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Mukund K, Veraksa D, Frankhouser D, Yang L, Tomsic J, Pillai R, Atti S, Mesrizadeh Z, Schmolze D, Wu XC, LeBlanc MA, Miele L, Ochoa A, Seewaldt V, Subramaniam S. Spatially distinct cellular and molecular landscapes define prognosis in triple negative breast cancer. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.02.10.637503. [PMID: 39990419 PMCID: PMC11844391 DOI: 10.1101/2025.02.10.637503] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 02/25/2025]
Abstract
Background- Triple-negative breast cancer is a prevalent breast cancer subtype with the lowest 5-year survival. Several factors contribute to its treatment response, but the inherent molecular and cellular tumor heterogeneity are increasingly acknowledged as crucial determinants. Methods- Spatial transcriptomic profiling was performed on FFPE tissues from a retrospective, treatment-naive group of women with differential prognoses (17 with >15 years survival- good prognosis (GPx) and 15 with <3 years survival-poor prognosis (PPx)) using GeoMX® Digital Spatial Profiler. Regions of interest were segmented on pan-cytokeratin and analyzed for tumor and stromal components, probed using GeoMx human whole transcriptome atlas (WTA) panel. Data quality control, normalization, and differential analysis was performed in R using GeomxTools and linear mixed models. Additional analyses including cell-type deconvolution, spatial entropy, functional enrichment, TF-target / ligand-receptor analysis and convolution neural networks were employed to identify significant gene signatures contributing to differential prognosis. Results- Here we report on the spatial and molecular heterogeneity underlying differential prognosis. We observe that the state of the epithelia and its microenvironment (TME) are transcriptionally distinct between the two groups. Invasive epithelia in GPx show a significant increase in immune transcripts with the TME exhibiting increased immune cell presence (via IF), while in PPx they are more metabolically and translationally active, with the TME being more mesenchymal/fibrotic. Specifically, pre-cancerous epithelia in PPx display a prescience of aggressiveness as evidenced by increased EMT-signaling. We identify distinct epithelial gene signatures for PPx and GPx, that can, with high accuracy, classify samples at the time of diagnosis and likely inform therapy. Conclusions- To the best of our knowledge, this is the first study to leverage spatial transcriptomics for an in-depth delineation of the cellular and molecular underpinnings of differential prognosis in TNBC. Our study highlights the potential of spatial transcriptomics to not only uncover the molecular drivers of differential prognosis in TNBC but also to pave the way for precision diagnostics and tailored therapeutic strategies, transforming the clinical landscape for this aggressive breast cancer subtype.
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Affiliation(s)
- Kavitha Mukund
- Department of Bioengineering, UC San Diego, Gilman Drive, La Jolla, CA 92093, USA
| | - Darya Veraksa
- Department of Bioengineering, UC San Diego, Gilman Drive, La Jolla, CA 92093, USA
| | - David Frankhouser
- City of Hope Comprehensive Cancer Center, 1500 East Duarte Road, Duarte, CA 91010, USA
| | - Lixin Yang
- City of Hope Comprehensive Cancer Center, 1500 East Duarte Road, Duarte, CA 91010, USA
| | - Jerneja Tomsic
- City of Hope Comprehensive Cancer Center, 1500 East Duarte Road, Duarte, CA 91010, USA
| | - Raju Pillai
- City of Hope Comprehensive Cancer Center, 1500 East Duarte Road, Duarte, CA 91010, USA
| | - Srijan Atti
- Del Norte High School, San Diego, CA 92127, USA
| | - Zahra Mesrizadeh
- Department of Bioengineering, UC San Diego, Gilman Drive, La Jolla, CA 92093, USA
| | - Daniel Schmolze
- City of Hope Comprehensive Cancer Center, 1500 East Duarte Road, Duarte, CA 91010, USA
| | - Xiao-Cheng Wu
- LSU Health Sciences Center, School of Medicine, New Orleans, LA 70112, USA
| | - Mary-Anne LeBlanc
- LSU Health Sciences Center, School of Medicine, New Orleans, LA 70112, USA
| | - Lucio Miele
- LSU Health Sciences Center, School of Medicine, New Orleans, LA 70112, USA
| | - Augusto Ochoa
- LSU Health Sciences Center, School of Medicine, New Orleans, LA 70112, USA
| | - Victoria Seewaldt
- City of Hope Comprehensive Cancer Center, 1500 East Duarte Road, Duarte, CA 91010, USA
| | - Shankar Subramaniam
- Department of Bioengineering, UC San Diego, Gilman Drive, La Jolla, CA 92093, USA
- Departments of Cellular & Molecular Medicine, Computer Science & Engineering, and Data Science, UC San Diego, Gilman Drive, La Jolla, CA 92093, USA
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WILCZAK MAGDALENA, SURMAN MAGDALENA, PRZYBYłO MA. Melanoma-derived extracellular vesicles transfer proangiogenic factors. Oncol Res 2025; 33:245-262. [PMID: 39866233 PMCID: PMC11753996 DOI: 10.32604/or.2024.055449] [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: 06/27/2024] [Accepted: 09/27/2024] [Indexed: 01/28/2025] Open
Abstract
Angiogenesis, the expansion of pre-existing vascular networks, is crucial for normal organ growth and tissue repair, but is also involved in various pathologies, including inflammation, ischemia, diabetes, and cancer. In solid tumors, angiogenesis supports growth, nutrient delivery, waste removal, and metastasis. Tumors can induce angiogenesis through proangiogenic factors including VEGF, FGF-2, PDGF, angiopoietins, HGF, TNF, IL-6, SCF, tryptase, and chymase. This balance is disrupted in tumors, and extracellular vesicles (EVs) contribute to this by transferring proangiogenic factors and increasing their expression in endothelial cells (ECs). Malignant melanoma, a particular type of skin cancer, accounts for only 1% of skin cancer cases but more than 75% of deaths. Its incidence has risen significantly, with a 40% increase between 2012 and 2022, especially in fair-skinned populations. Advanced metastatic stages have a high mortality due to delayed diagnosis. This review examines the molecular basis of angiogenesis in melanoma, focusing on melanoma-derived EVs and their possible use in new antiangiogenic therapies.
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Affiliation(s)
- MAGDALENA WILCZAK
- Department of Glycoconjugate Biochemistry, Faculty of Biology, Institute of Zoology and Biomedical Research, Jagiellonian University, Krakow, 30-387, Poland
- Doctoral School of Exact and Natural Sciences, Jagiellonian University, Krakow, 30-348, Poland
| | - MAGDALENA SURMAN
- Department of Glycoconjugate Biochemistry, Faculty of Biology, Institute of Zoology and Biomedical Research, Jagiellonian University, Krakow, 30-387, Poland
| | - MAłGORZATA PRZYBYłO
- Department of Glycoconjugate Biochemistry, Faculty of Biology, Institute of Zoology and Biomedical Research, Jagiellonian University, Krakow, 30-387, Poland
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Sarabia-Sánchez MA, Tinajero-Rodríguez JM, Ortiz-Sánchez E, Alvarado-Ortiz E. Cancer Stem Cell markers: Symphonic masters of chemoresistance and immune evasion. Life Sci 2024; 355:123015. [PMID: 39182567 DOI: 10.1016/j.lfs.2024.123015] [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: 04/21/2024] [Revised: 08/21/2024] [Accepted: 08/22/2024] [Indexed: 08/27/2024]
Abstract
Cancer Stem Cells (CSCs) are highly tumorigenic, chemoresistant, and immune evasive. They emerge as a central driver that gives rise to the bulk of tumoral mass, modifies the tumor microenvironment (TME), and exploits it, leading to poor clinical outcomes for patients with cancer. The existence of CSCs thus accounts for the failure of conventional therapies and immune surveillance. Identifying CSCs in solid tumors remains a significant challenge in modern oncology, with the use of cell surface markers being the primary strategy for studying, isolating, and enriching these cells. In this review, we explore CSC markers, focusing on the underlying signaling pathways that drive CSC self-renewal, which simultaneously makes them intrinsically chemoresistant and immune system evaders. We comprehensively discuss the autonomous and non-autonomous functions of CSCs, with particular emphasis on their interactions with the tumor microenvironment, especially immune cells. This reciprocal network enhances CSCs malignancy while compromising the surrounding niche, ultimately defining therapeutic vulnerabilities associated with each CSC marker. The most common CSCs surface markers addressed in this review-CD44, CD133, ICAM1/CD54, and LGR5-provide insights into the interplay between chemoresistance and immune evasion, two critically important phenomena in disease eradication. This new perspective on the state-of-the-art of CSCs will undoubtedly open new avenues for therapy.
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Affiliation(s)
- Miguel Angel Sarabia-Sánchez
- Subdirección de Investigación Básica, Instituto Nacional de Cancerología, Secretaría de Salud, Ciudad de México, México; Departamento de Bioquímica, Facultad de Medicina, Universidad Nacional Autónoma de México, México
| | - José Manuel Tinajero-Rodríguez
- Subdirección de Investigación Básica, Instituto Nacional de Cancerología, Secretaría de Salud, Ciudad de México, México; Tecnológico Nacional de México, Tecnológico de Estudios Superiores de Huixquilucan, México
| | - Elizabeth Ortiz-Sánchez
- Subdirección de Investigación Básica, Instituto Nacional de Cancerología, Secretaría de Salud, Ciudad de México, México
| | - Eduardo Alvarado-Ortiz
- Programa de Posgrado en Ciencias Biológicas, Universidad Nacional Autónoma de México, México; Departamento de Bioquímica, Facultad de Medicina, Universidad Nacional Autónoma de México, México.
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Galkina SI, Fedorova NV, Golenkina EA, Ksenofontov AL, Serebryakova MV, Kordyukova LV, Stadnichuk VI, Baratova LA, Sud'ina GF. Differential effects of angiotensin II and aldosterone on human neutrophil adhesion and concomitant secretion of proteins, free amino acids and reactive oxygen and nitrogen species. Int Immunopharmacol 2024; 139:112687. [PMID: 39018693 DOI: 10.1016/j.intimp.2024.112687] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2024] [Revised: 07/10/2024] [Accepted: 07/12/2024] [Indexed: 07/19/2024]
Abstract
Invasion and adhesion of neutrophils into tissues and their concomitant secretion play an important role in the development of vascular pathologies, including abdominal aortic aneurysm (AAA). Chronic administration of angiotensin II is used to initiate AAA formation in mice. The role of aldosterone in this process is being studied. We conducted for the first time a complex comparative study of the effects of angiotensin II and aldosterone on the adhesion of human neutrophils to fibronectin and the concomitant secretion of proteins, free amino acids as well as reactive oxygen (ROS) and nitrogen (NO) species. Neither angiotensin II nor aldosterone affected the attachment of neutrophils to fibronectin and the concomitant production of ROS. We showed for the first time that aldosterone stimulated the release of amino acid hydroxylysine, a product of lysyl hydroxylase, the activity of which is positively correlated with cell invasiveness. Aldosterone also initiates the secretion of matrix metalloproteinase 9 (MMP-9) and cathepsin G, which may reorganize the extracellular matrix and stimulate the recruitment and adhesion of neutrophils to the aortic walls. Angiotensin II did not affect protein secretion. It may contribute to neutrophil-induced vascular injury by inhibiting the production of NO or by increasing the secretion of isoleucine. Our results suggest that it is aldosterone-induced neutrophil secretion that may play a significant role in neutrophil-induced vascular wall destruction in angiotensin II-induced AAA or other vascular complications.
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Affiliation(s)
- Svetlana I Galkina
- A.N. Belozersky Institute of Physico-Chemical Biology, M.V. Lomonosov Moscow State University, Moscow 119991, Russia.
| | - Natalia V Fedorova
- A.N. Belozersky Institute of Physico-Chemical Biology, M.V. Lomonosov Moscow State University, Moscow 119991, Russia
| | - Ekaterina A Golenkina
- A.N. Belozersky Institute of Physico-Chemical Biology, M.V. Lomonosov Moscow State University, Moscow 119991, Russia
| | - Alexander L Ksenofontov
- A.N. Belozersky Institute of Physico-Chemical Biology, M.V. Lomonosov Moscow State University, Moscow 119991, Russia
| | - Marina V Serebryakova
- A.N. Belozersky Institute of Physico-Chemical Biology, M.V. Lomonosov Moscow State University, Moscow 119991, Russia
| | - Larisa V Kordyukova
- A.N. Belozersky Institute of Physico-Chemical Biology, M.V. Lomonosov Moscow State University, Moscow 119991, Russia
| | | | - Ludmila A Baratova
- A.N. Belozersky Institute of Physico-Chemical Biology, M.V. Lomonosov Moscow State University, Moscow 119991, Russia
| | - Galina F Sud'ina
- A.N. Belozersky Institute of Physico-Chemical Biology, M.V. Lomonosov Moscow State University, Moscow 119991, Russia.
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Bowman RL, Kim J, Eom DS. CD44 facilitates adhesive interactions in airineme-mediated intercellular signaling. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.02.27.582398. [PMID: 38463999 PMCID: PMC10925269 DOI: 10.1101/2024.02.27.582398] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/12/2024]
Abstract
Specialized cellular protrusions facilitate local intercellular communications in various species, including mammals. Among these, airinemes play a crucial role in pigment pattern formation in zebrafish by mediating long-distance Notch signaling between pigment cells. Remarkably, airinemes exhibit large vesicle-like structure at their tips, which are pulled by macrophages and delivered to target cells. The interaction between macrophages and Delta-ligand carrying airineme vesicles is essential for initiating airineme-mediated signaling, yet the molecular detail of this interaction remains elusive. Through high-resolution live imaging, genetic in vivo manipulations and in vitro adhesion assay, we found that adhesive interactions via the extracellular domain of CD44, a class I transmembrane glycoprotein, between macrophages and airineme vesicles are critical for airineme signaling. Mutants lacking the extracellular domain of CD44 lose their adhesiveness, resulting in a significant reduction in airineme extension and pigment pattern defects. Our findings provide valuable insights into the role of adhesive interactions between signal-sending cells and macrophages in a long-range intercellular signaling.
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Affiliation(s)
- Raquel Lynn Bowman
- Department of Developmental and Cell Biology, University of California, Irvine, CA 92617, USA
| | - Jiyea Kim
- Department of Developmental and Cell Biology, University of California, Irvine, CA 92617, USA
| | - Dae Seok Eom
- Department of Developmental and Cell Biology, University of California, Irvine, CA 92617, USA
- Center for Complex Biological Systems, University of California, Irvine, CA 92697, USA
- UC Irvine Skin Biology Resource Center, University of California, Irvine, CA 92697, USA
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Jiang A, Wang Z, Cheng R, Zhang S, Wu Q, Qin X. Long non-coding RNA SNHG12 regulates leptomeningeal collateral remodeling via RGMa after ischemic stroke. Neurotherapeutics 2024; 21:e00429. [PMID: 39138027 PMCID: PMC11579872 DOI: 10.1016/j.neurot.2024.e00429] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2024] [Revised: 07/26/2024] [Accepted: 07/26/2024] [Indexed: 08/15/2024] Open
Abstract
Leptomeningeal anastomoses or pial collateral arteries are crucial for restoring cerebral blood flow (CBF) after an ischemic stroke. Vascular smooth muscle cells (VSMCs) are hypothesized to regulate the extent of this adaptive response, while the specific molecular mechanisms underlying this process are still being investigated. SNHG12, a long non-coding RNA, has been shown to influence several diseases related angiogenesis, including osteosarcoma and gastric cancer. However, the role of SNHG12 in contractile VSMC dedifferentiation during collateral arteriogenesis-related strokes remains unclear. Here we demonstrated that SNHG12 is a positive regulator of MMP9 and VSMC dedifferentiation, which enhances pial collateral arteriogenesis following cerebrovascular occlusion. Pial collateral remodeling is limited by the crosstalk between SNHG12-MMP9 signaling in VSMCs, which is mediated through repulsive guidance molecule a (RGMa) regulation. Thus, targeting SNHG12 may represent a therapeutic strategy for improving collateral function, neural tissue health, and functional recovery following ischemic stroke.
