphasizing the dynamic interaction between different cell types and physicochemical factors within the TME. Among these factors, cancer-associated fibroblasts (CAFs) command attention for their profound influence on tumor behavior and patient prognoses. Despite their recognized importance, the biophysical and mechanical interactions of CAFs within the TME remain elusive. This review examines the distinctive physical characteristics of CAFs, their morphological attributes, and mechanical interactions within the TME. We discuss the impact of mechanotransduction on CAF function and highlight how these cells communicate mechanically with neighboring cancer cells, thereby shaping the path of tumor development and progression. By concentrating on the biomechanical regulation of CAFs, this review aims to deepen our understanding of their role in the TME and to illuminate new biomechanical-based therapeutic strategies.
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Affiliation(s)
- Somayadineshraj Devarasou
- Department of Mechanical Engineering, Korea Advanced Institute of Science & Technology (KAIST), Daejeon, Korea
| | - Minwoo Kang
- Department of Mechanical Engineering, Korea Advanced Institute of Science & Technology (KAIST), Daejeon, Korea
| | - Jennifer H. Shin
- Department of Mechanical Engineering, Korea Advanced Institute of Science & Technology (KAIST), Daejeon, Korea
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Li X, Lei Y. Construction of a prognostic risk model for Stomach adenocarcinoma based on endoplasmic reticulum stress genes. Wien Klin Wochenschr 2024; 136:319-330. [PMID: 37993598 DOI: 10.1007/s00508-023-02306-0] [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: 02/06/2023] [Accepted: 10/21/2023] [Indexed: 11/24/2023]
Abstract
OBJECTIVE Stomach adenocarcinoma (STAD) is caused by malignant transformation of gastric glandular cells and is characterized by a high incidence rate and a poor prognosis. This study was designed to establish a prognostic risk model for STAD according to endoplasmic reticulum (ER) stress feature genes as cancer cells are susceptible to ER stress. METHODS The TCGA-STAD dataset was downloaded to screen differentially expressed genes (DEGs). By intersecting DEGs with ER stress genes retrieved from GeneCards, ER stress-related DEGs in STAD were obtained. Kmeans cluster analysis of STAD subtypes and Single sample gene set enrichment analysis (ssGSEA) analysis of immune infiltration were performed. Cox regression analysis was utilized to construct a risk prognostic model. Samples were split into high-risk and low-risk groups according to the median risk score. Survival analysis and Receiver Operating Characteristic (ROC) curves were conducted to assess the validity of the model. Gene set enrichment analysis (GSEA) was performed to investigate differential pathways in the two risk groups. Cox analysis was performed to verify the independence of the risk model, and a nomogram was generated. RESULTS A total of 162 ER stress-related DEGs in STAD were identified by bioinformatics analysis. Kmeans cluster analysis showed that STAD was divided into 3 subgroups. The ssGSEA showed that the levels of immune infiltration in subgroups 2 and 3 were significantly higher than subgroup 1. With 12 prognostic genes (MATN3, ATP2A1, NOX4, AQP11, HP, CAV1, STARD3, FKBP10, EGF, F2, SERPINE1, CNGA3) selected from ER stress-related DEGs using Cox regression analysis, we then constructed a prognostic model. Kaplan-Meier (K‑M) survival curves and ROC curves showed good prediction performance of the model. Significant enrichment of genes in the high-risk group was found in extracellular matrix (ECM) receptor interaction. Cox regression analysis combined with clinical factors showed that the risk model could be used as an independent prognostic factor. The prediction correction curve showed that the good prediction ability of the nomogram. CONCLUSION The STAD could be divided into three subgroups, and the 12-gene model constructed by ER stress signatures had a good prognostic performance for STAD patients.
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Affiliation(s)
- Xi Li
- Department of General Surgery, Zigong Fourth People's Hospital, No. 19 Tanmulin Street, Ziliujing District, 643000, Zigong City, Sichuan Province, China
| | - Yuehua Lei
- Department of General Surgery, Zigong Fourth People's Hospital, No. 19 Tanmulin Street, Ziliujing District, 643000, Zigong City, Sichuan Province, China.
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Liu Y, Han X, Han Y, Bi J, Wu Y, Xiang D, Zhang Y, Bi W, Xu M, Li J. Integrated transcriptomic analysis systematically reveals the heterogeneity and molecular characterization of cancer-associated fibroblasts in osteosarcoma. Gene 2024; 907:148286. [PMID: 38367852 DOI: 10.1016/j.gene.2024.148286] [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: 11/15/2023] [Revised: 02/08/2024] [Accepted: 02/12/2024] [Indexed: 02/19/2024]
Abstract
BACKGROUND Osteosarcoma (OS), with a peak incidence during the adolescent growth spurt, is correlated with poor prognosis for its high malignancy. The tumor microenvironment (TME) is highly complicated, with frequent interactions between tumor and stromal cells. The cancer-associated fibroblasts (CAFs) in the TME have been considered to actively involve in the progression, metastasis, and drug resistance of OS. This study aimed to characterize cellular heterogeneity and molecular characterization in CAFs subtypes and explore the potential targeting therapeutic strategies to improve the prognosis of OS patients. METHODS The single-cell atlas of human OS tumor lesions were constructed from the GEO database. Then significant marker genes and potential biological functions for each CAFs subtype were identified and explored using the Seurat R package. Next, by performing the survival analyses and constructing the risk scores for CAFs subtypes, we aimed to identify and characterize the prognostic values of specific marker genes and different CAFs subtypes. Furthermore, we explored the therapeutic targets and innovative drugs targeting different CAFs subtypes based on the GDSC database. Finally, prognoses related CAFs subtypes were further validated through immunohistochemistry (IHC) on clinical OS specimens. RESULTS Overall, nine main cell clusters and five subtypes of CAFs were identified. The differentially expressed marker genes for each CAFs clusters were then identified. Moreover, through Gene Ontology (GO) enrichment analysis, we defined the CAFs_2 (upregulated CXCL14 and C3), which was closely related to leukocyte migration and chemotaxis, as inflammatory CAFs (iCAFs). Likewise, we defined the CAFs_4 (upregulated CD74, HLA-DRA and HLA-DRB1), which was closely related to antigen process and presentation, as antigen-presenting CAFs (apCAFs). Furthermore, Kaplan-Meier analyses showed that CAFs_2 and CAFs_4 were correlated with poor clinical prognosis of OS patients. Meanwhile, therapeutic drugs targeting CAFs_2 and CAFs_4, such as 17-AAG/Docetaxel/Bleomycin and PHA-793887/NG-25/KIN001-102, were also explored, respectively. Finally, IHC assay confirmed the abundant CAFs_2 and CAFs_4 subtypes infiltration in the OS microenvironment compared with adjacent tissues. CONCLUSION Our study revealed the diversity, complexity, and heterogeneity of CAFs in OS, and complemented the single-cell atlas in OS TME.
