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1
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Mahdavimehr M, Rahdari T, Nikfarjam N, Ehtesham S, Shafiee Ardestani M, Asghari SM. Development and application of dual-modality tumor-targeting SPIONs for precision breast cancer imaging. BIOMATERIALS ADVANCES 2025; 172:214236. [PMID: 40010023 DOI: 10.1016/j.bioadv.2025.214236] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/08/2024] [Revised: 02/05/2025] [Accepted: 02/16/2025] [Indexed: 02/28/2025]
Abstract
Superparamagnetic iron oxide nanoparticles (SPIONs) have gained attention as contrast agents in cancer imaging due to their unique magnetic properties, enhancing MRI's effectiveness. This study introduces an innovative approach by functionalizing SPIONs with diethylenetriaminepentaacetic acid (DTPA) and a novel C-peptide derived from endostatin, aimed at improved tumor targeting. This C-peptide targets integrin αv receptors, prominently overexpressed in breast cancer cells, enhancing specificity and imaging efficacy. The SPION-DTPA-C-peptide provided precise MRI capabilities and significantly inhibited cell viability and migration in vitro (p < 0.01). The DTPA coating also facilitates the chelation of technetium-99m (99mTc), allowing dual-modality imaging with SPECT. Comprehensive characterization via XRD, EDX, TEM, FT-IR, and VSM confirmed successful synthesis, functionalization, spherical morphology, optimal size, and superparamagnetic characteristics. In vitro studies demonstrated selective targeting of 4T1 mammary carcinoma cells by SPION-DTPA-C-Peptide, exerting cytotoxic effects and inhibiting cell migration. In vivo imaging in Balb-c mice bearing 4T1 xenograft tumors showed enhanced tumor targeting and contrast on both MRI and SPECT modalities. These findings highlight the potential of the SPION-DTPA-C-Peptide system for targeted cancer imaging, offering a promising strategy for integrated MRI and SPECT in cancer diagnosis and management.
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Affiliation(s)
- Mohsen Mahdavimehr
- Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran
| | - Tahereh Rahdari
- Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran
| | - Nasser Nikfarjam
- Department of Chemistry, Institute for Advanced Studies in Basic Sciences (IASBS), Zanjan, Iran
| | - Somayeh Ehtesham
- Department of Biology, Parand Branch, Islamic Azad University, Parand, Iran
| | - Mehdi Shafiee Ardestani
- Department of Radiopharmacy, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran; Research Center for Molecular Medicine, Shariati Hospital, North Kargar Ave., Tehran, Iran
| | - S Mohsen Asghari
- Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran.
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2
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Isogai T, Hirosawa KM, Kanno M, Sho A, Kasai RS, Komura N, Ando H, Furukawa K, Ohmi Y, Furukawa K, Yokota Y, Suzuki KG. Extracellular vesicles adhere to cells primarily by interactions of integrins and GM1 with laminin. J Cell Biol 2025; 224:e202404064. [PMID: 40304687 PMCID: PMC12042775 DOI: 10.1083/jcb.202404064] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2024] [Revised: 12/09/2024] [Accepted: 03/11/2025] [Indexed: 05/02/2025] Open
Abstract
Tumor-derived extracellular vesicles (EVs) have attracted significant attention, yet the molecular mechanisms that govern their specific binding to recipient cells remain elusive. Our in vitro study utilizing single-particle tracking demonstrated that integrin heterodimers comprising α6β4 and α6β1 and ganglioside, GM1, are responsible for the binding of small EV (sEV) subtypes to laminin. EVs derived from four distinct tumor cell lines, regardless of size, exhibited high binding affinities for laminin but not for fibronectin, although fibronectin receptors are abundant in EVs and have functional roles in EV-secreting cells. Our findings revealed that integrins in EVs bind to laminin via the conventional molecular interface, facilitated by CD151 rather than by inside-out signaling of talin-1 and kindlin-2. Super-resolution movie observation revealed that sEV integrins bind only to laminin on living recipient cells. Furthermore, sEVs bound to HUVEC and induced cell branching morphogenesis in a laminin-dependent manner. Thus, we demonstrated that EVs predominantly bind to laminin on recipient cells, which is indispensable for cell responses.
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Affiliation(s)
- Tatsuki Isogai
- The United Graduate School of Agricultural Science, Gifu University, Gifu, Japan
| | | | - Miki Kanno
- Graduate School of Natural Science and Technology, Gifu University, Gifu, Japan
| | - Ayano Sho
- Faculty of Applied Biological Sciences, Gifu University, Gifu, Japan
| | - Rinshi S. Kasai
- Division of Advanced Bioimaging, National Cancer Center Research Institute (NCCRI), Tokyo, Japan
| | - Naoko Komura
- Institute for Glyco-core Research (iGCORE), Gifu University, Gifu, Japan
| | - Hiromune Ando
- The United Graduate School of Agricultural Science, Gifu University, Gifu, Japan
- Institute for Glyco-core Research (iGCORE), Gifu University, Gifu, Japan
- Graduate School of Natural Science and Technology, Gifu University, Gifu, Japan
- Faculty of Applied Biological Sciences, Gifu University, Gifu, Japan
- Innovation Research Center for Quantum Medicine, Graduate School of Medicine, Gifu University, Gifu, Japan
| | - Keiko Furukawa
- Department of Biomedical Sciences, Chubu University, Kasugai, Japan
| | - Yuhsuke Ohmi
- Department of Biomedical Sciences, Chubu University, Kasugai, Japan
| | - Koichi Furukawa
- Department of Biomedical Sciences, Chubu University, Kasugai, Japan
| | - Yasunari Yokota
- Department of Information Science, Faculty of Engineering, Gifu University, Gifu, Japan
| | - Kenichi G.N. Suzuki
- The United Graduate School of Agricultural Science, Gifu University, Gifu, Japan
- Institute for Glyco-core Research (iGCORE), Gifu University, Gifu, Japan
- Graduate School of Natural Science and Technology, Gifu University, Gifu, Japan
- Faculty of Applied Biological Sciences, Gifu University, Gifu, Japan
- Division of Advanced Bioimaging, National Cancer Center Research Institute (NCCRI), Tokyo, Japan
- Innovation Research Center for Quantum Medicine, Graduate School of Medicine, Gifu University, Gifu, Japan
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3
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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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4
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Li F, Song L, He Y, Chen P, Wang J, Zeng M, Li C, Chen J, Chen H, Guo Q, Fan J, Huang X, Wang Q, Zhang Q. FLT1-enriched extracellular vesicles induce a positive feedback loop between nasopharyngeal carcinoma cells and endothelial cells to promote angiogenesis and tumour metastasis. Oncogene 2025:10.1038/s41388-025-03389-x. [PMID: 40223024 DOI: 10.1038/s41388-025-03389-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2024] [Revised: 03/29/2025] [Accepted: 04/01/2025] [Indexed: 04/15/2025]
Abstract
Distant metastasis is one of the main reasons for treatment failure in nasopharyngeal carcinoma (NPC) patients. Tumour angiogenesis is a key basis for the distant metastasis of NPC. However, the molecular mechanisms underlying the mutual interaction between endothelial and NPC cells in tumour angiogenesis and NPC metastasis are still unclear. Here, we found that extracellular vesicles (EVs) mediate intercellular communication between endothelial cells and NPC cells, thereby promoting NPC cell migration, invasion, colony formation, and angiogenesis. Further experiments indicated that EV-mediated information exchange between endothelial cells and NPC cells upregulated the expression of the vascular endothelial growth factor receptor FLT1 in both types of cells. Mechanistically, FLT1-enriched EVs promoted NPC metastasis through the PI3K/AKT pathway and increased tumour angiogenesis, tumour growth, and distant lung and liver metastasis of NPC in xenografted mice. This effect was achieved through the delivery and upregulation of FLT1 in both endothelial and NPC cells. Thus, our findings reveal that FLT1-enriched EVs induce a positive feedback loop between NPC cells and endothelial cells to promote tumour angiogenesis and tumour metastasis. These results increase our understanding of the intricate interplay between tumour angiogenesis and distant metastasis and have major implications for the diagnosis and management of NPC patients with increased levels of FLT1-enriched EVs.
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Affiliation(s)
- Fei Li
- State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China
| | - Lin Song
- School of Life Sciences, Huizhou University, Huizhou, China
| | - Yue He
- State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China
| | - Peiling Chen
- State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China
| | - Jiasheng Wang
- State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China
| | - Maozhen Zeng
- State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China
| | - Chunmou Li
- The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
| | - Junru Chen
- State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China
| | - Haisheng Chen
- State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China
| | - Qiqi Guo
- State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China
| | - Jiaxi Fan
- State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China
| | - Xuan Huang
- State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China
| | - Qi Wang
- State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China
| | - Qing Zhang
- State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China.