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Affiliation(s)
- Anan Jiang
- Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Zijie Wang
- Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Ruiqi Cheng
- Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Shaoru Zhang
- Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Qisi Wu
- Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.
| | - Xinyue Qin
- Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.
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Radisky ES. Extracellular proteolysis in cancer: Proteases, substrates, and mechanisms in tumor progression and metastasis. J Biol Chem 2024; 300:107347. [PMID: 38718867 PMCID: PMC11170211 DOI: 10.1016/j.jbc.2024.107347] [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: 02/09/2024] [Revised: 04/08/2024] [Accepted: 04/25/2024] [Indexed: 06/02/2024] Open
Abstract
A vast ensemble of extracellular proteins influences the development and progression of cancer, shaped and reshaped by a complex network of extracellular proteases. These proteases, belonging to the distinct classes of metalloproteases, serine proteases, cysteine proteases, and aspartic proteases, play a critical role in cancer. They often become dysregulated in cancer, with increases in pathological protease activity frequently driven by the loss of normal latency controls, diminished regulation by endogenous protease inhibitors, and changes in localization. Dysregulated proteases accelerate tumor progression and metastasis by degrading protein barriers within the extracellular matrix (ECM), stimulating tumor growth, reactivating dormant tumor cells, facilitating tumor cell escape from immune surveillance, and shifting stromal cells toward cancer-promoting behaviors through the precise proteolysis of specific substrates to alter their functions. These crucial substrates include ECM proteins and proteoglycans, soluble proteins secreted by tumor and stromal cells, and extracellular domains of cell surface proteins, including membrane receptors and adhesion proteins. The complexity of the extracellular protease web presents a significant challenge to untangle. Nevertheless, technological strides in proteomics, chemical biology, and the development of new probes and reagents are enabling progress and advancing our understanding of the pivotal importance of extracellular proteolysis in cancer.
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Affiliation(s)
- Evette S Radisky
- Department of Cancer Biology, Mayo Clinic Comprehensive Cancer Center, Jacksonville, Florida, USA.
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MacLean MR, Walker OL, Arun RP, Fernando W, Marcato P. Informed by Cancer Stem Cells of Solid Tumors: Advances in Treatments Targeting Tumor-Promoting Factors and Pathways. Int J Mol Sci 2024; 25:4102. [PMID: 38612911 PMCID: PMC11012648 DOI: 10.3390/ijms25074102] [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: 02/28/2024] [Revised: 03/30/2024] [Accepted: 04/02/2024] [Indexed: 04/14/2024] Open
Abstract
Cancer stem cells (CSCs) represent a subpopulation within tumors that promote cancer progression, metastasis, and recurrence due to their self-renewal capacity and resistance to conventional therapies. CSC-specific markers and signaling pathways highly active in CSCs have emerged as a promising strategy for improving patient outcomes. This review provides a comprehensive overview of the therapeutic targets associated with CSCs of solid tumors across various cancer types, including key molecular markers aldehyde dehydrogenases, CD44, epithelial cellular adhesion molecule, and CD133 and signaling pathways such as Wnt/β-catenin, Notch, and Sonic Hedgehog. We discuss a wide array of therapeutic modalities ranging from targeted antibodies, small molecule inhibitors, and near-infrared photoimmunotherapy to advanced genetic approaches like RNA interference, CRISPR/Cas9 technology, aptamers, antisense oligonucleotides, chimeric antigen receptor (CAR) T cells, CAR natural killer cells, bispecific T cell engagers, immunotoxins, drug-antibody conjugates, therapeutic peptides, and dendritic cell vaccines. This review spans developments from preclinical investigations to ongoing clinical trials, highlighting the innovative targeting strategies that have been informed by CSC-associated pathways and molecules to overcome therapeutic resistance. We aim to provide insights into the potential of these therapies to revolutionize cancer treatment, underscoring the critical need for a multi-faceted approach in the battle against cancer. This comprehensive analysis demonstrates how advances made in the CSC field have informed significant developments in novel targeted therapeutic approaches, with the ultimate goal of achieving more effective and durable responses in cancer patients.
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Affiliation(s)
- Maya R. MacLean
- Department of Pathology, Dalhousie University, Halifax, NS B3H 4R2, Canada; (M.R.M.); (O.L.W.); (R.P.A.); (W.F.)
| | - Olivia L. Walker
- Department of Pathology, Dalhousie University, Halifax, NS B3H 4R2, Canada; (M.R.M.); (O.L.W.); (R.P.A.); (W.F.)
| | - Raj Pranap Arun
- Department of Pathology, Dalhousie University, Halifax, NS B3H 4R2, Canada; (M.R.M.); (O.L.W.); (R.P.A.); (W.F.)
| | - Wasundara Fernando
- Department of Pathology, Dalhousie University, Halifax, NS B3H 4R2, Canada; (M.R.M.); (O.L.W.); (R.P.A.); (W.F.)
- Department of Biology, Acadia University, Wolfville, NS B4P 2R6, Canada
| | - Paola Marcato
- Department of Pathology, Dalhousie University, Halifax, NS B3H 4R2, Canada; (M.R.M.); (O.L.W.); (R.P.A.); (W.F.)
- Department of Microbiology and Immunology, Dalhousie University, Halifax, NS B3H 4R2, Canada
- Nova Scotia Health Authority, Halifax, NS B3H 4R2, Canada
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Yang K, Yi T. Tumor cell stemness in gastrointestinal cancer: regulation and targeted therapy. Front Mol Biosci 2024; 10:1297611. [PMID: 38455361 PMCID: PMC10918437 DOI: 10.3389/fmolb.2023.1297611] [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: 09/20/2023] [Accepted: 11/14/2023] [Indexed: 03/09/2024] Open
Abstract
The cancer stem cells are a rare group of self-renewable cancer cells capable of the initiation, progression, metastasis and recurrence of tumors, and also a key contributor to the therapeutic resistance. Thus, understanding the molecular mechanism of tumor stemness regulation, especially in the gastrointestinal (GI) cancers, is of great importance for targeting CSC and designing novel therapeutic strategies. This review aims to elucidate current advancements in the understanding of CSC regulation, including CSC biomarkers, signaling pathways, and non-coding RNAs. We will also provide a comprehensive view on how the tumor microenvironment (TME) display an overall tumor-promoting effect, including the recruitment and impact of cancer-associated fibroblasts (CAFs), the establishment of an immunosuppressive milieu, and the induction of angiogenesis and hypoxia. Lastly, this review consolidates mainstream novel therapeutic interventions targeting CSC stemness regulation.
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Affiliation(s)
- Kangqi Yang
- School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Tuo Yi
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
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Wang J, Ford JC, Mitra AK. Defining the Role of Metastasis-Initiating Cells in Promoting Carcinogenesis in Ovarian Cancer. BIOLOGY 2023; 12:1492. [PMID: 38132318 PMCID: PMC10740540 DOI: 10.3390/biology12121492] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Revised: 11/23/2023] [Accepted: 11/30/2023] [Indexed: 12/23/2023]
Abstract
Ovarian cancer is the deadliest gynecological malignancy with a high prevalence of transcoelomic metastasis. Metastasis is a multi-step process and only a small percentage of cancer cells, metastasis-initiating cells (MICs), have the capacity to finally establish metastatic lesions. These MICs maintain a certain level of stemness that allows them to differentiate into other cell types with distinct transcriptomic profiles and swiftly adapt to external stresses. Furthermore, they can coordinate with the microenvironment, through reciprocal interactions, to invade and establish metastases. Therefore, identifying, characterizing, and targeting MICs is a promising strategy to counter the spread of ovarian cancer. In this review, we provided an overview of OC MICs in the context of characterization, identification through cell surface markers, and their interactions with the metastatic niche to promote metastatic colonization.
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Affiliation(s)
- Ji Wang
- Indiana University School of Medicine-Bloomington, Indiana University, Bloomington, IN 47405, USA; (J.W.); (J.C.F.)
- Melvin and Bren Simon Comprehensive Cancer Center, Indiana University, Indianapolis, IN 46202, USA
| | - James C. Ford
- Indiana University School of Medicine-Bloomington, Indiana University, Bloomington, IN 47405, USA; (J.W.); (J.C.F.)
| | - Anirban K. Mitra
- Indiana University School of Medicine-Bloomington, Indiana University, Bloomington, IN 47405, USA; (J.W.); (J.C.F.)
- Melvin and Bren Simon Comprehensive Cancer Center, Indiana University, Indianapolis, IN 46202, USA
- Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA
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Galkina SI, Golenkina EA, Fedorova NV, Ksenofontov AL, Serebryakova MV, Stadnichuk VI, Baratova LA, Sud'ina GF. Effect of Dexamethasone on Adhesion of Human Neutrophils and Concomitant Secretion. BIOCHEMISTRY. BIOKHIMIIA 2023; 88:2094-2106. [PMID: 38462453 DOI: 10.1134/s000629792312012x] [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: 07/26/2023] [Revised: 10/17/2023] [Accepted: 10/20/2023] [Indexed: 03/12/2024]
Abstract
Neutrophils play a dual role in protecting the body. They are able to penetrate infected tissues and destroy pathogens there by releasing aggressive bactericidal substances. While into the surrounding tissues, the aggressive products secreted by neutrophils initiate development of inflammatory processes. Invasion of neutrophils into tissues is observed during the development of pneumonia in the patients with lung diseases of various etiologies, including acute respiratory distress syndrome caused by coronavirus disease. Synthetic corticosteroid hormone dexamethasone has a therapeutic effect in treatment of lung diseases, including reducing mortality in the patients with severe COVID-19. The acute (short-term) effect of dexamethasone on neutrophil adhesion to fibrinogen and concomitant secretion was studied. Dexamethasone did not affect either attachment of neutrophils to the substrate or their morphology. Production of reactive oxygen species (ROS) and nitric oxide (NO) by neutrophils during adhesion also did not change in the presence of dexamethasone. Dexamethasone stimulated release of metalloproteinases in addition to the proteins secreted by neutrophils during adhesion under control conditions, and selectively stimulated release of free amino acid hydroxylysine, a product of lysyl hydroxylase. Metalloproteinases play a key role and closely interact with lysyl hydroxylase in the processes of modification of the extracellular matrix. Therapeutic effect of dexamethasone could be associated with its ability to reorganize extracellular matrix in the tissues by changing composition of the neutrophil secretions, which could result in the improved gas exchange in the patients with severe lung diseases.
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Affiliation(s)
- Svetlana I Galkina
- Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, 119991, Russia.
| | - Ekaterina A Golenkina
- Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, 119991, Russia
| | - Natalia V Fedorova
- Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, 119991, Russia
| | - Alexander L Ksenofontov
- Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, 119991, Russia
| | - Marina V Serebryakova
- Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, 119991, Russia
| | | | - Ludmila A Baratova
- Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, 119991, Russia
| | - Galina F Sud'ina
- Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, 119991, Russia.
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Wendt TS, Gonzales RJ. Ozanimod differentially preserves human cerebrovascular endothelial barrier proteins and attenuates matrix metalloproteinase-9 activity following in vitro acute ischemic injury. Am J Physiol Cell Physiol 2023; 325:C951-C971. [PMID: 37642239 DOI: 10.1152/ajpcell.00342.2023] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Revised: 08/23/2023] [Accepted: 08/24/2023] [Indexed: 08/31/2023]
Abstract
Endothelial integrity is critical in mitigating a vicious cascade of secondary injuries following acute ischemic stroke (AIS). Matrix metalloproteinase-9 (MMP-9), a contributor to endothelial integrity loss, is elevated during stroke and is associated with worsened stroke outcome. We investigated the FDA-approved selective sphingosine-1-phosphate receptor 1 (S1PR1) ligand, ozanimod, on the regulation/activity of MMP-9 as well as endothelial barrier components [platelet endothelial cell adhesion molecule 1 (PECAM-1), claudin-5, and zonula occludens 1 (ZO-1)] in human brain microvascular endothelial cells (HBMECs) following hypoxia plus glucose deprivation (HGD). We previously reported that S1PR1 activation improves HBMEC integrity; however, mechanisms underlying S1PR1 involvement in endothelial cell barrier integrity have not been clearly elucidated. We hypothesized that ozanimod would attenuate an HGD-induced increase in MMP-9 activity that would concomitantly attenuate the loss of integral barrier components. Male HBMECs were treated with ozanimod or vehicle and exposed to 3 h of normoxia (21% O2) or HGD (1% O2). Immunoblotting, zymography, qRT-PCR, and immunocytochemical labeling techniques assessed processes related to MMP-9 and barrier markers. We observed that HGD acutely increased MMP-9 activity and reduced claudin-5 and PECAM-1 levels, and ozanimod attenuated these responses. In situ analysis, via PROSPER, suggested that attenuation of MMP-9 activity may be a primary factor in maintaining these integral barrier proteins. We also observed that HGD increased intracellular mechanisms associated with augmented MMP-9 activation; however, ozanimod had no effect on these select factors. Thus, we conclude that ozanimod has the potential to attenuate HGD-mediated decreases in HBMEC integrity in part by decreasing MMP-9 activity as well as preserving barrier properties.NEW & NOTEWORTHY We have identified a potential novel mechanism by which ozanimod, a selective sphingosine-1-phosphate receptor 1 (S1PR1) agonist, attenuates hypoxia plus glucose deprivation (HGD)-induced matrix metalloproteinase-9 (MMP-9) activity and disruptions in integral human brain endothelial cell barrier proteins. Our results suggest that ischemic-like injury elicits increased MMP-9 activity and alterations of barrier integrity proteins in human brain microvascular endothelial cells (HBMECs) and that ozanimod via S1PR1 attenuates these HGD-induced responses, adding to its therapeutic potential in cerebrovascular protection during the acute phase of ischemic stroke.
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Affiliation(s)
- Trevor S Wendt
- Department of Basic Medical Sciences, University of Arizona College of Medicine, Phoenix, Arizona, United States
| | - Rayna J Gonzales
- Department of Basic Medical Sciences, University of Arizona College of Medicine, Phoenix, Arizona, United States
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13
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Salardani M, Barcick U, Zelanis A. Proteolytic signaling in cancer. Expert Rev Proteomics 2023; 20:345-355. [PMID: 37873978 DOI: 10.1080/14789450.2023.2275671] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2023] [Accepted: 10/17/2023] [Indexed: 10/25/2023]
Abstract
INTRODUCTION Cancer is a disease of (altered) biological pathways, often driven by somatic mutations and with several implications. Therefore, the identification of potential markers of disease is challenging. Given the large amount of biological data generated with omics approaches, oncology has experienced significant contributions. Proteomics mapping of protein fragments, derived from proteolytic processing events during oncogenesis, may shed light on (i) the role of active proteases and (ii) the functional implications of processed substrates in biological signaling circuits. Both outcomes have the potential for predicting diagnosis/prognosis in diseases like cancer. Therefore, understanding proteolytic processing events and their downstream implications may contribute to advances in the understanding of tumor biology and targeted therapies in precision medicine. AREAS COVERED Proteolytic events associated with some hallmarks of cancer (cell migration and proliferation, angiogenesis, metastasis, as well as extracellular matrix degradation) will be discussed. Moreover, biomarker discovery and the use of proteomics approaches to uncover proteolytic signaling events will also be covered. EXPERT OPINION Proteolytic processing is an irreversible protein post-translational modification and the deconvolution of biological data resulting from the study of proteolytic signaling events may be used in both patient diagnosis/prognosis and targeted therapies in cancer.