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Affiliation(s)
- Yuyang Liu
- Department of Neurosurgery, 920th Hospital of Joint Logistics Support Force, Kunming 650032, Yunnan, China; Chinese PLA Spinal Cord Injury Treatment Center, Kunming, Yunnan 650032, China
| | - Xinli Han
- School of Medicine, Nankai University, Tianjin 300074, China
| | - Yuchen Han
- Senior Department of Orthopedics, the Fourth Medical Center of PLA General Hospital, Beijing 100048, China; Medical School of Chinese PLA, Beijing 100853, China
| | - Jingyou Bi
- Senior Department of Orthopedics, the Fourth Medical Center of PLA General Hospital, Beijing 100048, China
| | - Yanan Wu
- Senior Department of Orthopedics, the Fourth Medical Center of PLA General Hospital, Beijing 100048, China
| | - Dongquan Xiang
- Senior Department of Orthopedics, the Fourth Medical Center of PLA General Hospital, Beijing 100048, China
| | - Yinglong Zhang
- Senior Department of Orthopedics, the Fourth Medical Center of PLA General Hospital, Beijing 100048, China
| | - Wenzhi Bi
- Senior Department of Orthopedics, the Fourth Medical Center of PLA General Hospital, Beijing 100048, China; School of Medicine, Nankai University, Tianjin 300074, China; Medical School of Chinese PLA, Beijing 100853, China
| | - Meng Xu
- Senior Department of Orthopedics, the Fourth Medical Center of PLA General Hospital, Beijing 100048, China; Medical School of Chinese PLA, Beijing 100853, China.
| | - Jianxiong Li
- Senior Department of Orthopedics, the Fourth Medical Center of PLA General Hospital, Beijing 100048, China.
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Bugakova AS, Chudakova DA, Myzina MS, Yanysheva EP, Ozerskaya IV, Soboleva AV, Baklaushev VP, Yusubalieva GM. Non-Tumor Cells within the Tumor Microenvironment-The "Eminence Grise" of the Glioblastoma Pathogenesis and Potential Targets for Therapy. Cells 2024; 13:808. [PMID: 38786032 PMCID: PMC11119139 DOI: 10.3390/cells13100808] [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: 04/04/2024] [Revised: 04/26/2024] [Accepted: 04/30/2024] [Indexed: 05/25/2024] Open
Abstract
Glioblastoma (GBM) is the most common malignancy of the central nervous system in adults. GBM has high levels of therapy failure and its prognosis is usually dismal. The phenotypic heterogeneity of the tumor cells, dynamic complexity of non-tumor cell populations within the GBM tumor microenvironment (TME), and their bi-directional cross-talk contribute to the challenges of current therapeutic approaches. Herein, we discuss the etiology of GBM, and describe several major types of non-tumor cells within its TME, their impact on GBM pathogenesis, and molecular mechanisms of such an impact. We also discuss their value as potential therapeutic targets or prognostic biomarkers, with reference to the most recent works on this subject. We conclude that unless all "key player" populations of non-tumor cells within the TME are considered, no breakthrough in developing treatment for GBM can be achieved.
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Affiliation(s)
- Aleksandra S. Bugakova
- Federal Center for Brain and Neurotechnologies, Federal Medical and Biological Agency of Russia, 117513 Moscow, Russia
| | - Daria A. Chudakova
- Federal Center for Brain and Neurotechnologies, Federal Medical and Biological Agency of Russia, 117513 Moscow, Russia
| | - Maria S. Myzina
- Federal Center for Brain and Neurotechnologies, Federal Medical and Biological Agency of Russia, 117513 Moscow, Russia
| | - Elvira P. Yanysheva
- Federal Research and Clinical Center of Specialized Medical Care and Medical Technologies Federal Medical and Biological Agency of Russia, 115682 Moscow, Russia
| | - Iuliia V. Ozerskaya
- Pulmonology Research Institute, Federal Medical and Biological Agency of Russia, 115682 Moscow, Russia
| | - Alesya V. Soboleva
- Federal Center for Brain and Neurotechnologies, Federal Medical and Biological Agency of Russia, 117513 Moscow, Russia
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia
| | - Vladimir P. Baklaushev
- Federal Center for Brain and Neurotechnologies, Federal Medical and Biological Agency of Russia, 117513 Moscow, Russia
- Federal Research and Clinical Center of Specialized Medical Care and Medical Technologies Federal Medical and Biological Agency of Russia, 115682 Moscow, Russia
- Pulmonology Research Institute, Federal Medical and Biological Agency of Russia, 115682 Moscow, Russia
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia
- Department of Medical Nanobiotechnology of Medical and Biological Faculty, Pirogov Russian National Research Medical University, Ministry of Health of the Russian Federation, 117997 Moscow, Russia
| | - Gaukhar M. Yusubalieva
- Federal Center for Brain and Neurotechnologies, Federal Medical and Biological Agency of Russia, 117513 Moscow, Russia
- Federal Research and Clinical Center of Specialized Medical Care and Medical Technologies Federal Medical and Biological Agency of Russia, 115682 Moscow, Russia
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia
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Tomizawa Y, Wali KH, Surti M, Suhail Y, Kshitiz, Hoshino K. Lightsheet microscopy integrates single-cell optical visco-elastography and fluorescence cytometry of 3D live tissues. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.04.20.590392. [PMID: 38766194 PMCID: PMC11100606 DOI: 10.1101/2024.04.20.590392] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/22/2024]
Abstract
Most common cytometry methods, including flow cytometry, observe suspended or fixed cells and cannot evaluate their structural roles in 3D tissues. However, cellular physical interactions are critical in physiological, developmental, and pathological processes. Here, we present a novel optical visco-elastography that characterizes single-cellular physical interactions by applying in-situ micro-mechanical perturbation to live microtissues under 3D lightsheet microscopy. The 4D digital image correlation (DIC) analysis of ~20,000 nodes tracked the compressive deformation of 3D tissues containing ~500 cells. The computational 3D image segmentation allowed cell-by-cell qualitative observation and statistical analysis, directly correlating multi-channel fluorescence and viscoelasticity. To represent epithelia-stroma interactions, we used a 3D organoid model of maternal-fetal interface and visualized solid-like, well-aligned displacement and liquid-like random motion between individual cells. The statistical analysis through our unique cytometry confirmed that endometrial stromal fibroblasts stiffen in response to decidualization. Moreover, we demonstrated in the 3D model that interaction with placental extravillous trophoblasts partially reverses the attained stiffness, which was supported by the gene expression analysis. Placentation shares critical cellular and molecular significance with various fundamental biological events such as cancer metastasis, wound healing, and gastrulation. Our analysis confirmed existing beliefs and discovered new insights, proving the broad applicability of our method.