- Research Institute of Sun Yat-sen University in Shenzhen, Shenzhen, China.
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5
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Huilcaman R, Campos A, Contreras P, Simón L, Varas-Godoy M, Grünenwald F, Shao B, Heinecke J, Lobos-Gonzalez L, Leyton L, Quest AFG. Inclusion of ΑVβ3 integrin into extracellular vesicles in a caveolin-1 tyrosine-14- phosphorylation dependent manner and subsequent transfer to recipient melanoma cells promotes migration, invasion and metastasis. Cell Commun Signal 2025; 23:139. [PMID: 40098186 PMCID: PMC11912626 DOI: 10.1186/s12964-025-02131-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2024] [Accepted: 02/26/2025] [Indexed: 03/19/2025] Open
Abstract
Caveolin-1 (CAV1) is a membrane protein that promotes migration, invasion and metastasis of cancer cells when phosphorylated on tyrosine-14 (Y14) by a cell intrinsic mechanism involving the activation of a novel Rab5-Rac1 signaling axis. Moreover, CAV1 expressed in aggressive cancer cells is included into extracellular vesicles (EVs) and such EVs increase the metastatic potential of recipient lower grade cancer cells. However, the relevance of CAV1 Y14 phosphorylation in these extrinsic EV-stimulated events remained to be determined. Here we used B16F10 mouse melanoma cells over-expressing wild-type CAV1, phospho-mimetic CAV1(Y14E) or phospho-null CAV1(Y14F) as models to determine how the EV protein content was affected by Y14 phosphorylation and how these EVs modulated the metastatic potential of recipient B16F10 cells lacking CAV1. EVs from B16F10 cells over-expressing wild-type and CAV1(Y14/E) contain CAV1, and other proteins linked to signaling pathways associated with cell adhesion and migration. CAV1 inclusion in EVs was reduced by the Y14F mutation and global protein composition was also significantly different. Moreover, CAV1 wild-type and CAV1(Y14E) EVs promoted migration, as well as invasion of cells lacking CAV1 [B16F10(Mock) cells]. In addition, β3 integrin was transferred via CAV1(Y14E) EVs to B16F10 (Mock) cells, and treatment with such EVs promoted metastasis of recipient B16F10(Mock) cells. Finally, CAV1(Y14E) EV-enhanced migration, invasion and metastasis of recipient cells was blocked by anti-αVβ3 antibodies. In conclusion, CAV1 phosphorylated on Y14 not only intrinsically promotes migration, invasion and metastasis of cells expressing the protein (in cis), but also favors the inclusion of CAV1 into EVs, as well as the extrinsic acquisition of malignant traits in recipient cells, through integrin transfer (in trans).
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Grants
- FONDECYT grants 1210644 (A.F.G.Q.), 1200836, 1240888 (L.L.), 1211223 (L.L.-G.), 1190928 (M.V.G.), FONDAP grants 15130011 and 1523A0008 (A.F.G.Q., L.L., L.L.-G., M.V.G.), ANID/BASAL/FB210008 (M.V.G.), ANID postdoctoral fellowship award Becas Chile (A.C.), 3170169 (J.D.), ANID PhD fellowship awards 21130102 (AC), 21161246 (R.H.). FONDECYT, FONDAP, ANID/BASAL/, ANID postdoctoral fellowship award Becas Chile, ANID PhD fellowship awards
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Affiliation(s)
- R Huilcaman
- Cellular Communication Laboratory, Center for Studies on Exercise, Metabolism and Cancer (CEMC), Institute of Biomedical Sciences (ICBM), Faculty of Medicine, University of Chile, Santiago, Chile
- Advanced Center for Chronic Diseases (ACCDiS), Faculty of Medicine, University of Chile, Santiago, Chile
- Facultad de Ciencias de la Salud, Escuela de Tecnología Médica, Universidad Bernardo OHiggins, General Gana 1702, Santiago, 8370854, Chile
| | - A Campos
- Cellular Communication Laboratory, Center for Studies on Exercise, Metabolism and Cancer (CEMC), Institute of Biomedical Sciences (ICBM), Faculty of Medicine, University of Chile, Santiago, Chile
- Advanced Center for Chronic Diseases (ACCDiS), Faculty of Medicine, University of Chile, Santiago, Chile
- Cancer Research UK Scotland Institute, Garscube Estate. Switchback Road, Bearsden, Glasgow, G61 1BD, UK
| | - P Contreras
- Cellular Communication Laboratory, Center for Studies on Exercise, Metabolism and Cancer (CEMC), Institute of Biomedical Sciences (ICBM), Faculty of Medicine, University of Chile, Santiago, Chile
| | - L Simón
- Cellular Communication Laboratory, Center for Studies on Exercise, Metabolism and Cancer (CEMC), Institute of Biomedical Sciences (ICBM), Faculty of Medicine, University of Chile, Santiago, Chile
- Advanced Center for Chronic Diseases (ACCDiS), Faculty of Medicine, University of Chile, Santiago, Chile
- Nutrition and Dietetic School, Universidad Finis Terrae, Santiago, Chile
| | - M Varas-Godoy
- Advanced Center for Chronic Diseases (ACCDiS), Faculty of Medicine, University of Chile, Santiago, Chile
- Centro de Biología Celular y Biomedicina (CEBICEM), Facultad de Medicina y Ciencia, Universidad San Sebastián, Providencia, Santiago, 7510156, Chile
- Centro Científico y Tecnológico de Excelencia Ciencia & Vida, Fundación Ciencia & Vida, Huechuraba, Santiago, 8580702, Chile
| | - F Grünenwald
- Laboratory of Reproductive Biology, Center for Biomedical Research, Faculty of Medicine, Universidad de Los Andes, Santiago, Chile
| | - Baohai Shao
- Division of Metabolism, Endocrinology and Nutrition, University of Washington, Seattle, WA, 98195- 8055, USA
| | - Jay Heinecke
- Division of Metabolism, Endocrinology and Nutrition, University of Washington, Seattle, WA, 98195- 8055, USA
| | - L Lobos-Gonzalez
- Cellular Communication Laboratory, Center for Studies on Exercise, Metabolism and Cancer (CEMC), Institute of Biomedical Sciences (ICBM), Faculty of Medicine, University of Chile, Santiago, Chile
- Advanced Center for Chronic Diseases (ACCDiS), Faculty of Medicine, University of Chile, Santiago, Chile
| | - L Leyton
- Cellular Communication Laboratory, Center for Studies on Exercise, Metabolism and Cancer (CEMC), Institute of Biomedical Sciences (ICBM), Faculty of Medicine, University of Chile, Santiago, Chile.
- Advanced Center for Chronic Diseases (ACCDiS), Faculty of Medicine, University of Chile, Santiago, Chile.
| | - A F G Quest
- Cellular Communication Laboratory, Center for Studies on Exercise, Metabolism and Cancer (CEMC), Institute of Biomedical Sciences (ICBM), Faculty of Medicine, University of Chile, Santiago, Chile.
- Advanced Center for Chronic Diseases (ACCDiS), Faculty of Medicine, University of Chile, Santiago, Chile.