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Affiliation(s)
- Murilo Salardani
- Functional Proteomics Laboratory, Institute of Science and Technology, Federal University of São Paulo, São José dos Campos, SP, Brazil
| | - Uilla Barcick
- Functional Proteomics Laboratory, Institute of Science and Technology, Federal University of São Paulo, São José dos Campos, SP, Brazil
| | - André Zelanis
- Functional Proteomics Laboratory, Institute of Science and Technology, Federal University of São Paulo, São José dos Campos, SP, Brazil
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14
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Tsukamoto S, Koma YI, Kitamura Y, Tanigawa K, Azumi Y, Miyako S, Urakami S, Hosono M, Kodama T, Nishio M, Shigeoka M, Yokozaki H. Matrix Metalloproteinase 9 Induced in Esophageal Squamous Cell Carcinoma Cells via Close Contact with Tumor-Associated Macrophages Contributes to Cancer Progression and Poor Prognosis. Cancers (Basel) 2023; 15:cancers15112987. [PMID: 37296952 DOI: 10.3390/cancers15112987] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2023] [Revised: 05/18/2023] [Accepted: 05/24/2023] [Indexed: 06/12/2023] Open
Abstract
Tumor-associated macrophages (TAMs) contribute to disease progression in various cancers, including esophageal squamous cell carcinoma (ESCC). We have previously used an indirect co-culture system between ESCC cell lines and macrophages to analyze their interactions. Recently, we established a direct co-culture system to closely simulate actual ESCC cell-TAM contact. We found that matrix metalloproteinase 9 (MMP9) was induced in ESCC cells by direct co-culture with TAMs, not by indirect co-culture. MMP9 was associated with ESCC cell migration and invasion, and its expression was controlled by the Stat3 signaling pathway in vitro. Immunohistochemical analyses revealed that MMP9 expression in cancer cells at the invasive front ("cancer cell MMP9") was related to high infiltration of CD204 positive M2-like TAMs (p < 0.001) and was associated with worse overall and disease-free survival of patients (p = 0.036 and p = 0.038, respectively). Furthermore, cancer cell MMP9 was an independent prognostic factor for disease-free survival. Notably, MMP9 expression in cancer stroma was not associated with any clinicopathological factors or patient prognoses. Our results suggest that close interaction with TAMs infiltrating in cancer stroma or cancer nests induces MMP9 expression in ESCC cells, equipping them with more malignant features.
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Affiliation(s)
- Shuichi Tsukamoto
- Division of Pathology, Department of Pathology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan
| | - Yu-Ichiro Koma
- Division of Pathology, Department of Pathology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan
| | - Yu Kitamura
- Division of Pathology, Department of Pathology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan
- Division of Gastro-Intestinal Surgery, Department of Surgery, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan
| | - Kohei Tanigawa
- Division of Pathology, Department of Pathology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan
- Division of Gastro-Intestinal Surgery, Department of Surgery, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan
| | - Yuki Azumi
- Division of Pathology, Department of Pathology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan
- Division of Gastro-Intestinal Surgery, Department of Surgery, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan
| | - Shoji Miyako
- Division of Pathology, Department of Pathology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan
- Division of Gastro-Intestinal Surgery, Department of Surgery, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan
| | - Satoshi Urakami
- Division of Pathology, Department of Pathology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan
| | - Masayoshi Hosono
- Division of Gastro-Intestinal Surgery, Department of Surgery, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan
| | - Takayuki Kodama
- Division of Pathology, Department of Pathology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan
| | - Mari Nishio
- Division of Pathology, Department of Pathology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan
| | - Manabu Shigeoka
- Division of Pathology, Department of Pathology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan
| | - Hiroshi Yokozaki
- Division of Pathology, Department of Pathology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan
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15
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Kim M, Jo KW, Kim H, Han ME, Oh SO. Genetic heterogeneity of liver cancer stem cells. Anat Cell Biol 2023; 56:94-108. [PMID: 36384888 PMCID: PMC9989795 DOI: 10.5115/acb.22.161] [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: 08/22/2022] [Revised: 10/27/2022] [Accepted: 10/27/2022] [Indexed: 11/19/2022] Open
Abstract
Cancer cell heterogeneity is a serious problem in the control of tumor progression because it can cause chemoresistance and metastasis. Heterogeneity can be generated by various mechanisms, including genetic evolution of cancer cells, cancer stem cells (CSCs), and niche heterogeneity. Because the genetic heterogeneity of CSCs has been poorly characterized, the genetic mutation status of CSCs was examined using Exome-Seq and RNA-Seq data of liver cancer. Here we show that different surface markers for liver cancer stem cells (LCSCs) showed a unique propensity for genetic mutations. Cluster of differentiation 133 (CD133)-positive cells showed frequent mutations in the IRF2, BAP1, and ERBB3 genes. However, leucine-rich repeat-containing G protein-coupled receptor 5-positive cells showed frequent mutations in the CTNNB1, RELN, and ROBO1 genes. In addition, some genetic mutations were frequently observed irrespective of the surface markers for LCSCs. BAP1 mutations was frequently observed in CD133-, CD24-, CD13-, CD90-, epithelial cell adhesion molecule-, or keratin 19-positive LCSCs. ASXL2, ERBB3, IRF2, TLX3, CPS1, and NFATC2 mutations were observed in more than three types of LCSCs, suggesting that common mechanisms for the development of these LCSCs. The present study provides genetic heterogeneity depending on the surface markers for LCSCs. The genetic heterogeneity of LCSCs should be considered in the development of LCSC-targeting therapeutics.
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Affiliation(s)
- Minjeong Kim
- Department of Anatomy, School of Medicine, Pusan National University, Yangsan, Korea
| | - Kwang-Woo Jo
- Department of Anatomy, School of Medicine, Pusan National University, Yangsan, Korea
| | - Hyojin Kim
- Department of Anatomy, School of Medicine, Pusan National University, Yangsan, Korea
| | - Myoung-Eun Han
- Department of Anatomy, School of Medicine, Pusan National University, Yangsan, Korea
| | - Sae-Ock Oh
- Department of Anatomy, School of Medicine, Pusan National University, Yangsan, Korea
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16
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Mierke CT. The versatile roles of ADAM8 in cancer cell migration, mechanics, and extracellular matrix remodeling. Front Cell Dev Biol 2023; 11:1130823. [PMID: 36910158 PMCID: PMC9995898 DOI: 10.3389/fcell.2023.1130823] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Accepted: 02/15/2023] [Indexed: 02/25/2023] Open
Abstract
The posttranslational proteolytic cleavage is a unique and irreversible process that governs the function and half-life of numerous proteins. Thereby the role of the family of A disintegrin and metalloproteases (ADAMs) plays a leading part. A member of this family, ADAM8, has gained attention in regulating disorders, such as neurogenerative diseases, immune function and cancer, by attenuating the function of proteins nearby the extracellular membrane leaflet. This process of "ectodomain shedding" can alter the turnover rate of a number of transmembrane proteins that function in cell adhesion and receptor signal transduction. In the past, the major focus of research about ADAMs have been on neurogenerative diseases, such as Alzheimer, however, there seems to be evidence for a connection between ADAM8 and cancer. The role of ADAMs in the field of cancer research has gained recent attention, but it has been not yet been extensively addressed. Thus, this review article highlights the various roles of ADAM8 with particular emphasis on pathological conditions, such as cancer and malignant cancer progression. Here, the shedding function, direct and indirect matrix degradation, effects on cancer cell mobility and transmigration, and the interplay of ADAM8 with matrix-embedded neighboring cells are presented and discussed. Moreover, the most probable mechanical impact of ADAM8 on cancer cells and their matrix environment is addressed and debated. In summary, this review presents recent advances in substrates/ligands and functions of ADAM8 in its new role in cancer and its potential link to cell mechanical properties and discusses matrix mechanics modifying properties. A deeper comprehension of the regulatory mechanisms governing the expression, subcellular localization, and activity of ADAM8 is expected to reveal appropriate drug targets that will permit a more tailored and fine-tuned modification of its proteolytic activity in cancer development and metastasis.
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Affiliation(s)
- Claudia Tanja Mierke
- Faculty of Physics and Earth Science, Biological Physics Division, Peter Debye Institute of Soft Matter Physics, Leipzig University, Leipzig, Germany
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17
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Muacevic A, Adler JR, Mohiyuddin AS. Role of Matrix Metalloproteinase 9 in Predicting Lymph Node Metastases in Oral Squamous Cell Carcinoma. Cureus 2023; 15:e33495. [PMID: 36756017 PMCID: PMC9902810 DOI: 10.7759/cureus.33495] [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] [Accepted: 12/31/2022] [Indexed: 01/09/2023] Open
Abstract
Background Oral cancer is a common malignancy worldwide, with approximately 3,50,000 new cases diagnosed yearly. Out of many factors which affect the survival in patients with oral cancer, lymph node metastases are a major factor that reduces survival by 50%. Even though many biomarkers have been studied to predict lymph node metastasis, none have yet been accepted for routine use. Matrix metalloproteinases (MMPs) play a vital role in extracellular matrix (ECM) degradation, thus facilitating the invasive potential and the metastatic cascade of tumors. Of the different subtypes, multiple studies have demonstrated that matrix metalloproteinase 9 (MMP9) overexpression is often associated with the aggressive nature of the tumor. Therefore, this investigation is done to know the role of MMP9 in predicting lymph node metastasis in oral squamous cell carcinoma (OSCC). Aim To determine the immunohistochemical expression of MMP9 in OSCC and to find its association with lymph node metastasis. Settings and design It is a laboratory-based observational study. Materials and methods One hundred five histologically proven cases of OSCC were studied. Histopathological parameters like depth of invasion, presence of lymph node metastasis, grading, and TNM staging were done according to the 8th AJCC staging criteria. Both intensity and proportion of MMP9 expression were recorded. Statistical analysis For qualitative data, the Chi-square test was used as a test of significance. The p-value (probability that the result is true) of <0.05 was considered statistically significant after assuming all the rules of statistical tests. Results A higher expression of MMP9 was observed in 56.2% of cases and the higher expression correlated with the presence of lymph node metastases (p<0.001), an advanced stage of cancer (P <0.001), and grade of the tumor (p=0.003). Conclusion A positive association between MMP9 and lymph node metastasis and pathological TNM staging demonstrates MMP9 as a potential biomarker to predict the behavior of the tumor.
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18
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Mansoori-Kermani A, Khalighi S, Akbarzadeh I, Niavol FR, Motasadizadeh H, Mahdieh A, Jahed V, Abdinezhad M, Rahbariasr N, Hosseini M, Ahmadkhani N, Panahi B, Fatahi Y, Mozafari M, Kumar AP, Mostafavi E. Engineered hyaluronic acid-decorated niosomal nanoparticles for controlled and targeted delivery of epirubicin to treat breast cancer. Mater Today Bio 2022; 16:100349. [PMID: 35875198 PMCID: PMC9304880 DOI: 10.1016/j.mtbio.2022.100349] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Revised: 06/17/2022] [Accepted: 07/01/2022] [Indexed: 12/24/2022] Open
Abstract
Targeted drug delivery systems using nanocarriers offer a versatile platform for breast cancer treatment; however, a robust, CD44-targeted niosomal formulation has not been developed and deeply studied (both in vitro and in vivo) yet. Here, an optimized system of epirubicin (Epi)-loaded niosomal nanoparticles (Nio) coated with hyaluronic acid (HA) has been engineered for targeting breast cancer cells. The nanoformulation was first optimized (based on size, polydispersity index, and entrapment efficiency); then, we characterized the morphology, stability, and release behavior of the nanoparticles. Epirubicin release from the HA-coated system (Epi-Nio-HA) showed a 21% (acidic buffer) and 20% (neutral buffer) reduction in comparison with the non-coated group (Epi-Nio). The cytotoxicity and apoptosis results of 4T1 and SkBr3 cells showed an approximately 2-fold increase in the Epi-Nio-HA system over Epi-Nio and free epirubicin, which confirms the superiority of the engineered nanocarriers. Moreover, real-time PCR data demonstrated the down-regulation of the MMP-2, MMP-9, cyclin D, and cyclin E genes expression while caspase-3 and caspase-9 gene expression were up-regulated. Confocal microscopy and flow cytometry studies uncovered the cellular uptake mechanism of the Epi-Nio-HA system, which was CD44-mediated. Furthermore, in vivo studies indicated Epi-Nio-HA decreased mice breast tumor volume by 28% (compared to epirubicin) without side effects on the liver and kidney. Conclusively, our results indicated that the HA-functionalized niosomes provide a promising nanoplatform for efficient and targeted delivery of epirubicin to potentially treat breast cancer.
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Affiliation(s)
| | - Sadaf Khalighi
- Department of Chemical and Petrochemical Engineering, Sharif University of Technology, Tehran, Iran
| | - Iman Akbarzadeh
- Department of Chemical and Petrochemical Engineering, Sharif University of Technology, Tehran, Iran
| | - Fazeleh Ranjbar Niavol
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Hamidreza Motasadizadeh
- Department of Pharmaceutical Nanotechnology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
- Nanotechnology Research Centre, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Athar Mahdieh
- Department of Pharmaceutical Nanotechnology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Vahid Jahed
- Rudolfs Cimdins Riga Biomaterials Innovations and Development Centre of RTU, Institute of General Chemical Engineering, Faculty of Materials Science and Applied Chemistry, Riga Technical University, Pulka St. 3/3, Riga, LV, 1007, Latvia
| | - Masoud Abdinezhad
- School of Chemical Engineering, College of Engineering, University of Tehran, Tehran, Iran
| | - Nikoo Rahbariasr
- Polymer Research Laboratory, Department of Chemistry, Sharif University of Technology, Tehran, Iran
| | - Mahshid Hosseini
- Department of Chemical and Petrochemical Engineering, Sharif University of Technology, Tehran, Iran
| | - Nima Ahmadkhani
- Department of Chemical and Petrochemical Engineering, Sharif University of Technology, Tehran, Iran
| | - Behnam Panahi
- Department of Chemical and Petrochemical Engineering, Sharif University of Technology, Tehran, Iran
| | - Yousef Fatahi
- Department of Pharmaceutical Nanotechnology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
- Nanotechnology Research Centre, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Masoud Mozafari
- Department of Tissue Engineering and Regenerative Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Alan Prem Kumar
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore
- NUS Center for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore
| | - Ebrahim Mostafavi
- Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, 94305, USA
- Department of Medicine, Stanford University School of Medicine, Stanford, CA, 94305, USA
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19
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Guo Q, Yang C, Gao F. The state of CD44 activation in cancer progression and therapeutic targeting. FEBS J 2022; 289:7970-7986. [PMID: 34478583 DOI: 10.1111/febs.16179] [Citation(s) in RCA: 57] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2021] [Revised: 07/20/2021] [Accepted: 09/02/2021] [Indexed: 01/14/2023]
Abstract
CD44, a non-kinase transmembrane glycoprotein, is ubiquitously expressed on various types of cells, especially cancer stem cells (CSCs), and has been implicated in cancer onset and aggressiveness. The major ligand for the CD44, hyaluronan (HA), binds to and interacts with CD44, which in turn triggers downstream signaling cascades, thereby promoting cellular behaviors such as proliferation, motility, invasiveness and chemoresistance. The CD44-HA interaction is cell-specific and strongly affected by the state of CD44 activation. Therefore, the binding of HA to CD44 is essential for the activation of CD44 during which the detailed regulatory mechanism needs to be clarified. Different CD44 activation states distribute in human carcinoma and normal tissue; however, whether CD44 activation is a critical requirement for tumor initiation, progression and notorious CSC properties remains to be clarified. A deeper understanding of the regulation of CD44 activation may facilitate the development of novel targeted drugs in the future. Here, we review the current findings concerning the states of CD44 activation on the cell surface, the underlying regulatory mechanisms of CD44 activation, the known role for CD44 activation in tumor progression and CSC hallmarks, as well as the potential of HA-coated nanoparticle for targeting activated CD44 for cancer therapy.