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Affiliation(s)
- Yuji Tomizawa
- Department of Biomedical Engineering, University of Connecticut, CT
| | - Khadija H Wali
- Department of Biomedical Engineering, University of Connecticut Health, Farmington, CT
| | - Manav Surti
- Department of Biomedical Engineering, University of Connecticut, CT
| | - Yasir Suhail
- Department of Biomedical Engineering, University of Connecticut Health, Farmington, CT
| | - Kshitiz
- Department of Biomedical Engineering, University of Connecticut Health, Farmington, CT
- Systems Biology Institute, Yale University, West Haven, CT
| | - Kazunori Hoshino
- Department of Biomedical Engineering, University of Connecticut, CT
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Wu J, Chen J, Ge Y, Huang N, Luo Y. Neuroprotective effect of tanshinone IIA-modified mesenchymal stem cells in a lipopolysaccharide-induced neuroinflammation model. Heliyon 2024; 10:e29424. [PMID: 38638958 PMCID: PMC11024610 DOI: 10.1016/j.heliyon.2024.e29424] [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: 11/20/2023] [Revised: 04/04/2024] [Accepted: 04/08/2024] [Indexed: 04/20/2024] Open
Abstract
In this study, the neuroprotective potential of tanshinone IIA (TIIA)-modified mesenchymal stem cells (MSC) were investigated using a murine model of lipopolysaccharide (LPS)-induced neuroinflammation. The cognitive performance of the mice was assessed using the Y-maze and Morris water maze tests, while immunofluorescence and Western blot analyses were employed to evaluate the hippocampal expression of pertinent markers and inflammatory factors, respectively. The results from the behavioral experiments demonstrated discernible differences in learning and memory abilities between the model group and the control group (P < 0.05), confirming the successful induction of neuroinflammation. Both the MSC and TIIA-MSC groups exhibited enhancements in the cognitive abilities of neuroinflammatory mice, with the TIIA-MSC group demonstrating a more pronounced improvement (P < 0.01). Immunofluorescence analysis revealed significant activation of microglia in the model group, while the MSC and TIIA-MSC groups exhibited a reduction in hippocampal microglial activation, with the TIIA-MSC group displaying a more substantial decrease. A statistically significant difference in the expression levels of IL-1, IL-6, and TNF-α was observed between the model and control groups (P < 0.05), indicating that IL-1, IL-6, and TNF-α were downregulated in both the MSC and TIIA-MSC groups. Notably, the downregulatory effect was more prominent in the TIIA-MSC group (P < 0.01). Compared to MSC treatment alone, the administration of TIIA-modified MSC demonstrated a superior protective effect against lipopolysaccharide-induced neuroinflammation. These findings underscore the potential therapeutic efficacy of TIIA-modified MSC in mitigating neuroinflammatory responses.
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Affiliation(s)
- Jingjing Wu
- Medical College of Soochow University, Suzhou, Jiangsu, China
- Department of Neurology, Third Affiliated Hospital of Zunyi Medical University (The First People's Hospital of Zunyi), Zunyi, Guizhou, China
| | - Jian Chen
- Department of Neurology, Third Affiliated Hospital of Zunyi Medical University (The First People's Hospital of Zunyi), Zunyi, Guizhou, China
| | - Ying Ge
- Department of Neurology, Third Affiliated Hospital of Zunyi Medical University (The First People's Hospital of Zunyi), Zunyi, Guizhou, China
| | - Nanqu Huang
- National Drug Clinical Trial Institution, Third Affiliated Hospital of Zunyi Medical University (The First People's Hospital of Zunyi), Zunyi, Guizhou, China
| | - Yong Luo
- Department of Neurology, Third Affiliated Hospital of Zunyi Medical University (The First People's Hospital of Zunyi), Zunyi, Guizhou, China
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Stewart R, Sharma S, Wu T, Okuda S, Xie G, Zhou XZ, Shilton B, Lu KP. The role of the master cancer regulator Pin1 in the development and treatment of cancer. Front Cell Dev Biol 2024; 12:1343938. [PMID: 38745861 PMCID: PMC11091292 DOI: 10.3389/fcell.2024.1343938] [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: 11/24/2023] [Accepted: 03/28/2024] [Indexed: 05/16/2024] Open
Abstract
This review examines the complex role of Pin1 in the development and treatment of cancer. Pin1 is the only peptidyl-prolyl isomerase (PPIase) that can recognize and isomerize phosphorylated Ser/Thr-Pro peptide bonds. Pin1 catalyzes a structural change in phosphorylated Ser/Thr-Pro motifs that can modulate protein function and thereby impact cell cycle regulation and tumorigenesis. The molecular mechanisms by which Pin1 contributes to oncogenesis are reviewed, including Pin1 overexpression and its correlation with poor cancer prognosis, and the contribution of Pin1 to aggressive tumor phenotypes involved in therapeutic resistance is discussed, with an emphasis on cancer stem cells, the epithelial-to-mesenchymal transition (EMT), and immunosuppression. The therapeutic potential of Pin1 inhibition in cancer is discussed, along with the promise and the difficulties in identifying potent, drug-like, small-molecule Pin1 inhibitors. The available evidence supports the efficacy of targeting Pin1 as a novel cancer therapeutic by analyzing the role of Pin1 in a complex network of cancer-driving pathways and illustrating the potential of synergistic drug combinations with Pin1 inhibitors for treating aggressive and drug-resistant tumors.