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6
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López RR, Ben El Khyat CZ, Chen Y, Tsering T, Dickinson K, Bustamante P, Erzingatzian A, Bartolomucci A, Ferrier ST, Douanne N, Mounier C, Stiharu I, Nerguizian V, Burnier JV. A synthetic model of bioinspired liposomes to study cancer-cell derived extracellular vesicles and their uptake by recipient cells. Sci Rep 2025; 15:8430. [PMID: 40069225 PMCID: PMC11897354 DOI: 10.1038/s41598-025-91873-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2024] [Accepted: 02/24/2025] [Indexed: 03/15/2025] Open
Abstract
Extracellular vesicles (EVs) are secreted by most cell types and play a central role in cell-cell communication. These naturally occurring nanoparticles have been particularly implicated in cancer, but EV heterogeneity and lengthy isolation methods with low yield make them difficult to study. To circumvent the challenges in EV research, we aimed to develop a unique synthetic model by engineering bioinspired liposomes to study EV properties and their impact on cellular uptake. We produced EV-like liposomes mimicking the physicochemical properties as cancer EVs. First, using a panel of cancer and non-cancer cell lines, small EVs were isolated by ultracentrifugation and characterized by dynamic light scattering (DLS) and nanoparticle tracking analysis (NTA). Cancer EVs ranged in mean size from 107.9 to 161 nm by NTA, hydrodynamic diameter from 152 to 355 nm by DLS, with a zeta potential ranging from - 25 to -6 mV. EV markers TSG101 and CD81 were positive on all EVs. Using a microfluidics bottom-up approach, liposomes were produced using the nanoprecipitation method adapted to micromixers developed by our group. A library of liposome formulations was created that mimicked the ranges of size (90-222 nm) and zeta potential (anionic [-47 mV] to neutral [-1 mV]) at a production throughput of up to 41 mL/h and yielding a concentration of 1 × 1012 particles per mL. EV size and zeta potential were reproduced by controlling the flow conditions and lipid composition set by a statistical model based on the response surface methodology. The model was fairly accurate with an R-squared > 70% for both parameters between the targeted EV and the obtained liposomes. Finally, the internalization of fluorescently labeled EV-like liposomes was assessed by confocal microscopy and flow cytometry, and correlated with decreasing liposome size and less negative zeta potential, providing insights into the effects of key EV physicochemical properties. Our data demonstrated that liposomes can be used as a powerful synthetic model of EVs. By mimicking cancer cell-derived EV properties, the effects on cellular internalization can be assessed individually and in combination. Taken together, we present a novel system that can accelerate research on the effects of EVs in cancer models.
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Affiliation(s)
- Rubén R López
- Cancer Research Program, Research Institute of the McGill University Health Centre, 1001 Decarie Blvd, Montreal, QC, H4A 3J1, Canada
- Department of Pathology, McGill University, Quebec, Canada
- Department of Electrical Engineering, École de Technologie supérieure, 1100 Notre Dame West, Montreal, QC, H3C 1K3, Canada
| | - Chaymaa Zouggari Ben El Khyat
- Department of Electrical Engineering, École de Technologie supérieure, 1100 Notre Dame West, Montreal, QC, H3C 1K3, Canada
| | - Yunxi Chen
- Cancer Research Program, Research Institute of the McGill University Health Centre, 1001 Decarie Blvd, Montreal, QC, H4A 3J1, Canada
- Department of Pathology, McGill University, Quebec, Canada
| | - Thupten Tsering
- Cancer Research Program, Research Institute of the McGill University Health Centre, 1001 Decarie Blvd, Montreal, QC, H4A 3J1, Canada
- Department of Pathology, McGill University, Quebec, Canada
| | - Kyle Dickinson
- Cancer Research Program, Research Institute of the McGill University Health Centre, 1001 Decarie Blvd, Montreal, QC, H4A 3J1, Canada
| | - Prisca Bustamante
- Cancer Research Program, Research Institute of the McGill University Health Centre, 1001 Decarie Blvd, Montreal, QC, H4A 3J1, Canada
- Department of Pathology, McGill University, Quebec, Canada
| | - Armen Erzingatzian
- Cancer Research Program, Research Institute of the McGill University Health Centre, 1001 Decarie Blvd, Montreal, QC, H4A 3J1, Canada
| | - Alexandra Bartolomucci
- Cancer Research Program, Research Institute of the McGill University Health Centre, 1001 Decarie Blvd, Montreal, QC, H4A 3J1, Canada
- Department of Pathology, McGill University, Quebec, Canada
| | - Sarah Tadhg Ferrier
- Cancer Research Program, Research Institute of the McGill University Health Centre, 1001 Decarie Blvd, Montreal, QC, H4A 3J1, Canada
- Department of Pathology, McGill University, Quebec, Canada
| | - Noélie Douanne
- Cancer Research Program, Research Institute of the McGill University Health Centre, 1001 Decarie Blvd, Montreal, QC, H4A 3J1, Canada
- Department of Pathology, McGill University, Quebec, Canada
| | - Catherine Mounier
- Department of biological sciences, Université du Québec à Montréal, 141 avenue du président Kennedy, Montreal, QC, H2X 1Y4, Canada
- Department of Mechanical, Industrial and Aerospace Engineering, Concordia University, 1455 de Maisonneuve Blvd. West, Montreal, QC, H3G 1M8, Canada
| | - Ion Stiharu
- Gerald Bronfman Department of Oncology, McGill University, 5100 de Maisonneuve Blvd. West, Montreal, QC, H4A 3T2, Canada
| | - Vahé Nerguizian
- Department of Electrical Engineering, École de Technologie supérieure, 1100 Notre Dame West, Montreal, QC, H3C 1K3, Canada
| | - Julia V Burnier
- Cancer Research Program, Research Institute of the McGill University Health Centre, 1001 Decarie Blvd, Montreal, QC, H4A 3J1, Canada.
- Department of Pathology, McGill University, Quebec, Canada.
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7
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Huang Q, Wang J, Ning H, Liu W, Han X. Integrin β1 in breast cancer: mechanisms of progression and therapy. Breast Cancer 2025; 32:43-59. [PMID: 39343856 DOI: 10.1007/s12282-024-01635-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2024] [Accepted: 09/17/2024] [Indexed: 10/01/2024]
Abstract
The therapy for breast cancer (BC), to date, still needs improvement. Apart from traditional therapy methods, biological therapy being explored opens up a novel avenue for BC patients. Integrin β1 (ITGβ1), one of the largest subgroups in integrin family, is a key player in cancer evolution and therapy. Recent researches progress in the relationship of ITGβ1 level and BC, finding that ITGβ1 expression evidently concerns BC progression. In this chapter, we outline diverse ITGβ1-based mechanisms regarding to the promoted effect of ITGβ1 on BC cell structure rearrangement and malignant phenotype behaviors, the unfavorable patient prognosis conferred by ITGβ1, BC therapy tolerance induced by ITGβ1, and lastly novel inhibitors targeting ITGβ1 for BC therapy. As an effective biomarker, ITGβ1 undoubtedly emerges one of targeted-therapy opportunities of BC patients in future. It is a necessity focusing on scientific and large-scale clinical trials on the validation of targeted-ITGβ1 drugs for BC patients.
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Affiliation(s)
- Qionglian Huang
- Institute of Chinese Traditional Surgery, Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jue Wang
- Institute of Chinese Traditional Surgery, Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Hanjuan Ning
- Institute of Chinese Traditional Surgery, Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Weiwei Liu
- Institute of Chinese Traditional Surgery, Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Xianghui Han
- Institute of Chinese Traditional Surgery, Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China.
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8
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Zhan T, Zou Y, Han Z, Tian X, Chen M, Liu J, Yang X, Zhu Q, Liu M, Chen W, Chen M, Huang X, Tan J, Liu W, Tian X. Single-cell sequencing combined with spatial transcriptomics reveals that the IRF7 gene in M1 macrophages inhibits the occurrence of pancreatic cancer by regulating lipid metabolism-related mechanisms. Clin Transl Med 2024; 14:e1799. [PMID: 39118300 PMCID: PMC11310283 DOI: 10.1002/ctm2.1799] [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: 07/24/2024] [Revised: 07/24/2024] [Accepted: 07/26/2024] [Indexed: 08/10/2024] Open
Abstract
AIM The main focus of this study is to explore the molecular mechanism of IRF7 regulation on RPS18 transcription in M1-type macrophages in pancreatic adenocarcinoma (PAAD) tissue, as well as the transfer of RPS18 by IRF7 via exosomes to PAAD cells and the regulation of ILF3 expression. METHODS By utilising single-cell RNA sequencing (scRNA-seq) data and spatial transcriptomics (ST) data from the Gene Expression Omnibus database, we identified distinct cell types with significant expression differences in PAAD tissue. Among these cell types, we identified those closely associated with lipid metabolism. The differentially expressed genes within these cell types were analysed, and target genes relevant to prognosis were identified. Flow cytometry was employed to assess the expression levels of target genes in M1 and M2 macrophages. Cell lines with target gene knockout were constructed using CRISPR/Cas9 editing technology, and cell lines with target gene knockdown and overexpression were established using lentiviral vectors. Additionally, a co-culture model of exosomes derived from M1 macrophages with PAAD cells was developed. The impact of M1 macrophage-derived exosomes on the lipid metabolism of PAAD cells in the model was evaluated through metabolomics analysis. The effects of M1 macrophage-derived exosomes on the viability, proliferation, division, migration and apoptosis of PAAD cells were assessed using MTT assay, flow cytometry, EdU assay, wound healing assay, Transwell assay and TUNEL staining. Furthermore, a mouse PAAD orthotopic implantation model was established, and bioluminescence imaging was utilised to assess the influence of M1 macrophage-derived exosomes on the intratumoural formation capacity of PAAD cells, as well as measuring tumour weight and volume. The expression of proliferation-associated proteins in tumour tissues was examined using immunohistochemistry. RESULTS Through combined analysis of scRNA-seq and ST technologies, we discovered a close association between M1 macrophages in PAAD samples and lipid metabolism signals, as well as a negative correlation between M1 macrophages and cancer cells. The construction of a prognostic risk score model identified RPS18 and IRF7 as two prognostically relevant genes in M1 macrophages, exhibiting negative and positive correlations, respectively. Mechanistically, it was found that IRF7 in M1 macrophages can inhibit the transcription of RPS18, reducing the transfer of RPS18 to PAAD cells via exosomes, consequently affecting the expression of ILF3 in PAAD cells. IRF7/RPS18 in M1 macrophages can also suppress lipid metabolism, cell viability, proliferation, migration, invasion and intratumoural formation capacity of PAAD cells, while promoting cell apoptosis. CONCLUSION Overexpression of IRF7 in M1 macrophages may inhibit RPS18 transcription, reduce the transfer of RPS18 from M1 macrophage-derived exosomes to PAAD cells, thereby suppressing ILF3 expression in PAAD cells, inhibiting the lipid metabolism pathway, and curtailing the viability, proliferation, migration, invasion of PAAD cells, as well as enhancing cell apoptosis, ultimately inhibiting tumour formation in PAAD cells in vivo. Targeting IRF7/RPS18 in M1 macrophages could represent a promising immunotherapeutic approach for PAAD in the future.