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Affiliation(s)
- Qian Guo
- Department of Molecular Biology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Cuixia Yang
- Department of Molecular Biology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.,Department of Clinical Laboratory, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Feng Gao
- Department of Molecular Biology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.,Department of Clinical Laboratory, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
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20
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Ren G, Peng Q, Emmersen J, Zachar V, Fink T, Porsborg SR. A Comparative Analysis of the Wound Healing-Related Heterogeneity of Adipose-Derived Stem Cells Donors. Pharmaceutics 2022; 14:2126. [PMID: 36297561 PMCID: PMC9608503 DOI: 10.3390/pharmaceutics14102126] [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: 08/30/2022] [Revised: 09/30/2022] [Accepted: 10/04/2022] [Indexed: 11/16/2022] Open
Abstract
Adipose-derived Stem cells (ASCs) are on the verge of being available for large clinical trials in wound healing. However, for developing advanced therapy medicinal products (ATMPs), potency assays mimicking the mode of action are required to control the product consistency of the cells. Thus, greater effort should go into the design of product assays. Therefore, we analyzed three ASC-based ATMPs from three different donors with respect to their surface markers, tri-lineage differentiation, proliferation, colony-forming unit capacity, and effect on fibroblast proliferation and migration, endothelial proliferation, migration, and angiogenesis. Furthermore, the transcriptome of all three cell products was analyzed through RNA-sequencing. Even though all products met the criteria by the International Society for Cell and Gene Therapy and the International Federation for Adipose Therapeutics and Science, we found one product to be consistently superior to others when exploring their potency in the wound healing specific assays. Our results indicate that certain regulatory genes associated with extracellular matrix and angiogenesis could be used as markers of a superior ASC donor from which to use ASCs to treat chronic wounds. Having a panel of assays capable of predicting the potency of the product would ensure the patient receives the most potent product for a specific indication, which is paramount for successful patient treatment and acceptance from the healthcare system.
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Affiliation(s)
| | | | | | | | | | - Simone R. Porsborg
- Regenerative Medicine Group, Department of Health Science and Technology, Aalborg University, Fredrik Bajers Vej 3B, 9220 Aalborg, Denmark
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21
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Sin YJA, MacLeod R, Tanguay AP, Wang A, Braender-Carr O, Vitelli TM, Jay GD, Schmidt TA, Cowman MK. Noncovalent hyaluronan crosslinking by TSG-6: Modulation by heparin, heparan sulfate, and PRG4. Front Mol Biosci 2022; 9:990861. [PMID: 36275631 PMCID: PMC9579337 DOI: 10.3389/fmolb.2022.990861] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2022] [Accepted: 09/20/2022] [Indexed: 11/13/2022] Open
Abstract
The size, conformation, and organization of the glycosaminoglycan hyaluronan (HA) affect its interactions with soluble and cell surface-bound proteins. HA that is induced to form stable networks has unique biological properties relative to unmodified soluble HA. AlphaLISA assay technology offers a facile and general experimental approach to assay protein-mediated networking of HA in solution. Connections formed between two end-biotinylated 50 kDa HA (bHA) chains can be detected by signal arising from streptavidin-coated donor and acceptor beads being brought into close proximity when the bHA chains are bridged by proteins. We observed that incubation of bHA with the protein TSG-6 (tumor necrosis factor alpha stimulated gene/protein 6, TNFAIP/TSG-6) leads to dimerization or higher order multimerization of HA chains in solution. We compared two different heparin (HP) samples and two heparan sulfate (HS) samples for the ability to disrupt HA crosslinking by TSG-6. Both HP samples had approximately three sulfates per disaccharide, and both were effective in inhibiting HA crosslinking by TSG-6. HS with a relatively high degree of sulfation (1.75 per disaccharide) also inhibited TSG-6 mediated HA networking, while HS with a lower degree of sulfation (0.75 per disaccharide) was less effective. We further identified Proteoglycan 4 (PRG4, lubricin) as a TSG-6 ligand, and found it to inhibit TSG-6-mediated HA crosslinking. The effects of HP, HS, and PRG4 on HA crosslinking by TSG-6 were shown to be due to HP/HS/PRG4 inhibition of HA binding to the Link domain of TSG-6. Using the AlphaLISA platform, we also tested other HA-binding proteins for ability to create HA networks. The G1 domain of versican (VG1) effectively networked bHA in solution but required a higher concentration than TSG-6. Cartilage link protein (HAPLN1) and the HA binding protein segment of aggrecan (HABP, G1-IGD-G2) showed only low and variable magnitude HA networking effects. This study unambiguously demonstrates HA crosslinking in solution by TSG-6 and VG1 proteins, and establishes PRG4, HP and highly sulfated HS as modulators of TSG-6 mediated HA crosslinking.
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Affiliation(s)
- Yun Jin Ashley Sin
- Department of Biomedical Engineering, Tandon School of Engineering, New York University, New York, NY, United States
| | - Rebecca MacLeod
- Department of Biomedical Engineering, Tandon School of Engineering, New York University, New York, NY, United States
| | - Adam P. Tanguay
- Department of Biomedical Engineering, School of Dental Medicine, UConn Health, Farmington, CT, United States
| | - Andrew Wang
- New York Medical College, Valhalla, NY, United States
| | - Olivia Braender-Carr
- Department of Biomedical Engineering, Tandon School of Engineering, New York University, New York, NY, United States
| | - Teraesa M. Vitelli
- Department of Biomedical Engineering, Tandon School of Engineering, New York University, New York, NY, United States
| | - Gregory D. Jay
- Department of Emergency Medicine, Warren Alpert Medical School and School of Engineering, Brown University, Providence, RI, United States
| | - Tannin A. Schmidt
- Department of Biomedical Engineering, School of Dental Medicine, UConn Health, Farmington, CT, United States
- *Correspondence: Mary K. Cowman, ; Tannin A. Schmidt,
| | - Mary K. Cowman
- Department of Biomedical Engineering, Tandon School of Engineering, New York University, New York, NY, United States
- Department of Orthopedic Surgery, Grossman School of Medicine, New York University, New York, NY, United States
- *Correspondence: Mary K. Cowman, ; Tannin A. Schmidt,
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22
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Abd Elhakeem AAE, Essa AA, Soliman RK, Hamdan ARK. Novel evaluation of the expression patterns CD44 and MMP9 proteins in intracranial meningiomas and their relationship to the overall survival. EGYPTIAN JOURNAL OF NEUROSURGERY 2022. [DOI: 10.1186/s41984-022-00173-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
Abstract
Abstract
Background
Meningiomas are common primary brain neoplasms. CD44 is a cell surface glycoprotein receptor that is involved in matrix-mediated cell signaling and cell–matrix adhesion. Matrix metalloproteinase-9 (MMP-9) plays important role in angiogenesis and tumor invasion. The expression of CD44 protein membranous and cytoplasmic (CD44M and CD44C) has been reported in several tumors (such as lobular carcinoma, renal cell carcinoma, sinonasal melanoma, and lymphoma) except CNS tumors.
Methods
This study addressed the expression of CD44M and CD44C and MMP9 proteins in intracranial meningiomas and their relationship to overall survival. The expression patterns of CD44M&C and MMP-9 proteins were examined in 32 cases of benign meningiomas, 12 cases of atypical meningiomas, and 6 cases of anaplastic meningiomas using immunohistochemical staining methods.
Results
There was more evidence of CD44M expression in atypical and anaplastic meningioma (p = < 0.001). Interestingly, Spearman correlation analyses revealed significant positive correlation between CD44M and MMP9 protein (r = 0.572, p = < 0.001) in spite of the negative correlation between MMP9 and CD44 score (r = − 0.035 p = 0.405). There was a significant association between Ki67 protein expression and the grade of meningiomas (p < 0.001) and gender (p = 0.026). There was a significant correlation between overall survival (OS) and age, gender, tumor grade, and Ki-67.
Conclusions
Extensive CD44M expression in high-grade meningioma may reflect a tendency toward more invasive power of meningioma cells into surrounding structures (dura, bone, and brain).CD44M/MMP-9 axis presented by this study is open for future investigations.
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Carvalho AM, Valcarcel J, Soares da Costa D, Gomes M, Vázquez JA, Reis RL, Novoa-Carballal R, Pashkuleva I. Hyaluronan Brush-like Copolymers Promote CD44 Declustering in Breast Cancer Cells. ACS APPLIED MATERIALS & INTERFACES 2022; 14:41779-41789. [PMID: 36053163 DOI: 10.1021/acsami.2c11864] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
We report on the synthesis of hyaluronan (HA) brush-like copolymers and their application as antagonists of tumorigenic CD44-HA interactions. HA (4.8 kDa, ca. 24 saccharides) was grafted on 2-hydrohyethyl methacrylate (HEMA) by end-on oxime ligation. The obtained copolymers were compared with low and high molecular weight HA in terms of hydrolysis kinetics in the presence of hyaluronidase (isothermal titration calorimetry) and interactions with CD44 (surface plasmon resonance). The results evidenced that the high molecular weight HA and HA-g-HEMA have a much higher affinity to CD44 than low molecular weight HA. Additionally, slower enzymatic degradation was observed for the copolymer, making it an excellent candidate for active targeting of tumorigenic CD44-HA interactions. We, therefore, investigated the effect of the copolymer on cancer cell lines with different expression of CD44 and observed an efficient declustering of CD44 that is usually associated with reduction of metastasis and drug resistance.
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Affiliation(s)
- Ana M Carvalho
- 3B's Research Group, I3Bs - Research Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, Avepark, Parque de Ciência e Tecnologia, Zona Industrial da Gandra, 4805-017Barco, Portugal
- ICVS/3B's - PT Government Associate Laboratory, 4710-057Braga/Guimarães, Portugal
| | - Jesus Valcarcel
- Grupo de Reciclado y Valorización de Materiales Residuales (REVAL), Instituto de Investigacións Mariñas (IIM-CSIC), Eduardo Cabello 6, Vigo36208, Galicia, Spain
| | - Diana Soares da Costa
- 3B's Research Group, I3Bs - Research Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, Avepark, Parque de Ciência e Tecnologia, Zona Industrial da Gandra, 4805-017Barco, Portugal
- ICVS/3B's - PT Government Associate Laboratory, 4710-057Braga/Guimarães, Portugal
| | - Marisa Gomes
- 3B's Research Group, I3Bs - Research Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, Avepark, Parque de Ciência e Tecnologia, Zona Industrial da Gandra, 4805-017Barco, Portugal
- ICVS/3B's - PT Government Associate Laboratory, 4710-057Braga/Guimarães, Portugal
| | - José Antonio Vázquez
- Grupo de Reciclado y Valorización de Materiales Residuales (REVAL), Instituto de Investigacións Mariñas (IIM-CSIC), Eduardo Cabello 6, Vigo36208, Galicia, Spain
| | - Rui L Reis
- 3B's Research Group, I3Bs - Research Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, Avepark, Parque de Ciência e Tecnologia, Zona Industrial da Gandra, 4805-017Barco, Portugal
- ICVS/3B's - PT Government Associate Laboratory, 4710-057Braga/Guimarães, Portugal
| | - Ramon Novoa-Carballal
- 3B's Research Group, I3Bs - Research Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, Avepark, Parque de Ciência e Tecnologia, Zona Industrial da Gandra, 4805-017Barco, Portugal
- ICVS/3B's - PT Government Associate Laboratory, 4710-057Braga/Guimarães, Portugal
| | - Iva Pashkuleva
- 3B's Research Group, I3Bs - Research Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, Avepark, Parque de Ciência e Tecnologia, Zona Industrial da Gandra, 4805-017Barco, Portugal
- ICVS/3B's - PT Government Associate Laboratory, 4710-057Braga/Guimarães, Portugal
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24
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Itoh Y. Proteolytic modulation of tumor microenvironment signals during cancer progression. Front Oncol 2022; 12:935231. [PMID: 36132127 PMCID: PMC9483212 DOI: 10.3389/fonc.2022.935231] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Accepted: 08/10/2022] [Indexed: 11/13/2022] Open
Abstract
Under normal conditions, the cellular microenvironment is optimized for the proper functioning of the tissues and organs. Cells recognize and communicate with the surrounding cells and extracellular matrix to maintain homeostasis. When cancer arises, the cellular microenvironment is modified to optimize its malignant growth, evading the host immune system and finding ways to invade and metastasize to other organs. One means is a proteolytic modification of the microenvironment and the signaling molecules. It is now well accepted that cancer progression relies on not only the performance of cancer cells but also the surrounding microenvironment. This mini-review discusses the current understanding of the proteolytic modification of the microenvironment signals during cancer progression.
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Choi BH, Ryoo I, Sim KH, Ahn HJ, Lee YJ, Kwak MK. High Levels of Hyaluronic Acid Synthase-2 Mediate NRF2-Driven Chemoresistance in Breast Cancer Cells. Biomol Ther (Seoul) 2022; 30:368-379. [PMID: 35768333 PMCID: PMC9252875 DOI: 10.4062/biomolther.2022.074] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Revised: 06/02/2022] [Accepted: 06/02/2022] [Indexed: 01/06/2023] Open
Abstract
Hyaluronic acid (HA), a ligand of CD44, accumulates in some types of tumors and is responsible for tumor progression. The nuclear factor erythroid 2-like 2 (NRF2) regulates cytoprotective genes and drug transporters, which promotes therapy resistance in tumors. Previously, we showed that high levels of CD44 are associated with NRF2 activation in cancer stem like-cells. Herein, we demonstrate that HA production was increased in doxorubicin-resistant breast cancer MCF7 cells (MCF7-DR) via the upregulation of HA synthase-2 (HAS2). HA incubation increased NRF2, aldo-keto reductase 1C1 (AKR1C1), and multidrug resistance gene 1 (MDR1) levels. Silencing of HAS2 or CD44 suppressed NRF2 signaling in MCF7-DR, which was accompanied by increased doxorubicin sensitivity. The treatment with a HAS2 inhibitor, 4-methylumbelliferone (4-MU), decreased NRF2, AKR1C1, and MDR1 levels in MCF7-DR. Subsequently, 4-MU treatment inhibited sphere formation and doxorubicin resistance in MCF7-DR. The Cancer Genome Atlas (TCGA) data analysis across 32 types of tumors indicates the amplification of HAS2 gene is a common genetic alteration and is negatively correlated with the overall survival rate. In addition, high HAS2 mRNA levels are associated with increased NRF2 signaling and poor clinical outcome in breast cancer patients. Collectively, these indicate that HAS2 elevation contributes to chemoresistance and sphere formation capacity of drug-resistant MCF7 cells by activating CD44/NRF2 signaling, suggesting a potential benefit of HAS2 inhibition.
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Affiliation(s)
- Bo-Hyun Choi
- Department of Pharmacology, School of Medicine, Daegu Catholic University, Daegu 42472, Republic of Korea
| | - Ingeun Ryoo
- Department of Pharmacology and Integrated Research Institute for Pharmaceutical Sciences, The Catholic University of Korea, Bucheon 14662, Republic of Korea
| | - Kyeong Hwa Sim
- Department of Pharmacology, School of Medicine, Daegu Catholic University, Daegu 42472, Republic of Korea
| | - Hyeon-Jin Ahn
- Department of Pharmacology, School of Medicine, Daegu Catholic University, Daegu 42472, Republic of Korea
| | - Youn Ju Lee
- Department of Pharmacology, School of Medicine, Daegu Catholic University, Daegu 42472, Republic of Korea
| | - Mi-Kyoung Kwak
- Department of Pharmacology and Integrated Research Institute for Pharmaceutical Sciences, The Catholic University of Korea, Bucheon 14662, Republic of Korea.,College of Pharmacy, The Catholic University of Korea, Bucheon 14662, Republic of Korea
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26
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Fernández-Tabanera E, Melero-Fernández de Mera RM, Alonso J. CD44 In Sarcomas: A Comprehensive Review and Future Perspectives. Front Oncol 2022; 12:909450. [PMID: 35785191 PMCID: PMC9247467 DOI: 10.3389/fonc.2022.909450] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Accepted: 05/02/2022] [Indexed: 12/16/2022] Open
Abstract
It is widely accepted that the tumor microenvironment, particularly the extracellular matrix, plays an essential role in the development of tumors through the interaction with specific protein-membrane receptors. One of the most relevant proteins in this context is the transmembrane protein CD44. The role of CD44 in tumor progression, invasion, and metastasis has been well established in many cancers, although a comprehensive review concerning its role in sarcomas has not been published. CD44 is overexpressed in most sarcomas and several in vitro and in vivo experiments have shown a direct effect on tumor progression, dissemination, and drug resistance. Moreover, CD44 has been revealed as a useful marker for prognostic and diagnostic (CD44v6 isoform) in osteosarcoma. Besides, some innovative treatments such as HA-functionalized liposomes therapy have become an excellent CD44-mediated intracellular delivery system for osteosarcoma. Unfortunately, the reduced number of studies deciphering the prognostic/diagnostic value of CD44 in other sarcoma subgroups, neither than osteosarcoma, in addition to the low number of patients involved in those studies, have produced inconclusive results. In this review, we have gone through the information available on the role of CD44 in the development, maintenance, and progression of sarcomas, analyzing their implications at the prognostic, therapeutic, and mechanistic levels. Moreover, we illustrate how research involving the specific role of CD44 in the different sarcoma subgroups could suppose a chance to advance towards a more innovative perspective for novel therapies and future clinical trials.