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Affiliation(s)
- Robert Stewart
- Department of Biochemistry, Western University, London, ON, Canada
| | - Shaunik Sharma
- Department of Biochemistry, Western University, London, ON, Canada
| | - Timothy Wu
- Department of Biochemistry, Western University, London, ON, Canada
| | - Sho Okuda
- Department of Biochemistry, Western University, London, ON, Canada
| | - George Xie
- Department of Biochemistry, Western University, London, ON, Canada
| | - Xiao Zhen Zhou
- Department of Biochemistry, Western University, London, ON, Canada
- Robarts Research Institute, Western University, London, ON, Canada
- Department of Pathology and Laboratory Medicine, Western University, London, ON, Canada
- Lawson Health Research Institute, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada
| | - Brian Shilton
- Department of Biochemistry, Western University, London, ON, Canada
| | - Kun Ping Lu
- Department of Biochemistry, Western University, London, ON, Canada
- Robarts Research Institute, Western University, London, ON, Canada
- Lawson Health Research Institute, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada
- Department of Oncology, Western University, London, ON, Canada
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40
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Gonzalez‐Molina J, Hahn P, Falcão RM, Gultekin O, Kokaraki G, Zanfagnin V, Braz Petta T, Lehti K, Carlson JW. MMP14 expression and collagen remodelling support uterine leiomyosarcoma aggressiveness. Mol Oncol 2024; 18:850-865. [PMID: 37078535 PMCID: PMC10994236 DOI: 10.1002/1878-0261.13440] [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: 08/09/2022] [Revised: 03/14/2023] [Accepted: 04/18/2023] [Indexed: 04/21/2023] Open
Abstract
Fibrillar collagen deposition, stiffness and downstream signalling support the development of leiomyomas (LMs), common benign mesenchymal tumours of the uterus, and are associated with aggressiveness in multiple carcinomas. Compared with epithelial carcinomas, however, the impact of fibrillar collagens on malignant mesenchymal tumours, including uterine leiomyosarcoma (uLMS), remains elusive. In this study, we analyse the network morphology and density of fibrillar collagens combined with the gene expression within uLMS, LM and normal myometrium (MM). We find that, in contrast to LM, uLMS tumours present low collagen density and increased expression of collagen-remodelling genes, features associated with tumour aggressiveness. Using collagen-based 3D matrices, we show that matrix metalloproteinase-14 (MMP14), a central protein with collagen-remodelling functions that is particularly overexpressed in uLMS, supports uLMS cell proliferation. In addition, we find that, unlike MM and LM cells, uLMS proliferation and migration are less sensitive to changes in collagen substrate stiffness. We demonstrate that uLMS cell growth in low-stiffness substrates is sustained by an enhanced basal yes-associated protein 1 (YAP) activity. Altogether, our results indicate that uLMS cells acquire increased collagen remodelling capabilities and are adapted to grow and migrate in low collagen and soft microenvironments. These results further suggest that matrix remodelling and YAP are potential therapeutic targets for this deadly disease.
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Affiliation(s)
- Jordi Gonzalez‐Molina
- Department of Microbiology, Tumor and Cell BiologyKarolinska InstitutetStockholmSweden
- Department of Oncology‐PathologyKarolinska InstitutetStockholmSweden
| | - Paula Hahn
- Department of Microbiology, Tumor and Cell BiologyKarolinska InstitutetStockholmSweden
| | - Raul Maia Falcão
- Keck School of MedicineUniversity of Southern CaliforniaLos AngelesCAUSA
- Department of Cellular Biology and GeneticsFederal University of Rio Grande do NorteNatalBrazil
| | - Okan Gultekin
- Department of Microbiology, Tumor and Cell BiologyKarolinska InstitutetStockholmSweden
| | - Georgia Kokaraki
- Department of Oncology‐PathologyKarolinska InstitutetStockholmSweden
- Keck School of MedicineUniversity of Southern CaliforniaLos AngelesCAUSA
| | | | - Tirzah Braz Petta
- Keck School of MedicineUniversity of Southern CaliforniaLos AngelesCAUSA
- Department of Cellular Biology and GeneticsFederal University of Rio Grande do NorteNatalBrazil
| | - Kaisa Lehti
- Department of Microbiology, Tumor and Cell BiologyKarolinska InstitutetStockholmSweden
- Department of Biomedical Laboratory ScienceNorwegian University of Science and TechnologyTrondheimNorway
| | - Joseph W. Carlson
- Department of Oncology‐PathologyKarolinska InstitutetStockholmSweden
- Keck School of MedicineUniversity of Southern CaliforniaLos AngelesCAUSA
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41
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Feng Y, Qiao S, Chen J, Wen X, Chen Y, Song X, Xu J, Qiao X, Yang J, Zhang S, Feng Y, Gao Y. M2-Type Macrophages and Cancer-Associated Fibroblasts Combine to Promote Colorectal Cancer Liver Metastases. Onco Targets Ther 2024; 17:243-260. [PMID: 38558848 PMCID: PMC10981424 DOI: 10.2147/ott.s447502] [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: 11/08/2023] [Accepted: 03/19/2024] [Indexed: 04/04/2024] Open
Abstract
Purpose This research explored the association between CD163-labeled M2-type macrophages and cancer-associated fibroblasts (CAFs) in the tumor microenvironment (TME) of 38 colorectal cancer (CRC) liver metastases. In addition, we investigated the correlation differences between M2-type macrophages and CAFs in the tumor microenvironments of 38 primary colorectal cancer patients with confirmed liver metastases and 946 colorectal cancer patients, as well as possible mechanisms of action between the two cells. Methods The Immunohistochemistry (IHC) method was applied to detect the expression levels of M2-type macrophages and CAFs in the tissues of 984 cases of CRC and to analyze the correlation between M2-type macrophages and CAFs in colorectal cancer tissues. The IHC method was also applied to detect the expression levels of M2-type macrophages and CAFs in the liver metastases of 38 cases of CRC in the experimental group and to analyze the correlation between the two cells in liver metastases. Results 1. M2-type macrophages and CAFs expression were significantly higher in 38 primary colorectal cancer patients compared to 946 controls, and the expression of M2-type macrophages was significantly positively correlated with CAFs. 2. In 984 CRC cases, M2-type macrophages and CAFs expression levels were significantly higher in the cancer tissues than in the paired paracancerous tissues. 3. The expression levels of M2-type macrophages and CAFs in primary colorectal cancer were significantly higher in the experimental group than in colorectal cancer tissues without distant metastasis. Conclusion M2-type macrophages and CAFs are involved in the development of the colorectal cancer tumor microenvironment, and their interaction influences the initiation and progression of liver metastasis in colorectal cancer. It may provide new clinical ideas for early diagnosis of CRC liver metastases and searching for immune targets.