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Affiliation(s)
- Ting Zhan
- Department of GastroenterologyWuHan Third Hospital (Tongren Hospital of WuHan University)WuhanChina
| | - Yanli Zou
- Department of GastroenterologyWuHan Third Hospital (Tongren Hospital of WuHan University)WuhanChina
| | - Zheng Han
- Department of GastroenterologyWuHan Third Hospital (Tongren Hospital of WuHan University)WuhanChina
| | - XiaoRong Tian
- Department of GastroenterologyWuHan Third Hospital (Tongren Hospital of WuHan University)WuhanChina
- Department of GastroenterologyZhongnan Hospital of Wuhan UniversityWuhanChina
| | - Mengge Chen
- Department of GastroenterologyWuHan Third Hospital (Tongren Hospital of WuHan University)WuhanChina
- Department of GastroenterologyZhongnan Hospital of Wuhan UniversityWuhanChina
| | - Jiaxi Liu
- Department of GastroenterologyWuHan Third Hospital (Tongren Hospital of WuHan University)WuhanChina
- Department of GastroenterologyZhongnan Hospital of Wuhan UniversityWuhanChina
| | - Xiulin Yang
- Department of GastroenterologyWuHan Third Hospital (Tongren Hospital of WuHan University)WuhanChina
- Department of GastroenterologyZhongnan Hospital of Wuhan UniversityWuhanChina
| | - Qingxi Zhu
- Department of GastroenterologyWuHan Third Hospital (Tongren Hospital of WuHan University)WuhanChina
| | - Meng Liu
- Department of GastroenterologyWuHan Third Hospital (Tongren Hospital of WuHan University)WuhanChina
| | - Wei Chen
- Department of GastroenterologyWuHan Third Hospital (Tongren Hospital of WuHan University)WuhanChina
| | - Mingtao Chen
- Department of GastroenterologyWuHan Third Hospital (Tongren Hospital of WuHan University)WuhanChina
| | - Xiaodong Huang
- Department of GastroenterologyWuHan Third Hospital (Tongren Hospital of WuHan University)WuhanChina
- Department of GastroenterologyZhongnan Hospital of Wuhan UniversityWuhanChina
| | - Jie Tan
- Department of GastroenterologyWuHan Third Hospital (Tongren Hospital of WuHan University)WuhanChina
| | - Weijie Liu
- Department of GastroenterologyWuHan Third Hospital (Tongren Hospital of WuHan University)WuhanChina
| | - Xia Tian
- Department of GastroenterologyWuHan Third Hospital (Tongren Hospital of WuHan University)WuhanChina
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9
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Chen JY, Li JD, He RQ, Huang ZG, Chen G, Zou W. Bibliometric analysis of phosphoglycerate kinase 1 expression in breast cancer and its distinct upregulation in triple-negative breast cancer. World J Clin Oncol 2024; 15:867-894. [PMID: 39071464 PMCID: PMC11271732 DOI: 10.5306/wjco.v15.i7.867] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2024] [Revised: 05/27/2024] [Accepted: 06/24/2024] [Indexed: 07/16/2024] Open
Abstract
BACKGROUND Phosphoglycerate kinase 1 (PGK1) has been identified as a possible biomarker for breast cancer (BC) and may play a role in the development and advancement of triple-negative BC (TNBC). AIM To explore the PGK1 and BC research status and PGK1 expression and mechanism differences among TNBC, non-TNBC, and normal breast tissue. METHODS PGK1 and BC related literature was downloaded from Web of Science Core Collection Core Collection. Publication counts, key-word frequency, cooperation networks, and theme trends were analyzed. Normal breast, TNBC, and non-TNBC mRNA data were gathered, and differentially expressed genes obtained. Area under the summary receiver operating characteristic curves, sensitivity and specificity of PGK1 expression were determined. Kaplan Meier revealed PGK1's prognostic implication. PGK1 co-expressed genes were explored, and Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and Disease Ontology applied. Protein-protein interaction networks were constructed. Hub genes identified. RESULTS PGK1 and BC related publications have surged since 2020, with China leading the way. The most frequent keyword was "Expression". Collaborative networks were found among co-citations, countries, institutions, and authors. PGK1 expression and BC progression were research hotspots, and PGK1 expression and BC survival were research frontiers. In 16 TNBC vs non-cancerous breast and 15 TNBC vs non-TNBC datasets, PGK1 mRNA levels were higher in 1159 TNBC than 1205 non-cancerous breast cases [standardized mean differences (SMD): 0.85, 95% confidence interval (95%CI): 0.54-1.16, I² = 86%, P < 0.001]. PGK1 expression was higher in 1520 TNBC than 7072 non-TNBC cases (SMD: 0.25, 95%CI: 0.03-0.47, I² = 91%, P = 0.02). Recurrence free survival was lower in PGK1-high-expression than PGK1-low-expression group (hazard ratio: 1.282, P = 0.023). PGK1 co-expressed genes were concentrated in ATP metabolic process, HIF-1 signaling, and glycolysis/gluconeogenesis pathways. CONCLUSION PGK1 expression is a research hotspot and frontier direction in the BC field. PGK1 may play a strong role in promoting cancer in TNBC by mediating metabolism and HIF-1 signaling pathways.
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Affiliation(s)
- Jing-Yu Chen
- Department of Pathology, First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Jian-Di Li
- Department of Pathology, First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Rong-Quan He
- Department of Medical Oncology, First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Zhi-Guang Huang
- Department of Pathology, First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Gang Chen
- Department of Pathology, First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Wen Zou
- Department of Pathology, First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
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10
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Abdul-Rahman T, Roy P, Herrera-Calderón RE, Khidri FF, Omotesho QA, Rumide TS, Fatima M, Roy S, Wireko AA, Atallah O, Roy S, Amekpor F, Ghosh S, Agyigra IA, Horbas V, Teslyk T, Bumeister V, Papadakis M, Alexiou A. Extracellular vesicle-mediated drug delivery in breast cancer theranostics. Discov Oncol 2024; 15:181. [PMID: 38780753 PMCID: PMC11116322 DOI: 10.1007/s12672-024-01007-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2024] [Accepted: 05/03/2024] [Indexed: 05/25/2024] Open
Abstract
Breast cancer (BC) continues to be a significant global challenge due to drug resistance and severe side effects. The increasing prevalence is alarming, requiring new therapeutic approaches to address these challenges. At this point, Extracellular vesicles (EVs), specifically small endosome-released nanometer-sized EVs (SEVs) or exosomes, have been explored by literature as potential theranostics. Therefore, this review aims to highlight the therapeutic potential of exosomes in BC, focusing on their advantages in drug delivery and their ability to mitigate metastasis. Following the review, we identified exosomes' potential in combination therapies, serving as miRNA carriers and contributing to improved anti-tumor effects. This is evident in clinical trials investigating exosomes in BC, which have shown their ability to boost chemotherapy efficacy by delivering drugs like paclitaxel (PTX) and doxorubicin (DOX). However, the translation of EVs into BC therapy is hindered by various challenges. These challenges include the heterogeneity of EVs, the selection of the appropriate parent cell, the loading procedures, and determining the optimal administration routes. Despite the promising therapeutic potential of EVs, these obstacles must be addressed to realize their benefits in BC treatment.