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Affiliation(s)
- Enrique Fernández-Tabanera
- Unidad de Tumores Sólidos Infantiles, Instituto de Investigación de Enfermedades Raras (IIER), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Raras, Instituto de Salud Carlos III (U758; CB06/07/1009; CIBERER-ISCIII), Madrid, Spain
- Universidad Nacional de Educación a Distancia (UNED), Madrid, Spain
| | - Raquel M. Melero-Fernández de Mera
- Unidad de Tumores Sólidos Infantiles, Instituto de Investigación de Enfermedades Raras (IIER), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Raras, Instituto de Salud Carlos III (U758; CB06/07/1009; CIBERER-ISCIII), Madrid, Spain
| | - Javier Alonso
- Unidad de Tumores Sólidos Infantiles, Instituto de Investigación de Enfermedades Raras (IIER), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Raras, Instituto de Salud Carlos III (U758; CB06/07/1009; CIBERER-ISCIII), Madrid, Spain
- *Correspondence: Javier Alonso,
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Augoff K, Hryniewicz-Jankowska A, Tabola R, Stach K. MMP9: A Tough Target for Targeted Therapy for Cancer. Cancers (Basel) 2022; 14:cancers14071847. [PMID: 35406619 PMCID: PMC8998077 DOI: 10.3390/cancers14071847] [Citation(s) in RCA: 105] [Impact Index Per Article: 35.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Revised: 03/27/2022] [Accepted: 03/31/2022] [Indexed: 02/01/2023] Open
Abstract
Having the capability to proteolyze diverse structural and signaling proteins, matrix metalloproteinase 9 (MMP9), one of the best-studied secretory endopeptidases, has been identified as a crucial mediator of processes closely associated with tumorigenesis, such as the extracellular matrix reorganization, epithelial to mesenchymal transition, cell migration, new blood vessel formation, and immune response. In this review, we present the current state of knowledge on MMP9 and its role in cancer growth in the context of cell adhesion/migration, cancer-related inflammation, and tumor microenvironment formation. We also summarize recent achievements in the development of selective MMP9 inhibitors and the limitations of using them as anticancer drugs.
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Affiliation(s)
- Katarzyna Augoff
- Department of Surgical Education, Wroclaw Medical University, 50-367 Wroclaw, Poland
- Department of Chemistry and Immunochemistry, Wroclaw Medical University, 50-367 Wroclaw, Poland;
- Correspondence:
| | | | - Renata Tabola
- Department of Thoracic Surgery, Wroclaw Medical University, 50-367 Wroclaw, Poland;
| | - Kamilla Stach
- Department of Chemistry and Immunochemistry, Wroclaw Medical University, 50-367 Wroclaw, Poland;
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28
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Dolatabadi S, Jonasson E, Andersson L, Luna Santamaría M, Lindén M, Österlund T, Åman P, Ståhlberg A. FUS-DDIT3 Fusion Oncoprotein Expression Affects JAK-STAT Signaling in Myxoid Liposarcoma. Front Oncol 2022; 12:816894. [PMID: 35186752 PMCID: PMC8851354 DOI: 10.3389/fonc.2022.816894] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Accepted: 01/06/2022] [Indexed: 11/25/2022] Open
Abstract
Myxoid liposarcoma is one of the most common sarcoma entities characterized by FET fusion oncogenes. Despite a generally favorable prognosis of myxoid liposarcoma, chemotherapy resistance remains a clinical problem. This cancer stem cell property is associated with JAK-STAT signaling, but the link to the myxoid-liposarcoma-specific FET fusion oncogene FUS-DDIT3 is not known. Here, we show that ectopic expression of FUS-DDIT3 resulted in elevated levels of STAT3 and phosphorylated STAT3. RNA sequencing identified 126 genes that were regulated by both FUS-DDIT3 expression and JAK1/2 inhibition using ruxolitinib. Sixty-six of these genes were connected in a protein interaction network. Fifty-three and 29 of these genes were confirmed as FUS-DDIT3 and STAT3 targets, respectively, using public chromatin immunoprecipitation sequencing data sets. Enriched gene sets among the 126 regulated genes included processes related to cytokine signaling, adipocytokine signaling, and chromatin remodeling. We validated CD44 as a target gene of JAK1/2 inhibition and as a potential cancer stem cell marker in myxoid liposarcoma. Finally, we showed that FUS-DDIT3 interacted with phosphorylated STAT3 in association with subunits of the SWI/SNF chromatin remodeling complex and PRC2 repressive complex. Our data show that the function of FUS-DDIT3 is closely connected to JAK-STAT signaling. Detailed deciphering of molecular mechanisms behind tumor progression opens up new avenues for targeted therapies in sarcomas and leukemia characterized by FET fusion oncogenes.
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Affiliation(s)
- Soheila Dolatabadi
- Sahlgrenska Center for Cancer Research, Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
| | - Emma Jonasson
- Sahlgrenska Center for Cancer Research, Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
| | - Lisa Andersson
- Sahlgrenska Center for Cancer Research, Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
| | - Manuel Luna Santamaría
- Sahlgrenska Center for Cancer Research, Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.,Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Gothenburg, Sweden
| | - Malin Lindén
- Sahlgrenska Center for Cancer Research, Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
| | - Tobias Österlund
- Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Gothenburg, Sweden.,Region Västra Götaland, Department of Clinical Genetics and Genomics, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Pierre Åman
- Sahlgrenska Center for Cancer Research, Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
| | - Anders Ståhlberg
- Sahlgrenska Center for Cancer Research, Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.,Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Gothenburg, Sweden.,Region Västra Götaland, Department of Clinical Genetics and Genomics, Sahlgrenska University Hospital, Gothenburg, Sweden
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Leung WH, Shih JW, Chen JS, Mokgautsi N, Wei PL, Huang YJ. Preclinical Identification of Sulfasalazine's Therapeutic Potential for Suppressing Colorectal Cancer Stemness and Metastasis through Targeting KRAS/MMP7/CD44 Signaling. Biomedicines 2022; 10:377. [PMID: 35203586 PMCID: PMC8962339 DOI: 10.3390/biomedicines10020377] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Revised: 01/27/2022] [Accepted: 01/29/2022] [Indexed: 02/04/2023] Open
Abstract
Approximately 25% of colorectal cancer (CRC) patients will develop metastatic (m)CRC despite treatment interventions. In this setting, tumor cells are attracted to the epidermal growth factor receptor (EGFR) oncogene. Kirsten rat sarcoma (RAS) 2 viral oncogene homolog (KRAS) mutations were reported to drive CRC by promoting cancer progression in activating Wnt/β-catenin and RAS/extracellular signal-regulated kinase (ERK) pathways. In addition, KRAS is associated with almost 40% of patients who acquire resistance to EGFR inhibitors in mCRC. Multiple studies have demonstrated that cancer stem cells (CSCs) promote tumorigenesis, tumor growth, and resistance to therapy. One of the most common CSC prognostic markers widely reported in CRC is a cluster of differentiation 44 (CD44), which regulates matrix metalloproteinases 7/9 (MMP7/9) to promote tumor progression and metastasis; however, the molecular role of CD44 in CRC is still unclear. In invasive CRC, overexpression of MMP7 was reported in tumor cells compared to normal cells and plays a crucial function in CRC cetuximab and oxaliplatin resistance and distant metastasis. Here, we utilized a bioinformatics analysis and identified overexpression of KRAS/MMP7/CD44 oncogenic signatures in CRC tumor tissues compared to normal tissues. In addition, a high incidence of mutations in KRAS and CD44 were associated with some of the top tumorigenic oncogene's overexpression, which ultimately promoted a poor response to chemotherapy and resistance to some FDA-approved drugs. Based on these findings, we explored a computational approach to drug repurposing of the drug, sulfasalazine, and our in silico molecular docking revealed unique interactions of sulfasalazine with the KRAS/MMP7/CD44 oncogenes, resulting in high binding affinities compared to those of standard inhibitors. Our in vitro analysis demonstrated that sulfasalazine combined with cisplatin reduced cell viability, colony, and sphere formation in CRC cell lines. In addition, sulfasalazine alone and combined with cisplatin suppressed the expression of KRAS/MMP7/CD44 in DLD-1 and HCT116 cell lines. Thus, sulfasalazine is worthy of further investigation as an adjuvant agent for improving chemotherapeutic responses in CRC patients.
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Affiliation(s)
- Wai-Hung Leung
- Division of Colon and Rectal Surgery, Department of Surgery, Mackay Memorial Hospital, No. 92, Sec. 2, Zhongshan N. Rd., Taipei 10449, Taiwan; (W.-H.L.); (J.-S.C.)
| | - Jing-Wen Shih
- Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei 11031, Taiwan; (J.-W.S.); (N.M.)
- Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan
- TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei 11031, Taiwan
- Ph.D. Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan
| | - Jian-Syun Chen
- Division of Colon and Rectal Surgery, Department of Surgery, Mackay Memorial Hospital, No. 92, Sec. 2, Zhongshan N. Rd., Taipei 10449, Taiwan; (W.-H.L.); (J.-S.C.)
| | - Ntlotlang Mokgautsi
- Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei 11031, Taiwan; (J.-W.S.); (N.M.)
- Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan
| | - Po-Li Wei
- Division of Colorectal Surgery, Department of Surgery, Taipei Medical University Hospital, Taipei Medical University, Taipei 110, Taiwan;
- Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan
- Division of General Surgery, Department of Surgery, Taipei Medical University Hospital, Taipei Medical University, Taipei 110, Taiwan
| | - Yan-Jiun Huang
- Division of Colorectal Surgery, Department of Surgery, Taipei Medical University Hospital, Taipei Medical University, Taipei 110, Taiwan;
- Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan
- Division of General Surgery, Department of Surgery, Taipei Medical University Hospital, Taipei Medical University, Taipei 110, Taiwan
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Platelet Membrane: An Outstanding Factor in Cancer Metastasis. MEMBRANES 2022; 12:membranes12020182. [PMID: 35207103 PMCID: PMC8875259 DOI: 10.3390/membranes12020182] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Revised: 01/27/2022] [Accepted: 01/31/2022] [Indexed: 12/02/2022]
Abstract
In addition to being biological barriers where the internalization or release of biomolecules is decided, cell membranes are contact structures between the interior and exterior of the cell. Here, the processes of cell signaling mediated by receptors, ions, hormones, cytokines, enzymes, growth factors, extracellular matrix (ECM), and vesicles begin. They triggering several responses from the cell membrane that include rearranging its components according to the immediate needs of the cell, for example, in the membrane of platelets, the formation of filopodia and lamellipodia as a tissue repair response. In cancer, the cancer cells must adapt to the new tumor microenvironment (TME) and acquire capacities in the cell membrane to transform their shape, such as in the case of epithelial−mesenchymal transition (EMT) in the metastatic process. The cancer cells must also attract allies in this challenging process, such as platelets, fibroblasts associated with cancer (CAF), stromal cells, adipocytes, and the extracellular matrix itself, which limits tumor growth. The platelets are enucleated cells with fairly interesting growth factors, proangiogenic factors, cytokines, mRNA, and proteins, which support the development of a tumor microenvironment and support the metastatic process. This review will discuss the different actions that platelet membranes and cancer cell membranes carry out during their relationship in the tumor microenvironment and metastasis.
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31
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Inhibitor of Hyaluronic Acid Synthesis 4-Methylumbelliferone Suppresses the Secretory Processes That Ensure the Invasion of Neutrophils into Tissues and Induce Inflammation. Biomedicines 2022; 10:biomedicines10020314. [PMID: 35203523 PMCID: PMC8869632 DOI: 10.3390/biomedicines10020314] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Revised: 01/21/2022] [Accepted: 01/27/2022] [Indexed: 02/01/2023] Open
Abstract
Integrin-dependent adhesion of neutrophils to tissue, accompanied by the development of neutrophil-induced inflammation, occurs both in the focus of infection and in the absence of infection in metabolic disorders such as reperfusion after ischemia, diabetes mellitus, or the development of pneumonia in patients with cystic fibrosis or viral diseases. Hyaluronic acid (HA) plays an important role in the recruitment of neutrophils to tissues. 4-methylumbilliferon (4-MU), an inhibitor of HA synthesis, is used to treat inflammation, but its mechanism of action is unknown. We studied the effect of 4-MU on neutrophil adhesion and concomitant secretion using adhesion to fibronectin as a model for integrin-dependent adhesion. 4-MU reduced the spreading of neutrophils on the substrate and the concomitant secretion of granule proteins, including pro-inflammatory components. 4-MU also selectively blocked adhesion-induced release of the free amino acid hydroxylysine, a product of lysyl hydroxylase, which can influence cell invasion by modifying the extracellular matrix. Finally, 4-MU inhibited the formation of cytonemes, the extracellular membrane secretory structures containing the pro-inflammatory bactericides of the primary granules. The anti-inflammatory effect of 4-MU may be associated with the suppression of secretory processes that ensure the neutrophil invasion and initiate inflammation. We suggest that HA, due to the peculiarities of its synthesis, can promote the release of secretory carriers from the cell and 4-MU can block this process.
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Gouda G, Gupta MK, Donde R, Behera L, Vadde R. Tumor microenvironment in heptocellular carcinoma. THERANOSTICS AND PRECISION MEDICINE FOR THE MANAGEMENT OF HEPATOCELLULAR CARCINOMA 2022:109-124. [DOI: 10.1016/b978-0-323-98806-3.00007-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/06/2023]
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Hassn Mesrati M, Syafruddin SE, Mohtar MA, Syahir A. CD44: A Multifunctional Mediator of Cancer Progression. Biomolecules 2021; 11:1850. [PMID: 34944493 PMCID: PMC8699317 DOI: 10.3390/biom11121850] [Citation(s) in RCA: 218] [Impact Index Per Article: 54.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Revised: 10/23/2021] [Accepted: 11/02/2021] [Indexed: 12/15/2022] Open
Abstract
CD44, a non-kinase cell surface transmembrane glycoprotein, has been widely implicated as a cancer stem cell (CSC) marker in several cancers. Cells overexpressing CD44 possess several CSC traits, such as self-renewal and epithelial-mesenchymal transition (EMT) capability, as well as a resistance to chemo- and radiotherapy. The CD44 gene regularly undergoes alternative splicing, resulting in the standard (CD44s) and variant (CD44v) isoforms. The interaction of such isoforms with ligands, particularly hyaluronic acid (HA), osteopontin (OPN) and matrix metalloproteinases (MMPs), drive numerous cancer-associated signalling. However, there are contradictory results regarding whether high or low CD44 expression is associated with worsening clinicopathological features, such as a higher tumour histological grade, advanced tumour stage and poorer survival rates. Nonetheless, high CD44 expression significantly contributes to enhanced tumourigenic mechanisms, such as cell proliferation, metastasis, invasion, migration and stemness; hence, CD44 is an important clinical target. This review summarises current research regarding the different CD44 isoform structures and their roles and functions in supporting tumourigenesis and discusses CD44 expression regulation, CD44-signalling pathways and interactions involved in cancer development. The clinical significance and prognostic value of CD44 and the potential of CD44 as a therapeutic target in cancer are also addressed.