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Affiliation(s)
- Yunpeng Feng
- The Second Ward of Colorectal Surgery, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning, 12100, People’s Republic of China
| | - Shifeng Qiao
- The Second Ward of Colorectal Surgery, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning, 12100, People’s Republic of China
| | - Jie Chen
- The Second Ward of Colorectal Surgery, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning, 12100, People’s Republic of China
| | - Xin Wen
- Department of Pathology, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning, 12100, People’s Republic of China
| | - Yanlei Chen
- The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, People’s Republic of China
| | - Xiaoyu Song
- The Second Ward of Colorectal Surgery, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning, 12100, People’s Republic of China
| | - Jiaxin Xu
- The Second Ward of Colorectal Surgery, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning, 12100, People’s Republic of China
| | - Xiucheng Qiao
- The Second Ward of Colorectal Surgery, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning, 12100, People’s Republic of China
| | - Jing Yang
- Department of Pathology, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning, 12100, People’s Republic of China
| | - Shenshen Zhang
- The Second Ward of Colorectal Surgery, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning, 12100, People’s Republic of China
| | - Yang Feng
- The Second Ward of Colorectal Surgery, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning, 12100, People’s Republic of China
| | - Yu Gao
- School of Basic Medical Sciences, Jinzhou Medical University, Jinzhou, Liaoning, 12100, People’s Republic of China
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42
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Guo S, Wang Z. Unveiling the immunosuppressive landscape of pancreatic ductal adenocarcinoma: implications for innovative immunotherapy strategies. Front Oncol 2024; 14:1349308. [PMID: 38590651 PMCID: PMC10999533 DOI: 10.3389/fonc.2024.1349308] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Accepted: 03/12/2024] [Indexed: 04/10/2024] Open
Abstract
Pancreatic cancer, particularly pancreatic ductal adenocarcinoma (PDAC), stands as the fourth leading cause of cancer-related deaths in the United States, marked by challenging treatment and dismal prognoses. As immunotherapy emerges as a promising avenue for mitigating PDAC's malignant progression, a comprehensive understanding of the tumor's immunosuppressive characteristics becomes imperative. This paper systematically delves into the intricate immunosuppressive network within PDAC, spotlighting the significant crosstalk between immunosuppressive cells and factors in the hypoxic acidic pancreatic tumor microenvironment. By elucidating these mechanisms, we aim to provide insights into potential immunotherapy strategies and treatment targets, laying the groundwork for future studies on PDAC immunosuppression. Recognizing the profound impact of immunosuppression on PDAC invasion and metastasis, this discussion aims to catalyze the development of more effective and targeted immunotherapies for PDAC patients.
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Affiliation(s)
- Songyu Guo
- First Clinical Medical College, Inner Mongolia Medical University, Hohhot, China
- Department of Hepatic-Biliary-Pancreatic Surgery, The Affiliated Hospital of Inner Mongolia Medical University, Hohhot, China
| | - Zhenxia Wang
- Department of Hepatic-Biliary-Pancreatic Surgery, The Affiliated Hospital of Inner Mongolia Medical University, Hohhot, China
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43
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Liu W, Wang Y, Xia L, Li J. Research Progress of Plant-Derived Natural Products against Drug-Resistant Cancer. Nutrients 2024; 16:797. [PMID: 38542707 PMCID: PMC10975298 DOI: 10.3390/nu16060797] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2024] [Revised: 03/04/2024] [Accepted: 03/04/2024] [Indexed: 01/04/2025] Open
Abstract
As one of the malignant diseases globally, cancer seriously endangers human physical and mental health because of its high morbidity and mortality. Conventional cancer treatment strategies, such as surgical resection and chemoradiotherapy, are effective at the early stage of cancer but have limited efficacy for advanced cancer. Along with cancer progress and treatment, resistance develops gradually within the population of tumor cells. As a consequence, drug resistance become the major cause that leads to disease progression and poor clinical prognosis in some patients. The mechanisms of cancer drug resistance are quite complex and involve various molecular and cellular mechanisms. Therefore, exploring the mechanisms and finding specific targets are becoming imperative to overcome drug resistance. In recent years, plant-derived natural products have been evaluated as potential therapeutic candidates against cancer with drug resistance due to low side effects and high anticancer efficacy. A growing number of studies have shown that natural products can achieve superior antitumor effects through multiple signaling pathways. The mechanisms include regulation of multiple drug resistance (MDR)-related genes, inhibition of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway, induction of autophagy, and blockade of the cell cycle. This paper reviews the molecular and cellular mechanisms of cancer drug resistance, as well as the therapeutic effects and mechanisms of plant-derived natural products against cancer drug resistance. It provides references for developing therapeutic medication for drug-resistant cancer treatment with high efficacy and low side effects.
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Affiliation(s)
| | | | - Lijie Xia
- Xinjiang Key Laboratory of Biological Resources and Genetic Engineering, College of Life Science and Technology, Xinjiang University, Urumqi 830046, China; (W.L.); (Y.W.)
| | - Jinyao Li
- Xinjiang Key Laboratory of Biological Resources and Genetic Engineering, College of Life Science and Technology, Xinjiang University, Urumqi 830046, China; (W.L.); (Y.W.)
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Zheng J, Chen J, Wang S, Yang D, Zhou P. Genomic and immune landscape in hepatocellular carcinoma: Implications for personalized therapeutics. ENVIRONMENTAL TOXICOLOGY 2024; 39:1601-1616. [PMID: 38009667 DOI: 10.1002/tox.24062] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Revised: 11/06/2023] [Accepted: 11/14/2023] [Indexed: 11/29/2023]
Abstract
Hepatocellular carcinoma (HCC) is a globally prevalent malignancy, marked by genetic heterogeneity and intricate tumor microenvironment interactions. In this study, we undertook a detailed single-cell analysis of six active HCC patients, highlighting strong correlations between gene expression levels and cellular characteristics. UMAP clustering revealed seven distinct cell categories with associated gene expressions. A divergence was observed in tumor cells into high and low cuproptosis groups, each associated with distinct pathways: oxidative stress for the high cuproptosis group and inflammatory and angiogenesis pathways for the low group. CellChat analysis on the TCGA-LIHC cohort displayed unique intercellular interactions among hepatocytes, T cells, and other cells, with pathways like COLLAGEN and VEGF being pivotal. Functional enrichment analyses exposed pathways enriched between cuproptosis groups, with KEGG emphasizing diseases like Parkinson's. COX survival analysis identified key prognostic genes, revealing distinct survival rates between risk groups in TCGA and GSE14520 cohorts. Mutation data highlighted missense mutations, with TTN, TP53, and CTNNB1 being the most mutated in HCC. Immune infiltration analysis via CIBERSORTx indicated differences between risk groups in NK cells, neutrophils, and other cells. Our drug sensitivity investigation showed significant correlations between model genes and drug responsiveness, emphasizing the importance of patient risk stratification for therapeutic approaches. Further, ATP6V1G1 was recognized in its role in apoptosis and migration in HCC cells. In conclusion, our findings illuminate the complexities of HCC progression, potential predictive genetic markers for drug response, and the pivotal role of ATP6V1G1, suggesting avenues for targeted therapeutic strategies in HCC.