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Affiliation(s)
| | - Poulami Roy
- Department of Medicine, North Bengal Medical College and Hospital, Siliguri, India
| | - Ranferi Eduardo Herrera-Calderón
- Center for Research in Health Sciences (CICSA), Faculty of Medicine, Anahuac University North Campus, 52786, Huixquilucan, Mexico
| | | | | | | | | | - Sakshi Roy
- School of Medicine, Queens University Belfast, Northern Ireland, UK
| | | | - Oday Atallah
- Department of Neurosurgery, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625, Hannover, Germany
| | - Subham Roy
- Hull York Medical School, University of York, York, UK
| | - Felix Amekpor
- Noguchi Memorial Institute for Medical Research, University of Ghana, Accra, Ghana
| | - Shankhaneel Ghosh
- Institute of Medical Sciences and SUM Hospital, Siksha 'O' Anusandhan, Bhubaneswar, India
| | | | | | | | | | - Marios Papadakis
- Department of Surgery II, University Hospital Witten-Herdecke, Heusnerstrasse 40, University of Witten-Herdecke, 42283, Wuppertal, Germany.
| | - Athanasios Alexiou
- University Centre for Research and Development, Chandigarh University, Chandigarh-Ludhiana Highway, Mohali, Punjab, India.
- Department of Research and Development, Funogen, 11741, Athens, Greece.
- Department of Research and Development, AFNP Med, 1030, Vienna, Austria.
- Department of Science and Engineering, Novel Global Community Educational Foundation, Hebersham, NSW, 2770, Australia.
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11
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Souchak J, Mohammed NBB, Lau LS, Dimitroff CJ. The role of galectins in mediating the adhesion of circulating cells to vascular endothelium. Front Immunol 2024; 15:1395714. [PMID: 38840921 PMCID: PMC11150550 DOI: 10.3389/fimmu.2024.1395714] [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: 03/04/2024] [Accepted: 05/03/2024] [Indexed: 06/07/2024] Open
Abstract
Vascular cell adhesion is a complex orchestration of events that commonly feature lectin-ligand interactions between circulating cells, such as immune, stem, and tumor cells, and endothelial cells (ECs) lining post-capillary venules. Characteristically, circulating cell adherence to the vasculature endothelium is initiated through interactions between surface sialo-fucosylated glycoprotein ligands and lectins, specifically platelet (P)- or endothelial (E)-selectin on ECs or between leukocyte (L)-selectin on circulating leukocytes and L-selectin ligands on ECs, culminating in circulating cell extravasation. This lectin-ligand interplay enables the migration of immune cells into specific tissue sites to help maintain effective immunosurveillance and inflammation control, the homing of stem cells to bone marrow or tissues in need of repair, and, unfortunately, in some cases, the dissemination of circulating tumor cells (CTCs) to distant metastatic sites. Interestingly, there is a growing body of evidence showing that the family of β-galactoside-binding lectins, known as galectins, can also play pivotal roles in the adhesion of circulating cells to the vascular endothelium. In this review, we present contemporary knowledge on the significant roles of host- and/or tumor-derived galectin (Gal)-3, -8, and -9 in facilitating the adhesion of circulating cells to the vascular endothelium either directly by acting as bridging molecules or indirectly by triggering signaling pathways to express adhesion molecules on ECs. We also explore strategies for interfering with galectin-mediated adhesion to attenuate inflammation or hinder the metastatic seeding of CTCs, which are often rich in galectins and/or their glycan ligands.
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Affiliation(s)
- Joseph Souchak
- Department of Cellular and Molecular Medicine, Herbert Wertheim College of Medicine, Florida International University, Miami, FL, United States
| | - Norhan B. B. Mohammed
- Department of Cellular and Molecular Medicine, Herbert Wertheim College of Medicine, Florida International University, Miami, FL, United States
- Department of Medical Biochemistry, Faculty of Medicine, South Valley University, Qena, Egypt
| | - Lee Seng Lau
- Department of Cellular and Molecular Medicine, Herbert Wertheim College of Medicine, Florida International University, Miami, FL, United States
| | - Charles J. Dimitroff
- Department of Cellular and Molecular Medicine, Herbert Wertheim College of Medicine, Florida International University, Miami, FL, United States
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12
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Ancona P, Trentini A, Terrazzan A, Grassilli S, Navals P, Gates EWJ, Rosta V, Cervellati C, Bergamini CM, Pignatelli A, Keillor JW, Taccioli C, Bianchi N. Transcriptomics Studies Reveal Functions of Transglutaminase 2 in Breast Cancer Cells Using Membrane Permeable and Impermeable Inhibitors. J Mol Biol 2024; 436:168569. [PMID: 38604527 DOI: 10.1016/j.jmb.2024.168569] [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: 12/28/2023] [Revised: 04/02/2024] [Accepted: 04/05/2024] [Indexed: 04/13/2024]
Abstract
Transglutaminase 2 (TG2) performs many functions both under physiological and pathological conditions. In cancer, its expression is associated with aggressiveness, propensity to epithelial-mesenchymal transition, and metastasis. Since TG2 performs key functions both outside and inside the cell, using inhibitors with different membrane permeability we analyzed the changes in the transcriptome induced in two triple-negative cell lines (MDA-MB-436 and MDA-MB-231) with aggressive features. By characterizing pathways and gene networks, we were able to define the effects of TG2 inhibitors (AA9, membrane-permeable, and NCEG2, impermeable) in relation to the roles of the enzyme in the intra- and extracellular space within the context of breast cancer. The deregulated genes revealed p53 and integrin signaling to be the common pathways with some genes showing opposite changes in expression. In MDA-MB-436, AA9 induced apoptosis, modulated cadherin, Wnt, gastrin and cholecystokinin receptors (CCKR) mediated signaling, with RHOB and GNG2 playing significant roles, and affected the Warburg effect by decreasing glycolytic enzymes. In MDA-MB-231 cells, AA9 strongly impacted HIF-mediated hypoxia, including AKT and mTOR pathway. These effects suggest an anti-tumor activity by blocking intracellular TG2 functions. Conversely, the use of NCEG2 stimulated the expression of ATP synthase and proteins involved in DNA replication, indicating a potential promotion of cell proliferation through inhibition of extracellular TG2. To effectively utilize these molecules as an anti-tumor strategy, an appropriate delivery system should be evaluated to target specific functions and avoid adverse effects. Additionally, considering combinations with other pathway modulators is crucial.
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Affiliation(s)
- Pietro Ancona
- Department of Translational Medicine, University of Ferrara, 44121 Ferrara, Italy.
| | - Alessandro Trentini
- Department of Environmental Sciences and Prevention, University of Ferrara, Ferrara, Italy.
| | - Anna Terrazzan
- Department of Translational Medicine, University of Ferrara, 44121 Ferrara, Italy.
| | - Silvia Grassilli
- Department of Environmental Sciences and Prevention, University of Ferrara, Ferrara, Italy.
| | - Pauline Navals
- Department of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa, ON K1N 6N5, Canada.
| | - Eric W J Gates
- Department of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa, ON K1N 6N5, Canada.
| | - Valentina Rosta
- Department of Environmental Sciences and Prevention, University of Ferrara, Ferrara, Italy.
| | - Carlo Cervellati
- Department of Translational Medicine, University of Ferrara, 44121 Ferrara, Italy.
| | - Carlo M Bergamini
- Department of Neuroscience and Rehabilitation, University of Ferrara, 44121 Ferrara, Italy.
| | - Angela Pignatelli
- Department of Neuroscience and Rehabilitation, University of Ferrara, 44121 Ferrara, Italy.
| | - Jeffrey W Keillor
- Department of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa, ON K1N 6N5, Canada.
| | - Cristian Taccioli
- Department of Animal Medicine, Production and Health, University of Padua, Padua, Italy.
| | - Nicoletta Bianchi
- Department of Translational Medicine, University of Ferrara, 44121 Ferrara, Italy.