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Affiliation(s)
- Malak Hassn Mesrati
- Nanobiotechnology Research Group, Department of Biochemistry, Faculty of Biotechnology and Biomolecular Sciences, Universiti Putra Malaysia, Serdang 43400 UPM, Selangor, Malaysia;
| | - Saiful Effendi Syafruddin
- UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia, Cheras, Kuala Lumpur 56000, Malaysia; (S.E.S.); (M.A.M.)
| | - M. Aiman Mohtar
- UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia, Cheras, Kuala Lumpur 56000, Malaysia; (S.E.S.); (M.A.M.)
| | - Amir Syahir
- Nanobiotechnology Research Group, Department of Biochemistry, Faculty of Biotechnology and Biomolecular Sciences, Universiti Putra Malaysia, Serdang 43400 UPM, Selangor, Malaysia;
- UPM-MAKNA Cancer Research Laboratory, Institute of Bioscience, Universiti Putra Malaysia, Serdang 43400 UPM, Selangor, Malaysia
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Lee JW, Lee HY. Targeting Cancer Stem Cell Markers or Pathways: A Potential Therapeutic Strategy for Oral Cancer Treatment. Int J Stem Cells 2021; 14:386-399. [PMID: 34711702 PMCID: PMC8611309 DOI: 10.15283/ijsc21084] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 05/14/2021] [Accepted: 06/05/2021] [Indexed: 12/16/2022] Open
Abstract
Cancer stem cells (CSCs) are a small subset of cancer cells with stem cell-like properties, self-renewal potential, and differentiation capacity into multiple cell types. Critical genetic alterations or aberrantly activated signaling pathways associated with drug resistance and recurrence have been observed in multiple types of CSCs. In this context, CSCs are considered to be responsible for tumor initiation, growth, progression, therapeutic resistance, and metastasis. Therefore, to effectively eradicate CSCs, tremendous efforts have been devoted to identify specific target molecules that play a critical role in regulating their distinct functions and to develop novel therapeutics, such as proteins, monoclonal antibodies, selective small molecule inhibitors, and small antisense RNA (asRNA) drugs. Similar to other CSC types, oral CSCs can be characterized by certain pluripotency-associated markers, and oral CSCs can also survive and form 3D tumor spheres in suspension culture conditions. These oral CSC-targeting therapeutics selectively suppress specific surface markers or key signaling components and subsequently inhibit the stem-like properties of oral CSCs. A large number of new therapeutic candidates have been tested, and some products are currently in the pre-clinical or clinical development phase. In the present study, we review new oral CSC-targeted therapeutic strategies and discuss the various specific CSC surface markers and key signaling components involved in the stem-like properties, growth, drug resistance, and tumorigenicity of oral CSCs.
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Affiliation(s)
- Jin Woo Lee
- Department of Health Sciences and Technology, GAIHST, Gachon University, Incheon, Korea.,Department of Molecular Medicine, School of Medicine, Gachon University, Incheon, Korea
| | - Hwa-Yong Lee
- Department of Biomedical Science, Jungwon University, Goesan, Korea.,Division of Science Education, Kangwon National University, Chuncheon, Korea
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Itoh Y. Modulation of Microenvironment Signals by Proteolytic Shedding of Cell Surface Extracellular Matrix Receptors. Front Cell Dev Biol 2021; 9:736735. [PMID: 34796172 PMCID: PMC8593224 DOI: 10.3389/fcell.2021.736735] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Accepted: 09/20/2021] [Indexed: 01/02/2023] Open
Abstract
Multicellular organisms are composed of cells and extracellular matrix (ECM). ECM is a network of multidomain macromolecules that fills gaps between cells. It acts as a glue to connect cells, provides scaffolding for migrating cells, and pools cytokines and growth factors. ECM also directly sends signals to the cells through ECM receptors, providing survival signals and migration cues. Altogether, ECM provides a correct microenvironment for the cells to function in the tissue. Although ECM acts as a signaling molecule, they are insoluble solid molecules, unlike soluble receptor ligands such as cytokines and growth factors. Upon cell binding to the ECM through ECM receptors and signals transmitted, cells then need to have a mechanism to release from ECM to prevent prolonged signals, which may be tumorigenic, and migrate on ECM. One effective means to release the cells from ECM is to cleave the ECM receptors by proteinases. In this mini-review, current knowledge of ECM receptor shedding will be discussed.
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Affiliation(s)
- Yoshifumi Itoh
- Kennedy Institute of Rheumatology, University of Oxford, Oxford, United Kingdom
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36
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Basta MD, Paulson H, Walker JL. The local wound environment is a key determinant of the outcome of TGFβ signaling on the fibrotic response of CD44 + leader cells in an ex vivo post-cataract-surgery model. Exp Eye Res 2021; 213:108829. [PMID: 34774488 DOI: 10.1016/j.exer.2021.108829] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Revised: 10/22/2021] [Accepted: 11/03/2021] [Indexed: 01/17/2023]
Abstract
The cytokine transforming growth factor beta (TGFβ) has a role in regulating the normal and pathological response to wound healing, yet how it shifts from a pro-repair to a pro-fibrotic function within the wound environment is still unclear. Using a clinically relevant ex vivo post-cataract surgery model that mimics the lens fibrotic disease posterior capsule opacification (PCO), we investigated the influence of two distinct wound environments on shaping the TGFβ-mediated injury response of CD44+ vimentin-rich leader cells. The substantial fibrotic response of this cell population occurred within a rigid wound environment under the control of endogenous TGFβ. However, TGFβ was dispensable for the role of leader cells in wound healing on the endogenous basement membrane wound environment, where repair occurs in the absence of a major fibrotic outcome. A difference between leader cell function in these distinct environments was their cell surface expression of the latent TGFβ activator, αvβ3 integrin. This receptor is exclusively found on this CD44+ cell population when they localize to the leading edge of the rigid wound environment. Providing exogenous TGFβ to bypass any differences in the ability of the leader cells to sustain activation of TGFβ in different environments revealed their inherent ability to induce pro-fibrotic reactions on the basement membrane wound environment. Furthermore, exposure of the leader cells in the rigid wound environment to TGFβ led to an accelerated fibrotic response including the earlier appearance of pro-collagen + cells, alpha smooth muscle actin (αSMA)+ myofibroblasts, and increased fibrotic matrix production. Collectively, these findings show the influence of the local wound environment on the extent and severity of TGFβ-induced fibrotic responses. These findings have important implications for understanding the development of the lens fibrotic disease PCO in response to cataract surgery wounding.
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Affiliation(s)
- Morgan D Basta
- Department of Pathology, Anatomy and Cell Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, 19107, USA
| | - Heather Paulson
- Department of Pathology, Anatomy and Cell Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, 19107, USA
| | - Janice L Walker
- Department of Pathology, Anatomy and Cell Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, 19107, USA; Department of Ophthalmology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, 19107, USA.
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Xu S, Liu C, Zang S, Li J, Wang Y, Ren K, Li M, Zhang Z, He Q. Multifunctional self-delivery micelles targeting the invasion-metastasis cascade for enhanced chemotherapy against melanoma and the lung metastasis. Asian J Pharm Sci 2021; 16:794-805. [PMID: 35027954 PMCID: PMC8740406 DOI: 10.1016/j.ajps.2021.08.002] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Revised: 08/02/2021] [Accepted: 08/19/2021] [Indexed: 11/27/2022] Open
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Ishibashi JR, Keshri R, Taslim TH, Brewer DK, Chan TC, Lyons S, McManamen AM, Chen A, Del Castillo D, Ruohola-Baker H. Chemical Genetic Screen in Drosophila Germline Uncovers Small Molecule Drugs That Sensitize Stem Cells to Insult-Induced Apoptosis. Cells 2021; 10:cells10102771. [PMID: 34685753 PMCID: PMC8534514 DOI: 10.3390/cells10102771] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2021] [Revised: 09/23/2021] [Accepted: 09/27/2021] [Indexed: 11/16/2022] Open
Abstract
Cancer stem cells, in contrast to their more differentiated daughter cells, can endure genotoxic insults, escape apoptosis, and cause tumor recurrence. Understanding how normal adult stem cells survive and go to quiescence may help identify druggable pathways that cancer stem cells have co-opted. In this study, we utilize a genetically tractable model for stem cell survival in the Drosophila gonad to screen drug candidates and probe chemical-genetic interactions. Our study employs three levels of small molecule screening: (1) a medium-throughput primary screen in male germline stem cells (GSCs), (2) a secondary screen with irradiation and protein-constrained food in female GSCs, and (3) a tertiary screen in breast cancer organoids in vitro. Herein, we uncover a series of small molecule drug candidates that may sensitize cancer stem cells to apoptosis. Further, we have assessed these small molecules for chemical-genetic interactions in the germline and identified the NF-κB pathway as an essential and druggable pathway in GSC quiescence and viability. Our study demonstrates the power of the Drosophila stem cell niche as a model system for targeted drug discovery.
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Affiliation(s)
- Julien Roy Ishibashi
- Department of Biochemistry, University of Washington, Seattle, WA 98195, USA; (J.R.I.); (R.K.); (T.H.T.); (D.K.B.); (T.C.C.); (S.L.); (A.M.M.); (A.C.); (D.D.C.)
- Institute for Stem Cell and Regenerative Medicine, School of Medicine, University of Washington, Seattle, WA 98109, USA
| | - Riya Keshri
- Department of Biochemistry, University of Washington, Seattle, WA 98195, USA; (J.R.I.); (R.K.); (T.H.T.); (D.K.B.); (T.C.C.); (S.L.); (A.M.M.); (A.C.); (D.D.C.)
- Institute for Stem Cell and Regenerative Medicine, School of Medicine, University of Washington, Seattle, WA 98109, USA
| | - Tommy Henry Taslim
- Department of Biochemistry, University of Washington, Seattle, WA 98195, USA; (J.R.I.); (R.K.); (T.H.T.); (D.K.B.); (T.C.C.); (S.L.); (A.M.M.); (A.C.); (D.D.C.)
- Institute for Stem Cell and Regenerative Medicine, School of Medicine, University of Washington, Seattle, WA 98109, USA
| | - Daniel Kennedy Brewer
- Department of Biochemistry, University of Washington, Seattle, WA 98195, USA; (J.R.I.); (R.K.); (T.H.T.); (D.K.B.); (T.C.C.); (S.L.); (A.M.M.); (A.C.); (D.D.C.)
- Institute for Stem Cell and Regenerative Medicine, School of Medicine, University of Washington, Seattle, WA 98109, USA
| | - Tung Ching Chan
- Department of Biochemistry, University of Washington, Seattle, WA 98195, USA; (J.R.I.); (R.K.); (T.H.T.); (D.K.B.); (T.C.C.); (S.L.); (A.M.M.); (A.C.); (D.D.C.)
- Institute for Stem Cell and Regenerative Medicine, School of Medicine, University of Washington, Seattle, WA 98109, USA
| | - Scott Lyons
- Department of Biochemistry, University of Washington, Seattle, WA 98195, USA; (J.R.I.); (R.K.); (T.H.T.); (D.K.B.); (T.C.C.); (S.L.); (A.M.M.); (A.C.); (D.D.C.)
- Institute for Stem Cell and Regenerative Medicine, School of Medicine, University of Washington, Seattle, WA 98109, USA
| | - Anika Marie McManamen
- Department of Biochemistry, University of Washington, Seattle, WA 98195, USA; (J.R.I.); (R.K.); (T.H.T.); (D.K.B.); (T.C.C.); (S.L.); (A.M.M.); (A.C.); (D.D.C.)
- Institute for Stem Cell and Regenerative Medicine, School of Medicine, University of Washington, Seattle, WA 98109, USA
| | - Ashley Chen
- Department of Biochemistry, University of Washington, Seattle, WA 98195, USA; (J.R.I.); (R.K.); (T.H.T.); (D.K.B.); (T.C.C.); (S.L.); (A.M.M.); (A.C.); (D.D.C.)
- Institute for Stem Cell and Regenerative Medicine, School of Medicine, University of Washington, Seattle, WA 98109, USA
| | - Debra Del Castillo
- Department of Biochemistry, University of Washington, Seattle, WA 98195, USA; (J.R.I.); (R.K.); (T.H.T.); (D.K.B.); (T.C.C.); (S.L.); (A.M.M.); (A.C.); (D.D.C.)
- Institute for Stem Cell and Regenerative Medicine, School of Medicine, University of Washington, Seattle, WA 98109, USA
| | - Hannele Ruohola-Baker
- Department of Biochemistry, University of Washington, Seattle, WA 98195, USA; (J.R.I.); (R.K.); (T.H.T.); (D.K.B.); (T.C.C.); (S.L.); (A.M.M.); (A.C.); (D.D.C.)
- Institute for Stem Cell and Regenerative Medicine, School of Medicine, University of Washington, Seattle, WA 98109, USA
- Correspondence:
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Park Y, Jeong J, Seong S, Kim W. In Silico Evaluation of Natural Compounds for an Acidic Extracellular Environment in Human Breast Cancer. Cells 2021; 10:2673. [PMID: 34685653 PMCID: PMC8534855 DOI: 10.3390/cells10102673] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Revised: 10/01/2021] [Accepted: 10/03/2021] [Indexed: 12/11/2022] Open
Abstract
The survival rates for breast cancer (BC) have improved in recent years, but resistance, metastasis, and recurrence still remain major therapeutic challenges for BC. The acidic tumor microenvironment (TME) has attracted attention because of its association with tumorigenesis, metastasis, drug resistance, and immune surveillance. In this study, we evaluated natural compounds from traditional herbal medicine used to treat cancer that selectively target genes regulated by extracellular acidosis. We integrated four transcriptomic data including BC prognostic data from The Cancer Genome Atlas database, gene expression profiles of MCF-7 cells treated with 102 natural compounds, patterns of gene profiles by acidic condition, and single-cell RNA-sequencing from BC patient samples. Bruceine D (BD) was predicted as having the highest therapeutic potential, having an information gain (IG) score of 0.24, to regulate reprogrammed genes driven by acidosis affecting the survival of BC patients. BD showed the highest IG on EMT (IG score: 0.11) and invasion (IG score: 0.1) compared to the other phenotypes with the CancerSEA database. BD also demonstrated therapeutic potential by interfering with the tumor cell-TME interactions by reducing the amyloid beta precursor protein and CD44 expression. Therefore, BD is a potential candidate to target the acidic TME induced metastatic process in BC.
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Affiliation(s)
- YoungJoon Park
- Cnh Center for Cancer Research, Cnh Corporation, Gangnam-gu, Seoul 06154, Korea;
| | - Jaekwang Jeong
- Section of Endocrinology and Metabolism, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06519, USA;
| | - Shin Seong
- Soram Korean Medicine Hospital, Gangnam-gu, Seoul 06154, Korea;
| | - Wonnam Kim
- Cnh Center for Cancer Research, Cnh Corporation, Gangnam-gu, Seoul 06154, Korea;
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Chaudhry GES, Akim A, Naveed Zafar M, Safdar N, Sung YY, Muhammad TST. Understanding Hyaluronan Receptor (CD44) Interaction, HA-CD44 Activated Potential Targets in Cancer Therapeutics. Adv Pharm Bull 2021; 11:426-438. [PMID: 34513617 PMCID: PMC8421618 DOI: 10.34172/apb.2021.050] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2020] [Revised: 07/14/2020] [Accepted: 07/15/2020] [Indexed: 12/11/2022] Open
Abstract
Cancer is a complex mechanism involving a series of cellular events. The glycoproteins such as hyaluronan (HA) are a significant element of extracellular matrix (ECM), involve in the onset of cancer developmental process. The pivotal roles of HA in cancer progression depend on dysregulated expression in various cancer. HA, also gain attention due to consideration as a primary ligand of CD44 receptor. The CD44, complex transmembrane receptor protein, due to alternative splicing in the transcription process, various CD44 isoforms predominantly exist. The overexpression of distinct CD44 isoforms (CD44v) standard (CD44s) depends on the tumour type and stage. The receptor proteins, CD44 engage in a variety of biological processes, including cell growth, apoptosis, migration, and angiogenesis. HA-CD44 interaction trigger survival pathways that result in cell proliferation, invasion ultimately complex metastasis. The interaction and binding of ligand-receptor HA-CD44 regulate the downstream cytoskeleton pathways involve in cell survival or cell death. Thus, targeting HA, CD44 (variant and standard) isoform, and HA-CD44 binding consider as an attractive and useful approach towards cancer therapeutics. The use of various inhibitors of HA, hyaluronidases (HYALs), and utilizing targeted Nano-delivery of anticancer agents and antibodies against CD44, peptides gives promising results in vitro and in vivo. However, they are in clinical trials with favourable and unfavourable outcomes, which reflects the need for various modifications in targeting agents and a better understanding of potential targets in tumour progression pathways.