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Affiliation(s)
- Jiaoyun Zheng
- Department of Pathology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
- Department of Physiology, School of Basic Medical Science, Central South University, Changsha, Hunan, China
- Hunan Clinical Medical Research Center for Cancer Pathogenic Genes Testing and Diagnosis, Hunan, Changsha, China
| | - Junyan Chen
- The Third Clinical Department, China Medical University, Shenyang, Liaoning, China
| | - Shuchao Wang
- Center for Medical Research, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Dun Yang
- Department of Pathology, Taoyuan People's Hospital, Changde, Hunan, China
| | - Peng Zhou
- Department of Pathology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
- Hunan Clinical Medical Research Center for Cancer Pathogenic Genes Testing and Diagnosis, Hunan, Changsha, China
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45
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Li C, Wang Z, Zhang Y, Zhu Y, Xu M, Lei H, Zhang D. Efficient Sequential Co-Delivery Nanosystem for Inhibition of Tumor and Tumor-Associated Fibroblast-Induced Resistance and Metastasis. Int J Nanomedicine 2024; 19:1749-1766. [PMID: 38414527 PMCID: PMC10898601 DOI: 10.2147/ijn.s427783] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Accepted: 12/20/2023] [Indexed: 02/29/2024] Open
Abstract
Purpose Triple-negative breast cancer (TNBC) is the most lethal subtype of breast cancer. However, the effect of current treatment strategies by inducing tumor cell apoptosis alone is not satisfactory. The growth, metastasis and treatment sensitivity of tumors can be strongly influenced by cancer-associated fibroblasts (CAFs) in the microenvironment. Effective cancer therapies may need to target not only the tumor cells directly but also the CAFs that protect them. Methods Celastrol and small-sized micelles containing betulinic acid were co-encapsulated into liposomes using the thin-film hydration method (CL@BM). Folic acid was further introduced to modify liposomes as the targeting moiety (F/CL@BM). We established a novel NIH3T3+4T1 co-culture model to mimic the tumor microenvironment and assessed the nanocarrier's inhibitory effects on CAFs-induced drug resistance and migration in the co-culture model. The in vivo biological distribution, fluorescence imaging, biological safety evaluation, and combined therapeutic effect evaluation of the nanocarrier were carried out based on a triple-negative breast cancer model. Results In the present study, a novel multifunctional nano-formulation was designed by combining the advantages of sequential release, co-loading of tretinoin and betulinic acid, and folic acid-mediated active targeting. As expected, the nano-formulation exhibited enhanced cytotoxicity in different cellular models and effectively increased drug accumulation at the tumor site by disrupting the cellular barrier composed of CAFs by tretinoin. Notably, the co-loaded nano-formulations proved to be more potent in inhibiting tumor growth in mice and also showed better anti-metastatic effects in lung metastasis models compared to the formulations with either drug alone. This novel drug delivery system has the potential to be used to develop more effective cancer therapies. Conclusion Targeting CAFs with celastrol sensitizes tumor cells to chemotherapy, increasing the efficacy of betulinic acid. The combination of drugs targeting tumor cells and CAFs may lead to more effective therapies against various cancers.
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Affiliation(s)
- Chunhong Li
- Department of Pharmaceutical Sciences, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646000, People’s Republic of China
| | - Zhen Wang
- Department of Pharmaceutical Sciences, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646000, People’s Republic of China
| | - Yifeng Zhang
- Department of Pharmaceutical Sciences, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646000, People’s Republic of China
| | - Yuqing Zhu
- Department of Pharmaceutical Sciences, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646000, People’s Republic of China
| | - Maochang Xu
- Department of Pharmaceutical Sciences, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646000, People’s Republic of China
| | - Hui Lei
- Department of Pharmaceutical Sciences, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646000, People’s Republic of China
| | - Dan Zhang
- Department of Pharmaceutical Sciences, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646000, People’s Republic of China
- Green Pharmaceutical Technology Key Laboratory of Luzhou, School of Pharmacy, Southwest Medical University, Luzhou, 646000, People’s Republic of China
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46
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Rizvi SF, Zhang L, Zhang H, Fang Q. Peptide-Drug Conjugates: Design, Chemistry, and Drug Delivery System as a Novel Cancer Theranostic. ACS Pharmacol Transl Sci 2024; 7:309-334. [PMID: 38357281 PMCID: PMC10863443 DOI: 10.1021/acsptsci.3c00269] [Citation(s) in RCA: 15] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2023] [Revised: 12/23/2023] [Accepted: 12/27/2023] [Indexed: 02/16/2024]
Abstract
The emergence of peptide-drug conjugates (PDCs) that utilize target-oriented peptide moieties as carriers of cytotoxic payloads, interconnected with various cleavable/noncleavable linkers, resulted in the key-foundation of the new era of targeted therapeutics. They are capable of retaining the integrity of conjugates in the blood circulatory system as well as releasing the drugs at the tumor microenvironment. Other valuable advantages are specificity and selectivity toward targeted-receptors, higher penetration ability, and drug-loading capacity, making them a suitable candidate to play their vital role as promising carrier agents. In this review, we summarized the types of cell-targeting (CTPs) and cell-penetrating peptides (CPPs) that have broad applications in the advancement of targeted drug-delivery systems (DDS). Moreover, the techniques to overcome the limitations of peptide-chemistry for their extensive implementation to construct the PDCs. Besides this, the diversified breakthrough of linker chemistry, and ample knowledge of various cytotoxic payloads used in PDCs in recent years, as well as the mechanism of action of PDCs was critically discussed. The principal aim is to provide scattered and diversified knowledge in one place and to help researchers understand the pinching knots in the science of PDC development, also their progression toward a bright future for PDCs as novel theranostics in clinical practice.