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13
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Su M, Hou Y, Cai S, Li W, Wei Y, Wang R, Wu M, Liu M, Chang J, Yang K, Yiu K, Chen C. Elevated ITGA1 levels in type 2 diabetes: implications for cardiac function impairment. Diabetologia 2024; 67:850-863. [PMID: 38413438 PMCID: PMC10954979 DOI: 10.1007/s00125-024-06109-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2023] [Accepted: 01/04/2024] [Indexed: 02/29/2024]
Abstract
AIMS/HYPOTHESIS Type 2 diabetes mellitus is known to contribute to the development of heart failure with preserved ejection fraction (HFpEF). However, identifying HFpEF in individuals with type 2 diabetes early on is often challenging due to a limited array of biomarkers. This study aims to investigate specific biomarkers associated with the progression of HFpEF in individuals with type 2 diabetes, for the purpose of enabling early detection and more effective management strategies. METHODS Blood samples were collected from individuals with type 2 diabetes, both with and without HFpEF, for proteomic analysis. Plasma integrin α1 (ITGA1) levels were measured and compared between the two groups. Participants were further categorised based on ITGA1 levels and underwent detailed transthoracic echocardiography at baseline and during a median follow-up period of 30 months. Multivariable linear and Cox regression analyses were conducted separately to assess the associations between plasma ITGA1 levels and changes in echocardiography indicators and re-hospitalisation risk. Additionally, proteomic data for the individuals' left ventricles, from ProteomeXchange database, were analysed to uncover mechanisms underlying the change in ITGA1 levels in HFpEF. RESULTS Individuals with type 2 diabetes and HFpEF showed significantly higher plasma ITGA1 levels than the individuals with type 2 diabetes without HFpEF. These elevated ITGA1 levels were associated with left ventricular remodelling and impaired diastolic function. Furthermore, during a median follow-up of 30 months, multivariable analysis revealed that elevated ITGA1 levels independently correlated with deterioration of both diastolic and systolic cardiac functions. Additionally, higher baseline plasma ITGA1 levels independently predicted re-hospitalisation risk (HR 2.331 [95% CI 1.387, 3.917], p=0.001). Proteomic analysis of left ventricular myocardial tissue provided insights into the impact of increased ITGA1 levels on cardiac fibrosis-related pathways and the contribution made by these changes to the development and progression of HFpEF. CONCLUSIONS/INTERPRETATION ITGA1 serves as a biomarker for monitoring cardiac structural and functional damage, can be used to accurately diagnose the presence of HFpEF, and can be used to predict potential deterioration in cardiac structure and function as well as re-hospitalisation for individuals with type 2 diabetes. Its measurement holds promise for facilitating risk stratification and early intervention to mitigate the adverse cardiovascular effects associated with diabetes. DATA AVAILABILITY The proteomic data of left ventricular myocardial tissue from individuals with type 2 diabetes, encompassing both those with and without HFpEF, is available from the ProteomeXchange database at http://proteomecentral.proteomexchange.org .
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Affiliation(s)
- Mengqi Su
- Department of Cardiology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
- Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - Yilin Hou
- Department of Otorhinolaryngology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Sidong Cai
- Department of Cardiology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
| | - Wenpeng Li
- Department of Cardiology, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Yinxia Wei
- Department of Cardiology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
| | - Run Wang
- Department of Cardiology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
| | - Min Wu
- Department of Cardiology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
| | - Mingya Liu
- Department of Cardiology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
| | - Junlei Chang
- Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - Kelaier Yang
- Department of Endocrinology and Metabolism, Shenzhen University General Hospital, Shenzhen, China
| | - Kaihang Yiu
- Department of Cardiology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China.
- Department of Cardiology, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China.
| | - Cong Chen
- Department of Cardiology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China.
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14
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Sun L, Guo S, Xie Y, Yao Y. The characteristics and the multiple functions of integrin β1 in human cancers. J Transl Med 2023; 21:787. [PMID: 37932738 PMCID: PMC10629185 DOI: 10.1186/s12967-023-04696-1] [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: 08/22/2023] [Accepted: 11/02/2023] [Indexed: 11/08/2023] Open
Abstract
Integrins, which consist of two non-covalently linked α and β subunits, play a crucial role in cell-cell adhesion and cell-extracellular matrix (ECM) interactions. Among them, integrin β1 is the most common subunit and has emerged as a key mediator in cancer, influencing various aspects of cancer progression, including cell motility, adhesion, migration, proliferation, differentiation and chemotherapy resistance. However, given the complexity and sometimes contradictory characteristics, targeting integrin β1 for therapeutics has been a challenge. The emerging understanding of the mechanisms regulating by integrin β1 may guide the development of new strategies for anti-cancer therapy. In this review, we summarize the multiple functions of integrin β1 and signaling pathways which underlie the involvement of integrin β1 in several malignant cancers. Our review suggests the possibility of using integrin β1 as a therapeutic target and highlights the need for patient stratification based on expression of different integrin receptors in future clinical studies.
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Affiliation(s)
- Li Sun
- Department of Clinical Laboratory, Kunshan First People's Hospital, Affiliated to Jiangsu University, Kunshan, 215300, People's Republic of China
| | - Shuwei Guo
- Department of Clinical Laboratory, Jiangsu Province Hospital of Chinese Medicine, Nanjing, 210029, People's Republic of China
| | - Yiping Xie
- Department of Clinical Laboratory, Kunshan First People's Hospital, Affiliated to Jiangsu University, Kunshan, 215300, People's Republic of China
| | - Yongliang Yao
- Department of Clinical Laboratory, Kunshan First People's Hospital, Affiliated to Jiangsu University, Kunshan, 215300, People's Republic of China.
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15
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Lin W, Fang J, Wei S, He G, Liu J, Li X, Peng X, Li D, Yang S, Li X, Yang L, Li H. Extracellular vesicle-cell adhesion molecules in tumours: biofunctions and clinical applications. Cell Commun Signal 2023; 21:246. [PMID: 37735659 PMCID: PMC10512615 DOI: 10.1186/s12964-023-01236-8] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2023] [Accepted: 07/18/2023] [Indexed: 09/23/2023] Open
Abstract
Cell adhesion molecule (CAM) is an umbrella term for several families of molecules, including the cadherin family, integrin family, selectin family, immunoglobulin superfamily, and some currently unclassified adhesion molecules. Extracellular vesicles (EVs) are important information mediators in cell-to-cell communication. Recent evidence has confirmed that CAMs transported by EVs interact with recipient cells to influence EV distribution in vivo and regulate multiple cellular processes. This review focuses on the loading of CAMs onto EVs, the roles of CAMs in regulating EV distribution, and the known and possible mechanisms of these actions. Moreover, herein, we summarize the impacts of CAMs transported by EVs to the tumour microenvironment (TME) on the malignant behaviour of tumour cells (proliferation, metastasis, immune escape, and so on). In addition, from the standpoint of clinical applications, the significance and challenges of using of EV-CAMs in the diagnosis and therapy of tumours are discussed. Finally, considering recent advances in the understanding of EV-CAMs, we outline significant challenges in this field that require urgent attention to advance research and promote the clinical applications of EV-CAMs. Video Abstract.
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Affiliation(s)
- Weikai Lin
- Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China
- Shenyang Clinical Medical Research Center for Diagnosis, Treatment and Health Management of Early Digestive Cancer, Shenyang, 110032, China
| | - Jianjun Fang
- Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China
- Shenyang Clinical Medical Research Center for Diagnosis, Treatment and Health Management of Early Digestive Cancer, Shenyang, 110032, China
| | - Shibo Wei
- Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China
- Shenyang Clinical Medical Research Center for Diagnosis, Treatment and Health Management of Early Digestive Cancer, Shenyang, 110032, China
| | - Guangpeng He
- Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China
- Shenyang Clinical Medical Research Center for Diagnosis, Treatment and Health Management of Early Digestive Cancer, Shenyang, 110032, China
| | - Jiaxing Liu
- Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China
- Shenyang Clinical Medical Research Center for Diagnosis, Treatment and Health Management of Early Digestive Cancer, Shenyang, 110032, China
| | - Xian Li
- Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China
- Shenyang Clinical Medical Research Center for Diagnosis, Treatment and Health Management of Early Digestive Cancer, Shenyang, 110032, China
| | - Xueqiang Peng
- Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China
- Shenyang Clinical Medical Research Center for Diagnosis, Treatment and Health Management of Early Digestive Cancer, Shenyang, 110032, China
| | - Dai Li
- Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China
- Shenyang Clinical Medical Research Center for Diagnosis, Treatment and Health Management of Early Digestive Cancer, Shenyang, 110032, China
| | - Shuo Yang
- Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China
- Shenyang Clinical Medical Research Center for Diagnosis, Treatment and Health Management of Early Digestive Cancer, Shenyang, 110032, China
| | - Xinyu Li
- Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China
- Shenyang Clinical Medical Research Center for Diagnosis, Treatment and Health Management of Early Digestive Cancer, Shenyang, 110032, China
| | - Liang Yang
- Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China.