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Affiliation(s)
- Gul-E-Saba Chaudhry
- Institute of Marine Biotechnology, Universiti Malaysia Terengganu, 21030 Kuala Terengganu, Malaysia
| | - Abdah Akim
- Department of Biomedical Sciences, Universiti Putra Malaysia, Seri Kembangan, Selangor, Malaysia
| | | | - Naila Safdar
- Department of Environmental Sciences, Fatima Jinnah University, Rawalpindi, Pakistan
| | - Yeong Yik Sung
- Institute of Marine Biotechnology, Universiti Malaysia Terengganu, 21030 Kuala Terengganu, Malaysia
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Simultaneous targeting of CD44 and MMP9 catalytic and hemopexin domains as a therapeutic strategy. Biochem J 2021; 478:1139-1157. [PMID: 33600567 PMCID: PMC7959692 DOI: 10.1042/bcj20200628] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Revised: 02/09/2021] [Accepted: 02/17/2021] [Indexed: 12/11/2022]
Abstract
Crosstalk of the oncogenic matrix metalloproteinase-9 (MMP9) and one of its ligands, CD44, involves cleavage of CD44 by the MMP9 catalytic domain, with the CD44–MMP9 interaction on the cell surface taking place through the MMP9 hemopexin domain (PEX). This interaction promotes cancer cell migration and invasiveness. In concert, MMP9-processed CD44 induces the expression of MMP9, which degrades ECM components and facilitates growth factor release and activation, cancer cell invasiveness, and metastasis. Since both MMP9 and CD44 contribute to cancer progression, we have developed a new strategy to fully block this neoplastic process by engineering a multi-specific inhibitor that simultaneously targets CD44 and both the catalytic and PEX domains of MMP9. Using a yeast surface display technology, we first obtained a high-affinity inhibitor for the MMP9 catalytic domain, which we termed C9, by modifying a natural non-specific MMP inhibitor, N-TIMP2. We then conjugated C9 via a flexible linker to PEX, thereby creating a multi-specific inhibitor (C9-PEX) that simultaneously targets the MMP9 catalytic and PEX domains and CD44. It is likely that, via its co-localization with CD44, C9-PEX may compete with MMP9 localization on the cell surface, thereby inhibiting MMP9 catalytic activity, reducing MMP9 cellular levels, interfering with MMP9 homodimerization, and reducing the activation of downstream MAPK/ERK pathway signaling. The developed platform could be extended to other oncogenic MMPs as well as to other important target proteins, thereby offering great promise for creating novel multi-specific therapeutics for cancer and other diseases.
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Figuerêdo SH, Neto RSC, Ferreira E, Cassali GD, Estrela-Lima A, Damasceno KA. Expression of VCAN and its receptors in canine mammary carcinomas with or without myoepithelial proliferation. Res Vet Sci 2021; 140:56-63. [PMID: 34399281 DOI: 10.1016/j.rvsc.2021.08.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Revised: 07/13/2021] [Accepted: 08/06/2021] [Indexed: 12/24/2022]
Abstract
The proteoglycan versican (VCAN) plays a complex role in cancer. The expression of this molecule has been related to invasion and progression in malignant mixed tumors, such as carcinoma in mixed tumors (CMT) of the canine mammary gland. In addition, its interaction with surface cell receptors EGFR, HER-2 and CD44 in malignant epithelial cells may be responsible for proliferation and cellular motility in early stages of cancer. We comparatively evaluated the expression of this proteoglycan and its receptors in in situ and invasive areas of simple carcinomas (SC) and CMT to investigate similarities and differences between these histological types. Immunohistochemistry was performed with anti-VCAN, anti-CD44, anti-EGFR and anti-HER-2 antibodies in 32 cases of SC or CMT. VCAN was highly expressed in stroma adjacent to invasive areas in SC and CMT. CMTs presented comparatively higher expression of VCAN in stroma adjacent to in situ and in invasive areas than in corresponding areas in SCs. In CMT, EGFR and HER-2 expressions were higher in situ compared to invasive areas. In contrast, increased CD44 and EGFR expression was found in invasive areas in SC compared to CMT. These results indicate that versican expression is similarly associated with invasiveness in SC and CMT, however higher levels were seen in CMT suggesting that the presence of myoepithelial proliferation in this tumor type participates in stromal composition and promoting an increase in the expression of versican.
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Affiliation(s)
- S H Figuerêdo
- Laboratory of Experimental Pathology, Gonçalo Moniz Institute, Oswaldo Cruz Foundation, 121 Rua Waldemar Falcão., Salvador BA 40296-710, Brazil
| | - R S Carmo Neto
- Department of Pathology and Clinics, School of Veterinary Medicine and Zootechny, Federal University of Bahia, s/n° Adhemar de Barros., Salvador BA 40170-110, Brazil
| | - E Ferreira
- Department of General Pathology, Institute of Biological Sciences, Federal University of Minas Gerais, 6627 Av. Pres. Antônio Carlos, Belo Horizonte MG 31270-901, Brazil
| | - G D Cassali
- Department of General Pathology, Institute of Biological Sciences, Federal University of Minas Gerais, 6627 Av. Pres. Antônio Carlos, Belo Horizonte MG 31270-901, Brazil
| | - A Estrela-Lima
- Department of Pathology and Clinics, School of Veterinary Medicine and Zootechny, Federal University of Bahia, s/n° Adhemar de Barros., Salvador BA 40170-110, Brazil
| | - K A Damasceno
- Laboratory of Experimental Pathology, Gonçalo Moniz Institute, Oswaldo Cruz Foundation, 121 Rua Waldemar Falcão., Salvador BA 40296-710, Brazil.
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Khan S, Suryavanshi M, Kaur J, Nayak D, Khurana A, Manchanda RK, Tandon C, Tandon S. Stem cell therapy: A paradigm shift in breast cancer treatment. World J Stem Cells 2021; 13:841-860. [PMID: 34367480 PMCID: PMC8316873 DOI: 10.4252/wjsc.v13.i7.841] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 04/30/2021] [Accepted: 06/17/2021] [Indexed: 02/07/2023] Open
Abstract
As per the latest Globocan statistics, the high prevalence rate of breast cancer in low- and middle-income countries has led to it becoming the most common cancer to be diagnosed, hence posing a major public health challenge. As per this data, more than 11.7% of the estimated new cancer cases in 2020 were due to breast cancer. A small but significant subpopulation of cells with self- renewing ability are present in the tumor stroma and have been given the nomenclature of cancer stem cells (CSCs). These cells display a high degree of plasticity owing to their ability to transition from the slowly cycling quiescent phase to the actively proliferating phenotype. This attribute of CSCs allows them to differentiate into various cell types having diverse functions. Breast CSCs have a pivotal role in development, metastasis, treatment resistance and relapse of breast cancers. This review focuses on the pathways regulating breast CSC maintenance and the current strategies that are being explored for directing the development of novel, targeted, therapeutic approaches for limiting and eradicating this aberrant stem cell population.
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Affiliation(s)
- Sabiha Khan
- Amity Institute of Molecular Medicine and Stem Cell Research, Amity University, Noida 201313, Uttar Pradesh, India
| | - Moushumi Suryavanshi
- Department of Pathology, Rajiv Gandhi Cancer Institute and Research Centre, New Delhi 110085, India
| | - Jasamrit Kaur
- Department of Chemistry, Goswami Ganesh Dutta Sanatan Dharma College, Chandigarh 160030, India
| | - Debadatta Nayak
- Central Council for Research in Homeopathy, New Delhi 110058, India
| | - Anil Khurana
- Central Council for Research in Homeopathy, New Delhi 110058, India
| | | | - Chanderdeep Tandon
- Amity Institute of Biotechnology, Amity University, Noida 201313, Uttar Pradesh, India
| | - Simran Tandon
- Amity Institute of Molecular Medicine and Stem Cell Research, Amity University, Noida 201313, Uttar Pradesh, India
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Soltantoyeh T, Akbari B, Karimi A, Mahmoodi Chalbatani G, Ghahri-Saremi N, Hadjati J, Hamblin MR, Mirzaei HR. Chimeric Antigen Receptor (CAR) T Cell Therapy for Metastatic Melanoma: Challenges and Road Ahead. Cells 2021; 10:cells10061450. [PMID: 34207884 PMCID: PMC8230324 DOI: 10.3390/cells10061450] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2021] [Revised: 05/31/2021] [Accepted: 06/09/2021] [Indexed: 12/11/2022] Open
Abstract
Metastatic melanoma is the most aggressive and difficult to treat type of skin cancer, with a survival rate of less than 10%. Metastatic melanoma has conventionally been considered very difficult to treat; however, recent progress in understanding the cellular and molecular mechanisms involved in the tumorigenesis, metastasis and immune escape have led to the introduction of new therapies. These include targeted molecular therapy and novel immune-based approaches such as immune checkpoint blockade (ICB), tumor-infiltrating lymphocytes (TILs), and genetically engineered T-lymphocytes such as chimeric antigen receptor (CAR) T cells. Among these, CAR T cell therapy has recently made promising strides towards the treatment of advanced hematological and solid cancers. Although CAR T cell therapy might offer new hope for melanoma patients, it is not without its shortcomings, which include off-target toxicity, and the emergence of resistance to therapy (e.g., due to antigen loss), leading to eventual relapse. The present review will not only describe the basic steps of melanoma metastasis, but also discuss how CAR T cells could treat metastatic melanoma. We will outline specific strategies including combination approaches that could be used to overcome some limitations of CAR T cell therapy for metastatic melanoma.
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Affiliation(s)
- Tahereh Soltantoyeh
- Department of Medical Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran 1417613151, Iran; (T.S.); (B.A.); (G.M.C.); (N.G.-S.); (J.H.)
| | - Behnia Akbari
- Department of Medical Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran 1417613151, Iran; (T.S.); (B.A.); (G.M.C.); (N.G.-S.); (J.H.)
| | - Amirali Karimi
- School of Medicine, Tehran University of Medical Sciences, Tehran 1417613151, Iran;
| | - Ghanbar Mahmoodi Chalbatani
- Department of Medical Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran 1417613151, Iran; (T.S.); (B.A.); (G.M.C.); (N.G.-S.); (J.H.)
| | - Navid Ghahri-Saremi
- Department of Medical Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran 1417613151, Iran; (T.S.); (B.A.); (G.M.C.); (N.G.-S.); (J.H.)
| | - Jamshid Hadjati
- Department of Medical Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran 1417613151, Iran; (T.S.); (B.A.); (G.M.C.); (N.G.-S.); (J.H.)
| | - Michael R. Hamblin
- Laser Research Centre, Faculty of Health Science, University of Johannesburg, Doornfontein 2028, South Africa;
- Radiation Biology Research Center, Iran University of Medical Sciences, Tehran 1449614535, Iran
| | - Hamid Reza Mirzaei
- Department of Medical Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran 1417613151, Iran; (T.S.); (B.A.); (G.M.C.); (N.G.-S.); (J.H.)
- Correspondence: ; Tel.: +98-21-64053268; Fax: +98-21-66419536
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Nishikawa M, Inoue A, Ohnishi T, Yano H, Ozaki S, Kanemura Y, Suehiro S, Ohtsuka Y, Kohno S, Ohue S, Shigekawa S, Watanabe H, Kitazawa R, Tanaka J, Kunieda T. Hypoxia-induced phenotypic transition from highly invasive to less invasive tumors in glioma stem-like cells: Significance of CD44 and osteopontin as therapeutic targets in glioblastoma. Transl Oncol 2021; 14:101137. [PMID: 34052625 PMCID: PMC8175402 DOI: 10.1016/j.tranon.2021.101137] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 05/10/2021] [Accepted: 05/21/2021] [Indexed: 01/13/2023] Open
Abstract
CD44, upregulated by HIF-1α under 1%O2, induces highly invasive phenotype GSCs. HIF-2α-activated OPN under 5%O2 promotes less-invasive/proliferative type GSCs. CD44 and OPN knockdowns inhibit in vitro/vivo GSCs invasion and proliferation. The poor prognosis of glioblastoma multiforme (GBM) is primarily due to highly invasive glioma stem-like cells (GSCs) in tumors. Upon GBM recurrence, GSCs with highly invasive and highly migratory activities must assume a less-motile state and proliferate to regenerate tumor mass. Elucidating the molecular mechanism underlying this transition from a highly invasive phenotype to a less-invasive, proliferative tumor could facilitate the identification of effective molecular targets for treating GBM. Here, we demonstrate that severe hypoxia (1% O2) upregulates CD44 expression via activation of hypoxia-inducible factor (HIF-1α), inducing GSCs to assume a highly invasive tumor. In contrast, moderate hypoxia (5% O2) upregulates osteopontin expression via activation of HIF-2α. The upregulated osteopontin inhibits CD44-promoted GSC migration and invasion and stimulates GSC proliferation, inducing GSCs to assume a less-invasive, highly proliferative tumor. These data indicate that the GSC phenotype is determined by interaction between CD44 and osteopontin. The expression of both CD44 and osteopontin is regulated by differential hypoxia levels. We found that CD44 knockdown significantly inhibited GSC migration and invasion both in vitro and in vivo. Mouse brain tumors generated from CD44-knockdown GSCs exhibited diminished invasiveness, and the mice survived significantly longer than control mice. In contrast, siRNA-mediated silencing of the osteopontin gene decreased GSC proliferation. These results suggest that interaction between CD44 and osteopontin plays a key role in tumor progression in GBM; inhibition of both CD44 and osteopontin may represent an effective therapeutic approach for suppressing tumor progression, thus resulting in a better prognosis for patients with GBM.