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Affiliation(s)
- Syed Faheem
Askari Rizvi
- Key
Laboratory of Preclinical Study for New Drugs of Gansu Province, and
Institute of Pathology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, 730000, Gansu P.R. China
- State
Key Laboratory of Applied Organic Chemistry, College of Chemistry
and Chemical Engineering, Lanzhou University, Lanzhou, 730000, Gansu P.R. China
- Institute
of Molecular Biology and Biotechnology (IMBB), The University of Lahore, Lahore, 54000, Punjab Pakistan
| | - Linjie Zhang
- State
Key Laboratory of Applied Organic Chemistry, College of Chemistry
and Chemical Engineering, Lanzhou University, Lanzhou, 730000, Gansu P.R. China
| | - Haixia Zhang
- State
Key Laboratory of Applied Organic Chemistry, College of Chemistry
and Chemical Engineering, Lanzhou University, Lanzhou, 730000, Gansu P.R. China
| | - Quan Fang
- Key
Laboratory of Preclinical Study for New Drugs of Gansu Province, and
Institute of Pathology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, 730000, Gansu P.R. China
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Kumar MA, Baba SK, Sadida HQ, Marzooqi SA, Jerobin J, Altemani FH, Algehainy N, Alanazi MA, Abou-Samra AB, Kumar R, Al-Shabeeb Akil AS, Macha MA, Mir R, Bhat AA. Extracellular vesicles as tools and targets in therapy for diseases. Signal Transduct Target Ther 2024; 9:27. [PMID: 38311623 PMCID: PMC10838959 DOI: 10.1038/s41392-024-01735-1] [Citation(s) in RCA: 276] [Impact Index Per Article: 276.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2023] [Revised: 12/20/2023] [Accepted: 12/24/2023] [Indexed: 02/06/2024] Open
Abstract
Extracellular vesicles (EVs) are nano-sized, membranous structures secreted into the extracellular space. They exhibit diverse sizes, contents, and surface markers and are ubiquitously released from cells under normal and pathological conditions. Human serum is a rich source of these EVs, though their isolation from serum proteins and non-EV lipid particles poses challenges. These vesicles transport various cellular components such as proteins, mRNAs, miRNAs, DNA, and lipids across distances, influencing numerous physiological and pathological events, including those within the tumor microenvironment (TME). Their pivotal roles in cellular communication make EVs promising candidates for therapeutic agents, drug delivery systems, and disease biomarkers. Especially in cancer diagnostics, EV detection can pave the way for early identification and offers potential as diagnostic biomarkers. Moreover, various EV subtypes are emerging as targeted drug delivery tools, highlighting their potential clinical significance. The need for non-invasive biomarkers to monitor biological processes for diagnostic and therapeutic purposes remains unfulfilled. Tapping into the unique composition of EVs could unlock advanced diagnostic and therapeutic avenues in the future. In this review, we discuss in detail the roles of EVs across various conditions, including cancers (encompassing head and neck, lung, gastric, breast, and hepatocellular carcinoma), neurodegenerative disorders, diabetes, viral infections, autoimmune and renal diseases, emphasizing the potential advancements in molecular diagnostics and drug delivery.
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Affiliation(s)
- Mudasir A Kumar
- Watson-Crick Centre for Molecular Medicine, Islamic University of Science and Technology, Awantipora, Kashmir, 192122, India
| | - Sadaf K Baba
- Watson-Crick Centre for Molecular Medicine, Islamic University of Science and Technology, Awantipora, Kashmir, 192122, India
| | - Hana Q Sadida
- Department of Human Genetics-Precision Medicine in Diabetes, Obesity and Cancer Program, Sidra Medicine, Doha, Qatar
| | - Sara Al Marzooqi
- Department of Human Genetics-Precision Medicine in Diabetes, Obesity and Cancer Program, Sidra Medicine, Doha, Qatar
| | - Jayakumar Jerobin
- Qatar Metabolic Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Faisal H Altemani
- Department of Medical Laboratory Technology, Prince Fahad Bin Sultan Chair for Biomedical Research, Faculty of Applied Medical Sciences, University of Tabuk, Tabuk, Saudi Arabia
| | - Naseh Algehainy
- Department of Medical Laboratory Technology, Prince Fahad Bin Sultan Chair for Biomedical Research, Faculty of Applied Medical Sciences, University of Tabuk, Tabuk, Saudi Arabia
| | - Mohammad A Alanazi
- Department of Medical Laboratory Technology, Prince Fahad Bin Sultan Chair for Biomedical Research, Faculty of Applied Medical Sciences, University of Tabuk, Tabuk, Saudi Arabia
| | - Abdul-Badi Abou-Samra
- Qatar Metabolic Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Rakesh Kumar
- School of Biotechnology, Shri Mata Vaishno Devi University, Katra, India
| | - Ammira S Al-Shabeeb Akil
- Department of Human Genetics-Precision Medicine in Diabetes, Obesity and Cancer Program, Sidra Medicine, Doha, Qatar
| | - Muzafar A Macha
- Watson-Crick Centre for Molecular Medicine, Islamic University of Science and Technology, Awantipora, Kashmir, 192122, India
| | - Rashid Mir
- Department of Medical Laboratory Technology, Prince Fahad Bin Sultan Chair for Biomedical Research, Faculty of Applied Medical Sciences, University of Tabuk, Tabuk, Saudi Arabia.
| | - Ajaz A Bhat
- Department of Human Genetics-Precision Medicine in Diabetes, Obesity and Cancer Program, Sidra Medicine, Doha, Qatar.
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Ghosh A, Mitra AK. Metastasis and cancer associated fibroblasts: taking it up a NOTCH. Front Cell Dev Biol 2024; 11:1277076. [PMID: 38269089 PMCID: PMC10806909 DOI: 10.3389/fcell.2023.1277076] [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: 08/14/2023] [Accepted: 12/27/2023] [Indexed: 01/26/2024] Open
Abstract
Metastasis is the least understood aspect of cancer biology. 90% of cancer related deaths occur due extensive metastatic burden in patients. Apart from metastasizing cancer cells, the pro-tumorigenic and pro-metastatic role of the tumor stroma plays a crucial part in this complex process often leading to disease relapse and therapy resistance. Cellular signaling processes play a crucial role in the process of tumorigenesis and metastasis when aberrantly turned on, not just in the cancer cells, but also in the cells of the tumor microenvironment (TME). One of the most conserved pathways includes the Notch signaling pathway that plays a crucial role in the development and progression of many cancers. In addition to its well documented role in cancer cells, recent evidence suggests crucial involvement of Notch signaling in the stroma as well. This review aims to highlight the current findings focusing on the oncogenic role of notch signaling in cancer cells and the TME, with a specific focus on cancer associated fibroblasts (CAFs), which constitute a major part of the tumor stroma and are important for tumor progression. Recent efforts have focused on the development of anti-cancer and anti-metastatic therapies targeting TME. Understanding the importance of Notch signaling in the TME would help identify important drivers for stromal reprogramming, metastasis and importantly, drive future research in the effort to develop TME-targeted therapies utilizing Notch.