- Shenyang Clinical Medical Research Center for Diagnosis, Treatment and Health Management of Early Digestive Cancer, Shenyang, 110032, China.
| | - Hangyu Li
- Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China.
- Shenyang Clinical Medical Research Center for Diagnosis, Treatment and Health Management of Early Digestive Cancer, Shenyang, 110032, China.
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16
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Whitley JA, Cai H. Engineering extracellular vesicles to deliver CRISPR ribonucleoprotein for gene editing. J Extracell Vesicles 2023; 12:e12343. [PMID: 37723839 PMCID: PMC10507228 DOI: 10.1002/jev2.12343] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Revised: 06/16/2023] [Accepted: 06/19/2023] [Indexed: 09/20/2023] Open
Abstract
Clustered regularly interspaced palindromic repeats (CRISPR) is a gene editing tool with tremendous therapeutic potential. Recently, ribonucleoprotein (RNP) complex-based CRISPR systems have gained momentum due to their reduction of off-target editing. This has coincided with the emergence of extracellular vesicles (EVs) as a therapeutic delivery vehicle due to its low immunogenicity and high capacity for manipulation. EVs are cell-derived membranous nanoparticles which mediate the intercellular transfer of molecular components. Current technologies achieve CRISPR RNP encapsulation into EVs through EVs biogenesis, thereby avoiding unnecessary physical, chemical or biological manipulations to the vesicles directly. Herein, we identify sixteen EVs-based CRISPR RNP encapsulation strategies, each with distinct genetic features to encapsulate CRISPR RNP. According to the molecular mechanism facilitating the encapsulation process, there are six strategies of encapsulating Cas9 RNP into virus-like particles based on genetic fusion, seven into EVs based on protein tethering, and three based on sgRNA-coupled encapsulation. Additionally, the incorporation of a targeting moiety to the EVs membrane surface through EVs biogenesis confers tropism and increases delivery efficiency to specific cell types. The targeting moieties include viral envelope proteins, recombinant proteins containing a ligand peptide, single-chain fragment variable (scFv) antibodies, and integrins. However, current strategies still have a number of limitations which prevent their use in clinical trials. Among those, the incorporation of viral proteins for encapsulation of Cas9 RNP have raised issues of biocompatibility due to host immune response. Future studies should focus on genetically engineering the EVs without viral proteins, enhancing EVs delivery specificity, and promoting EVs-based homology directed repair. Nevertheless, the integration of CRISPR RNP encapsulation and tropism technologies will provide strategies for the EVs-based delivery of CRISPR RNP in gene therapy and disease treatment.
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Affiliation(s)
- Joseph Andrew Whitley
- Department of Pharmaceutical and Biomedical SciencesCollege of PharmacyUniversity of GeorgiaAthensGeorgiaUSA
| | - Houjian Cai
- Department of Pharmaceutical and Biomedical SciencesCollege of PharmacyUniversity of GeorgiaAthensGeorgiaUSA
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17
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Tsai CC, Yang YCSH, Chen YF, Huang LY, Yang YN, Lee SY, Wang WL, Lee HL, Whang-Peng J, Lin HY, Wang K. Integrins and Actions of Androgen in Breast Cancer. Cells 2023; 12:2126. [PMID: 37681860 PMCID: PMC10486718 DOI: 10.3390/cells12172126] [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: 07/05/2023] [Revised: 08/16/2023] [Accepted: 08/19/2023] [Indexed: 09/09/2023] Open
Abstract
Androgen has been shown to regulate male physiological activities and cancer proliferation. It is used to antagonize estrogen-induced proliferative effects in breast cancer cells. However, evidence indicates that androgen can stimulate cancer cell growth in estrogen receptor (ER)-positive and ER-negative breast cancer cells via different types of receptors and different mechanisms. Androgen-induced cancer growth and metastasis link with different types of integrins. Integrin αvβ3 is predominantly expressed and activated in cancer cells and rapidly dividing endothelial cells. Programmed death-ligand 1 (PD-L1) also plays a vital role in cancer growth. The part of integrins in action with androgen in cancer cells is not fully mechanically understood. To clarify the interactions between androgen and integrin αvβ3, we carried out molecular modeling to explain the potential interactions of androgen with integrin αvβ3. The androgen-regulated mechanisms on PD-L1 and its effects were also addressed.
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Affiliation(s)
- Chung-Che Tsai
- Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan; (C.-C.T.); (Y.-F.C.)
- Graduate Institute of Nanomedicine and Medical Engineering, College of Medical Engineering, Taipei Medical University, Taipei 11031, Taiwan
| | - Yu-Chen S. H. Yang
- Joint Biobank, Office of Human Research, Taipei Medical University, Taipei 11031, Taiwan;
| | - Yi-Fong Chen
- Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan; (C.-C.T.); (Y.-F.C.)
| | - Lin-Yi Huang
- Department of Pediatrics, E-DA Hospital, I-Shou University, Kaohsiung 82445, Taiwan; (L.-Y.H.); (Y.-N.Y.)
| | - Yung-Ning Yang
- Department of Pediatrics, E-DA Hospital, I-Shou University, Kaohsiung 82445, Taiwan; (L.-Y.H.); (Y.-N.Y.)
- School of Medicine, I-Shou University, Kaohsiung 82445, Taiwan
| | - Sheng-Yang Lee
- Dentistry, Wan-Fang Medical Center, Taipei Medical University, Taipei 11031, Taiwan;
- School of Dentistry, College of Oral Medicine, Taipei Medical University, Taipei 11031, Taiwan
| | - Wen-Long Wang
- Department of Life Science, Fu Jen Catholic University, New Taipei City 242, Taiwan;
| | - Hsin-Lun Lee
- Department of Radiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan;
- Department of Radiation Oncology, Taipei Medical University Hospital, Taipei 110, Taiwan
- The Ph.D. Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei 11031, Taiwan
| | | | - Hung-Yun Lin
- Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan; (C.-C.T.); (Y.-F.C.)
- Cancer Center, Wan Fang Hospital, Taipei Medical University, Taipei 11031, Taiwan;
- TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei 11031, Taiwan
- Traditional Herbal Medicine Research Center of Taipei Medical University Hospital, Taipei Medical University, Taipei 11031, Taiwan
- Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Albany, NY 12208, USA
| | - Kuan Wang
- Graduate Institute of Nanomedicine and Medical Engineering, College of Medical Engineering, Taipei Medical University, Taipei 11031, Taiwan
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18
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Sanati M, Afshari AR, Aminyavari S, Kesharwani P, Jamialahmadi T, Sahebkar A. RGD-engineered nanoparticles as an innovative drug delivery system in cancer therapy. J Drug Deliv Sci Technol 2023; 84:104562. [DOI: 10.1016/j.jddst.2023.104562] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/28/2024]
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19
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Lee Y, Graham P, Li Y. Extracellular vesicles as a novel approach for breast cancer therapeutics. Cancer Lett 2023; 555:216036. [PMID: 36521658 DOI: 10.1016/j.canlet.2022.216036] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Revised: 11/28/2022] [Accepted: 12/05/2022] [Indexed: 12/14/2022]
Abstract
Breast cancer (BC) still lacks effective management approaches to control metastatic and therapy-resistant disease. Extracellular vesicles (EVs), with a diameter of 50-1000 nm, are secreted by all types of living cells, are protected by a lipid bilayer and encapsulate biological cargos including RNAs, proteins and lipids. They play an important role in intercellular communications and are significantly associated with pathological conditions. Accumulating evidence indicates that cancer cells secrete EVs and communicate with neighboring cells within the tumor microenvironment (TME), which plays an important role in BC metastasis, immune escape and chemoresistance, thus providing a new therapeutic window. EVs can stimulate angiogenesis and extracellular matrix remodeling, establish premetastatic niches, inhibit immune response and promote cancer metastasis. Recent advances have demonstrated that EVs are a potential therapeutic target or carrier and have emerged as promising strategies for BC treatment. In this review, we summarize the role of EVs in BC metastasis, chemoresistance and immune escape, which provides the foundation for developing novel therapeutic approaches. We also focus on current EV-based drug delivery strategies in BC and EV cargo-targeted BC therapy and discuss the limitations and future perspectives of EV-based drug delivery in BC.