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Affiliation(s)
- Masahiro Nishikawa
- Department of Neurosurgery, Ehime University Graduate School of Medicine, Toon, Ehime 791-0295, Japan
| | - Akihiro Inoue
- Department of Neurosurgery, Ehime University Graduate School of Medicine, Toon, Ehime 791-0295, Japan.
| | - Takanori Ohnishi
- Department of Neurosurgery, Washokai Sadamoto Hospital, Matsuyama, Ehime 790-0052, Japan
| | - Hajime Yano
- Department of Molecular and Cellular Physiology, Ehime University Graduate School of Medicine, Toon, Ehime 791-0295, Japan
| | - Saya Ozaki
- Department of Neurosurgery, Ehime University Graduate School of Medicine, Toon, Ehime 791-0295, Japan
| | - Yonehiro Kanemura
- Department of Biomedical Research and Innovation, Institute for Clinical Research, National Hospital Organization Osaka National Hospital, Osaka 540-0006, Japan; Department of Neurosurgery, National Hospital Organization Osaka National Hospital, Osaka 540-0006, Japan
| | - Satoshi Suehiro
- Department of Neurosurgery, Ehime University Graduate School of Medicine, Toon, Ehime 791-0295, Japan
| | - Yoshihiro Ohtsuka
- Department of Neurosurgery, Ehime University Graduate School of Medicine, Toon, Ehime 791-0295, Japan
| | - Shohei Kohno
- Department of Neurosurgery, Ehime University Graduate School of Medicine, Toon, Ehime 791-0295, Japan
| | - Shiro Ohue
- Department of Neurosurgery, Ehime Prefectural Central Hospital, Matsuyama, Ehime 790-0024, Japan
| | - Seiji Shigekawa
- Department of Neurosurgery, Ehime University Graduate School of Medicine, Toon, Ehime 791-0295, Japan
| | - Hideaki Watanabe
- Department of Neurosurgery, Ehime University Graduate School of Medicine, Toon, Ehime 791-0295, Japan
| | - Riko Kitazawa
- Division of Diagnostic Pathology, Ehime University Hospital, Toon, Ehime 791-0295, Japan
| | - Junya Tanaka
- Department of Molecular and Cellular Physiology, Ehime University Graduate School of Medicine, Toon, Ehime 791-0295, Japan
| | - Takeharu Kunieda
- Department of Neurosurgery, Ehime University Graduate School of Medicine, Toon, Ehime 791-0295, Japan
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Bódi N, Mezei D, Chakraborty P, Szalai Z, Barta BP, Balázs J, Rázga Z, Hermesz E, Bagyánszki M. Diabetes-related intestinal region-specific thickening of ganglionic basement membrane and regionally decreased matrix metalloproteinase 9 expression in myenteric ganglia. World J Diabetes 2021; 12:658-672. [PMID: 33995853 PMCID: PMC8107976 DOI: 10.4239/wjd.v12.i5.658] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Revised: 03/10/2021] [Accepted: 04/22/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The importance of the neuronal microenvironment has been recently highlighted in gut region-specific diabetic enteric neuropathy. Regionally distinct thickening of endothelial basement membrane (BM) of intestinal capillaries supplying the myenteric ganglia coincide with neuronal damage in different intestinal segments. Accelerated synthesis of matrix molecules and reduced degradation of matrix components may also contribute to the imbalance of extracellular matrix dynamics resulting in BM thickening. Among the matrix degrading proteinases, matrix metalloproteinase 9 (MMP9) and its tissue inhibitor (TIMP1) are essential in regulating extracellular matrix remodelling.
AIM To evaluate the intestinal segment-specific effects of diabetes and insulin replacement on ganglionic BM thickness, MMP9 and TIMP1 expression.
METHODS Ten weeks after the onset of hyperglycaemia gut segments were taken from the duodenum and ileum of streptozotocin-induced diabetic, insulin-treated diabetic and sex- and age-matched control rats. The thickness of BM surrounding myenteric ganglia was measured by electron microscopic morphometry. Whole-mount preparations of myenteric plexus were prepared from the different gut regions for MMP9/TIMP1 double-labelling fluorescent immunohistochemistry. Post-embedding immunogold electron microscopy was applied on ultrathin sections to evaluate the MMP9 and TIMP1 expression in myenteric ganglia and their microenvironment from different gut segments and conditions. The MMP9 and TIMP1 messenger ribonucleic acid (mRNA) level was measured by quantitative polymerase chain reaction.
RESULTS Ten weeks after the onset of hyperglycaemia, the ganglionic BM was significantly thickened in the diabetic ileum, while it remained intact in the duodenum. The immediate insulin treatment prevented the diabetes-related thickening of the BM surrounding the ileal myenteric ganglia. Quantification of particle density showed an increasing tendency for MMP9 and a decreasing tendency for TIMP1 from the proximal to the distal small intestine under control conditions. In the diabetic ileum, the number of MMP9-indicating gold particles decreased in myenteric ganglia, endothelial cells of capillaries and intestinal smooth muscle cells, however, it remained unchanged in all duodenal compartments. The MMP9/TIMP1 ratio was also decreased in ileal ganglia only. However, a marked segment-specific induction was revealed in MMP9 and TIMP1 at the mRNA levels.
CONCLUSION These findings support that the regional decrease in MMP9 expression in myenteric ganglia and their microenvironment may contribute to extracellular matrix accumulation, resulting in a region-specific thickening of ganglionic BM.
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Affiliation(s)
- Nikolett Bódi
- Department of Physiology, Anatomy and Neuroscience, Faculty of Science and Informatics, University of Szeged, Szeged 6726, Hungary
| | - Diána Mezei
- Department of Physiology, Anatomy and Neuroscience, Faculty of Science and Informatics, University of Szeged, Szeged 6726, Hungary
| | - Payal Chakraborty
- Department of Biochemistry and Molecular Biology, Faculty of Science and Informatics, University of Szeged, Szeged 6726, Hungary
| | - Zita Szalai
- Department of Physiology, Anatomy and Neuroscience, Faculty of Science and Informatics, University of Szeged, Szeged 6726, Hungary
| | - Bence Pál Barta
- Department of Physiology, Anatomy and Neuroscience, Faculty of Science and Informatics, University of Szeged, Szeged 6726, Hungary
| | - János Balázs
- Department of Physiology, Anatomy and Neuroscience, Faculty of Science and Informatics, University of Szeged, Szeged 6726, Hungary
| | - Zsolt Rázga
- Department of Pathology, Faculty of Medicine, University of Szeged, Szeged 6720, Hungary
| | - Edit Hermesz
- Department of Biochemistry and Molecular Biology, Faculty of Science and Informatics, University of Szeged, Szeged 6726, Hungary
| | - Mária Bagyánszki
- Department of Physiology, Anatomy and Neuroscience, Faculty of Science and Informatics, University of Szeged, Szeged 6726, Hungary
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Li HL, Li QY, Jin MJ, Lu CF, Mu ZY, Xu WY, Song J, Zhang Y, Zhang SY. A review: hippo signaling pathway promotes tumor invasion and metastasis by regulating target gene expression. J Cancer Res Clin Oncol 2021; 147:1569-1585. [PMID: 33864521 DOI: 10.1007/s00432-021-03604-8] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Accepted: 03/16/2021] [Indexed: 12/15/2022]
Abstract
BACKGROUND The Hippo pathway is widely considered to inhibit cell growth and play an important role in regulating the size of organs. However, recent studies have shown that abnormal regulation of the Hippo pathway can also affect tumor invasion and metastasis. Therefore, finding out how the Hippo pathway promotes tumor development by regulating the expression of target genes provides new ideas for future research on targeted drugs that inhibit tumor progression. METHODS PubMed, Embase, Web of Science, and the Cochrane Library were systematically searched. RESULTS The search strategy identified 1892 hits and 196 publications were finally included in this review. As the core molecule of the Hippo pathway, YAP/TAZ are usually highly expressed in tumors that undergo invasion and migration and are accompanied by abnormally strong nuclear metastasis. Through its interaction with nuclear transcription factors TEADs, it directly or indirectly regulates and the expressions of target genes related to tumor metastasis and invasion. These target genes can induce the formation of invasive pseudopodia in tumor cells, reduce intercellular adhesion, degrade extracellular matrix (ECM), and cause epithelial-mesenchymal transition (EMT), or indirectly promote through other signaling pathways, such as mitogen-activated protein kinases (MAPK), TGF/Smad, etc, which facilitate the invasion and metastasis of tumors. CONCLUSION This article mainly introduces the research progress of YAP/TAZ which are the core molecules of the Hippo pathway regulating related target genes to promote tumor invasion and metastasis. Focus on the target genes that affect tumor invasion and metastasis, providing the possibility for the selection of clinical drug treatment targets, to provide some help for a more in-depth study of tumor invasion and migration mechanism and the development of clinical drugs.
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Affiliation(s)
- Hong-Li Li
- School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China
| | - Qian-Yu Li
- School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China
| | - Min-Jie Jin
- School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China
| | - Chao-Fan Lu
- School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China
| | - Zhao-Yang Mu
- School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China
| | - Wei-Yi Xu
- School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China
| | - Jian Song
- School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China. .,School of Pharmaceutical Sciences, Key Laboratory of Advanced Drug Preparation Technologies (Ministry of Education), Zhengzhou University, Institute of Drug Discovery and Development, Zhengzhou, 450001, China.
| | - Yan Zhang
- School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China.
| | - Sai-Yang Zhang
- School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China. .,School of Pharmaceutical Sciences, Key Laboratory of Advanced Drug Preparation Technologies (Ministry of Education), Zhengzhou University, Institute of Drug Discovery and Development, Zhengzhou, 450001, China. .,Zhengzhou University, Henan Institute of Advanced Technology, Zhengzhou, 450001, China.
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Neutrophil Adhesion and the Release of the Free Amino Acid Hydroxylysine. Cells 2021; 10:cells10030563. [PMID: 33807594 PMCID: PMC7999338 DOI: 10.3390/cells10030563] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Revised: 02/25/2021] [Accepted: 03/02/2021] [Indexed: 12/21/2022] Open
Abstract
During infection or certain metabolic disorders, neutrophils can escape from blood vessels, invade and attach to other tissues. The invasion and adhesion of neutrophils is accompanied and maintained by their own secretion. We have previously found that adhesion of neutrophils to fibronectin dramatically and selectively stimulates the release of the free amino acid hydroxylysine. The role of hydroxylysine and lysyl hydroxylase in neutrophil adhesion has not been studied, nor have the processes that control them. Using amino acid analysis, mass spectrometry and electron microscopy, we found that the lysyl hydroxylase inhibitor minoxidil, the matrix metalloproteinase inhibitor doxycycline, the PI3K/Akt pathway inhibitors wortmannin and the Akt1/2 inhibitor and drugs that affect the actin cytoskeleton significantly and selectively block the release of hydroxylysine and partially or completely suppress spreading of neutrophils. The actin cytoskeleton effectors and the Akt 1/2 inhibitor also increase the phenylalanine release. We hypothesize that hydroxylysine release upon adhesion is the result of the activation of lysyl hydroxylase in interaction with matrix metalloproteinase, the PI3K/Akt pathway and intact actin cytoskeleton, which play important roles in the recruitment of neutrophils into tissue through extracellular matrix remodeling.
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Wu W, Zhang S, Zhang T, Mu Y. Immobilized Droplet Arrays in Thermosetting Oil for Dynamic Proteolytic Assays of Single Cells. ACS APPLIED MATERIALS & INTERFACES 2021; 13:6081-6090. [PMID: 33504155 DOI: 10.1021/acsami.0c21696] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/12/2023]
Abstract
Matrix metalloproteinases (MMPs) play an important role in tumor progression. The study of dynamic MMPs activity at the single-cell level can dissect tumor heterogeneity in the time domain and facilitate finding out more efficient clinical solutions for tumor treatment. Due to the fluidity of the carrier oil, the existing droplet-based methods for single-cell MMP analysis rarely have the capability to track proteolytic assays in droplets continuously. Therefore, we describe a thermosetting oil for real-time monitoring of MMP assays in droplets, which can immobilize droplets by transforming into solid after droplet generation. The solidification of this oil can be accomplished in 33 min at 37 °C, basing on the hydrosilation of vinyl silicone oil and hydrosilicone oil without other inducers (e.g. UV, Ca2+). Through monitoring the MMP assays of single cells, the reaction rates can be calculated according to real-time fluorescent curves, showing significant cell heterogeneity in MMP activity. Moreover, the dynamic MMP activity reveals that some of the A549 cells transiently secrete MMP. In conclusion, the thermosetting oil enables immobilize droplets to achieve real-time monitoring of single-cell proteolytic activity without impairing the flexibility of droplet microfluidics and has a potential in other cell-based assays for providing dynamic information at high resolutions.
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Affiliation(s)
- Wenshuai Wu
- Research Center for Analytical Instrumentation, Institute of Cyber-Systems and Control, State Key Laboratory of Industrial Control Technology, Zhejiang University, Hangzhou 310027, P. R. China
- College of Life Sciences, Zhejiang University, Hangzhou 310058, P. R. China
| | - Shan Zhang
- Research Center for Analytical Instrumentation, Institute of Cyber-Systems and Control, State Key Laboratory of Industrial Control Technology, Zhejiang University, Hangzhou 310027, P. R. China
- College of Life Sciences, Zhejiang University, Hangzhou 310058, P. R. China
| | - Tao Zhang
- Research Center for Analytical Instrumentation, Institute of Cyber-Systems and Control, State Key Laboratory of Industrial Control Technology, Zhejiang University, Hangzhou 310027, P. R. China
| | - Ying Mu
- Research Center for Analytical Instrumentation, Institute of Cyber-Systems and Control, State Key Laboratory of Industrial Control Technology, Zhejiang University, Hangzhou 310027, P. R. China
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Hong M, He G, Goh S, Low AWX, Tay KJ, Lim TKH, Yeong J, Khor LY, Lim TS. Biomarkers for Precision Urothelial Carcinoma Diagnosis: Current Approaches and the Application of Single-Cell Technologies. Cancers (Basel) 2021; 13:cancers13020260. [PMID: 33445605 PMCID: PMC7827267 DOI: 10.3390/cancers13020260] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Revised: 12/30/2020] [Accepted: 01/08/2021] [Indexed: 12/12/2022] Open
Abstract
Simple Summary Urothelial carcinoma (UC) is the most frequently diagnosed cancer of the urinary tract and is ranked the sixth most diagnosed cancer in men worldwide. About 70–75% of newly diagnosed UCs are non-invasive or low grade. Different tests such as urine cytology and cystoscopy are used to detect UC. If abnormal tissue is found during cystoscopy, then a biopsy will be performed. Cytology has low sensitivity for low-grade cancer while cystoscopy is invasive and costly. Detecting UC early improves the chances of treatment success. Therefore, many researchers have painstakingly identified urine biological markers for non-invasive UC diagnosis. In this review, we summarize some of the latest and most promising biological markers (including FDA-approved and investigational markers). We also discuss some new technologies that can aid research efforts in biological marker discovery for early UC detection. Abstract Urothelial carcinoma (UC) is the most frequent malignancy of the urinary system and is ranked the sixth most diagnosed cancer in men worldwide. Around 70–75% of newly diagnosed UC manifests as the non-muscle invasive bladder cancer (NMIBC) subtype, which can be treated by a transurethral resection of the tumor. However, patients require life-long monitoring due to its high rate of recurrence. The current gold standard for UC diagnosis, prognosis, and disease surveillance relies on a combination of cytology and cystoscopy, which is invasive, costly, and associated with comorbidities. Hence, there is considerable interest in the development of highly specific and sensitive urinary biomarkers for the non-invasive early detection of UC. In this review, we assess the performance of current diagnostic assays for UC and highlight some of the most promising biomarkers investigated to date. We also highlight some of the recent advances in single-cell technologies that may offer a paradigm shift in the field of UC biomarker discovery and precision diagnostics.
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Affiliation(s)
- Michelle Hong
- A. Menarini Biomarkers Singapore Pte Ltd., Singapore 117440, Singapore;
| | - George He
- Department of Pathology, Singapore General Hospital, Singapore 169856, Singapore; (G.H.); (S.G.); (T.K.H.L.)
| | - Siting Goh
- Department of Pathology, Singapore General Hospital, Singapore 169856, Singapore; (G.H.); (S.G.); (T.K.H.L.)
| | - Alvin Wei Xiang Low
- Department of Urology, Singapore General Hospital, Singapore 169854, Singapore; (A.W.X.L.); (K.J.T.)
| | - Kae Jack Tay
- Department of Urology, Singapore General Hospital, Singapore 169854, Singapore; (A.W.X.L.); (K.J.T.)
| | - Tony Kiat Hon Lim
- Department of Pathology, Singapore General Hospital, Singapore 169856, Singapore; (G.H.); (S.G.); (T.K.H.L.)
| | - Joe Yeong
- Department of Pathology, Singapore General Hospital, Singapore 169856, Singapore; (G.H.); (S.G.); (T.K.H.L.)
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore 138673, Singapore
- Correspondence: (J.Y.); (L.Y.K.); (T.S.L.)
| | - Li Yan Khor
- Department of Pathology, Singapore General Hospital, Singapore 169856, Singapore; (G.H.); (S.G.); (T.K.H.L.)
- Correspondence: (J.Y.); (L.Y.K.); (T.S.L.)
| | - Tong Seng Lim
- A. Menarini Biomarkers Singapore Pte Ltd., Singapore 117440, Singapore;
- Correspondence: (J.Y.); (L.Y.K.); (T.S.L.)
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