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Affiliation(s)
- Argha Ghosh
- Indiana University School of Medicine-Bloomington, Bloomington, IN, United States
- Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, IN, United States
| | - Anirban K. Mitra
- Indiana University School of Medicine-Bloomington, Bloomington, IN, United States
- Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, IN, United States
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, United States
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Zhu S, Kubota N, Wang S, Wang T, Xiao G, Hoshida Y. Single-cell level deconvolution, convolution, and clustering in spatial transcriptomics by aligning spot level transcriptome to nuclear morphology. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.12.17.572084. [PMID: 38187541 PMCID: PMC10769305 DOI: 10.1101/2023.12.17.572084] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/09/2024]
Abstract
In spot-based spatial transcriptomics, spots that are of the same size and printed at the fixed location cannot precisely capture the actual randomly located single cells, therefore failing to profile the transcriptome at the single-cell level. The current studies primarily focused on enhancing the spot resolution in size via computational imputation or technical improvement, however, they largely overlooked that single-cell resolution, i.e., resolution in cellular or even smaller size, does not equal single-cell level. Using both real and simulated spatial transcriptomics data, we demonstrated that even the high-resolution spatial transcriptomics still has a large number of spots partially covering multiple cells simultaneously, revealing the intrinsic non-single-cell level of spot-based spatial transcriptomics regardless of spot size. To this end, we present STIE, an EM algorithm that aligns the spatial transcriptome to its matched histology image-based nuclear morphology and recovers missing cells from up to ~70% gap area between spots via the nuclear morphological similarity and neighborhood information, thereby achieving the real single-cell level and whole-slide scale deconvolution/convolution and clustering for both low- and high-resolution spots. On both real and simulation spatial transcriptomics data, STIE characterizes the cell-type specific gene expression variation and demonstrates the outperforming concordance with the single-cell RNAseq-derived cell type transcriptomic signatures compared to the other spot- and subspot-level methods. Furthermore, STIE enabled us to gain novel insights that failed to be revealed by the existing methods due to the lack of single-cell level, for instance, lower actual spot resolution than its reported spot size, the additional contribution of cellular morphology to cell typing beyond transcriptome, unbiased evaluation of cell type colocalization, superior power of high-resolution spot in distinguishing nuanced cell types, and spatially resolved cell-cell interactions at the single-cell level other than spot level. The STIE code is publicly available as an R package at https://github.com/zhushijia/STIE.
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Affiliation(s)
- Shijia Zhu
- Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota, USA
- Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Naoto Kubota
- Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Shidan Wang
- Quantitative Biomedical Research Center, Department of Population and Data Sciences, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Tao Wang
- Quantitative Biomedical Research Center, Department of Population and Data Sciences, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Guanghua Xiao
- Quantitative Biomedical Research Center, Department of Population and Data Sciences, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Yujin Hoshida
- Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA
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Obreque J, Vergara-Gómez L, Venegas N, Weber H, Owen GI, Pérez-Moreno P, Leal P, Roa JC, Bizama C. Advances towards the use of gastrointestinal tumor patient-derived organoids as a therapeutic decision-making tool. Biol Res 2023; 56:63. [PMID: 38041132 PMCID: PMC10693174 DOI: 10.1186/s40659-023-00476-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Accepted: 11/16/2023] [Indexed: 12/03/2023] Open
Abstract
In December 2022 the US Food and Drug Administration (FDA) removed the requirement that drugs in development must undergo animal testing before clinical evaluation, a declaration that now demands the establishment and verification of ex vivo preclinical models that closely represent tumor complexity and that can predict therapeutic response. Fortunately, the emergence of patient-derived organoid (PDOs) culture has enabled the ex vivo mimicking of the pathophysiology of human tumors with the reassembly of tissue-specific features. These features include histopathological variability, molecular expression profiles, genetic and cellular heterogeneity of parental tissue, and furthermore growing evidence suggests the ability to predict patient therapeutic response. Concentrating on the highly lethal and heterogeneous gastrointestinal (GI) tumors, herein we present the state-of-the-art and the current methodology of PDOs. We highlight the potential additions, improvements and testing required to allow the ex vivo of study the tumor microenvironment, as well as offering commentary on the predictive value of clinical response to treatments such as chemotherapy and immunotherapy.
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Affiliation(s)
- Javiera Obreque
- Department of Pathology, School of Medicine, Pontificia Universidad Católica de Chile, Diagonal Paraguay 362, Office 526, 8330024, Santiago, Chile
- Millennium Institute on Immunology and Immunotherapy, Pontificia Universidad Católica de Chile, 8331150, Santiago, Chile
- Centro de Prevención y Control de Cáncer (CECAN), Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Luis Vergara-Gómez
- Centre of Excellence in Translational Medicine (CEMT) and Scientific and Technological Bioresource Nucleus (BIOREN), Biomedicine and Translational Research Lab, Universidad de La Frontera, 4810296, Temuco, Chile
| | - Nicolás Venegas
- Department of Pathology, School of Medicine, Pontificia Universidad Católica de Chile, Diagonal Paraguay 362, Office 526, 8330024, Santiago, Chile
| | - Helga Weber
- Centre of Excellence in Translational Medicine (CEMT) and Scientific and Technological Bioresource Nucleus (BIOREN), Biomedicine and Translational Research Lab, Universidad de La Frontera, 4810296, Temuco, Chile
| | - Gareth I Owen
- Millennium Institute on Immunology and Immunotherapy, Pontificia Universidad Católica de Chile, 8331150, Santiago, Chile
- Department of Physiology, Faculty of Biological Sciences, Pontificia Universidad Católica de Chile, 8331150, Santiago, Chile
- Advanced Center for Chronic Diseases, Pontificia Universidad Católica de Chile, Santiago, Chile
- Centro de Prevención y Control de Cáncer (CECAN), Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Pablo Pérez-Moreno
- Department of Pathology, School of Medicine, Pontificia Universidad Católica de Chile, Diagonal Paraguay 362, Office 526, 8330024, Santiago, Chile
- Millennium Institute on Immunology and Immunotherapy, Pontificia Universidad Católica de Chile, 8331150, Santiago, Chile
| | - Pamela Leal
- Centre of Excellence in Translational Medicine (CEMT) and Scientific and Technological Bioresource Nucleus (BIOREN), Biomedicine and Translational Research Lab, Universidad de La Frontera, 4810296, Temuco, Chile
| | - Juan Carlos Roa
- Department of Pathology, School of Medicine, Pontificia Universidad Católica de Chile, Diagonal Paraguay 362, Office 526, 8330024, Santiago, Chile
- Millennium Institute on Immunology and Immunotherapy, Pontificia Universidad Católica de Chile, 8331150, Santiago, Chile
- Centro de Prevención y Control de Cáncer (CECAN), Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Carolina Bizama
- Department of Pathology, School of Medicine, Pontificia Universidad Católica de Chile, Diagonal Paraguay 362, Office 526, 8330024, Santiago, Chile.
- Millennium Institute on Immunology and Immunotherapy, Pontificia Universidad Católica de Chile, 8331150, Santiago, Chile.
- Advanced Center for Chronic Diseases, Pontificia Universidad Católica de Chile, Santiago, Chile.
- Centro de Prevención y Control de Cáncer (CECAN), Pontificia Universidad Católica de Chile, Santiago, Chile.
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