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Affiliation(s)
- Yujin Lee
- St George and Sutherland Clinical Campuses, School of Clinical Medicine, UNSW Sydney, Kensington, NSW, 2052, Australia; Cancer Care Centre, St. George Hospital, Kogarah, NSW, 2217, Australia
| | - Peter Graham
- St George and Sutherland Clinical Campuses, School of Clinical Medicine, UNSW Sydney, Kensington, NSW, 2052, Australia; Cancer Care Centre, St. George Hospital, Kogarah, NSW, 2217, Australia
| | - Yong Li
- St George and Sutherland Clinical Campuses, School of Clinical Medicine, UNSW Sydney, Kensington, NSW, 2052, Australia; Cancer Care Centre, St. George Hospital, Kogarah, NSW, 2217, Australia.
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20
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Naito Y, Yoshioka Y, Ochiya T. Intercellular crosstalk between cancer cells and cancer-associated fibroblasts via extracellular vesicles. Cancer Cell Int 2022; 22:367. [PMID: 36424598 PMCID: PMC9686122 DOI: 10.1186/s12935-022-02784-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Accepted: 10/20/2022] [Indexed: 11/25/2022] Open
Abstract
Intercellular communication plays an important role in cancer initiation and progression through direct contact and indirect interactions, such as via secretory molecules. Cancer-associated fibroblasts (CAFs) are one of the principal components of such communication with cancer cells, modulating cancer metastasis and tumour mechanics and influencing angiogenesis, the immune system, and therapeutic resistance. Over the past few years, there has been a significant increase in research on extracellular vesicles (EVs) as regulatory agents in intercellular communication. EVs enable the transfer of functional molecules, including proteins, mRNAs and microRNAs (miRNAs), to recipient cells. Cancer cells utilize EVs to dictate the specific characteristics of CAFs within the tumour microenvironment, thereby promoting cancer progression. In response to such "education" by cancer cells, CAFs contribute to cancer progression via EVs. In this review, we summarize experimental data indicating the pivotal roles of EVs in intercellular communication between cancer cells and CAFs.
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Affiliation(s)
- Yutaka Naito
- grid.410821.e0000 0001 2173 8328Department of Bioregulation, Institute for Advanced Medical Sciences, Nippon Medical School, 1-1-5, Sendagi, Bunkyo-Ku, Tokyo, 113-8602 Japan
| | - Yusuke Yoshioka
- grid.410793.80000 0001 0663 3325Department of Molecular and Cellular Medicine, Institute of Medical Science, Tokyo Medical University, 6-7-1, Nishishinjuku, Shinjuku-Ku, Tokyo, 160-0023 Japan
| | - Takahiro Ochiya
- grid.410793.80000 0001 0663 3325Department of Molecular and Cellular Medicine, Institute of Medical Science, Tokyo Medical University, 6-7-1, Nishishinjuku, Shinjuku-Ku, Tokyo, 160-0023 Japan
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21
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Farhat W, Yeung V, Kahale F, Parekh M, Cortinas J, Chen L, Ross AE, Ciolino JB. Doxorubicin-Loaded Extracellular Vesicles Enhance Tumor Cell Death in Retinoblastoma. Bioengineering (Basel) 2022; 9:bioengineering9110671. [PMID: 36354582 PMCID: PMC9687263 DOI: 10.3390/bioengineering9110671] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Revised: 11/08/2022] [Accepted: 11/08/2022] [Indexed: 11/11/2022] Open
Abstract
Chemotherapy is often used to treat retinoblastoma; however, this treatment method has severe systemic adverse effects and inadequate therapeutic effectiveness. Extracellular vesicles (EVs) are important biological information carriers that mediate local and systemic cell-to-cell communication under healthy and pathological settings. These endogenous vesicles have been identified as important drug delivery vehicles for a variety of therapeutic payloads, including doxorubicin (Dox), with significant benefits over traditional techniques. In this work, EVs were employed as natural drug delivery nanoparticles to load Dox for targeted delivery to retinoblastoma human cell lines (Y-79). Two sub-types of EVs were produced from distinct breast cancer cell lines (4T1 and SKBR3) that express a marker that selectively interacts with retinoblastoma cells and were loaded with Dox, utilizing the cells’ endogenous loading machinery. In vitro, we observed that delivering Dox with both EVs increased cytotoxicity while dramatically lowering the dosage of the drug. Dox-loaded EVs, on the other hand, inhibited cancer cell growth by activating caspase-3/7. Direct interaction of EV membrane moieties with retinoblastoma cell surface receptors resulted in an effective drug delivery to cancer cells. Our findings emphasize the intriguing potential of EVs as optimum methods for delivering Dox to retinoblastoma.
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Affiliation(s)
- Wissam Farhat
- Department of Ophthalmology, Schepens Eye Research Institute of Mass Eye and Ear, Harvard Medical School, Boston, MA 02114, USA
- Correspondence: (W.F.); (J.B.C.)
| | - Vincent Yeung
- Department of Ophthalmology, Schepens Eye Research Institute of Mass Eye and Ear, Harvard Medical School, Boston, MA 02114, USA
| | - Francesca Kahale
- Department of Ophthalmology, Schepens Eye Research Institute of Mass Eye and Ear, Harvard Medical School, Boston, MA 02114, USA
| | - Mohit Parekh
- Department of Ophthalmology, Schepens Eye Research Institute of Mass Eye and Ear, Harvard Medical School, Boston, MA 02114, USA
| | - John Cortinas
- Division of Newborn Medicine, Department of Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - Lin Chen
- Department of Ophthalmology, Schepens Eye Research Institute of Mass Eye and Ear, Harvard Medical School, Boston, MA 02114, USA
- Department of Ophthalmology, Affiliated Hospital of Zunyi Medical University, Zunyi 563000, China
| | - Amy E. Ross
- Department of Ophthalmology, Schepens Eye Research Institute of Mass Eye and Ear, Harvard Medical School, Boston, MA 02114, USA
| | - Joseph B. Ciolino
- Department of Ophthalmology, Schepens Eye Research Institute of Mass Eye and Ear, Harvard Medical School, Boston, MA 02114, USA
- Correspondence: (W.F.); (J.B.C.)
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22
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Yi X, Huang D, Li Z, Wang X, Yang T, Zhao M, Wu J, Zhong T. The role and application of small extracellular vesicles in breast cancer. Front Oncol 2022; 12:980404. [PMID: 36185265 PMCID: PMC9515427 DOI: 10.3389/fonc.2022.980404] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Accepted: 08/23/2022] [Indexed: 11/13/2022] Open
Abstract
Breast cancer (BC) is the most common malignancy and the leading cause of cancer-related deaths in women worldwide. Currently, patients’ survival remains a challenge in BC due to the lack of effective targeted therapies and the difficult condition of patients with higher aggressiveness, metastasis and drug resistance. Small extracellular vesicles (sEVs), which are nanoscale vesicles with lipid bilayer envelopes released by various cell types in physiological and pathological conditions, play an important role in biological information transfer between cells. There is growing evidence that BC cell-derived sEVs may contribute to the establishment of a favorable microenvironment that supports cancer cells proliferation, invasion and metastasis. Moreover, sEVs provide a versatile platform not only for the diagnosis but also as a delivery vehicle for drugs. This review provides an overview of current new developments regarding the involvement of sEVs in BC pathogenesis, including tumor proliferation, invasion, metastasis, immune evasion, and drug resistance. In addition, sEVs act as messenger carriers carrying a variety of biomolecules such as proteins, nucleic acids, lipids and metabolites, making them as potential liquid biopsy biomarkers for BC diagnosis and prognosis. We also described the clinical applications of BC derived sEVs associated MiRs in the diagnosis and treatment of BC along with ongoing clinical trials which will assist future scientific endeavors in a more organized direction.
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Affiliation(s)
- Xiaomei Yi
- The First School of Clinical Medicine, Gannan Medical University, Ganzhou, China
- Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Defa Huang
- Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Zhengzhe Li
- The First School of Clinical Medicine, Gannan Medical University, Ganzhou, China
- Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Xiaoxing Wang
- The First School of Clinical Medicine, Gannan Medical University, Ganzhou, China
- Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Tong Yang
- The First School of Clinical Medicine, Gannan Medical University, Ganzhou, China
- Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Minghong Zhao
- The First School of Clinical Medicine, Gannan Medical University, Ganzhou, China
- Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Jiyang Wu
- The First School of Clinical Medicine, Gannan Medical University, Ganzhou, China
- Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Tianyu Zhong
- The First School of Clinical Medicine, Gannan Medical University, Ganzhou, China
- Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
- *Correspondence: Tianyu Zhong,
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